U.S. patent application number 14/018121 was filed with the patent office on 2014-06-19 for bupropion hydrobromide polymorphs.
This patent application is currently assigned to VALEANT INTERNATIONAL BERMUDA. The applicant listed for this patent is VALEANT INTERNATIONAL BERMUDA. Invention is credited to Stefano Turchetta, Maurizio Zenoni.
Application Number | 20140170216 14/018121 |
Document ID | / |
Family ID | 41404470 |
Filed Date | 2014-06-19 |
United States Patent
Application |
20140170216 |
Kind Code |
A1 |
Turchetta; Stefano ; et
al. |
June 19, 2014 |
BUPROPION HYDROBROMIDE POLYMORPHS
Abstract
Polymorphous and amorphous forms of bupropion hydrobromide are
described.
Inventors: |
Turchetta; Stefano;
(Patrica, IT) ; Zenoni; Maurizio; (Patrica,
IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
VALEANT INTERNATIONAL BERMUDA |
Hamilton |
|
BM |
|
|
Assignee: |
VALEANT INTERNATIONAL
BERMUDA
Hamilton
BM
|
Family ID: |
41404470 |
Appl. No.: |
14/018121 |
Filed: |
September 4, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13653503 |
Oct 17, 2012 |
8604085 |
|
|
14018121 |
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|
12536772 |
Aug 6, 2009 |
8349900 |
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13653503 |
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Current U.S.
Class: |
424/465 ;
424/490; 514/649; 564/345 |
Current CPC
Class: |
C07C 225/10 20130101;
A61P 25/24 20180101; A61P 3/10 20180101; A61P 19/02 20180101; A61P
25/00 20180101; A61P 3/04 20180101; A61K 45/06 20130101; C07B
2200/13 20130101; A61P 25/22 20180101; A61P 25/06 20180101; A61P
15/10 20180101; A61P 25/20 20180101; A61K 9/2886 20130101; A61K
31/137 20130101; A61P 31/12 20180101; C07C 225/16 20130101 |
Class at
Publication: |
424/465 ;
564/345; 514/649; 424/490 |
International
Class: |
C07C 225/10 20060101
C07C225/10; A61K 9/28 20060101 A61K009/28; A61K 45/06 20060101
A61K045/06; A61K 31/137 20060101 A61K031/137 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 7, 2008 |
EP |
08425545.4 |
Sep 8, 2008 |
EP |
08425617.1 |
Claims
1. Bupropion hydrobromide in crystalline form, characterized by at
least one of the following properties: PXRD as in FIG. 39, DSC as
in FIG. 40, TGA as in FIG. 41, IR as in FIG. 42.
2. Bupropion hydrobromide in crystalline form, characterized by at
least one of the following properties: PXRD as in FIG. 43, DSC as
in FIG. 44, TGA as in FIG. 45, IR as in FIG. 46.
3. Bupropion hydrobromide in amorphous form, characterized by a
PXRD as in FIG. 47.
4. Bupropion hydrobromide in amorphous form, characterized by a
PXRD as in FIG. 48.
5. A composition comprising the bupropion hydrobromide according to
claim 1, 2, 3, or 4 and a pharmaceutically acceptable carrier or
excipient.
6. The composition according to claim 5, further comprising at
least one other drug other than bupropion hydrobromide selected
from the group consisting of anti-depressants, anti-anxiety agents,
steroidal inflammatories, non-steroidal inflammatories, SSRIs,
antimigraine agents, anti-emetics, drugs for treating abuse,
appetite modulators, anti-virals, vasodilators, anti-pain agents,
and combinations thereof.
7. The composition according to claim 5 further comprising at least
one other drug other than bupropion hydro bromide selected from the
group consisting of a monoamine oxidase (MAO) inhibitor, a
tricyclic antidepressant, a serotonin reuptake inhibitor, a
selective norepinephrine reuptake inhibitor (SNRIs), amino ketones,
serotonin antagonists, dopamine reuptake inhibitors, dual reuptake
inhibitors, norepinephrine enhancers, serotonin activity enhancers,
dopamine activity enhancers, and combinations thereof.
8. The composition of claim 5, in the form of a microparticle
comprising a solid core, said core comprising the bupropion
hydrobromide and the at least one pharmaceutically acceptable
excipient, said core of said microparticle being at least partially
surrounded by a controlled release coat which permits entry of an
aqueous liquid into the core and delivery of the bupropion
hydrobromide from the core to the exterior of the microparticle
through the controlled release coat.
9. The composition of claim 5, in the form of a tablet comprising a
core comprising the bupropion hydrobromide and a controlled release
coating at least partially surrounding said core, the coating
comprising at least one water-soluble polymer, at least one
water-insoluble polymer, and optionally a plasticizer.
10. A method of treating depression, seasonal effective disorder,
obesity, anxiety, obsessive compulsive disorder, post-traumatic
stress disorder (PTSD), panic disorder, disorders requiring a
stimulant effect, attention deficit hyperactivity disorder (ADHD),
narcolepsy, hypersomnia, female sexual dysfunction, male sexual
dysfunction, premenstrual syndrome, premenstrual dysphoric
disorder, neuropathic pain, fibromyalgia, diabetic neuropathy,
viral infection, sleep apnea, sleep disorders or migraines
comprising administering an effective amount of the bupropion
hydrobromide of claim 1, 2, 3, or 4 to treat depression, seasonal
effective disorder, obesity, anxiety, obsessive compulsive
disorder, post-traumatic stress disorder (PTSD), panic disorder,
disorders requiring a stimulant effect, attention
deficit/hyperactivity disorder (ADHD), narcolepsy, hypersomnia,
female sexual dysfunction, male sexual dysfunction, premenstrual
syndrome, premenstrual dysphoric disorder, neuropathic pain,
fibromyalgia, diabetic neuropathy, viral infection, sleep apnea,
sleep disorders or migraines to a subject in need thereof.
11. A composition comprising two or more of the following forms of
bupropion hydrobromide: i. a crystalline form having the following
properties PXRD as in FIG. 39, DSC as in FIG. 40, TGA as in FIG.
41, IR as in FIG. 42; ii. a crystalline form having the following
properties PXRD as in FIG. 43, DSC as in FIG. 44, TGA as in FIG.
45, IR as in FIG. 46; iii. an amorphous form having the following
property PXRD as in FIG. 47; and iv. an amorphous form having the
following property PXRD as in FIG. 48.
Description
RELATED APPLICATIONS
[0001] This application claims priority to EP 08425545.4, filed
Aug. 7, 2008, and to EP 08425617.1 filed Sep. 22, 2008.
FIELD OF THE INVENTION
[0002] The present invention relates to polymorphs of bupropion
hydrobromide and formulations containing polymorphs of bupropion
hydrobromide, as well as their use for the treatment of conditions
(e.g. major depressive disorder, bipolar depression mood disorder,
other mood disorder, anxiety disorders, generalized anxiety
disorder, panic disorder, post-traumatic stress disorder, nicotine
addiction, obesity, attention-deficit hyperactivity disorder,
restless legs syndrome, sexual dysfunction, and seasonal affective
disorders).
BACKGROUND
[0003] Bupropion hydrobromide or
3'-chloro-2-t-butylamino-1-propiophenone hydrobromide is a known
antidepressant. See e.g., U.S. Pat. Nos. 7,241,805; 7,569,611;
7,563,992; 7,563,823; and 7,569,610. Its structural formula is:
##STR00001##
[0004] The neurochemical mechanism of the antidepressant effect of
bupropion is not well known. Bupropion affects chemicals within the
brain that nerves use to send messages to each other. These
chemical messengers are called neurotransmitters. The
neurotransmitters that are released by nerves are taken up again by
the nerves that release them for reuse (this is referred to as
reuptake). Many skilled artisans believe that depression is caused
by an imbalance among the amounts of neurotransmitters that are
released. Bupropion is a selective catecholamine (dopamine and
norepinephrine) reuptake inhibitor, and works by inhibiting the
reuptake of the neurotransmitters dopamine and norepinephrine, an
action which results in more dopamine and norepinephrine made
available to transmit messages to other nerves. It has a small
effect, if any, on the serotonin reuptake mechanism. Accordingly,
bupropion is unique in that its major effect is on dopamine, an
effect which is not shared by selective serotonin re-uptake
inhibitors (SSRIs), e.g. paroxetine (PAXIL.RTM.), fluoxetine
(PROZAC.RTM.), sertraline (ZOLOFT.RTM.) or the tricyclic
antidepressants or TCAs, e.g. amitriptyline (ELAVIL.RTM.),
imipramine (TOFRANIL.RTM.), desipramine (NORPRAMIN.RTM.).
[0005] Bupropion can also be used to treat other conditions,
non-limiting examples of which include nicotine addition (e.g.
smoking cessation), weight gain (e.g. obesity), Parkinson's
disease, and seasonal affective disorder.
[0006] Bupropion hydrochloride is commercially available as an
immediate release form (WELLBUTRIN.RTM.), a sustained release form
(WELLBUTRIN.RTM. SR and ZYBAN.RTM.), and an extended release form
((WELLBUTRIN.RTM. XL). Both WELLBUTRIN.RTM. SR and ZYBAN.RTM. are
chemically and pharmaceutically identical. WELLBUTRIN.RTM.,
WELLBUTRIN.RTM. SR and WELLBUTRIN.RTM. XL are used clinically for
the management of major depressive disorder, bipolar depression
mood disorder, other mood disorder, anxiety disorders, generalized
anxiety disorder, panic disorder, post-traumatic stress disorder,
and seasonal affective disorders, and have been approved for use in
the treatment of major depressive disorder. ZYBAN.RTM. has been
approved as an aid to patients wanting to quit smoking.
WELLBUTRIN.RTM., the immediate release formulation of bupropion, is
dosed three times a day, suitably with 6 or more hours in between
doses. For patients requiring more than 300 mg bupropion a day,
each dose is prescribed not to exceed 150 mg. This requires
administration of the tablets at least 4 times a day with at least
4 hours in between doses. The immediate release formulation results
in more than a 75% release of the bupropion into the dissolution
media in 45 minutes. The sustained release products are dosed twice
daily, and the extended release products are dosed once daily.
[0007] Certain advantages exist in using bupropion for the
treatment of diseases and conditions. For example, bupropion does
not inhibit monoamine oxidase, and does not significantly block the
reuptake of serotonin, unlike other neuronal monoamine reuptake
inhibitors. Administration of bupropion can thus avoid or lessen
many adverse effects commonly associated with other antidepressants
such as tricyclic agents and monoamine oxidase inhibitors.
[0008] It is known that different crystalline forms of one and the
same active drug can display different characteristics of
solubility and hence bioavailability, and thus permit more
appropriate use of the active drug according to whether one
requires slow release (in that case using a less-soluble
polymorphous form) or quicker availability of the active drug
(using a more-soluble polymorphous form), accordingly providing
easier modulation of the availability of the drug. Accordingly, it
is useful to have different polymorphous forms, with different
chemical and physical properties, at one's disposal.
[0009] The development of a stable bupropion formulation would be
an advance in the art.
DESCRIPTION
[0010] While bupropion hydrobromide and three polymorphic forms (I,
II, and II) have been previously described (see Background above),
the invention here concerns the discovery of new crystalline forms
of bupropion hydrobromide designated as Forms IV, V, VI and VII
respectively. In addition, certain other embodiments of the present
invention relate to the amorphous form of bupropion
hydrobromide.
[0011] Certain embodiments of the present invention relate to a
bupropion composition that comprises a safe and pharmaceutically
effective amount of bupropion hydrobromide and/or a polymorph of
bupropion hydrobromide; wherein the composition unexpectedly
provides for fewer incidences of seizures and/or less severe
seizures associated with the administration of bupropion than an
otherwise similar or identical composition containing an equivalent
molar amount of bupropion hydrochloride.
[0012] Certain embodiments of the present invention relate to a
bupropion composition that comprises a safe and pharmaceutically
effective amount of bupropion hydrobromide and/or a polymorph of
bupropion hydrobromide; wherein said composition is more stable,
than an otherwise similar or identical composition containing an
equivalent molar amount of bupropion hydrochloride and/or a
polymorph of bupropion hydrobromide. In particular, such a
bupropion hydrobromide composition is more stable than an otherwise
similar or identical composition containing an equivalent molar
amount of bupropion hydrochloride under certain storage conditions,
(for example when stored for 3 months or 6 months at 40 degrees C.
and 75% relative humidity) as evidenced by a reduced amount of at
least one moiety (e.g. degradation product) that is characteristic
of bupropion degradation and/or a reduced fluctuation or reduction
in potency after being stored under accelerated storage conditions
(for example after storage for 3 months or 6 months), and/or by a
reduced fluctuation in the in-vitro dissolution profile in at least
one dissolution medium over a 24 hour period.
[0013] Certain embodiments of the present invention relate to
methods of treating a condition comprising administering a safe and
effective amount of bupropion hydrobromide and/or a polymorph of
bupropion hydrobromide to a subject in need of bupropion
administration.
[0014] Certain embodiments of the present invention further
contemplate a method of preparing a medicament for the treatment of
a condition which can benefit from the administration of bupropion,
comprising bringing an effective amount of bupropion hydrobromide
and/or a polymorph of bupropion hydrobromide into contact with one
or more pharmaceutically acceptable excipients.
[0015] Certain embodiments relate to compositions comprising a
compound of formula I (bupropion hydrobromide):
##STR00002##
and/or a polymorph of bupropion hydrobromide, and pharmaceutically
acceptable carriers, excipients and/or diluents; said composition
having greater stability than a corresponding pharmaceutical
composition comprising bupropion hydrochloride and pharmaceutically
acceptable carriers, excipients and/or diluents.
[0016] In certain embodiments of the present invention, the
bupropion salt can be in the form of its anhydrous, hydrated, and
solvated forms, in the form of prodrugs, and in the individually
optically active enantiomers of the bupropion salt, such as for
example (+)-bupropion and (-)-bupropion. Suitable pharmaceutically
acceptable salts of bupropion for use in the present invention are
more stable than bupropion hydrochloride. In certain embodiments
the bupropion hydrobromide salt can also provide for the reduction
or avoidance of incidences of seizures associated with the
administration of bupropion. Suitable salts of bupropion also
include for example, pharmaceutically acceptable acid addition
salts. In certain embodiments, the acid addition salt of bupropion
can be indirectly obtained by the separate addition of bupropion
and an acid to the core formulation.
[0017] Certain embodiments of the present invention contemplate the
use of bupropion hydrobromide and/or a polymorph of bupropion
hydrobromide to prepare a medicament to treat a condition which can
benefit from administration of bupropion, wherein said medicament
has greater stability than a corresponding medicament comprising
bupropion hydrochloride.
[0018] As discussed infra and generally known in the art,
appropriate dissolution medium and appropriate conditions for
assaying the dissolution characteristics of pharmaceutical dosage
forms such as tablets are well known in the art and are contained
in the United States Pharmacopoeia and its European or Japanese
counterparts, and include by way of example dissolution in USP Type
1 apparatus (Rotating Basket Method) in 900 ml water; 0.1 N HCl;
0.1N HCl+0.1% Cetrimide; USP buffer pH 1.5; Acetate buffer pH 4.5;
Phosphate Buffer pH 6.5; or Phosphate Buffer pH 7.4 at 75 RPM at 37
degrees C.+/-0.5 degrees C. Additionally, other examples of
appropriate dissolution media include USP-3 media and USP-3
dissolution conditions e.g, SGF pH 1.2; Acetate buffer pH 4.5 and
Phosphate Buffer pH 6.8.
[0019] Certain embodiments of the present invention contemplate the
use of bupropion hydrobromide and/or a polymorph of bupropion
hydrobromide to produce once-daily administrable tablets or other
dosage forms that are bioequivalent to WELLBUTRIN.TM. or
ZYBAN.TM./WELLBUTRIN.TM. SR tablets as defined by FDA criteria when
administered once daily to a subject in need thereof. In particular
at least one of the Tmax, Cmax, or AUC profile of certain
embodiments of the present invention is within 80-125% of
WELLBUTRIN.TM. and ZYBAN.TM./WELLBUTRIN.TM. when administered once
daily to a subject in need thereof. In certain embodiments these
formulations are also free of any significant food effect.
[0020] Certain embodiments of the present invention provide
bupropion hydrobromide dosage forms (e.g. tablets) containing at
least one coating (e.g. SMARTCOAT.TM. coating) which is resistant
to dose dumping in high alcohol, (e.g., 40% ethanol).
[0021] Certain embodiments of the invention include dosage forms
that avoid the so-called dose dumping effect, for example in the
presence of ethanol, e.g., 5-40% ethanol. This means that the
dosage forms do not deliver the active ingredient significantly
more quickly in the presence of, e.g., ethanol as compared to
normal stomach contents. Such dosage forms are resistant to dose
dumping.
[0022] Certain embodiments of the present invention include both
oral and non-oral bupropion hydrobromide containing medicaments.
For example, the invention embraces compositions suitable for oral,
topical, injectable, inhalation and other modes of
administration.
[0023] Certain embodiments of the present invention include
extended release formulations, delayed release formulations, and/or
enhanced absorption formulations.
[0024] In a more particular implementation of certain embodiments
of the invention, a bupropion medicament composition comprises (i)
a core that includes bupropion hydrobromide and/or a polymorph of
bupropion hydrobromide, a binder and a lubricant; and (ii) a
controlled release coat substantially surrounding said core;
wherein said composition provides controlled release of said
bupropion hydrobromide. Such compositions optionally can comprise
one or more additional coatings surrounding the core and/or the
controlled release coat such as a moisture barrier coat, enteric
coat or a coating that affects the physical integrity and/or
appearance of the composition. The binder can be selected from
known pharmaceutical binders such as polyvinyl alcohol. The
lubricant also can be selected from known pharmaceutical lubricants
such as glyceryl behenate. The controlled release coat can include
a water-insoluble polymer, a water-soluble polymer, and optionally
a plasticizer. The water-insoluble polymer can be selected from a
range of water insoluble polymers useful in extended release
pharmaceutical compositions such as ethylcellulose. The
water-soluble polymer can be selected from a variety of
water-soluble polymers useful in extended release pharmaceutical
compositions such as polyvinylpyrrolidone. The plasticizer if
present can be selected from a range of known plasticizers such as
mixtures of polyethylene glycol 4000 and dibutyl sebacate. Certain
embodiments of these compositions include once-daily administrable
compositions that are bioequivalent to WELLBUTRIN.TM. or
ZYBAN.TM./WELLBUTRIN.TM. SR tablets when administered once-daily to
a subject in need thereof. These compositions may or may not
exhibit a food effect. Further, certain embodiments of these
compositions can be resistant to dose dumping in the presence of
high alcohol concentrations (e.g., 40% by weight of ethanol).
[0025] In another particular implementation of certain embodiments
of the present invention, the bupropion composition comprises (i) a
core that includes bupropion hydrobromide and/or a polymorph of
bupropion hydrobromide, a binder and a lubricant; and (ii) a
controlled release coat substantially surrounding said core;
wherein said controlled release coat includes an aqueous dispersion
of a neutral ester copolymer without any functional groups, a
polyglycol having a melting point greater than 55.degree. C., and
one or more pharmaceutically acceptable excipients, wherein said
coat is coated onto said core and cured at a temperature at least
equal to or greater than the melting point of the polyglycol. The
composition provides controlled release of said bupropion
hydrobromide. Optionally, this medicament can comprise one or more
additional coatings surrounding the core and/or controlled release
coating such as a moisture barrier coat, enteric coat, coat that
precludes dose dumping in specific media such as alcohol, and/or a
coating that affects the physical stability or integrity of the
medicament and/or its physical appearance.
[0026] In a particular implementation of certain embodiments of the
present invention, the bupropion composition comprises
multiparticulates.
[0027] Certain embodiments of the present invention include
controlled release matrix tablet formulations.
[0028] Certain embodiments of the present invention include a
bupropion composition that comprises a second drug. The second drug
(e.g. other anti-depressants, SSRI's, anti-anxiety agents, atypical
antipsychotic drugs, medications that interact with serotonin
neurotransmission, medications that interact with norepinephrine
neurotransmission, medications that interact with dopamine
neurotransmission) can be administered in combination with the
subject bupropion hydrobromide salt. The second drug can elicit a
synergistic benefit on bupropion efficacy as well as
non-synergistic drug combinations. Non-limiting examples of the
second drug include citalopram, escitalopram, venlafaxine,
quetiapene, buspirone and mixtures thereof.
[0029] In accordance with one aspect of certain embodiments of the
present invention, there is provided a controlled release
composition comprising (i) a core comprising an effective amount of
a bupropion hydrobromide and/or a polymorph of bupropion
hydrobromide, a binder, a lubricant; and (ii) a controlled release
coat surrounding said core; and optionally (iii) a moisture barrier
surrounding said controlled release coat or the core; and; wherein
the composition exhibits a dissolution profile such that after 2
hours from about more than 0% to about 20%, including all values
and subranges therebetween; preferably from about 2% to about 18%,
more preferably from about 4% to about 8%, or about 5%, of the
bupropion hydrobromide content is released; after 4 hours from
about 15% to about 45%, including all values and subranges
therebetween; preferably from about 21% to about 37%, more
preferably from about 28% to about 34%, or about 32%, of the
bupropion hydrobromide content is released; after 8 hours from
about 40% to about 90%, including all values and subranges
therebetween, preferably from about 60% to about 85%; more
preferably from about 68% to about 74%; or about 74%, of the
bupropion hydrobromide content is released, and after 16 hours from
about 80% to about 100% including all values and subranges
therebetween, preferably not less than about 93%; more preferably
not less than about 96%, still more preferably not less than about
99%, of the bupropion hydrobromide content is released, when using
a USP apparatus design with a dissolution medium as found in the
USP (e.g. USP Apparatus Type 1 at 75 rpm, 900 ml, 0.1N HCl, at
37.degree. C..+-.0.5.degree. C.); and wherein the bupropion
hydrobromide composition is more stable than an otherwise similar
or identical composition comprising the equivalent molar amount of
bupropion hydrochloride when each are stored under accelerated
storage conditions (e.g. stored for 3 months or 6 months at about
40 degrees C. and at about 75% relative humidity).
[0030] In certain embodiments the composition exhibits a
dissolution profile such that after 2 hours not more than about 0%
to about 40%, including all values and subranges therebetween, of
the bupropion hydrobromide is released, after 4 hours from about
40% to about 75%, including all values and subranges therebetween,
of the bupropion hydrobromide is released, after 8 hours not less
than about 75% to about 99%, including all values and subranges
therebetween, of the bupropion hydrobromide is released, and after
16 hours not less than about 85% to about 100%, including all
values and subranges therebetween of the bupropion hydrobromide is
released, when using a USP apparatus design with a dissolution
medium as found in the USP (e.g. USP Apparatus Type 1 at 75 rpm,
900 ml, 0.1N HCl, at 37.degree. C..+-.0.5.degree. C.).
[0031] Certain embodiments of the present invention include a
bupropion composition that comprises from about 50 mg to about 1000
mg of bupropion hydrobromide or a polymorph of bupropion
hydrobromide, including 75 mg, 100 mg, 125 mg, 150 mg, 174 mg, 175
mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 348 mg, 350 mg,
375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 510 mg, 520 mg, 522
mg, 525 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 575 mg, 580 mg,
590 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775
mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg,
and all values and ranges therebetween. For example, certain
embodiments include a composition which comprises 174 mg, 348 mg or
522 mg of bupropion hydrobromide per unit dose.
[0032] In accordance with one aspect of certain embodiments of the
present invention, there is provided an enhanced-absorption tablet
comprising (i) a core comprising an effective amount of bupropion
hydrobromide and/or a polymorph of bupropion hydrobromide, a
binder, a lubricant; and (ii) a controlled release coat surrounding
said core; and wherein the enhanced absorption tablet exhibits a
dissolution profile such that after 2 hours, from about 0% to about
25%, preferably from about 10% to about 20%, including all values
and subranges therebetween of the bupropion hydrobromide content is
released; after 4 hours from about 25% to about 55%, preferably
from about 30% to about 50%, including all values and subranges
therebetween of the bupropion hydrobromide content is released;
after 8 hours from about 60% to about 99%, preferably from about
70% to about 90%, including all values and subranges therebetween
of the bupropion hydrobromide content is released, and after 16
hours from about 70% to about 100%, preferably more than about 80%,
including all values and subranges therebetween, of the bupropion
hydrobromide content is released, when using a USP apparatus design
with a dissolution medium as found in the USP (e.g. USP Apparatus
Type 1 at 75 rpm, 900 ml, 0.1N HCl, at 37.degree. C..+-.0.5.degree.
C.); and wherein the bupropion hydrobromide enhanced-absorption
tablet is more stable than an otherwise similar or identical
composition comprising the equivalent molar amount of bupropion
hydrochloride when each are stored under accelerated storage
conditions (e.g. stored for 3 months or 6 months at about 40
degrees C. and at about 75% relative humidity.
[0033] In certain embodiments the bupropion hydrobromide
composition can comprise a dissolution profile such that after 2
hours from more than about 0% to about 40%, including all values
and subranges therebetween, of bupropion hydrobromide is released
therefrom; after 4 hours from about 40% to about 75%, including all
values and subranges therebetween, of bupropion hydrobromide is
released therefrom; after 8 hours from about 75% to about 99%,
including all values and subranges therebetween, of bupropion
hydrobromide is released therefrom, and after 16 hours from about
85% to about 100%, including all values and subranges therebetween,
of bupropion hydrobromide is released therefrom, when using a USP
apparatus design with a dissolution medium as found in the USP
(e.g. USP Apparatus Type 1 at 75 rpm, 900 ml, 0.1N HCl, at
37.degree. C..+-.0.5.degree. C.).
[0034] As discussed infra, in-vitro dissolution of bupropion from
controlled or extended release formulations according to certain
embodiments of the invention can be determined by methods well
known to those skilled in the pharmaceutical art. Suitable methods
are contained in the United States Pharmacopoeia (USP) as well as
European and Japanese counterparts of the USP and are exemplified
infra. This includes by way of example effecting dissolution in a
USP 1 apparatus (Rotating Type Basket Method) in 900 ml water, 0.1N
HCl, 0.1N HCl+0.1% Cetrimide, USP Buffer pH 1.5, Acetate Buffer pH
6.5 or Phosphate Buffer pH 7.4 at 75 RPM at 37 degrees C.+/-0.5
degrees C. or by effecting dissolution using a USPS dissolution
medium such as SGF having a pH 1.2; acetate buffer having a pH of
4.5 or phosphate buffer having a pH of 6.8.
[0035] Stable compositions of bupropion hydrobromide (e.g
compositions of bupropion hydrobromide or a polymorph of bupropion
hydrobromide with enhanced stability as compared to otherwise
similar compositions containing bupropion hydrochloride) are known
for example from U.S. Pat. No. 7,241,805, U.S. patent application
Ser. No. 11/834,848 (Pub. No. 2008-0075774), and U.S. patent
application Ser. No. 11/930,644 (Pub. No. 2008-0274181), the
contents of which are incorporated herein by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 is a flow chart showing the overall process for the
development of bupropion HBr XL tablets.
[0037] FIG. 2 is a flow chart demonstrating the granulation process
of the bupropion HBr XL and EA tablets.
[0038] FIG. 3 is a flow chart showing the overall tabletting
process of bupropion HBr XL.
[0039] FIG. 4 is a flow chart showing the overall coating process
of bupropion HBr XL.
[0040] FIG. 5 is a dissolution profile of the 4 kp, 6-7 kp and 9-10
kp tablets, comparing the effects of hardness on dissolution in the
study on Batch BUP-HBr-XL-009-5.
[0041] FIG. 6 is a dissolution profile of the 348 mg Bupropion HBr
cores which have been compressed using 9 mm tooling in the study on
Batch BUP-HBr-XL-009-5.
[0042] FIG. 7 is a dissolution profile of the 348 mg Bupropion HBr
cores which have been compressed using 10 mm tooling in the study
on Batch BUP-HBr-XL-009-5.
[0043] FIG. 8 is a dissolution profile comparison of the 9 mm and
10 mm diameter 348 mg Bupropion HBr cores in the study on Batch
BUP-HBr-XL-009-5.
[0044] FIG. 9 is a dissolution profile of the 174 mg in the study
on Batch BUP-HBr-XL-021-5.
[0045] FIG. 10 is a dissolution profile of BUP-HBr-XL-348 mg-013-5
(28 mg, 30 mg, 32 mg and 34 mg weight gains).
[0046] FIG. 11 is a dissolution profile of BUP-HBr-XL-348 mg-013-5
(5 mg, 6 mg, and 7 mg weight gains).
[0047] FIG. 12 is a dissolution profile of BUP-HBr-XL-348 mg-018-5
(26 mg, 28 mg, 30 mg and 32 mg weight gains).
[0048] FIG. 13 is a dissolution profile of BUP-HBr-XL-348 mg-018-5
(7 mg weight gain).
[0049] FIG. 14 is a dissolution profile of BUP-HBr-XL-174 mg-022-5
(22 mg, 24 mg, 28 mg and 30 mg weight gains).
[0050] FIG. 15 is a dissolution profile of BUP-HBr-XL-174 mg-022-5
(5 mg, 6 mg, and 7 mg weight gains).
[0051] FIG. 16 is a dissolution profile of BUP-HBr-XL-348 mg-023-5
(26 mg, 28 mg, 30 mg and 32 mg weight gains).
[0052] FIG. 17 is a dissolution profile of BUP-HBr-XL-348 mg-025-5
(26 mg, 28 mg, 30 mg, and 32 mg weight gains).
[0053] FIG. 18 is a dissolution profile of BUP-HBr-XL-348 mg-025-5
(5 mg, 6 mg, and 7 mg weight gains).
[0054] FIG. 19 is a dissolution profile of BUP-HBr-XL-348 mg-026-5
(26 mg, 28 mg, 30 mg, and 32 mg weight gains).
[0055] FIG. 20 is a dissolution profile of BUP-HBr-XL-174 mg-027-5
(22 mg, 24 mg, and 26 mg weight gains).
[0056] FIG. 21 is a dissolution profile of BUP-HBr-XL-174 mg-027-5
(4 mg, 5 mg, 6 mg, and 7 mg weight gains).
[0057] FIG. 22 is a graph showing the relative powder X-ray
diffraction (PXRD) for bupropion hydrobromide polymorphic form
I.
[0058] FIG. 23 is a graph showing the differential scanning
calorimetry (DSC) profile of bupropion hydrobromide polymorphic
form I.
[0059] FIG. 24 is a graph of the relative PXRD of a sample of
bupropion hydrobromide polymorphic form I after 6 months under the
ICH (International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use)
conditions (40.degree. C., 75% R.H.).
[0060] FIG. 25 is a graph showing the relative PXRD for bupropion
hydrobromide polymorphic form II.
[0061] FIG. 26 is a graph showing the DSC profile of bupropion
hydrobromide polymorphic form II.
[0062] FIG. 27 is a graph of the PXRD of a sample of bupropion
hydrobromide polymorphic form II after 1 month under ICH conditions
(40.degree. C., 75% R.H.).
[0063] FIG. 28 is a graph showing the relative PXRD for bupropion
hydrobromide polymorphic form III.
[0064] FIG. 29 is a graph showing the DSC profile of bupropion
hydrobromide polymorphic form III.
[0065] FIG. 30 is a graph of the PXRD of a sample of bupropion
hydrobromide polymorphic form III after 1 month under ICH
conditions (40.degree. C., 75% R.H.).
[0066] FIG. 31 is a graph showing the relative PXRD for bupropion
hydrobromide polymorphic form IV.
[0067] FIG. 32 is a graph showing the DSC profile of bupropion
hydrobromide polymorphic form IV.
[0068] FIG. 33 is a graph showing the TGA profile of bupropion
hydrobromide polymorphic form IV.
[0069] FIG. 34 is a graph showing the IR profile of bupropion
hydrobromide polymorphic form IV.
[0070] FIG. 35 is a graph showing the relative PXRD for bupropion
hydrobromide polymorphic form V.
[0071] FIG. 36 is a graph showing the DSC profile of bupropion
hydrobromide polymorphic form V.
[0072] FIG. 37 is a graph showing the TGA profile of bupropion
hydrobromide polymorphic form V.
[0073] FIG. 38 is a graph showing the IR profile of bupropion
hydrobromide polymorphic form V.
[0074] FIG. 39 is a graph showing the relative PXRD for bupropion
hydrobromide polymorphic form VI.
[0075] FIG. 40 is a graph showing the DSC profile of bupropion
hydrobromide polymorphic form VI.
[0076] FIG. 41 is a graph showing the TGA profile of bupropion
hydrobromide polymorphic form VI.
[0077] FIG. 42 is a graph showing the IR profile of bupropion
hydrobromide polymorphic form VI.
[0078] FIG. 43 is a graph showing the relative PXRD for bupropion
hydrobromide polymorphic form VII.
[0079] FIG. 44 is a graph showing the DSC profile of bupropion
hydrobromide polymorphic form VII.
[0080] FIG. 45 is a graph showing the TGA profile of bupropion
hydrobromide polymorphic form VII.
[0081] FIG. 46 is a graph showing the IR profile of bupropion
hydrobromide polymorphic form VII.
[0082] FIG. 47 is a graph showing the relative PXRD for an
amorphous form of bupropion hydrobromide.
[0083] FIG. 48 is a graph showing the relative PXRD for an
amorphous form of bupropion hydrobromide.
DEFINITIONS
[0084] The following definitions are provided in order to more
specifically describe the invention. Otherwise all terms are to be
accorded their ordinary meaning as they would be construed by one
of ordinary skill in the art, i.e. pharmaceutical drug
formulations.
[0085] The term "bupropion hydrobromide" as used herein means the
bupropion hydrobromide salt, and can also mean the anhydrous,
hydrated and solvated forms, prodrugs, polymorphs, and the
individually optically active enantiomers of bupropion
hydrobromide.
[0086] The terms "adverse effects associated with bupropion" or
"side effects of bupropion" as used herein are used
interchangeably, and mean the adverse drug reactions resulting from
the administration of bupropion or a mixture of bupropion with one
or more other drugs, non-limiting examples of which include
seizures, nausea, vomiting, excitement, agitation, blurred or
blurry vision, restlessness, postural tremors,
hallucinations/confusional states with the potential for abuse,
anxiety, insomnia, headaches and/or migraines, dry mouth,
constipation, tremors, sleeping disturbances, dermatologic problems
(e.g., rashes), neuropsychiatric signs and symptoms (e.g.,
delusions and paranoia), weight gain, and combinations thereof.
[0087] The term "depression" as used herein refers to any nervous
system disorder and/or mental condition. Non-limiting examples of
"depression" include major depressive disorder, bipolar depressed
mood disorder, adjustment mood disorder, and post-partum mood
disorder.
[0088] The term "condition" as used herein when referring to the
administration of bupropion, means a condition, disease or disorder
which can be treated with bupropion. Non-limiting examples of which
include depression, seasonal affective disorder, anxiety disorders,
generalized anxiety disorder, social anxiety disorder, obsessive
compulsive disorder, post traumatic stress disorder (PTSD), panic
disorder, disorders requiring a stimulant effect,
attention-deficit/hyperactivity disorder (ADHD), narcolepsy,
hypersomnia, substance-abuse disorders, stimulant dependence,
marijuana dependence, nicotine dependence, obesity, female and male
sexual dysfunction (e.g. premature ejaculation), premenstrual
syndrome, premenstrual dysphoric disorder, neuropathic pain,
fibromyalgia, diabetic neuropathy, viral infection, sleep apnea,
sleep disorders, migraines, Parkinson's disease, restless legs
syndrome, and combinations thereof.
[0089] The terms "treatment", "treating" or "treat" as used herein
when referring to a condition, and as understood in the art, are
defined to mean an approach for obtaining beneficial or desired
results, including clinical results. "Treatment" can also mean
prolonging survival of a subject as compared to the expected
survival of the subject if not receiving treatment.
[0090] The term "palliating" as used herein when referring to a
condition means that the extent and/or undesirable clinical
manifestations of a condition or disease state are lessened and/or
time course of the progression is slowed or lengthened, as compared
to not treating the condition.
[0091] The term "effective amount" or "pharmaceutically effective
amount" as used herein are used interchangeably, and are defined to
mean the amount or quantity of the active drug (e.g. bupropion
hydrobromide) or polymorph or enantiomer thereof which is
sufficient to elicit an appreciable biological response when
administered to a patient. It will be appreciated that the precise
therapeutic dose will depend on the age and condition of the
patient and the nature of the condition to be treated and will be
at the ultimate discretion of the attendant physician.
[0092] The terms "enhanced stability", "greater stability",
"increased stability" or "more stable" as used herein when
referring to bupropion hydrobromide, can be used interchangeably in
this application, and are defined to mean that the bupropion
hydrobromide or composition containing bupropion hydrobromide,
shows less degradation as determined by the formation of less of at
least one degradation product characteristic of bupropion
degradation, than an equivalent molar amount of bupropion
hydrochloride or an otherwise similar or identical composition
containing an equivalent molar amount of bupropion hydrochloride,
when exposed to similar or identical conditions. Non-limiting
examples of conditions are those described for example in U.S. Pat.
No. 7,241,805.
[0093] The term "less degradation" as used herein when referring to
bupropion hydrobromide or a composition containing bupropion
hydrobromide, is defined to mean any measurable decrease in the
amount of at least one bupropion degradation impurity
characteristic of bupropion degradation, and/or any measurable
difference in the retention of potency, relative to an equivalent
molar amount of bupropion hydrochloride or an otherwise similar or
identical composition containing an equivalent molar amount of
bupropion hydrochloride, when exposed to similar or identical
conditions.
[0094] The terms "degradation product", "bupropion degradation
product", "bupropion degradation impurity" or "impurity" as used
herein when referring to the degradation of bupropion, are used
interchangeably and are defined to include those listed on page 281
of the 26th edition of the USP and any other degradation product
that may appear as peaks on a chromatogram during the assay that
are characteristic of bupropion degradation.
[0095] The term "dissolution profile" or "release profile" as used
herein are used interchangeably in this application, and are
defined to mean a quality control test conducted according to
instructions found in the United States Pharmacopoeia ("USP"), i.e.
using a USP apparatus design with a dissolution medium as found in
the USP. Dissolution tests in-vitro measure the rate and extent of
dissolution of the active drug in an aqueous dissolution medium.
The dissolution rate or in-vitro release rates of drug from the
modified release dosage forms of the present invention can be
measured using one of many USP apparatus designs and dissolution
media; non-limiting examples of which include a USP Type 1
apparatus design or USP Type 2 apparatus design, with a dissolution
medium selected from water; 0.1N HCl; 0.1N HCl with added Sodium
Chloride (e.g. 15.7 g NaCl/Litre); 0.1N HCl with added 0.1%
Cetrimide; USP Buffer pH 1.5; Acetate Buffer pH 4.5; Phosphate
Buffer pH 6.5; Phosphate Buffer pH 6.8; and Phosphate Buffer pH
7.4. The terms "% released" and "% dissolved", when referring to a
dissolution profile, are used interchangeably in this application
and are defined to mean the extent (%) of active drug released in
an aqueous dissolution medium (in vitro).
[0096] The term "dose dumping" as used herein in respect of
"alcohol induced dose dumping" is defined to mean the unintended
premature release (in-vitro) of at least one drug from a modified
release dosage form. The term "premature release" as used herein is
defined to mean a release of at least one drug from a modified
release dosage form in 0.1 N HCl containing alcohol (e.g.
dissolution medium containing from about 5% to about 40% ethanol,
the balance being 0.1 N HCl) wherein the rate of release is faster
than the rate of release of the identical drug(s) from the
identical modified release dosage form in the otherwise identical
0.1 N HCl not containing alcohol. A non-limiting example of an
"alcohol induced dose dumping" is the premature release of
bupropion from a modified release tablet over a period of about 2
hours when dissolution is tested in 900 ml of Alcohol USP
comprising dissolution media using USP Apparatus Type 1 at 75 rpm
at 37.degree. C. In certain embodiments the term "Alcohol USP
comprising dissolution media" means any dissolution media
comprising from about 5% to about 40% (v/v) of Alcohol USP (e.g. 5%
ethanol and 95% 0.1N HCl; 20% ethanol and 80% 0.1N HCl; and 40%
ethanol and 60% 0.1N HCl).
[0097] The terms "resistant to alcohol", "resistant to ethanol",
"resistant to dose dumping", "resistant to alcohol-induced dose
dumping" and "resisting dose dumping" as used herein are used
interchangeably, and are defined to mean the ability of the dosage
form to modify release (in-vitro) of the at least one drug while in
the presence of alcohol (e.g. from about 5% to about 40% ethanol),
such that there is not a premature release of the at least one drug
from the modified release dosage form. For example, in certain
embodiments the rate of release of at least one drug from a
modified release dosage form in dissolution media containing
alcohol (e.g. dissolution medium containing from about 5% to about
40% ethanol) is slower than the rate of release of the identical
drug(s) from the identical modified release dosage form in
dissolution media not containing alcohol (e.g. dissolution medium
containing about 100% 0.1 N HCl).
[0098] The term "other drug" or "second drug" as used herein means
a drug other than bupropion, including but not limited to
anti-depression agents, other neuropsychiatric drugs, atypical
antipsychotics, drug that affects central or peripheral serotonin
neurotransmission, drugs that affect central norepinephrine
neurotransmission, drugs that affect central dopamine
neurotransmission, vasodilators, anti-anxiety agents, appetite
modulators, sleep modulating drugs, SSRIs, anti-viral agents,
anti-pain agents, anti-migraine agents, anti-inflammatories (both
steroidal and non-steroidal) serotonin receptor agonists, and more
particularly can include citalopram, escitalopram, venlafaxine,
clozapine, melperone, amperozide, iloperidone, risperidone,
quetiapene, olanzapine, ziprasidone, aripiprazole, reboxetine,
Viagra.RTM., sertraline, paroxetine, fluoxetine, gabapentin,
valproic acid, amitriptyline, lofepramine, fluvoxamine, imipramine,
mirtazapine, nefazodone, nortriptyline, SAM-E, buspirone,
combinations thereof, and their pharmaceutically acceptable salts
(e.g. the hydrochloride salts, the hydrobromide salts, the
hydroiodide salts, and the saccharinate salts), as well as the
anhydrous, hydrated, and solvated forms, polymorphs, prodrugs, and
the individually optically active enantiomers of the other
drug.
[0099] The term "dosage form" as used herein is defined to mean a
pharmaceutical preparation or system in which a dose of at least
one active drug is included. For example, a dosage form can include
at least one modified release dosage form, at least one osmotic
dosage form, at least one erosion modified release dosage form, at
least one dissolution modified release dosage form, at least one
diffusion modified release dosage form, at least one modified
release matrix core, at least one modified release matrix core
coated with at least one modified release coat, at least one
enteric coated dosage form, at least one dosage form surrounded by
at least one osmotic subcoat, capsules, minitablets, caplets,
uncoated microparticles, microparticles coated with at least one
modified release coat, or any combination thereof.
[0100] The term "medicament" as used herein refers to oral and
non-oral dosage forms, including but not limited to, all modified
release dosage forms, osmosis controlled release systems, erosion
controlled release systems, dissolution controlled release systems,
diffusion controlled release systems, matrix tablets, enteric
coated tablets, single and double coated tablets (including the
extended release and enhanced absorption tablets as described
herein), capsules, minitablets, caplets, coated beads, granules,
spheroids, pellets, microparticles, suspensions, topicals such as
transdermal and transmucosal compositions and delivery systems
(containing or not containing matrices), injectables, and inhalable
compositions.
[0101] "Modified release dosage forms" as used herein is defined
(e.g. as by the United States Pharmacopoeia "USP") as those whose
drug release characteristics of time course and/or location are
chosen to accomplish therapeutic or convenience objectives not
offered by conventional immediate release dosage forms. The rate of
release of the active drug from a modified release dosage form is
controlled by features of the dosage form and/or in combination
with physiologic or environmental conditions rather than by
physiologic or environmental conditions alone. The modified release
dosage forms of certain embodiments can be contrasted with
conventional immediate release dosage forms which typically produce
large maximum/minimum plasma drug concentrations (Cmax/Cmin) due to
rapid absorption of the drug into the body (i.e., in-vivo, relative
to the drug's therapeutic index; i.e., the ratio of the maximum
drug concentration needed to produce and maintain a desirable
pharmacological response). In conventional immediate release dosage
forms, the drug content is released into the gastrointestinal tract
within a short period of time, and plasma drug levels peak shortly
after dosing. The design of conventional immediate release dosage
forms is generally based on getting the fastest possible rate of
drug release, and therefore absorbed, often at the risk of creating
undesirable dose related side effects. The modified release dosage
forms of certain embodiments of the invention, on the other hand,
improve the therapeutic value of the active drug by reducing the
ratio of the maximum/minimum plasma drug concentration (Cmax/Cmin)
while maintaining drug plasma levels within the therapeutic window.
The modified release dosage forms of certain embodiments attempt to
deliver therapeutically effective amounts of bupropion hydrobromide
and mixtures of bupropion hydrobromide with at least one other drug
as a once-daily dose so that the ratio Cmax/Cmin in the plasma at
steady state is less than the therapeutic index, and to maintain
drug levels at constant effective levels to provide a therapeutic
benefit over a period of time (e.g. 24-hour period). The modified
release dosage forms of certain embodiments of the invention,
therefore, avoid large peak-to-trough fluctuations normally seen
with conventional or immediate release dosage forms and can provide
a substantially flat serum concentration curve throughout the
therapeutic period. Modified-release dosage forms can be designed
to provide a quick increase in the plasma concentration of the
bupropion salt which remains substantially constant within the
therapeutic range of bupropion salt for a period of time (e.g.
24-hour period). Alternatively, modified-release dosage forms can
be designed to provide a quick increase in the plasma concentration
of the drug, which although may not remain constant, declines at a
rate such that the plasma concentration remains within the
therapeutic range for a period of time (e.g. 24-hour period). The
modified release dosage forms of certain embodiments of the
invention can be constructed in many forms known to one of ordinary
skill in the drug delivery arts and described in the prior art. The
USP considers that the terms controlled release, prolonged release
and sustained release are interchangeable. Accordingly, the terms
"modified-release", controlled-release", "control-releasing",
"rate-controlled release", "extended release", "prolonged-release",
and "sustained-release" are used interchangeably herein. For the
discussion herein, the definition of the term "modified-release"
encompasses the scope of the definitions for the terms "extended
release", "enhanced-absorption", "controlled release", "sustained
release" and "delayed release".
[0102] "Controlled release dosage forms", "control-releasing dosage
forms", "rate-controlled release dosage forms", or dosage forms
which exhibit a "controlled release" of the bupropion hydrobromide
or mixtures of bupropion hydrobromide and a second drug, as used
herein are used interchangeably in this application and are defined
to mean dosage forms which release the bupropion hydrobromide in a
controlled manner per unit time in-vivo. For example, controlled
release dosage forms can be administered once daily, and release
the bupropion hydrobromide at a controlled rate and provide plasma
concentrations of the drug that remain controlled with time within
the therapeutic range of bupropion over a 24-hour period.
[0103] "Sustained-release dosage forms" or dosage forms which
exhibit a "sustained-release" of bupropion hydrobromide or mixtures
of bupropion hydrobromide and a second drug as used herein is
defined to mean dosage forms administered at least once-daily that
provide a release of bupropion hydrobromide sufficient to provide a
therapeutic dose soon after administration, and then a gradual
release over a period of time such that the sustained-release
dosage form provides a therapeutic benefit over a period of time
(e.g. a 12-hour or 24-hour period).
[0104] "Extended-release dosage forms" or dosage forms which
exhibit an "extended release" of bupropion hydrobromide or mixtures
of bupropion hydrobromide and a second drug as used herein is
defined to mean dosage forms administered at least once-daily that
release the bupropion hydrobromide slowly, so that plasma
concentrations of the bupropion hydrobromide are maintained at a
therapeutic level for an extended period of time such that the
extended release dosage form provides therapeutic benefit over a
period of time (e.g. 24-hour period).
[0105] "Delayed-release dosage forms" or dosage forms which exhibit
a "delayed release" of bupropion hydrobromide or mixtures of
bupropion hydrobromide and a second drug as used herein is defined
to mean dosage forms administered at least once-daily that do not
effectively release drug immediately following administration but
at a later time. Delayed-release dosage forms provide a time delay
prior to the commencement of drug-absorption. This time delay is
referred to as "lag time" and should not be confused with "onset
time" which represents latency, that is, the time required for the
drug to reach minimum effective concentration.
[0106] "Enhanced absorption dosage forms" or dosage forms which
exhibit an "enhanced absorption" of the active drug as used herein
is defined to mean dosage forms that when exposed to like
conditions, will show higher release and/or more absorption of the
bupropion base as compared to other dosage forms with the same or
higher amount of bupropion base. The same therapeutic effect can be
achieved with less bupropion base in the enhanced absorption dosage
form as compared to other dosage forms.
[0107] The term "microparticle", as used herein refers to a drug
formulation in discrete particulate form, and is interchangeable
with the terms "microspheres", "spherical particles",
"microcapsules", "particles", "multiparticulates", "granules",
"spheroids", beads" and "pellets".
[0108] The term "tablet" as used herein refers to a single dosage
form, i.e. the single entity containing the active pharmaceutical
agent that is administered to the subject. The term "tablet" also
includes a tablet that may be the combination of one or more
"minitablets".
[0109] The term "controlled release matrix" as used herein is
defined to mean a dosage form in which the bupropion hydrobromide
or mixtures of bupropion hydrobromide and a second drug, is
dispersed within a matrix, which matrix can be either insoluble,
soluble, or a combination thereof. Controlled release matrix dosage
forms of the insoluble type are also referred to as "insoluble
polymer matrices", "swellable matrices", or "lipid matrices"
depending on the components that make up the matrix. Controlled
release matrix dosage forms of the soluble type are also referred
to as "hydrophilic colloid matrices", "erodible matrices", or
"reservoir systems". Controlled release matrix dosage forms of the
invention refer to dosage forms comprising an insoluble matrix, a
soluble matrix or a combination of insoluble and soluble matrices
in which the rate of release is slower than that of an uncoated
non-matrix conventional or immediate release dosage forms or
uncoated "normal release matrix" dosage forms. Controlled release
matrix dosage forms can be coated with a "control-releasing coat"
to further slow the release of the bupropion salt from the
controlled release matrix dosage form. Such coated controlled
release matrix dosage forms can exhibit "modified-release",
controlled-release", "sustained-release", "extended-release",
"prolonged-release", "delayed-release" or combinations thereof of
the active drug.
[0110] The term "normal release matrix" as used herein is defined
to mean dosage forms in which the bupropion hydrobromide or
mixtures of bupropion hydrobromide and a second drug, is dispersed
within a matrix, which matrix can be either insoluble, soluble, or
combinations thereof but constructed such that the release of the
active drug mimics the release rate of an uncoated non-matrix
conventional or immediate release dosage form comprising the drug.
The release rate from normal release matrix dosage forms can be
slowed down or modified in conjunction with a controlled release
coat.
[0111] The terms "osmotic dosage form", "osmotic delivery device",
"modified release osmotic dosage form" or "controlled release
osmotic dosage form" as used herein are used interchangeably in
this application, and are defined to mean dosage forms which
dispense the bupropion hydrobromide or mixture of bupropion
hydrobromide and a second drug, all or in part as a result of the
presence of an osmotic agent in the dosage form driving solvent
(e.g. water, dissolution media, gastric fluid, intestinal fluid, or
mixtures thereof) into the core of the dosage form, which
subsequently facilitates the release of drug from the core.
[0112] The terms "osmotic agent", "osmagent", "osmotically
effective solute", "osmotic enhancer" "osmotically effective
compounds", "osmotic solutes", "osmopolymer" and "osmotic fluid
imbibing agents" as used herein are used interchangeably, and
define any material that is soluble (i.e. can be partially or
totally solubilized) or swellable in a solvent (e.g. water) that
enters the composition, and which exhibits an osmotic pressure
gradient across the selectively-permeable membrane (e.g. controlled
release coat), thus increasing the hydrostatic pressure inside the
osmotic dosage form.
[0113] The terms "controlled release coat", "control releasing
coat", "modified release coat" and "rate-controlling coat" as used
herein are used interchangeably in this application, and are
defined to mean a functional coat which comprises at least one
modified release polymer. Non-limiting examples of modified release
polymers include pH independent polymers, pH dependent polymers
(such as for example enteric or reverse enteric types), soluble
polymers, insoluble polymers, lipids, lipidic materials, and
mixtures thereof. When applied onto a dosage form, the controlled
release coat can modify (e.g. slow) the rate of release of the
active drug. For example, the controlled release coat can be
designed such that when the coat is applied onto a dosage form, the
dosage form in conjunction with the controlled release coat,
exhibits a "modified-release", "controlled-release",
"sustained-release", "extended-release" and/or "delayed-release"
profile. Combinations thereof are permissible. The controlled
release coat can optionally comprise additional materials that can
alter the functionality of the controlled release coat. The term
"modified release" is interchangeable with the terms "controlled
release", "control releasing" and "rate controlling". The term
"coat" is interchangeable with the term "coating".
[0114] The terms "moisture barrier" and "moisture barrier coat" as
used herein are used interchangeably and are defined to mean a
coating which impedes or retards the absorption of moisture. It is
known that bupropion salts are hygroscopic and, as such, are
susceptible to decomposition over time under high humidity
conditions. Other active drugs can also be susceptible to
decomposition over time under high humidity conditions. The
proportion of the components of the moisture barrier and the amount
of the moisture barrier applied onto the controlled release coat is
such that the moisture barrier does not fall within the USP
definition and requirement for an enteric coat. Suitably, the
moisture barrier is comprised of an enteric and/or acrylic polymer,
suitably an acrylic polymer, optionally a plasticizer, and a
permeation enhancer. The permeation enhancer is a hydrophilic
substance, which allows water to enter without physical disruption
of the coating. The moisture barrier can additionally contain other
conventional inert excipients, which can improve processing of the
extended-release formulation described herein.
[0115] The term "enteric coat" as used herein is defined to mean a
coating or barrier applied to a dosage form that can control the
location in the digestive system where the active drug(s) is
absorbed. For example, an enteric coating can be used to: (i)
protect the drug from the destructive action of the enzymes or low
pH environment of the stomach; (ii) prevent nausea or bleeding
associated with the irritation of the gastric mucosa by the drug;
and/or (iii) deliver the drug in an undiluted form in the
intestine. Based on these criteria, in certain embodiments, the
enteric coated dosage form can be regarded as a type of delayed
release dosage form. They differ from sustained release dosage
forms in that with sustained release dosage forms, the drug release
is extended over a period of time to maintain therapeutic blood
levels and to decrease the incidence of side effects caused by a
rapid release; whereas, with enteric coatings, the primary
objective is to confine the release of the drug to a predetermined
region of the gastrointestinal tract. Enteric coatings work by
presenting a surface that is substantially stable at acidic pH, but
breaks down at higher pH to allow release of the drug in the
intestine.
[0116] The term "enteric polymer" as used herein is defined to mean
a polymeric substance that when used in an enteric coat
formulation, is substantially insoluble and/or substantially stable
under acidic conditions exhibiting a pH of less than about 5 and
which are substantially soluble or can decompose under conditions
exhibiting a pH of about 5 or more. Non-limiting examples of such
enteric polymers include carboxymethylethylcellulose, cellulose
acetate phthalate, cellulose acetate succinate, methylcellulose
phthalate, hydroxymethylethylcellulose phthalate,
hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose acetate succinate, polyvinyl alcohol
phthalate, polyvinyl butyrate phthalate, polyvinyl acetal
phthalate, a copolymer of vinyl acetate/maleic anhydride, a
copolymer of vinylbutylether/maleic anhydride, a copolymer of
styrene/maleic acid monoester, a copolymer of methyl
acrylate/methacrylic acid, a copolymer of styrene/acrylic acid, a
copolymer of methyl acrylate/methacrylic acid/octyl acrylate, a
copolymer of methacrylic acid/methyl methacrylate and mixtures
thereof. Enteric polymers can be used individually or in
combination with other hydrophobic or hydrophilic polymers in an
enteric coat, a normal release matrix core, a controlled release
matrix core, and/or in a controlled release coat. Enteric polymers
can be combined with other pharmaceutically acceptable excipients
to either facilitate processing of a coat comprising the enteric
polymer or to alter the functionality of the coat.
[0117] The term "functional coat" as used herein is defined to mean
a coating that affects the rate of release in-vitro or in-vivo of
the active drug(s).
[0118] The term "non-functional coat" as used herein is defined to
mean a coating that does not substantially affect the rate of
release in-vitro or in-vivo of the active drug, but can enhance the
chemical, biological, physical stability characteristics, or the
physical appearance of the modified release dosage form.
[0119] The term "core" as used herein is defined to mean a solid
vehicle in which at least one active drug is uniformly or
non-uniformly dispersed. The core can be formed by methods and
materials well known in the art, such as for example by
compressing, fusing, or extruding the active drug together with at
least one pharmaceutically acceptable excipient. The core can be
manufactured into, for example, a homogenous or non-homogenous
unitary core, a multiparticle, or a plurality of microparticles
compressed into a unitary core. Non-limiting examples of cores
include microparticle cores, matrix cores, and osmotic cores. The
core(s) can be coated with at least one functional coat and/or
non-functional coat.
[0120] The terms "modified release matrix core", "controlled
release matrix core" or "matrix core" when referring to a
controlled release matrix dosage form, as used herein are used
interchangeably, and are defined to mean a core in which at least
one active drug is dispersed within a matrix which controls or
delays the release of the active drug over a 24-hour period so as
to allow a composition comprising the modified release matrix core
to be administered as a once-a-day composition. The release rate of
the active drug from the modified release matrix core can be
modified by the porosity and tortuosity of the matrix, (i.e. its
pore structure). The addition of pore-forming hydrophilic salts,
solutes, or wicking agents can influence the release rate, as can
the manipulation of processing parameters. For example, the
compression force used in the manufacture of the modified release
matrix core can alter the porosity of the matrix core and hence the
rate of release of the active drug. It will be understood by one of
ordinary skill in the art of drug delivery that a more rigid matrix
will be less porous and hence release the active drug more slowly
compared to a less rigid modified release matrix core. The modified
release matrix core can comprise insoluble or inert matrix dosage
forms, swellable matrix dosage forms, swellable and erodable matrix
dosage form, hydrophobic matrix dosage forms, hydrophilic matrix
dosage forms, erodable matrix dosage forms, reservoir dosage forms,
or any combination thereof. The modified release matrix core can
comprise at least one insoluble matrix, at least one swellable
matrix, at least one swellable and erodable matrix, at least one
hydrophobic matrix, at least one hydrophilic matrix, at least one
erodable matrix, or a combination thereof in which the rate of
release is slower than that of uncoated immediate-release dosage
forms. Modified release matrix cores can be coated with at least
one controlled release coat to further slow the release of the
active drug from the modified release matrix core. Such coated
modified release matrix cores can exhibit modified-release,
controlled-release, sustained-release, extended-release,
prolonged-release, bi-phasic release, delayed-release or
combinations thereof of the active drug. Modified release matrix
cores can also be coated with a non-functional soluble coat.
[0121] The term "plasticizer" as used herein includes any compounds
capable of plasticizing or softening a polymer or a binder used in
the present invention. The use of plasticizers is optional, and can
be included in the dosage form to modify the properties and
characteristics of the polymers used in the coat(s) or core of the
dosage form for convenient processing during manufacture of the
coat(s) and/or the core of the dosage form. Once the coat(s) and/or
core have been manufactured, certain plasticizers can function to
increase the hydrophilicity of the coat(s) and/or the core of the
dosage form in the environment of use. During manufacture of the
coat(s) and/or core, the plasticizer can lower the melting
temperature or glass transition temperature (softening point
temperature) of the polymer or binder. Plasticizers can be included
with a polymer and lower its glass transition temperature or
softening point. Plasticizers also can reduce the viscosity of a
polymer. Plasticizers can impart some particularly advantageous
physical properties to the dosage forms of the invention.
[0122] The terms "pore former", "pore forming agent", and "pore
forming additive" as used herein are used interchangeably in this
application, and are defined to mean an excipient that can be added
to a coating (e.g. the controlled release coat), wherein upon
exposure to fluids in the environment of use, the pore former
dissolves or leaches from the coating to form pores, channels or
paths in the coating, that can fill with the environmental fluid
and allow the fluid to enter the core and dissolve the active drug,
and modify the release characteristics of the formulation. The pore
formers can be inorganic or organic, and include materials that can
be dissolved, extracted or leached from the coating in the
environment of use.
[0123] The term "steady state" as used herein means that the blood
plasma concentration curve for a given drug does not substantially
fluctuate after repeated doses to dose of the formulation.
[0124] "AUC" as used herein means area under the plasma
concentration-time curve, as calculated by the trapezoidal rule
over a time interval (e.g. complete 24-hour interval); and
signifies the extent of the absorption of a drug.
[0125] "Cmax" as used herein means the highest plasma concentration
of the drug attained within the dosing interval (e.g., 24
hours).
[0126] "Cmin" as used herein means the minimum plasma concentration
of the drug attained within the dosing interval (e.g. 24
hours).
[0127] "Cavg" as used herein means the plasma concentration of the
drug within the dosing interval (e.g. 24-hours), and is calculated
as AUC/dosing interval.
[0128] "Tmax" as used herein means the time period which elapses
after administration of the dosage form at which the plasma
concentration of the drug attains the highest plasma concentration
of drug attained within the dosing interval (e.g. 24 hours).
[0129] The term "bioequivalence" as used herein is defined as there
being about a 90% or greater probability that the bioavailability
(AUC) of the active drug as determined by standard methods is from
about 80% to about 125% of the second orally administrable dosage
form comprising the same dose of the active drug and that there is
about 90% or greater probability that the maximum blood plasma
concentration (Cmax) of the active drug as measured by standard
methods is from about 80% to about 125% of the second orally
administrable dosage form. For example, the reader is referred to
the final version of the guidance approved by the US Food and Drug
Administration at the time of filing of this patent application
i.e., the March 2003 Guidance for Industry Bioavailability and
Bioequivalence Studies for Orally Administered Drug Products
General Considerations, U.S. Department of Health and Human
Services, Food and Drug Administration, Center for Drug Evaluation
and Research (CDER), for a detailed discussion on
bioequivalence.
[0130] The terms "a", "an" or "at least one" as used herein are
used interchangeably in this application, and are defined to mean
"one" or "one or more".
[0131] The numerical parameters set forth in the following
specification and attached claims that are modified by the term
"about", are approximations that can vary depending upon the
technological properties of the particular case. For example, the
term "about" can mean within an acceptable error range (e.g.
standard deviations) for the particular value as determined by one
of ordinary skill in the art, which will depend in part on how the
value is measured or determined, e.g., the limitation's of the
measurement system.
[0132] Other terms are defined as they appear in the following
description and should be construed in the context with which they
appear.
[0133] The present invention encompasses the bupropion hydrobromide
salt and polymorphs of bupropion hydrobromide, and compositions
containing safe and pharmaceutically effective levels of the
bupropion hydrobromide salt and/or polymorph of bupropion
hydrobromide, that can be used for the treatment of a condition in
subjects that can benefit from bupropion administration, wherein
the bupropion hydrobromide salt and compositions containing safe
and pharmaceutically effective levels of the bupropion hydrobromide
salt unexpectedly provide for the reduction of incidences of and/or
the reduction in severity of bupropion-induced seizures, and are
more stable, as compared with equivalent molar amounts of bupropion
hydrochloride or otherwise similar or identical compositions
containing equivalent molar amounts of bupropion hydrochloride.
Results are described for example in U.S. Pat. No. 7,241,805, and
U.S. patent application Ser. No. 11/834,848 (Pub. No.
2008-0075774), the contents of which are incorporated herein by
reference.
[0134] Also, the present invention encompasses polymorphs thereof
and specific purified enantiomeric forms thereof. The present
invention also encompasses the use of such bupropion hydrobromide
salt and compositions containing the bupropion hydrobromide salt
for the treatment of one or more conditions in a subject suitable
for treatment by bupropion or pharmaceutically acceptable salts
thereof (e.g. depression, obesity, nicotine addiction, and other
conditions treatable with bupropion such as are disclosed herein);
wherein the incidences of and/or the severity of bupropion-induced
seizures is reduced as compared with an equivalent molar amount of
bupropion hydrochloride or an otherwise similar or identical
composition containing an equivalent molar amount of bupropion
hydrochloride.
[0135] The present invention encompasses any medicament containing
a pharmaceutically effective amount of bupropion hydrobromide
and/or a polymorph of bupropion hydrobromide. This includes both
oral and non-orally administrable medicaments such as topicals,
injectables, aerosols and other inhalable medicaments. Particularly
such medicament compositions include orally administrable modified
release dosage forms containing bupropion hydrobromide. The dosages
can be conveniently presented in unit dosage form and prepared by
any of the methods well-known in the art of pharmacy. A "solid
dosage form" as used herein, means a dosage form that is neither
liquid nor gaseous. Dosage forms include solid dosage forms, such
as tablets, powders, microparticles, capsules, suppositories,
sachets, troches, patches and lozenges as well as liquid
suspensions and elixirs. Capsule dosages contain the solid
composition within a capsule that can be made of gelatin or other
conventional encapsulating material.
[0136] The modified release dosage forms contemplated in the
present invention can be multiparticulate or monolithic. For
example, those skilled in the pharmaceutical art and the design of
medicaments are aware of modified release matrices conventionally
used in oral pharmaceutical compositions adopted for modified
release and means for their preparation.
[0137] A modified release formulation containing bupropion
hydrobromide and/or a polymorph of bupropion hydrobromide according
to the present invention can be coated with one or more functional
or non-functional coatings. Non-limiting examples of functional
coatings include controlled release polymeric coatings, moisture
barrier coatings, enteric polymeric coatings, and the like. In at
least one embodiment of the present invention a bupropion
hydrobromide composition comprises a controlled release polymeric
coating that includes an acrylic polymer. Suitable acrylic polymers
include but are not limited to acrylic acid and methacrylic acid
copolymers, methyl methacrylate copolymers, ethoxyethyl
methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate
copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic
acid alkylamine copolymer, poly(methyl methacrylate),
poly(methacrylic acid) (anhydride), polyacrylamide,
poly(methacrylic acid anhydride), glycidyl methacrylate copolymers
and mixtures thereof.
[0138] In at least one embodiment polymerizable quaternary ammonium
compounds are employed in the controlled release coat, of which
non-limiting examples include quaternized aminoalkyl esters and
aminoalkyl amides of acrylic acid and methacrylic acid, for example
.beta.-methacryl-oxyethyl-trimethyl-ammonium methosulfate,
.beta.-acryloxy-propyl-trimethyl-ammonium chloride,
trimethylaminomethyl-methacrylamide methosulfate and mixtures
thereof. The quaternary ammonium atom can also be part of a
heterocycle, as in methacryloxyethylmethyl-morpholiniom chloride or
the corresponding piperidinium salt, or it can be joined to an
acrylic acid group or a methacrylic acid group by way of a group
containing hetero atoms, such as a polyglycol ether group. Further
suitable polymerizable quaternary ammonium compounds include
quaternized vinyl-substituted nitrogen heterocycles such as
methyl-vinyl pyridinium salts, vinyl esters of quaternized amino
carboxylic acids, styryltrialkyl ammonium salts, and mixtures
thereof. Other polymerizable quaternary ammonium compounds useful
in the present invention include acryl- and
methacryl-oxyethyltrimethyl-ammonium chloride and methosulfate,
benzyldimethylammoniumethyl-methacrylate chloride,
diethylmethylammoniumethyl-acrylate and -methacrylate methosulfate,
N-trimethylammoniumpropylmethacrylamide chloride,
N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride and
mixtures thereof.
[0139] In at least one embodiment the acrylic polymer of the
controlled release coat is comprised of one or more ammonio
methacrylate copolymers. Ammonio methacrylate copolymers (e.g.
EUDRAGIT.RTM. RS and RL) are described in National Formulary (NF)
XVII as fully polymerized copolymers of acrylic and methacrylic
acid esters with a low content of quaternary ammonium groups. Two
or more ammonio methacrylate copolymers having differing physical
properties can be incorporated in the controlled release coat of
certain embodiments. For example, it is known that by changing the
molar ratio of the quaternary ammonium groups to the neutral
(meth)acrylic esters, the permeability properties of the resultant
coating can be modified.
[0140] In certain other embodiments of the present invention, the
controlled release coat further includes a polymer whose
permeability is pH dependent, such as anionic polymers synthesized
from methacrylic acid and methacrylic acid methyl ester (e.g.
EUDRAGIT.RTM. L and EUDRAGIT.RTM. S). The ratio of free carboxyl
groups to the esters is known to be 1:1 in EUDRAGIT.RTM. L and 1:2
in EUDRAGIT.RTM. S. EUDRAGIT.RTM. L is insoluble in acids and pure
water, but becomes increasingly permeable above pH 5.0.
EUDRAGIT.RTM. S is similar, except that it becomes increasingly
permeable above pH 7. The hydrophobic acrylic polymer coatings can
also include a polymer which is cationic in character based on
dimethylaminoethyl methacrylate and neutral methacrylic acid esters
(e.g. EUDRAGIT.RTM. E). The hydrophobic acrylic polymer coatings of
certain embodiments of the present invention can further include a
neutral copolymer based on poly (meth)acrylates, such as
EUDRAGIT.RTM. NE. EUDRAGIT.RTM. NE 30D lacquer films are insoluble
in water and digestive fluids, but permeable and swellable.
[0141] In at least one other embodiment of the invention, the
controlled release coat comprises a dispersion of poly
(ethylacrylate, methyl methacrylate) 2:1 (KOLLICOAT.RTM. EMM 30
D).
[0142] In at least one other embodiment of the invention, the
controlled release coat comprises a polyvinyl acetate stabilized
with polyvinylpyrrolidone and sodium lauryl sulfate such as
KOLLICOAT.RTM. SR30D. The dissolution profile can be altered by
changing the relative amounts of different acrylic resin lacquers
included in the coating. Also, by changing the molar ratio of
polymerizable permeability-enhancing agent (e.g., the quaternary
ammonium compounds) to the neutral (meth)acrylic esters, the
permeability properties (and thus the dissolution profile) of the
resultant coating can be modified.
[0143] In at least one embodiment of the invention the controlled
release coat comprises ethylcellulose, which can be used as a dry
polymer (e.g. ETHOCEL.RTM.) solubilised in organic solvent prior to
use, or as an aqueous dispersion. One suitable
commercially-available aqueous dispersion of ethylcellulose is
AQUACOAT.RTM.. AQUACOAT.RTM. can be prepared by dissolving the
ethylcellulose in a water-immiscible organic solvent and then
emulsifying the same in water in the presence of a surfactant and a
stabilizer. After homogenization to generate submicron droplets,
the organic solvent can be evaporated under vacuum to form a
pseudolatex. The plasticizer is not incorporated in the pseudolatex
during the manufacturing phase. Thus, prior to using the same as a
coating, the AQUACOAT.RTM. can be intimately mixed with a suitable
plasticizer prior to use. Another suitable aqueous dispersion of
ethylcellulose is commercially available as SURELEASE.RTM.. This
product can be prepared by incorporating plasticizer into the
dispersion during the manufacturing process. A hot melt of a
polymer, plasticizer (e.g. dibutyl sebacate), and stabilizer (e.g.
oleic acid) can be prepared as a homogeneous mixture, which can
then be diluted with an alkaline solution to obtain an aqueous
dispersion which can be applied directly onto substrates.
[0144] Other examples of polymers that can be used in the
controlled release coat include cellulose acetate phthalate,
cellulose acetate trimaletate, hydroxy propyl methylcellulose
phthalate, polyvinyl acetate phthalate, polyvinyl alcohol
phthalate, shellac; hydrogels and gel-forming materials, such as
carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium
carmellose, sodium carboxymethyl starch, poly vinyl alcohol,
hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin,
starch, and cellulose based cross-linked polymers in which the
degree of crosslinking is low so as to facilitate adsorption of
water and expansion of the polymer matrix, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked
starch, microcrystalline cellulose, chitin, pullulan, collagen,
casein, agar, gum arabic, sodium carboxymethyl cellulose,
(swellable hydrophilic polymers) poly(hydroxyalkyl methacrylate)
(molecular weight from about 5 k to about 5000 k),
polyvinylpyrrolidone (molecular weight from about 10 k to about 360
k), anionic and cationic hydrogels, zein, polyamides, polyvinyl
alcohol having a low acetate residual, a swellable mixture of agar
and carboxymethyl cellulose, copolymers of maleic anhydride and
styrene, ethylene, propylene or isobutylene, pectin (molecular
weight from about 30 k to about 300 k), polysaccharides such as
agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides,
POLYOX.RTM. polyethylene oxides (molecular weight from about 100 k
to about 5000 k), AQUAKEEP.RTM. acrylate polymers, diesters of
polyglucan, crosslinked polyvinyl alcohol and poly
N-vinyl-2-pyrrolidone, hydrophilic polymers such as
polysaccharides, methyl cellulose, sodium or calcium carboxymethyl
cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose,
hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose,
cellulose ethers, methyl ethyl cellulose, ethylhydroxy
ethylcellulose, cellulose acetate, cellulose butyrate, cellulose
propionate, gelatin, starch, maltodextrin, pullulan, polyvinyl
pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty
acid esters, polyacrylamide, polyacrylic acid, natural gums,
lecithins, pectin, alginates, ammonia alginate, sodium, calcium,
potassium alginates, propylene glycol alginate, agar, and gums such
as arabic, karaya, locust bean, tragacanth, carrageens, guar,
xanthan, scleroglucan and mixtures thereof.
[0145] In at least one embodiment the dosage forms are coated with
polymers in order to facilitate mucoadhsion within the
gastrointestinal tract. Non-limiting examples of polymers that can
be used for mucoadhesion include carboxymethylcellulose,
polyacrylic acid, CARBOPOL.TM., POLYCARBOPHIL.TM., gelatin, other
natural or synthetic polymers, and mixtures thereof.
[0146] In at least one embodiment of the invention, the dosage form
is an extended release tablet comprising: (i) a core that includes
bupropion hydrobromide or a polymorph of bupropion hydrobromide in
an amount of from about 40% to about 99% by weight of tablet dry
weight, including all values and ranges therebetween, a binder such
as polyvinyl alcohol in an amount of from about 0.5% to about 25%
by weight of tablet dry weight, including all values and ranges
therebetween, and a lubricant such as glyceryl behenate in an
amount of from about 0.1% to about 5% by weight of tablet dry
weight, including all values and ranges therebetween; and (ii) a
controlled release coat that includes a water-insoluble
water-permeable film-forming polymer such as ethylcellulose in an
amount of from about 1% to about 12% by weight of tablet dry
weight, including all values and ranges therebetween, a
water-soluble polymer such as polyvinylpyrrolidone (POVIDONE.RTM.
USP) in an amount of from about 1.5% to about 10% by weight of
tablet dry weight, including all values and ranges therebetween,
optionally a plasticizer such as dibutyl sebacate, polyethylene
glycol 4000 or a mixture thereof, in an amount of from about 0.5%
to about 4% by weight of tablet dry weight, including all values
and ranges therebetween, and optionally a wax such as carnauba wax
in an amount of from about 0.01% to about 0.05% by weight of tablet
dry weight, including all values and ranges therebetween.
[0147] In at least one embodiment of the invention, the dosage form
is a 174 mg extended release tablet comprising: (i) a core that
includes bupropion hydrobromide or a polymorph of bupropion
hydrobromide (e.g. about 81% by weight of tablet dry weight), a
binder such as polyvinyl alcohol (e.g. about 3% by weight of tablet
dry weight), and a lubricant such as glyceryl behenate (e.g. about
3% by weight of tablet dry weight); and (ii) a controlled release
coat that includes a water-insoluble water-permeable film-forming
polymer such as ethylcellulose (e.g. about 7% by weight of tablet
dry weight), a water-soluble polymer such as polyvinylpyrrolidone
(POVIDONE.RTM. USP), (e.g. about 4% by weight of tablet dry
weight), optionally a plasticizer such as dibutyl sebacate,
polyethylene glycol 4000 or a mixture thereof (e.g. about 2% by
weight of tablet dry weight), and optionally a wax such as carnauba
wax (e.g. about 0.03% by weight of tablet dry weight).
[0148] In at least one embodiment of the invention, the dosage form
is a 348 mg extended release tablet comprising: (i) a core that
includes bupropion hydrobromide or a polymorph of bupropion
hydrobromide (e.g. about 87% by weight of tablet dry weight), a
binder such as polyvinyl alcohol (e.g. about 3% by weight of tablet
dry weight), and a lubricant such as glyceryl behenate (e.g. about
3% by weight of tablet dry weight); and (ii) a controlled release
coat that includes a water-insoluble water-permeable film-forming
polymer such as ethylcellulose (e.g. about 4% by weight of tablet
dry weight), a water-soluble polymer such as polyvinylpyrrolidone
(POVIDONE.RTM. USP), (e.g. about 2% by weight of tablet dry
weight), optionally a plasticizer such as dibutyl sebacate,
polyethylene glycol 4000 or a mixture thereof (e.g. about 1% by
weight of tablet dry weight), and optionally a wax such as carnauba
wax (e.g. about 0.01% by weight of tablet dry weight).
[0149] In at least one embodiment of the invention, the dosage form
is a 522 mg XL tablet comprising: (i) a core that includes
bupropion hydrobromide or a polymorph of bupropion hydrobromide
(e.g. about 85% by weight of tablet dry weight), a binder such as
polyvinyl alcohol (e.g. about 3.5% by weight of tablet dry weight),
and a lubricant such as glyceryl behenate (e.g. about 3.5% by
weight of tablet dry weight); and (ii) a controlled release coat
that includes a water-insoluble water-permeable film-forming
polymer such as ethylcellulose (e.g. about 3% by weight of tablet
dry weight), a water-soluble polymer such as polyvinylpyrrolidone
(POVIDONE.RTM. USP), (e.g. about 3.5% by weight of tablet dry
weight), optionally a plasticizer such as dibutyl sebacate,
polyethylene glycol 4000 or a mixture thereof (e.g. about 1.5% by
weight of tablet dry weight), and optionally a wax such as carnauba
wax (e.g. about 0.01% by weight of tablet dry weight).
[0150] In at least one embodiment a modified release pharmaceutical
composition releases bupropion hydrobromide or a polymorph of
bupropion hydrobromide in a first dissolution medium consisting of
0.1 N HCl and 5%-40% v/v ethanol at a rate that is less than or
equal to about 1.1 times the rate of release of bupropion
hydrobromide or a polymorph of bupropion hydrobromide from an
identical modified release pharmaceutical composition in a second
dissolution medium consisting of 0.1 N HCl measured over the time
period of at least from 0 to 2 hours. In certain embodiments the
term "less than or equal to about 1.1" includes values below 1.1,
such as 1.05, 1.00, 0.95, 0.90, 0.85, 0.80, etc, including all
values and subranges between about 1.1 and about 0, but preferably
does not equal 0, and more preferably is 0.5-1.1, more preferably
0.75-1.1, even more preferably 0.8-1.0. These measurements are
preferably made using a USP Apparatus I at 75 rpm and at
37.+-.0.5.degree. C. In certain embodiments the modified release
pharmaceutical composition is placed in 900 ml of dissolution
medium for the measurement. In other embodiments the value of
"about 1.1" includes values immediately above 1.1, such as 1.30,
1.29, 1.28, 1.27, 1.26, 1.25, 1.24, 1.23, 1.22, 1.21, 1.20, 1.19,
1.18, 1.17, 1.16, 1.15, 1.14, 1.13, 1.12, 1.11, etc, including all
values and subranges therebetween. The results are described in
greater detail in U.S. patent application Ser. No. 11/930,644 (Pub.
No. 2008-0274181), the contents of which are incorporated herein by
reference.
[0151] In addition to the modified release dosage forms described
herein, other modified release technologies known to those skilled
in the art can be used in order to achieve the modified release
formulations of certain embodiments of the present invention. Such
formulations can be manufactured as a modified release oral
formulation, for example, in a suitable tablet or multiparticulate
formulation known to those skilled in the art. In either case, the
modified release dosage form can optionally include a controlled
release carrier which is incorporated into a matrix along with the
drug, or which is applied as a controlled release coating.
Polymorphic Forms I, II and III
[0152] It is well known that organic molecules can crystallize into
solid forms. Moreover the same organic compound may assume
different crystalline arrangements in solid form, depending on the
conditions under which the crystal product is formed. This
phenomenon is commonly known as polymorphism. A number of studies
were undertaken to explore the polymorphic forms of bupropion
hydrobromide. The crystal forms of the products obtained in the
studies were determined by powder X-ray diffraction (PXRD). A
RIGAKU miniflex instrument (Radiation Cu K.varies., generator 30
KV, filter Ni) was used to obtain the PXRD data.
[0153] A standard procedure was established to generate bupropion
hydrobromide, this standard procedure produces a first polymorphic
form which has been termed polymorphic form I. The relative PXRD
for Form I is shown in FIG. 22. The differential scanning
calorimetry (DSC) profile for Form I is shown in FIG. 23. This
procedure was scaled up and generated three industrial batches. The
material obtained from the three industrial batches consistently
gave the same PXRD profile of crystalline form I. Samples of these
batches of form I were tested for accelerated stability at 3 and 6
months under ICH conditions (40.degree. C., 75% R.H.). All the
three batches gave exactly the same PXRD after 3 and 6 months of
stability testing. The PXRD profile of one of the three batches of
form I after 6 months stability testing is shown in FIG. 24. The
complete survey of the stability data is reported in Table 39.
[0154] Bupropion hydrobromide of form I has been used as the
starting material in experiments to identify other polymorphic
forms. Two additional polymorphic forms were identified and have
been named form II and form III. FIGS. 25 and 26 show the PXRD data
and DSC profile respectively of polymorphic form II. FIG. 27 shows
the PXRD profile of form II after 1 month stability testing in ICH
conditions (40.degree. C., 75% R.H.). FIGS. 28 and 29 show the PXRD
data and DSC profile respectively of form III. FIG. 30 shows the
PXRD profile of form III after 1 month stability testing in ICH
conditions (40.degree. C., 75% R.H.).
[0155] Polymorphic form II was obtained by recrystallization of
form I from solvents or mixtures of solvents such as acetone-water,
methanol, dichloromethane, toluene-methanol and
dimethylcarbonate-methanol. Polymorphic form III was obtained by
recrystallization of polymorphic form I in methanol. Table 39
provides a list of recrystallization conditions and the polymorphic
form obtained under each set of conditions.
[0156] Samples of the polymorphic forms II and III were tested
after 1 month under the same accelerated stability conditions (ICH
conditions of 40.degree. C., 75% R.H.). Polymorphic form II showed
no change in the PXRD profile at that time while the PXRD profile
of form III showed conversion to form II. This data suggests that
polymorphic forms I and II are quite stable while polymorphic form
III is not as stable as forms I and II under the test conditions.
See Example 3 below.
Polymorphic Forms IV, V, VI and VII, and Amorphous Form
[0157] During additional experiments of crystallization of
bupropion hydrobromide it was found, unexpectedly, that even though
numerous experiments had been conducted previously with the aim of
identifying new crystalline forms of bupropion hydrobromide (i.e.
forms I, II and III, see Table 39), bupropion hydrobromide can be
obtained in additional polymorphous forms not previously known
(i.e. forms IV, V, VI and VII).
[0158] Moreover, surprisingly, bupropion hydrobromide was isolated
in amorphous form in an experiment with lyophilization of an
aqueous solution of bupropion hydrobromide and in an experiment
with evaporation of a solution of the product in p-xylene. These
last two results are particularly unexpected, since test 122 in
table 39 (for forms I, II and III) describes how, by treating
aqueous solutions of bupropion hydrobromide by the "spray drying"
technique, which usually gives products in amorphous form, we
obtain instead a product in crystalline form I.
[0159] The polymorphous form designated as form IV is characterized
by the PXRD profile shown in FIG. 31, by the DSC profile shown in
FIG. 32, by the TGA profile shown in FIG. 33 and by the IR profile
shown in FIG. 34.
[0160] The polymorphous form designated as form V is characterized
by the PXRD profile shown in FIG. 35, by the DSC profile shown in
FIG. 36, by the TGA profile shown in FIG. 37 and by the IR profile
shown in FIG. 38.
[0161] The polymorphous form designated as form VI is characterized
by the PXRD profile shown in FIG. 39, by the DSC profile shown in
FIG. 40, by the TGA profile shown in FIG. 41 and by the IR profile
shown in FIG. 42.
[0162] The polymorphous form designated as form VII is
characterized by the PXRD profile shown in FIG. 43, by the DSC
profile shown in FIG. 44, by the TGA profile shown in FIG. 45 and
by the IR profile shown in FIG. 46.
[0163] The amorphous form is characterized by the PXRD profile
shown in FIG. 47 and by the PXRD profile shown in FIG. 48.
[0164] The PXRD diffraction patterns were obtained on X-ray powder
diffraction PANalytical X'pert Pro equipped with X'Celerator, in a
measurement range between 3 and 40 2theta. All the DSC experiments
were performed with a DSC 7 Perkin Elmer instrument in a
temperature range between 25.degree. C. and 250.degree. C. with a
heating rate of 10.degree. C./min.
[0165] All the TGA experiments were conducted with a TGA 7 Perkin
Elmer instrument in a temperature range between 39.degree. C. and
310.degree. C. with a heating rate of 10.degree. C./min.
[0166] All the IR spectra were recorded on FT-IR Nicolet from
ThermoFischer.
[0167] In total, the polymorph screening has identified seven
crystalline forms and an amorphous form for Bupropion Hydrobromide.
Form II is the thermodynamically stable crystal form as shown by
slurry experiments. Form I is a metastable form produced by
different experiments but converts into Form II by slurry for 1
week at both room and high temperature. Form I and Form II are the
crystalline forms obtained in the majority of experiments. Form VII
is also found to be a stable form after 28 days storage. Form IV is
only produced by evaporation of a chloroform solution of bupropion
hydrobromide. Form V is only produced by interaction of bupropion
hydrobromide with dioxane. Form VI is only produced by interaction
of bupropion hydrobromide with n-propanol and ethyl acetate. Form
VII is only produced by interaction of bupropion hydrobromide with
benzonitrile, methyl benzoate, and tetrahydrofuran. Form I, Form
II, Form V, Form VI, Form VII and the amorphous form are anhydrous
forms. Form III is a solvate of ethanol. Form IV is a solvated
crystal form.
Tablets
[0168] In certain embodiments of the present invention, there is
provided a modified-release tablet having a core comprising
bupropion hydrobromide or a polymorph of bupropion hydrobromide and
conventional excipients. In certain embodiments the bupropion
hydrobromide salt or the polymorph of bupropion hydrobromide or the
composition comprising the bupropion hydrobromide or polymorph
provides for the reduction of incidences of and/or severity of
bupropion-induced seizures, and is more stable as compared with
equivalent molar amounts of bupropion hydrochloride or otherwise
similar or identical compositions containing equivalent molar
amounts of bupropion hydrochloride. The core can be surrounded by a
controlled release coat which can control the release of bupropion
hydrobromide or mixture of bupropion hydrobromide with a second
drug. In other embodiments, a moisture barrier can optionally be
added to surround the controlled release coat. This moisture
barrier is optional given the enhanced stability of bupropion
hydrobromide relative to bupropion hydrochloride and by selection
of an appropriate controlled release coating. If present, this
moisture barrier can affect in-vitro drug release as well as
precluding moisture from coming into contact with the bupropion
hydrobromide salt. Optionally, this tablet can further comprise one
or more additional functional or non-functional coatings
surrounding the core, moisture barrier and/or controlled release
coat.
Extended Release (XL) Tablets
[0169] In certain embodiments of the present invention, there is
provided an extended-release (XL) tablet having a core comprising
bupropion hydrobromide and/or a polymorph of bupropion hydrobromide
and conventional excipients. In certain embodiments the bupropion
hydrobromide salt and/or polymorph of bupropion hydrobromide
provides for the reduction of incidences of and/or severity of
bupropion-induced seizures, and is more stable, as compared with
equivalent molar amounts of bupropion hydrochloride. The core can
be surrounded by a controlled release coat, which controls the
release of the bupropion hydrobromide salt or polymorph of
bupropion hydrobromide. The tablet optionally can comprise one or
more additional functional or non-functional coats surrounding the
core or controlled release coat. The extended-release tablet of
certain embodiments has unexpected enhanced stability.
The XL Core
[0170] The core of the extended-release tablet comprises an
effective amount of the bupropion hydrobromide salt and/or a
polymorph of bupropion hydrobromide, a binder, and a lubricant; and
can contain other conventional inert excipients. The amount of the
bupropion hydrobromide salt or polymorph of bupropion hydrobromide
present in the XL core can vary in an amount from about 40% to
about 99% by weight of the tablet dry weight, including all values
and ranges therebetween. For example, in certain embodiments
bupropion hydrobromide and/or a polymorph of bupropion hydrobromide
is present in an amount from about 70% to about 95% by weight of
the tablet dry weight, including all values and ranges
therebetween. For example, in certain embodiments, the core
comprises bupropion hydrobromide and/or a polymorph of bupropion
hydrobromide in a proportion of about 40%, about 45%, about 50%,
about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,
about 85%, about 90%, about 95% or about 99% of the core dry
weight.
[0171] In at least one embodiment of a 174 mg dose tablet, the
bupropion hydrobromide is present in an amount of from about 75% to
about 85% by weight of the tablet dry weight, including all values
and ranges therebetween. In at least one embodiment of a 348 mg
dose tablet, the amount of bupropion hydrobromide can be present in
an amount of from about 80% to about 90% by weight of the tablet
dry weight, including all values and ranges therebetween. In at
least one embodiment of a 522 mg dose tablet, the bupropion
hydrobromide is present in an amount of from about 75% to about 90%
by weight of the tablet dry weight, including all values and ranges
therebetween. In certain embodiments of the 174 mg, 348 mg and 522
mg dose bupropion hydrobromide extended-release tablets of the
invention, the amount of bupropion hydrobromide is present in an
amount of from about 85% to about 99% by weight of the dry core for
each dose, including all values and ranges therebetween.
[0172] A binder (also sometimes called adhesive) can be added to a
drug-filler mixture to increase the mechanical strength of the
granules and tablets during formation. Binders can be added to the
formulation in different ways: (1) as a dry powder, which is mixed
with other ingredients before wet agglomeration, (2) as a solution,
which is used as agglomeration liquid during wet agglomeration, and
is referred to as a solution binder, and (3) as a dry powder, which
is mixed with the other ingredients before compaction. In this form
the binder is referred to as a dry binder. Solution binders are a
common way of incorporating a binder into granules. In certain
embodiments, the binder used in the XL tablets is in the form of a
solution binder. Non-limiting examples of binders useful for the
core include hydrogenated vegetable oil, castor oil, paraffin,
higher aliphatic alcohols, higher aliphatic acids, long chain fatty
acids, fatty acid esters, wax-like materials such as fatty
alcohols, fatty acid esters, fatty acid glycerides, hydrogenated
fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol,
hydrophobic and hydrophilic polymers having hydrocarbon backbones,
and mixtures thereof. Specific examples of water-soluble polymer
binders include modified starch, gelatin, polyvinylpyrrolidone,
cellulose derivatives (such as for example hydroxypropyl
methylcellulose (HPMC) and hydroxypropyl cellulose (HPC)),
polyvinyl alcohol and mixtures thereof. The amount of binder
present can vary from about 0.5% to about 25% by weight of the
tablet dry weight, including all values and ranges therebetween.
For example, in certain embodiments the binder is present in an
amount of from about 0.5% to about 15% by weight of the tablet dry
weight, including all values and ranges therebetween For example,
in certain embodiments of the 174 mg, 348 mg and 522 mg dose
tablets, the binder is present in an amount of from about 1% to
about 6% by weight of each dry core weight, including all values
and ranges therebetween; and in other embodiments at about 3% by
weight of each dry core weight. In at least one embodiment of the
522 mg dose tablet, the binder is present in an amount of about 4%
by weight of dry core weight. In at least one embodiment of the
invention the binder is polyvinyl alcohol.
[0173] Lubricants can be added to pharmaceutical formulations to
decrease any friction that occurs between the solid and the die
wall during tablet manufacturing. High friction during tabletting
can cause a series of problems, including inadequate tablet quality
(capping or even fragmentation of tablets during ejection, and
vertical scratches on tablet edges) and may even stop production.
Accordingly, lubricants are added to tablet formulations of certain
embodiments of the XL tablet formulation described herein.
Non-limiting examples of lubricants useful for the core include
glyceryl behenate, stearic acid, hydrogenated vegetable oils (such
as hydrogenated cottonseed oil (STERPTEX.RTM.), hydrogenated
soybean oil (STEROTEX.RTM. HM) and hydrogenated soybean oil &
castor wax (STERPTEX.RTM. K), stearyl alcohol, leucine,
polyethylene glycol (MW 1450, suitably 4000, and higher), magnesium
stearate, glyceryl monostearate, stearic acid, polyethylene glycol,
ethylene oxide polymers (e.g. CARBOWAX.RTM.), sodium lauryl
sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl
fumarate, DL-leucine, colloidal silica, mixtures thereof and others
as known in the art. In at least one embodiment of the present
invention, the lubricant is glyceryl behenate (e.g. COMPRITOL.RTM.
888). The amount of lubricant present can vary from about 0.1% to
about 6% by weight of the tablet dry weight, including all values
and ranges therebetween. For example, in certain embodiments the
amount of lubricant present is from about 2% to about 3% by weight
of the tablet dry weight, including all values and ranges
therebetween; and in other embodiments the amount of lubricant
present is at about 3% by weight of the tablet dry weight. In
certain embodiments of the 174 mg, 348 mg and 522 mg dose XL
tablets of the invention, the lubricant is present in an amount of
about 3% by weight of the tablet dry weight, or from about 1% to
about 6% by weight of the dry core weight, including all values and
ranges therebetween. For example, in certain embodiments the
lubricant is present in an amount of about 3% by weight of the dry
core weight for the 174 mg, 348 mg and 522 mg dose XL tablets. In
at least one embodiment of the 522 mg dose tablet, the lubricant is
present in an amount of about 4% by weight of dry core weight.
[0174] At this stage, the XL core formulation of certain
embodiments of the present invention is an uncoated immediate
release formulation resulting in about 100% dissolution of the
bupropion hydrobromide salt or a polymorph of bupropion
hydrobromide within about 1 hour. In at least one embodiment the XL
core is a normal release matrix formulation. In certain embodiments
the core comprises an effective pharmaceutical amount of bupropion
hydrobromide and/or a polymorph of bupropion hydrobromide, a binder
(e.g. polyvinyl alcohol), and a lubricant (e.g. glyceryl behenate).
Additional inert excipients consistent with the objects of the
invention can also be added to the core formulation. The additional
inert excipients can be added to facilitate the preparation and/or
improve patient acceptability of the final extended-release dosage
form as described herein. The additional inert excipients are well
known to the skilled artisan and can be found in the relevant
literature, for example in the Handbook of Pharmaceutical
Excipients. Non-limiting examples of such excipients include spray
dried lactose, sorbitol, mannitol, and any cellulose
derivative.
[0175] In certain embodiments the core of the bupropion
hydrobromide composition (e.g. core of an XL tablet) can be made
according to any one of the methods described in U.S. Pat. No.
7,241,805, U.S. patent application Ser. No. 11/834,848 (Pub. No.
2008-0075774), or U.S. patent application Ser. No. 11/930,644 (Pub.
No. 2008-0274181).
[0176] In at least one embodiment of the invention, the granules to
be compressed to form the core of the bupropion hydrobromide XL
tablet of the invention described herein, are manufactured by the
wet granulation process. Wet granulation involves agitation of a
powder (the active drug) by convention in the presence of a liquid
(the solution binder) followed by drying. For forming the granules,
which are to be eventually compressed into the tablet cores, the
bupropion hydrobromide salt is first granulated, for example, with
a solution binder, in a granulator, for example using a fluidized
bed granulator (e.g. a fluidized bed granulator manufactured by
Glatt (Germany) or Aeromatic (Switzerland)). The binder (e.g.
polyvinyl alcohol) is first dissolved or dispersed in a suitable
solvent (e.g. water). The solution binder is then top sprayed onto
the drug in a granulator (e.g. a fluidized bed granulator).
Alternatively, granulation can also be performed in a conventional
or high shear mixer. If necessary, the additional inert excipients
(e.g. a filler) can be mixed with the bupropion hydrobromide salt
prior to the granulation step.
[0177] The granules formed are subsequently dried and then sieved
prior to blending the granules with the lubricant. In certain
embodiments, the dried granules are sieved through a 1.4 mm mesh
screen. The sieved granules are then blended with the lubricant,
and if necessary, any other additional inert excipients, which can
improve processing of the extended-release tablets of the
invention. Blending of the granules with the lubricant, and if
necessary, any additional inert excipients, such as for example a
glidant, can be performed in a V-blender or any other suitable
blending apparatus. Glidants can improve the flowability of the
powder. This for example, can be helpful during tablet production
at high production speeds and during direct compaction. However,
because the requirement for adequate flow is high, a glidant is
often also added to a granulation before tabletting. The blended
granules are subsequently pressed into tablets and are hereinafter
referred to as tablet cores. Tablet cores can be obtained by the
use of standard techniques and equipment well known to the skilled
artisan. For example, the XL tablet cores can be obtained by a
rotary press (also referred to as a multi-station press) fitted
with suitable punches.
[0178] The granules can also be manufactured by using other
processes known to the skilled artisan. Examples of other granule
manufacturing processes include dry granulation (e.g. slugging,
roller compaction), direct compression, extrusion, spheronization,
melt granulation, and rotary granulation.
[0179] An example of the granulation process for the XL cores (60
kg batch) is as follows: A Fluid Bed Processor is used for
granulation in order to agglomerate the particles of the materials
to obtain a uniform particle size for the final blend. The
granulating solution is prepared by dissolving the binder (e.g.
polyvinyl alcohol) in hot purified water while mixing. The percent
solids content can be adjusted to obtain a viscosity to control the
build up (agglomeration size) of the material. A lower viscosity
leads to smaller particles, and a higher viscosity leads to larger
particles. In addition, the application rate (e.g. from about 150
gm/min to about 250 gm/min, including all values and ranges
therebetween; or about 200 gm/min), position of Spray gun (e.g.
center position) and nozzle size (e.g. from about 0.5 mm to about 2
mm, including all values and ranges therebetween; or about 1 mm)
and atomization pressure (e.g. from 20 psi to about 40 psi,
including all values and ranges therebetween; or about 30 psi)
contribute further to control particle size. The active material is
fluidized and heated (e.g. from about 35.degree. C. to about
45.degree. C., including all values and ranges therebetween; or
about 40.degree. C.) prior to start of solution application. During
the spray cycle, the bed temperature (e.g. from about 35.degree. C.
to about 45.degree. C.; including all values and ranges
therebetween, or about 40.degree. C.) is kept at a constant
temperature to avoid over-wetting. Once all the required binder
solution is applied, the material is further dried to the targeted
LOD value (i.e. loss on drying) (e.g. below about 1%) prior to
unloading. The amount of binder (e.g. polyvinyl alcohol) is from
about 2% to about 6%, including all values and ranges therebetween,
e.g. about 3%; and the solution concentration is from about 3% to
about 7%, including all values and ranges therebetween, e.g. about
4.5%. The time of agglomeration process for the 60 kg batch is from
about 45 minutes to about 220 minutes including all values and
ranges therebetween e.g. about 150 minutes. Once the granulate is
dry, material is passed through a 1.4 and 2.00 mm screen to remove
any oversized particles. The oversized particles are passed through
the mill to reduce oversize particles. Oversized particles are
generally not present in an amount to exceed about 5% of total
yield. The screened and milled materials are placed into a shell
blender (e.g. V-Blender, Bin blender) and the lubricant (e.g.
glyceryl behenate) is added. The lubricant is screened and added to
the granules and blended at the predetermined number of revolutions
or time (e.g. mix time of about 5 min to about 15 min, including
all values and ranges therebetween; e.g. including about 10 min).
The percent lubricant is from about 0.5% to about 4%, including all
values and ranges therebetween (e.g. including about 2%). The level
of lubrication is established for sufficient coverage of either
larger or smaller particle size distribution. Additional
characteristics include bulk density (e.g. from about 0.3 gm/ml to
about 0.8 gm/ml, including all values and ranges therebetween, e.g.
including about 0.5 gm/ml), and moisture content (e.g. not more
than about 1%). Particle size and flow of final blend are factors
in obtaining uniform fill of cavities on a rotary press. The flow
and top rotation speed of the press are adjusted (dependant on the
type/size of press) so as to not jeopardize the weight uniformity
of individual tablets. The product blend is passed through a hopper
into a feed frame to fill the die cavities passing under the feed
frame. Weight adjustments are made to keep the weight within the
specified range, and adjustments made to the pressure settings to
obtain the required hardness. Some components monitored for the
tablets are tablet thickness and friability (e.g. less than about
0.5%). Suitable thickness (related to overall surface area) and
lower friability help reduce core damage and loss of active during
coating. Tablet samples are removed at predetermined intervals to
monitor specifications.
Coatings
[0180] The tablet cores can be coated for administration to a
subject. In at least one embodiment of the invention, the tablet
cores are coated with a controlled release coating ("XL Controlled
Release Coat") that can provide an extended release of the
bupropion hydrobromide salt or mixture of the bupropion
hydrobromide salt and other drug. In at least one other embodiment,
the tablet cores are coated with an aqueous controlled release
coating that comprises an aqueous dispersion of a neutral ester
copolymer without any functional groups ("AQ Controlled Release
Coat").
[0181] In certain embodiments the tablet dosage form comprises an
optional moisture barrier in addition to the controlled release
coat. The controlled release coat and the moisture barrier can be
applied in two stages. The controlled release coat can be applied
directly onto the surface of the tablet cores and functions to
control the release of the bupropion hydrobromide salt. The
moisture barrier can be applied directly onto the surface of the
controlled release coat to impede or retard the absorption of
moisture.
[0182] Prophetic examples of controlled release coat formulations
are provided below. It should be understood that the constituents
and/or proportions of the constituents in these coatings as well as
the amounts thereof can be varied in order to achieve formulations
possessing different release characteristics. In all instances
wherein prophetic examples are provided these compositions are
intended to be exemplary and it should be understood that the
specific procedures, constituents, amounts thereof and the like can
be varied in order to obtain a composition possessing desired
properties.
[0183] In at least one embodiment the controlled release coat is a
coating formulation that provides a delayed release of the active
drug(s) from the tablet core. In such embodiments the coating
formulation to be applied to the core can comprise:
TABLE-US-00001 EUDRAGIT .RTM. L12.5 about 50% by weight of coating
suspension Triethyl citrate about 0.63% by weight of coating
suspension Talc about 1.25% by weight of coating suspension
Isopropyl alcohol about 48.12% by weight of coating suspension
Solids total = about 8.1% Polymer content of about 6.3% suspension
=
[0184] In certain embodiments the controlled release coating of the
bupropion hydrobromide dosage form (e.g. controlled release coat of
an XL tablet) can be made according to any one of the methods
described herein.
[0185] Preparation of the controlled release coating formulation of
such embodiments (e.g. controlled release coat that can provide a
delayed release of the active drug) can be as follows: Talc and
triethyl citrate are homogenized in the solvent by means of a
homogenizer for approximately 10 minutes. The suspension is poured
directly into the EUDRAGIT.RTM. L12.5 dispersion and stirred gently
to avoid sedimentation. The coating is sprayed onto tablets until
approximately 5 mg/cm2 of EUDRAGIT.RTM. L has been applied to the
tablet core.
[0186] In at least one embodiment the controlled release coat can
provide a sustained release of the active drug from the tablet
core. The coating formulation can comprise:
TABLE-US-00002 EUDRAGIT .RTM. RL 12.5 about 10% by weight of
coating suspension EUDRAGIT .RTM. RS 12.5 about 30% by weight of
coating suspension Dibutyl sebacate about 0.5% by weight of coating
suspension Talc about 3.5 g by weight of coating suspension
Magnesium stearate about 1% by weight of coating suspension Acetone
about 27.5% by weight of coating suspension Isopropyl alcohol about
27.5% by weight of coating suspension Solids total = about 10%
Polymer content of about 5% suspension =
[0187] Preparation of the controlled release coating formulation of
such embodiments (i.e. controlled release coat that can provide a
sustained release of the active drug) can be as follows: Dibutyl
sebacate, talc and magnesium stearate are mixed and finely
dispersed together with the diluents acetone and isopropyl alcohol.
The suspension is then combined with the EUDRAGIT.RTM. polymer
dispersions. The coating is sprayed onto the core until
approximately 10 mg/cm2 of polymer has been applied to the
core.
[0188] In at least one embodiment the controlled release coat is a
polymer blend coating possessing pH dependent polymer (e.g.
EUDRAGIT.RTM. L30D55) in combination with a sustained release
polymer (e.g. AQUACOAT.RTM.). Such a coating formulation can
comprise:
TABLE-US-00003 AQUACOAT .RTM. about 21% by weight of coating
suspension (ethylcellulose 30%) EUDRAGIT .RTM. L30 D 55 about 21%
by weight of coating suspension Triethyl citrate about 3% by weight
of coating suspension Water about 55% by weight of coating
suspension Solids total = about 15.6% Polymer content of about
12.6% suspension =
[0189] Application of the polymer blend coating can be as follows:
Coating applied to a 10 mg/cm2 application of polymer to the drug
core.
[0190] In at least one embodiment the controlled release coat is a
drug coating containing at least one other drug (e.g. Citalopram)
on top of a core containing bupropion hydrobromide salt. The
coating formulation can comprise:
TABLE-US-00004 KOLLIDON .RTM. VA64 about 2.5% by weight of drug
coating (Vinylpyrrolidone-vinyl suspension acetate copolymer)
KLUCEL .TM.EF about 2.5% by weight of drug coating
(Hydroxypropylcellulose) suspension Citalopram about 2% by weight
of drug coating suspension Talc about 3% by weight of drug coating
suspension 2-propanol about 90% by weight of drug coating
suspension Solids total = about 10% Polymer content of about 5%
suspension =
[0191] Application of the drug coating formulation can be as
follows: Drug coating is sprayed onto tablets until the desired
amount of other drug (e.g. Citalopram) is applied.
[0192] A top-coat can subsequently be applied as a cosmetic coating
and also to prevent tablet sticking.
[0193] The top-coat formulation applied to the drug coated core can
comprise:
TABLE-US-00005 KOLLIDON .RTM. VA64 about 2.5% by weight of top-coat
suspension (Vinylpyrrolidone-vinyl acetate copolymer) KLUCEL .TM.
EF about 2.5% by weight of top-coat suspension
(Hydroxypropylcellulose) Talc about 2.5% by weight of top-coat
suspension Isopropyl alcohol about 92.5% by weight of top-coat
suspension Solids total = about 7.5% Polymer content of about 5%
suspension =
[0194] Application of the top-coating formulation can be as
follows: Coating is applied to about a 2% weight gain (expressed as
% of drug coated tablet core)
[0195] The Extended Release (XL) Controlled Release Coat
[0196] The XL controlled release coat is a semi-permeable coat
comprising a water-insoluble, water-permeable film-forming polymer,
a water-soluble polymer, and optionally a plasticizer.
[0197] Non-limiting examples of water-insoluble, water-permeable
film-forming polymers useful for the XL controlled release coat of
certain embodiments include cellulose ethers, cellulose esters,
polyvinyl alcohol and mixtures thereof. In certain embodiments the
water-insoluble, water-permeable film forming polymers can be the
ethyl celluloses, and can be selected from the following
non-limiting examples: ethyl cellulose grades PR100, PR45, PR20,
PR10 and PR7 (ETHOCEL.RTM., Dow), and any combination thereof. In
at least one embodiment of the invention, ethyl cellulose grade PR
100 is the water-insoluble, water-permeable film-forming polymer.
In certain embodiments the amount of the water-insoluble
water-permeable film-forming polymer can vary from about 1% to
about 12% by weight of the tablet dry weight, including all values
and ranges therebetween. For example, in certain embodiments the
amount of the water-insoluble water-permeable film-forming polymer
is present in an amount from about 5% to about 10%, and in other
embodiments from about 6% to about 8% by weight of the tablet dry
weight. In certain embodiments of the 174 mg dose modified-release
tablets of the invention, the amount of water-insoluble water
permeable film-forming polymer is from about 3% to about 8% by
weight of the tablet dry weight, preferably from about 6% to about
7% of the tablet dry weight, including all values and ranges
therebetween. With respect to the controlled release coat itself,
the amount of water-insoluble water-permeable film-forming polymer
in certain embodiments of the 174 mg dose tablet can be from about
35% to about 60% by weight of the controlled release coat dry
weight, including all values and ranges therebetween; and in
certain embodiments from about 40% to about 50% by weight of the
controlled release coat dry weight. In certain embodiments of the
348 mg dose modified-release tablet of the invention, the amount of
water-insoluble water-permeable film-forming polymer can be from
about 2% to about 5% by weight of the tablet dry weight, including
all values and ranges therebetween, and in other embodiments from
about 3% to about 4% by weight of the tablet dry weight. With
respect to the controlled release coat itself, the water-insoluble
water-permeable film-forming polymer in certain embodiments of the
348 mg dose tablet is present in an amount of about 40% by weight
of the controlled release coat dry weight. In certain embodiments
of the 522 mg dose modified-release tablet of the invention, the
amount of water-insoluble water-permeable film-forming polymer can
be from about 0.5% to about 10% by weight of the tablet dry weight,
including all values and ranges therebetween, and in other
embodiments from about 1% to about 6% by weight of the tablet dry
weight. With respect to the controlled release coat itself, the
water-insoluble water-permeable film-forming polymer in certain
embodiments of the 522 mg dose tablet is present in an amount of
about 37% by weight of the controlled release coat dry weight.
[0198] Non-limiting examples of water-soluble polymers useful for
the XL controlled release coat include polyvinylpyrrolidone,
hydroxypropyl methylcellulose, hydroxypropyl cellulose and mixtures
thereof. In at least one embodiment the water-soluble polymer is
polyvinylpyrrolidone (POVIDONE.RTM. USP). The amount of
water-soluble polymer can vary from about 1.5% to about 10% by
weight of the tablet dry weight, including all values and ranges
therebetween. For example, in certain embodiments the amount of
water-soluble polymer is from about 3% to about 8%, and in other
embodiments at about 4% by weight of the tablet dry weight. With
respect to the controlled release coat itself, in certain
embodiments the amount of water-soluble polymer present is from
about 25% to about 55% by weight of the controlled release coat dry
weight, including all values and ranges therebetween. For certain
embodiments of the 174 mg dose of the extended release tablet of
the invention, the amount of water-soluble polymer is from about 3%
to about 5% by weight of the tablet dry weight, including all
values and ranges therebetween and from about 25% to about 50% by
weight of the controlled release coat dry weight, including all
values and ranges therebetween. For certain embodiments of the 348
mg dose of the extended release tablet of the invention, the amount
of water-soluble polymer present is from about 2% to about 5% of
the tablet dry weight including all values and ranges therebetween;
and from about 40% to about 50% by weight of the controlled release
coat dry weight, including all values and ranges therebetween. For
certain embodiments of the 522 mg dose of the extended release
tablet of the invention, the amount of water-soluble polymer
present is from about 2% to about 5% of the tablet dry weight,
including all values and ranges therebetween; and from about 40% to
about 50% by weight of the controlled release coat dry weight,
including all values and ranges therebetween.
[0199] In certain embodiments, the XL controlled release coat
further comprises a plasticizer. The use of plasticizers is
optional, and they can be added to film coating formulations to
modify the physical properties of a polymer to make it more usable
during manufacturing. Plasticizers can be high boiling point
organic solvents used to impart flexibility to otherwise hard or
brittle polymeric materials. Plasticizers generally cause a
reduction in the cohesive intermolecular forces along the polymer
chains resulting in various changes in polymer properties including
a reduction in tensile strength, and increase in elongation and a
reduction in the glass transition or softening temperature of the
polymer. The amount and choice of the plasticizer can affect the
hardness of a tablet and can even affect its dissolution or
disintegration characteristics, as well as its physical and
chemical stability. Certain plasticizers can increase the
elasticity and/or pliability of a coat, thereby decreasing the
coat's brittleness. Once the dosage form is manufactured, certain
plasticizers can function to increase the hydrophilicity of the
coat(s) and/or the core of the dosage form in the environment of
use (in-vitro or in-vivo). Non-limiting examples of plasticizers
that can be used in the controlled release coat described herein
include acetylated monoglycerides; acetyltributyl citrate, butyl
phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate;
dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin;
propylene glycol; triacetin; tripropioin; diacetin; dibutyl
phthalate; acetyl monoglyceride; acetyltriethyl citrate,
polyethylene glycols; castor oil; rape seed oil, olive oil, sesame
oil, triethyl citrate; polyhydric alcohols, glycerol, glycerin
sorbitol, acetate esters, gylcerol triacetate, acetyl triethyl
citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl
phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl
azelate, epoxidized tallate, triisoctyl trimellitate, diethylhexyl
phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl
phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate,
tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate,
di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl
sebacate, diethyloxalate, diethylmalate, diethylfumerate,
dibutylsuccinate, diethylmalonate, dibutylphthalate,
dibutylsebacate, glyceroltributyrate, polyols (e.g. polyethylene
glycol) of various molecular weights, and mixtures thereof. It is
contemplated and within the scope of the invention, that a
combination of plasticizers can be used in the present formulation.
In at least one embodiment of the invention, the plastizer is
polyethylene glycol 4000, dibutyl sebacate or a mixture thereof.
The amount of plasticizer for the controlled release coat can vary
in an amount of from about 0.5% to about 4% by weight of the tablet
dry weight, including all values and ranges therebetween. For
example, in certain embodiments the plasticizer is present in an
amount of from about 2% to about 3% by weight of the tablet dry
weight. For certain embodiments of the 174 mg dose extended-release
tablet of the invention, the amount of plasticizer present in the
controlled release coat is from about 1% to about 4% by weight of
the tablet dry weight, including all values and ranges
therebetween. For certain embodiments of the 348 mg dose extended
release tablet of the invention, the amount of plasticizer present
is from about 0.5% to about 4% by weight of the tablet dry weight,
including all values and ranges therebetween. For certain
embodiments of the 522 mg dose extended release tablet of the
invention, the amount of plasticizer present is from about 0.5% to
about 4% by weight of the tablet dry weight, including all values
and ranges therebetween. In certain embodiments of the 174 mg, 348
mg and 522 mg dosage forms, the plasticizer is present in an amount
of from about 6% to about 30% by weight of the controlled release
coat dry weight, including all values and ranges therebetween. For
example, in certain embodiments the plasticizer is present in an
amount of about 12% by weight of the controlled release coat dry
weight.
[0200] The ratio of water-insoluble water-permeable film forming
polymer:plasticizer:water-soluble polymer for the XL controlled
release coat of certain embodiments of the invention described
herein can vary from about 3:1:4 to about 5:1:2, including all
values and ranges therebetween. For example, in certain embodiments
the ratio of water-insoluble water-permeable film forming
polymer:plasticizer:water-soluble polymer for the XL controlled
release coat is about 4:1:3. For certain other embodiments of the
XL tablet the ratio of the water-insoluble water-permeable
film-forming polymer:plasticizer:water-soluble polymer in the XL
controlled release coat is from about 7:2:6 to about 19:5:18,
including all values and ranges therebetween. In at least one
embodiment the ratio of water-insoluble water-permeable film
forming polymer:plasticizer:water-soluble polymer for the XL
controlled release coat is about 13:4:12. In at least one
embodiment of the 522 mg dosage form, the ratio of water-insoluble
water-permeable film forming polymer:plasticizer:water-soluble
polymer for the XL controlled release coat is about 13:6:16.
[0201] In certain embodiments the XL controlled release coat of the
bupropion hydrobromide tablet can be made according to any one of
the methods described herein.
[0202] Preparation and application of the XL controlled release
coat can be as follows. The water-insoluble water-permeable
film-forming polymer (e.g. ethylcellulose), and the plasticizer
(e.g. polyethylene glycol 4000), are dissolved in an organic
solvent (e.g. a mixture of ethyl alcohol). In the manufacture of
embodiments that do not require a plasticizer, the water-insoluble
water-permeable film-forming polymer can be dissolved in the
organic solvent without the plasticizer. The water-soluble polymer
(e.g. polyvinyl pyrrolidone) is next added until a homogenous
mixture is achieved. The resulting controlled release coat solution
is then sprayed onto the tablet cores using a tablet coater,
fluidized bed apparatus or any other suitable coating apparatus
known in the art until the desired weight gain is achieved. The
tablet cores coated with the controlled release coat are
subsequently dried. In the manufacture of embodiments that have a
moisture barrier, the controlled release coat is dried before the
moisture barrier is applied.
[0203] An example of the coating process for the XL controlled
release coat is as follows: The XL controlled release coat solution
is prepared by dissolving the water insoluble polymer (e.g.
ethylcellulose) and water soluble polymer (e.g.
polyvinylpyrrolidone) and an ethyl alcohol mixture while mixing and
is followed with the addition of the plasticizer(s) (e.g. mixture
of polyethylene glycol 4000 and dibutyl sebacate). Once completely
dissolved, the solution is homogenized to obtain a uniform mixture
of appropriate viscosity. This procedure helps obtain a complex mix
of a water permeable film to control the release of the active
drug. The composition of the solution can be formulated to contain
various levels of the water insoluble polymer and water soluble
polymer and a mix of the plasticizer(s). The release function is
further controlled by the film thickness applied and measured as
weight gain of solids in the coating required. Tablets are coated
in a perforated coating pan with control of pan speed (e.g. from
about 8 rpm to about 14 rpm, including all values and ranges
therebetween; and in some cases about 12 rpm), spray rate (e.g.
from about 150 gm/min to about 250 gm/min, including all values and
ranges therebetween; and in some cases about 200 gm/min),
atomization pressure (e.g. from about 15 psi to about 25 psi,
including all values and ranges therebetween; and in some cases
about 20 psi), supply volume (from about 800 to about 1000 cubic
ft/min, including all values and ranges therebetween, and in some
cases about 900 cubic ft/min), and air temperature (e.g. from about
50.degree. C. to about 60.degree. C., including all values and
ranges therebetween; and in some cases about 55.degree. C.),
monitored through a bed temperature and/or outlet temperature of
from about 38.degree. C. to about 42.degree. C., including all
values and ranges therebetween; and in some cases about 40.degree.
C. On completion of the coating cycle, tablets are dried and
unloaded into bulk containers. The printing process comprises the
transfer of a print image from a print plate covered with edible
black ink and transferred via a print roll or print pad onto the
surface of the tablets. The printed tablets are transferred through
a drying element prior to discharging into bulk containers. Samples
for final testing are taken throughout the printing process.
[0204] The skilled artisan will appreciate that controlling the
permeability can control the release of the bupropion hydrobromide
salt and/or the amount of coating applied to the tablet cores. The
permeability of the XL controlled release coat can be altered by
varying the ratio of the water-insoluble, water-permeable
film-forming polymer:plasticizer:water-soluble polymer and/or the
quantity of coating applied to the tablet core. A more extended
release can be obtained with a higher amount of water-insoluble,
water-permeable film forming polymer. The addition of other
excipients to the tablet core can also alter the permeability of
the controlled release coat. For example, if it is desired that the
tablet core further comprise an expanding agent, the amount of
plasticizer in the controlled release coat could be increased to
make the coat more pliable, as the pressure exerted on a less
pliable coat by the expanding agent could rupture the coat.
Further, the proportion of the water-insoluble water-permeable film
forming polymer and water-soluble polymer can also be altered
depending on whether a faster or slower dissolution and/or release
profile is desired.
[0205] Depending on the dissolution or in-vivo release profile
desired, the weight gained after coating the tablet core with the
XL controlled release coat typically can vary from about 3% to
about 30% of the weight of the dry tablet core, including all
values and ranges therebetween. For a 174 mg dose extended release
tablet according to certain embodiments, the weight gain can
typically vary from about 10% to about 17% of the weight of the dry
tablet core, including all values and ranges therebetween. For the
348 mg dose extended release tablet of certain embodiments, the
weight gain can vary from about 7% to about 10% of the weight of
the dry tablet core, including all values and ranges therebetween
For the 522 mg dose extended release tablet of certain embodiments,
the weight gain can vary from about 5% to about 15% of the weight
of the dry tablet core, including all values and ranges
therebetween
AQ Controlled Release Coat
[0206] The AQ controlled release coat is a stable monolithic
controlled release coating comprising an aqueous dispersion of a
neutral ester copolymer without any functional groups, a poly
glycol having a melting point greater than about 55.degree. C., and
one or more pharmaceutically acceptable excipients; wherein said
coating composition is coated onto the dosage form and cured at a
temperature at least equal to or greater than the melting point of
the poly glycol. The coating formulation is quite versatile in that
it can be used to coat a variety of drug cores and can be easily
manipulated to obtain the desired drug release profile.
[0207] In certain other embodiments, the AQ controlled release coat
comprises an aqueous dispersion of an ethylcellulose, a poly glycol
having a melting point greater than about 55.degree. C., and one or
more pharmaceutically acceptable excipients; wherein said coating
composition is coated onto the dosage form and cured at a
temperature at least equal to or greater than the melting point of
the poly glycol. Non limiting examples of aqueous dispersions of an
ethylcellulose include SURELEASE.RTM. (Colorcon, Inc., West Point,
Pa., U.S.A.), and AQUACOAT.RTM. (FMC Corp., Philadelphia, Pa.,
U.S.A.). Combinations are operable.
[0208] In certain embodiments the AQ controlled release coat is a
stable controlled release monolithic coating that is formed by a
process that comprises coating the core with a coating composition
to form a coated core with an intermediate coating, and curing the
coated core to form the AQ controlled release coat. In at least one
embodiment the coating composition comprises an aqueous dispersion
of a neutral ester copolymer without any functional groups, a poly
glycol having a melting point of at least 55.degree. C., and one or
more pharmaceutically acceptable excipients. The curing is
conducted at a temperature at least equal to or greater than the
melting point of the poly glycol. In at least one embodiment the
stable AQ controlled release coat comprises a neutral ester
copolymer without any functional groups, a poly glycol having a
melting point of at least 55.degree. C., and one or more
pharmaceutically acceptable excipients.
[0209] The aqueous dispersion of a neutral ester copolymer without
any functional groups can be an ethyl acrylate and methyl
methacrylate copolymer dispersion. Non-limiting examples of ethyl
acrylate and methyl methacrylate copolymer dispersions include a
30% aqueous dispersion of a neutral copolymer based on ethyl
acrylate and methyl methacrylate (e.g. EUDRAGIT.RTM. NE30D), a 40%
aqueous dispersion of a neutral copolymer based on ethyl acrylate
and methyl methacrylate (e.g. EUDRAGIT.RTM. NE40D), EUDRAGIT.RTM.
NM30D, KOLLICOAT.RTM. EMM30D, and combinations thereof. In at least
one embodiment the neutral ester copolymer without any functional
groups used in the controlled release coating composition is
EUDRAGIT.RTM. NE30D, EUDRAGIT.RTM. NE40D, or a mixture thereof. The
neutral ester copolymer without any functional groups can be
present in certain embodiments in an amount of from about 1% to
about 35% by weight of the coating composition, including all
values and subranges therebetween, depending on the therapeutically
active agent used and the controlled release profile desired. In
certain embodiments the neutral ester copolymer without any
functional groups is present in an amount from about 20% to about
99.5% by dry weight of the AQ controlled release coat, including
all values and subranges therebetween. In other embodiments the
neutral ester copolymer without any functional groups is present in
an amount from about 25% to about 60% by dry weight of the AQ
controlled release coat, including all values and subranges
therebetween. In still other embodiments the neutral ester
copolymer without any functional groups is present in an amount
from about 37% to about 50% by dry weight of the AQ controlled
release coat, including all values and subranges therebetween; for
example, including about 38%, about 39%, about 40%, about 41%,
about 42%, about 43%, about 44%, about 45%, about 46%, about 47%,
about 48%, and about 49% by dry weight of the AQ controlled release
coat. In certain embodiments the neutral ester copolymer without
any functional groups is present in the coating composition in an
amount of from about 0.4% to about 39.8% by dry weight of the
tablet including all values and subranges therebetween; in other
embodiments in an amount of from about 0.8% to about 24.0% by dry
weight of the tablet, including all values and subranges
therebetween; and in still other embodiments in an amount of from
about 2.0% to about 5.5% by dry weight of the tablet, including all
values and subranges therebetween.
[0210] Hydrophilic agents can also be included in the AQ controlled
release coat to promote wetting of the coat when in contact with
gastrointestinal fluids. Non-limiting examples of such hydrophilic
agents include hydrophilic water soluble polymers such as
hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC)
and combinations thereof. In at least one embodiment, HPMC is the
hydrophilic water soluble polymer. If hydrophilic agents are to be
included in the coat composition, the agents can be present in an
amount from about 0.1% to about 10% by weight of the coating
composition, including all values and ranges therebetween. For
example, in certain embodiments the hydrophilic agents are present
in an amount of from about 0.1% to about 5%, and in other
embodiments from about 0.1% to about 3% by weight of the controlled
release coat composition. In certain embodiments the hydrophilic
agent is present in an amount of from greater than about 0% to
about 35% by dry weight of the AQ controlled release coat,
including all values and subranges therebetween; preferably from
about 8% to about 30% by dry weight of the AQ controlled release
coat, including all values and subranges therebetween and still
further preferably from about 12% to about 26% by dry weight of the
AQ controlled release coat, including all values and subranges
therebetween. In certain embodiments the hydrophilic agent is
present in the coating formulation in an amount of from about 0% to
about 14.0% by dry weight of the tablet, including all values and
subranges therebetween; preferably from about 0.2% to about 6.0% by
dry weight of the tablet, including all values and subranges
therebetween; and still further preferably from about 0.8% to about
2.5% by dry weight of the tablet, including all values and
subranges therebetween.
[0211] The AQ controlled release coat formulation also comprises a
poly glycol with a melting point of greater than about 55.degree.
C. The poly glycol used in the AQ controlled release coat can be a
polyethylene glycol with an average molecular weight ranging from
about 4,000 daltons to about 35,000 daltons. Non-limiting examples
of a poly glycol with a melting point of greater than 55.degree. C.
include polyethylene glycol 4000, polyethylene glycol 4600,
polyethylene glycol 6000, polyethylene glycol 8000, polyethylene
glycol 10000, polyethylene glycol 12000, polyethylene glycol 20000,
polyethylene glycol 35000, and mixtures thereof. In certain
embodiments, the poly glycol is selected from the group consisting
of polyethylene glycol 6000, polyethylene glycol 8000, polyethylene
glycol 10000, polyethylene glycol 12000, and mixtures thereof. In
at least one embodiment the poly glycol used in the coating
composition of the AQ controlled release coat is polyethylene
glycol 8000. The poly glycol can be present in certain embodiments
in an amount of from about 0.1% to about 10% by weight of the
coating composition, including all values and subranges
therebetween. In certain embodiments the poly glycol is present in
an amount of from about 0.5% to about 28% by dry weight of the AQ
controlled release coat, including all values and subranges
therebetween. In other embodiments the poly glycol is present in an
amount from about 4% to about 17% by dry weight of the AQ
controlled release coat, including all values and subranges
therebetween. In still other embodiments the poly glycol is present
in an amount from about 7.2% to about 15.2% by dry weight of the AQ
controlled release coat, including all values and subranges
therebetween; In certain embodiments the poly glycol is present in
the coating composition in an amount of from about 0.1% to about
11.2% by dry weight of the tablet, including all values and
subranges therebetween; in other embodiments in an amount of from
about 0.1% to about 8.0% by dry weight of the tablet, including all
values and subranges therebetween; and in still other embodiments
in an amount of from about 0.2% to about 2.8% by dry weight of the
tablet, including all values and subranges therebetween. Other
examples of suitable polyglycol derivatives having a melting point
of at least about 55.degree. C. include, but are not limited to,
Poloxamer 188, Poloxamer 338, Poloxamer 407, Polyethylene Oxides,
Polyoxyethylene Alkyl Ethers, Polyoxyethylene Stearates and
mixtures thereof.
[0212] In addition to the copolymers and the poly glycol, the AQ
controlled release coat formulation comprises at least one
pharmaceutically acceptable excipient. The excipients can include
but are not limited to anti-tacking agents, emulsifying agents,
antifoaming agents, flavourants, colourants, and mixtures thereof.
It is known in the art that depending on the intended main
function, excipients can affect the properties of the coat in a
series of ways, and many substances used in coat formulations can
thus be described as multifunctional. A skilled worker will know,
based on his technical knowledge, which pharmaceutically acceptable
excipients are suitable for the desired AQ controlled release coat
composition.
[0213] The tackiness of polymeric films is a factor for the coating
of solid dosage forms and for the subsequent curing step (post
coating thermal treatment). During coating with either cellulosic
or acrylic polymers, sometimes an unwanted agglomeration of several
granules or beads can occur, for example at higher product
processing temperatures. Accordingly, the addition of anti-tacking
agents to coating formulations can be desirable in certain
embodiments. The anti-tacking agents which can be used in certain
embodiments include but are not limited to adipic acid, magnesium
stearate, calcium stearate, zinc stearate, hydrogenated vegetable
oils, sterotex, glyceryl monostearate, talc (e.g. talc 400), sodium
benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and
mixtures thereof. In at least one embodiment, talc is the
anti-tacking agent. Talc can also function as a wetting agent.
Mixtures of the anti-tacking agents are operable. The amount of
anti-tacking agent in the controlled release coat composition can
range from about 1% to about 15% by weight of the controlled
release coating composition, including all values and ranges
therebetween. For example, in certain embodiments the anti-tacking
agent is present in an amount of from about 1% to about 7% by
weight of the controlled release coating composition. In certain
embodiments the anti-tacking agent is present in an amount of from
greater than about 0% to about 50% by dry weight of the AQ
controlled release coat including all values and subranges
therebetween; preferably from about 2% to about 40% by dry weight
of the AQ controlled release coat including all values and
subranges therebetween and still further preferably from about 10%
to about 30% by dry weight of the AQ controlled release coat
including all values and subranges therebetween. In certain
embodiments the anti-tacking agent is present in the coating
formulation in an amount of from about 0% to about 20.0% by dry
weight of the tablet, including all values and subranges
therebetween; in other embodiments in an amount of from about 0% to
about 12.0% by dry weight of the tablet, including all values and
subranges therebetween; and in still other embodiments in an amount
of from about 0.6% to about 7.0% by dry weight of the tablet,
including all values and subranges therebetween.
[0214] Certain embodiments can include anti-foaming agents in the
AQ controlled release coat composition. Non-limiting examples of
useful anti-foaming agents include silicon oil, simethicone, and
mixtures thereof. In at least one embodiment, simethicone is the
anti-foaming agent used in the AQ controlled release coat
composition. The anti-foaming agent can be present in an amount of
up to about 0.5% by weight of the AQ controlled release coat
composition. For example, in certain embodiment the anti-foaming
agent is present in an amount of from about 0.1% to about 0.4% by
weight of the AQ controlled release coat composition, including all
values and ranges therebetween. In certain embodiments the
anti-foaming agent is present in an amount of from greater than
about 0% to about 3% by dry weight of the AQ controlled release
coat, including all values and subranges therebetween. In other
embodiments the anti-foaming agent is present in an amount from
about 0.4% to about 2% by dry weight of the AQ controlled release
coat, including all values and subranges therebetween. In still
other embodiments the anti-foaming agent is present in an amount
from about 0.8% to about 1.5% by dry weight of the AQ controlled
release coat, including all values and subranges therebetween; for
example, including about 0.9%, about 1.0%, about 1.1%, about 1.2%,
about 1.3%, and about 1.4% by dry weight of the AQ controlled
release coat. In certain embodiments the anti-foaming agent is
present in the coating formulation in an amount of from about 0% to
about 1.2% by dry weight of the tablet, including all values and
subranges therebetween; in other embodiments in an amount of from
about 0% to about 0.8% by dry weight of the tablet, including all
values and subranges therebetween; and in still other embodiments
in an amount of from about 0% to about 0.2% by dry weight of the
tablet, including all values and subranges therebetween; for
example, including about 0.01%, about 0.02%, about 0.03%, about
0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about
0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about
0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, and
about 0.19% by dry weight of the tablet.
[0215] Certain embodiments can include emulsifying agents (also
called emulsifiers or emulgents) in the AQ controlled release coat.
Emulsifying agents can facilitate emulsification during manufacture
of the AQ controlled release coat, and also provide emulsion
stability during the shelf-life of the product. Non-limiting
examples of emulsifying agents include naturally occurring
materials and their semi synthetic derivatives, such as the
polysaccharides, as well as glycerol esters, cellulose ethers,
sorbitan esters and polysorbates. Mixtures are operable. In at
least one embodiment the emulsifying agent is Polysorbate 80
(polyoxyethylene sorbitan mono-oleate) (e.g. TWEEN.RTM. 80). The
emulsifying agent can be present in an amount of from about 0% to
about 0.5% by weight of the AQ controlled release coat composition,
including all values and subranges therebetween. For example, in
certain embodiments the emulsifying agent is present in an amount
of from about 0.1% to about 0.3% by weight of the AQ controlled
release coat composition, including all values and ranges
therebetween. In certain embodiments the emulsifying agent is
present in an amount of from greater than about 0% to about 2% by
dry weight of the AQ controlled release coat, including all values
and subranges therebetween. In other embodiments the emulsifying
agent is present in an amount from about 0.1% to about 1% by dry
weight of the AQ controlled release coat, including all values and
subranges therebetween. In still other embodiments the emulsifying
agent is present in an amount from about 0.25% to about 0.75% by
dry weight of the AQ controlled release coat, including all values
and subranges therebetween; for example, including about 0.30%,
about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%,
about 0.60%, about 0.65%, and about 0.70% by dry weight of the AQ
controlled release coat. In certain embodiments the emulsifying
agent is present in the coating formulation in an amount of from
greater than about 0% to about 0.8% by dry weight of the tablet,
including all values and subranges therebetween; in other
embodiments in an amount of from greater than about 0% to about
0.4% by dry weight of the tablet, including all values and
subranges therebetween; and in still other embodiments in an amount
of from greater than about 0% to about 0.2% by dry weight of the
tablet, including all values and subranges therebetween; for
example, including about 0.01%, about 0.02%, about 0.03%, about
0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about
0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about
0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, and
about 0.19% by dry weight of the tablet.
[0216] Certain embodiments can include colorants in the film coat
formula. Such colorants can be water-insoluble colors (pigments).
Pigments have certain advantages over water-soluble colors in that
they tend to be more chemically stable towards light, provide
better opacity and covering power, and optimize the impermeability
of a given film to water vapor. Non-limiting examples of suitable
colorants include iron oxide pigments, titanium dioxide, and
aluminum Lakes. Mixtures are operable. In at least one embodiment
the pigment is titanium dioxide. The pigment or colorant can be
present in an amount of from about 0.1% to about 10% by weight of
the AQ controlled release coat composition, including all values
and ranges therebetween. For example, in certain embodiments the
pigment or colorant is present in an amount of from about 0.1% to
about 5%, and in other embodiments from about 0.1% to about 2% by
weight of the AQ controlled release coat composition. In certain
embodiments the colorant is present in an amount of from greater
than about 0% to about 20% by dry weight of the AQ controlled
release coat, including all values and subranges therebetween. In
other embodiments the colorant is present in an amount from greater
than about 0% to about 10% by dry weight of the AQ controlled
release coat, including all values and subranges therebetween. In
still other embodiments the colorant is present in an amount from
about 2.2% to about 6.2% by dry weight of the AQ controlled release
coat, including all values and subranges therebetween. In certain
embodiments the colorant is present in the coating formulation in
an amount of from greater than about 0% to about 8.0% by dry weight
of the tablet, including all values and subranges therebetween; in
other embodiments in an amount of from greater than about 0% to
about 5.0% by dry weight of the tablet, including all values and
subranges therebetween; and in still other embodiments in an amount
of from greater than about 0% to about 1.0% by dry weight of the
tablet, including all values and subranges therebetween; for
example, including about 0.1%, about 0.2%, about 0.3%, about 0.4%,
about 0.5%, about 0.6%, about 0.7%, about 0.8%, and about 0.9% by
dry weight of the tablet.
[0217] In at least one embodiment, the AQ controlled release coat
hydrates when placed into water. In at least one embodiment the
dosage form that is coated with the AQ controlled release coat
floats in water. In at least one embodiment, the controlled release
dosage form, upon oral administration to a patient, provides
controlled release of an effective amount of the bupropion
hydrobromide to at least one region of the patient's upper
gastrointestinal tract (e.g. the stomach).
[0218] In certain embodiments the AQ controlled release coat is
formed by a process that does not involve the use of an organic
solvent. In such embodiments the AQ controlled release coat
composition is aqueous based and not solvent based, in contrast to
prior art coating compositions that are solvent based (e.g.
"PharmaPASS" composition).
[0219] In certain embodiments the AQ controlled release coat of the
bupropion hydrobromide tablet can be made according to any one of
the methods described herein.
[0220] The AQ controlled release coat can be applied onto a core
comprising an effective amount of the bupropion hydrobromide salt
by a process which involves the atomization (spraying) of the
coating solution or suspension onto a bed of the tablet cores. Some
examples of equipment suitable for film coating include: ACCELA
COTA.RTM. (Manesty Machines, Liverpool, UK), HI-COATER.RTM. (Freund
Company, Japan), DRIACOATER.TM. (Driam Metallprodukt GmbH,
Germany), HTF/150 (GS, Italy), and IDA.TM. (Dumoulin, France).
Examples of units that function on a fluidized-bed principle
include: AEROMATIC.TM. (Fielder, Switzerland and UK) and GLATT.TM.
AG (Switzerland). In at least one embodiment, the apparatus used
for film coating is the ACCELA COTA.RTM..
[0221] The coating fluid can be delivered to the coating apparatus
from a peristaltic pump at the desired rate and sprayed onto the
rotating or fluidizing tablet cores. The tablet cores are
pre-warmed to about 30.degree. C. During the coating process, the
product temperature range is maintained at from about 25.degree. C.
to about 35.degree. C. by adjusting the flow rate of the inlet and
outlet air, temperature of the inlet air and spray rate. A single
layer of coat is applied and once spraying is complete, the coated
tablet cores are dried from about 30.degree. C. to about 40.degree.
C. for a time period of from about 3 to about 5 minutes at a low
pan speed and low air flow. The pan is readjusted to jog speed, and
drying continues for a time period of from about 12 to about 15
minutes.
[0222] The coated tablet cores are placed onto a tray and cured
(post coating thermal treatment) in an electrical or steam oven at
a temperature above the temperature of the melting point of the
polyethylene glycol or derivative thereof. In certain embodiments
the curing temperature is greater than the melting point of the
polyethylene glycol or derivative thereof. In certain embodiments
the curing time is from about 2 to about 7 hours. The cured coated
tablets are subsequently cooled to room temperature.
[0223] The AQ controlled release coat is quite versatile. The
length and time for the delay can be controlled by rate of
hydration and the thickness of the coat. The drug release rate
subsequent to the delay can be determined by the thickness and
permeability of the hydrated coat. Thus, it is possible to regulate
the rate of hydration and permeability of the AQ controlled release
coat so that the desired controlled-release drug profile can be
achieved. There is no preferred coat thickness, as this will depend
on the controlled release profile desired. Other parameters in
combination with the thickness of the coat include varying the
concentrations of some of the ingredients of the stable coat
composition of the invention described and/or varying the curing
temperature and length of curing the coated tablet cores. The
skilled artisan will know which parameters or combination of
parameters to change for a desired controlled release profile.
[0224] As will be seen from the non-limiting examples described
herein, the coatings used in certain embodiments of the present
invention are quite versatile. For example, the length and time for
the lag time can be controlled by the rate of hydration and the
thickness of the controlled release coat. Other parameters in
combination with the thickness of the coatings include varying the
concentrations of some of the ingredients of the coating
compositions of certain embodiments described and/or varying the
curing temperature and length of curing the coated tablet cores.
The skilled artisan will know which parameters or combination of
parameters to change for a desired controlled release profile.
The Moisture Barrier Coat
[0225] In certain embodiments, an optional moisture barrier is
applied directly onto the controlled release coat. In other
embodiments a moisture barrier coat is not included in the dosage
form. In certain embodiments the moisture barrier comprises an
enteric polymer (e.g. acrylic polymer), a permeation enhancer and
optionally a plasticizer.
[0226] In certain embodiments, the enteric polymer is an acrylic
polymer. For example, the acrylic polymer can be a methacrylic acid
copolymer type C [poly(methacrylic acid, methyl methacrylate) 1:1]
(e.g. EUDRAGIT.RTM. L 30 D-55). The methacrylic acid copolymer can
be present in an amount, which can vary from about 1% to about 3%
of the tablet dry weight including all values and ranges
therebetween and from about 55% to about 70% of the moisture
barrier dry weight including all values and ranges therebetween.
For the 174 mg dose of the extended release tablet of certain
embodiments of the present invention, the methacrylic acid
copolymer can vary from about 2% to about 3% of the tablet dry
weight including all values and ranges therebetween. For example in
the 174 mg tablet of certain embodiments, the amount of methacrylic
acid copolymer is present in an amount of about 2.5% of the tablet
dry weight. With respect to the moisture barrier itself, the amount
of the methacrylic acid copolymer in the 174 mg tablet can be
present in an amount of from about 55% to about 70% by weight of
the moisture barrier dry weight including all values and ranges
therebetween. For example, in the 174 mg tablet of certain
embodiments the methacrylic acid copolymer is present in an amount
of about 60% of the moisture barrier dry weight. For the 348 mg
dose of the extended release tablet of certain embodiments, the
amount of the methacrylic acid copolymer can vary from about 1.5%
to about 3% of the tablet dry weight including all values and
ranges therebetween. For example, in the 348 mg tablet of certain
embodiments, the amount of methacrylic acid copolymer is present at
an amount of about 2% by weight of the tablet dry weight. With
respect to the moisture barrier itself, the methacrylic acid
copolymer in the 348 mg tablet typically will be present in an
amount of from about 55% to about 70% of the moisture barrier dry
weight including all values and ranges therebetween. For example in
certain embodiments of the 348 mg tablet the methacrylic acid
copolymer is present in an amount of about 60% of the moisture
barrier dry weight. For the 522 mg dose of the extended release
tablet of certain embodiments, the amount of the methacrylic acid
copolymer can vary from about 0.5% to about 5% of the tablet dry
weight including all values and ranges therebetween. For example,
in the 522 mg tablet of certain embodiments, the amount of
methacrylic acid copolymer is present at about 2% by weight of the
tablet dry weight. With respect to the moisture barrier itself, the
methacrylic acid copolymer in the 522 mg tablet typically will be
present in an amount of from about 40% to about 80% of the moisture
barrier dry weight. For example, in certain embodiments of the 522
mg tablet the methacrylic acid copolymer is present in an amount of
about 65% of the moisture barrier dry weight.
[0227] It is known in the art that methacrylic acid copolymers can
become brittle, and that coatings that contain methacrylic acid
copolymers could be made more elastic and pliable by the addition
of a plasticizer. In certain embodiments the moisture barrier coat
comprises a plasticizer. Non-limiting examples of plasticizers
useful for the moisture barrier coat of certain embodiments include
acetylated monoglycerides; acetyltributyl citrate, butyl phthalyl
butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl
phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene
glycol; triacetin; tripropioin; diacetin; dibutyl phthalate; acetyl
monoglyceride; acetyltriethyl citrate, polyethylene glycols; castor
oil; rape seed oil, olive oil, sesame oil, triethyl citrate;
polyhydric alcohols, glycerol, glycerin sorbitol, acetate esters,
gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate,
dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate,
butyl octyl phthalate, dioctyl azelate, epoxidized tallate,
triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl
phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl
phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate,
di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl
azelate, dibutyl sebacate, diethyloxalate, diethylmalate,
diethylfumerate, dibutylsuccinate, diethylmalonate,
dibutylphthalate, dibutylsebacate, glyceroltributyrate, and
mixtures thereof, polyols (e.g. polyethylene glycol) of various
molecular weights, and mixtures thereof. In certain embodiments,
the plasticizer in the moisture barrier coat comprises a
combination of triethyl citrate and polyethylene glycol 4000 (e.g.
CARBOWAX.RTM. 4000). In certain of these embodiments, the ratio of
triethyl citrate to polyethylene glycol 4000 is about 1:2. The
plasticizer can be present in the moisture barrier coat of certain
embodiments in an amount which can vary from about 0.2% to about
0.5%, including all values and ranges therebetween (e.g. including
about 0.3%, and about 0.4% of the tablet dry weight). For example
in certain embodiments the plasticizer can be present in an amount
of about 0.35% of the tablet dry weight for a 174 mg tablet; in an
amount of from about 0.2% to about 0.4% of the tablet dry weight
for a 348 mg tablet; and in an amount of from about 0.05% to about
0.5% of the tablet dry weight for a 522 mg tablet, including all
values and ranges therebetween. With respect to the moisture
barrier itself, the plasticizer if present in certain embodiments
can be present in an amount of from about 1% to about 30% by weight
of the moisture barrier dry weight, including all values and ranges
therebetween. For example, in certain embodiments the plasticizer
is present in an amount of from about 10% to about 14% of the
moisture barrier dry weight for the 174 mg, 348 mg and 522 mg dose
extended release tablet of the present invention. It is well known
in the art that depending on the intended main function, excipients
to be used in tablets are subcategorized into different groups.
However, one excipient can affect the properties of a drug or the
tablet as a whole in a series of ways, and many substances used in
tablet formulations can therefore be described as multifunctional.
For example, the polyethylene glycol used in the plasticizer
combination for the moisture barrier can serve not only to increase
the hydrophilicity of the moisture barrier, but can also act as a
glidant.
[0228] In certain embodiments the moisture barrier can further
comprise a permeation enhancer that can increase its
hydrophilicity, and can also act as a glidant. The permeation
enhancer can be a hydrophilic substance and can be selected from
the following non-limiting examples: hydrophilic polymers such as
hydroxypropylmethylcellulose, cellulose ethers and protein-derived
materials of these polymers, the cellulose ethers, such as
hydroxyalkylcelluloses, carboxyalkylcelluloses, and mixtures
thereof. Also, synthetic water-soluble polymers can be used, such
as polyvinylpyrrolidone, cross-linked polyvinyl-pyrrolidone,
polyethylene oxide, water-soluble polydextrose, saccharides and
polysaccharides, such as pullulan, dextran, sucrose, glucose,
lactose, fructose, mannitol, mannose, galactose, sorbitol and
mixtures thereof. In at least one embodiment of the present
invention, the hydrophilic polymer comprises
hydroxypropyl-methylcellulose. Other non-limiting examples of
permeation enhancers that can be used in the moisture barrier of
certain embodiments include alkali metal salts such as aluminum
oxidelithium carbonate, sodium chloride, sodium bromide, potassium
chloride, potassium sulfate, potassium phosphate, sodium acetate,
sodium citrate, and mixtures thereof. The permeation enhancers or
pore-formers, can also be polymers which are soluble in the
environment of use, such as CARBOWAX.RTM., CARBOPOL.RTM., and
mixtures thereof. Non-limiting examples of pore formers include
diols, polyols, polyhydric alcohols, polyalkylene glycols,
polyglycols, poly(a-w)alkylenediols, and mixtures thereof. Other
permeation enhancers which can be useful in the formulations of the
present invention include starch, modified starch, and starch
derivatives, gums, including but not limited to xanthan gum,
alginic acid, other alginates, benitonite, veegum, agar, guar,
locust bean gum, gum arabic, quince psyllium, flax seed, okra gum,
arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose,
amylopectin, dextrin, cross-linked polyvinylpyrrolidone,
ion-exchange resins, such as potassium polymethacrylate,
carrageenan, kappa-carrageenan, lambda-carrageenan, gum karaya,
biosynthetic gum, and mixtures thereof. Other permeation enhancers
include materials useful for making microporous lamina in the
environment of use, such as polycarbonates comprised of linear
polyesters of carbonic acid in which carbonate groups reoccur in
the polymer chain, microporous materials such as bisphenol, a
microporous poly(vinylchloride), micro-porous polyamides,
microporous modacrylic copolymers, microporous styrene-acrylic and
its copolymers, porous polysulfones, halogenated poly(vinylidene),
polychloroethers, acetal polymers, polyesters prepared by
esterification of a dicarboxylic acid or anhydride with an alkylene
polyol, poly(alkylenesulfides), phenolics, polyesters, asymmetric
porous polymers, cross-linked olefin polymers, hydrophilic
microporous homopolymers, copolymers or interpolymers having a
reduced bulk density, and other similar materials, poly(urethane),
cross-linked chain-extended poly(urethane), poly(imides),
poly(benzimidazoles), collodion, regenerated proteins, semi-solid
cross-linked poly(vinylpyrrolidone), silicon dioxide, colloidal
silica, microcrystalline cellulose and any combination thereof. In
at least one embodiment of the invention the permeation enhancer is
silicon dioxide (e.g. SYLOID.RTM. 244FP). The amount of permeation
enhancer can vary from about 0.5% to about 1% by weight of the
tablet dry weight including all values and ranges therebetween and
from about 25% to about 30% by weight of the moisture barrier dry
weight including all values and ranges therebetween. For the 174 mg
dose extended-release tablet or the 348 mg dose extended-release
tablet of certain embodiments of the invention, the permeation
enhancer can be present in an amount of about 0.5% to about 2% of
the tablet dry weight including all values and ranges therebetween
and from about 20% to about 40% by weight of the moisture barrier
dry weight including all values and ranges therebetween For
example, in certain embodiments of the 174 mg dose tablet, the
permeation enhancer is present in an amount of from about 25% to
about 30% by weight of the moisture barrier dry weight. For the 348
mg dose extended release tablet of the invention, the permeation
enhancer can be present in an amount which can vary from about 0.5%
to about 2% by weight of the tablet dry weight, and from about 20%
to about 40% by weight of the moisture barrier dry weight. For
example, in certain embodiments of the 348 mg dose tablet, the
permeation enhancer is present in an amount of from about 25% to
about 30% by weight of the moisture barrier dry weight. For the 522
mg dose extended release tablet of the invention, the permeation
enhancer can be present in an amount which can vary from about 0.1%
to about 2% by weight of the tablet dry weight including all values
and ranges therebetween, and from about 20% to about 40% by weight
of the moisture barrier dry weight including all values and ranges
therebetween. For example, in certain embodiments of the 522 mg
dose tablet, the permeation enhancer is present in an amount of
from about 25% to about 30% by weight of the moisture barrier dry
weight.
[0229] In at least one embodiment of the invention, the ratio of
the methacrylic acid copolymer:plasticizer:permeation enhancer in
the moisture barrier is about 13:2:5.
[0230] In certain embodiments the moisture barrier of the bupropion
hydrobromide dosage form can be made according to any one of the
methods described herein.
[0231] The preparation and application of the moisture barrier
process can be as follows. The optional plasticizer (e.g. a
combination of polyethylene glycol 4000 and triethyl citrate), can
be first added to water and the mixture mixed to homogeneity. The
methacrylic acid copolymer (e.g. EUDRAGIT.RTM. L 30 D-55), is next
sieved and added to the plasticizer mixture and mixed to
homogeneity. In a separate container the permeation enhancer (e.g.
silicon dioxide) is dissolved in water until a homogeneous mixture
is achieved. The plasticizer and methacrylic acid copolymer mixture
is then combined with the permeation enhancer solution and mixed to
homogeneity. The resulting moisture barrier solution is then
sprayed onto the tablet cores coated with the controlled release
coat using a tablet coater, fluidized bed apparatus or any other
suitable coating apparatus known in the art until the desired
weight gain is achieved. The tablets coated with the moisture
barrier are subsequently dried prior to packaging.
[0232] The moisture barrier is applied to the controlled release
coated tablet cores such that the weight gain is not more than
about 6% of the tablet dry weight for the 174 mg, 348 mg and 522 mg
extended release tablets of certain embodiments of the present
invention. In certain embodiments the weight gain is not more than
about 3.5% of the tablet dry weight for the 174 mg, 348 mg and 522
mg extended release tablets. The amount of the moisture barrier
applied typically does not significantly render the extended
release tablet described herein more resistant to gastric fluid.
However, in certain embodiments the moisture barrier can have an
impact on the drug release characteristics.
[0233] The moisture barrier as used in certain embodiments, does
not function as an enteric coat. Even though the methacrylic acid
copolymer, EUDRAGIT.RTM. L 30 D-55, is referenced and is used in
enteric coating formulations in the art, its functionality is
formulation dependent and on the quantity of the material applied.
As is known in the art, an enteric coating is applied where a drug
may be destroyed or inactivated by gastric juice or where the drug
may irritate the gastric mucosa. To meet the requirements for an
enteric coat, the test as described in the USP (method A or B)
stipulates that after 2 hours in acidic media (e.g. 0.1N HCl), no
individual values of at least six experiments exceed about 10% of
the active drug dissolved and not less than about 75% dissolved at
about 45 minutes in pH about 6.8. The moisture barrier of certain
embodiments does not meet this requirement for the following
reasons even though the bupropion hydrobromide salt is not
negatively affected in acidic media nor is it irritating the
gastric mucosa: (1) to obtain enteric integrity with a film
containing EUDRAGIT.RTM. L 30 D-55, a weight gain of from about 6%
to about 8% based on the dry polymer per dosage unit is
recommended. The amount of EUDRAGIT.RTM. L 30 D-55 solid applied
onto the controlled release coated tablet cores is not more than
about 6%, and in at least one embodiment, is not more than about
3%, (2) if enteric integrity would be required, the dissolution
test for the finished product (i.e., the moisture barrier coated
tablet cores) at the 2 hour time point would not stipulate a limit
of no more than about 20%, and (3) analytical tests performed on
these coatings indicate that the coatings do not meet all the test
requirements as an enteric coated product as defined by USP test
methods.
[0234] The XL tablet of certain embodiments of the invention
provides an extended release of the bupropion hydrobromide salt. In
at least one embodiment no pore forming agent is present in the XL
coating formulation. An extended release bupropion hydrobromide
formulation is provided in certain embodiments such that after
about 2 hours, not more than about 20% of the bupropion
hydrobromide content is released. For example, in certain
embodiments, from about 2% to about 18%, preferably from about 4%
to about 8%, or about 5% of the bupropion hydrobromide content is
released after about 2 hours. After about 4 hours, from about 15%
to about 45% of the bupropion hydrobromide content is released. For
example, in certain embodiments from about 21% to about 37%, more
preferably from about 28% to about 34%, or about 32% of the
bupropion hydrobromide content is released after about 4 hours.
After about 8 hours, about 40% to about 90% of the bupropion
hydrobromide content is released. For example, in certain
embodiments from about 60% to about 85%, from about 68% to about
74%, or about 74% of the bupropion hydrobromide content is released
after about 8 hours. After about 16 hours not less than about 80%
of the bupropion hydrobromide content is released. For example, in
certain embodiments of the bupropion hydrobromide content is
released after about 16 hours.
[0235] Also, extended release tablets are provided in certain
embodiments wherein after about 2 hours not more than about 40%
(e.g., about 33%) of the bupropion hydrobromide is released; after
about 4 hours from about 40 to about 75% of the bupropion
hydrobromide is released (e.g., about 59%); after about 8 hours at
least about 75% of the bupropion hydrobromide is released (e.g.,
about 91%); and after about 16 hours at least about 85% of the
bupropion hydrobromide is released (e.g., about 97%). In all
instances herein when actual or prophetic dissolution profiles are
provided this means that the medicament possesses such a profile in
at least one dissolution medium under prescribed conditions such as
are identified herein and are well known to those skilled in the
art. Such dissolution media, dissolution conditions and apparatus
for use therein are disclosed in the United States Pharmacopoeia
(USP) and European and Japanese counterparts thereof. Additionally,
specific examples thereof are provided in this application.
Enhanced Absorption (EA) Tablets
[0236] In certain embodiments of the present invention, there is
provided an enhanced absorption (EA) tablet having a core
comprising a bupropion hydrobromide salt and conventional
excipients, wherein the bupropion hydrobromide salt provides for
the reduction of incidences of and/or severity of bupropion-induced
seizures, and is more stable, as compared with equivalent molar
amounts of bupropion hydrochloride. The core is surrounded by an EA
coating, which controls the release of the bupropion hydrobromide
salt. In certain embodiments, the EA coating consists of one coat.
An advantage of the EA tablet includes the lower amount of drug
required in the composition to be an effective amount, which in
turn can lead to a reduction of side effects. The EA tablet
optionally can comprise one or more additional functional or
non-functional coats surrounding the core or EA coating.
The EA Core
[0237] The core of the EA tablet comprises an effective amount of a
bupropion hydrobromide salt, a binder and a lubricant, and can
contain other conventional inert excipients. In certain embodiments
the core of the EA tablet can comprise the same excipients as, and
can be processed in the same manner as the core of the extended
release tablet. The amount of the bupropion hydrobromide salt
present in the EA core can vary from about 40% to about 99% by
weight of the EA tablet dry weight, including all values and ranges
therebetween. The EA tablet comprises an effective amount of
bupropion hydrobromide salt that can vary from about 50 mg to about
1000 mg, including 100, 150, 200, 250, 300, 350, 400, 450, 500,
510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 650, 700, 750,
800, 85, 900, 950 mg and all values and ranges therebetween. For
example, certain embodiments of the EA tablet can comprise about
150 mg, about 300 mg or about 450 mg of bupropion hydrobromide. For
a 150 mg dose tablet the bupropion hydrobromide can be present in
an amount of from about 76% to about 84% by weight of the tablet
dry weight. For a 300 mg dose, the amount of bupropion hydrobromide
can be present in an amount of from about 80% to about 83% by
weight of the tablet dry weight. For a 450 mg dose, the amount of
bupropion hydrobromide can be present in an amount of from about
75% to about 90% by weight of the tablet dry weight. For the 150
mg, 300 mg and 450 mg dose bupropion hydrobromide EA tablets of
certain embodiments of the invention, the amount of bupropion
hydrobromide can be present at about 94% by weight of the dry core
for each dose.
The EA Tablet Coating
[0238] The EA tablet cores can be coated in one stage. The EA
coating is applied directly onto the surface of the tablet cores
and functions to control the release of the bupropion hydrobromide
salt. The EA coating is a semi-permeable coat comprising a
water-insoluble, water-permeable film-forming polymer, a
water-soluble polymer, and optionally a plasticizer. In certain
embodiments the EA coating can comprise the same ingredients as,
and can be processed in the same manner as the XL controlled
release coat.
[0239] Non-limiting examples of water-insoluble, water-permeable
film-forming polymers useful for the EA coating include those that
can be used in the XL controlled release coat. The amount of the
water-insoluble water-permeable film-forming polymer can vary from
about 1% to about 8% by weight of the tablet dry weight, including
all values and ranges therebetween. For example, in certain
embodiments the amount of the water-insoluble water-permeable
film-forming polymer is from about 2% to about 6% by weight of the
tablet dry weight. For certain embodiments of the 150 mg, 300 mg or
450 mg dose EA tablets of certain embodiments of the invention, the
amount of water-insoluble water permeable film-forming polymer is
from about 1% to about 15% by weight of the tablet dry weight. For
example, in certain embodiments of the 150 mg dose EA tablets, the
amount of the water-insoluble water-permeable film-forming polymer
is present at about 10.5% by weight of the tablet dry weight. With
respect to the EA coat itself, the amount of water-insoluble
water-permeable film-forming polymer in certain embodiments of the
150 mg dose EA tablets is from about 35% to about 60% by weight of
the EA coat dry weight. For example, in certain embodiments of the
150 mg dose EA tablet, the amount of water-insoluble
water-permeable polymer is present at about 55% by weight of the EA
coat dry weight. For certain embodiments of the 300 mg dose EA
tablet of the invention, the amount of water-insoluble
water-permeable film-forming polymer is from about 1% to about 8%
by weight of the tablet dry weight. For example, in certain
embodiments of the 300 mg dose EA tablet, the amount of
water-insoluble water-permeable film forming polymer is present at
about 6.3% by weight of the tablet dry weight. With respect to the
EA coat itself, the water-insoluble water-permeable film-forming
polymer in the 300 mg dose EA tablet can be present in an amount of
about 55% by weight of the EA coat dry weight. For certain
embodiments of the 450 mg dose EA tablet of the invention, the
amount of water-insoluble water-permeable film-forming polymer is
from about 0.5% to about 10% by weight of the tablet dry weight,
and in other embodiments is from about 1% to about 6% by weight of
the tablet dry weight. With respect to the EA coat itself, the
water-insoluble water-permeable film-forming polymer in the 450 mg
dose EA tablet can be present in an amount of about 37% by weight
of the EA coat dry weight.
[0240] In certain embodiments, the EA coat further comprises a
plasticizer. Non-limiting examples of plasticizers that can be used
in the EA coat include those that can be used in the XL controlled
release coat. The amount of plasticizer that can be used in the EA
coat can vary in an amount from about 0.5% to about 4% by weight of
the tablet dry weight, including all values and ranges
therebetween. In a further embodiment of the invention, when a
mixture of two plasticizers is used, the ratio of the two
plasticizers can range from about 5:95 to about 95:5, including all
values and ranges therebetween. In at least one embodiment of the
invention, the plasticizer is polyethylene glycol 4000, dibutyl
sebacate, or a mixture thereof. The ratio of polyethylene glycol
4000:dibutyl sebacate can range from about 5:95 to about 95:5. For
certain embodiments of the 150 mg dose EA tablet of the invention,
the amount of plasticizer present in the EA coat is from about 0.5%
to about 4% by weight of the tablet dry weight. For example, in
certain embodiments of the 150 mg dose EA tablet, the amount of
plasticizer is present at about 3.1% by weight of the tablet dry
weight. For certain embodiments of the 300 mg dose EA tablet of the
invention, the amount of plasticizer present is from about 0.5% to
about 3% by weight of the tablet dry weight. For example, in
certain embodiments of the 300 mg dose EA tablet, the amount of
plasticizer is present at about 2.0% by weight of the tablet dry
weight. For certain embodiments of the 450 mg dose EA tablet of the
invention, the amount of plasticizer present is from about 0.5% to
about 4% by weight of the tablet dry weight. For certain
embodiments of the 150 mg, 300 mg and 450 mg dosage forms, the
plasticizer is present in an amount of from about 6% to about 30%
by weight of the EA coat dry weight. For example, in certain
embodiments the amount of plasticizer is present at about 17% by
weight of the EA coat dry weight
[0241] Non-limiting examples of water-soluble polymers useful for
the EA coat include those that can be used in the XL controlled
release coat. In at least one embodiment of the invention, the
water-soluble polymer is polyvinylpyrrolidone (e.g. Povidone.RTM.
USP) the amount of which can vary from about 1.5% to about 10% by
weight of the tablet dry weight, including all values and ranges
therebetween. With respect to the EA coat itself, the amount of
water-soluble polymer present can vary from about 20% to about 50%
by weight of the EA coat dry weight. For certain embodiments of the
150 mg dose of the EA tablet of the invention, the amount of
water-soluble polymer present is from about 1.5% to about 10% by
weight of the tablet dry weight or from about 20% to about 50% by
weight of the EA coat dry weight. For example, in certain
embodiments of the 150 mg dose EA tablet, the water-soluble polymer
is present in an amount of about 28% by weight of the EA coat dry
weight. For certain embodiments of the 300 mg dose of the EA tablet
of the invention, the amount of water-soluble polymer present is
from about 1.5% to about 10% of the tablet dry weight and from
about 20% to about 50% by weight of the EA coat dry weight. For
example, in certain embodiments of the 300 mg dose EA tablet, the
water-soluble polymer is present in an amount of about 28% by
weight of the EA coat dry weight. For certain embodiments of the
450 mg dose of the EA tablet of the invention, the amount of
water-soluble polymer present is from about 2% to about 5% of the
tablet dry weight and from about 40% to about 50% by weight of the
EA coat dry weight.
[0242] The ratio of water-insoluble water-permeable film forming
polymer:plasticizer:water-soluble polymer for the EA tablet coating
typically will vary from about 3:1:4 to about 5:1:2, including all
values and ranges therebetween. For example in certain embodiments
the ratio of water-insoluble water-permeable film forming
polymer:plasticizer:water-soluble polymer for the EA tablet coating
is about 4:1:3. In at least one embodiment of the EA tablet
coating, the ratio of the water-insoluble water-impermeable
film-forming polymer:plasticizer:water-soluble polymer is from
about 7:2:6 to about 19:5:18, and in another embodiment is about
13:4:12. In at least one embodiment of the 450 mg dosage form, the
ratio of water-insoluble water-permeable film forming
polymer:plasticizer:water-soluble polymer for the EA coating is
about 13:6:16.
[0243] In certain embodiments the EA coat of the bupropion
hydrobromide dosage form can be made according to any one of the
methods described for the XL controlled release coat.
[0244] Depending on the dissolution or in-vivo release profile
desired, the weight gained after coating the tablet core with the
EA coat can vary from about 3% to about 30% of the weight of the
dry tablet core, including all values and ranges therebetween. For
certain embodiments of the 150 mg dose EA tablet of the invention
the weight gain is from about 8% to about 20% of the weight of the
dry tablet core. For example, in certain embodiments of the 150 mg
dose EA tablet, the weight gain is about 14% of the weight of the
dry tablet core. For certain embodiments of the 300 mg dose EA
tablet of the invention the weight gain is from about 10% to about
15% of the weight of the dry tablet core. For example, in certain
embodiments of the 300 mg dose EA tablet, the weight gain is about
13% of the weight of the dry tablet core. For certain embodiments
of the 450 mg dose EA tablet of the invention the weight gain is
from about 5% to about 15% of the weight of the dry tablet core.
For example, in certain embodiments of the 450 mg dose EA tablet,
the weight gain is about 8.5% of the weight of the dry tablet
core.
[0245] The EA tablet provides an enhanced-absorption of the
bupropion hydrobromide salt wherein typically no pore forming agent
is present in the formulation. An enhanced absorption bupropion
hydrobromide formulation is provided such that after about 2 hours,
not more than about 25% of the bupropion hydrobromide content is
released. For example, in certain embodiments from about 10% to
about 20% of the bupropion hydrobromide content is released after
about 2 hours. After about 4 hours, from about 25% to about 55% of
the bupropion hydrobromide content is released. For example, in
certain embodiments from about 30% to about 50% of the bupropion
hydrobromide content is released after about 4 hours. After about 8
hours, more than about 60% of the bupropion hydrobromide content is
released. For example, in certain embodiments from about 70% to
about 90% of the bupropion hydrobromide content is released after
about 8 hours. After about 16 hours more than about 70% of the
bupropion hydrobromide content is released. For example, in certain
embodiments more than about 80% of the bupropion hydrobromide
content is released after about 16 hours.
[0246] In certain embodiments an enhanced absorption formulation is
provided wherein not more than about 40% is released after about 2
hours; after about 4 hours from about 40% to about 75% is released;
after about 8 hours at least about 75% is released; and after about
16 hours at least about 85% is released. For example, in at least
one embodiment, the bupropion hydrobromide release profile is about
33% after about 2 hours; about 59% after about 4 hours; about 91%
after about 8 hours; and about 97% after about 16 hours.
Controlled Release Matrix
[0247] In other embodiments of the present invention, a controlled
release matrix is provided from which the kinetics of drug release
from the matrix core are dependent at least in part upon the
diffusion and/or erosion properties of excipients within the
composition. In this embodiment controlled release matrices contain
an effective amount of a bupropion hydrobromide salt and at least
one pharmaceutically acceptable excipient. The amount of the
bupropion hydrobromide salt present in the controlled release
matrix can vary in an amount of from about 40% to about 90% by
weight of the matrix tablet dry weight, including all values and
ranges therebetween. For example, in certain embodiments bupropion
hydrobromide is present in an amount from about 60% to about 80%,
and in other embodiment at about 70% by weight of the matrix tablet
dry weight. The controlled release matrix can be multiparticulate
or uniparticulate, and can be coated with at least one functional
or non-functional coating, or an immediate release coating
containing another drug. Functional coatings include by way of
example controlled release polymeric coatings, enteric polymeric
coatings, and the like. Non-functional coatings are coatings that
do not affect drug release but which affect other properties (e.g.,
they can enhance the chemical, biological, or the physical
appearance of the controlled release formulation). Those skilled in
the pharmaceutical art and the design of medicaments are well aware
of controlled release matrices conventionally used in oral
pharmaceutical compositions adopted for controlled release and
means for their preparation.
[0248] Suitable excipient materials for use in such controlled
release matrices are known by those of skill in the art, and
include, by way of example, release-resistant or controlled release
materials such as hydrophobic polymers, hydrophilic polymers,
lipophilic materials and mixtures thereof. Non-limiting examples of
hydrophobic, or lipophilic components include glyceryl
monostearate, mixtures of glyceryl monostearate and glyceryl
monopalmitate (MYVAPLEX.TM., Eastman Fine Chemical Company),
glycerylmonooleate, a mixture of mono, di and tri-glycerides
(ATMUL.TM. 84S), glycerylmonolaurate, paraffin, white wax, long
chain carboxylic acids, long chain carboxylic acid esters, long
chain carboxylic acid alcohols, and mixtures thereof. The long
chain carboxylic acids can contain from about 6 to about 30 carbon
atoms; in certain embodiments at least about 12 carbon atoms, and
in other embodiments from about 12 to about 22 carbon atoms. In
some embodiments this carbon chain is fully saturated and
unbranched, while others contain one or more double bonds. In at
least one embodiment the long chain carboxylic acids contain about
3-carbon rings or hydroxyl groups. Non-limiting examples of
saturated straight chain acids include n-dodecanoic acid,
n-tetradecanoic acid, n-hexadecanoic acid, caproic acid, caprylic
acid, capric acid, lauric acid, myristic acid, palmitic acid,
stearic acid, arachidic acid, behenic acid, montanic acid, melissic
acid and mixtures thereof. Also useful are unsaturated monoolefinic
straight chain monocarboxylic acids. Non-limiting examples of these
include oleic acid, gadoleic acid, erucic acid and mixtures
thereof. Also useful are unsaturated (polyolefinic) straight chain
monocaboxyic acids. Non-limiting examples of these include linoleic
acid, linolenic acid, arachidonic acid, behenolic acid and mixtures
thereof. Useful branched acids include, for example, diacetyl
tartaric acid. Non-limiting examples of long chain carboxylic acid
esters include glyceryl monostearates; glyceryl monopalmitates;
mixtures of glyceryl monostearate and glyceryl monopalmitate
(MYVAPLEX.TM. 600, Eastman Fine Chemical Company); glyceryl
monolinoleate; glyceryl monooleate; mixtures of glyceryl
monopalmitate, glyceryl monostearate glyceryl monooleate and
glyceryl monolinoleate (MYVEROL.TM. 18-92, Eastman Fine Chemical
Company); glyceryl monolinolenate; glyceryl monogadoleate; mixtures
of glyceryl monopalmitate, glyceryl monostearate, glyceryl
monooleate, glyceryl monolinoleate, glyceryl monolinolenate and
glyceryl monogadoleate (MYVEROL.TM. 18-99, Eastman Fine Chemical
Company); acetylated glycerides such as distilled acetylated
monoglycerides (MYVACET.TM. 5-07, 7-07 and 9-45, Eastman Fine
Chemical Company); mixtures of propylene glycol monoesters,
distilled monoglycerides, sodium stearoyl lactylate and silicon
dioxide (MYVATEX.TM. TL, Eastman Fine Chemical Company); mixtures
of propylene glycol monoesters, distilled monoglycerides, sodium
stearoyl lactylate and silicon dioxide (MYVATEX.TM. TL, Eastman
Fine Chemical Company) d-alpha tocopherol polyethylene glycol 1000
succinate (Vitamin E TPGS, Eastman Chemical Company); mixtures of
mono- and diglyceride esters such as ATMUL.TM. (Humko Chemical
Division of Witco Chemical); calcium stearoyl lactylate;
ethoxylated mono- and di-glycerides; lactated mono- and
di-glycerides; lactylate carboxylic acid ester of glycerol and
propylene glycol; lactylic esters of long chain carboxylic acids;
polyglycerol esters of long chain carboxylic acids, propylene
glycol mono- and di-esters of long chain carboxylic acids; sodium
stearoyl lactylate; sorbitan monostearate; sorbitan monooleate;
other sorbitan esters of long chain carboxylic acids; succinylated
monoglycerides; stearyl monoglyceryl citrate; stearyl heptanoate;
cetyl esters of waxes; cetearyl octanoate; C10-C30
cholesterol/lavosterol esters; sucrose long chain carboxylic acid
esters; and mixtures thereof. The alcohols useful as excipient
materials for controlled release matrices can include the hydroxyl
forms of the carboxylic acids exemplified above and also cetearyl
alcohol.
[0249] In addition, waxes can be useful alone or in combination
with the materials listed above, as excipient materials for the
controlled release matrix embodiments of the present invention.
Non-limiting examples of these include white wax, paraffin,
microcrystalline wax, carnauba wax, and mixtures thereof.
[0250] The lipophilic agent can be present in an amount of from
about 5% to about 90% by weight of the controlled release matrix
dosage form, including all values and ranges therebetween. For
example, in certain embodiments the lipophilic agent is present in
an amount of from about 10% to about 85%, and in other embodiments
from about 30% to about 60% by weight of the controlled release
matrix dosage form.
[0251] Non-limiting examples of hydrophilic polymers that can be
used in certain embodiments of the controlled release matrix dosage
form include hydroxypropylmethylcellulose (HPMC),
hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC),
carboxymethylcellulose (CMC) or other cellulose ethers,
polyoxyethylene, alginic acid, acrylic acid derivatives such as
polyacrylic acid, CARBOPOL.TM., polymethacrylate polymer such as
EUDRAGIT.RTM. RL, RS, R, S, NE and E, acrylic acid polymer,
methacrylic acid polymer, hydroyethyl methacrylic acid (HEMA)
polymer, hydroxymethyl methacrylic acid (HMMA) polymer, polyvinyl
alcohols and mixtures thereof.
[0252] The hydrophilic polymer can be present in an amount of from
about 10% to about 90% by weight of the controlled release matrix
dosage form, including all values and ranges therebetween. For
example, in certain embodiments the hydrophilic polymer is present
in an amount of from about 20% to about 75%, and in other
embodiments from about 30% to about 60% by weight of the controlled
release matrix dosage form.
[0253] In at least one embodiment, the controlled release matrix
dosage form comprises hydroxypropylmethylcellulose (HPMC).
Non-limiting examples of hydroxypropyl methylcelluloses that can be
used include METHOCEL.RTM. E (USP type 2910), METHOCEL.RTM. F (USP
type 2906), METHOCEL.RTM. J (USP type 1828), METHOCEL.RTM. K (USP
type 2201), and METHOCEL.RTM. 310 Series, products of The Dow
Chemical Company, Midland, Mich., USA. The average degree of
methoxyl substitution in these products can range from about 1.3 to
about 1.9 including all values and ranges therebetween (of the
three positions on each unit of the cellulose polymer that are
available for substitution) while the average degree of
hydroxypropyl substitution per unit expressed in molar terms can
range from about 0.13 to about 0.82 including all values and ranges
therebetween. The dosage form can comprise the different HPMC
grades having different viscosities. The size of a HPMC polymer is
expressed not as molecular weight but instead in terms of its
viscosity as about a 2% solution by weight in water. Different HPMC
grades can be combined to achieve the desired viscosity
characteristics. For example, the at least one pharmaceutically
acceptable polymer can comprise two HPMC polymers such as for
example METHOCEL.RTM. K3 LV (which has a viscosity of about 3 cps)
and METHOCEL.RTM. K100M CR (which has a viscosity of about 100,000
cps). In addition, the polymer can comprise two
hydroxypropylcellulose forms such as KLUCEL.RTM. LF and KLUCEL.RTM.
EF. In addition, the at least one polymer can comprise a mixture of
a KLUCEL.RTM. and a METHOCEL.RTM..
[0254] In at least one embodiment the controlled release matrix
dosage form comprises a polyethylene oxide (PEO). PEO is a linear
polymer of unsubstituted ethylene oxide. In certain embodiments
poly(ethylene oxide) polymers having viscosity-average molecular
weights of about 100,000 Daltons and higher are used. Non-limiting
examples of poly(ethylene oxide)s that are commercially available
include: POLYOX.RTM. NF, grade WSR Coagulant, molecular weight 5
million; POLYOX.RTM. grade WSR 301, molecular weight 4 million;
POLYOX.RTM. grade WSR 303, molecular weight 7 million; POLYOX.RTM.
grade WSR N-60K, molecular weight 2 million; and mixtures thereof.
These particular polymers are products of Dow Chemical Company,
Midland, Mich., USA. Other examples of polyethylene oxides exist
and can likewise be used. The required molecular weight for the PEO
can be obtained by mixing PEO of differing molecular weights that
are available commercially.
[0255] In at least one embodiment of the controlled release matrix
dosage form, PEO and HPMC are combined within the same controlled
release matrix. In certain embodiments, the poly(ethylene oxide)s
have molecular weights ranging from about 2,000,000 to about
10,000,000 Da including all values and ranges therebetween. For
example, in at least one embodiment the polyethylene oxides have
molecular weights ranging from about 4,000,000 to about 7,000,000
Da. In certain embodiments the HPMC polymers have a viscosity
within the range of about 4,000 centipoises to about 200,000
centipoises. For example, in at least one embodiment the HPMC
polymers have a viscosity of from about 50,000 centipoises to about
200,000 centipoises, and in other embodiments from about 80,000
centipoises to about 120,000 centipoises. The relative amounts of
PEO and HPMC within the controlled release matrix can vary within
the scope of the invention. In at least one embodiment the PEO:HPMC
weight ratio is from about 1:3 to about 3:1 including all values
and ranges therebetween. For example, in certain embodiments the
PEO:HPMC weight ratio is from about 1:2 to about 2:1. As for the
total amount of polymer relative to the entire matrix, this can
vary as well and can depend on the desired drug loading. In at
least one embodiment the total amount of polymer in the matrix can
constitute from about 15% to about 90% by weight of the matrix
dosage form including all values and ranges therebetween. For
example, in certain embodiments the total amount of polymer in the
matrix is from about 20% to about 75%, in other embodiments from
about 30% to about 60%, and in still other embodiments from about
10% to about 20% by weight of the matrix dosage form.
[0256] In at least one embodiment of the invention the controlled
release matrix dosage form comprises a hydrophobic polymer such as
ethylcellulose. The viscosity of ethylcellulose can be selected in
order to influence of rate the drug release. In certain embodiments
the ethylcellulose has a viscosity from about 7 to about 100 cP
including all values and ranges therebetween (when measured as a 5%
solution at 25.degree. C. in an Ubbelohde viscometer, using a 80:20
toluene:ethanol solvent). In certain embodiments the hydrophobic
polymer can constitute from about 10% to about 90% by weight of the
matrix dosage form including all values and ranges therebetween.
For example, in at least one embodiment the hydrophobic polymer
constitutes from about 20% to about 75%, and in other embodiments
from about 30% to about 60% by weight of the matrix dosage
form.
[0257] In at least one embodiment of the invention the controlled
release matrix dosage form comprises at least one binder. In
certain embodiments the binder is water-insoluble. Examples of
binders include hydrogenated vegetable oil, castor oil, paraffin,
higher aliphatic alcohols, higher aliphatic acids, long chain fatty
acids, fatty acid esters, wax-like materials such as fatty
alcohols, fatty acid esters, fatty acid glycerides, hydrogenated
fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol,
hydrophobic and hydrophilic polymers having hydrocarbon backbones,
and mixtures thereof. Non-limiting examples of water-soluble
polymer binders include modified starch, gelatin,
polyvinylpyrrolidone, cellulose derivatives (such as for example
hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose
(HPC)), polyvinyl alcohol and mixtures thereof. In at least one
embodiment, the binder can be present in an amount of from about
0.1% to about 20% by weight of the matrix dosage form including all
values and ranges therebetween. For example, in certain embodiments
the binder is present in an amount of from about 0.5% to about 15%,
and in other embodiments from about 2% to about 10% by weight of
the matrix dosage form.
[0258] In at least one embodiment of the invention the controlled
release matrix dosage form comprises at least one lubricant.
Non-limiting examples of lubricants include stearic acid,
hydrogenated vegetable oils (such as hydrogenated cottonseed oil
(Sterotex.RTM.), hydrogenated soybean oil (STEROTEX.RTM. HM) and
hydrogenated soybean oil & castor wax (STEROTEX.RTM. K))
stearyl alcohol, leucine, polyethylene glycol (MW 1450, suitably
4000, and higher), magnesium stearate, glyceryl monostearate,
stearic acid, glycerylbehenate, polyethylene glycol, ethylene oxide
polymers (e.g. CARBOWAX.RTM.), sodium lauryl sulfate, magnesium
lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine,
colloidal silica, and mixtures thereof. The lubricant can be
present in an amount of from about 0 to about 4% by weight of the
compressed uncoated matrix including all values and ranges
therebetween. For example, in certain embodiments the lubricant is
present in an amount of from about 0% to about 2.5% by weight of
the compressed, uncoated matrix.
[0259] In at least one embodiment of the invention the controlled
release matrix dosage form comprises a plasticizer. Non-limiting
examples of plasticizers include dibutyl sebacate, diethyl
phthalate, triethyl citrate, tributyl citrate, triacetin, citric
acid esters such as triethyl citrate NF XVI, tributyl citrate,
dibutyl phthalate, 1,2-propylene glycol, polyethylene glycols,
propylene glycol, diethyl phthalate, castor oil, acetylated
monoglycerides, phthalate esters, and mixtures thereof. In at least
one embodiment, the plasticizer can be present in an amount of from
about 1% to about 70% by weight of the controlled release polymer
in the matrix dosage form including all values and ranges
therebetween. For example, in certain embodiments the plasticizer
is present in an amount of from about 5% to about 50%, and in other
embodiments from about 10% to about 40% by weight of the controlled
release polymer in the matrix dosage form.
[0260] In at least one embodiment of the invention the controlled
release matrix dosage form comprises at least one diluent,
non-limiting examples of which include dicalcium phosphate, calcium
sulfate, lactose or sucrose or other disaccharides, cellulose,
cellulose derivatives, kaolin, mannitol, dry starch, glucose or
other monosaccharides, dextrin or other polysaccharides, sorbitol,
inositol, sucralfate, calcium hydroxyl-apatite, calcium phosphates,
fatty acid salts such as magnesium stearate, and mixtures thereof.
In certain embodiments the diluent can be added in an amount so
that the combination of the diluent and the active substance
comprises up to about 60%, and in other embodiments up to about
50%, by weight of the composition.
[0261] In at least one embodiment of the invention the controlled
release matrix dosage form comprises a solubilizer. The solubilizer
can act to increase the instantaneous solubility of the bupropion
salt. The solubilizer can be selected from hydrophilic surfactants
or lipophilic surfactants or mixtures thereof. The surfactants can
be anionic, nonionic, cationic, and zwitterionic surfactants. The
hydrophilic non-ionic surfactants can be selected from the group
comprised of, but not limited to: polyethylene glycol sorbitan
fatty acid esters and hydrophilic transesterification products of a
polyol with at least one member of the group from triglycerides,
vegetable oils, and hydrogenated vegetable oils such as glycerol,
ethylene glycol, polyethylene glycol, sorbitol, propylene glycol,
pentaerythritol, or a saccharide, tocopheryl polyethylene glycol
1000 succinate. The ionic surfactants can be selected from the
group comprised of, but not limited to: alkylammonium salts;
fusidic acid salts; fatty acid derivatives of amino acids,
oligopeptides, and polypeptides; glyceride derivatives of amino
acids, oligopeptides, and polypeptides; lecithins and hydrogenated
lecithins; lysolecithins and hydrogenated lysolecithins;
phospholipids and derivatives thereof; lysophospholipids and
derivatives thereof; carnitine fatty acid ester salts; salts of
alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates;
mono- and di-acetylated tartaric acid esters of mono- and
di-glycerides; succinylated mono- and di-glycerides; citric acid
esters of mono- and di-glycerides; and mixtures thereof. The
lipophilic surfactants can be selected from the group comprised of,
but not limited to: fatty alcohols; glycerol fatty acid esters;
acetylated glycerol fatty acid esters; lower alcohol fatty acids
esters; propylene glycol fatty acid esters; sorbitan fatty acid
esters; polyethylene glycol sorbitan fatty acid esters; sterols and
sterol derivatives; polyoxyethylated sterols and sterol
derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar
ethers; lactic acid derivatives of mono- and di-glycerides;
hydrophobic transesterification products of a polyol with at least
one member of the group from glycerides, vegetable oils,
hydrogenated vegetable oils, fatty acids and sterols; oil-soluble
vitamins/vitamin derivatives; PEG sorbitan fatty acid esters, PEG
glycerol fatty acid esters, polyglycerized fatty acid,
polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty
acid esters; and mixtures thereof. In at least one embodiment the
solubilizer can be selected from: PEG-20-glyceryl stearate (e.g.
CAPMUL.RTM. by Abitec), PEG-40 hydrogenated castor oil (e.g.
CREMOPHOR RH 40.RTM. by BASF), PEG 6 corn oil (e.g. LABRAFIL.RTM.
by Gattefosse), lauryl macrogol-32 glyceride (e.g.
GELUCIRE44/14.RTM. by Gattefosse) stearoyl macrogol glyceride (e.g.
GELUCIRE50/13.RTM. by Gattefosse), polyglyceryl-10 mono dioleate
(e.g. CAPROL.RTM. PEG860 by Abitec), propylene glycol oleate (e.g.
LUTROL.RTM. by BASF), Propylene glycol dioctanoate (e.g.
CAPTEX.RTM. by Abitec), Propylene glycol caprylate/caprate (e.g.
LABRAFAC.RTM. by Gattefosse), Glyceryl monooleate (e.g. PECEOL.RTM.
by Gattefrosse), Glycerol monolinoleate (e.g. MAISINE.RTM. by
Gattefrosse), Glycerol monostearate (e.g. CAPMUL.RTM. by Abitec),
PEG-20 sorbitan monolaurate (e.g. TWEEN20.RTM. by ICI), PEG-4
lauryl ether (e.g. BRIJ30.RTM. by ICI), Sucrose distearate (e.g.
SUCROESTER7.RTM. by Gattefosse), Sucrose monopalmitate (e.g.
SUCROESTER15.RTM. by Gattefosse), polyoxyethylene-polyoxypropylene
block copolymer (e.g. LUTROL.RTM. series BASF), polyethylene glycol
660 hydroxystearate, (e.g. SOLUTOL.RTM. by BASF), Sodium lauryl
sulfate, Sodium dodecyl sulphate, Dioctyl suphosuccinate,
L-hydroxypropyl cellulose, hydroxylethylcellulose,
hydroxylpropylcellulose, Propylene glycol alginate, sodium
taurocholate, sodium glycocholate, sodium deoxycholate, betains,
polyethylene glycol (e.g. CARBOWAX.RTM. by DOW),
d-.alpha.-tocopheryl polyethylene glycol 1000 succinate, (Vitamin E
TPGS.RTM. by Eastman), and mixtures thereof. In at least one other
embodiment the solubilizer can be selected from PEG-40 hydrogenated
castor oil (e.g. CREMOPHOR RH 40.RTM. by BASF), lauryl macrogol-32
glyceride (e.g. GELUCIRE44/14.RTM. by Gattefosse) stearoyl macrogol
glyceride (e.g. GELUCIRE 50/13.RTM. by Gattefosse), PEG-20 sorbitan
monolaurate (e.g. TWEEN 20.RTM. by ICI), PEG-4 lauryl ether (e.g.
BRIJ30.RTM. by ICI), polyoxyethylene-polyoxypropylene block
copolymer (e.g. LUTROL.RTM. series BASF), Sodium lauryl sulphate,
Sodium dodecyl sulphate, polyethylene glycol (e.g. CARBOWAX.RTM. by
DOW), and mixtures thereof.
[0262] In at least one embodiment of the invention the controlled
release matrix dosage form comprises a swelling enhancer. Swelling
enhancers are members of a category of excipients that swell
rapidly to a large extent resulting in an increase in the size of
the tablet. At lower concentrations, these excipients can be used
as superdisintegrants; however at concentrations above 5% w/w these
agents can function as swelling enhancers and help increase the
size of the matrix dosage form. According to certain embodiments of
the matrix dosage forms of the invention, examples of swelling
enhancers include but are not limited to: low-substituted
hydroxypropyl cellulose, microcrystalline cellulose, cross-linked
sodium or calcium carboxymethyl cellulose, cellulose fiber,
cross-linked polyvinyl pyrrolidone, cross-linked polyacrylic acid,
cross-linked Amberlite resin, alginates, colloidal
magnesium-aluminum silicate, corn starch granules, rice starch
granules, potato starch granules, pregelatinised starch, sodium
carboxymethyl starch and mixtures thereof. In at least one
embodiment of the matrix dosage forms, the swelling enhancer is
cross-linked polyvinyl pyrrolidone. The content of the swelling
enhancer can be from about 5% to about 90% by weight of the matrix
dosage form including all values and ranges therebetween. For
example, in certain embodiments the swelling enhancer is present in
an amount of from about 10% to about 70%, and in other embodiments
from about 15% to about 50% by weight of the matrix dosage
form.
[0263] In at least one embodiment of the invention the controlled
release matrix dosage form comprises additives for allowing water
to penetrate into the core of the preparation (hereinafter referred
to as "hydrophilic base"). In certain embodiments, the amount of
water required to dissolve 1 g of the hydrophilic base is not more
than about 5 ml, and in other embodiments is not more than about 4
ml at the temperature of about 20.degree. C..+-.5.degree. C. The
higher the solubility of the hydrophilic base in water, the more
effective is the base in allowing water into the core of the
preparation. The hydrophilic base includes, inter alia, hydrophilic
polymers such as polyethylene glycol (PEG); (e.g. PEG400, PEG1500,
PEG4000, PEG6000 and PEG20000, produced by Nippon Oils and Fats
Co.) and polyvinylpyrrolidone (PVP); (e.g. PVP K30, of BASF), sugar
alcohols such as D-sorbitol, xylitol, or the like, sugars such as
sucrose, anhydrous maltose, D-fructose, dextran (e.g. dextran 40),
glucose or the like, surfactants such as
polyoxyethylene-hydrogenated castor oil (HCO; e.g. CREMOPHOR.RTM.
RH40 produced by BASF, HCO-40 and HCO-60 produced by Nikko
Chemicals Co.), polyoxyethylene-polyoxypropylene glycol (e.g.
Pluronic.RTM. F68 produced by Asahi Denka Kogyo K.K.),
polyoxyethylene-sorbitan high molecular fatty acid ester
(TWEEN.RTM.; e.g. TWEEN.RTM. 80 produced by Kanto Kagaku K.K.), or
the like; salts such as sodium chloride, magnesium chloride, or the
like; organic acids such as citric acid, tartaric acid, or the
like; amino acids such as glycine, .beta.-alanine, lysine
hydrochloride, or the like; and amino sugars such as meglumine. In
at least one embodiment the hydrophilic base is PEG6000, PVP,
D-sorbitol, or mixtures thereof.
[0264] In another embodiment of the invention the controlled
release matrix dosage form comprises at least one disintegrant.
Non-limiting examples of disintegrants for use in the matrix dosage
form include croscarmellose sodium, crospovidone, alginic acid,
sodium alginate, methacrylic acid DVB, cross-linked PVP,
microcrystalline cellulose, polacrilin potassium, sodium starch
glycolate, starch, pregelatinized starch and mixtures thereof. In
at least one embodiment the disintegrant is selected from
cross-linked polyvinylpyrrolidone (e.g. KOLLIDON.RTM. CL),
cross-linked sodium carboxymethylcellulose (e.g. AC-DI-SOL.TM.),
starch or starch derivatives such as sodium starch glycolate (e.g.
EXPLOTAB.RTM.), or combinations with starch (e.g. PRIMOJEL.TM.),
swellable ion-exchange resins, such as AMBERLITE.TM. IRP 88,
formaldehyde-casein (e.g. ESMA SPRENG.TM.), and mixtures thereof.
In at least one embodiment the disintegrant is sodium starch
glycolate. The disintegrant can be present in certain embodiments
in an amount of from about 0% to about 20% of the total weight of
the matrix including all values and ranges therebetween.
[0265] The controlled release matrices of the present invention can
further contain one or more pharmaceutically acceptable excipients
such as granulating aids or agents, colorants, flavorants, pH
adjusters, anti-adherents, glidants and like excipients
conventionally used in pharmaceutical compositions.
[0266] In at least one embodiment of the invention comprising water
swellable polymers formulated into the matrix, the release kinetics
of the bupropion hydrobromide salt from the matrix are dependent
upon the relative magnitude of the rate of polymer swelling at the
moving rubbery/glassy front and the rate of polymer erosion at the
swollen polymer/dissolution medium front. The release kinetics for
the release of the bupropion hydrobromide salt from the matrix can
be approximated by the following equation:
Mt/MT=ktn
[0267] where t is time,
[0268] Mt is the amount of the pharmaceutical agent which has been
released at time t,
[0269] MT is the total amount of the pharmaceutical agent contained
in the matrix,
[0270] k is a constant, and
[0271] n is the release kinetics exponent
[0272] This equation is valid so long as n remains nearly constant.
When n is equal to one, the release of the pharmaceutical agent
from the matrix has zero-order kinetics. The amount of
pharmaceutical agent released is then directly proportional to the
time.
[0273] Where the swelling process of the polymer chosen for the
excipient is the primary process controlling the drug release
(compared to erosion of the swollen polymer), non-zero order
release kinetics can result. Generally, these release kinetics
dictate a value of n approaching 0.5, leading to square-root
Fickian-type release kinetics.
[0274] In at least one embodiment of the invention, polymers are
selected for inclusion into the formulation to achieve zero order
kinetics. The release kinetics of the matrix can also be dictated
by the pharmaceutical agent itself. A drug which is highly soluble
(e.g. bupropion) can tend to be released faster than drugs which
have low solubility. Where a drug has high solubility, polymer
swelling and erosion takes place rapidly to maintain zero order
release kinetics. If the swelling and erosion take place too
slowly, the swelling process of the polymer is the primary process
controlling the drug release (since the drug will diffuse from the
swollen polymer before the polymer erodes). In this situation,
non-zero order release kinetics can result. As a result, the
administration of a highly soluble pharmaceutical agent requires a
relatively rapidly swelling and eroding excipient. To use such a
material to produce a matrix which will last for 24 hours can
require a large matrix. To overcome this difficulty, a
doughnut-shaped matrix with a hole though the middle can be used
with a less rapidly swelling and eroding polymer. With such a
matrix, the surface area of the matrix increases as the matrix
erodes. This exposes more polymer, resulting in more polymer
swelling and erosion as the matrix shrinks in size. This type of
matrix can also be used with very highly soluble pharmaceutical
agents to maintain zero order release kinetics.
[0275] In at least one other embodiment of the invention, zero
order drug release kinetics can be achieved by controlling the
surface area of the matrix dosage form that is exposed to erosion.
When water is allowed to diffuse into a polymer matrix composition
zero order release is obtained when the release rate is governed or
controlled by erosion of a constant surface area per time unit. In
order to ensure that the erosion of the polymer matrix composition
is the predominant release mechanism, it is helpful to provide a
polymer matrix composition which has properties that ensures that
the diffusion rate of water into the polymer matrix composition
substantially corresponds to the dissolution rate of the polymer
matrix composition into the aqueous medium. Thus, by adjusting the
nature and amount of constituents in the polymer matrix composition
a zero order release mechanism can be achieved. The compositions
employed are coated in such a manner that at least one surface is
exposed to the aqueous medium and this surface has a substantially
constant or controlled surface area during erosion. In the present
context controlled surface area relates to a predetermined surface
area typically predicted from the shape of the coat of the unit
dosage system. It may have a simple uniform cylindrical shape or
the cylindrical form can have one or more tapered ends in order to
decrease (or increase) the initial release period.
[0276] Accordingly, these embodiments provide a method for
controlling the release of a bupropion salt into an aqueous medium
by erosion of at least one surface of a pharmaceutical composition
comprising
[0277] (i) a matrix composition comprising (a) a polymer or a
mixture of polymers, (b) a bupropion hydrobromide salt and,
optionally, (c) one or more pharmaceutically acceptable excipients,
and
[0278] (ii) a coating having at least one opening exposing at the
one surface of said matrix, the coating comprising: (a) a first
cellulose derivative which has thermoplastic properties and which
is substantially insoluble in the aqueous medium in which the
composition is to be used, and at least one of (b) a second
cellulose derivative which is soluble or dispersible in water, (c)
optionally a plasticizer, or (d) a filler, the method comprising
adjusting the concentration and/or the nature of the ingredients
making up the matrix composition in such a manner that the
diffusion rate of the aqueous medium into the matrix composition
corresponds to 100%.+-.30% such as, for example 100%.+-.25%,
100%.+-.20%, 100%.+-.15% or 100%.+-.10%, or 100% of the dissolution
rate of the matrix composition so as to obtain a zero order release
of at least about 60% w/w such as, for example at least about 65%
w/w, at least about 70% w/w, at least about 75% w/w, at least about
80% w/w, at least about 85% w/w, at least about 90% w/w, at least
about 95% w/w or at least about 97% to about 98% w/w of the
bupropion hydrobromide salt from the pharmaceutical composition
when subject to an in-vitro dissolution test.
[0279] In at least one other embodiment of the invention, zero
order drug release is approached through the use of: (a) a
deposit-core comprising the bupropion hydrobromide salt and having
defined geometric form, (b) a support-platform applied to said
deposit-core, and is characterized in that the deposit-core
contains, mixed with the bupropion hydrobromide salt, a polymeric
material having a high degree of swelling on contact with water or
aqueous liquids, a gellable polymeric material, said polymeric
materials being replaceable by a single polymeric material having
both swelling and gelling properties, and other adjuvants able to
provide the mixture with suitable characteristics for its
compression and for its intake of water, said support-platform
comprising a polymeric material insoluble in aqueous liquids and
partially coating said deposit-core.
[0280] These and further characteristics and advantages of the
system according to certain embodiments of the matrix dosage form
will be more apparent from the description of embodiments of the
invention given hereinafter by way of non-limiting example. The
deposit-core can generally be obtained by compressing the mixture
containing the bupropion hydrobromide salt to a pressure of from
about 1000 to about 4000 kg/cm2 including all values and ranges
therebetween, to thus assume a defined geometric form. Polymeric
materials having a high degree of swelling can generally be
cross-linked insoluble polymers, whereas gellable polymeric
materials are soluble, and can control the intake of water.
[0281] The coating platform comprises a polymeric material
insoluble in water and optionally insoluble in biodegradable
biological liquids, and able to maintain its impermeability
characteristics at least until the complete transfer of the
bupropion hydrobromide salt contained in the deposit-core. It is
applied to a part of the external deposit-core surface chosen such
as to suitably direct and quantitatively regulate the release of
the bupropion hydrobromide salt. In this respect, as the
support-platform is impermeable to water, the polymeric material of
the deposit-core in certain embodiments can swell only in that
portion of the deposit not coated with the platform.
[0282] The support-platform can be obtained by compressing
prechosen polymeric materials onto the deposit-core, by immersing
the deposit-core in a solution of said polymeric materials in
normal organic solvents, or by spraying said solutions. Polymeric
materials usable for preparing the support-platform can be chosen
from the class comprising acrylates, celluloses and derivatives
such as ethylcellulose, cellulose acetate-propionate, polyethylenes
and methacrylates and copolymers of acrylic acid, polyvinylalcohols
and mixtures thereof. This platform can have a thickness of from
about 2 mm (for example, if applied by compression) to about 10
microns (for example, if applied by spraying or immersion)
including all values and ranges therebetween, and comprises from
about 10% to about 90% of the total surface of the system including
all values and ranges therebetween.
[0283] A factor in controlling the release of the bupropion
hydrobromide salt is the intensity and duration of the swelling
force developed by the swellable polymeric materials contained in
the deposit-core on contact with aqueous fluids. In this respect,
the energy for activating, executing and regulating the release of
the bupropion hydrobromide salt can be determined by the swelling
force developed in the deposit-core when this comes into contact
with water or with biological liquids. Said force has an intensity
and duration which can vary in relation to the type and quantity of
the polymeric materials used in formulating the deposit, and it
lies between limits having a maximum value which occurs in the case
of a deposit mainly containing the swellable polymer, and a minimum
value which occurs in the case of a deposit mainly containing the
gellable polymer. Said swellable polymer can be present in an
amount of from about 5% to about 80% by weight including all values
and ranges therebetween, and said gellable polymer present in an
amount of from about 10% to about 90% by weight including all
values and ranges therebetween, with respect to the mixture forming
the deposit-core.
[0284] A further control factor is the geometry of the
support-platform, which limits the swelling of the deposit and
directs the emission of material from it. Within the scope of these
embodiments it is possible to conceive many systems for the
controlled release of bupropion hydrobromide, which base their
operation on the swelling force and differ from each other by the
type of support-platform used.
[0285] In at least one other embodiment of the invention designed
to achieve zero order release of the bupropion hydrobromide salt,
the kinetics of drug release from a controlled release matrix is
governed by a combination of different polymers with different
swelling characteristics. More specifically, the bupropion
hydrobromide salt is first granulated with or encapsulated in a
less swellable polymer, such as a gum, to form a granule. This
granule is disposed in a matrix of a more swellable, erodible
polymer. The more swellable erodible polymer has a diffusion rate
coefficient which is greater than the diffusion rate coefficient of
the relatively less swellable polymer. Averaged over the entire
period of drug release, the diffusion rate for the more swellable
polymer is greater than the diffusion rate for the less swellable
polymer. It is this general difference in rates of diffusion
between the first and second polymers which controls the rate of
drug release and allows the system to approach zero order drug
delivery over the drug release period. In at least one embodiment,
pectin and HPMC are present as the more swellable polymers in
ratios of from about 2:7 to about 4:5 including all values and
ranges therebetween, and gelatin is present as the less swellable
polymer.
[0286] In at least one other embodiment of the invention there is
provided a controlled release matrix composition comprising
bupropion hydrobromide incorporated within a homogeneous matrix
including effective amounts of at least two polymers having
opposing wettability characteristics, wherein at least one polymer
is selected which demonstrates a stronger tendency towards
hydrophobicity and the other polymer(s) is selected which
demonstrates a stronger tendency towards hydrophilicity. In at
least one embodiment the polymer demonstrating a stronger tendency
towards hydrophobicity is ethylcellulose (EC) whereas the polymer
demonstrating a stronger tendency towards hydrophilicity is
hydroxyethylcellulose (HEC) and/or hydroxypropyl methylcellulose
(HPMC). The composition and device of the present invention can be
provided as a matrix and can be optionally encased in a coating
material which prevents the burst and/or food effect associated
with orally ingested medicaments and imparts gastrointestinal
"stealth" characteristics. In accordance with at least one
embodiment is a method for preparing a device for the controlled
release of the bupropion hydrobromide salt, the method comprising
blending bupropion hydrobromide with from about 5% to about 25% by
weight of hydrophilic polymer including all values and ranges
therebetween, and from about 1% to about 25% by weight of
hydrophobic polymer including all values and ranges therebetween,
adding suitable pharmaceutical excipients, surface active agents
and lubricants, granulating the mixture with solvents such as
isopropyl alcohol, drying the granular mixture, milling the dried
mixture, adding from about 5% to about 70% by weight of
ethylcellulose including all values and ranges therebetween, adding
a lubricant and optionally a glidant and compressing the granules
into matrices. The matrices are optionally encased in a
gastrointestinal encasement or a pharmaceutically acceptable film
coat.
[0287] In another embodiment of the present invention, a swellable
matrix dosage form is provided in which the bupropion hydrobromide
salt is dispersed in a polymeric matrix that is water-swellable
rather than merely hydrophilic, that has an erosion rate that is
substantially slower than its swelling rate, and that releases the
bupropion hydrobromide salt primarily by diffusion. The rate of
diffusion of the bupropion hydrobromide salt out of the swellable
matrix can be slowed by increasing the drug particle size, by the
choice of polymer used in the matrix, and/or by the choice of
molecular weight of the polymer. The swellable matrix is comprised
of a relatively high molecular weight polymer that swells upon
ingestion. In at least one embodiment the swellable matrix swells
upon ingestion to a size that is at least twice its unswelled
volume, and that promotes gastric retention during the fed mode.
Upon swelling, the swellable matrix can also convert over a
prolonged period of time from a glassy polymer to a polymer that is
rubbery in consistency, or from a crystalline polymer to a rubbery
one. The penetrating fluid then causes release of the bupropion
hydrobromide salt in a gradual and prolonged manner by the process
of solution diffusion, i.e., dissolution of the bupropion
hydrobromide salt in the penetrating fluid and diffusion of the
dissolved bupropion hydrobromide salt back out of the swellable
matrix. The swellable matrix itself is solid prior to
administration and, once administered, remains undissolved in
(i.e., is not eroded by) the gastric fluid for a period of time
sufficient to permit the majority of the bupropion hydrobromide
salt to be released by the solution diffusion process during the
fed mode. The rate-limiting factor in the release of the bupropion
hydrobromide salt from the swellable matrix is therefore controlled
diffusion of the bupropion hydrobromide salt from the swellable
matrix rather than erosion, dissolving or chemical decomposition of
the swellable matrix.
[0288] As such, the swelling of the polymeric matrix can achieve at
least the following objectives: (i) renders the matrix sufficiently
large to cause retention in the stomach during the fed mode; (ii)
localizes the release of the drug to the stomach and small
intestine so that the drug will have its full effect without
colonic degradation, inactivation, or loss of bioavailability;
(iii) retards the rate of diffusion of the drug long enough to
provide multi-hour, controlled delivery of the drug into the
stomach.
[0289] The bupropion hydrobromide salt in the swellable matrix can
be present in an effective amount of from about 0.1% to about 99%
by weight of the matrix including all values and ranges
therebetween. For example, in certain embodiments bupropion
hydrobromide is present in the swellable matrix in an amount of
from about 0.1% to about 90%, in other embodiments from about 5% to
about 90%, in still other embodiments from about 10% to about 80%,
and in even still other embodiments from about 25% to about 80% by
weight of the swellable matrix.
[0290] The water-swellable polymer forming the swellable matrix in
accordance with these embodiments of the present invention can be
any polymer that is non-toxic, that swells in a dimensionally
unrestricted manner upon imbibition of water, and that provides for
a modified release of the bupropion hydrobromide salt. Non-limiting
examples of polymers suitable for use in the swellable matrix
include cellulose polymers and their derivatives, such as for
example, hydroxyethylcellulose, hydroxypropylcellulose,
carboxymethylcellulose, and microcrystalline cellulose,
polysaccharides and their derivatives, polyalkylene oxides,
polyethylene glycols, chitosan, poly(vinyl alcohol), xanthan gum,
maleic anhydride copolymers, poly(vinyl pyrrolidone), starch and
starch-based polymers, poly (2-ethyl-2-oxazoline),
poly(ethyleneimine), polyurethane hydrogels, and crosslinked
polyacrylic acids and their derivatives, and mixtures thereof.
Further examples include copolymers of the polymers listed in the
preceding sentence, including block copolymers and grafted
polymers. Specific examples of copolymers include PLURONIC.RTM. and
TECTONIC.RTM., which are polyethylene oxide-polypropylene oxide
block copolymers.
[0291] The terms "cellulose" and "cellulosic", as used within this
section regarding the swellable matrix embodiments of the present
invention, can denote a linear polymer of anhydroglucose.
Non-limiting examples of cellulosic polymers include
alkyl-substituted cellulosic polymers that ultimately dissolve in
the gastrointestinal (GI) tract in a predictably delayed manner. In
certain embodiments the alkyl-substituted cellulose derivatives are
those substituted with alkyl groups of 1 to 3 carbon atoms each.
Non-limiting examples include methylcellulose,
hydroxymethyl-cellulose, hydroxyethylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulose,
carboxymethylcellulose, and mixtures thereof. In terms of their
viscosities, one class of alkyl-substituted celluloses includes
those whose viscosity is within the range of about 100 to about
110,000 centipoises as a 2% aqueous solution at 20.degree. C.
Another class includes those whose viscosity is within the range of
about 1,000 to about 4,000 centipoises as a 1% aqueous solution at
20.degree. C. In certain embodiments the alkyl-substituted
celluloses are hydroxyethylcellulose and
hydroxypropylmethylcellulose. In at least one embodiment the
hydroxyethylcellulose is NATRASOL.RTM. 250HX NF.
[0292] Polyalkylene oxides that can be used in certain embodiments
of the swellable matrices include those having the properties
described above for alkyl-substituted cellulose polymers. In at
least one embodiment the polyalkylene oxide is poly(ethylene
oxide), which term is used herein to denote a linear polymer of
unsubstituted ethylene oxide. In at least one embodiment the
poly(ethylene oxide) polymers have molecular weights of about
4,000,000 and higher. For example, in certain embodiment the
poly(ethylene oxide) polymers have molecular weights within the
range of about 4,500,000 to about 10,000,000 including all values
and ranges therebetween, and in other embodiments have molecular
weights within the range of about 5,000,000 to about 8,000,000. In
certain embodiments the poly(ethylene oxide)s are those with a
weight-average molecular weight within the range of about
1.times.105 to about 1.times.107, and in other embodiments within
the range of about 9.times.105 to about 8.times.106. Poly(ethylene
oxide)s are often characterized by their viscosity in solution. For
example, in certain embodiments the poly(ethylene oxide)s have a
viscosity range of about 50 to about 2,000,000 centipoises for a 2%
aqueous solution at 20.degree. C. In at least one embodiment the
poly(ethylene oxide) is one or more of POLYOX.RTM. NF, grade WSR
Coagulant, molecular weight 5 million, and grade WSR 303, molecular
weight 7 million. Mixtures thereof are operable.
[0293] Polysaccharide gums, both natural and modified
(semi-synthetic) can be used in the swellable matrix embodiments of
the present invention. Non-limiting examples include dextran,
xanthan gum, gellan gum, welan gum, rhamsan gum, and mixtures
thereof. In at least one embodiment the polysaccharide gum is
xanthan gum.
[0294] Crosslinked polyacrylic acids that can be used in the
swellable matrices of the present invention include those whose
properties are the same as those described above for
alkyl-substituted cellulose and polyalkylene oxide polymers. In
certain embodiments the crosslinked polyacrylic acids are those
with a viscosity ranging from about 4,000 to about 40,000
centipoises for a 1% aqueous solution at 25.degree. C. Non-limiting
examples of suitable crosslinked polyacrylic acids include
CARBOPOL.RTM. NF grades 971P, 974P and 934P. Further examples of
suitable crosslinked polyacrylic acids include polymers known as
WATER LOCK.RTM., which are starch/acrylates/acrylamide
copolymers.
[0295] The hydrophilicity and water swellability of these polymers
can cause the drug-containing swellable matrices to swell in size
in the gastric cavity due to ingress of water in order to achieve a
size that can be retained in the stomach when introduced during the
fed mode. These qualities also cause the swellable matrices to
become slippery, which provides resistance to peristalsis and
further promotes their retention in the stomach. The release rate
of drug from the swellable matrix is primarily dependent upon the
rate of water imbibition and the rate at which the drug dissolves
and diffuses from the swollen polymer, which in turn is related to
the drug concentration in the swellable matrix. Also, because these
polymers dissolve very slowly in gastric fluid, the swellable
matrix maintains its physical integrity over at least a substantial
period of time, for example in many cases at least about 90% and in
certain embodiments over about 100% of the dosing period. The
particles will then slowly dissolve or decompose. Complete
dissolution or decomposition may not occur until about 24 hours or
more after the intended dosing period ceases, although in most
cases, complete dissolution or decomposition will occur within
about 10 to about 24 hours after the dosing period.
[0296] The amount of polymer relative to the drug can vary,
depending on the drug release rate desired and on the polymer, its
molecular weight, and excipients that may be present in the
formulation. The amount of polymer will typically be sufficient to
retain at least about 40% of the drug within the swellable matrix
about one hour after ingestion (or immersion in the gastric fluid).
In certain embodiments, the amount of polymer is such that at least
about 50% of the drug remains in the matrix about one hour after
ingestion; in other embodiments at least about 60%, and in still
other embodiments at least about 80% of the drug remains in the
swellable matrix about one hour after ingestion. In certain
embodiments the drug will be substantially all released from the
swellable matrix within about 10 hours; and in other embodiments
within about 8 hours, after ingestion, and the polymeric matrix
will remain substantially intact until all of the drug is released.
In other embodiments the amount of polymer will be such that after
about 2 hours no more than about 40% is released; after about 4
hours from about 40% to about 75% is released; after about 8 hours
at least about 75% is released, and after about 16 hours at least
about 85% is released. The term "substantially intact" is used
herein to denote a polymeric matrix in which the polymer portion
substantially retains its size and shape without deterioration due
to becoming solubilized in the gastric fluid or due to breakage
into fragments or small particles.
[0297] In other exemplary embodiments the swellable matrix after
about 2 hours will release no more than about 40% of the bupropion
hydrobromide, after about 4 hours from about 40% to about 75%,
after about 8 hours at least about 75%, and after about 16 hours at
least about 85% of the bupropion hydrobromide.
[0298] The water-swellable polymers of the swellable matrices can
be used individually or in combination. Certain combinations will
often provide a more controlled release of the drug than their
components when used individually. Examples include cellulose-based
polymers combined with gums, such as hydroxyethyl cellulose or
hydroxypropyl cellulose combined with xanthan gum. Another example
is poly(ethylene oxide) combined with xanthan gum.
[0299] The benefits of certain embodiments of this invention can be
achieved over a wide range of drug loadings and polymer levels,
with the weight ratio of drug to polymer ranging in general from
about 0.01:99.99 to about 80:20, including all values and ranges
therebetween. For example, in certain embodiments the drug loadings
(expressed in terms of the weight percent of drug relative to total
of drug and polymer) are within the range of about 15% to about 80%
including all values and ranges therebetween; in other embodiments
within the range of about 30% to about 80% including all values and
ranges therebetween; and in still other embodiments within the
range of about 30% to about 70% including all values and ranges
therebetween. In at least one embodiment the drug loading is within
the range of about 0.01% to about 80% including all values and
ranges therebetween, and in at least one other embodiment from
about 15% to about 80% including all values and ranges
therebetween. In at least one embodiment the weight ratio of
bupropion hydrobromide to polymer in the swellable matrix is from
about 15:85 to about 80:20 including all values and ranges
therebetween.
[0300] The formulations of the swellable matrices of the present
invention can assume the form of microparticles, tablets, or
microparticles retained in capsules. In at least one embodiment the
formulation comprises microparticles consolidated into a packed
mass for ingestion, even though the packed mass will separate into
individual particles after ingestion. Conventional methods can be
used for consolidating the microparticles in this manner. For
example, the microparticles can be placed in gelatin capsules known
in the art as "hard-filled" capsules and "soft-elastic" capsules.
The compositions of these capsules and procedures for filling them
are known among those skilled in drug formulations and manufacture.
The encapsulating material should be highly soluble so that the
particles are freed and rapidly dispersed in the stomach after the
capsule is ingested.
[0301] In certain embodiments of the swellable matrices of the
present invention, the formulation contains an additional amount of
bupropion hydrobromide salt or other drug applied as a quickly
dissolving coating on the outside of the microparticle or tablet.
This coating is referred to as a "loading dose" and it is included
for immediate release into the recipient's bloodstream upon
ingestion of the formulation without first undergoing the diffusion
process that the remainder of the drug in the formulation must pass
before it is released. The "loading dose" can be high enough to
quickly raise the blood concentration of the drug but not high
enough to produce the transient overdosing that is characteristic
of immediate release dosage forms that are not formulated in
accordance with this invention.
[0302] In at least one embodiment of the swellable matrices of the
present invention, the dosage form is a size 0 gelatin capsule
containing either two or three pellets of drug-impregnated polymer.
For two-pellet capsules, the pellets are cylindrically shaped,
about 6.6 mm or about 6.7 mm in diameter (or more generally, from
about 6.5 mm to about 7 mm in diameter including all values and
ranges therebetween) and about 9.5 mm or about 10.25 mm in length
(or more generally, from about 9 mm to about 12 mm in length
including all values and ranges therebetween). For three-pellet
capsules, the pellets are again cylindrically shaped, about 6.6 mm
in diameter and about 7 mm in length. For a size 00 gelatin capsule
with two pellets, the pellets are cylindrical, about 7.5 mm in
diameter and about 11.25 mm in length. For a size 00 gelatin
capsule with three pellets, the pellets are cylindrical, about 7.5
mm in diameter and about 7.5 mm in length. In at least one other
embodiment, the dosage form is a single, elongated tablet, with
dimensions of about 18 mm to about 22 mm in length including all
values and ranges therebetween, from about 6.5 mm to about 10 mm in
width including all values and ranges therebetween, and from about
5 mm to about 7.5 mm in height including all values and ranges
therebetween. In at least one other embodiment, the dosage form is
a single, elongated tablet, with dimensions of from about 18 mm to
about 22 mm in length including all values and ranges therebetween,
from about 6.5 mm to about 7.8 mm in width including all values and
ranges therebetween, and from about 6.2 mm to about 7.5 mm in
height including all values and ranges therebetween. In at least
one embodiment the dimensions are about 20 mm in length, about 6.7
mm in width, and about 6.4 mm in height. These are merely examples;
the shapes and sizes can be varied considerably.
[0303] In certain embodiments the bupropion hydrobromide-containing
matrix can be made according to any one of the methods described
herein.
[0304] The particulate drug/polymer mixture or drug-impregnated
swellable polymer matrix of certain embodiments can be prepared by
various conventional mixing, comminution and fabrication techniques
readily apparent to those skilled in the chemistry of drug
formulations. Examples of such techniques include: (1) Direct
compression, using appropriate punches and dies, such as those
available from Elizabeth Carbide Die Company, Inc., McKeesport,
Pa., USA; the punches and dies are fitted to a suitable rotary
tableting press, such as the Elizabeth-Hata single-sided Hata Auto
Press machine, with either 15, 18 or 22 stations, and available
from Elizabeth-Hata International, Inc., North Huntington, Pa.,
USA; (2) Injection or compression molding using suitable molds
fitted to a compression unit, such as those available from
Cincinnati Milacron, Plastics Machinery Division, Batavia, Ohio,
USA.; (3) Granulation followed by compression; and (4) Extrusion in
the form of a paste, into a mold or to an extrudate to be cut into
lengths.
[0305] In regards to the swellable matrices of certain embodiments
of the present invention, when microparticles are made by direct
compression, the addition of lubricants can be helpful and, in
certain embodiments, helpful to promote powder flow and to prevent
capping of the microparticle (breaking off of a portion of the
particle) when the pressure is relieved. Non-limiting examples of
suitable lubricants include magnesium stearate (in a concentration
of from about 0.25% to about 3% by weight including all values and
ranges therebetween, and in certain embodiments less than about 1%
by weight, in the powder mix), and hydrogenated vegetable oil (in
certain embodiments hydrogenated and refined triglycerides of
stearic and palmitic acids at from about 1% to about 5% by weight
including all values and ranges therebetween, for example in at
least one embodiment at about 2% by weight). Additional excipients
can be added to enhance powder flowability and reduce
adherence.
[0306] Certain embodiments of the swellable matrices of the present
invention can find utility when administered to a subject who is in
the digestive state (also referred to as the postprandial or "fed"
mode). The postprandial mode is distinguishable from the
interdigestive (or "fasting") mode by their distinct patterns of
gastroduodenal motor activity, which determine the gastric
retention or gastric transit time of the stomach contents.
[0307] The controlled release matrices of certain embodiments of
the present invention can be manufactured by methods known in the
art. An example of a method of manufacturing controlled release
matrices is melt-extrusion of a mixture containing the bupropion
salt, hydrophobic polymer(s), hydrophilic polymer(s), and
optionally a binder, plasticizer, and other excipient(s) as
described above. Other examples of methods of manufacturing
controlled release matrices include wet granulation, dry
granulation (e.g. slugging, roller compaction), direct compression,
melt granulation, and rotary granulation.
[0308] Additionally, controlled release particles which can be
compressed or placed in capsules can be produced by combining the
bupropion hydrobromide salt and a hydrophobic fusible component
and/or a diluent, optionally with a release modifying agent
including a water soluble fusible material or a particulate soluble
or insoluble organic or inorganic material. Examples of potential
hydrophobic fusible components include hydrophobic materials such
as natural or synthetic waxes or oils (e.g., hydrogenated vegetable
oil, hydrogenated castor oil, microcrystalline wax, Beeswax,
carnauba wax and glyceyl monostearate). In at least one embodiment
the hydrophobic fusible component has a melting point from about
35.degree. C. to about 140.degree. C. including all values and
ranges therebetween. Examples of release modifying agents include
polyethylene glycol and particulate materials such as dicalcium
phosphate and lactose.
[0309] In certain embodiments, controlled release matrices can be
produced by mechanically working a mixture of bupropion
hydrobromide salt, a hydrophobic fusible component, and optionally
a release component including a water soluble fusible material or a
particulate soluble or insoluble organic or inorganic material
under mixing conditions that yield aglomerates, breaking down the
agglomerates to produce controlled release seeds having desired
release properties; and optionally adding more carrier or diluent
and repeating the mixing steps until controlled release seeds
having desired release properties are obtained. These particles
also can be size separated (e.g. by sieving and encapsulated in
capsules or compressed into a matrix).
[0310] The amount of the hydrophobic fusible material used in the
foregoing methods can range from about 10% to about 90% by weight
including all values and ranges therebetween.
[0311] Mixers useful in such methods are known and include
conventional high-speed mixers with stainless steel interiors. For
example, a mixture can be processed until a bed temperature of
about 40.degree. C. or higher is realized, and the mixture achieves
a cohesive granular texture comprising desired particle sizes.
[0312] As noted if the mixture contains agglomerates, they can be
broken down using conventional methods to produce a mixture of
powder and particles of the desired size which, can be
size-separated using a sieve, screen or mesh of the appropriate
size. This material can be returned to a high-speed mixer and
further processed as desired until the hydrophobic fusible
materials begin to soften/melt, and optionally additional
hydrophobic material can be added and mixing continued until
particles having a desired size range are obtained. Still further,
particles containing bupropion hydrobromide salt can be produced by
melt processing as known in the art and combined into capsules or
compressed into matrices.
[0313] These particles can be combined with one or more excipients
such as diluents, lubricants, binding agents, flow aids,
disintegrating agents, surface acting agents, water soluble
materials, colorants, and the like.
[0314] In addition, the controlled release matrices can optionally
be coated with one or more functional or non-functional coatings
using well-known coating methods. Examples of coatings can include
the XL controlled release coat and the EA matrix coating described
herein, which can further control the release of the bupropion
hydrobromide salt and/or other drug.
[0315] In at least one embodiment, the controlled release matrices
can each be coated with at least one taste-masking coating. The
taste-masking coating can mask the taste of the bupropion
hydrobromide salt in the matrices. In at least one embodiment the
taste-masking coating formulations contain polymeric ingredients.
It is contemplated that other excipients consistent with the
objects of the present invention can also be used in the
taste-masking coating.
[0316] In at least one embodiment of the matrix dosage form, the
taste-masking coating comprises a polymer such as ethylcellulose,
which can be used as a dry polymer (such as ETHOCEL) solubilised in
organic solvent prior to use, or as an aqueous dispersion. One
commercially-available aqueous dispersion of ethylcellulose is
AQUACOAT.RTM.. AQUACOAT.RTM. can be prepared by dissolving the
ethylcellulose in a water-immiscible organic solvent and then
emulsifying the same in water in the presence of a surfactant and a
stabilizer. After homogenization to generate submicron droplets,
the organic solvent is evaporated under vacuum to form a
pseudolatex. The plasticizer is not incorporated in the pseudolatex
during the manufacturing phase. Thus, prior to using the same as a
coating, the Aquacoat is intimately mixed with a suitable
plasticizer prior to use. Another aqueous dispersion of
ethylcellulose is commercially available as SURELEASE.RTM.. This
product can be prepared by incorporating plasticizer into the
dispersion during the manufacturing process. A hot melt of a
polymer, plasticizer (e.g. dibutyl sebacate), and stabilizer (e.g.
oleic acid) is prepared as a homogeneous mixture, which is then
diluted with an alkaline solution to obtain an aqueous dispersion
which can be applied directly onto substrates.
[0317] In other embodiments of the matrix dosage form,
polymethacrylate acrylic polymers can be employed as taste masking
polymers. In at least one embodiment, the taste masking coating is
an acrylic resin lacquer used in the form of an aqueous dispersion,
such as EUDRAGIT.RTM. or KOLLICOAT.RTM.. In further embodiments,
the acrylic coating comprises a mixture of two acrylic resin
lacquers EUDRAGIT.RTM. RL and EUDRAGIT.RTM. RS, respectively.
EUDRAGIT.RTM. RL and EUDRAGIT.RTM. RS are copolymers of acrylic and
methacrylic esters with a low content of quaternary ammonium
groups, the molar ratio of ammonium groups to the remaining neutral
(meth)acrylic esters being 1:20 in EUDRAGIT.RTM. RL and 1:40 in
EUDRAGIT.RTM. RS. The mean molecular weight is 150,000. The code
designations RL (high permeability) and RS (low permeability) refer
to the permeability properties of these agents. EUDRAGIT.RTM. RL/RS
mixtures are insoluble in water and in digestive fluids. However,
coatings formed from the same are swellable and permeable in
aqueous solutions and digestive fluids. EUDRAGIT.RTM. RL/RS
dispersions or solutions of the certain embodiments can be mixed
together in any desired ratio in order to ultimately obtain a taste
masking coating having a desirable drug dissolution profile.
Controlled release formulations of certain embodiments can be
obtained, for example, from a retardant coating derived from 100%
EUDRAGIT.RTM. RL; 50% EUDRAGIT.RTM. RL with 50% EUDRAGIT.RTM. RS;
and 10% EUDRAGIT.RTM. RL with 90% EUDRAGIT.RTM. RS.
[0318] In other embodiments of the matrix dosage form, the taste
masking polymer can be an acrylic polymer which is cationic in
character based on dimethylaminoethyl methacrylate and neutral
methacrylic acid esters (such as EUDRAGIT.RTM. E). The hydrophobic
acrylic polymer coatings of the present invention can further
include a neutral copolymer based on poly (meth)acrylates, such as
EUDRAGIT.RTM. NE. EUDRAGIT.RTM. NE 30D lacquer films are insoluble
in water and digestive fluids, but permeable and swellable.
[0319] In other embodiments of the matrix dosage form, the taste
masking polymer is a dispersion of poly (ethylacrylate, methyl
methacrylate) 2:1 (KOLLICOAT.RTM. EMM 30 D).
[0320] In other embodiments of the matrix dosage form, the taste
masking polymer can be a polyvinyl acetate stabilized with
polyvinylpyrrolidone and sodium lauryl sulfate such as
KOLLICOAT.RTM. SR30D.
[0321] Other taste masking polymers that can be used in the matrix
dosage forms include hydroxypropylcellulose (HPC);
hydroxypropylmethylcellulose (HPMC); hydroxyethylcellulose;
gelatin; gelatin/acacia; gelatin/acacia/vinvylmethylether maleic
anhydride; gelatin/acacia/ethylenemaleic anhydride; carboxymethyl
cellulose; polyvinvylalcohol; nitrocellulose;
polyvinylalcohol-polyethylene glycol graft-copolymers; shellac; wax
and mixtures thereof.
[0322] The taste-masking coatings can be applied to the matrices
from one or more organic or aqueous solvent solutions or
suspensions. In at least one embodiment of the matrix dosage forms
the organic solvents that can be used to apply the taste-masking
coatings include one or more of acetone, lower alcohols such as
ethanol, isopropanol and alcohol/water mixtures, chlorinated
hydrocarbons, and the like. Devices used to coat the matrices of
certain embodiments with a taste-masking coating include those
conventionally used in pharmaceutical processing, such as fluidized
bed coating devices. The controlled release coatings applied to the
matrices can contain ingredients other than the cellulosic
polymers. One or more colorants, flavorants, sweeteners, can also
be used in the taste-masking coating.
[0323] In some embodiments of the matrix dosage forms, a pore
former can be included into the taste masking coat in order to
influence the rate of release of bupropion hydrobromide from the
matrix. In other embodiments, a pore former is not included in the
taste masking coat. The pore formers can be inorganic or organic,
and may be particulate in nature and include materials that can be
dissolved, extracted or leached from the coating in the environment
of use. Upon exposure to fluids in the environment of use, the
pore-formers can for example be dissolved, and channels and pores
are formed that fill with the environmental fluid.
[0324] For example, the pore-formers of certain embodiments of the
matrix dosage forms can comprise one or more water-soluble
hydrophilic polymers in order to modify the release characteristics
of the formulation. Examples of suitable hydrophilic polymers that
can be used as pore-formers include hydroxypropylmethylcellulose,
cellulose ethers and protein-derived materials of these polymers,
the cellulose ethers, such as hydroxyalkylcelluloses,
carboxyalkylcelluloses and mixtures thereof. Also, synthetic
water-soluble polymers can be used, examples of which include
polyvinylpyrrolidone, cross-linked polyvinyl-pyrrolidone,
polyethylene oxide, water-soluble polydextrose, saccharides and
polysaccharides, such as pullulan, dextran, sucrose, glucose,
fructose, mannitol, lactose, mannose, galactose, sorbitol and
mixtures thereof. In at least one embodiment, the hydrophilic
polymer comprises hydroxypropyl-methylcellulose.
[0325] Other non-limiting examples of pore-formers that can be used
in the taste masking coat include alkali metal salts such as
lithium carbonate, sodium chloride, sodium bromide, potassium
chloride, potassium sulfate, potassium phosphate, sodium acetate,
sodium citrate and mixtures thereof. The pore-forming solids can
also be polymers which are soluble in the environment of use, such
as CARBOWAX.TM. and CARBOPOL.TM.. In addition, the pore-formers
embrace diols, polyols, polyhydric alcohols, polyalkylene glycols,
polyglycols, poly(a-w)alkylenediols and mixtures thereof. Other
pore-formers which can be useful in the formulations of certain
embodiments of the present invention include starch, modified
starch, and starch derivatives, gums, including but not limited to
xanthan gum, alginic acid, other alginates, benitoniite, veegum,
agar, guar, locust bean gum, gum arabic, quince psyllium, flax
seed, okra gum, arabinoglactin, pectin, tragacanth, scleroglucan,
dextran, amylose, amylopectin, dextrin, etc., cross-linked
polyvinylpyrrolidone, ion-exchange resins, such as potassium
polymethacrylate, carrageenan, kappa-carrageenan,
lambda-carrageenan, gum karaya, biosynthetic gum, and mixtures
thereof. Other pore-formers include materials useful for making
microporous lamina in the environment of use, such as
polycarbonates comprised of linear polyesters of carbonic acid in
which carbonate groups reoccur in the polymer chain, microporous
materials such as bisphenol, a microporous poly(vinylchloride),
micro-porous polyamides, microporous modacrylic copolymers,
microporous styrene-acrylic and its copolymers, porous
polysulfones, halogenated poly(vinylidene), polychloroethers,
acetal polymers, polyesters prepared by esterification of a
dicarboxylic acid or anhydride with an alkylene polyol,
poly(alkylenesulfides), phenolics, polyesters, asymmetric porous
polymers, cross-linked olefin polymers, hydrophilic microporous
hiomopolymers, copolymers or interpolymers having a reduced bulk
density, and other similar materials, poly(urethane), cross-linked
chain-extended poly(urethane), poly(imides), poly(benzimidazoles),
collodion, regenerated proteins, semi-solid cross-linked
poly(vinylpyrrolidone), and mixtures thereof.
[0326] In general, the amount of pore-former included in the taste
masking coatings of certain embodiments of the matrix dosage forms
can be from about 0.1% to about 80%, by weight including all values
and ranges therebetween, relative to the combined weight of polymer
and pore-former. The percentage of pore former as it relates to the
dry weight of the taste-masking polymer, can have an influence on
the drug release properties of the coated matrix. In at least one
embodiment that uses water soluble pore formers such as
hydroxypropylmethylcellulose, a taste masking polymer:pore former
dry weight ratio of from about 10:1 to about 1:1 including all
values and ranges therebetween can be present. In certain
embodiments the taste masking polymer:pore former dry weight ratio
is from about 8:1 to about 1.5:1 including all values and ranges
therebetween; and in other embodiments from about 6:1 to about 2:1
including all values and ranges therebetween. In at least one
embodiment using EUDRAGIT.RTM. NE30D as the taste masking polymer
and a hydroxypropylmethylcellulose (approx 5 cps viscosity (in a 2%
aqueous solution)) such as METHOCEL.RTM. E5, PHARMACOAT.RTM. 606G
as the water soluble pore former, a taste masking polymer:pore
former dry weight ratio of about 2:1 is present.
[0327] Colorants that can be used in the taste-masking coating of
certain embodiments of the matrix dosage forms include food, drug
and cosmetic colors (FD&C), drug and cosmetic colors (D&C)
or external drug and cosmetic colors (Ext. D&C). These colors
are dyes, lakes, and certain natural and derived colorants. Useful
lakes include dyes absorbed on aluminum hydroxide or other suitable
carriers.
[0328] Flavorants that can be used in the taste-masking coating of
certain embodiments of the matrix dosage forms include natural and
synthetic flavoring liquids. An illustrative list of such
flavorants includes volatile oils, synthetic flavor oils, flavoring
aromatics, oils, liquids, oleoresins and extracts derived from
plants, leaves, flowers, fruits, stems and combinations thereof. A
non-limiting representative list of these includes citric oils,
such as lemon, orange, grape, lime and grapefruit, and fruit
essences, including apple, pear, peach, grape, strawberry,
raspberry, cherry, plum, pineapple, apricot, or other fruit
flavors. Other useful flavorants include aldehydes and esters, such
as benzaldehyde (cherry, almond); citral, i.e., alpha-citral
(lemon, lime); neral, i.e., beta-citral (lemon, lime); decanal
(orange, lemon); aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus
fruits); aldehyde C-12 (citrus fruits); tolyl aldehyde (cherry,
almond); 2,6-dimethyloctanal (green fruit); 2-dodenal (citrus
mandarin); and mixtures thereof.
[0329] Sweeteners that can be used in the taste-masking coating of
certain embodiments of the matrix dosage forms include glucose
(corn syrup), dextrose, invert sugar, fructose, and mixtures
thereof (when not used as a carrier); saccharin and its various
salts, such as sodium salt; dipeptide sweeteners such as aspartame;
dihydrochalcone compounds, glycyrrhizin; Steva Rebaudiana
(Stevioside); chloro derivatives or sucrose such as sucralose; and
sugar alcohols such as sorbitol, mannitol, xylitol, and the like.
Also contemplated are hydrogenated starch hydrolysates and the
synthetic sweeteners such as
3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-1-2,2-dioxide,
particularly the potassium salt (acesulfame-K), and sodium and
calcium salts thereof. The sweeteners can be used alone or in any
combination thereof.
[0330] The matrix taste masking coat can also include one or more
pharmaceutically acceptable excipients such as lubricants,
emulsifiers, anti-foaming agents, plasticizers, solvents and the
like.
[0331] Lubricants can be included to help reduce friction of coated
matrices during manufacturing. The lubricants that can be used in
the taste masking coat of certain embodiments of the present
invention include but are not limited to adipic acid, magnesium
stearate, calcium stearate, zinc stearate, calcium silicate,
magnesium silicate, hydrogenated vegetable oils, sodium chloride,
sterotex, polyoxyethylene, glyceryl monostearate, talc,
polyethylene glycol, sodium benzoate, sodium lauryl sulfate,
magnesium lauryl sulfate, sodium stearyl fumarate, light mineral
oil, waxy fatty acid esters such as glyceryl behenate, (e.g.
COMPRITOL.TM.), STEAR-O-WET.TM., MYVATEX.TM. TL and mixtures
thereof. In at least one embodiment, the lubricant is selected from
magnesium stearate, talc and a mixture thereof. The lubricant can
be present in an amount of from about 1% to about 100% by weight of
the polymer dry weight in the taste masking coat including all
values and ranges therebetween. For example, in certain embodiments
wherein the taste masking polymer is EUDRAGIT.RTM. NE30D or
EUDRAGIT.RTM. NE40D together with a hydrophilic pore former, the
lubricant is present in an amount of from about 1% to about 30% by
weight of the polymer dry weight including all values and ranges
therebetween; in other embodiments from about 2% to about 20%
including all values and ranges therebetween; and in still other
embodiments at about 10% by weight of the matrix taste masking coat
dry weight. In another embodiment where the taste masking polymer
is ethylcellulose (ETHOCEL.TM. PR100, PR45, PR20, PR10 or PR7
polymer, or a mixture thereof), the lubricant can be present in an
amount of from about 10% to about 100% by weight of the matrix
taste-masking coat dry weight including all values and ranges
therebetween; in another embodiment from about 20% to about 80%
including all values and ranges therebetween; and in still another
embodiments at about 50% by weight of the matrix taste masking coat
dry weight. In other embodiments, the taste masking coat does not
include a pore former.
[0332] Emulsifying agent(s) (also called emulsifiers or emulgents)
can be included in the matrix taste masking coat to facilitate
actual emulsification during manufacture of the coat, and also to
ensure emulsion stability during the shelf-life of the product.
Emulsifying agents useful for the matrix taste masking coat
composition of certain embodiments include, but are not limited to
naturally occurring materials and their semi synthetic derivatives,
such as the polysaccharides, as well as glycerol esters, cellulose
ethers, sorbitan esters (e.g. sorbitan monooleate or SPAN.TM. 80),
and polysorbates (e.g. TWEEN.TM. 80). Combinations of emulsifying
agents are operable. In at least one embodiment, the emulsifying
agent is TWEEN.TM. 80. The emulsifying agent(s) can be present in
an amount of from about 0.01% to about 5% by weight of the matrix
taste masking polymer dry weight including all values and ranges
therebetween. For example, in certain embodiments the emulsifying
agent is present in an amount of from about 0.05% to about 3%
including all values and ranges therebetween; in other embodiments
from about 0.08% to about 1.5% including all values and ranges
therebetween, and in still other embodiments at about 0.1% by
weight of the matrix taste masking polymer dry weight.
[0333] Anti-foaming agent(s) can be included in the matrix taste
masking coat to reduce frothing or foaming during manufacture of
the coat. Anti-foaming agents useful for the coat composition
include, but are not limited to simethicone, polyglycol, silicon
oil, and mixtures thereof. In at least one embodiment the
anti-foaming agent is Simethicone C. The anti-foaming agent can be
present in an amount of from about 0.1% to about 10% of the matrix
taste masking coat weight including all values and ranges
therebetween. For example, in certain embodiments the anti-foaming
agent is present in an amount of from about 0.2% to about 5%
including all values and ranges therebetween; in other embodiments
from about 0.3% to about 1% including all values and ranges
therebetween, and in still other embodiments at about 0.6% by
weight of the matrix taste masking polymer dry weight.
[0334] Plasticizer(s) can be included in the matrix taste masking
coat to provide increased flexibility and durability during
manufacturing. Plasticizers that can be used in the matrix taste
masking coat of certain embodiments include acetylated
monoglycerides; acetyltributyl citrate, butyl phthalyl butyl
glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate;
ethyl phthalyl ethyl glycolate; glycerin; propylene glycol;
triacetin; tripropioin; diacetin; dibutyl phthalate; acetyl
monoglyceride; acetyltriethyl citrate, polyethylene glycols; castor
oil; rape seed oil, olive oil, sesame oil, triethyl citrate;
polyhydric alcohols, glycerol, glycerin sorbitol, acetate esters,
gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate,
dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate,
butyl octyl phthalate, dioctyl azelate, epoxidized tallate,
triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl
phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl
phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate,
di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl
azelate, dibutyl sebacate, diethyloxalate, diethylmalate,
diethylfumerate, dibutylsuccinate, diethylmalonate,
dibutylphthalate, dibutylsebacate, glyceroltributyrate, and
mixtures thereof. The plasticizer can be present in an amount of
from about 1% to about 80% of the taste masking polymer dry weight
including all values and ranges therebetween. For example, in
certain embodiments the plasticizer is present in an amount of from
about 5% to about 50% including all values and ranges therebetween,
in other embodiments from about 10% to about 40% including all
values and ranges therebetween, and in still other embodiments at
about 20% of the taste masking polymer dry weight.
[0335] In some embodiments mixtures of plasticizers are provided,
e.g., a mixture of PEG 4000 and Dibutyl Sebacate (DBS). For
example, in a 174 mg bupropion hydrobromide tablet, PEG4000 is
present in an amount of 1.6% by weight of the total formulation and
DBS is present in an amount of 0.8% by weight of the total
formulation, in a 348 mg bupropion hydrobromide tablet, PEG4000 is
present in an amount of 0.9% by weight of the total formulation and
DBS is present in an amount of 0.4% by weight of the total
formulation, and in a 522 mg bupropion hydrobromide tablet, PEG4000
is present in an amount of 0.9% by weight of the total formulation
and DBS is present in an amount of 0.4% by weight of the total
formulation,
[0336] The taste-masking coating can be present in an amount of
from about 1% to about 90% by weight of the matrix including all
values and ranges therebetween, depending upon the choice of
polymer, the ratio of polymer:pore former, and the total surface
area of the matrix formulation. Since a certain thickness of taste
masking coating has to be achieved in order to achieve effective
taste masking, the amount of taste masking polymer coating used
during manufacture is related to the total surface area of the
batch of uncoated matrices that requires a coating. For example,
the taste masking polymer surface area coverage can range from
about 0.5 mg/cm2 to about 20 mg/cm2 including all values and ranges
therebetween. For example, in certain embodiments the surface area
coverage of the taste masking polymer is from about 0.6 mg/cm2 to
about 10 mg/cm2 including all values and ranges therebetween, and
in other embodiments is from about 1 mg/cm2 to about 5 mg/cm2
including all values and ranges therebetween. In at least one
embodiment of the invention, EUDRAGIT.RTM. E is employed as the
taste masking polymer at a surface area coverage of about 4
mg/cm2.
[0337] In the absence of an accurate determination of total surface
area of a matrix, the amount of taste masking polymer to be applied
can be expressed as a percentage of the uncoated matrix. For
example, in certain embodiments the taste-masking coating is
present in an amount of from about 5% to about 60% including all
values and ranges therebetween; in other embodiments from about 10%
to about 40% including all values and ranges therebetween; and in
still other embodiments from about 15% to about 35% by weight of
the matrix including all values and ranges therebetween. In at
least one embodiment the taste-masking coating is present in an
amount of about 30% by weight of the matrix.
[0338] Prophetic examples of matrix tablet formulations are
described below. It should be understood that these examples are
intended to be exemplary and that the specific constituents,
amounts thereof, and formulation methods may be varied therefrom in
order to achieve different release characteristics:
[0339] In at least one embodiment, the controlled matrices
comprise:
TABLE-US-00006 Bupropion HBr about 30.0% by weight of the matrix
Hydroxypropylmethylcellulose E50 about 10.0% by weight of the
matrix Hydroxypropylmethylcellulose about 30.0% by weight of the
matrix K15M Calcium phosphate dehydrate about 9.5% by weight of the
matrix ATMUL .TM. 84S about 20.0% by weight of the matrix
(mono/di/tri glycerides) Magnesium stearate about 0.5% by weight of
the matrix
[0340] Preparation of the matrix formulation can be as follows:
Combine the drug, a portion of each HPMC, calcium phosphate and
Atmul 84S in a planetary mixer and dry mix for 15 minutes. Add a
solution of the remainder of the HPMC in water to the mixer while
mixing, until a wet mass is obtained. Pass the wet material through
a screen to make the resultant granules of uniform size (to achieve
uniform drying) and dry in an oven at about 40.degree. C. for about
24 hours. Mill the dried granules through a Fitzpatrick Mill,
knives forward, and collect the material in a mixer. Add the
magnesium stearate and mix for about 5 minutes. The resultant
mixture is tableted on a suitable tablet press.
[0341] In at least one embodiment, the controlled release matrices
comprise a deposit-core and support-platform. Preparation of the
deposit-core can be as follows: Deposit-cores can be prepared using
the following materials in the stated quantities:
TABLE-US-00007 Bupropion HBr about 45.0 g
hydroxypropylmethylcellulose (METHOCEL .RTM. K about 35.0 g
100M-Colorcon) mannitol about 10.0 g ethylcellulose (high
viscosity-BDH) about 3.75 g 3.75 g magnesium stearate about 1.0 g
5:1 ethanol-chloroform mixture about 75.0 ml
[0342] The bupropion hydrobromide is mixed intimately with the
mannitol and hydroxypropylmethylcellulose in a suitable mixer. The
solution of ethylcellulose in ethanol-chloroform is prepared
separately, and is used for wetting the previously obtained powder
mixture. The resultant homogeneous mass is forced through an 800
micron screen and then dried to obtain a granulate which is passed
through a 420 micron screen. The homogeneous granulate obtained is
mixed with the magnesium stearate and then compressed using concave
punches of diameter 7 mm (radius of curvature 9 mm) using a
pressure of about 3000 kg/cm2 to obtain cylindrical deposit-cores
with convex bases.
[0343] Application of the support-platform can be as follows: The
support-platform can be applied by coating one or both the convex
bases of the deposit-core with a solution of about 15 g
low-permeability acrylic-methacrylic copolymer (EUDRAGIT.RTM. RS)
in methylene chloride of a quantity to make up to 100 ml.
Thereafter about 0.3 ml of said solution is applied to each base to
be covered, taking care to protect the lateral core surface. The
system is then dried with tepid air. The quantity of polymeric
material deposited is sufficient to keep the structure intact
during transfer.
[0344] In at least one embodiment, the matrix formulation is a
polyethylene oxide (PEO) based tablet matrix formulation
comprising:
TABLE-US-00008 Bupropion Hydrobromide about 50% PEO WSR Coagulant
about 15% (polyethylene oxide) METHOCEL .RTM. K100M about 15%
(hydroxypropylmethyl cellulose) Avicel PH101 about 19%
(microcrystalline cellulose) Magnesium Stearate about 1%
[0345] Preparation of the PEO based tablet matrix formulation can
be as follows: Excipients dry blended in an appropriate mixer and
compressed into tablets using conventional apparatus.
Multiparticulates
[0346] In certain embodiments of the present invention, a
multiparticulate system is provided which contains multiple
microparticles each containing an effective amount of bupropion
hydrobromide and at least one pharmaceutically acceptable
excipient. The multiparticulates can be contained within a capsule,
or can be compressed into a matrix or tablet, that upon ingestion
dissolves into multiple units (e.g. pellets), wherein the sub-units
or pellets possess the desired controlled release properties of the
dosage form. The multiparticulates or the multiple unit dosage
forms can be surrounded by one or more coatings. Examples of such
coatings include polymeric controlled release coatings, delayed
release coatings, enteric coatings, immediate release coatings,
taste-masking coatings, extended release coatings, and
non-functional coatings.
[0347] The bupropion hydrobromide salt in the microparticles of
certain embodiments can be present in an effective amount of from
about 0.1% to about 99% by weight of the microparticles including
all values and ranges therebetween. For example, in certain
embodiments bupropion hydrobromide is present in the microparticles
in an amount of from about 0.1% to about 90% including all values
and ranges therebetween, in other embodiments from about 5% to
about 90% including all values and ranges therebetween, in still
other embodiments from about 10% to about 80% including all values
and ranges therebetween, and in even still other embodiments from
about 25% to about 80% by weight of the microparticle including all
values and ranges therebetween. In certain embodiments wherein the
microparticles are manufactured using a spheronization process, the
bupropion hydrobromide can be present in the microparticles in an
amount of from about 0.1% to about 60% including all values and
ranges therebetween; in other such embodiments from about 5% to
about 50% including all values and ranges therebetween; and in
still other such embodiments from about 10% to about 40% by weight
of the microparticle including all values and ranges therebetween.
In at least one embodiment wherein the microparticles are
manufactured using a spheronization process, the bupropion
hydrobromide is present in the microparticle in an amount of about
30% by weight of the microparticle.
[0348] In addition to the bupropion hydrobromide salt, the
microparticles of the present invention also include at least one
pharmaceutically acceptable excipient. Excipients can be added to
facilitate in the preparation, patient acceptability and
functioning of the dosage form as a drug delivery system. Examples
of possible excipients include spheronization aids, solubility
enhancers, disintegrating agents, diluents, lubricants, binders,
fillers, glidants, suspending agents, emulsifying agents,
anti-foaming agents, flavoring agents, coloring agents, chemical
stabilizers, pH modifiers, and mixtures thereof. Depending on the
intended main function, excipients to be used in formulating
compositions are subcategorized into different groups. However, one
excipient can affect the properties of a composition in a series of
ways, and many excipients used in compositions can thus be
described as being multifunctional.
[0349] The microparticles of certain embodiments of the present
invention can be manufactured using standard techniques known to
one of skill in the art. In certain embodiments the microparticles
can be made according to any one of the methods described herein.
Useful microparticles include drug-layered microparticles and
drug-containing microparticles.
Drug-Containing Microparticles
[0350] Microparticles containing drug in the core can be prepared
by a number of different procedures. For example: In a spray drying
process, an aqueous solution of core material and hot solution of
polymer is atomized into hot air, the water then evaporates, and
the dry solid is separated in the form of pellets, for example by
air suspension. A spray-drying process can produce hollow pellets
when the liquid evaporates at a rate that is faster than the
diffusion of the dissolved substances back into the droplet
interior, or if due to capillary action the dissolved substance
migrates out with the liquid to the droplet surface, leaving behind
a void. Another example is a spray congealing process, where a
slurry of drug material that is insoluble in a molten mass is spray
congealed to obtain discrete particles of the insoluble materials
coated with the congealed substance. A further example is a
fluidized bed based granulation/pelletization process, where a dry
drug is suspended in a stream of hot air to form a constantly
agitated fluidized bed. An amount of binder or granulating liquid
is then introduced in a finely dispersed form to cause
pelletization.
[0351] The drug-containing microparticles of certain embodiments of
the present invention can also be made by, for example, a
spheronization process. One method of manufacturing the
drug-containing microparticles is the applicant's proprietary
CEFORM.TM. (Centrifugally Extruded & Formed
Microspheres/Microparticles) technology, which is the simultaneous
use of flash heat and centrifugal force, using proprietary designed
equipment, to convert dry powder systems into microparticles of
uniform size and shape. The production of microparticles containing
an active drug using this CEFORM.TM. technology is known. Certain
embodiments of the present invention deal with the use of
LIQUIFLASH.RTM. processing to spheronize compositions containing
one or more active drugs to form LIQUIFLASH.RTM.
microparticles.
[0352] With the CEFORM.TM. technology, the processing of the
drug-containing microparticles of certain embodiments of the
present invention is carried out in a continuous fashion, whereby a
pre-blend of drug and excipients is fed into a spinning
"microsphere head", also termed as a "spheronizing head". The
microsphere head, which is a multi-aperture production unit, spins
on its axis and is heated by electrical power. The drug and
excipient(s) pre-blend is fed into the center of the head with an
automated feeder. The material moves, via centrifugal force, to the
outer rim where the heaters, located in the rim of the head, heat
the material. Microparticles are formed when the molten material
exits the head, which are then cooled by convection as they fall to
the bottom of the microparticle chamber. The product is then
collected and stored in suitable product containers. Careful
selection of the types and levels of excipient(s) control
microparticle properties such as sphericity, surface morphology,
and dissolution rate. One advantage of such a process is that the
microparticles are produced and collected from a dry feedstock
without the use of any solvents.
[0353] There are at least two approaches that can be used to
produce drug-containing microparticles using the CEFORM process:
(i) the encapsulation approach and (ii) the co-melt approach. In
the encapsulation approach, the process is conducted below the
melting point of the drug. Therefore, the excipients are designed
to melt and entrain the drug particles on passing through the
apertures to form microparticles. The resulting microparticles
contain the drug, in its native state, essentially enveloped by or
as an intimate matrix with the resolidified excipients. In the
co-melt approach, the process is conducted above the melting point
of the drug. In this case, the drug and the excipients melt or
become fluid simultaneously upon exposure to the heat. The molten
mixture exits the head and forms microparticles, which cool as they
fall to the bottom of the collection bin where they are
collected.
[0354] In at least one embodiment the microparticles are
manufactured using the encapsulation approach. In the encapsulation
approach the excipient(s) which are chosen have a lower melting
point than the drug (e.g. bupropion hydrobromide) with which they
will be combined. Therefore the spheronizing process can be
performed at lower temperatures, than the melting point of the
drug. As a result, this can reduce the risk of polymeric
interconversion, which can occur when using processing temperatures
close to the melting point.
[0355] In a prophetic example of certain embodiments of the present
invention, the manufacturing process for the microparticles can
hypothetically be as follows: Spheronization aid is screened
through a 425 micron (.mu.m) screen. In at least one embodiment,
the spheronization aid is distilled glyceryl monostearate (i.e.
DMG-03VF). About 50% of the spheronization aid is added to a bowl
in a high shear mixer. In at least one embodiment, the bowl is a 6
litre bowl and the high shear mixer is a Diosna P1-6 high speed
mixer granulator. The active drug is then added to the bowl of the
mixer, and then the remainder of the spheronization aid is added.
The material is then blended in the mixer for a time from about 1
minute to about 30 minutes including all values and ranges
therebetween; in certain embodiments from about 3 minutes to about
10 minutes; and in at least one embodiment at about 6 minutes. The
mixer motor speed is from about 50 rpm to about 2000 rpm including
all values and ranges therebetween; in certain embodiments from
about 200 rpm to about 500 rpm; and in at least one embodiment at
about 300 rpm. The chopper motor speed is from about 50 rpm to
about 2000 rpm including all values and ranges therebetween; in
certain embodiments from about 200 rpm to about 500 rpm; and in at
least one embodiment at about 400 rpm. The blended material is then
spheronized in a CEFORM.TM. spheronizing head. The spheronizing
head speed is from about 5 Hz to about 60 Hz including all values
and ranges therebetween; in certain embodiments from about 10 Hz to
about 30 Hz; and in at least one embodiment at about 15 Hz. In at
least one embodiment the CEFORM.TM. spheronizing head is a 5 inch
head. The spheronizing head temperature is maintained at a
temperature from about 70.degree. C. to about 130.degree. C.
including all values and ranges therebetween; in certain
embodiments from about 90.degree. C. to about 110.degree. C.; and
in at least one embodiment at about 100.degree. C. The
microparticles obtained from the spinning process are then screened
through a screen that is from about 150 .mu.m to about 800 .mu.m
including all values and ranges therebetween.
[0356] For microparticles manufactured using a spheronization
process such as the CEFORM.TM. process, the microparticles include,
in addition to the bupropion hydrobromide salt, at least one
spheronization aid. Spheronization aids can assist the
drug-containing mix to form robust durable spherical particles.
Some examples of materials useful as spheronization aids include,
but are not limited to glyceryl monostearate, glyceryl behenate,
glyceryl dibehenate, glyceryl palmitostearate, hydrogenated oils
such as hydrogenated castor oil marketed under the name CUTINA.TM.
HR, fatty acid salts such as magnesium or calcium stearate, polyols
such as mannitol, sorbitol, xylitol, stearic acid, palmitic acid,
sodium lauryl sulfate, polyoxyethylene ethers, esterified
polyoxyethylenes such as PEG-32 distearate, PEG-150 distearate,
cetostearyl alcohol, waxes (e.g. carnauba wax, white wax, paraffin
wax) and wax-like materials. Certain thermo-plastic or
thermo-softening polymers can also function as spheronization aids.
Some non-limiting examples of such thermo-plastic or
thermo-softening polymers include Povidone, cellulose ethers and
polyvinylalcohols. Combinations of spheronization aids can be used.
In at least one embodiment, the spheronization aid includes
glyceryl monostearate (i.e. DMG-03VF). The spheronization aid can
be present in an amount of from about 0.1% to about 99% by weight
of the microparticle including all values and ranges therebetween.
For example, in certain embodiments the spheronization aid is
present in an amount of from about 5% to about 90% including all
values and ranges therebetween; in other embodiments from about 10%
to about 80% including all values and ranges therebetween; in still
other embodiments from about 20% to about 70% including all values
and ranges therebetween; and in even still other embodiments from
about 30% to about 60% by weight of the microparticle including all
values and ranges therebetween. In at least one embodiment the
spheronization aid is present in an amount of about 50% by weight
of the microparticle. In at least one other embodiment, the
microparticles include about 50% (w/w) of bupropion hydrobromide
and about 50% (w/w) of the spheronization aid.
[0357] In certain embodiments, each microparticle can also include
at least one solubility enhancer. Solubility enhancers can be
surfactants. Certain embodiments of the invention include a
solubility enhancer that is a hydrophilic surfactant. Hydrophilic
surfactants can be used to provide any of several advantageous
characteristics to the compositions, including: increased
solubility of the bupropion hydrobromide salt in the microparticle;
improved dissolution of the bupropion hydrobromide salt; improved
solubilization of the bupropion hydrobromide salt upon dissolution;
enhanced absorption and/or bioavailability of the bupropion
hydrobromide salt. The hydrophilic surfactant can be a single
hydrophilic surfactant or a mixture of hydrophilic surfactants, and
can be ionic or non-ionic.
[0358] Likewise, various other embodiments of the invention include
a lipophilic component, which can be a lipophilic surfactant,
including a mixture of lipophilic surfactants, a triglyceride, or a
mixture thereof. The lipophilic surfactant can provide any of the
advantageous characteristics listed above for hydrophilic
surfactants, as well as further enhancing the function of the
surfactants. These various embodiments are described in more detail
below.
[0359] As is well known in the art, the terms "hydrophilic" and
"lipophilic" are relative terms. To function as a surfactant, a
compound includes polar or charged hydrophilic moieties as well as
non-polar hydrophobic (lipophilic) moieties; i.e., a surfactant
compound is amphiphilic. An empirical parameter commonly used to
characterize the relative hydrophilicity and lipophilicity of
non-ionic amphiphilic compounds is the hydrophilic-lipophilic
balance (the "HLB" value). Surfactants with lower HLB values are
more lipophilic, and have greater solubility in oils, whereas
surfactants with higher HLB values are more hydrophilic, and have
greater solubility in aqueous solutions.
[0360] Using HLB values as a rough guide, hydrophilic surfactants
can generally be considered to be those compounds having an HLB
value greater than about 10, as well as anionic, cationic, or
zwitterionic compounds for which the HLB scale is not generally
applicable. Similarly, lipophilic surfactants can be compounds
having an HLB value less than about 10.
[0361] It should be appreciated that the HLB value of a surfactant
is merely a rough guide generally used to enable formulation of
industrial, pharmaceutical and cosmetic emulsions. For many
surfactants, including several polyethoxylated surfactants, it has
been reported that HLB values can differ by as much as about 8 HLB
units, depending upon the empirical method chosen to determine the
HLB value (Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)).
Likewise, for certain polypropylene oxide containing block
copolymers (poloxamers, available commercially as PLURONIC.RTM.
surfactants), the HLB values may not accurately reflect the true
physical chemical nature of the compounds. Finally, commercial
surfactant products are generally not pure compounds, but are often
complex mixtures of compounds, and the HLB value reported for a
particular compound may more accurately be characteristic of the
commercial product of which the compound is a major component.
Different commercial products having the same primary surfactant
component can, and typically do, have different HLB values. In
addition, a certain amount of lot-to-lot variability is expected
even for a single commercial surfactant product. Keeping these
inherent difficulties in mind, and using HLB values as a guide, one
skilled in the art can readily identify surfactants having suitable
hydrophilicity or lipophilicity for use in the present invention,
as described herein.
[0362] Solubility enhancers can be any surfactant suitable for use
in pharmaceutical compositions as known in the art. Suitable
surfactants can be anionic, cationic, zwitterionic or non-ionic.
Refined, distilled or fractionated surfactants, purified fractions
thereof, or re-esterified fractions, are within the scope of the
invention.
[0363] Although polyethylene glycol (PEG) itself does not function
as a surfactant, a variety of suitable PEG-fatty acid esters have
useful surfactant properties, as is known in the art. Polyethylene
glycol (PEG) fatty acid diesters are also suitable for use as
surfactants in the compositions of the present invention, as is
known in the art. In general, mixtures of surfactants are also
useful in the present invention, including mixtures of two or more
commercial surfactant products as is known in the art (e.g.
PEG-fatty acid esters are marketed commercially as mixtures or
mono- and diesters).
[0364] A large number of suitable surfactants of different degrees
of lipophilicity or hydrophilicity can be prepared by reaction of
alcohols or polyalcohols with a variety of natural and/or
hydrogenated oils, as is known in the art. In certain embodiments,
the oils used are castor oil or hydrogenated castor oil or an
edible vegetable oil such as corn oil, olive oil, peanut oil, palm
kernel oil, apricot kernel oil, or almond oil. Non-limiting
examples of alcohols include glycerol, propylene glycol, ethylene
glycol, polyethylene glycol, sorbitol, pentaerythritol and mixtures
thereof.
[0365] Polyglycerol esters of fatty acids as is known in the art,
are also suitable surfactants for the present invention. Esters of
propylene glycol and fatty acids as is known in the art are also
suitable surfactants for use in the present invention. In general,
mixtures of surfactants are also suitable for use in the present
invention. In particular, mixtures of propylene glycol fatty acid
esters and glycerol fatty acid esters, as is known in the art, are
suitable and are commercially available. Another class of suitable
surfactants is the class of mono- and diglycerides, as are known in
the art. These surfactants are generally lipophilic. Sterols and
derivatives of sterols are also suitable surfactants for use in the
present invention as is known in the art. These surfactants can be
hydrophilic or lipophilic. A variety of PEG-sorbitan fatty acid
esters are known in the art and are available and suitable for use
as surfactants in the present invention. In general, these
surfactants are hydrophilic, although several lipophilic
surfactants of this class can be used. Suitable ethers of
polyethylene glycol and alkyl alcohols are known in the art and are
suitable surfactants for use in the present invention. Esters of
sugars are known in the art and are suitable surfactants for use in
the present invention. Several hydrophilic PEG-alkyl phenol
surfactants are known in the art and are available, and are
suitable for use in the present invention.
[0366] The POE-POP block copolymers are a unique class of polymeric
surfactants. The unique structure of the surfactants, with
hydrophilic POE and lipophilic POP moieties in well-defined ratios
and positions, provides a wide variety of surfactants suitable for
use in the present invention. These surfactants are available under
various trade names, including SYNPERONIC.TM. PE series (ICI);
PLURONIC.RTM. series, EMKALYX.TM., LUTROL.TM., SUPRONIC.TM.
MONOLAN.TM., PLURACARE.TM., and PLURODAC.TM.. The generic term for
these polymers is "poloxamer" (CAS 9003-11-6). These polymers have
the formula: HO(C2H4O)a(C3H6O)b(C2H4O)aH
where "a" and "b" denote the number of polyoxyethylene and
polyoxypropylene units, respectively. The suitable surfactants of
this class are known in the art.
[0367] Sorbitan esters of fatty acids are suitable surfactants for
use in the present invention and are known in the art. Esters of
lower alcohols (C2 to C4) and fatty acids (C8 to C18) are suitable
surfactants for use in the present invention and are known in the
art. Ionic surfactants, including cationic, anionic and
zwitterionic surfactants, are suitable hydrophilic surfactants for
use in the present invention and are known in the art. In certain
embodiments, the surfactant is an anionic surfactant such as a
fatty acid salt, a bile salt, or a combination thereof. In other
embodiments the surfactant is a cationic surfactant such as a
carnitine.
[0368] Examples of ionic surfactants include sodium oleate, sodium
lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl
sulfosuccinate, sodium cholate, sodium taurocholate; lauroyl
carnitine; palmitoyl carnitine; and myristoyl carnitine.
[0369] Ionizable surfactants, when present in their unionized
(neutral, non-salt) form, are lipophilic surfactants suitable for
use in the compositions of the present invention, and are known in
the art. Particular examples of such surfactants include free fatty
acids, particularly C6-C22 fatty acids, and bile acids. More
specifically, suitable unionized ionizable surfactants include the
free fatty acid and bile acid forms of any of the fatty acid salts
and bile salts.
[0370] Derivatives of oil-soluble vitamins, such as vitamins A, D,
E, K, etc., are also useful surfactants for the compositions of the
present invention. An example of such a derivative is tocopheryl
PEG-1000 succinate (TPGS).
[0371] In certain embodiments, surfactants or mixtures of
surfactants that solidify at ambient room temperature are used. In
other embodiments, surfactants or mixtures of surfactants that
solidify at ambient room temperature in combination with particular
lipophilic components, such as triglycerides, or with addition of
appropriate additives, such as viscosity modifiers, binders,
thickeners, and the like, are used.
[0372] Examples of non-ionic hydrophilic surfactants include
alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl
macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene
alkylphenols; polyethylene glycol fatty acids esters; polyethylene
glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty
acid esters; polyoxyethylene-polyoxypropylene block copolymers;
polyglycerol fatty acid esters; polyoxyethylene glycerides;
polyoxyethylene sterols, derivatives, and analogues thereof;
polyoxyethylene vegetable oils; polyoxyethylene hydrogenated
vegetable oils; reaction mixtures of polyols with fatty acids,
glycerides, vegetable oils, hydrogenated vegetable oils, and
sterols; sugar esters, sugar ethers; sucroglycerides;
polyethoxylated fat-soluble vitamins or derivatives; and mixtures
thereof.
[0373] In certain embodiments, the non-ionic hydrophilic surfactant
is selected from the group comprising polyoxyethylene alkylethers;
polyethylene glycol fatty acids esters; polyethylene glycol
glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid
esters; polyoxyethylene-polyoxypropylene block copolymers;
polyglyceryl fatty acid esters; polyoxyethylene glycerides;
polyoxyethylene vegetable oils; polyoxyethylene hydrogenated
vegetable oils, and mixtures thereof. The glyceride can be a
monoglyceride, diglyceride, triglyceride, or a mixture thereof.
[0374] In certain other embodiments, the surfactants used are
non-ionic hydrophilic surfactants that are reaction mixtures of
polyols and fatty acids, glycerides, vegetable oils, hydrogenated
vegetable oils or sterols. These reaction mixtures are largely
composed of the transesterification products of the reaction, along
with often complex mixtures of other reaction products. The polyol
can be glycerol, ethylene glycol, polyethylene glycol, sorbitol,
propylene glycol, pentaerythritol, a saccharide, or a mixture
thereof.
[0375] The hydrophilic surfactant can also be, or include as a
component, an ionic surfactant. Examples of ionic surfactants
include alkyl ammonium salts; bile acids and salts, analogues, and
derivatives thereof; fusidic acid and derivatives thereof; fatty
acid derivatives of amino acids, oligopeptides, and polypeptides;
glyceride derivatives of amino acids, oligopeptides, and
polypeptides; acyl lactylates; mono-diacetylated tartaric acid
esters of mono-diglycerides; succinylated monoglycerides; citric
acid esters of mono-diglycerides; alginate salts; propylene glycol
alginate; lecithins and hydrogenated lecithins; lysolecithin and
hydrogenated lysolecithins; lysophospholipids and derivatives
thereof; phospholipids and derivatives thereof; salts of
alkylsulfates; salts of fatty acids; sodium docusate; carnitines;
and mixtures thereof.
[0376] In certain embodiments the ionic surfactants include bile
acids and salts, analogues, and derivatives thereof; lecithins,
lysolecithin, phospholipids, lysophospholipids and derivatives
thereof; salts of alkylsulfates; salts of fatty acids; sodium
docusate; acyl lactylates; mono-diacetylated tartaric acid esters
of mono-diglycerides; succinylated monoglycerides; citric acid
esters of mono-diglycerides; carnitines; and mixtures thereof.
[0377] Examples of ionic surfactants include lecithin,
lysolecithin, phosphatidylcholine, phosphatidylethanolamine,
phosphatidylglycerol, phosphatidic acid, phosphatidylserine,
lysophosphatidylcholine, lysophosphatidylethanolamine,
lysophosphatidylglycerol, lysophosphatidic acid,
lysophosphatidylserine, PEG-phosphatidylethanolamine,
PVP-phosphatidylethanolamine, lactylic esters of fatty acids,
stearoyl-2-lactylate, stearoyl lactylate, succinylated
monoglycerides, mono/diacetylated tartaric acid esters of
mono/diglycerides, citric acid esters of mono/diglycerides,
cholate, taurocholate, glycocholate, deoxycholate,
taurodeoxycholate, chenodeoxycholate, glycodeoxycholate,
glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate,
tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine,
N-methyl taurocholate, caproate, caprylate, caprate, laurate,
myristate, palmitate, oleate, ricinoleate, linoleate, linolenate,
stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl
carnitines, palmitoyl carnitines, myristoyl carnitines, and salts
and mixtures thereof.
[0378] In certain embodiments, ionic surfactants used include
lecithin, lysolecithin, phosphatidylcholine,
phosphatidylethanolamine, phosphatidylglycerol,
lysophosphatidylcholine, PEG-phosphatidylethanolamine, lactylic
esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate,
succinylated monoglycerides, mono/diacetylated tartaric acid esters
of mono/diglycerides, citric acid esters of mono/diglycerides,
cholate, taurocholate, glycocholate, deoxycholate,
taurodeoxycholate, glycodeoxycholate, cholylsarcosine, caproate,
caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, and
salts and mixtures thereof. In at least one embodiment, the ionic
surfactant is selected from lecithin, lactylic esters of fatty
acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated
monoglycerides, mono/diacetylated tartaric acid esters of
mono/diglycerides, citric acid esters of mono/diglycerides,
taurocholate, caprylate, caprate, oleate, lauryl sulfate, docusate,
and salts and mixtures thereof.
[0379] Examples of lipophilic surfactants include alcohols;
polyoxyethylene alkylethers; fatty acids; glycerol fatty acid
esters; acetylated glycerol fatty acid esters; lower alcohol fatty
acids esters; polyethylene glycol fatty acids esters; polyethylene
glycol glycerol fatty acid esters; polypropylene glycol fatty acid
esters; polyoxyethylene glycerides; lactic acid derivatives of
mono/diglycerides; propylene glycol diglycerides; sorbitan fatty
acid esters; polyoxyethylene sorbitan fatty acid esters;
polyoxyethylene-polyoxypropylene block copolymers; transesterified
vegetable oils; sterols; sterol derivatives; sugar esters; sugar
ethers; sucroglycerides; polyoxyethylene vegetable oils;
polyoxyethylene hydrogenated vegetable oils; and mixtures
thereof.
[0380] As with the hydrophilic surfactants, lipophilic surfactants
can be reaction mixtures of polyols and fatty acids, glycerides,
vegetable oils, hydrogenated vegetable oils, and sterols.
[0381] In certain embodiments, the lipophilic surfactants include
one or more selected from the group comprising fatty acids; lower
alcohol fatty acid esters; polyethylene glycol glycerol fatty acid
esters; polypropylene glycol fatty acid esters; polyoxyethylene
glycerides; glycerol fatty acid esters; acetylated glycerol fatty
acid esters; lactic acid derivatives of mono/diglycerides; sorbitan
fatty acid esters; polyoxyethylene sorbitan fatty acid esters;
polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylene
vegetable oils; polyoxyethylene hydrogenated vegetable oils; and
reaction mixtures of polyols and fatty acids, glycerides, vegetable
oils, hydrogenated vegetable oils, sterols, and mixtures
thereof.
[0382] In certain other embodiments, the lipophilic surfactants
include one or more selected from the group comprising lower
alcohol fatty acids esters; polypropylene glycol fatty acid esters;
propylene glycol fatty acid esters; glycerol fatty acid esters;
acetylated glycerol fatty acid esters; lactic acid derivatives of
mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene
vegetable oils; and mixtures thereof. Among the glycerol fatty acid
esters, the esters can be mono- or diglycerides, or mixtures of
mono- and diglycerides, where the fatty acid moiety is a C6 to C22
fatty acid.
[0383] Other embodiments include lipophilic surfactants which are
the reaction mixture of polyols and fatty acids, glycerides,
vegetable oils, hydrogenated vegetable oils, and sterols. Examples
of polyols are polyethylene glycol, sorbitol, propylene glycol,
pentaerythritol, and mixtures thereof.
[0384] Combinations of solubility enhancers (i.e. surfactants) can
be used. Examples of macrogol fatty acid esters useful as
solubility enhancers include GELUCIRE.RTM. 50/13 and GELUCIRE.RTM.
44/14. In at least one embodiment the solubility enhancer is
GELUCIRE.RTM. 50/13. The solubility enhancer can be present in an
amount of from about 0.1% to about 70% by weight of the
microparticle including all values and ranges therebetween. For
example, in certain embodiments, the solubility enhancer is present
in an amount of from about 1% to about 50% including all values and
ranges therebetween; in other embodiments from about 10% to about
30% including all values and ranges therebetween; in still other
embodiments from about 15% to about 25% by weight of the
microparticle including all values and ranges therebetween. In at
least one embodiment the solubility enhancer is present in an
amount of about 20% by weight of the microparticle.
[0385] It is contemplated that in some embodiments, one or more
other pharmaceutically acceptable excipients consistent with the
objects of the present invention can be used in the microparticles,
such as a lubricant, a binder, a pH modifier, a filler and/or a
glidant.
[0386] The process for manufacturing the drug-containing
microparticles of certain embodiments of the present invention by
spheronization are not limited to the CEFORM.TM. technology, and
any other technology resulting in the formation of the
microparticles consistent with the objects of the present invention
can also be used. For example, microparticles of certain
embodiments of the invention can also be manufactured by
extrusion/spheronization, granulation or pelletization.
[0387] Extrusion/spheronization is a multi-step process used to
make uniformly sized spherical particles. The technique offers the
ability to incorporate high levels of active ingredients without
producing excessively large particles. The main steps in the
process are:
[0388] Dry-mixing of ingredients to achieve a homogenous powder
dispersion;
[0389] Wet massing using for example a high-shear wet granulator to
form rod shaped particles of uniform diameter;
[0390] Extrusion to form rod-shaped particles of uniform
diameter;
[0391] Spheronization to round off the rods into spherical
particles;
[0392] Screening to achieve the desired narrow particle size
distribution.
[0393] The mixing vessel used for dry-mixing can be of any size and
shape compatible with the size of the formulation to be produced.
For example, commercially available mixing devices such as
planetary mixers, high shear mixers, or twin cone blenders can be
used. If relatively small quantities of formulation are to be
prepared, a simple mortar and pestle can be sufficient to mix the
ingredients. The type of mixing vessel would be apparent to one
skilled in the pharmaceutical art. The moistened mass formed by
wet-massing in conventional granulation equipment is extruded
through a perforated mesh in order to produce cylindrical
filaments.
[0394] The port of the meshes can determine the diameter of the
filaments. A port ranging from about 0.2 mm to about 3 mm including
all values and ranges therebetween, can be used in this process. In
at least one embodiment utilizing this process, the port ranges
from about 0.4 mm to about 2 mm including all values and ranges
therebetween. The extrusion can be carried out using screw, double
screw, "sieve and basket" kind, "roll extruder", "ram extruder"
extruders or any other pharmaceutically acceptable means to produce
cylindrical filaments. In certain embodiments utilizing this
extrusion/spheronization process, a double screw coaxial extruder
is used. The spheronization device comprises a hollow cylinder with
a horizontal rotating plate. The filaments are broken in short
segments which are transformed in spherical or quasi-spherical
particles on the upper surface of the rotating plate at a velocity
ranging from about 200 rpm to about 2,000 rpm including all values
and ranges therebetween. The particles can be dried in any
pharmaceutically acceptable way, such as for example by air drying
in a static condition. The particles are used as they are or they
are coated to obtain granules to use in tablets, capsules, packets
or other pharmaceutical formulations.
[0395] A prophetic example of an extrusion/spheronization
formulation comprising bupropion hydrobromide can be as follows: In
this example, the bupropion hydrobromide can be present in an
amount of from about 1% to about 80% w/w including all values and
ranges therebetween. In certain embodiments within this example,
the bupropion hydrobromide is present in an amount of from about 1%
to about 50% w/w; in other embodiments from about 10% to about 30%;
and in still other embodiments about 10% w/w. In this example, the
filler can be present in an amount of from about 0% to about 80%
w/w including all values and ranges therebetween. In certain
embodiments of this example, the filler is present in an amount of
from about 10% to about 60%; and in other embodiments at about 40%
w/w. In this example, the microcrystalline cellulose can be present
in an amount of from about 10% to about 90% w/w including all
values and ranges therebetween. In certain embodiments of this
example, the microcrystalline cellulose is present in an amount of
from about 10% to about 70%; and in other embodiments from about
20% to about 50% w/w. In this example, the binder can be present in
an amount of from about 0% to about 10% w/w including all values
and ranges therebetween. In certain embodiments of this example,
the binder is present in an amount of from about 1% to about 8%;
and in other embodiments from about 2% to about 4% w/w. In this
example, water can be present in an amount of from about 10% to
about 80% w/w including all values and ranges therebetween. In
certain embodiments of this example, water is present in an amount
of from about 15% to about 70%; and in other embodiments from about
20% to about 50% w/w. Suitable fillers that can be used in this
example include but are not limited to calcium phosphate dibasic,
tricalcium phosphate, calcium carbonate, starch (such as corn,
maize, potato and rice starches), modified starches (such as
carboxymethyl starch, etc.), microcrystalline cellulose, sucrose,
dextrose, maltodextrins, lactose, and fructose. Suitable lubricants
that can be used in this example include but are not limited to
metal stearates (such as calcium, magnesium on zinc stearates),
stearic acid, hydrogenated vegetable oils, talc, starch, light
mineral oil, sodium benzoate, sodium chloride, sodium lauryl
sulfate, magnesium lauryl sulfate, sodium stearyl fumarate,
glyceryl behenate and polyethylene glycol (such as CARBOWAX.TM.
4000 and 6000). Suitable antiadherents in this example include but
are not limited to colloidal silicon dioxide. Suitable binders in
this example include but are not limited to ethyl cellulose, a
polymethacrylate polymer, polyvinylalcohol, polyvinyl pyrrolidone,
polyvinylpyrrolidone-vinylacetate copolymer (e.g. KOLLIDON.RTM.
VA64) hydroxyethylcellulose, low molecular weight
hydroxypropylmethylcellulose (e.g. viscosity of about 1-50 cps at
about 20.degree. C.; about 2-12 cps at about 20.degree. C.; or
about 4-6 cps at about 20.degree. C.), hydroxypropylcellulose
polymethacrylates, and mixtures thereof.
[0396] The drug-containing microparticles formed by
extrusion/spheronization in this prophetic example can be produced
using cross-linked amphiphilic polymers by the following steps: (a)
the mixing of one or more cross-linked amphiphilic polymers with
bupropion hydrobromide and optionally other pharmaceutical
excipients in order to obtain a uniform mixture in the form of dry
powder to which a suitable amount of liquid is added to obtain a
pasty consistency; (b) the extrusion of the mixture obtained from
step (a) through a perforated mesh in order to obtain cylindrical
filaments having desired length and diameter; (c) the
spheronization of the filaments in order to obtain a product in the
form of spherical multiparticulates; (d) the drying of the product;
and (e) the optional depositing of a drug on the surface of the
microparticles. "Cross-linked amphiphilic polymer" refers in this
example to polymers showing characteristics of swellability in the
whole pH range of aqueous solutions and also in solvents or solvent
mixtures having different polarity characteristics. The polymers
can be cross-linked either physically through the interpenetration
of the macromolecular meshes, or chemically, thus showing points of
link among the macromolecular chains. Non-limiting examples of such
polymers include cross-linked polyvinyl pyrrolidone, sodium
carboxymethylcellulose, sodium glycolate starch and dextrans.
Optional excipients include dispersing, emulsifying, wetting agents
and coloring agents. The expression "uniform mixture" in this
example means that the components of the mixture are uniformly
dispersed in the formulation by a mixing process which assures the
uniform distribution of each component. A reasonable mixing time
can range from about 1 to about 60 minutes including all values and
ranges therebetween, using one of the mixing equipments
conventionally used for the dry mixing of the powders (e.g. "V",
fixed body, rotating body, sigma mixers). The term "liquid" in this
example means any liquid substance or mix (solution or emulsion) of
liquids of normal pharmaceutical use able to moisten the powder
mix, as for example water, aqueous solutions having different pH,
organic solvents of normal pharmaceutical use (e.g. alcohols,
chlorinated solvents), and oils. Among the oils and surfactants
which can be used in this example are: natural oils, either
saturated or unsaturated (olive, peanut, soybean, corn, coconut,
palm, sesame and similar oils); semisynthetic and synthetic mono-,
di- and triglycerides containing saturated and/or unsaturated fatty
acids and their polyhydroxyethylated derivatives (caprico-caprilic
triglycerides [MYGLIOL.TM., CAPTEX.TM., LABRAFAC.TM., LIPO.TM.],
saturated or unsaturated polyhydroxylated triglycerides of various
kind [LABRAFIL.TM., LABRAFAC.TM. Hydro, GELUCIRE.TM.]); liquid
waxes (isopropyl myristate, isopropyl-caprinate, -caprylate,
-laurate, -palmitate, -stearate); fatty acids esters (ethyl oleate,
oleyl oleate); silicone oils; polyethylene glycols (PEG 200, PEG
400, PEG 600, PEG 1000, and so on); polyglycolic glycerides (for
example LABRASOL.TM.); polyglycols (propylene glycol, tetraglycol,
and ethoxydiglycol (TRANSCUTOL.TM.), sorbitan-esters of fatty acids
(for example SPAN.RTM., ARLACEL.RTM., BRIJ.RTM.),
polyoxyethylenesorbitan esters of fatty acids (for example
TWEEN.RTM., CAPMUL.RTM., LIPOSORB.RTM.), polypropylene
oxide-polyethylene oxide (Poloxamer) copolymers, polyethylene
glycol esters (PEG)-glycerol (LABRASOL.RTM., LABRAFIL.RTM.), PEG
esters and long chain aliphatic acids or alcohols (for example
CREMOPHOR.RTM.), polyglycerid esters (PLUROL.RTM.), saccharide,
fatty acid esters (sucro-esters), and mixtures thereof. Moreover,
anionic surfactants (for example sodium lauryl sulfate, sodium
stearate, sodium oleate) or cationic surfactants (for example
tricetol), can be used as well as lecithins, phospholipids and
their semi-synthetic or synthetic derivatives. Also bupropion
hydrobromide and/or excipients can be dissolved, dispersed and/or
emulsified in such liquids.
[0397] In a particular embodiment formed by an
extrusion/spheronization process from the prophetic example
described above, the moistening liquid comprises an oil/surfactant
system wherein the bupropion hydrobromide optionally emulsified
with an aqueous phase is dissolved or dispersed. The amount of
liquid with respect to the solid used in the preparation of the
mixture can range from about 1% to about 80% by weight including
all values and ranges therebetween. As a prophetic example of this
embodiment, a mixture of bupropion hydrobromide and KOLLIDON.TM. CL
in a ratio equal to about 1:3 by weight is co-milled obtaining the
mixture in the form of powder having about 100% of granulometry
lower than about 50 microns. The mixture is moistened using a
liquid demineralized water containing KOLLIDON.TM. 25 (polyvinyl
pyrrolidone, BASF) in a solution 3% w/w. The extrusion is carried
out forcing the moistened mass through a threader having diameter
of the holes equal to about 1 mm. The operative parameters in this
prophetic example can be as follows: powder flow rate: about 4.5
kg/h; liquid flow rate: about 4.1 kg/h; torsional stress: about
27%; head temperature: about 46.degree. C.; and screw rotation
velocity: about 140 rpm. The extrusion filaments are then processed
in a spheronizator adjusted at a velocity equal to about 1,000 rpm
for about 2 minutes. The obtained microparticles are then dried in
a fluid bed for about 2 hours to a maximum temperature equal to
about 59.degree. C. At the end of the drying the product is
discharged and is mechanically screened separating the fraction
ranging from about 0.7 mm to about 1.2 mm.
[0398] Another prophetic example of a drug-containing microparticle
embodiment of the invention formed by an extrusion/spheronization
process, uses a charged resin, the steps of which can comprise: (a)
adding the charged resin, bupropion hydrobromide and other
excipients, to a mixing vessel; (b) mixing the ingredients to
obtain a uniform mixture; (c) adding a granulating solution--a
liquid capable of wetting the dry mixture. Liquids resulting in
conversion of the dry powder mixture into a wet granulation that
supports subsequent extrusion and spheronization (marumerization)
are included. Typically, water or aqueous solutions are employed.
Alcohols, typically ethanol or isopropanol, can be included with
the granulating water to enhance the workability of the
granulation. In another embodiment of this invention, one or more
of the components of the formulation is first dissolved in water
and this solution is used to produce the wet granulation. An active
ingredient or an excipient which is present at very low
concentration can initially be dissolved or suspended in the
granulating solvent to assure more uniform distribution throughout
the formulation. (d) granulating the mixture until a uniform
granulation results; (e) extruding the wet granulation through a
screen to produce strands of granulation; (f) spheronizing the
strands of granulation to produce spherical multiparticulates; and
(g) collecting and drying the spherical multiparticulates. By
"charged resin" is meant in this example to mean a polymer with
ionizable functional groups that becomes useful in the embodiment
of this invention. This broadly encompasses any polymer that upon
ionization, is capable of producing cationic or anionic polymeric
chains and which support spheronization. Typically from about 10%
to about 70% by weight of the spherical multiparticulate is charged
resin. Non limiting examples of these charged resins include sodium
polystyrene sulfonate (e.g. AMBERLITE IRP69.TM.; the chloride salt
of cholestyramine resin USP (e.g. AMBERLITE IRP276.TM.; the acid
form of methacrylic acid-divinyl benzene (e.g. AMBERLITE IRP64.TM.;
carboxypolymethylenes (e.g. CARBOPOL.TM. 974P and CARBOPOL.TM.
934P, and sodium polyacrylate (e.g. AQUAKEEP.TM. J-550. In order
for the resin to maintain the desired degree of ionization, agents
which produce an acidic or basic environment during granulation and
spheronization can be included within the formulation. Among the
groups of compounds that can exert this effect are acids, bases,
and the salts of acids and bases such as adipic acid, citric acid,
fumaric acid, tartaric acid, succinic acid, sodium carbonate,
sodium bicarbonate, sodium citrate, sodium acetate, sodium
phosphates, potassium phosphates, ammonium phosphate, magnesium
oxide, magnesium hydroxide, sodium tartrate, and tromethamine.
Certain compounds can be added to the granulation to provide the
proper degree of hydration of the charged resin, medicament and
excipients. These hydrating agents include sugars such as lactose,
sucrose, mannitol, sorbitol, pentaerythritol, glucose and dextrose.
Polymers such as polyethylene glycol as well as surfactants and
other organic and inorganic salts can also be used to modulate
polymer hydration.
[0399] In another prophetic example, multiparticulates containing
bupropion hydrobromide can be obtained as follows:
TABLE-US-00009 Component Percent w/w Bupropion HBr about 8.7
Disodium Phosphate about 7.0 Monosodium phosphate about 1.7 Sodium
dodecyl sulfate about 21.7 Sodium Chloride about 17.4 Povidone
29-32K about 8.7 AMBERLITE IRP-69 about 34.8 Butylated
Hydroxyanisol about 0.0002
[0400] In this prophetic example, approximately 5.75 kg of the
above formulation is mixed in a planetary mixer for about 15
minutes. The butylated hydroxyanisol is dissolved in about 60 cc of
ethanol and water is added to bring the final solution to a volume
of about 133 cc. This solution is added to the planetary mixer over
about a two (2) minute period. The mixer is then granulated with
seven aliquots of about 250 cc of water added over about a fifteen
minute period. The granulation thus formed is extruded through a
1.0 mm screen and aliquots spheronized by marumerization at
approximately 1200 rpm for approximately 10 minutes each. The
spherical multiparticulates formed are then dried at about
50.degree. C. for about 24 hours.
[0401] Another embodiment of this invention involves the production
of drug containing microparticles in the form of `pearls`. Pearls
can be manufactured by mixing bupropion hydrobromide with one or
more pharmaceutical excipients in molten form; the melt is forced
to pass through a nozzle which is subjected to a vibration; the
pearls formed are allowed to fall in a tower countercurrentwise to
a gas; and the solid pearls are collected in the bottom of the
tower. In this example, the quantity of bupropion hydrobromide can
vary from about 5% to about 95% by weight including all values and
ranges therebetween; and in certain embodiments from about 40% to
about 60% by weight including all values and ranges therebetween.
The additives which enable the crystallization of the supercooled
product to be induced in this example can be chosen from the
following: fatty alcohols such as: cetyl alcohol, stearyl alcohol,
fatty acids such as: stearic acid, palmitic acid, glycerol esters
such as: glycerol palmitostearate, glycerol stearate (e.g.
PRECIROL.TM.), glycerol behenate (e.g. COMPRITOL.TM.), hydrogenated
oils such as: hydrogenated castor oil (e.g. CUTINA.TM. HR), fatty
acid salts such as: magnesium or calcium stearate, polyols such as:
mannitol, sorbitol, xylitol, waxes such as: white wax, carnauba
wax, paraffin wax, polyoxyethylene glycols of high molecular
weight, and esterified polyoxyethylenes such as: PEG-32 distearate,
and PEG-150 distearate. To these crystallization additives it can
be desirable in this example to add polymers which are soluble or
dispersible in the melt, and which provide a controlled and
adjustable dissolution of the pearls when they are used, examples
of which include: cellulose derivatives (hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, hydroxyethyl cellulose, ethyl
cellulose, carboxymethyl cellulose), acrylic resins (e.g.
EUDRAGIT.RTM.), polyvinyl acetates (e.g. RHODOPAS.RTM.),
polyalkylene (ethylene propylene), polylactic, maleic anhydride,
silicone resins, and mixtures thereof. In addition, inorganic
additives can be added to accelerate the solidification of the
active substances, examples of which include: silicas, inorganic
oxides such as titanium or iron oxide, phosphates, carbonates,
clays, and talc. In addition, a surface-active agent can be added
to improve the dispersion of the active substance in the
crystallization additive, examples of which include: sorbitol
esters, the polyoxyethylene polysorbates (e.g. TWEEN.RTM.), and
glycols such as glycerine or propylene glycol. The process for the
preparation of pearls comprise preparing a melt of the bupropion
hydrobromide with one or more excipients. This melt can be prepared
by separately melting the various constituents and then mixing them
or by melting the mixture of the constituents, possible insoluble
compounds being added at the end of the melting so as to obtain a
homogeneous mass. The nature of the constituents of the melt is
chosen by the person skilled in the art, which is considered as a
function of the compatibility of the constituents, the viscosity of
the mixture of constituents, the nozzle diameter, the
hydrophilicity of the active substance, the surface tension of the
active substance, the particle size of the insoluble additives, the
flow rate of the nozzle, the temperature of the tower, its height
and, above all, the size of the desired pearls, the proportion of
bupropion hydrobromide to be included therein and the desired
release time of the active substance.
[0402] Alternative procedures other than extrusion or
spheronization for manufacturing drug-containing microparticles can
include wet granulation, solvent granulation and melt granulation.
All of these techniques involve the addition of an inactive binder
to aggregate smaller particles into larger granules. For example,
wet granulation and solvent granulation involve the addition of a
liquid binder which aggregates the active materials and excipients
into granules. After granulation, the liquid can be removed by a
separate drying step. Melt granulation is similar to wet
granulation, but uses a low melting point solid material as a
binder. The solid binder in melt granulation is melted and acts as
a liquid binder thereby aggregating the powdered active material
and excipients into granules. The binder thereby, can be
incorporated into the granules when the granules cool.
[0403] Certain embodiments of the present invention include
microparticles manufactured by a process for producing granules by
rotomelt granulation that comprises mixing bupropion hydrobromide
and a powdered excipient material that has a higher melting point
than bupropion hydrobromide in a zone wherein both powdered
materials are maintained in a fluidized state by a rising stream of
gas in an apparatus having a rapidly rotating horizontal-disk
located within a vertical vessel having a bottom surface; wherein
said rapidly rotating disk is located on the bottom surface of the
vertical vessel wherein said gas is at a temperature sufficient to
cause the bupropion hydrobromide to at least partially melt thereby
causing said powdered materials to aggregate and form granules.
Other embodiments of the present invention include microparticles
manufactured by a process for producing granules by rotomelt
granulation comprising mixing powdered binder material and
bupropion hydrobromide wherein the bupropion hydrobromide has a
higher melting point than the powdered binder material in a zone
wherein both powdered materials are maintained in a fluidized state
by a rising stream of gas in an apparatus having a rapidly rotating
horizontal-disk located within a vertical vessel having a bottom
surface; and wherein said rapidly rotating disk is located on the
bottom surface of the vertical vessel wherein said gas is at a
temperature sufficient to cause the powdered binder material to at
least partially melt thereby causing said powdered materials to
aggregate and form granules.
[0404] In rotomelt granulation, one of the feed powders must have a
lower melting point than the other powder in order to serve as a
binder. The feed powders are introduced into a vertical vessel with
rotatable horizontal-disk located in the bottom of the vessel. The
powder is maintained in fluidized state by at least one stream of
filtered air being circulated from the bottom of the vertical
vessel through one or more inlets. The rotatable horizontal disk is
then rotated while the air supplied to fluidize the powder is
maintained at a temperature sufficient to soften or melt the lower
melting point powder. The temperature to which the binder must be
heated to soften can be empirically determined by observing the
formation of granules at various temperatures for various binders.
It is presently believed that temperatures from about 3.degree. C.
to about 5.degree. C. below the melting point or melting range,
including all values and ranges therebetween, provides sufficient
softening to result in granule formation. The lower melting point
powder then acts as a binding agent to promote the aggregation of
powder particles into granules. Suitable powders for use in
rotomelt granulation have a diameter size in the range of from
about 5 microns to about 150 microns including all values and
ranges therebetween; and in certain embodiments have a diameter
size in the range of about 35 microns to about 80 microns. The
temperature which the components will be exposed to depends on the
binder employed to aggregate the powders. Generally, the melting
point of the binder is above about 30.degree. C.; and in certain
embodiments is below about 100.degree. C.
[0405] The powders used in these microparticles manufactured by
rotomelt granulation can be formed into granules by at least two
alternative granulation mechanisms. The first mechanism for granule
formation utilizes a larger particulate binder and a smaller
particulate powder. The temperature during the rotomelt granulation
is then elevated only to the point where the external surface of
the binder particles become tacky. As the second powdered material
of a smaller size is contacted with the tacky surface it forms a
microlayer on the surface of the binder particle. This granulation
mechanism results in granules which have size distribution similar
to the original binder particles employed. Alternatively, the
rotomelt granulation can be conducted at a temperature at which the
binder acts as a cement bridging the gaps between the unmelted
particles (this is referred to as agglomeration). This mechanism
results in the formation of granules where the components are
intermingled. For each binder used the mechanism can be controlled
primarily by the temperature at which the rotomelt granulation is
performed. Those skilled in the art will appreciate that the
granules formed can be observed by electron microscopy to determine
the type of granulation process occurring. If one particular type
of granule is desired, the process conditions or starting materials
can be varied to produce the desired granules.
[0406] In at least one embodiment of the present invention,
bupropion hydrobromide is melted to act as a binding agent in the
rotomelt granulation process. Examples of suitable excipients
include those selected from the following: fillers, lubricants,
glidants and antiadherents. Suitable fillers include but are not
limited to calcium phosphate dibasic, tricalcium phosphate, calcium
carbonate, starch (such as corn, maize, potato and rice starches),
modified starches (such as carboxymethyl starch, etc.),
microcrystalline cellulose, sucrose, dextrose, maltodextrins,
lactose, and fructose. The amount of binder added to aggregate the
particles into granules can be in the range of from about 10% w/w
to about 80% w/w including all values and ranges therebetween; and
in certain embodiments is in the range of from about 30% w/w to
about 70% w/w of the powdered materials in the rotomelt
granulation. The remaining weight percentage to provide a total of
about 100% w/w can be one or more suitable powdered pharmaceutical
actives. Optionally the rotomelt granulation can also contain from
about 0% to about 60% w/w including all values and ranges
therebetween, of one or more powdered excipients wherein the total
weight of all the powdered materials equals about 100% w/w. The
binder used in these embodiment of the invention can be a
pharmaceutically acceptable dry powder having a particle size in
the range of from about 5 .mu.m to about 150 .mu.m including all
values and ranges therebetween; and in certain embodiments in the
range of from about 35 .mu.m to about 80 .mu.m. Suitable binders
for rotomelt granulation are low melting point powdered binders,
examples of which include: polyethylene glycol 4000, polyethylene
glycol 6000, stearic acid, and low melting point waxes. Suitable
low melting point waxes include but are not limited to glyceryl
monostearate, hydrogenated tallow, myristyl alcohol, myristic acid,
stearyl alcohol, substituted monoglycerides, substituted
diglycerides, substituted triglycerides, white beeswax, carnauba
wax, castor wax, japan wax, acetylate monoglycerides and
combinations thereof. The binders can have a melting point of from
about 30.degree. C. to about 100.degree. C. including all values
and ranges therebetween; and in certain embodiments from about
40.degree. C. to about 85.degree. C.
[0407] As a prophetic example of these embodiments that are
manufactured by a rotomelt granulation process, about 320 g of
bupropion hydrobromide and about 80 g PEG 8000 is dry blended and
poured into a Glatt 1.1 chamber set-up as a rotary granulator with
a longitudinal plate. Inlet air temperature is set to about
60.degree. C. and the product chamber heated to approximately
50.degree. C. The blend is fluidized at approximately 120 m3/hr and
the frictional plate set to about 900 rpm. The product chamber
temperature is raised to about 60.degree. C. and then gradually
reduced to about 20.degree. C. over a period of approximately 20
minutes, during which spheronization is achieved.
[0408] Other embodiments of the invention involve the formation of
a microparticle that has a core which includes bupropion
hydrobromide and a compound which is sweet in taste and which has a
negative heat of solution. Examples of compounds falling into this
category include mannitol and sorbitol. Sugars or artificial
sweeteners to which, for example, menthol have been added can also
work as well. A binder and/or other excipient can also be disposed
within the core. The amount of sweetening compound used can depend
on a number of factors including the size of the resulting
microparticles, the size or volume of the resulting tablet, the
sturdiness of the microparticle-coated microparticulant, the speed
at which the tablet will disintegrate in the mouth, the degree of
sweetness imparted by the particular sweetener used, either in the
microparticle or in the tablet, or both, the amount of drug used,
and the like. For example, particularly rugged microparticles can
be less likely to break during chewing and/or compression.
Therefore, the amount of material provided to protect against the
release of objectionably flavored material can be lessened. In
other cases a greater relative amount of sweetening compound can be
used. Generally, the amount of sweetening material used will range
from greater than zero to about 80% of the weight of the resulting
microparticles including all values and ranges therebetween. The
sweetener and bupropion hydrobromide can be combined in any number
of known ways, such as for example by wet granulation, dry
granulation, agglomeration, or spray coating. For example, the
sweetener can be used as an adsorbent for the active agent.
Alternatively, particles of each can also be simply mixed together.
One or more binders, or other adjuvants can also be used in the
formulation of a tablet as well. Binders in these embodiments
include, for example: starch (for example, in an amount of from
about 5% to about 10% including all values and ranges therebetween,
as an aqueous paste); pregelatinized starch (for example, in an
amount of about 5% to about 10% including all values and ranges
therebetween, added dry to powder); gelatin (for example, in an
amount of from about 2% to about 10% including all values and
ranges therebetween, as an aqueous solution, or about 2% in starch
paste); polyvinylpyrrolidone (for example, in an amount of from
about 2% to about 20% including all values and ranges therebetween,
in an aqueous or alcoholic solution); methylcellulose (for example,
in an amount of from about 2% to about 10% including all values and
ranges therebetween, as an aqueous solution); sodium carboxy
methylcellulose (for example, in an amount of from about 2% to
about 10% including all values and ranges therebetween, as an
aqueous solution); ethylcellulose (for example, in an amount of
from about 5% to about 10% including all values and ranges
therebetween, as an alcohol or hydroalcoholic solution);
polyacrylamides (Polymer JR) (for example, in an amount of from
about 2% to about 8% including all values and ranges therebetween,
as an aqueous solution); polyvinyloxoazolidone (Devlex) (for
example, in an amount of from about 5% to about 10% including all
values and ranges therebetween, as an aqueous or hydroalcoholic
solution); and polyvinyl alcohols (for example, in an amount of
from about 5% to about 20% including all values and ranges
therebetween, in aqueous solutions). Other adjuvants can also be
used in forming the core of the microparticles of the present
embodiments of the invention, non-limiting examples of which
include: calcium sulfate NF, Dibasic Calcium phosphate NF, Tribasic
calcium sulfate NF, starch, calcium carbonate, microcrystalline
cellulose, modified starches, lactose, sucrose and the like,
STA-RXT.TM., AVICEL.TM., SOLKA-FLOC.TM. BW40, alginic acid,
EXPLOTAB.TM., AUTOTAB.TM., guar gum, kaolin VECGUM.TM., and
bentonite. These adjuvants can be used in up to about 20% w/w; and
in certain embodiments are present in an amount of from about 3% to
about 5% w/w including all values and ranges therebetween.
[0409] As a prophetic example of these embodiments that have a core
comprising bupropion hydrobromide and a compound which is sweet in
taste, bupropion hydrobromide can be granulated using the following
procedure: Polyvinylpyrrolidone K-30 USP (about 240.0 gm) is
dissolved into distilled water (about 1,890.0 gm) with agitation.
Mannitol powder USP (about 11,160 gm) and bupropion hydrobromide
(about 600.0 gm) are placed in a Zanchetta 50-liter
granulator/processor. After an initial two-minute dry mix of the
powders with the chopper on and the propeller adjusted to about 200
rpm, the polyvinylpyrrolidone K-30 solution is slowly sprayed into
the mixing powder bed using an air-driven spray system. The total
time of granulation including the time of solution addition is
approximately eight minutes. The granulation end-point is
determined visually and by the consistency of the resulting
material. The material is then discharged onto trays and dried at
about 80.degree. C. utilizing supplied dry air for a period of
about six hours to a moisture content of not more than about 0.08
percent. The dried material is then passed through a hammermill
(knives forward) equipped with a U.S. #40 (420 micron) screen.
[0410] Other embodiments of this invention involve the combined
granulation and coating of bupropion hydrobromide into
microparticles in which the drug is at least partly located within
the microparticle core but capable of immediate release. To do
this, the bupropion hydrobromide and a granular disintegrant are
first dry-mixed; the powder obtained is then granulated, in the
presence of a mixture of excipients comprising at least one binder
capable of binding the particles together to give grains; the
grains thus formed are then coated by spraying with a suspension
comprising at least one coating agent and a membrane disintegrant;
and then the coated granules obtained are dried. The distinction
between the actual granulation and coating steps is relatively
theoretical, insofar as, even though the primary function of the
binder used in the granulation step is to bind together the
particles, it nevertheless already partially coats the grains
formed. Similarly, even though the primary function of the coating
agent used in the actual coating step is to complete the final
coating of each of the grains, it may, however, arbitrarily bind
other coated grains by a mechanism of granular agglomeration. The
binder and the coating agent are chosen from the group comprising
cellulose polymers and acrylic polymers. However, even though the
binder and the coating agent are chosen from the same group of
compounds, they nevertheless differ from each other in their
function as previously mentioned. Among the cellulose polymers that
can be advantageously chosen are ethylcellulose,
hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC) and
hydroxypropylmethylcel lu-lose (HPMC), or mixtures thereof. Among
the acrylic polymers that can be advantageously chosen are the
ammonio-methacrylate copolymer (EUDRAGIT.RTM. RL or RS), the
polyacrylate (EUDRAGIT.RTM. NE) and the methacrylic acid copolymer
(EUDRAGIT.RTM. L or S). In at least one embodiment, the binder is
of the same nature as the coating agent. To further accelerate the
release of the bupropion hydrobromide, the coating suspension also
comprises a permeabilizer which, on account of its intrinsic
solubility properties, causes perforation of the membrane coating,
thus allowing the bupropion hydrobromide to be released.
Non-limiting examples of permeabilizers include povidone and its
derivatives, polyethylene glycol, silica, polyols and low-viscosity
cellulose polymers. Polymers of the type such as hypromellose,
whose viscosity is equal to about 6 centipoises, are used, for
example, as low-viscosity cellulose polymer. In at least one
embodiment, the dry-mixing of initial powder and the granulation,
coating and drying steps are performed in a fluidized bed. In this
case, the initial powder mixture is first fluidized before being
granulated by spraying said powder with the excipient mixture
comprising at least the binder, the grains obtained then being
coated by spraying with the coating suspension, the coated granules
formed finally being dried in the fluidized bed. In at least one
embodiment, the mixture of excipients used during the granulation
step and the coating suspension used during the coating step form a
single mixture. In this case, the granulation step can be
distinguished from the spraying step by varying different
parameters, such as the rate of spraying of the mixture and the
atomization pressure of said mixture. Thus, only some of the
mixture of excipients is used during the granulation step, while
the other portion can be used during the coating step.
[0411] Thus, the rate of spraying of the coating suspension is
higher during the granulation step than during the coating step,
whereas the atomization pressure of the coating suspension is lower
during the granulation step than during the coating step. In
practice, at the laboratory scale in a fluidized-bed device, for
example of the type such as Glatt GPCG1, during the granulation
step, the rate of spraying of the coating suspension is from about
10 grams/minute to about 25 grams/minute including all values and
ranges therebetween, and the atomization pressure is from about 1
bar to about 1.8 bar including all values and ranges therebetween.
During the coating step, the rate of spraying of the coating
suspension is from about 5 grams/minute to about 15 grams/minute
including all values and ranges therebetween, while the atomization
pressure is from about 1.5 bar to about 2.5 bar including all
values and ranges therebetween. In at least one embodiment, from
about 10% to about 20% including all values and ranges
therebetween, of the mixture of excipients is sprayed during the
granulation step, the remainder being sprayed during the coating
step.
[0412] As a prophetic example of these embodiments that involve the
combined granulation and coating of bupropion hydrobromide into
microparticles in which the drug is at least partly located within
the microparticle core but capable of immediate release, the
microparticles can be manufactured according to the following
process: A granulation solution is first prepared by dissolving
about 48 g of ethylcellulose in about 273 g of ethyl alcohol. A
coating suspension is then prepared by mixing about 97 g of
ethylcellulose, about 28.5 g of polyethylene glycol 6000, about 26
g of sodium croscarmellose, about 10 g of precipitated silica and
about 27.5 g of aspartam in about 1900 g of ethyl alcohol, until a
homogeneous suspension is obtained. The powder mixture consisting
of about 700 grams of bupropion hydrobromide and about 35 grams of
Acdisol is then fluidized. The granulation is then started by
spraying the granulation solution for about 15 to about 20 minutes
at a spraying rate of about 25 grams/minute and a suspension
atomization pressure of about 0.8 bar. The actual coating is then
performed by spraying the coating suspension for about 1 hour 30
minutes at a spraying rate of about 15 to about 20 grams/minute and
a suspension spraying pressure of about 1.5 bar.
[0413] Other embodiments of the invention involve coating the
bupropion hydrobromide material, thereby forming a drug-containing
microparticle. One such process for achieving this involves:
[0414] Blending and fluidizing a powder mix of active principle and
an adjuvant in order to obtain individual grains,
[0415] Separately liquefying under warm conditions a lipid matrix
agent comprising either an ester of behenic acid and alcohol or an
ester of palmitic/stearic acid and alcohol,
[0416] Coating the fluidized powder mix under warm conditions by
spraying the lipid matrix agent over the individual grains,
[0417] Lowering the temperature of the combined product in order to
allow the lipid matrix agent to solidify.
[0418] This process does not require an evaporation phase or a
drying phase, since it does not require a wet-route or
solvent-route granulation step, thus making it possible to be freed
from any risk due to the presence of toxic residues in the final
product. Furthermore, it is not necessary to carry out the
quantitative determination of the traces of solvents, an analysis
that can be very expensive. According to the process of this
embodiment of the invention, the spraying conditions and thus the
coating characteristics can be modified, in order to vary the
release profile of bupropion hydrobromide, by varying several
parameters, the adjustment characteristics of which remain simple.
Thus, the spraying air pressure can be increased in order to
promote the formation of a homogeneous film of lipid matrix agent
around the grains. Advantageously, the rate of spraying of the
lipid matrix agent can simultaneously be decreased. In this case,
the bupropion hydrobromide release profile, that is to say a
percentage of dissolution as a function of the time, is obtained
which can be low, corresponding to a slow release of the drug.
Conversely, the spraying air pressure can be decreased in order to
promote the agglomeration of the grains with one another.
Advantageously, the rate of spraying of the lipid matrix agent can
simultaneously be increased. In this case, a release profile of the
grains obtained can be obtained which is high, corresponding to a
rapid release of bupropion hydrobromide. In practice and according
to the mass of powder employed, the value of the rate of spraying
of the lipid matrix agent can be from two to four times higher when
it is desired to promote the agglomeration of the grains with one
another than when it is desired to promote the formation of a
homogeneous film around the grains. On the other hand, the value of
the spraying air pressure can be from one to two times lower when
it is desired to promote the agglomeration of the grains with one
another than when it is desired to promote the formation of a
homogeneous film around the grains. According to the process for
manufacturing these embodiments, it is possible, after having
determined a given drug release profile, to vary the values of
spraying air pressure and of spraying rate throughout the coating
stage, making it possible to promote the formation of a homogeneous
film around the grains or to promote the agglomeration of the
grains. Once the sequence of the duration of the spraying air
pressure and of the spraying rate has been determined, the coating
operation can be carried out continuously and automatically.
According to another characteristic of the process of manufacturing
these embodiments, the temperature of the mixture of liquefied
matrix agent and of spraying air is greater by about 35.degree. C.
to about 60.degree. C. than the melting temperature of the lipid
matrix agent. Likewise, the temperature of the fluidization air and
that of the powder is approximately equal to the melting
temperature of the lipid matrix agent, plus or minus about
10.degree. C. Furthermore, in order to obtain a mixture of
individual grains, an air-operated fluidized bed device or a
turbine device can be used. Furthermore, the lipid matrix agent can
be sprayed by the air spray technique, that is to say liquid
spraying under pressure in the presence of compressed air.
According to at least one embodiment, use is made of a powder
comprising the drug and the adjuvant. In other words, after mixing
and fluidizing the combined constituents of the powder, the lipid
matrix agent is sprayed over the individual grains obtained. In
order to avoid adhesion of the coated grains obtained, whether in
the case where all the grains are treated or whether in the case
where only a portion of the grains is treated, a stage of
lubrication of the grains is inserted between the coating stage and
the stage of putting into a pharmaceutical form. Furthermore, in
order to obtain greater stability of the pharmaceutical
composition, that is to say in order to minimize modifications
relating to the release of the bupropion hydrobromide over time,
the granules or tablets obtained in certain embodiments of this
example can be subjected to a maturing stage in an oven, for at
least about 8 hours, at a temperature of from about 45.degree. C.
to about 60.degree. C.; and in certain embodiments at about
55.degree. C.
[0419] As a prophetic example of these drug-containing
microparticle embodiments that are formed by coating the bupropion
hydrobromide material, the drug-containing microparticles can be
manufactured according to the following process: A mixture of
powder is prepared comprising: bupropion hydrobromide; dicalcium
phosphate dehydrate; and polyvinylpyrrolidone. Batches of granules
are prepared by a process comprising the following stages: the
mixture of powder obtained is sieved; the said powder is mixed,
heating while by means of an air-operated fluidized bed, in order
to obtain individual grains; the lipid matrix agent (glyceryl
behenate, e.g. COMPRITOL.RTM. 880 ATO) is liquefied separately at
about 120.degree. C.; the lipid matrix agent is sprayed over the
heated powder mixture, and, finally, the temperature is lowered in
order to allow the lipid matrix agent to solidify. These stages are
carried out while varying various parameters, either in order to
promote the formation of a homogeneous film around the grains or in
order to promote the agglomeration of the grains, in accordance
with the following table:
TABLE-US-00010 Parameters Batch 1 Batch 2 Batch 3 Batch 4 % by
weight of lipid matrix agent (COMPRITOL .RTM. 888 ATO) 5 4 4 5
Fluidization air flow rate (m3/h) 80 110 80 80 Agglomeration
Atomization air pressure (bar) 2 1.5 1.5 Temperature of the powder
bed 70 70 74 (.degree. C.) Spraying rate for COMPRITOL .RTM. 42 40
40 (g/min) Coating Atomization air pressure (bar) 2.5 3.5 2 2
Temperature of the powder bed 70 66 71 70 (.degree. C.) Spraying
rate for COMPRITOL .RTM. 41 20 40 40 (g/min)
[0420] Another embodiment of the invention for coating the
bupropion hydrobromide material, thereby forming a drug-containing
microparticle, involves the formation of coated microcrystals that
can subsequently be incorporated into a tablet. Through selection
of the appropriate polymer the microcrystals can possess
diversified features such as gastroresistance and controlled
release due to the fact that the said coated or non-coated
microcrystals and microgranules preserve, after having been shaped
in the form of a multiparticulate tablet, their initial properties
amongst which are included masking of taste, gastroresistance and
controlled release of the bupropion hydrobromide. In certain
embodiments of this example, the following non-limiting list of
polymers can be selected for coating of the bupropion hydrobromide
in conventional fluidized based coating equipment: ethylcellulose
(EC); hydroxypropylcellulose (HPC); hydroxypropylmethylcellulose
(HPMC); gelatin; gelatin/acacia; gelatin/acacia/vinvylmethylether
maleic anhydride; gelatin/acacia/ethylenemaleic anhydride;
carboxymethyl cellulose; polyvinvylalcohol; cellulose acetate
phthalate; nitrocellulose; shellac; wax; polymethacrylate polymers
such as EUDRAGIT.RTM. RS; EUDRAGIT.RTM. RL or combinations of both,
EUDRAGIT.RTM. E and EUDRAGIT.RTM. NE30D; KOLLICOAT.TM. SR30D; and
mixtures thereof.
Drug-Layered Microparticles
[0421] The drug-layered microparticles of certain embodiments can
be made by coating an inert particle or core, such as a non-pareil
sphere (e.g. sugar sphere), with the bupropion hydrobromide salt
and a polymeric binder. In certain embodiments of the drug-layered
microparticles, the inert cores include water-insoluble materials
such as cellulose spheres or silicon dioxide. In other embodiments,
the inert cores include water-soluble materials such as starch,
salt or sugar spheres. The inert cores can have a diameter ranging
from about 100 microns to about 2000 microns including all values
and ranges therebetween. For example, in certain embodiments the
diameter of the inert cores range from about 150 microns to about
1500 microns. In at least one embodiment, the inert cores are sugar
spheres NF, containing not less than about 62.5% and not more than
about 91.5% of sucrose including all values and ranges
therebetween. In at least one embodiment the inert cores have
substantially consistent bulk density, low friability, and low dust
generation properties. In at least one embodiment, the inert cores
are coated with an osmotic sub-coat comprising an osmotic agent and
a polymeric binding agent. Further, the inert cores can initially
be coated with a seal-coat to provide a more consistent core
surface and to minimize any osmotic effects. The seal-coat layer
can be applied to the core prior to the application of the drug,
polymeric binder, and any polymeric film layers. In at least one
embodiment, the seal-coat layer does not substantially modify the
release of the bupropion hydrobromide salt. Examples of suitable
sealants that can be used in the seal-coat include permeable or
soluble agents such as hydroxypropyl methylcellulose, hydroxypropyl
cellulose, ethylcellulose, a polymethacrylate polymer,
hydroxypropyl ethylcellulose, xanthan gum, and mixtures thereof. In
at least one embodiment the sealant used in the seal-coat is
hydroxypropyl methylcellulose. Other agents can be added to improve
the processability of the sealant. Examples of such agents include
talc, colloidal silica, polyvinyl alcohol, titanium dioxide,
micronised silica, fumed silica, glycerol monostearate, magnesium
trisilicate, magnesium stearate, and mixtures thereof. The
seal-coat layer can be applied from solution (e.g. aqueous) or
suspension using a fluidised bed coater (e.g. Wurster coating), or
in a pan coating system. Examples of such seal-coats coatings are
commercially available (e.g. OPADRY.RTM. White Y-1-7000 and
OPADRY.RTM. OY/B/28920 White).
[0422] The binding agent of these drug-layered embodiments is used
to adhere the bupropion hydrobromide salt layer to the inert core
or seal-coat of the core. In certain embodiments, the binding agent
is water soluble, possesses sufficiently high adhesivity in order
to adhere the bupropion hydrobromide salt layer to the inert core,
and possesses an appropriate viscosity to provide substantial
adhesion between the inert core and the bupropion hydrobromide
salt. In other embodiments the binding agent is water-insoluble. In
at least one embodiment the binding agent is ethyl cellulose, a
polymethacrylate polymer, polyvinylalcohol, polyvinyl pyrrolidone,
polyvinylpyrrolidone-vinylacetate copolymer (such as KOLLIDON.RTM.
VA64), hydroxyethylcellulose, low molecular weight
hydroxypropylmethylcellulose (e.g. viscosity of about 1-50 cps at
about 20.degree. C.; about 2-12 cps at about 20.degree. C.; or
about 4-6 cps at about 20.degree. C.), hydroxypropylcellulose
polymethacrylates, or mixtures thereof. For example, in certain
embodiments the composition of the binder for bupropion
hydrobromide is from about 1% to about 25% w/w including all values
and ranges therebetween; in other embodiments from about 2% to
about 10% w/w; and in still other embodiments from about 3% to
about 5% w/w, expressed as a percentage of the total weight of the
core.
[0423] Solvents can be used to apply the bupropion hydrobromide
salt to the inert core, examples of which include lower alcohols
such as ethanol, isopropanol and alcohol/water mixtures, acetone
and chlorinated hydrocarbons.
[0424] The drug-layered microparticles can be prepared by forming a
suspension or solution of the binder and the bupropion hydrobromide
salt and then layering the suspension or solution on to the inert
or sub-coated core using any of the layering techniques known in
the art, such as fluidized bed coating or pan coating. This can be
affected in a single coating or the process can be carried out in
multiple layers, optionally with intervening drying/evaporation
steps. This process can be conducted so as to produce
microparticles containing a desired amount of bupropion
hydrobromide salt and achieve the desired dosage and release
thereof upon in-vivo administration.
[0425] In certain embodiments, the drug-layered microparticles can
be manufactured using for example, the procedure in the following
hypothetical experiment: Bupropion hydrobromide (about 2.8 kg) and
hydroxypropyl methylcellulose (METHOCEL.RTM. E5) (about 0.40 kg) is
dissolved in a mixture of water and isopropyl alcohol. The active
drug solution can then be sprayed onto sugar spheres 30/35 (about
1.06 kg) in a fluidized bed processor with a Wurster insert. The
active core microparticles can then be dried in a fluidized bed
processor until the loss on drying is below about 1%. The bupropion
microparticles can then be passed through a 16 mesh screen and a 30
mesh screen and microparticles can be collected that are smaller
than 16 mesh and larger than 30 mesh.
Microparticle Taste-Masking Coatings
[0426] The microparticles of the present invention can each be
coated with at least one taste-masking coating. The taste-masking
coating can mask the taste of the active drug in the
microparticles. In at least one embodiment the taste-masking
coating formulations contain polymeric ingredients. It is
contemplated that other excipients consistent with the objects of
the present invention can also be used in the taste-masking
coating.
[0427] In at least one embodiment, the taste-masking coating
comprises a polymer such as ethylcellulose, which can be used as a
dry polymer (e.g. ETHOCEL.RTM.) solubilised in organic solvent
prior to use, or as an aqueous dispersion. One
commercially-available aqueous dispersion of ethylcellulose is
AQUACOAT.RTM.. AQUACOAT.RTM. can be prepared by dissolving the
ethylcellulose in a water-immiscible organic solvent and then
emulsifying the same in water in the presence of a surfactant and a
stabilizer. After homogenization to generate submicron droplets,
the organic solvent is evaporated under vacuum to form a
pseudolatex. The plasticizer is not incorporated in the pseudolatex
during the manufacturing phase. Thus, prior to using the same as a
coating, the AQUACOAT.RTM. is intimately mixed with a suitable
plasticizer prior to use. Another aqueous dispersion of
ethylcellulose is commercially available as SURELEASE.RTM.. This
product can be prepared by incorporating plasticizer into the
dispersion during the manufacturing process. A hot melt of a
polymer, plasticizer (e.g. dibutyl sebacate), and stabilizer (e.g.
oleic acid) is prepared as a homogeneous mixture, which is then
diluted with an alkaline solution to obtain an aqueous dispersion
which can be applied directly onto substrates.
[0428] In other embodiments, polymethacrylate acrylic polymers can
be employed as taste masking polymers. In at least one embodiment,
the taste masking coating is an acrylic resin lacquer used in the
form of an aqueous dispersion (e.g. EUDRAGIT.RTM. or
KOLLICOAT.RTM.). In further embodiments, the acrylic coating
comprises a mixture of two acrylic resin lacquers (e.g.
EUDRAGIT.RTM. RL and EUDRAGIT.RTM. RS, respectively).
[0429] EUDRAGIT.RTM. RL and EUDRAGIT.RTM. RS are copolymers of
acrylic and methacrylic esters with a low content of quaternary
ammonium groups, the molar ratio of ammonium groups to the
remaining neutral (meth)acrylic esters being 1:20 in EUDRAGIT.RTM.
RL and 1:40 in EUDRAGIT.RTM. RS. The mean molecular weight is
150,000. The code designations RL (high permeability) and RS (low
permeability) refer to the permeability properties of these agents.
EUDRAGIT.RTM. RL/RS mixtures are insoluble in water and in
digestive fluids. However, coatings formed from the same are
swellable and permeable in aqueous solutions and digestive fluids.
EUDRAGIT.RTM. RL/RS dispersions or solutions of certain embodiments
can be mixed together in any desired ratio in order to ultimately
obtain a taste masking coating having a desirable drug dissolution
profile. In certain embodiments formulations can be obtained, for
example, from a coating derived from 100% EUDRAGIT.RTM. RL; 50%
EUDRAGIT.RTM. RL with 50% EUDRAGIT.RTM. RS; and 10% EUDRAGIT.RTM.
RL with 90% EUDRAGIT.RTM. RS.
[0430] In other embodiments, the taste masking polymer can be an
acrylic polymer which is cationic in character based on
dimethylaminoethyl methacrylate and neutral methacrylic acid esters
(e.g. EUDRAGIT.RTM. E). The hydrophobic acrylic polymer coatings of
the present invention can further include a neutral copolymer based
on poly (meth)acrylates, such as EUDRAGIT.RTM. NE. EUDRAGIT.RTM. NE
30D lacquer films are insoluble in water and digestive fluids, but
permeable and swellable.
[0431] In other embodiments, the taste masking polymer is a
dispersion of poly (ethylacrylate, methyl methacrylate) 2:1
(KOLLICOAT.RTM. EMM 30 D, BASF).
[0432] In other embodiments, the taste masking polymer can be a
polyvinyl acetate stabilized with polyvinylpyrrolidone and sodium
lauryl sulfate such as KOLLICOAT.RTM. SR30D (BASF).
[0433] Other taste masking polymers include hydroxypropylcellulose
(HPC); hydroxypropylmethylcellulose (HPMC); hydroxyethylcellulose;
gelatin; gelatin/acacia; gelatin/acacia/vinvylmethylether maleic
anhydride; gelatin/acacia/ethylenemaleic anhydride; carboxymethyl
cellulose; polyvinvylalcohol; nitrocellulose;
polyvinylalcohol-polyethylene glycol graft-copolymers; shellac; wax
and mixtures thereof.
[0434] The taste-masking coatings can be applied to the
microparticles from one or more organic or aqueous solvent
solutions or suspensions. In at least one embodiment the organic
solvents that can be used to apply the taste-masking coatings
include one or more of acetone, lower alcohols such as ethanol,
isopropanol and alcohol/water mixtures, chlorinated hydrocarbons,
and the like. Devices used to coat the microparticles of the
invention with a taste-masking coating include those conventionally
used in pharmaceutical processing, such as fluidized bed coating
devices. The coatings applied to the microparticles can contain
ingredients other than the functional polymers. One or more
colorants, flavorants, sweeteners, can also be used in the
taste-masking coating.
[0435] In some embodiments a pore former can be included into the
taste masking coat in order to influence the rate of release of
bupropion hydrobromide from the microparticle. In other
embodiments, a pore former is not included in the taste masking
coat. The pore formers can be inorganic or organic, and include
materials such as particulate materials that can be dissolved,
extracted or leached from the coating in the environment of use.
Upon exposure to fluids in the environment of use, the pore-formers
can for example be dissolved, and channels and pores are formed
that fill with the environmental fluid.
[0436] For example, the pore-formers of certain embodiments can
comprise one or more water-soluble hydrophilic polymers in order to
modify the release characteristics of the formulation. Examples of
suitable hydrophilic polymers used as pore-formers include
hydroxypropylmethylcellulose, cellulose ethers and protein-derived
materials of these polymers, the cellulose ethers, such as
hydroxyalkylcelluloses and carboxyalkylcelluloses. Also, synthetic
water-soluble polymers can be used, examples of which include
polyvinylpyrrolidone, cross-linked polyvinyl-pyrrolidone,
polyethylene oxide, water-soluble polydextrose, saccharides and
polysaccharides, such as pullulan, dextran, sucrose, glucose,
fructose, mannitol, lactose, mannose, galactose, sorbitol and
mixtures thereof. In at least one embodiment, the hydrophilic
polymer comprises hydroxypropyl-methylcellulose.
[0437] Other non-limiting examples of pore-formers that can be used
in certain embodiments containing a taste masking coat include
alkali metal salts such as lithium carbonate, sodium chloride,
sodium bromide, potassium chloride, potassium sulfate, potassium
phosphate, sodium acetate, sodium citrate and mixtures thereof. The
pore-forming solids can also be polymers which are soluble in the
environment of use, such as CARBOWAX.TM., and CARBOPOL.TM.. In
addition, the pore-formers embrace diols, polyols, polyhydric
alcohols, polyalkylene glycols, polyglycols, poly(a-w)alkylenediols
and mixtures thereof. Other pore-formers which can be useful in the
formulations of certain embodiments of the present invention
include starch, modified starch, and starch derivatives, gums,
including but not limited to xanthan gum, alginic acid, other
alginates, benitoniite, veegum, agar, guar, locust bean gum, gum
arabic, quince psyllium, flax seed, okra gum, arabinoglactin,
pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin,
dextrin, etc., cross-linked polyvinylpyrrolidone, ion-exchange
resins, such as potassium polymethacrylate, carrageenan,
kappa-carrageenan, lambdacarrageenan, gum karaya, biosynthetic gum,
and mixtures thereof. Other pore-formers include materials useful
for making microporous lamina in the environment of use, such as
polycarbonates comprised of linear polyesters of carbonic acid in
which carbonate groups reoccur in the polymer chain, microporous
materials such as bisphenol, a microporous poly(vinylchloride),
micro-porous polyamides, microporous modacrylic copolymers,
microporous styrene-acrylic and its copolymers, porous
polysulfones, halogenated poly(vinylidene), polychloroethers,
acetal polymers, polyesters prepared by esterification of a
dicarboxylic acid or anhydride with an alkylene polyol,
poly(alkylenesulfides), phenolics, polyesters, asymmetric porous
polymers, cross-linked olefin polymers, hydrophilic microporous
homopolymers, copolymers or interpolymers having a reduced bulk
density, and other similar materials, poly(urethane), cross-linked
chain-extended poly(urethane), poly(imides), poly(benzimidazoles),
collodion, regenerated proteins, semi-solid cross-linked
poly(vinylpyrrolidone), and mixtures thereof.
[0438] In general, the amount of pore-former included in the taste
masking coatings of certain embodiments of the present invention
can be from about 0.1% to about 80%, by weight including all values
and ranges therebetween, relative to the combined weight of polymer
and pore-former. The percentage of pore former as it relates to the
dry weight of the taste-masking polymer, can have an influence on
the drug release properties of the coated microparticle. In at
least one embodiment that uses water soluble pore formers such as
hydroxypropylmethylcellulose, a taste masking polymer:pore former
dry weight ratio of from about 10:1 to about 1:1 including all
values and ranges therebetween, can be present. In certain
embodiments the taste masking polymer:pore former dry weight ratio
is from about 8:1 to about 1.5:1; and in other embodiments from
about 6:1 to about 2:1. In at least one embodiment using
EUDRAGIT.RTM. NE30D as the taste masking polymer and a
hydroxypropylmethylcellulose (approx 5 cps viscosity (in a 2%
aqueous solution)) such as METHOCEL.RTM. E5, Pharmacoat 606G as the
water soluble pore former, a taste masking polymer:pore former dry
weight ratio of about 2:1 is present.
[0439] Colorants that can be used in the taste-masking coating
include food, drug and cosmetic colors (FD&C), drug and
cosmetic colors (D&C) or external drug and cosmetic colors
(Ext. D&C). These colors are dyes, lakes, and certain natural
and derived colorants. Useful lakes include dyes absorbed on
aluminum hydroxide or other suitable carriers.
[0440] Flavorants that can be used in the taste-masking coating
include natural and synthetic flavoring liquids. An illustrative
list of such flavorants includes volatile oils, synthetic flavor
oils, flavoring aromatics, oils, liquids, oleoresins and extracts
derived from plants, leaves, flowers, fruits, stems and
combinations thereof. A non-limiting representative list of these
includes citric oils, such as lemon, orange, grape, lime and
grapefruit, and fruit essences, including apple, pear, peach,
grape, strawberry, raspberry, cherry, plum, pineapple, apricot, or
other fruit flavors. Other useful flavorants include aldehydes and
esters, such as benzaldehyde (cherry, almond); citral, i.e.,
alpha-citral (lemon, lime); neral, i.e., beta-citral (lemon, lime);
decanal (orange, lemon); aldehyde C-8 (citrus fruits); aldehyde C-9
(citrus fruits); aldehyde C-12 (citrus fruits); tolyl aldehyde
(cherry, almond); 2,6-dimethyloctanal (green fruit); 2-dodenal
(citrus mandarin); and mixtures thereof.
[0441] Sweeteners that can be used in the taste-masking coating
include glucose (corn syrup), dextrose, invert sugar, fructose, and
mixtures thereof (when not used as a carrier); saccharin and its
various salts, such as sodium salt; dipeptide sweeteners such as
aspartame; dihydrochalcone compounds, glycyrrhizin; Steva
Rebaudiana (Stevioside); chloro derivatives or sucrose such as
sucralose; and sugar alcohols such as sorbitol, mannitol, xylitol,
and the like. Also contemplated are hydrogenated starch
hydrolysates and the synthetic sweeteners such as
3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-1-2,2-dioxide,
particularly the potassium salt (acesulfame-K), and sodium and
calcium salts thereof. The sweeteners can be used alone or in any
combination thereof.
[0442] The microparticle taste masking coat can also include one or
more pharmaceutically acceptable excipients such as lubricants,
emulsifiers, anti-foaming agents, plasticizers, solvents and the
like.
[0443] Lubricants can be included to help reduce friction of coated
microparticles during manufacturing. The lubricants that can be
used in the taste masking coat of the present invention include but
are not limited to adipic acid, magnesium stearate, calcium
stearate, zinc stearate, calcium silicate, magnesium silicate,
hydrogenated vegetable oils, sodium chloride, sterotex,
polyoxyethylene, glyceryl monostearate, talc, polyethylene glycol,
sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate,
sodium stearyl fumarate, light mineral oil, waxy fatty acid esters
such as glyceryl behenate, (i.e. COMPRITOL.TM.), STEAR-O-WETT.TM.,
MYVATEX.TM. TL and mixtures thereof. In at least one embodiment,
the lubricant is selected from magnesium stearate, talc and a
mixture thereof. Combinations of these lubricants are operable. The
lubricant can each be present in an amount of from about 1% to
about 100% by weight of the polymer dry weight in the taste masking
coat including all values and ranges therebetween. For example, in
certain embodiments wherein the taste masking polymer is
EUDRAGIT.RTM. NE30D or EUDRAGIT.RTM. NE40D together with a
hydrophilic pore former, the lubricant is present in an amount of
from about 1% to about 30% by weight of the polymer dry weight; in
other embodiments from about 2% to about 20%; and in still other
embodiments at about 10% by weight of the microparticle taste
masking coat dry weight. In another embodiment where the taste
masking polymer is ethylcellulose (ETHOCEL.TM. PR100, PR45, PR20,
PR10 or PR7 polymer, or a mixture thereof), the lubricant can be
present in an amount of from about 10% to about 100% by weight of
the microparticle taste masking coat dry weight; in another
embodiment from about 20% to about 80%; and in still another
embodiments at about 50% by weight of the microparticle taste
masking coat dry weight. In other embodiments, the taste masking
coat does not include a pore former.
[0444] Emulsifying agent(s) (also called emulsifiers or emulgents)
can be included in the microparticle taste masking coat to
facilitate actual emulsification during manufacture of the coat,
and also to ensure emulsion stability during the shelf-life of the
product. Emulsifying agents useful for the microparticle taste
masking coat composition of certain embodiments include, but are
not limited to naturally occurring materials and their semi
synthetic derivatives, such as the polysaccharides, as well as
glycerol esters, cellulose ethers, sorbitan esters (e.g. sorbitan
monooleate or SPAN.TM. 80), and polysorbates (e.g. TWEEN.TM. 80).
Combinations of emulsifying agents are operable. In at least one
embodiment, the emulsifying agent is TWEEN.TM. 80. The emulsifying
agent(s) can be present in an amount of from about 0.01% to about
5% by weight of the microparticle taste masking polymer dry weight
including all values and ranges therebetween. For example, in
certain embodiments the emulsifying agent is present in an amount
of from about 0.05% to about 3%; in other embodiments from about
0.08% to about 1.5%, and in still other embodiments at about 0.1%
by weight of the microparticle taste masking polymer dry
weight.
[0445] Anti-foaming agent(s) can be included in the microparticle
taste masking coat to reduce frothing or foaming during manufacture
of the coat. Anti-foaming agents useful for the coat composition
include, but are not limited to simethicone, polyglycol, silicon
oil, and mixtures thereof. In at least one embodiment the
anti-foaming agent is Simethicone C. The anti-foaming agent can be
present in an amount of from about 0.1% to about 10% of the
microparticle taste masking coat weight including all values and
ranges therebetween. For example, in certain embodiments the
anti-foaming agent is present in an amount of from about 0.2% to
about 5%; in other embodiments from about 0.3% to about 1%, and in
still other embodiments at about 0.6% by weight of the
microparticle taste masking polymer dry weight.
[0446] Plasticizer(s) can be included in the microparticle taste
masking coat to provide increased flexibility and durability during
manufacturing. Plasticizers that can be used in the microparticle
taste masking coat of certain embodiments include acetylated
monoglycerides; acetyltributyl citrate, butyl phthalyl butyl
glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate;
ethyl phthalyl ethyl glycolate; glycerin; propylene glycol;
triacetin; tripropioin; diacetin; dibutyl phthalate; acetyl
monoglyceride; acetyltriethyl citrate, polyethylene glycols; castor
oil; rape seed oil, olive oil, sesame oil, triethyl citrate;
polyhydric alcohols, glycerol, glycerin sorbitol, acetate esters,
gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate,
dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate,
butyl octyl phthalate, dioctyl azelate, epoxidized tallate,
triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl
phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl
phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate,
di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl
azelate, dibutyl sebacate, diethyloxalate, diethylmalate,
diethylfumerate, dibutylsuccinate, diethylmalonate,
dibutylphthalate, dibutylsebacate, glyceroltributyrate, and
mixtures thereof. The plasticizer can be present in an amount of
from about 1% to about 80% of the taste masking polymer dry weight
including all values and ranges therebetween. For example, in
certain embodiments the plasticizer is present in an amount of from
about 5% to about 50%, in other embodiments from about 10% to about
40%, and in still other embodiments at about 20% of the taste
masking polymer dry weight.
[0447] The taste-masking coating can be present in an amount of
from about 1% to about 90% by weight of the microparticle including
all values and ranges therebetween, depending upon the choice of
polymer, the ratio of polymer:pore former, and the total surface
area of the microparticle formulation. Since a certain thickness of
taste masking coating has to be achieved in order to achieve
effective taste masking, the amount of taste masking polymer
coating used during manufacture is related to the total surface
area of the batch of uncoated microparticles that requires a
coating. The taste masking polymer surface area coverage can range
from about 0.5 mg/cm.sup.2 to about 20 mg/cm.sup.2 including all
values and ranges therebetween. For example, in certain embodiments
the surface area coverage of the taste masking polymer is from
about 0.6 mg/cm.sup.2 to about 10 mg/cm.sup.2, and in other
embodiments is from about 1 mg/cm.sup.2 to about 5 mg/cm.sup.2. In
at least one embodiment of the invention, EUDRAGIT.RTM. E is
employed as the taste masking polymer at a surface area coverage of
about 4 mg/cm.sup.2. One approach in estimating the total surface
area of a multiparticulate batch is the permeability method
according to Blaine (ASTM Des. C 205-55), which is based upon the
mathematical model of laminar flow through capillaries arranged in
parallel.
[0448] In the absence of an accurate determination of total surface
area of a microparticle, the amount of taste masking polymer to be
applied can be expressed as a percentage of the uncoated
microparticle. For example, in certain embodiments the
taste-masking coating is present in an amount of from about 5% to
about 60% including all values and ranges therebetween; in other
embodiments from about 10% to about 40%; and in still other
embodiments from about 15% to about 35% by weight of the
microparticle. In at least one embodiment the taste-masking coating
is present in an amount of about 30% by weight of the
microparticle.
[0449] In certain embodiments, the diameter of the microparticles
(with or without the taste-masking coating) range from about 50
.mu.m to about 800 .mu.m including all values and ranges
therebetween. For example, in certain embodiments the diameter of
the microparticles range from about 100 .mu.m to about 600 .mu.m,
and in other embodiments from about 150 .mu.m to about 450
.mu.m.
Microparticle Controlled Release Coat
[0450] The microparticles of the present invention can each be
coated with at least one controlled release coat. As used herein,
the term "microparticle controlled release coat" refers to the
controlled release coat that substantially surrounds each
microparticle. The microparticle controlled release coat is
designed to achieve a controlled release of the bupropion
hydrobromide salt from the microparticle. For example, the
microparticle controlled release coat can be an enteric coat with
low solubility at a gastric pH to reduce or minimize the drug
release in the lumen of the stomach, whilst possessing pH dependent
solubility to facilitate drug release in the duodenum. In another
embodiment, the controlled release coat can be a delayed release
coating that provides a delayed release of the bupropion
hydrobromide salt with a predetermined lagtime that is independent
of, or alternatively dependent on, the pH of the dissolution
medium. For example, by increasing the thickness of the
microparticle controlled release coat using a pH independent
diffusion polymer, lagtimes of about 1 hour, about 2 hours, about 3
hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours,
about 8 hours, about 9 hours, about 10 hours, about 11 hours, or
about 12 hours can be achieved. Alternatively, controlled release
polymers can be selected that become soluble above a certain pH.
Drug release from such a system is reduced or minimized until the
certain pH for the polymer of choice is exceeded. With either
approach, following the predetermined lag, drug is released, for
example within about 1 hour for an immediate release pulse, or
alternatively over a prolonged period of time, for example from
about 3 to about 24 hours. In other embodiments, the microparticle
controlled release coat can provide a diffusion barrier that is
independent of pH, thus facilitating a sustained release profile,
with substantially full release of the bupropion hydrobromide salt
occurring in from about 3 to about 24 hours following
administration. In at least one embodiment, the microparticle
controlled release coat provides a delayed and sustained release of
the bupropion hydrobromide salt from the microparticle with
substantially full release in about 24 hours following
administration.
[0451] In certain embodiments, the microparticle controlled release
coat can provide substantially full release of the bupropion
hydrobromide salt from the microparticle without requiring the use
of any pore formers. Unnecessary pore formers that are not required
in the microparticle controlled release coat include hydrophilic
polymers such as hydroxypropyl methylcellulose.
[0452] The microparticle controlled release coat includes at least
one polymer in an amount sufficient to achieve a controlled release
of the bupropion hydrobromide salt. In at least one embodiment of
the invention the controlled release polymer is an acrylic polymer.
Suitable acrylic polymers include but are not limited to acrylic
acid and methacrylic acid copolymers, methyl methacrylate
copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate,
aminoalkyl methacrylate copolymer, poly(acrylic acid),
poly(methacrylic acid, methacrylic acid alkylamine copolymer,
poly(methyl methacrylate), poly(methacrylic acid) (anhydride),
glycidyl methacrylate copolymers, and mixtures thereof.
[0453] In at least one embodiment the controlled release coat
comprises polymerizable quaternary ammonium compounds, of which
non-limiting examples include quaternized aminoalkyl esters and
aminoalkyl amides of acrylic acid and methacrylic acid, for example
.beta.-methacryl-oxyethyl-trimethyl-ammonium methosulfate,
.beta.-acryloxy-propyl-trimethyl-ammonium chloride,
trimethylaminomethyl-methacrylamide methosulfate and mixtures
thereof. The quaternary ammonium atom can also be part of a
heterocycle, as in methacryloxyethylmethyl-morpholiniom chloride or
the corresponding piperidinium salt, or it can be joined to an
acrylic acid group or a methacrylic acid group by way of a group
containing hetero atoms, such as a polyglycol ether group. Further
suitable polymerizable quaternary ammonium compounds include
quaternized vinyl-substituted nitrogen heterocycles such as
methyl-vinyl pyridinium salts, vinyl esters of quaternized amino
carboxylic acids, and styryltrialkyl ammonium salts. Other
polymerizable quaternary ammonium compounds useful in the present
invention include acryl- and methacryl-oxyethyltrimethyl-ammonium
chloride and methosulfate, benzyldimethylammoniumethyl-methacrylate
chloride, diethylmethylammoniumethyl-acrylate and -methacrylate
methosulfate, N-trimethylammoniumpropylmethacrylamide chloride,
N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride and
mixtures thereof.
[0454] In at least one embodiment, the polymer of the controlled
release coat is an acrylic polymer comprised of one or more ammonio
methacrylate copolymers. Ammonio methacrylate copolymers (e.g.
EUDRAGIT.RTM. RS and RL) are described in NF XVII as fully
polymerized copolymers of acrylic and methacrylic acid esters with
a low content of quaternary ammonium groups. In order to obtain a
desirable dissolution profile for a given therapeutically active
agent such as bupropion hydrobromide, it may be helpful in some
embodiments to incorporate two or more ammonio methacrylate
copolymers having differing physical properties. For example, it is
known that by changing the molar ratio of the quaternary ammonium
groups to the neutral (meth)acrylic esters, the permeability
properties of the resultant controlled release coat can be
modified.
[0455] In other embodiments of the present invention, the acrylic
polymer coating further includes a polymer whose permeability is pH
dependent, such as anionic polymers synthesized from methacrylic
acid and methacrylic acid methyl ester (e.g. EUDRAGIT.RTM. L and
EUDRAGIT.RTM. S). EUDRAGIT.RTM. L is insoluble in acids and pure
water, but becomes increasingly permeable above pH 5.0.
EUDRAGIT.RTM. S is similar, except that it becomes increasingly
permeable above pH 7. The hydrophobic acrylic polymer coatings can
also include a polymer which is cationic in character based on
dimethylaminoethyl methacrylate and neutral methacrylic acid esters
(e.g. EUDRAGIT.RTM. E). The hydrophobic acrylic polymer coatings of
certain embodiments can further include a neutral copolymer based
on poly (meth)acrylates, such as EUDRAGIT.RTM. NE
[0456] In other embodiments of the invention the controlled release
polymer is a dispersion of poly (ethylacrylate, methyl
methacrylate) 2:1 (e.g. KOLLICOAT.RTM. EMM 30 D). In other
embodiments the controlled release polymer can be a polyvinyl
acetate stabilized with polyvinylpyrrolidone and sodium lauryl
sulfate such as KOLLICOAT.RTM. SR30D. The dissolution profile can
be altered by changing the relative amounts of different acrylic
resin lacquers included in the coating. Also, by changing the molar
ratio of polymerizable permeability-enhancing agent (e.g., the
quaternary ammonium compounds) in certain embodiments to the
neutral (meth)acrylic esters, the permeability properties (and thus
the dissolution profile) of the resultant coating can be
modified.
[0457] In at least one embodiment the controlled release polymer is
ethylcellulose, which can be used as a dry polymer (e.g.
ETHOCEL.RTM.) solubilised in organic solvent prior to use, or as an
aqueous dispersion. One commercially available aqueous dispersion
of ethylcellulose is AQUACOAT.RTM.. AQUACOAT.RTM. can be prepared
by dissolving the ethylcellulose in a water-immiscible organic
solvent and then emulsifying the same in water in the presence of a
surfactant and a stabilizer. After homogenization to generate
submicron droplets, the organic solvent is evaporated under vacuum
to form a pseudolatex. The plasticizer is not incorporated in the
pseudolatex during the manufacturing phase. Thus, prior to using
the same as a coating, the AQUACOAT.RTM. is intimately mixed with a
suitable plasticizer prior to use. Another aqueous dispersion of
ethylcellulose is SURELEASE.RTM.. This product can be prepared by
incorporating a plasticizer into the dispersion during the
manufacturing process. A hot melt of a polymer, plasticizer (e.g.
dibutyl sebacate), and stabilizer (e.g. oleic acid) is prepared as
a homogeneous mixture, which is then diluted with an alkaline
solution to obtain an aqueous dispersion which can be applied
directly onto substrates.
[0458] Other examples of polymers that can be used in the
microparticle controlled release coat include cellulose acetate
phthalate, cellulose acetate trimaletate, hydroxy propyl
methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl
alcohol phthalate, shellac; hydrogels and gel-forming materials,
such as carboxyvinyl polymers, sodium alginate, sodium carmellose,
calcium carmellose, sodium carboxymethyl starch, poly vinyl
alcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose,
gelatin, starch, and cellulose based cross-linked polymers in which
the degree of crosslinking is low so as to facilitate adsorption of
water and expansion of the polymer matrix, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked
starch, microcrystalline cellulose, chitin, pullulan, collagen,
casein, agar, gum arabic, sodium carboxymethyl cellulose,
(swellable hydrophilic polymers) poly(hydroxyalkyl methacrylate)
(molecular weight from about 5 k to about 5000 k),
polyvinylpyrrolidone (molecular weight from about 10 k to about 360
k), anionic and cationic hydrogels, zein, polyamides, polyvinyl
alcohol having a low acetate residual, a swellable mixture of agar
and carboxymethyl cellulose, copolymers of maleic anhydride and
styrene, ethylene, propylene or isobutylene, pectin (molecular
weight from about 30 k to about 300 k), polysaccharides such as
agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides,
POLYOX.RTM. polyethylene oxides (molecular weight from about 100 k
to about 5000 k), AQUAKEEP.RTM. acrylate polymers, diesters of
polyglucan, crosslinked polyvinyl alcohol and poly
N-vinyl-2-pyrrolidone, hydrophilic polymers such as
polysaccharides, methyl cellulose, sodium or calcium carboxymethyl
cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose,
hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose,
cellulose ethers, methyl ethyl cellulose, ethylhydroxy
ethylcellulose, cellulose acetate, cellulose butyrate, cellulose
propionate, gelatin, starch, maltodextrin, pullulan, polyvinyl
pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty
acid esters, polyacrylamide, polyacrylic acid, natural gums,
lecithins, pectin, alginates, ammonia alginate, sodium, calcium,
potassium alginates, propylene glycol alginate, agar, and gums such
as arabic, karaya, locust bean, tragacanth, carrageens, guar,
xanthan, scleroglucan and mixtures and blends thereof.
[0459] In at least one embodiment the controlled release coat of
the microparticles comprises polymers that can facilitate
mucoadhsion within the gastrointestinal tract. Non-limiting
examples of polymers that can be used for mucoadhesion include
carboxymethylcellulose, polyacrylic acid, CARBOPOL.TM.,
POLYCARBOPHIL.TM., gelatin and other natural or synthetic
polymers.
[0460] In at least one embodiment the microparticles are coated
with a controlled release coat comprised of: at least one
film-forming polymer which is insoluble in the liquids of the
digestive tract, present in an amount of from about 50% to about
90% including all values and ranges therebetween (e.g. from about
50% to about 80%) by weight of dry matter of the controlled release
coat composition, and including at least one non-hydrosoluble
cellulose derivate, (e.g. ethylcellulose, cellulose acetate, or
mixtures thereof); at least one nitrogen-containing polymer,
present in an amount of from about 2% to about 25% including all
values and ranges therebetween (e.g. from about 5% to about 15%) by
weight of dry matter of the controlled release coat composition,
and including at least one polyacrylamide, poly-N-vinylaride,
poly-N-vinyl-lactame, polyvinylpyrrolidone, or mixtures thereof;
optionally a plasticizer present in an amount of from about 2% to
about 20% including all values and ranges therebetween (e.g. from
about 4% to about 15%) by weight of dry matter of the controlled
release coat composition, and including at least one of the
following compounds: glycerol esters, phtalates, citrates,
sebacates, cetylalcohol esters, castor oil, cutin, or mixtures
thereof; at least one surface-active and/or lubricating agent,
present in an amount of from about 2% to about 20% including all
values and ranges therebetween (e.g. from about 4% to about 15%) by
weight of dry matter of the controlled release coat composition,
and chosen from anionic surfactants such as the alkali metal and
alkakine-earth metal salts of fatty acids, (e.g. stearic acid,
oleic acid, and mixtures thereof), and/or from nonionic surfactants
such as polyoxyethylenated esters of sorbitan, polyoxyethylenated
esters of sorbitan, polyoxyethylenated derivatives of castor oil,
and/or from lubricants such as stearates (e.g. calcium, magnesium,
aluminium, zinc stearate and mixtures thereof), stearylfumarates
(e.g. sodium stearylfumarate, glyceryl behenate and mixtures
thereof); and mixtures thereof; wherein the coated microparticles
are designed so as to be able to remain in the small intestine for
a period of at least about 5 hours; in certain embodiments at least
about 7 hours; and in certain other embodiments for a period of
from about 8 hours to about 24 hours; so as to allow absorption of
the bupropion hydrobromide during at least part of its time in the
small intestine.
[0461] In a prophetic example of this embodiment of the invention,
the microparticles are coated in a fluidized bead coater with the
following coating solution:
TABLE-US-00011 Ethylcellulose about 44.7 g PVP about 4.8 g Castor
oil about 4.8 g Magnesium Stearate about 6.1 g Acetone about 479 g
Isopranol about 53 g
[0462] In other embodiments of the present invention, the release
of the bupropion hydrobromide from a controlled release formulation
can be further influenced, i.e., adjusted to a desired rate, by the
addition of one or more pore-formers to the controlled release
coat, where the pore-formers can be inorganic or organic, and can
include materials that can be dissolved, extracted or leached from
the controlled release coat in the environment of use. Upon
exposure to fluids in the environment of use, the pore-formers are,
for example, dissolved, and channels and pores are formed that fill
with the environmental fluid. For example, the pore-formers can
include one or more water-soluble hydrophilic polymers in order to
modify the release characteristics of the formulation. Non-limiting
examples of suitable hydrophilic polymers include
hydroxypropylmethylcellulose, cellulose ethers and protein-derived
materials of these polymers, the cellulose ethers, (e.g.
hydroxyalkylcelluloses and carboxyalkylcelluloses), and mixtures
thereof. Also, synthetic water-soluble polymers can be used, such
as polyvinylpyrrolidone, cross-linked polyvinyl-pyrrolidone,
polyethylene oxide, water-soluble polydextrose, saccharides and
polysaccharides, such as pullulan, dextran, sucrose, glucose,
fructose, mannitol, lactose, mannose, galactose, sorbitol, and
mixtures thereof. In at least one embodiment the hydrophilic
polymer(s) include hydroxypropyl-methylcellulose. Other examples of
pore-formers include alkali metal salts such as lithium carbonate,
sodium chloride, sodium bromide, potassium chloride, potassium
sulfate, potassium phosphate, sodium acetate, sodium citrate, and
mixtures thereof. The pore-forming solids can also be polymers
which are soluble in the environment of use, such as CARBOWAX.RTM.,
CARBOPOL.RTM., and the like. The possible pore-formers embrace
diols, polyols, polyhydric alcohols, polyalkylene glycols,
polyglycols, poly(a-w)alkylenediols, and mixtures thereof. Other
pore-formers which can be useful in the formulations of the present
invention include starch, modified starch, and starch derivatives,
gums, including but not limited to xanthan gum, alginic acid, other
alginates, benitoniite, veegum, agar, guar, locust bean gum, gum
arabic, quince psyllium, flax seed, okra gum, arabinoglactin,
pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin,
dextrin, etc., cross-linked polyvinylpyrrolidone, ion-exchange
resins, such as potassium polymethacrylate, carrageenan,
kappa-carrageenan, lambda-carrageenan, gum karaya, biosynthetic
gum, and mixtures thereof. Other pore-formers include materials
useful for making microporous lamina in the environment of use,
such as polycarbonates comprised of linear polyesters of carbonic
acid in which carbonate groups reoccur in the polymer chain,
microporous materials such as bisphenol, a microporous
poly(vinylchloride), micro-porous polyamides, microporous
modacrylic copolymers, microporous styrene-acrylic and its
copolymers, porous polysulfones, halogenated poly(vinylidene),
polychloroethers, acetal polymers, polyesters prepared by
esterification of a dicarboxylic acid or anhydride with an alkylene
polyol, poly(alkylenesulfides), phenolics, polyesters, asymmetric
porous polymers, cross-linked olefin polymers, hydrophilic
microporous hiomopolymers, copolymers or interpolymers having a
reduced bulk density, and other similar materials, poly(urethane),
cross-linked chain-extended poly(urethane), poly(imides),
poly(benzimidazoles), collodion, regenerated proteins, semi-solid
cross-linked poly(vinylpyrrolidone), and mixtures thereof.
[0463] In other embodiments a surfactant or an effervescent base
can be included in the controlled release coat, which can reduce
and in certain embodiments overcome surface tension effects. In
addition, the controlled release coat of certain embodiments can
include one or more osmagents (i.e., which can osmotically deliver
the active agent from the device by providing an osmotic pressure
gradient against the external fluid), swelling agents (i.e., which
can include, but are not limited to hydrophilic pharmaceutically
acceptable compounds with various swelling rates in water), or
other pharmaceutically acceptable agents (i.e., provided in an
amount sufficient to facilitate the entry of the environmental
fluid without causing the disruption of the impermeable coating).
The surfactants that can be used in the controlled release coat of
certain embodiments can be anionic, cationic, nonionic, or
amphoteric. Non-limiting examples of such surfactants include
sodium lauryl sulfate, sodium dodecyl sulfate, sorbitan esters,
polysorbates, pluronics, potassium laurate, and mixtures thereof.
Non-limiting examples of effervescent bases that can be used in the
controlled release coat of certain embodiments include sodium
glycine carbonate, sodium carbonate, potassium carbonate, sodium
bicarbonate, potassium bicarbonate, calcium bicarbonate, and
mixtures thereof. Non-limiting examples of osmagents that can be
used in the controlled release coat of certain embodiments include
sodium chloride, calcium chloride, calcium lactate, sodium sulfate,
lactose, glucose, sucrose, mannitol, urea, other organic and
inorganic compounds known in the art, and mixtures thereof. The
swelling agent can include, but is not limited to at least one
pharmaceutically acceptable hydrophilic compound, having a swelling
rate or swelling amount in water at about 25.degree. C. that is:
greater than or equal to at least about 10% by weight (wt/wt),
greater than or equal to at least about 15% by weight (wt/wt), or
greater than or equal to at least about 20% by weight (wt/wt).
Non-limiting examples of swelling agents that can be used in the
controlled release coat of certain embodiments of the present
invention include crosslinked polyvinylpyrrolidones (e.g.
polyplasdone, crospovidone and mixtures thereof), crosslinked
carboxyalkylcelluloses, crosslinked carboxymethylcellulose (e.g.
crosslinked sodium croscarmellose), hydrophilic polymers of high
molar mass (i.e., which can be, but are not limited to being
greater than or equal to 100,000 Daltons) which can include, but
are not limited to: polyvinylpyrrolidone(s), polyalkylene oxides
(e.g. polyethylene oxide, polypropylene oxide, and mixtures
thereof), hydroxyalkylcelluloses (e.g. hydroxypropylcellulose,
hydroxypropylmethylcellulose and mixtures thereof),
carboxyalkylcellulose (e.g. carboxymethylcellulose), modified
starch (e.g. sodium glycolate), starch or natural starch (e.g.
corn, wheat, rice, potato and mixtures thereof), cellulose (i.e.
which can be, but is not limited to being in powder form or
microcrystalline form), sodium alginate, potassium polacriline, and
corresponding blends or mixtures thereof. In other embodiments,
non-limiting examples of the swelling agent include the following
sub-set of compounds: crosslinked polyvinylpyrrolidone (e.g.
polyplasdone, crospovidone or mixtures thereof), crosslinked
carboxyalkylcelluloses (e.g. crosslinked carboxymethylcelluloses
such as crosslinked sodium croscarmellose), and mixtures thereof.
In other embodiments, the swelling agent can be a nitrogen
containing polymer, non-limiting examples of which can include
polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone and mixtures
thereof. The concentration of the swelling agent in the controlled
release coat of certain embodiments of the present invention can be
from about 3% to about 40% by weight of the microparticle including
all values and ranges therebetween. For example, in certain
embodiments the concentration of the swelling agent in the
controlled release coat is from about 4% to about 30%, and in other
embodiments from about 5% to about 25% by weight of the
microparticle.
[0464] In certain embodiments one or more pharmaceutically
acceptable excipients consistent with the objects of the present
invention can be used in the controlled release coat, such as a
lubricant, an emulsifying agent, an anti-foaming agent, and/or a
plasticizer.
[0465] Lubricants can be included in the controlled release coat to
help reduce friction of coated microparticles during manufacturing.
The lubricants that can be used in the controlled release coat of
certain embodiments of the present invention include but are not
limited to adipic acid, magnesium stearate, calcium stearate, zinc
stearate, calcium silicate, magnesium silicate, hydrogenated
vegetable oils, sodium chloride, sterotex, polyoxyethylene,
glyceryl monostearate, talc, polyethylene glycol, sodium benzoate,
sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl
fumarate, light mineral oil, waxy fatty acid esters such as
glyceryl behenate, (e.g. COMPRITOL.TM.), STEAR-O-WET.TM. and
MYVATEX.TM. TL. In at least one embodiment, the lubricant is
selected from magnesium stearate, talc and mixtures thereof.
Combinations of these lubricants are operable. The lubricant can
each be present in an amount of from about 1% to about 100% by
weight of the controlled release coat dry weight including all
values and ranges therebetween. For example, in certain embodiments
wherein the controlled release polymer is EUDRAGIT.RTM. NE30D or
EUDRAGIT.RTM. NE40D together with a hydrophilic pore former, the
lubricant is present in an amount of from about 1% to about 30% by
weight of the controlled release coat dry weight; in other
embodiments from about 2% to about 20%; and in still other
embodiments at about 10% by weight of the microparticle controlled
release coat dry weight. In another embodiments where the
controlled release polymer is ethylcellulose (ETHOCELT.TM. PR100,
PR45, PR20, PR10 or PR7 polymer, or a mixture thereof), the
lubricant can be present in an amount of from about 10% to about
100% by weight of the microparticle control-releasing coat dry
weight; in another embodiment from about 20% to about 80%; and in
still another embodiments at about 50% by weight of the
microparticle control-releasing coat dry weight.
[0466] Emulsifying agent(s) (also called emulsifiers or emulgents)
can be included in the microparticle controlled release coat to
facilitate actual emulsification during manufacture of the coat,
and also to ensure emulsion stability during the shelf-life of the
product. Emulsifying agents useful for the microparticle
control-releasing coat composition include, but are not limited to
naturally occurring materials and their semi synthetic derivatives,
such as the polysaccharides, as well as glycerol esters, cellulose
ethers, sorbitan esters (e.g. sorbitan monooleate or SPAN.TM. 80),
and polysorbates (e.g. TWEEN.TM. 80). Combinations of emulsifying
agents are operable. In at least one embodiment, the emulsifying
agent is TWEEN.TM. 80. The emulsifying agent(s) can be present in
an amount of from about 0.01% to about 5% by weight of the
microparticle controlled release coat dry weight including all
values and ranges therebetween. For example, in certain embodiments
the emulsifying agent is present in an amount of from about 0.05%
to about 3%; in other embodiments from about 0.08% to about 1.5%,
and in still other embodiments at about 0.1% by weight of the
microparticle controlled release coat dry weight.
[0467] Anti-foaming agent(s) can be included in the microparticle
controlled release coat to reduce frothing or foaming during
manufacture of the coat. Anti-foaming agents useful for the coat
composition include, but are not limited to simethicone, polyglycol
and silicon oil. In at least one embodiment the anti-foaming agent
is Simethicone C. The anti-foaming agent can be present in an
amount of from about 0.1% to about 10% of the microparticle
controlled release coat weight including all values and ranges
therebetween. For example, in certain embodiments the anti-foaming
agent is present in an amount of from about 0.2% to about 5%; in
other embodiments from about 0.3% to about 1%, and in still other
embodiments at about 0.6% by weight of the microparticle controlled
release coat dry weight.
[0468] Plasticizer(s) can be included in the microparticle
controlled release coat to modify the properties and
characteristics of the polymers used in the coat for convenient
processing during manufacturing (e.g. provide increased flexibility
and durability during manufacturing). As used herein, the term
"plasticizer" includes any compounds capable of plasticizing or
softening a polymer or binder used in the present invention. Once
the coat has been manufactured, certain plasticizers can function
to increase the hydrophilicity of the coat in the environment of
use. During manufacture of the coat, the plasticizer can lower the
melting temperature or glass transition temperature (softening
point temperature) of the polymer or binder. The addition of a
plasticizer, such as low molecular weight PEG, generally broadens
the average molecular weight of a polymer in which they are
included thereby lowering its glass transition temperature or
softening point. Plasticizers can also generally reduce the
viscosity of a polymer. Non-limiting examples of plasticisers that
can be used in the microparticle controlled release coat include
acetylated monoglycerides; acetyltributyl citrate, butyl phthalyl
butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl
phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene
glycol; triacetin; tripropioin; diacetin; dibutyl phthalate; acetyl
monoglyceride; acetyltriethyl citrate, polyethylene glycols; castor
oil; rape seed oil, olive oil, sesame oil, triethyl citrate;
polyhydric alcohols, glycerol, glycerin sorbitol, acetate esters,
gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate,
dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate,
butyl octyl phthalate, dioctyl azelate, epoxidized tallate,
triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl
phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl
phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate,
di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl
azelate, dibutyl sebacate, diethyloxalate, diethylmalate,
diethylfumerate, dibutylsuccinate, diethylmalonate,
dibutylphthalate, dibutylsebacate, glyceroltributyrate, and
mixtures thereof. The plasticizer can be present in an amount of
from about 1% to about 80% of the controlled release coat dry
weight including all values and ranges therebetween. For example,
in certain embodiments the plasticizer is present in an amount of
from about 5% to about 50%, in other embodiments from about 10% to
about 40%, and in still other embodiments at about 20% of the
controlled release coat dry weight.
[0469] The controlled release coat can be present in an amount of
from about 1% to about 100% by weight of the microparticle
including all values and ranges therebetween, depending upon the
choice of polymer, the ratio of polymer:pore former, and the total
surface area of the microparticle formulation. Since a certain
thickness of controlled release coating has to be achieved in order
to achieve the desired dissolution profile, the amount of polymer
coating required during manufacture is related to the total surface
area of the batch of uncoated microparticles that requires a
coating. The controlled release polymer surface area coverage can
range from about 0.5 mg/cm.sup.2 to about 30 mg/cm.sup.2 including
all values and ranges therebetween. For example in certain
embodiments the surface area coverage of the controlled release
polymer is from about 0.6 mg/cm.sup.2 to about 20 mg/cm.sup.2, and
in other embodiments from about 1 mg/cm.sup.2 to about 5
mg/cm.sup.2. In at least one embodiment of the invention,
EUDRAGIT.RTM. NE30D is used as the controlled release polymer at a
surface area coverage of about 10 mg/cm.sup.2. One approach to
estimate the total surface area of a multiparticulate batch is the
permeability method according to Blaine (ASTM Des. C 205-55), which
is based upon the mathematical model of laminar flow through
capillaries arranged in parallel. In the absence of an accurate
determination of total surface area of a microparticle, the amount
of controlled release polymer to be applied can be expressed as a
percentage of the uncoated microparticle.
[0470] The controlled release polymer can be present in an amount
of from about 1% to about 99% by weight of the coated microparticle
including all values and ranges therebetween, depending on the
controlled release profile desired. For example, in certain
embodiments the polymer is present in an amount of from about 5% to
about 80%, and in other embodiments from about 10% to about 50% by
weight of the coated microparticle. In at least one embodiment
wherein the controlled release polymer is EUDRAGIT.RTM. NE30D,
EUDRAGIT.RTM. NE40D, KOLLICOAT.RTM. SR 30D, or a mixture thereof,
the polymer is present in an amount of from about 1% to about 50%;
in other embodiments from about 5% to about 30%; and in still other
embodiments is about 15% by weight of the coated microparticle. In
at least one embodiment wherein the controlled release polymer is
ethylcellulose, the polymer is present in an amount of from about
1% to about 99% by weight of the coated microparticle; in other
embodiments from about 5% to about 50%; and in still other
embodiments at about 20% by weight of the coated microparticle. In
at least one embodiment wherein the controlled release polymer is
ETHOCEL.TM., an ethyl cellulose grade PR100, PR45, PR20, PR10, PR7
polymer, or a mixture thereof, the polymer is present in an amount
of from about 5% to about 30% by weight of the coated
microparticle; in other embodiments from about 10% to about 25%;
and in still other embodiments at about 20% by weight of the coated
microparticle.
[0471] In certain embodiments, the diameter of the microparticles
(with or without the controlled release coat) can range from about
50 .mu.m to about 800 .mu.m including all values and ranges
therebetween. For example, in certain embodiments the diameter of
the microparticles range from about 100 .mu.m to about 600 .mu.m,
and in other embodiments from about 150 .mu.m to about 450
.mu.m.
[0472] It is contemplated that in alternative embodiments, other
excipients consistent with the objects of the present invention can
also be used in the microparticle controlled release coat.
[0473] In at least one embodiment, the microparticle controlled
release coat includes about 96% EUDRAGIT.RTM. NE30D, about 1.9%
Magnesium stearate, about 1.9% Talc, about 0.04% TWEEN.RTM. 80, and
about 0.19% Simethicone C, when expressed as percentage by weight
of the dry controlled release coat composition. In another
embodiment, the microparticle controlled release coat includes
about 68% ethylcellulose, about 17% glyceryl monostearate and about
15% acetyl tributylcitrate when expressed as percentage by weight
of the dry controlled release coat composition.
[0474] In certain embodiments the microparticle controlled release
coat can be made according to any one of the methods described
herein.
[0475] The manufacturing process for the microparticle controlled
release coat can be as follows. Water is split into two portions of
about 15% and about 85%. The anti-foaming agent and the emulsifying
agent are then added to the 15% water portion, and mixed at about
300 rpm to form portion A. In at least one embodiment, the
anti-foaming agent is Simethicone C, and the emulsifying agent is
TWEEM.TM. 80. A first lubricant is then added to the 85% water
portion and mixed at about 9500 rpm to form portion B. In at least
one embodiment, the first lubricant is talc. Then portion A is
mixed with portion B, a second lubricant is slowly added, and mixed
at about 700 rpm overnight. In at least one embodiment, the second
lubricant is magnesium stearate. Finally, an aqueous dispersion of
a neutral ester copolymer is added and mixed for about 30 minutes
at about 500 rpm. In at least one embodiment, the aqueous
dispersion of a neutral ester copolymer is EUDRAGIT.RTM. NE30D. The
resultant controlled release coat solution can then be used to coat
the microparticles to about a 35% weight gain with the following
parameters: An inlet temperature of from about 10.degree. C. to
about 60.degree. C. including all values and ranges therebetween,
in certain embodiments from about 20.degree. C. to about 40.degree.
C., and in at least one embodiment from about 25.degree. C. to
about 35.degree. C.; an outlet temperature of from about 10.degree.
C. to about 60.degree. C. including all values and ranges
therebetween, in certain embodiments from about 20.degree. C. to
about 40.degree. C., and in at least one embodiment from about
25.degree. C. to about 35.degree. C.; a product temperature of from
about 10.degree. C. to about 60.degree. C. including all values and
ranges therebetween, in certain embodiments from about 15.degree.
C. to about 35.degree. C., and in at least one embodiment from
about 22.degree. C. to about 27.degree. C.; an air flow of from
about 10 cm/h to about 180 cm/h including all values and ranges
therebetween, in certain embodiments from about 40 cm/h to about
120 cm/h, and in at least one embodiment from about 60 cm/h to
about 80 cm/h; and an atomizing pressure of from about 0.5 bar to
about 4.5 bar including all values and ranges therebetween, in
certain embodiments from about 1 bar to about 3 bar, and in at
least one embodiment at about 2 bar. The resultant controlled
release coated microparticles can then be discharged from the
coating chamber and oven cured with the following parameters: A
curing temperature of from about 20.degree. C. to about 65.degree.
C. including all values and ranges therebetween, in certain
embodiments from about 30.degree. C. to about 55.degree. C., and in
at least one embodiment at about 40.degree. C.; and a curing time
of from about 2 hours to about 120 hours including all values and
ranges therebetween, in certain embodiments from about 10 hours to
about 40 hours, and in at least one embodiment at about 24 hours.
Any other technology resulting in the formulation of the
microparticle controlled release coat consistent with the objects
of the invention can also be used.
Microparticle Dosage Forms
[0476] Highly useful dosage forms result when microparticles made
from compositions containing a bupropion hydrobromide salt,
spheronization aids, and other excipient(s) are coated with
controlled release polymer(s). The controlled release coated
microparticles can then be combined with an excipient mass and/or
other pharmaceutical excipients, and compressed into tablets.
Conventional tablets can be manufactured by compressing the coated
microparticles with suitable excipients using known compression
techniques. The dissolution profile of the controlled release
coated multiparticles is not substantially affected by the
compression of the microparticles into a tablet. The resultant
dosage forms enjoy the processing ease associated with the use of
excipient masses and the release properties associated with
controlled release coated microparticles. Alternatively, the coated
microparticles can be filled into capsules.
[0477] The forms of administration according to the invention are
suitable for oral administration. In certain embodiments the forms
of administration are tablets and capsules. However, the
composition of the invention can also take the form of pellets,
beads or microtablets, which can then be packaged into capsules or
compressed into a unitary solid dosage form. Other solid oral
dosage forms as disclosed herein can be prepared by the skilled
artisan, despite the fact that such other solid oral dosage forms
may be more difficult to commercially manufacture.
[0478] The present invention also contemplates combinations of
differently coated microparticles into a dosage form to provide a
variety of different release profiles. For example, in certain
embodiments, microparticles with a delayed release profile can be
combined with other microparticles having a sustained release
profile to provide a multiple component controlled release
bupropion formulation. In addition, other embodiments can include
one or more further components of immediate release bupropion. The
immediate release bupropion component can take the form of uncoated
bupropion microparticles or powders; bupropion microparticles
coated with a highly soluble immediate release coating, such as an
OPADRY.RTM. type coating, as are known to those skilled in the art,
or a combination of any of the foregoing. The multiple components
can then be blended together in the desired ratio and placed in a
capsule, or formed into a tablet. Examples of multiple component
controlled release bupropion formulations are described in U.S.
Pat. No. 6,905,708.
Dose Sipping Technology
[0479] The present invention also contemplates an oral delivery
system for delivering microparticles containing bupropion
hydrobromide in admixture with a fluid. For example, an oral
delivery system is provided which comprises a hollow drug
formulation chamber. In at least one embodiment, the chamber has a
first end and a second end and contains a formulation in the form
of microparticles. The drug formulation comprises bupropion
hydrobromide. The system further comprises a fluid passing drug
formulation retainer in the first end of the chamber. The retainer
prevents release of the microparticles from the first end while
permitting fluid entry into the chamber. In other embodiments, the
microparticles contained within the chamber comprise bupropion
hydrobromide and at least one other drug.
[0480] Certain embodiments of the present invention further provide
a method for orally delivering microparticles containing bupropion
hydrobromide formulation in admixture with a fluid. The method
involves inserting microparticles of bupropion hydrobromide
formulation into a hollow drug delivery chamber of a drug delivery
device. The chamber has a first end and a second end. The first end
of the chamber has a fluid passing drug formulation retainer. The
drug delivery device has a first and second end. The first end of
the drug delivering device is inserted into a fluid and the second
end is inserted into the mouth of a patient. The patient then
applies suction to the second end of the device to cause delivery
of the fluid and microparticles of bupropion hydrobromide
formulation into the patient's mouth.
[0481] The term "drug formulation retainer" as used herein, refers
to a valve, plug or restriction, or the like that prevents passage
of the drug formulation from the device. By "fluid passing drug
formulation retainer" is intended a valve, plug or restriction or
the like that allows for passage of fluids but does not allow for
passage of other ingredients such as the drug formulation that is
contained in the delivery device.
[0482] The dispensing device of this embodiment of the invention
finds use where it is inconvenient or unsafe to use solid oral
dosage forms such as capsules or tablets. The devices can be
particularly useful in geriatric or pediatric patient populations
but they can also be useful for those who have difficulty
swallowing capsules or tablets. A single delivery device or several
devices can be administered to a patient during a therapeutic
program.
[0483] Generally the device is in prepared form prior to placement
in a fluid. In at least one embodiment the dispensing device
comprises a hollow drug formulation chamber with a first end and a
second end. Contained within the chamber are drug formulation and
fluid passing drug formulation retainers. The fluid passing drug
formulation retainer comprises a restriction and a one-way plug.
The diameter of the opening is smaller than the plug. In at least
one embodiment the restriction is made by crimping an end of the
chamber. The second end of the chamber has a drug formulation
retainer for preventing release of the plug. In at least one
embodiment the retainer is prepared by crimping the end of the
chamber. Microparticles of bupropion hydrobromide are then placed
in the chamber. An end-cap is placed over the second end of the
chamber prior to use to prevent release of the drug formulation. In
prepared form, the plug substantially seals the first end of the
chamber, thereby preventing loss of the drug formulation from the
first end.
[0484] The device can be formed from any suitable material that is
physically and/or chemically compatible with both the active drug
and the liquid diluent to be mixed therein. In certain embodiments,
representative materials for forming devices including the drug
formulation chamber, the elongated tubular member, the end caps and
tabs, include, without limitation, paper, plastic such as
propylene/styrene copolymers, polyproylene, high density
polyethylene, low density polyethylene and the like. The devices
can have an inner diameter of from about 3 mm to about 8 mm
including all values and ranges therebetween, and a wall thickness
of from about 0.1 mm to about 0.4 mm including all values and
ranges therebetween. The devices can be from about 10 cm to about
30 cm in length including all values and ranges therebetween.
[0485] The fluid passing drug formulation retainer permits the free
flow of liquid medium but prohibits passage of the drug formulation
from the device prior to delivery. Where the retainer comprises a
one-way plug or valve, the plug or valve will seal the straw at
atmospheric pressure. When suction is applied, fluid will be drawn
around the plug and into the drug formulation chamber. Further, the
plug has a density of less than one so that it will ascend to the
top as the drug formulation is delivered into the oral cavity. When
suction is no longer applied, the plug will remain in the highest
position it reached during sipping. The plug can be prepared from
closed cell polyethylene foam such as ETHAFOAM.RTM.. Other forms of
one way plugs can be a balloon of elastomeric material, a one-way
mechanical ball valve and the like.
[0486] Examples of fluid that can be used for suspending the drug
formulation by sipping through the drug formulation chamber include
any palatable liquid such as water, juice, milk, soda, coffee, tea
etc. Care must be taken to ensure compatibility of the fluid with
the drug formulation.
[0487] In at least one embodiment, a dose sipping delivery device
according to the present invention can be prepared as follows.
Jumbo size straws with an inside diameter of about 0.21 inches and
a length of about 8 inches are heat sealed at one end. The seal is
partially cut off so that the "one-way" plug cannot escape. The
partially sealed end is enclosed by half of a size 1 hard gelatin
capsule. Microparticles are then placed inside the open end of the
straw. A "one-way" plug made of closed cell polyethylene foam (e.g.
MICROFOAM.RTM.) is trimmed to snugly fit inside the straw. The plug
is then placed inside the straw, on top of the microparticles.
During operation, the plug end of the straw is placed into a glass
of water and the protective gelatin capsule on the top of the straw
is removed. By slowly applying suction through the partially sealed
end of the straw, the microparticles are sucked into the mouth and
easily swallowed.
Osmotic Dosage Forms
[0488] Osmotic dosage forms, osmotic delivery devices, modified
release osmotic dosage forms, or osmosis-controlled
extended-release systems are terms used interchangeably herein and
are defined to mean dosage forms which forcibly dispense the
bupropion hydrobromide salt by pressure created by osmosis or by
osmosis and diffusion of fluid into a material which expands and
forces the bupropion hydrobromide salt to be dispensed from the
osmotic dosage form. Osmosis can be defined as the flow of solvent
from a compartment with a low concentration of solute to a
compartment with a high concentration of solute. The two
compartments are separated by a membrane, wall, or coat, which
allows flow of solvent (a liquid, aqueous media, or biological
fluids) but not the solute. Non-limiting examples of such membranes
include a semipermeable membrane, microporous, asymmetric membrane,
which asymmetric membrane can be permeable, semipermeable,
perforated, or unperforated. Such membrane can deliver the
bupropion hydrobromide salt by osmotic pumping, diffusion or the
combined mechanisms of diffusion and osmotic pumping. Thus, in
principle, osmosis controlled release of the bupropion hydrobromide
salt involves osmotic transport of an aqueous media into the
osmotic dosage form followed by dissolution of the bupropion
hydrobromide salt and the subsequent transport of the saturated
solution of the bupropion hydrobromide salt by osmotic pumping of
the solution through at least one passageway in the semipermeable
membrane or by a combination of osmosis and diffusion through the
semipermeable membrane.
[0489] It is well known to one of ordinary skill in the art that
the desired in-vitro release rate and the in-vivo pharmacokinetic
parameters can be influenced by several factors, such as for
example, the amount of the bupropion hydrobromide salt used to form
the core, the amount of pharmaceutically acceptable excipient used
to form the core, the type of pharmaceutically acceptable excipient
used to form the core, the amount or type of any other materials
used to form the core such as, for example, osmagents (the term
osmagent, osmotically effective solutes, osmotically effective
compound and osmotic agents are used interchangeably herein)
osmopolymers, and any combination thereof. The release profile can
also be influenced by the material used to form the semipermeable
membrane covering the core or by the material used to form any
coating, such as a controlled release coating. With these factors
in mind, an osmotic device can therefore be designed to exhibit an
in-vitro release rate such that in certain embodiments, after about
2 hours from about 0 to about 20% by weight of the bupropion
hydrobromide salt is released, after about 4 hours from about 15%
to about 45% by weight of the bupropion hydrobromide salt is
released, after about 8 hours, from about 40% to about 90% by
weight of the bupropion hydrobromide salt is released, and after
about 16 hours, more than about 80% by weight of the bupropion
hydrobromide salt is released, when measured for example by using a
USP Type 1 apparatus (Rotating Basket Method) in 900 ml water, 0.1N
HCl, 0.1N HCl+0.1% Cetrimide, USP Buffer pH 1.5, Acetate Buffer pH
4.5, Phosphate Buffer, pH 6.5 or Phosphate Buffer pH 7.4 at 75 rpm
at 37.degree. C..+-.0.5.degree. C. Alternatively dissolution may be
effected in USP-3 media such as SGF pH 1.2, Acetate Buffer at pH
4.5 or phosphate buffer at pH 6.8.
[0490] Osmotic devices also may be designed to achieve an in-vitro
release of no more than about 40% after about 2 hours, from about
40% to about 75% release after about 4 hours, at least about 75%
after about 8 hours, and at least about 85% after about 16 hours
when assayed using a dissolution medium such as identified above or
known in the art.
[0491] In certain embodiments of the present invention, an osmotic
dosage form is provided having a core comprising the bupropion
hydrobromide salt and one or more excipients. In at least one
embodiment the osmotic dosage form comprises an osmagent. The
osmotic delivery system for example, can be in the form of a tablet
or capsule containing microparticles.
[0492] In certain embodiments, the core of the osmotic dosage form
comprises a water swellable polymer, non-limiting examples of which
include hydroxypropyl cellulose, alkylcellulose,
hydroxyalkylcellulose, polyalkylene oxide, polyethylene oxide, and
mixtures thereof. A binder can be included in the core of certain
embodiments of the osmotic dosage form to increase the core's
mechanical strength. Non-limiting examples of binders include
polyvinyl pyrollidine, carboxyvinyl polymer, methylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, a low molecular weight polyethylene
oxide polymer, hydroxypropylmethylcellulose, dextrin, maltodextrin,
gelatin, polyvinyl alcohol, xanthan gum, carbomers, caragheen,
starch derivatives, and mixtures thereof. Lubricants can be
included in certain embodiments of the osmotic dosage form to
provide decreased friction between the solid and die wall during
tablet manufacturing. Non-limiting examples of lubricants include
stearic acid, magnesium stearate, glyceryl behenate, talc, mineral
oil, sodium stearyl fumarate, hydrogenated vegetable oil, sodium
benzoate, calcium stearate, and mixtures thereof. In other
embodiments, additional inert excipients consistent with the
objects of the invention can also be included in the core of the
osmotic dosage form to facilitate the preparation and/or improve
patient acceptability of the final osmotic dosage form as described
herein. Suitable inert excipients are well known to the skilled
artisan and can be found in the relevant literature, for example in
the Handbook of Pharmaceutical Excipients (Rowe et. al., 4th Ed.,
Pharmaceutical Press, 2003).
[0493] In at least one embodiment, a modified release osmotic
dosage form comprises bupropion hydrobromide in a therapeutically
effective amount, which releases the bupropion hydrobromide by
forcibly dispensing the bupropion hydrobromide from a core via a
semipermeable membrane by diffusion and/or at least one passageway
in the membrane by osmotic pumping (i) all or in part by pressure
created in the core by osmosis i.e., positive hydrostatic pressure
of a liquid, solvent, biological fluid or aqueous media and/or all
or in part by the expansion of a swellable material which forces
the bupropion hydrobromide to be dispensed from the core of the
dosage form, and (ii) is formulated such that the dosage form
exhibits an in-vitro release rate such that after about 2 hours
from about 0% to about 20% by weight of the bupropion hydrobromide
salt is released, after about 4 hours from about 15% to about 45%
by weight of the bupropion hydrobromide salt is released, after
about 8 hours, from about 40% to about 90% by weight of the
bupropion hydrobromide salt is released, and after about 16 hours,
more than about 80% by weight of the bupropion hydrobromide salt is
released.
[0494] In at least one embodiment, the modified release dosage form
comprises an osmotic delivery device comprising a homogenous solid
core comprising substantially the bupropion hydrobromide salt
present in a therapeutically effective amount with at least one
pharmaceutically acceptable excipient, said core surrounded by a
semipermeable membrane which permits entry of an aqueous liquid
into the core and delivery of the bupropion hydrobromide salt from
the core to the exterior of the dosage form through at least one
passageway or by a combination of osmosis and diffusion such that
the dosage form exhibits an in-vitro release rate such that after
about 2 hours from about 0% to about 20% by weight of the bupropion
hydrobromide salt is released, after about 4 hours from about 15%
to about 45% by weight of the bupropion hydrobromide salt is
released, after about 8 hours, from about 40% to about 90% by
weight of the bupropion hydrobromide salt is released, and after
about 16 hours, more than about 80% by weight of the bupropion
hydrobromide salt is released. In at least one such embodiment the
in-vitro release rate of the bupropion hydrobromide salt is such
that after about 2 hours no more than about 40% is released, after
about 4 hours from about 40% to about 75% is released, after about
8 hours at least about 75% is released, and after about 16 hours at
least about 85% is released.
[0495] In at least one embodiment, the modified release dosage form
comprises a multiparticulate dosage form, each microparticle
comprising an osmotic delivery device, each microparticle
comprising a homogenous solid core comprising substantially the
bupropion hydrobromide salt with at least one pharmaceutically
acceptable excipient, said core of each microparticle surrounded by
a semipermeable membrane which permits entry of an aqueous liquid
into the core and delivery of the bupropion hydrobromide salt from
the core to the exterior of the dosage form through a plurality of
pores formed in the semipermeable membrane by inclusion of a pore
forming agent in the membrane or by a combination of osmosis and
diffusion so as to allow communication of the core with the outside
of the device for delivery of the bupropion hydrobromide salt and
is formulated such that the dosage form comprises a therapeutically
effective amount of the bupropion hydrobromide salt and exhibits an
in-vitro release rate such that after about 2 hours from about 0%
to about 20% by weight of the bupropion hydrobromide salt is
released, after about 4 hours from about 15% to about 45% by weight
of the bupropion hydrobromide salt is released, after about 8
hours, from about 40% to about 90% by weight of the bupropion
hydrobromide salt is released, and after about 16 hours, more than
about 80% by weight of the bupropion hydrobromide salt is released.
In at least one such embodiment the in-vitro release rate of the
bupropion hydrobromide salt is such that after about 2 hours no
more than about 40% is released, after about 4 hours from about 40%
to about 75% is released, after about 8 hours at least about 75% is
released and after about 16 hours at least about 85% is
released.
[0496] In at least one embodiment, the modified release dosage form
comprises a multiparticulate dosage form, each microparticle
comprising an osmotic delivery device, each microparticle
comprising a homogenous solid core comprising substantially the
bupropion hydrobromide salt in admixture with at least one
pharmaceutically acceptable excipient, an osmagent and/or an
osmopolymer, said core of each microparticle surrounded by a
semipermeable membrane which permits entry of an aqueous liquid
into the core and delivery of the bupropion hydrobromide salt from
the core to the exterior of the dosage form through a plurality of
pores formed in the semipermeable membrane by inclusion of a pore
forming agent in the membrane or by a combination of osmosis and by
diffusion so as to allow communication of the core with the outside
of the device for delivery of the bupropion hydrobromide salt and
is formulated such that the dosage form comprises a therapeutically
effective amount of the bupropion hydrobromide salt and exhibits an
in-vitro release rate such that after about 2 hours from about 0%
to about 20% by weight of the bupropion hydrobromide salt is
released, after about 4 hours from about 15% to about 45% by weight
of the bupropion hydrobromide salt is released, after about 8
hours, from about 40% to about 90% by weight of the bupropion
hydrobromide salt is released, and after about 16 hours, more than
about 80% by weight of the bupropion hydrobromide salt is released.
In at least one such embodiment the in-vitro release rate of the
bupropion hydrobromide salt is such that after about 2 hours no
more than about 40% is released, after about 4 hours from about 40%
to about 75% is released, after about 8 hours at least about 75% is
released and after about 16 hours at least about 85% is
released.
[0497] In at least one embodiment, the modified release dosage form
comprises a multiparticulate dosage form, each microparticle
comprising a homogenous solid core comprising substantially the
bupropion hydrobromide salt with at least one pharmaceutically
acceptable excipient in admixture with an osmagent, and/or an
osmopolymer, and/or an absorption enhancer, said microparticles
compressed into a tablet together with at least one
pharmaceutically acceptable excipient, said tablet surrounded by a
semipermeable membrane which permits entry of an aqueous liquid
into the core and delivery of the bupropion hydrobromide salt from
the tablet interior to the exterior of the dosage form through at
least one passageway in the semipermeable membrane and/or by
diffusion through the semipermeable membrane so as to allow
communication of the tablet interior with the exterior of the
tablet for delivery of the bupropion hydrobromide salt and is
formulated such that the dosage form comprises a therapeutically
effective amount of the bupropion hydrobromide salt and exhibits an
in-vitro release rate such that after about 2 hours from about 0%
to about 20% by weight of the bupropion hydrobromide salt is
released, after about 4 hours from about 15% to about 45% by weight
of the bupropion hydrobromide salt is released, after about 8
hours, from about 40% to about 90% by weight of the bupropion
hydrobromide salt is released, and after about 16 hours, more than
about 80% by weight of the bupropion hydrobromide salt is released.
In at least one such embodiment the in-vitro release profile of the
bupropion hydrobromide salt is such that after about 2 hours no
more than about 40% is released, after about 4 hours from about 40%
to about 75% is released, after about 8 hours at least about 75% is
released, and after about 16 hours at least about 85% is
released.
[0498] In at least one embodiment, the modified release dosage form
comprises a multiparticulate dosage form, each microparticle
comprising a sugar sphere or nonpareil bead coated with at least
one layer comprising substantially the bupropion hydrobromide salt
with at least one pharmaceutically acceptable excipient, said at
least one layer surrounded by a semipermeable membrane which
permits entry of an aqueous liquid into the layer and delivery of
the bupropion hydrobromide salt from the layer to the exterior of
the dosage form through a plurality of pores formed in the
semipermeable membrane by inclusion of a pore forming agent in the
membrane and/or by diffusion so as to allow communication of the
core with the outside of the device for delivery of the bupropion
hydrobromide salt and is formulated such that the dosage form
comprises a therapeutically effective amount of the bupropion
hydrobromide salt and exhibits an in-vitro release rate such that
after about 2 hours from about 0% to about 20% by weight of the
bupropion hydrobromide salt is released, after about 4 hours from
about 15% to about 45% by weight of the bupropion hydrobromide salt
is released, after about 8 hours, from about 40% to about 90% by
weight of the bupropion hydrobromide salt is released, and after
about 16 hours, more than about 80% by weight of the bupropion
hydrobromide salt is released. In at least one such embodiment the
in-vitro release profile of the bupropion hydrobromide salt is such
that after about 2 hours no more than about 40% is released, after
about 4 hours from about 40% to about 75% is released, after about
8 hours at least about 75% is released and after about 16 hours at
least about 85% is released.
[0499] In at least one embodiment, the modified release dosage form
comprises a multiparticulate dosage form, each microparticle
comprising a sugar sphere or nonpareil bead coated with at least
one layer comprising substantially the bupropion hydrobromide salt
in admixture with at least one pharmaceutically acceptable
excipient, an osmagent and/or an osmopolymer, said at least one
layer surrounded by a semipermeable membrane which permits entry of
an aqueous liquid into the layer and delivery of the bupropion
hydrobromide salt from the layer to the exterior of the dosage form
through a plurality of pores formed in the semipermeable membrane
by inclusion of a pore forming agent in the membrane and/or by
diffusion so as to allow communication of the core with the outside
of the device for delivery of the bupropion hydrobromide salt and
is formulated such that the dosage form comprises a therapeutically
effective amount of the bupropion hydrobromide salt and exhibits an
in-vitro release rate such that after about 2 hours from about 0%
to about 20% by weight of the bupropion hydrobromide salt is
released, after about 4 hours from about 15% to about 45% by weight
of the bupropion hydrobromide salt is released, after about 8
hours, from about 40% to about 90% by weight of the bupropion
hydrobromide salt is released, and after about 16 hours, more than
about 80% by weight of the bupropion hydrobromide salt is released.
In at least one such embodiment the in-vitro release profile of
bupropion hydrobromide salt is such that after about 2 hours no
more than about 40% is released, after about 4 hours from about 40%
to about 75% is released, after about 8 hours at least about 75% is
released and after about 16 hours at least about 85% is
released.
[0500] In at least one embodiment, the modified release dosage form
comprises a modified release osmotic dosage form comprising a
homogenous core comprising a therapeutically effective amount of
the bupropion hydrobromide salt in admixture with an osmagent,
and/or an osmopolymer, and/or and absorption enhancer, said core
surrounded by a nontoxic wall, membrane or coat, such as for
example a semipermeable membrane which permits entry of an aqueous
liquid into the core and delivery of the bupropion hydrobromide
salt from the core to the exterior of the dosage form through at
least one passageway in the semipermeable membrane and/or by
diffusion through the membrane so as to allow communication of the
core with the outside of the dosage form for delivery of the
bupropion hydrobromide salt and is formulated such that the dosage
form exhibits an in-vitro release rate such that after about 2
hours from about 0% to about 20% by weight of the bupropion
hydrobromide salt is released, after about 4 hours from about 15%
to about 45% by weight of the bupropion hydrobromide salt is
released, after about 8 hours, from about 40% to about 90% by
weight of the bupropion hydrobromide salt is released, and after
about 16 hours, more than about 80% by weight of the bupropion
hydrobromide salt is released. In at least one such embodiment the
in-vitro release profile of bupropion hydrobromide salt is such
that after about 2 hours no more than about 40% is released, after
about 4 hours from about 40% to about 75% is released, after about
8 hours at least about 75% is released and after about 16 hours at
least about 85% is released.
[0501] In at least one embodiment the modified release dosage form
comprises an osmotic delivery device comprising the bupropion
hydrobromide salt present in a therapeutically effective amount in
a layered, contacting arrangement with a swellable material
composition to yield a solid core with two or more layers, which
core is surrounded by a nontoxic wall, membrane or coat, such as
for example a semipermeable membrane which permits entry of an
aqueous liquid into the core and delivery of the bupropion
hydrobromide salt from the core to the exterior of the dosage form
through at least one passageway in the semipermeable membrane or by
osmosis and diffusion through the membrane so as to allow
communication of the core with the outside of the dosage form for
delivery of the bupropion hydrobromide salt and is formulated such
that the dosage form exhibits an in-vitro release rate such that
after about 2 hours from about 0% to about 20% by weight of the
bupropion hydrobromide salt is released, after about 4 hours from
about 15% to about 45% by weight of the bupropion hydrobromide salt
is released, after about 8 hours, from about 40% to about 90% by
weight of the bupropion hydrobromide salt is released, and after
about 16 hours, more than about 80% by weight of the bupropion
hydrobromide salt is released. In at least one such embodiment the
in-vitro release profile of the bupropion hydrobromide salt is such
that after about 2 hours no more than about 40% is released, after
about 4 hours about 40% to about 75% is released, after about 8
hours at least about 75% is released and after about 16 hours at
least about 85% is released.
[0502] In at least one embodiment, the modified release dosage form
comprises an osmotic delivery device comprising a core and a
membrane surrounding said core, said core comprising a
therapeutically effective amount of the bupropion hydrobromide
salt, and optionally at least one means for forcibly dispensing the
bupropion hydrobromide salt from the device, said membrane
comprising at least one means for the exit of the bupropion
hydrobromide salt from the device, said device formulated such that
when the device is in an aqueous medium, the bupropion hydrobromide
salt, and optionally the at least one means for forcibly dispensing
the bupropion hydrobromide salt from the device and the at least
one means for the exit of the bupropion hydrobromide salt from the
device cooperatively function to exhibit an in-vitro release rate
such that after about 2 hours from about 0% to about 20% by weight
of the bupropion hydrobromide salt is released, after about 4 hours
from about 15% to about 45% by weight of the bupropion hydrobromide
salt is released, after about 8 hours, from about 40% to about 90%
by weight of the bupropion hydrobromide salt is released, and after
about 16 hours, more than about 80% by weight of the bupropion
hydrobromide salt is released. In at least one such embodiment the
in-vitro release profile of the bupropion hydrobromide salt is such
that after about 2 hours no more than about 40% is released, after
about 4 hours from about 40% to about 75% is released, after about
8 hours at least about 75% is released and after about 16 hours at
least about 85% is released.
[0503] In at least one embodiment, the modified release dosage form
comprises an osmotic delivery device comprising a core and a
membrane surrounding said core, said core comprising a
therapeutically effective amount of the bupropion hydrobromide
salt, at least one means for increasing the hydrostatic pressure
inside the membrane and optionally at least one means for forcibly
dispensing the bupropion hydrobromide salt from the device, said
membrane comprising at least one means for the exit of the
bupropion hydrobromide salt from the device, said device formulated
such that when the device is in an aqueous medium, the at least one
means for increasing the hydrostatic pressure inside the membrane,
and optionally the at least one means for forcibly dispensing the
bupropion hydrobromide salt from the device and the at least one
means for the exit of the bupropion hydrobromide salt cooperatively
function to exhibit an in-vitro release rate such that after about
2 hours from about 0% to about 20% by weight of the bupropion
hydrobromide salt is released, after about 4 hours from about 15%
to about 45% by weight of the bupropion hydrobromide salt is
released, after about 8 hours, from about 40% to about 90% by
weight of the bupropion hydrobromide salt is released, and after
about 16 hours, more than about 80% by weight of the bupropion
hydrobromide salt is released. In at least one such embodiment the
in-vitro release profile of the bupropion hydrobromide salt is such
that after about 2 hours no more than about 40% is released, after
about 4 hours from about 40% to about 75% is released, after about
8 hours at least about 75% is released and after about 16 hours at
least about 85% is released.
[0504] Certain embodiments of the invention are directed to
once-a-day bupropion hydrobromide sustained release formulations
that are bioequivalent according to FDA guidelines to
WELLBUTRIN.TM. ER or ZYBAN.TM./WELLBUTRIN.TM. SR when administered
once-daily to a subject in need thereof and wherein the bupropion
hydrobromide salt contained is more stable than an equivalent molar
amount of the bupropion hydrochloride salt contained in
WELLBUTRIN.TM. ER or ZYBAN.TM. when exposed to like conditions, for
example when stored for 10 days, 13 days, 14 days, 20 days, 24
days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or
more under accelerated storage conditions (e.g. 40 degrees C., 75%
relative humidity). In at least one embodiment the invention
encompasses 174 mg, 348 mg and 522 mg bupropion hydrobromide
formulations that are bioequivalent to bupropion hydrochloride
formulations.
[0505] At least one embodiment is directed to topical formulations
containing bupropion hydrobromide that can be administered
topically, e.g., transmucosally or transdermally. Particularly, the
at least one embodiment embraces topically administrable gels and
patch type delivery devices which can comprise another active agent
such as nicotine.
[0506] At least one embodiment is directed to inhalable pulmonary
deliverable compositions containing bupropion hydrobromide that can
be administered via pulmonary delivery to a subject in need
thereof. These compositions can be produced according to the
aerosol technology as known in the art.
[0507] At least one embodiment is directed to injectable
compositions comprising an effective amount of bupropion
hydrobromide and a pharmaceutically acceptable carrier or
excipient.
[0508] At least one embodiment is directed to a method of treating
a condition comprising administering any one of the above described
osmotic dosage forms to a patient in need of such administration
once-daily.
[0509] At least one embodiment is directed to a method for
administering a bupropion hydrobromide salt to the gastrointestinal
tract of a human for the treatment or management of a condition,
wherein the method comprises: (a) admitting orally into the human a
modified release dosage form comprising a bupropion hydrobromide
salt, the modified release dosage form comprising an osmotic dosage
form; and (b) administering the bupropion hydrobromide salt from
the osmotic dosage form in a therapeutically responsive dose to
produce the treatment or management of the condition such that the
osmotic dosage form exhibits an in-vitro release rate such that
after about 2 hours from about 0% to about 20% by weight of the
bupropion hydrobromide salt is released, after about 4 hours from
about 15% to about 45% by weight of the bupropion hydrobromide salt
is released, after about 8 hours, from about 40% to about 90% by
weight of the bupropion hydrobromide salt is released, and after
about 16 hours, more than about 80% by weight of the bupropion
hydrobromide salt is released. In at least one such embodiment the
in-vitro release profile of the bupropion hydrobromide salt is such
that after about 2 hours no more than about 40% is released, after
about 4 hours from about 40% to about 75% is released, after about
8 hours at least about 75% is released and after about 16 hours at
least about 85% is released.
[0510] At least one embodiment is directed to a method for
administering a bupropion hydrobromide salt to the gastrointestinal
tract of a human for the treatment or management of a condition,
wherein the method comprises: (a) admitting orally into the human a
modified release dosage form comprising a core and a membrane
surrounding said core, said core comprising the bupropion
hydrobromide salt and optionally a means for forcibly dispensing
the bupropion hydrobromide salt from the device, said membrane
comprising at least one means for the exit of the bupropion
hydrobromide salt from the dosage form, and (b) administering the
bupropion hydrobromide salt from the dosage form which is
formulated such that when the dosage form is in an aqueous medium,
the bupropion hydrobromide salt and optionally the means for
forcibly dispensing the bupropion hydrobromide salt and the at
least one means for the exit of the bupropion hydrobromide salt
cooperatively function to exhibit an in-vitro release rate such
that after about 2 hours from about 0% to about 20% by weight of
the bupropion hydrobromide salt is released, after about 4 hours
from about 15% to about 45% by weight of the bupropion hydrobromide
salt is released, after about 8 hours, from about 40% to about 90%
by weight of the bupropion hydrobromide salt is released, and after
about 16 hours, more than about 80% by weight of the bupropion
hydrobromide salt is released. In at least one such embodiment the
in-vitro release profile of the bupropion hydrobromide salt is such
that after about 2 hours no more than about 40% is released, after
about 4 hours from about 40% to about 75% is released, after about
8 hours at least about 75% is released and after about 16 hours at
least about 85% is released.
[0511] At least one embodiment is directed to a method for
administering a bupropion hydrobromide salt to the gastrointestinal
tract of a human for the treatment or management of a condition,
wherein the method comprises: (a) admitting orally into the human a
modified release dosage form comprising a core and a membrane
surrounding said core, said core comprising the bupropion
hydrobromide salt, a means for increasing the hydrostatic pressure
within the core and optionally a means for forcibly dispensing the
bupropion hydrobromide salt from the device, said membrane
comprising at least one means for the exit of the bupropion
hydrobromide salt from the dosage form, and (b) administering the
bupropion hydrobromide salt from the dosage form which is
formulated such that when the dosage form is in an aqueous medium,
the bupropion hydrobromide salt, the means for increasing the
hydrostatic pressure within the core and optionally the means for
forcibly dispensing the bupropion hydrobromide salt and the at
least one means for the exit of the bupropion hydrobromide salt
cooperatively function to exhibit an in-vitro release rate such
that after about 2 hours from about 0% to about 20% by weight of
the bupropion hydrobromide salt is released, after about 4 hours
from about 15% to about 45% by weight of the bupropion hydrobromide
salt is released, after about 8 hours, from about 40% to about 90%
by weight of the bupropion hydrobromide salt is released, and after
about 16 hours, more than about 80% by weight of the bupropion
hydrobromide salt is released. In at least one such embodiment the
in-vitro release profile of the bupropion hydrobromide salt is such
that after about 2 hours no more than about 40% is released, after
about 4 hours from about 40% to about 75% is released, after about
8 hours at least about 75% is released and after about 16 hours at
least about 85% is released.
[0512] In at least one other embodiment, the osmotic dosage form
further comprises an immediate release coat for the immediate
release of the bupropion hydrobromide salt from the immediate
release coat. In embodiments comprising the immediate release coat,
the osmotic dosage form exhibits an in-vitro release rate such that
after about 2 hours from about 0% to about 20% by weight of the
bupropion hydrobromide salt is released, after about 4 hours from
about 15% to about 45% by weight of the bupropion hydrobromide salt
is released, after about 8 hours, from about 40% to about 90% by
weight of the bupropion hydrobromide salt is released, and after
about 16 hours, more than about 80% by weight of the bupropion
hydrobromide salt is released. In at least one such embodiment the
in-vitro release profile of the bupropion hydrobromide salt is such
that after about 2 hours no more than about 40% is released, after
about 4 hours from about 40% to about 75% is released, after about
8 hours at least about 75% is released and after about 16 hours at
least about 85% is released.
[0513] In at least one other embodiment, the osmotic dosage forms
further comprise an inert water-soluble coat covering the
semipermeable membrane or coat. This inert water-soluble coat can
be impermeable in a first external fluid, while being soluble in a
second external fluid. In embodiments comprising the inert
water-soluble coat, the osmotic dosage form exhibits an in-vitro
release rate such that after about 2 hours from about 0% to about
20% by weight of the bupropion hydrobromide salt is released, after
about 4 hours from about 15% to about 45% by weight of the
bupropion hydrobromide salt is released, after about 8 hours, from
about 40% to about 90% by weight of the bupropion hydrobromide salt
is released, and after about 16 hours, more than about 80% by
weight of the bupropion hydrobromide salt is released. In at least
one such embodiment the in-vitro release profile of the bupropion
hydrobromide salt is such that after about hours no more than about
40% is released, after about 4 hours from about 40% to about 75% is
released, after about 8 hours at least about 75% is released and
after about 16 hours at least about 85% is released.
[0514] In at least one other embodiment, the osmotic dosage forms
further comprise an osmotic subcoat. In certain embodiments
comprising the osmotic subcoat, the osmotic dosage form exhibits an
in-vitro release rate such that after about 2 hours from about 0%
to about 20% by weight of the bupropion hydrobromide salt is
released, after about 4 hours from about 15% to about 45% by weight
of the bupropion hydrobromide salt is released, after about 8
hours, from about 40% to about 90% by weight of the bupropion
hydrobromide salt is released, and after about 16 hours, more than
about 80% by weight of the bupropion hydrobromide salt is released.
In at least one such embodiment the in-vitro release profile of the
bupropion hydrobromide salt is such that after about 2 hours no
more than about 40% is released, after about 4 hours from about 40%
to about 75% is released, after about 8 hours at least about 75% is
released and after about 16 hours at least about 85% is
released.
[0515] In at least one other embodiment, the osmotic dosage forms
further comprise a controlled release coat. The controlled release
coat of the osmotic dosage form can, for example, control, extend,
and/or delay the release of the bupropion hydrobromide salt. In
certain embodiments comprising the controlled release coat, the
osmotic dosage form exhibits an in-vitro release rate such that
after about 2 hours from about 0% to about 20% by weight of the
bupropion hydrobromide salt is released, after about 4 hours from
about 15% to about 45% by weight of the bupropion hydrobromide salt
is released, after about 8 hours, from about 40% to about 90% by
weight of the bupropion hydrobromide salt is released, and after
about 16 hours, more than about 80% by weight of the bupropion
hydrobromide salt is released. In at least one such embodiment the
in-vitro release profile of the bupropion hydrobromide salt is such
that after about 2 hours no more than about 40% is released, after
about 4 hours from about 40% to about 75% is released, after about
8 hours at least about 75% is released and after about 16 hours at
least about 85% is released.
[0516] In at least one embodiment, the controlled release coat of
the osmotic dosage form comprises a material that is soluble or
erodible in intestinal juices, substantially pH neutral or basic
fluids of fluids having a pH higher than gastric fluid, but for the
most part insoluble in gastric juices or acidic fluids.
[0517] In at least one embodiment, the controlled release coat of
the osmotic dosage form comprises at least one water-insoluble
water-permeable film-forming polymer and at least one water-soluble
polymer.
[0518] In at least one embodiment, the controlled release coat of
the osmotic dosage form comprises at least one water-insoluble
water-permeable film-forming polymer and at least one water-soluble
polymer and optionally at least one plasticizer.
[0519] In at least one embodiment, the controlled release coat of
the osmotic dosage form comprises at least one water-insoluble
water-permeable film-forming polymer, at least one water-soluble
polymer and at least one means for the exit of the bupropion
hydrobromide salt from the core of the osmotic dosage form.
[0520] In at least one embodiment, the controlled release coat of
the osmotic dosage form comprises at least one water-insoluble
water-permeable film-forming polymer, at least one water-soluble
polymer and at least one passageway.
[0521] In at least one embodiment, the controlled release coat of
the osmotic dosage form comprises at least one water-insoluble
water-permeable film-forming polymer, at least one water-soluble
polymer and at least one plasticizer.
[0522] In at least one embodiment, the controlled release coat of
the osmotic dosage form comprises at least one water-insoluble
water-permeable film-forming polymer, at least one water-soluble
polymer, optionally at least one plasticizer, and at least one
means for the exit of the bupropion hydrobromide salt from the core
of the osmotic dosage form.
[0523] In at least one embodiment, the controlled release coat of
the osmotic dosage form comprises at least one water-insoluble
water-permeable film-forming polymer, at least one water-soluble
polymer, optionally at least one plasticizer, and at least one
passageway.
[0524] In at least one embodiment, the controlled release coat of
the osmotic dosage form comprises an aqueous dispersion of a
neutral ester copolymer without any functional groups; a poly
glycol having a melting point greater than about 55.degree. C., one
or more pharmaceutically acceptable excipients, and optionally at
least one means for the exit of the bupropion hydrobromide salt
form the core of the osmotic dosage form. This controlled release
coat is cured at a temperature at least equal to or greater than
the melting point of the polyglycol.
[0525] In at least one other embodiment, the controlled release
coat of the osmotic dosage form comprises at least one enteric
polymer.
[0526] In certain embodiments the membrane or wall is permeable to
the passage of aqueous media but not to the passage of the
bupropion hydrobromide salt present in the core. The membrane can
be, for example, a semipermeable membrane or an asymmetric
membrane, which can be permeable, semipermeable, perforated, or
unperforated and can deliver the bupropion hydrobromide salt by
osmotic pumping, or the combined mechanisms of diffusion and
osmotic pumping. The structural integrity of such membranes
preferably remain substantially intact during the period of
delivery of the bupropion hydrobromide salt. By "substantially
intact" it is meant that the semipermeable property of the membrane
is not compromised during the period of delivery of the bupropion
hydrobromide salt.
[0527] The semipermeable membrane of the osmotic dosage form of
certain embodiments comprises at least one pharmaceutically
acceptable excipient, at least one polymer, wax, or combination
thereof, although appropriately treated inorganic materials such as
ceramics, metals or glasses can be used. When the semipermeable
membrane comprises at least one polymer, the molecular weight of
the at least one polymer or combination of polymers are preferably
such that the polymer or combination of polymers is solid at the
temperature of use i.e., both in-vitro and in-vivo.
[0528] In certain embodiments, the at least one polymer included in
the semipermeable membrane of the osmotic dosage form can be a
cellulose ester, such as for example, cellulose acetate, cellulose
acetate acetoacetate, cellulose acetate benzoate, cellulose acetate
butylsulfonate, cellulose acetate butyrate, cellulose acetate
butyrate sulfate, cellulose acetate butyrate valerate. cellulose
acetate caprate, cellulose acetate caproate, cellulose acetate
caprylate, cellulose acetate carboxymethoxypropionate, cellulose
acetate chloroacetate, cellulose acetate dimethaminoacetate,
cellulose acetate dimethylaminoacetate, cellulose acetate
dimethylsulfamate, cellulose acetate dipalmitate, cellulose acetate
dipropylsulfamate, cellulose acetate ethoxyacetate, cellulose
acetate ethyl carbamate, cellulose acetate ethyl carbonate,
cellulose acetate ethyl oxalate. cellulose acetate furoate,
cellulose acetate heptanoate, cellulose acetate heptylate,
cellulose acetate isobutyrate, cellulose acetate laurate, cellulose
acetate methacrylate, cellulose acetate methoxyacetate, cellulose
acetate methylcarbamate, cellulose acetate methylsulfonate,
cellulose acetate myristate, cellulose acetate octanoate, cellulose
acetate palmitate, cellulose acetate phthalate, cellulose acetate
propionate, cellulose acetate propionate sulfate, cellulose acetate
propionate valerate, cellulose acetate p-toluene sulfonate,
cellulose acetate succinate, cellulose acetate sulfate, cellulose
acetate trimellitate, cellulose acetate tripropionate, cellulose
acetate valerate, cellulose benzoate, cellulose butyrate
napthylate, cellulose butyrate, cellulose chlorobenzoate, cellulose
cyanoacetates, cellulose dicaprylate, cellulose dioctanoate,
cellulose dipentanate, cellulose dipentanlate, cellulose formate,
cellulose methacrylates, cellulose methoxybenzoate, cellulose
nitrate, cellulose nitrobenzoate, cellulose phosphate (sodium
salt), cellulose phosphinates, cellulose phosphites, cellulose
phosphonates, cellulose propionate, cellulose propionate crotonate,
cellulose propionate isobutyrate, cellulose propionate succinate,
cellulose stearate, cellulose sulfate (sodium salt), cellulose
triacetate, cellulose tricaprylate, cellulose triformate, cellulose
triheptanoate, cellulose triheptylate, cellulose trilaurate,
cellulose trimyristate, cellulose trinitrate, cellulose
trioctanoate, cellulose tripalmitate, cellulose tripropionate,
cellulose trisuccinate, cellulose trivalerate, cellulose valerate
palmitate; a cellulose ether, such as for example, 2-cyanoethyl
cellulose, 2-hydroxybutyl methyl cellulose, 2-hydroxyethyl
cellulose, 2-hydroxyethyl ethyl cellulose, 2-hydroxyethyl methyl
cellulose, 2-hydroxypropyl cellulose, 2-hydroxypropyl methyl
cellulose, dimethoxyethyl cellulose acetate, ethyl 2-hydroxylethyl
cellulose, ethyl cellulose, ethyl cellulose sulfate, ethylcellulose
dimethylsulfamate, methyl cellulose, methyl cellulose acetate,
methylcyanoethyl cellulose, sodium carboxymethyl 2-hydroxyethyl
cellulose, sodium carboxymethyl cellulose; a polysulfone, such as
for example, polyethersulfones; a polycarbonate; a polyurethane; a
polyvinyl acetate; a polyvinyl alcohol; a polyester; a polyalkene
such as polyethylene, ethylene vinyl alcohol copolymer,
polypropylene, poly(1,2-dimethyl-1-butenylene),
poly(1-bromo-1-butenylene), poly(l, butene),
poly(1-chloro-1-butenylene), poly(1-decyl-1-butenylene),
poly(1-hexane), poly(1-isopropyl-1-butenylene), poly(1-pentene),
poly(3-vinylpyrene), poly(4-methoxyl 1-butenylene),
poly(ethylene-co-methyl styrene), poly vinyl-chloride,
poly(ethylene-co-tetrafluoroethylene),
poly(ethylene-terephthalate), poly(dodecafluorobutoxylethylene),
poly(hexafluoroprolylene), poly(hexyloxyethylene), poly(isobutene),
poly(isobutene-co-isoprene), poly(isoprene), poly-butadiene,
poly[(pentafluoroethyl)ethylene], poly[2-ethylhexyloxy)ethylene],
poly(butylethylene), poly(tertbutylethylene),
poly(cylclohexylethylene), poly[(cyclohexylmethyl)ethylene],
poly(cyclopentylethylene), poly(decylethylene),
poly-dodecy-lethylene), poly(neopentylethylene),
poly(propylethylene); a polystyrene, such as for example,
poly(2,4-dimethyl styrene), poly(3-methyl styrene),
poly(4-methoxystyrene), poly(4-methoxystyrene-stat-styrene),
poly(4-methyl styrene), poly(isopentyl styrene), poly(isopropyl
styrene), polyvinyl esters or polyvinyl ethers, such as form
example, poly(benzoylethylene), poly(butoxyethylene),
poly(chloroprene), poly(cyclohexloxyethylene),
poly(decyloxyethylene), poly(dichloroethylene),
poly(difluoroethylene), poly(vinyl acetate),
poly(vinyltrimethyllstyrene); a polysiloxane, such as for example,
poly(dimethylsiloxane); a polyacrylic acid derivative, such as for
example, polyacrylates, polymethyl methacrylate, poly(acrylic acid)
higher alkyl esters, poly(ethylmethacrylate), poly(hexadecyl
methacrylate-co-methylmethacrylate),
poly-(methylacrylate-co-styrene), poly(n-butyl methacrylate),
poly(n-butyl-acrylate), poly (cyclododecyl acrylate), poly(benzyl
acrylate), poly(butylacrylate), poly(secbutylacrylate), poly(hexyl
acrylate), poly(octyl acrylate), poly(decyl acrylate), poly(dodecyl
acrylate), poly(2-methyl butyl acrylate), poly(adamantyl
methacrylate), poly(benzyl methacrylate), poly(butyl methacrylate),
poly(2-ethylhexyl methacrylate), poly(octyl methacrylate), acrylic
resins; a polyamide, such as for example,
poly(iminoadipoyliminododecamethylene),
poly(iminoadipoyliminohexamethylene), polyethers, such as for
example, poly(octyloxyethylene), poly(oxyphenylethylene),
poly(oxypropylene), poly(pentyloxyethylene), poly(phenoxy styrene),
poly(secbutroxylethylene), poly(tert-butoxyethylene); and
combinations thereof.
[0529] In at least one embodiment, the at least one wax included in
the semipermeable membrane of the osmotic dosage form can be, for
example, insect and animal waxes, such as for example, chinese
insect wax, beeswax, spermaceti, fats and wool wax; vegetable
waxes, such as for example, bamboo leaf wax, candelilla wax,
carnauba wax, Japan wax, ouricury wax, Jojoba wax, bayberry wax,
Douglas-Fir wax, cotton wax, cranberry wax, cape berry wax,
rice-bran wax, castor wax, indian corn wax, hydrogenated vegetable
oils (e.g., castor, palm, cottonseed, soybean), sorghum grain wax,
Spanish moss wax, sugarcane wax, caranda wax, bleached wax, Esparto
wax, flax wax, Madagascar wax, orange peel wax, shellac wax, sisal
hemp wax and rice wax; mineral waxes, such as for example, Montan
wax, peat waxes, petroleum wax, petroleum ceresin, ozokerite wax,
microcrystalline wax and paraffins; synthetic waxes, such as for
example, polyethylene wax, Fischer-Tropsch wax, chemically modified
hydrocarbon waxes, cetyl esters wax; and combinations thereof.
[0530] In at least one embodiment, the semipermeable membrane of
the osmotic dosage form can comprise a combination of at least one
polymer, wax, or combinations thereof and optionally at least one
excipient.
[0531] In embodiments where the bupropion hydrobromide salt is
released through the membrane or wall in a controlled manner by the
combined mechanisms of diffusion and osmotic pumping, the membrane
or wall can comprise at least one of the above described polymers
and/or waxes or a combination of polymers, such as for example,
cellulose esters, copolymers of methacrylate salts and optionally a
plasticizer.
[0532] The poly(methacrylate) copolymer salts used in the
manufacturing of the membrane for the osmotic dosage form can be,
for example, insoluble in water and in digestive fluids, but are
permeable to different degrees. Examples of such copolymers are
poly(ammonium methacrylate) copolymer RL (EUDRAGIT.RTM.RL),
poly(ammonium methacrylate) copolymer (type A-USP/NF),
poly(aminoalkyl methacrylate) copolymer RL-JSP I), and (ethyl
acrylate)-(methyl
methacrylate)-[(trimethylammonium)-ethylmethacrylate] (1:2:0.2)
copolymer, MW 150,000. Other examples of such copolymers include
EUDRAGIT.RTM.RS 100: solid polymer, EUDRAGIT.RTM.RL 12.5:12.5%
solution in solvent, EUDRAGIT.RTM.RL 30D: 30% aqueous dispersion,
and other equivalent products. The following poly (ammonium
methacrylate) copolymers can also be used: ammonium methacrylate
copolymer RS (EUDRAGIT.RTM.RS), poly(ammonium methacrylate)
copolymer (type B-USP/NF), poly(aminoalkyl methacrylate) copolymer
(RSL-JSP I), (ethyl acrylate)-(methyl
methacrylate)-[(trimethylammonium)-ethyl methacrylate] (1:2:0.1)
copolymer, PM 150,000. Specific polymers include: EUDRAGIT.RTM.RS
100: solid polymer, EUDRAGIT.RTM.RS 12.5: 12.5% solution in
solvent, EUDRAGIT.RTM.RS 30D: 30% aqueous dispersion and other
equivalent products. RL is readily water permeable while
EUDRAGIT.RTM.RS is hardly water permeable. By employing mixtures of
both EUDRAGIT.RTM.RL and EUDRAGIT.RTM.RS, membranes having the
desired degree of permeability to achieve the in-vitro dissolution
rates and in-vivo pharmacokinetic parameters can be prepared.
[0533] The use of plasticizers is optional but can be included in
the osmotic dosage forms of certain embodiments to modify the
properties and characteristics of the polymers used in the coats or
core of the osmotic dosage forms for convenient processing during
manufacture of the coats and/or the core of the osmotic dosage
forms if necessary. As used herein, the term "plasticizer" includes
any compounds capable of plasticizing or softening a polymer or
binder used in invention. Once the coat or membrane has been
manufactured, certain plasticizers can function to increase the
hydrophilicity of the coat(s) and/or the core of the osmotic dosage
form in the environment of use. During manufacture of the coat, the
plasticizer lowers the melting temperature or glass transition
temperature (softening point temperature) of the polymer or binder.
Plasticizers, such as low molecular weight PEG, can be included
with a polymer and lower its glass transition temperature or
softening point. Plasticizers also can reduce the viscosity of a
polymer. The plasticizer can impart some particularly advantageous
physical properties to the osmotic device of the invention.
[0534] Plasticizers useful in the osmotic dosage form of certain
embodiments of the invention can include, for example, low
molecular weight polymers, oligomers, copolymers, oils, small
organic molecules, low molecular weight polyols having aliphatic
hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene
glycol), multi-block polymers, single block polymers, low molecular
weight poly(ethylene glycol), citrate ester-type plasticizers,
triacetin, propylene glycol, glycerin, ethylene glycol,
1,2-butylene glycol, 2,3-butylene glycol, styrene glycol,
diethylene glycol, triethylene glycol, tetraethylene glycol and
other poly(ethylene glycol) compounds, monopropylene glycol
monoisopropyl ether, propylene glycol monoethyl ether, ethylene
glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol
lactate, ethyl lactate, butyl lactate, ethyl glycolate,
dibutylsebacate, acetyltributylcitrate, triethyl citrate, acetyl
triethyl citrate, tributyl citrate, allyl glycolate and mixtures
thereof. It is also contemplated and within the scope of the
invention, that a combination of plasticizers can be used in the
present formulation. The PEG based plasticizers are available
commercially or can be made by a variety of methods, such as
disclosed in Poly(ethylene glycol) Chemistry: Biotechnical and
Biomedical Applications (J. M. Harris, Ed.; Plenum Press, NY). Once
the osmotic dosage form is manufactured, certain plasticizers can
function to increase the hydrophilicity of the coat(s) and/or the
core of the osmotic dosage form in the environment of use may it be
in-vitro or in-vivo. Accordingly, certain plasticizers can function
as flux enhancers.
[0535] The ratio of cellulose esters:copolymers of methacrylate
salts:plasticizer of the osmotic dosage forms can be, for example,
about 1% to about 99% of the cellulose ester by weight: about 0.5%
to about 84% of the copolymers of methacrylate salt by weight:
about 0.5% to about 15% of the plasticizer by weight including all
values and ranges therebetween. The total weight percent of all
components comprising the wall is 100%.
[0536] Aside from the semipermeable membranes of the osmotic dosage
form described above, asymmetric membranes can also be used to
surround the core of an osmotic dosage form for the controlled
release of the bupropion hydrobromide salt to provide the in-vitro
release rates described above and the therapeutically beneficial
in-vivo pharmacokinetic parameters for the treatment or management
of a condition. Such asymmetric membranes can be permeable,
semipermeable, perforated, or unperforated and can deliver the
bupropion hydrobromide salt by osmotic pumping, diffusion or the
combined mechanisms of diffusion and osmotic pumping. The
manufacture and use thereof of asymmetric membranes for the
controlled-release of an active drug through one or more asymmetric
membranes by osmosis or by a combination of diffusion osmotic
pumping is known.
[0537] In certain embodiments of the osmotic dosage form, the
semipermeable membrane can further comprise a flux enhancing, or
channeling agent. "Flux enhancing agents" or "channeling agents"
are any materials which function to increase the volume of fluid
imbibed into the core to enable the osmotic dosage form to dispense
substantially all of the bupropion hydrobromide salt through at
least one passageway in the semipermeable membrane by osmosis or by
osmosis and by diffusion through the semipermeable membrane. The
flux enhancing agent dissolves to form paths in the semipermeable
membrane for the fluid to enter the core and dissolve the bupropion
hydrobromide salt in the core together with the osmagent, if one is
present, but does not allow exit of the bupropion hydrobromide
salt. The flux enhancing agent can be any water soluble material or
an enteric material which allows an increase in the volume of
liquid imbibed into the core but does not allow for the exit of the
bupropion hydrobromide salt. Such materials can be, for example,
sodium chloride, potassium chloride, sucrose, sorbitol, mannitol,
polyethylene glycol, propylene glycol, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, hydroxypropyl methylcellulose
phthalate, cellulose acetate phthalate, polyvinyl alcohols,
methacrylic copolymers, and combinations thereof. Some plasticizers
can also function as flux enhancers by increasing the
hydrophilicity of the semipermeable membrane and/or the core of the
osmotic dosage form. Flux enhancers or channeling agents can also
function as a means for the exit of the bupropion hydrobromide salt
from the core if the flux enhancing or channeling agent is used in
a sufficient amount.
[0538] The expression "passageway" as used herein comprises means
and methods suitable for the metered release of the bupropion
hydrobromide salt from the core of the osmotic dosage form. The
means for the exit of the bupropion hydrobromide salt comprises at
least one passageway, including orifice, bore, aperture, pore,
porous element, hollow fiber, capillary tube, porous overlay, or
porous element that provides for the osmotic controlled release of
the bupropion hydrobromide salt. The means for the exit can be
linear or tortuous. The means for the exit includes a weakened area
of the semipermeable membrane or a material that erodes or is
leached from the wall in a fluid environment of use to produce at
least one dimensioned passageway. The means for the exit of the
bupropion hydrobromide salt can comprise any leachable material,
which when leaches out of the semipermeable membrane forms a
passageway suitable for the exit of the bupropion hydrobromide salt
from the core of the osmotic dosage form. Such leachable materials
can comprise, for example, a leachable poly(glycolic) acid or
poly(lactic) acid polymer in the semipermeable membrane, a
gelatinous filament, poly(vinyl alcohol), leachable
polysaccharides, salts, oxides, sorbitol, sucrose or mixtures
thereof. The means for exit can also comprise a flux enhancer or
channeling agent if present in a sufficient amount. The means for
the exit possesses controlled-release dimensions, such as round,
triangular, square and elliptical, for the metered release of the
bupropion hydrobromide salt from the dosage form. The dimensions of
the means of the exit for the bupropion hydrobromide salt is sized
such so as to allow the bupropion hydrobromide salt to pass through
the means for the exit. The dosage form can be constructed with one
or more means for the exit in spaced apart relationship on a single
surface or on more than one surface of the wall.
[0539] The expression "fluid environment" denotes an aqueous or
biological fluid as in a human patient, including the
gastrointestinal tract. The means for the exit can be preformed for
example by mechanical means after the semipermeable membrane is
applied to the core of the osmotic dosage form, such as for example
by mechanical perforation, laser perforation, or by using a
properly sized projection on the interior of a tablet punch to form
the means for the exit of the bupropion hydrobromide salt, such as
for example a cylindrical or frustoconical pin which is integral
with the inside surface of the upper punch of a punch used to form
the osmotic dosage form. Alternatively, the means for the exit of
the bupropion hydrobromide salt can be formed by incorporating a
leachable material or pore forming agent into the semipermeable
composition before the semipermeable membrane is applied to the
core of the osmotic dosage form. The means for the exit of the
bupropion hydrobromide salt can comprise a combination of the
different exit means described above. The osmotic dosage form can
comprise more than one means for the exit of the bupropion
hydrobromide salt including two, three, four, five, six seven,
eight, nine ten or more exit means and can be formed in any place
of the osmotic dosage form. The various positions of the means for
the exit are disclosed. The type, number, and dimension(s) of the
means for the exit of the bupropion hydrobromide salt is such that
the dosage form exhibits the desired in-vitro release rates
described herein and can be determined by routine experimentation
by those skilled in the pharmaceutical delivery arts. The means for
the exit and equipment for forming the means for the exit are
known.
[0540] The osmotic device can further comprise a controlled release
coat surrounding the semipermeable membrane comprising an enteric
or delayed release coat that is soluble or erodible in intestinal
juices, substantially pH neutral or basic fluids of fluids having a
pH higher than gastric fluid, but for the most part insoluble in
gastric juices or acidic fluids. A wide variety of other polymeric
materials are known to possess these various solubility properties.
Such other polymeric materials include, for example, cellulose
acetate phthalate (CAP), cellulose acetate trimelletate (CAT),
poly(vinyl acetate) phthalate (PVAP), hydroxypropyl methyl
cellulose phthalate (HP), poly(methacrylate ethylacrylate) (1:1)
copolymer (MA-EA), poly(methacrylate methylmethacrylate) (1:1)
copolymer (MA-MMA), poly(methacrylate methylmethacrylate) (1:2)
copolymer, EUDRAGIT.RTM. L-30-D (MA-EA, 1:1), EUDRAGIT.RTM.
L-100-55 (MA-EA, 1:1), hyciroxypropyl methylcellulose acetate
succinate (HPMCAS), COATERIC.RTM. (PVAP), AQUATERIC.RTM. (CAP),
AQUACOAT.RTM. (HPMCAS) and combinations thereof. The enteric coat
can also comprise dissolution aids, stability modifiers, and
bioabsorption enhancers.
[0541] In at least one embodiment the controlled release coat of
certain osmotic dosage forms include materials such as
hydroxypropylcellulose, microcrystalline cellulose (e.g. MCC,
AVICEL.TM.), poly (ethylene-vinyl acetate) (60:40) copolymer
(EVAC), 2-hydroxyethylmethacrylate (HEMA), MMA, terpolymers of
HEMA: MMA:MA synthesized in the presence of
N,N'-bis(methacryloyloxyethyloxycarbonylamino)-azobenzene,
azopolymers, enteric coated timed release system (TIME CLOCK.RTM.),
calcium pectinate, and mixtures thereof.
[0542] Polymers that can be used in the controlled release coat of
osmotic dosage forms of certain embodiments can be, for example,
enteric materials that resist the action of gastric fluid avoiding
permeation through the semipermeable wall while one or more of the
materials in the core of the dosage form are solubilized in the
intestinal tract thereby allowing delivery of the bupropion
hydrobromide salt in the core by osmotic pumping in the osmotic
dosage form to begin. A material that adapts to this kind of
requirement can be, for example, a poly(vinylpyrrolidone)-vinyl
acetate copolymer (e.g. KOLLIDON.RTM. VA64), mixed with magnesium
stearate and other similar excipients. The coat can also comprise
povidone (e.g. KOLLIDON.RTM. K 30), and hydroxypropyl
methylcellulose (e.g. METHOCEL.RTM. E-15). The materials can be
prepared in solutions having different concentrations of polymer
according to the desired solution viscosity. For example, a 10% P/V
aqueous solution of KOLLIDON.RTM. K 30 has a viscosity of about 5.5
to about 8.5 cps at 20.degree. C., and a 2% P/V aqueous solution of
METHOCEL.RTM. E-15 has a viscosity of about 13 to about 18 cps at
20.degree. C.
[0543] The controlled release coat of osmotic dosage forms of
certain embodiments can comprise one or more materials that do not
dissolve, disintegrate, or change their structural integrity in the
stomach and during the period of time that the tablet resides in
the stomach, such as for example a member chosen from the group (a)
keratin, keratin saridarac-tolu, salol (phenyl salicylate), salol
beta-naphthylbenzoate and acetotannin, salol with balsam of Peru,
salol with tolu, salol with gum mastic, salol and stearic acid, and
salol and shellac; (b) a member chosen from the group of formalized
protein, formalized gelatin, and formalized cross-linked gelatin
and exchange resins; (c) a member chosen from the group of myristic
acid-hydrogenated castor oil-cholesterol, stearic acid-mutton
tallow, stearic acid-balsam of tolu, and stearic acid-castor oil;
(d) a member chosen from the group of shellac, ammoniated shellac,
ammoniated shellac-salol, shellac-wool fat, shellac-acetyl alcohol,
shellac-stearic acid-balsam of tolu, and shellac n-butyl stearate;
(e) a member chosen from the group of abietic acid, methyl
abictate, benzoin, balsam of tolu, sandarac, mastic with tolu, and
mastic with tolu, and mastic with acetyl alcohol; (f) acrylic
resins represented by anionic polymers synthesized from
methacrylate acid and methacrylic acid methyl ester, copolymeric
acrylic resins of methacrylic and methacrylic acid and methacrylic
acid alkyl esters, copolymers of alkacrylic acid and alkacrylic
acid alkyl esters, acrylic resins such as
dimethylaminoethylmethacrylate-butylmethacrylate-methylmethacrylate
copolymer of about 150,000 molecular weight, methacrylic
acid-methylmethacrylate 50:50 copolymer of about 135,000 molecular
weight, methacrylic acid-methylmethacrylate-30:70-copolymer of
about 135,000 mol. wt., methacrylic
acid-dimethylaminoethyl-methacrylate-ethylacrylate of about 750,000
mol. wt., methacrylic acid-methylmethacrylate-ethylacrylate of
about 1,000,000 mol. wt., and
ethylacrylate-methylmethacrylate-ethylacrylate of about 550,000
mol. wt; and, (g) an enteric composition chosen from the group of
cellulose acetyl phthalate, cellulose diacetyl phthalate, cellulose
triacetyl phthalate, cellulose acetate phthalate, hydroxypropyl
methylcellulose phthalate, sodium cellulose acetate phthalate,
cellulose ester phthalate, cellulose ether phthalate,
methylcellulose phthalate, cellulose ester-ether phthalate,
hydroxypropyl cellulose phthalate, alkali salts of cellulose
acetate phthalate, alkaline earth salts of cellulose acetate
phthalate, calcium salt of cellulose acetate phthalate, ammonium
salt of hydroxypropyl methylcellulose phthalate, cellulose acetate
hexahydrophthalate, hydroxypropyl methylcellulose
hexahydrophthalate, polyvinyl acetate phthalate diethyl phthalate,
dibutyl phthalate, dialkyl phthalate wherein the alkyl comprises
from about 1 to about 7 straight and branched alkyl groups, aryl
phthalates, and other materials known to one or ordinary skill in
the art. Combinations thereof are operable.
[0544] Accordingly, in at least one other embodiment, the
controlled release coat of osmotic dosage forms of certain
embodiments comprises a water-insoluble water-permeable
film-forming polymer, water-soluble polymer, and optionally a
plasticizer and/or a pore-forming agent. The water-insoluble,
water-permeable film-forming polymers useful for the manufacture of
the controlled release coat can be cellulose ethers, such as for
example, ethyl celluloses chosen from the group of ethyl cellulose
grade PR100, ethyl cellulose grade PR20, cellulose esters,
polyvinyl alcohol, and any combination thereof. The water-soluble
polymers useful for the controlled release coat can be, for
example, polyvinylpyrrolidone, hydroxypropyl methylcellulose,
hydroxypropyl cellulose, and any combination thereof.
[0545] The skilled artisan will appreciate that that the desired
in-vitro release rates described herein for the bupropion
hydrobromide salt can be achieved by controlling the permeability
and/or the amount of coating applied to the core of the osmotic
dosage form. The permeability of the controlled release coat, can
be altered by varying the ratio of the water-insoluble,
water-permeable film-forming polymer:water-soluble
polymer:optionally the plasticizer and/or the quantity of coating
applied to the core of the osmotic dosage form. A more extended
release is generally obtained with a higher amount of
water-insoluble, water-permeable film forming polymer. The addition
of other excipients to the core of the osmotic dosage form can also
alter the permeability of the controlled release coat. For example,
if the core of the osmotic dosage form comprises a swellable
polymer, the amount of plasticizer in the controlled release coat
can be increased to make the coat more pliable as the pressure
exerted on a less pliable coat by the swellable polymer could
rupture the coat. Further, the proportion of the water-insoluble
water-permeable film forming polymer and water-soluble polymer can
also be altered depending on whether a faster or slower in-vitro
dissolution is desired.
[0546] In at least one other embodiment, the controlled release
coat of the osmotic dosage form comprises an aqueous dispersion of
a neutral ester copolymer without any functional groups; a poly
glycol having a melting point greater than about 55.degree. C., and
one or more pharmaceutically acceptable excipients and cured at a
temperature at least equal to or greater than the melting point of
the poly glycol. The manufacture and use of such coating
formulations are known. In brief, examples of neutral ester
copolymers without any functional groups comprising the coat can be
EUDRAGIT.RTM. NE30D, EUDRAGIT.RTM. NE40D, or mixtures thereof. This
coat can comprise hydrophilic agents to promote wetting of the coat
when in contact with gastrointestinal fluids. Such hydrophilic
agents include, for example, hydrophilic water-soluble polymers
such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl
cellulose (HPC) and combinations thereof. The poly glycol can be,
for example, chosen from the group of polyethylene glycol 6000,
polyethylene glycol 8000, polyethylene glycol 10000, polyethylene
glycol 20000, Poloxamer 188, Poloxamer 338, Poloxamer 407,
Polyethylene Oxides, Polyoxyethylene Alkyl Ethers, and
Polyoxyethylene Stearates, and combinations thereof. This
controlled release coat of the osmotic dosage form can further
comprise a pore-forming agent. In at least one embodiment the pore
former is sufficiently insoluble in the aqueous dispersion, and is
sufficiently soluble in the environment of use. Methods for
producing such coats are known.
[0547] The controlled release coat of certain embodiments of the
osmotic dosage form of certain embodiments of the present invention
includes at least one polymer in an amount sufficient to achieve a
controlled release of the bupropion hydrobromide salt. Examples of
polymers that can be used in the controlled release coat of these
embodiments include cellulose acetate phthalate, cellulose acetate
trimaletate, hydroxy propyl methylcellulose phthalate, polyvinyl
acetate phthalate, ammonio methacrylate copolymers such as
EUDRAGIT.RTM. RS and RL, poly acrylic acid and poly acrylate and
methacrylate copolymers such as EUDRAGIT.RTM. S and L, polyvinyl
acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate
succinate, shellac; hydrogels and gel-forming materials, such as
carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium
carmellose, sodium carboxymethyl starch, poly vinyl alcohol,
hydroxyethyl cellulose, methyl cellulose, gelatin, starch, and
cellulose based cross-linked polymers in which the degree of
crosslinking is low so as to facilitate adsorption of water and
expansion of the polymer matrix, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked
starch, microcrystalline cellulose, chitin, aminoacryl-methacrylate
copolymer (e.g. EUDRAGIT.RTM. RS-PM), pullulan, collagen, casein,
agar, gum arabic, sodium carboxymethyl cellulose, (swellable
hydrophilic polymers) poly(hydroxyalkyl methacrylate) (molecular
weight from about 5K to about 5000K), polyvinylpyrrolidone
(molecular weight from about 10K to about 360K), anionic and
cationic hydrogels, polyvinyl alcohol having a low acetate
residual, a swellable mixture of agar and carboxymethyl cellulose,
copolymers of maleic anhydride and styrene, ethylene, propylene or
isobutylene, pectin (molecular weight from about 30K to about
300K), polysaccharides such as agar, acacia, karaya, tragacanth,
algins and guar, polyacrylamides, POLYOX.RTM. polyethylene oxides
(molecular weight from about 100K to about 5000K), AQUAKEEP.RTM.
acrylate polymers, diesters of polyglucan, crosslinked polyvinyl
alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glycolate
(e.g. EXPLOTAB.RTM.); hydrophilic polymers such as polysaccharides,
methyl cellulose, sodium or calcium carboxymethyl cellulose,
hydroxypropyl methyl cellulose, hydroxypropyl cellulose,
hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose,
cellulose ethers, polyethylene oxides (e.g. POLYOX), methyl ethyl
cellulose, ethylhydroxy ethylcellulose, cellulose acetate,
cellulose butyrate, cellulose propionate, gelatin, collagen,
starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl
alcohol, polyvinyl acetate, glycerol fatty acid esters,
polyacrylamide, polyacrylic acid, copolymers of methacrylic acid or
methacrylic acid (e.g. EUDRAGIT.RTM.), other acrylic acid
derivatives, sorbitan esters, natural gums, lecithins, pectin,
alginates, ammonia alginate, sodium, calcium, potassium alginates,
propylene glycol alginate, agar, and gums such as arabic, karaya,
locust bean, tragacanth, carrageens, guar, xanthan, scleroglucan
and mixtures and blends thereof. In at least one embodiment of the
osmotic dosage form of the present invention, the polymer is an
acrylate dispersion such as EUDRAGIT.RTM. NE30D, EUDRAGIT.RTM.
NE40D, KOLLICOAT.RTM. SR 30D, SURELEASE.RTM., or a mixture thereof.
The polymer can be present in an amount of from about 20% to about
90% by weight of the controlled release coat including all values
and ranges therebetween, depending on the controlled release
profile desired. For example, in certain embodiments of the osmotic
dosage form, the polymer is present in an amount of from about 50%
to about 95%, in other embodiments from about 60% to about 90%, and
in still other embodiments about 75% of the controlled release coat
weight.
[0548] The controlled release coat of certain embodiments of the
osmotic dosage form of the present invention can also include one
or more pharmaceutically acceptable excipients such as lubricants,
emulsifiers, anti-foaming agents, plasticisers, solvents and the
like.
[0549] Lubricants can be included in the controlled release coat of
certain embodiments of the osmotic dosage form of the present
invention to help reduce friction of coated microparticles during
manufacturing. The lubricants that can be used in the controlled
release coat include but are not limited to adipic acid, magnesium
stearate, calcium stearate, zinc stearate, calcium silicate,
magnesium silicate, hydrogenated vegetable oils, sodium chloride,
sterotex, polyoxyethylene, glyceryl monostearate, talc,
polyethylene glycol, sodium benzoate, sodium lauryl sulfate,
magnesium lauryl sulfate, sodium stearyl fumarate, light mineral
oil, waxy fatty acid esters such as glyceryl behenate, (i.e.
COMPRITOL.TM.), STEAR-O-WET.TM. and MYVATEX.TM. TL. Combinations of
these lubricants are operable. In at least one embodiment, the
lubricant is selected from magnesium stearate, talc and a mixture
thereof. The lubricant(s) can each be present in an amount of from
about 0.1% to about 80% of the controlled release coat weight
including all values and ranges therebetween. For example, in
certain embodiments the lubricant is present in an amount of from
about 0.5% to about 20%, in other embodiments from about 0.8% to
about 10%, and in still other embodiments about 1.5% of the
controlled release coat weight.
[0550] Emulsifying agent(s) (also called emulsifiers or emulgents)
can be included in the controlled release coat of the osmotic
dosage forms of certain embodiments of the present invention to
facilitate actual emulsification during manufacture of the coat,
and also to increase or ensure emulsion stability during the
shelf-life of the product. Emulsifying agents useful for the
controlled release coat composition of the osmotic dosage form
include, but are not limited to naturally occurring materials and
their semi synthetic derivatives, such as the polysaccharides, as
well as glycerol esters, cellulose ethers, sorbitan esters (e.g.
sorbitan monooleate or SPAN.TM. 80), and polysorbates (e.g.
TWEEN.TM. 80). Combinations of emulsifying agents are operable. The
emulsifying agent(s) can be present in an amount of from about
0.01% to about 0.25% of the controlled release coat weight
including all values and ranges therebetween. For example, in
certain embodiments the emulsifying agent is present in an amount
of from about 0.01% to about 0.15%, in other embodiments from about
0.01% to about 0.07%, and in still other embodiments about 0.03% of
the controlled release coat weight.
[0551] Anti-foaming agent(s) can be included in the controlled
release coat of the osmotic dosage form of certain embodiments of
the present invention to reduce frothing or foaming during
manufacture of the coat. Anti-foaming agents useful for the
controlled release coat composition of the osmotic dosage form
include, but are not limited to simethicone, polyglycol, silicon
oil and mixtures thereof. In at least one embodiment the
anti-foaming agent is Simethicone C. The anti-foaming agent can be
present in an amount of from about 0.01% to about 10% of the
controlled release coat weight including all values and ranges
therebetween. For example, in certain embodiments the anti-foaming
agent is present in an amount of from about 0.05% to about 1%, in
other embodiments from about 0.1% to about 0.3%, and in still other
embodiments about 0.15% of the controlled release coat weight.
[0552] It is contemplated that in certain embodiments, other
excipients consistent with the objects of the present invention can
also be used in the controlled release coat of the osmotic dosage
form.
[0553] In at least one embodiment, the controlled release coat of
the osmotic dosage form includes about 75% EUDRAGIT.RTM. NE30D,
about 1.5% Magnesium stearate, about 1.5% Talc, about 0.03%
TWEEN.TM. 80, about 0.15% Simethicone C, and about 21.82% water, by
weight of the controlled release coat composition.
[0554] The osmotic dosage form of certain embodiments can be made
according to any one of the methods described herein. In a
prophetic example of certain embodiments of osmotic dosage forms of
the present invention, the manufacturing process for the controlled
release coat of the osmotic dosage form can hypothetically be as
follows: Water is split into two portions of about 15% and about
85%. The anti-foaming agent and the emulsifying agent are then
added to the 15% water portion, and mixed at about 300 rpm to form
portion A. In at least one embodiment, the anti-foaming agent is
Simethicone C, and the emulsifying agent is TWEEN.TM. 80. A first
lubricant is then added to the 85% water portion and mixed at about
9500 rpm to form portion B. In at least one embodiment, the first
lubricant is talc. Then portion A is mixed with portion B, a second
lubricant is slowly added, and mixed at about 700 rpm overnight. In
at least one embodiment, the second lubricant is magnesium
stearate. Finally, an aqueous dispersion of a neutral ester
copolymer is added and mixed for about 30 minutes at about 500 rpm.
In at least one embodiment, the aqueous dispersion of a neutral
ester copolymer is EUDRAGIT.RTM. NE30D. The resultant coat solution
can then be used to coat the osmotic subcoated microparticles to
about a 35% weight gain with the following parameters: An inlet
temperature of from about 10.degree. C. to about 60.degree. C.
including all values and ranges therebetween, in certain
embodiments from about 20.degree. C. to about 40.degree. C., and in
at least one embodiment from about 25.degree. C. to about
35.degree. C.; an outlet temperature of from about 10.degree. C. to
about 60.degree. C. including all values and ranges therebetween,
in certain embodiments from about 20.degree. C. to about 40.degree.
C., and in at least one embodiment from about 25.degree. C. to
about 35.degree. C.; a product temperature of from about 10.degree.
C. to about 60.degree. C. including all values and ranges
therebetween, in certain embodiments from about 15.degree. C. to
about 35.degree. C., and in at least one embodiment from about
22.degree. C. to about 27.degree. C.; an air flow of from about 10
cm/h to about 180 cm/h including all values and ranges
therebetween, in certain embodiments from about 40 cm/h to about
120 cm/h, and in at least one embodiment from about 60 cm/h to
about 80 cm/h; and an atomizing pressure of from about 0.5 bar to
about 4.5 bar including all values and ranges therebetween, in
certain embodiments from about 1 bar to about 3 bar, and in at
least one embodiment at about 2 bar. The resultant coated
microparticles can then be discharged from the coating chamber and
overcured with the following parameters: A curing temperature of
from about 20.degree. C. to about 65.degree. C. including all
values and ranges therebetween, in certain embodiments from about
30.degree. C. to about 55.degree. C., and in at least one
embodiment at about 40.degree. C.; and a curing time of from about
2 hours to about 120 hours including all values and ranges
therebetween, in certain embodiments from about 10 hours to about
40 hours, and in at least one embodiment at about 24 hours. Any
other technology resulting in the coating formulation of the
controlled release coat of the osmotic dosage form that is
consistent with the objects of the invention can also be used.
[0555] In at least one other embodiment, the osmotic dosage forms
comprise a water-soluble or rapidly dissolving coat between the
semipermeable membrane and the controlled release coat. The rapidly
dissolving coat can be soluble in the buccal cavity and/or upper GI
tract, such as the stomach, duodenum, jejunum or upper small
intestines. Materials suitable for the manufacture of the
water-soluble coat are known. In certain embodiments, the rapidly
dissolving coat can be soluble in saliva, gastric juices, or acidic
fluids. Materials which are suitable for making the water soluble
coat or layer can comprise, for example, water soluble
polysaccharide gums such as carrageenan, fucoidan, gum ghatti,
tragacanth, arabinogalactan, pectin, and xanthan; water-soluble
salts of polysaccharide gums such as sodium alginate, sodium
tragacanthin, and sodium gum ghattate; water-soluble
hydroxyalkylcellulose wherein the alkyl member is straight or
branched of 1 to 7 carbons such as, for example,
hydroxymethylcellulose, hydroxyethylcellulose, and
hydroxypropylcellulose; synthetic water-soluble cellulose-based
lamina formers such as, for example, methyl cellulose and its
hydroxyalkyl methylcellulose cellulose derivatives such as a member
chosen from the group of hydroxyethyl methylcellulose,
hydroxypropyl methylcellulose, and hydroxybutyl methylcellulose;
croscarmellose sodium; other cellulose polymers such as sodium
carboxymethylcellulose; and mixtures thereof. Other lamina forming
materials that can be used for this purpose include, for example,
poly(vinylpyrrolidone), polyvinylalcohol, polyethylene oxide, a
blend of gelatin and polyvinyl-pyrrolidone, gelatin, glucose,
saccharides, povidone, copovidone,
poly(vinylpyrrolidone)-poly(vinyl acetate) copolymer and mixtures
thereof. The water soluble coating can comprise other
pharmaceutical excipients that in certain embodiments can alter the
way in which the water soluble coating behaves. The artisan of
ordinary skill will recognize that the above-noted materials
include film-forming polymers. The inert water-soluble coat
covering the semipermeable wall and blocking the passageway of
osmotic dosage forms of the present invention, is made of synthetic
or natural material which, through selective dissolution or erosion
can allow the passageway to be unblocked thus allowing the process
of osmotic delivery to start. This water-soluble coat can be
impermeable to a first external fluid, while being soluble in a
second external fluid. This property can help to achieve a
controlled and selective release of the bupropion hydrobromide salt
from the osmotic dosage form so as to achieve the desired in-vitro
release rates.
[0556] In embodiments where the core of the osmotic dosage form
does not comprise an osmagent, the osmotic dosage forms can
comprise an osmotic subcoat, which can surround the core of the
osmotic dosage form. The osmotic subcoat comprises at least one
osmotic agent and at least one hydrophilic polymer. The osmotic
subcoat of these embodiments provides for the substantial
separation of the bupropion hydrobromide salt from the osmotic
agent into substantially separate compartments/layers. This
separation can potentially increase the stability of the bupropion
hydrobromide salt by reducing possible unfavorable interactions
between the bupropion hydrobromide salt and the osmagent, and/or
between the bupropion hydrobromide salt and the components of the
controlled release coat. For example, the osmagent can be
hygroscopic in nature, and can attract water that can lead to the
degradation of the bupropion hydrobromide salt. Since the osmotic
agent of these embodiments can be substantially separated from the
bupropion hydrobromide salt, the bupropion hydrobromide salt can be
less prone to degradation from the water drawn in by the osmagent.
The controlled release coat comprises at least one controlled
release polymer and optionally a plasticizer. The coated cores of
the osmotic dosage form can be filled into capsules, or
alternatively can be compressed into tablets using suitable
excipients. In these embodiments the osmotic dosage form can
utilize both diffusion and osmosis to control drug release, and can
be incorporated into sustained release and/or delayed release
dosage forms. In addition, in certain embodiments the osmotic
pressure gradient and rate of release of the bupropion hydrobromide
salt can be controlled by varying the level of the osmotic agent
and/or the level of the hydrophilic polymer in the osmotic subcoat,
without the need for a seal coat around the osmotic subcoat.
[0557] The hydrophilic polymer used in an osmotic subcoat of
certain embodiments of the present invention functions as a carrier
for the osmotic agent. In certain embodiments the hydrophilic
polymer in the osmotic subcoat does not substantially affect the
drug release. In at least one embodiment, the hydrophilic polymer
used in the osmotic subcoat does not act as a diffusion barrier to
the release of the bupropion hydrobromide salt. In at least one
embodiment the release profile of the osmotic agent is
substantially the same as the release profile of the bupropion
hydrobromide salt. Such hydrophilic polymers useful in an osmotic
subcoat of certain embodiments of the present invention include by
way of example, polyvinyl pyrrolidone, hydroxyethyl cellulose,
hydroxypropyl cellulose, low molecular weight hydroxypropyl
methylcellulose (HPMC), polymethacrylate, ethyl cellulose, and
mixtures thereof. In at least one embodiment, the hydrophilic
polymer of the osmotic subcoat is a low molecular weight and a low
viscosity hydrophilic polymer. A wide variety of low molecular
weight and low viscosity hydrophilic polymers can be used in the
osmotic subcoat. Examples of HPMC polymers that can be used in the
osmotic subcoat include PHARMACOAT.RTM. 606, PHARMACOAT.RTM. 606G,
PHARMACOAT.RTM. 603, METHOCEL.RTM. E3, METHOCEL.RTM. E5,
METHOCEL.RTM. E6, and mixtures thereof. The hydrophilic polymer of
the osmotic subcoat can be present in an amount of from about 1% to
about 30% by weight of the osmotic subcoat composition including
all values and ranges therebetween. For example, in certain
embodiments the hydrophilic polymer is present in an amount of from
about 1% to about 20%, in other embodiments from about 3% to about
10%, and in still other embodiments about 7% by weight of the
osmotic subcoat composition.
[0558] In at least one embodiment, the osmotic subcoat comprises
about 7% PHARMACOAT.RTM. 606, about 1% sodium chloride, and about
92% water, by weight of the osmotic subcoat composition.
[0559] One method for producing the osmotic subcoat can be as
follows. The at least one osmotic agent, for example sodium
chloride, is dissolved in water. The solution of osmotic agent and
water is then heated to about 60.degree. C. The hydrophilic polymer
is then added gradually to the solution. A magnetic stirrer can be
used to aid in the mixing of the hydrophilic polymer to the
solution of osmotic agent and water. The resultant osmotic
subcoating solution can then be used to coat the core of the
osmotic dosage form in a fluidized bed granulator, such as a
granulator manufactured by Glatt (Germany) or Aeromatic
(Switzerland) to the desired weight gain. An inlet temperature of
from about 10.degree. C. to about 70.degree. C. including all
values and ranges therebetween, in certain embodiments from about
30.degree. C. to about 55.degree. C., and in at least one
embodiment from about 40.degree. C. to about 45.degree. C.; an
outlet temperature of from about 10.degree. C. to about 70.degree.
C. including all values and ranges therebetween, in certain
embodiments from about 20.degree. C. to about 45.degree. C., and in
at least one embodiment from about 30.degree. C. to about
35.degree. C.; a product temperature of from about 10.degree. C. to
about 70.degree. C. including all values and ranges therebetween,
in certain embodiments from about 20.degree. C. to about 45.degree.
C., and in at least one embodiment from about 30.degree. C. to
about 35.degree. C.; an air flow of from about 10 cm/h to about 180
cm/h including all values and ranges therebetween; in certain
embodiments from about 40 cm/h to about 120 cm/h; and in at least
one embodiment from about 60 cm/h to about 80 cm/h; an atomizing
pressure of from about 0.5 bar to about 4.5 bar including all
values and ranges therebetween, in certain embodiments from about 1
bar to about 3 bar, and in at least one embodiment at about 2 bar;
a curing temperature of from about 10.degree. C. to about
70.degree. C. including all values and ranges therebetween, in
certain embodiments from about 20.degree. C. to about 50.degree.
C., and in at least one embodiment from about 30.degree. C. to
about 40.degree. C.; and a curing time of from about 5 minutes to
about 720 minutes including all values and ranges therebetween; in
certain embodiments from about 10 minutes to about 120 minutes, and
in at least one embodiment at about 30 minutes. Any other
technology resulting in the coating formulation of the osmotic
subcoat consistent with the objects of the invention can also be
used.
[0560] The ratio of the components in the core, semipermeable
membrane and/or water-soluble membrane and/or at least one
controlled release coat and/or osmotic subcoat as well as the
amount of the various membranes or coats applied can be varied to
control delivery of the bupropion hydrobromide salt either
predominantly by diffusion across the surface of the semipermeable
membrane to predominantly by osmotic pumping through the at least
one passageway in the semipermeable membrane, and combinations
thereof such that the dosage form can exhibit a modified-release,
controlled-release, sustained-release, extended-release,
prolonged-release, bi-phasic release, delayed-release profile or a
combination of release profiles whereby the in-vitro release rates
of the bupropion hydrobromide salt is such that after about 2 hours
from about 0% to about 20% by weight of the bupropion hydrobromide
salt is released, after about 4 hours from about 15% to about 45%
by weight of the bupropion hydrobromide salt is released, after
about 8 hours, from about 40% to about 90% by weight of the
bupropion hydrobromide salt is released, and after about 16 hours,
more than about 80% by weight of the bupropion hydrobromide salt is
released. In embodiments where the mode of exit of the bupropion
hydrobromide salt comprises a plurality of pores, the amount of
pore forming agent employed to achieve the desired in-vitro
dissolution rates can be readily determined by those skilled in the
drug delivery art.
[0561] In at least one embodiment of the osmotic dosage form, the
core comprises bupropion hydrobromide in an amount of from about
40% to about 99% of the core dry weight including all values and
ranges therebetween. For example in certain embodiments the core
comprises bupropion hydrobromide in an amount of about 40%, about
45%, about 50%, about 55%, about 60%, about 65%, about 70%, about
75%, about 80%, about 85%, about 90%, about 95% or about 99% of the
core dry weight.
[0562] In certain embodiments, the core of the osmotic dosage form
comprises at least one means for increasing the hydrostatic
pressure inside the membrane or coat. The membrane or coat can be a
semipermeable membrane, a controlled release coat, a water-soluble
coat, an osmotic subcoat, or any combination thereof. The core of
the osmotic dosage form has an effective osmotic pressure greater
than that of the surrounding fluid in the environment of use so
that there is a net driving force for water to enter the core. The
at least one means for increasing the hydrostatic pressure inside
the membrane or coat can be any material that increases the osmotic
pressure of the core of the osmotic dosage form. The at least one
means for increasing the hydrostatic pressure inside the membrane
or coat can be, for example, the bupropion hydrobromide salt, an
osmagent, any material which can interact with water and/or an
aqueous biological fluid, swell and retain water within their
structure, such as for example an osmopolymer, and any combination
thereof. The osmagent can be soluble or swellable. Examples of
osmotically effective solutes are inorganic and organic salts and
sugars. The bupropion hydrobromide salt can itself be an osmagent
or can be combined with one or more other osmagents, such as for
example, magnesium sulfate, magnesium chloride, sodium chloride,
lithium chloride, potassium sulfate, sodium carbonate, sodium
sulfite, lithium sulfate, potassium chloride, calcium carbonate,
sodium sulfate, calcium sulfate, potassium acid phosphate, calcium
lactate, d-mannitol, urea, inositol, magnesium succinate, tartaric
acid, water soluble acids, alcohols, surfactants, and carbohydrates
such as raffinose, sucrose, glucose, lactose, fructose, algin,
sodium alginate, potassium alginate, carrageenan, fucoridan,
furcellaran, laminaran, hypnea, gum arabic, gum ghatti, gum karaya,
locust bean gum, pectin, starch and mixtures thereof. In certain
embodiments the core comprises osmagent in an amount of about 15%,
about 20%, about 25%, about 30%, about 35%, about 40%, about 45%,
about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,
about 80%, about 85%, about 90%, or about 95% of the core dry
weight.
[0563] The osmagent useful in certain embodiments of the present
invention can be any agent that can generate an osmotic pressure
gradient for the transport of water from the external environment
of use into the osmotic dosage form. Osmagents are also known as
osmotically effective compounds, osmotic solutes, and osmotic fluid
imbibing agents. Osmagents useful in certain embodiments of the
present invention are soluble in aqueous and biological fluids,
such as ionizing compounds, inherently polar compounds, inorganic
acids, organic acids, bases and salts. In at least one embodiment
the osmagent is a solid and dissolves to form a solution with
fluids imbibed into the osmotic dosage form. A wide variety of
osagents can be used to provide the osmotic pressure gradient used
to drive the bupropion hydrobromide salt from the core of the
osmotic dosage form. Examples of inorganic salts useful as
osmagents include lithium chloride, lithium sulfate, lithium
phosphate, magnesium chloride, magnesium sulfate, potassium
chloride, potassium sulfate, potassium phosphate, potassium acid
phosphate, sodium chloride, sodium sulfate, sodium phosphate,
sodium sulfite, sodium nitrate, sodium nitrite, and mixtures
thereof. Examples of salts of organic acids useful as osagents
include sodium citrate, potassium acid tartrate, potassium
bitartrate, sodium bitartrate, and mixtures thereof. Examples of
ionizable solid acids useful as osmagents include tartaric, citric,
maleic, malic, fumaric, tartronic, itaconic, adipic, succinic,
mesaconic acid, and mixtures thereof. Examples of other compounds
useful as osmagents include potassium carbonate, sodium carbonate,
ammonium carbonate, calcium lactate, mannitol, urea, inositol,
magnesium succinate, sorbitol, and carbohydrates such as raffinose,
sucrose, glucose, lactose, lactose monohydrate, a blend of fructose
glucose and mixtures thereof. In at least one embodiment the
osmagent is selected from sodium chloride, sodium bromide, sodium
bisulfate, potassium acid tartrate, citric acid, mannitol, sucrose
and mixtures thereof. Combinations of these osmagents is
permissible. The osmagent can be present in an amount of from about
0.1% to about 50% of the dosage form weight including all values
and ranges therebetween. For example, in certain embodiments the
osmagent is present in an amount of from about 1% to about 40%, and
in other embodiments from about 1% to about 20% of the dosage form
weight.
[0564] In certain embodiments, the at least one means for
increasing the hydrostatic pressure can comprise, in addition to an
osmagent, any material which can interact with water and/or an
aqueous biological fluid, swell and retain water within their
structure. In certain embodiments where the at least one means for
increasing the hydrostatic pressure is an osmopolymer, which can be
slightly cross-linked or uncross-linked. The uncross-linked
polymers to be used as osmopolymers, when in contact with water
and/or aqueous biological fluid, preferably do not dissolve in
water, hence maintaining their physical integrity. Such polymers
can be, for example, chosen from the group of polyacrylic acid
derivatives (e.g., polyacrylates, poly-methyl methacrylate,
poly(acrylic acid) higher alkyl esters, poly(ethylmethacrylate),
poly(hexadecyl methacrylate-co-methylmethacrylate),
poly(methylacrylate-co-styrene), poly(n-butyl methacrylate),
poly(n-butyl-acrylate), poly(cyclododecyl acrylate), poly(benzyl
acrylate), poly(butylacrylate), poly(secbutylacrylate), poly(hexyl
acrylate), poly(octyl acrylate), poly(decyl acrylate), poly(dodecyl
acrylate), poly(2-methyl butyl acrylate), poly(adamantyl
methacrylate), poly(benzyl methacrylate), poly(butyl methacrylate),
poly(2-ethylhexyl methacrylate), poly(octyl methacrylate), acrylic
resins), polyacrylamides, poly(hydroxy ethyl methacrylate),
poly(vinyl alcohol), poly(ethylene oxide), poly
N-vinyl-2-pyrrolidone, naturally occurring resins such as
polysaccharides (e.g., dextrans, water-soluble gums, starches,
chemically modified starches), cellulose derivatives (e.g.,
cellulose esters, cellulose ethers, chemically modified cellulose,
microcrystalline cellulose, sodium carboxymethylcellulose and
methylcellulose), starches, CARBOPOL.TM., acidic carboxy polymer,
CYANAMER.TM., polyacrylamides, cross-linked water-swellable
indene-maleic anhydride polymers, GOOD-RITE.TM., polyacrylic acid,
polyethyleneoxide, starch graft copolymers, AQUA-KEEPS.TM.,
acrylate polymer, diester cross-linked polyglucan, and any
combination thereof.
[0565] In certain embodiments, the core of the osmotic dosage form
further comprises a means for forcibly dispensing the bupropion
hydrobromide salt from the core to the exterior of the dosage form.
The at least one means for forcibly dispensing the bupropion
hydrobromide salt can be any material which can swell in water
and/or aqueous biological fluid and retain a significant fraction
of water within its structure, and will not dissolve in water
and/or aqueous biological fluid, a means for generating a gas, an
osmotically effective solute or any combination thereof which can
optionally be surrounded by a membrane or coat depending on the
particular means used. The membrane or coat can be, for example, a
membrane or coat that is essentially impermeable to the passage of
the bupropion hydrobromide salt, gas and compounds, and is
permeable to the passage of water and/or aqueous biological fluids.
Such a coat or membrane comprises, for example, a semipermeable
membrane, microporous membrane, asymmetric membrane, which
asymmetric membrane can be permeable, semipermeable, perforated, or
unperforated. In at least one embodiment, the at least one means
for forcibly dispensing the bupropion hydrobromide salt from the
core of the osmotic dosage form comprises a means for generating
gas, which means for generating gas is surrounded by, for example,
a semipermeable membrane. In operation, when the gas generating
means imbibes water and/or aqueous biological fluids, the means for
generating gas reacts and generates gas, thereby enlarging and
expanding the at least one means for forcibly dispensing the
bupropion hydrobromide salt unidirectionally or multidirectionally.
The means for generating a gas comprises any compound or compounds,
which can produce effervescence, such as for example, at least one
solid acid compound and at least one solid basic compound, which in
the presence of a fluid can react to form a gas, such as for
example, carbon dioxide. Examples of acid compounds include,
organic acids such as malic, fumaric, tartaric, itaconic, maleic,
citric, adipic, succinic and mesaconic, and inorganic acids such as
sulfamic or phosphoric, also acid salts such as monosodium citrate,
potassium acid tartrate and potassium bitartrate. The basic
compounds include, for example, metal carbonates and bicarbonates
salts, such as alkali metal carbonates and bicarbonates. The acid
and base materials can be used in any convenient proportion from
about 1 to about 200 parts of the at least one acid compound to the
at least one basic compound or from about 1 to about 200 parts of
the at least one basic compound to the at least one acid compound.
The means for generating gas is known.
[0566] In at least one embodiment, the at least one means for
forcibly dispensing the bupropion hydrobromide salt form the core
of the osmotic dosage form comprises any material which can swell
in water and/or aqueous biological fluid and retain a significant
fraction of water within its structure, and will not dissolve in
water and/or aqueous biological fluid, such as for example, a
hydrogel. Hydrogels include, for example, lightly cross-linked
hydrophilic polymers, which swell in the presence of fluid to a
high degree without dissolution, usually exhibiting a 5-fold to a
50-fold volume increase. Non-limiting examples of hydrogels include
poly(hydroxyalkyl methacrylates), poly(acrylamide),
poly(methacrylamide), poly(N-vinyl-2-pyrrolidone), anionic and
cationic hydrogels, polyelectrolyte complexes, a water-insoluble,
water-swellable copolymer produced by forming a dispersion of
finely divided copolymers of maleic anhydride with styrene,
ethylene, propylene butylene or isobutylene cross-linked with from
about 0.001 to about 0.5 moles of a polyunsaturated cross-linking
agent per mole of maleic anhydride in a copolymer, water-swellable
polymers or N-vinyl lactams, semi-solid cross-linked poly(vinyl
pyrrolidone), diester cross-linked polyglucan hydrogels, anionic
hydrogels of heterocyclic N-vinyl monomers, ionogenic hydrophilic
gels, and mixtures thereof. Some of the osmopolymers and hydrogels
are interchangeable. Such means can optionally be covered by a
membrane or coat impermeable to the passage of the bupropion
hydrobromide salt, and compounds, and is permeable to the passage
of water and/or aqueous biological fluids. Such a coat or membrane
comprises, for example, a semipermeable membrane, microporous
membrane, asymmetric membrane, which asymmetric membrane can be
permeable, semipermeable, perforated, or unperforated.
[0567] In at least one other embodiment, the at least one means for
forcibly dispensing the bupropion hydrobromide salt from the core
of the osmotic dosage form comprises at least one osmotically
effective solute surrounded by a membrane or coat impermeable to
the passage of the bupropion hydrobromide salt, and compounds, and
is permeable to the passage of water and/or aqueous biological
fluids such that the osmotically effective solute exhibits an
osmotic pressure gradient across a membrane or coat. Such coat or
membrane comprises, for example, a semipermeable membrane,
microporous membrane, asymmetric membrane, which asymmetric
membrane can be permeable, semipermeable, perforated, or
unperforated. The osmotically effective solutes include, for
example, the osmagents described above.
[0568] In embodiments of the osmotic dosage form where the means
for forcibly dispensing the bupropion hydrobromide salt is
surrounded by a membrane or coat, at least one plasticizer can be
added to the membrane composition to impart flexibility and
stretchability to the membrane or coat. In embodiments where the
means for forcibly dispensing the bupropion hydrobromide salt
comprises a means for generating a gas, the membrane or coat
preferably is stretchable so as to prevent rupturing of the
membrane or coat during the period of delivery of the bupropion
hydrobromide salt. Methods of manufacturing such a membrane or coat
is known. Plasticizers, which can be used in these embodiments
include, for example, cyclic and acyclic plasticizers, phthalates,
phosphates, citrates, adipates, tartrates, sebacates, succinates,
glycolates, glycerolates, benzoates, myristates, sulfonamides
halogenated phenyls, poly(alkylene glycols), poly(alkylenediols),
polyesters of alkylene glycols, dialkyl phthalates, dicycloalkyl
phthalates, diaryl phthalates and mixed alkyl-aryl phthalates, such
as for example, dimethyl phthalate, dipropyl phthalate,
di(2-ethylhexyl)phthalate, di-isopropyl phthalate, diamyl phthalate
and dicapryl phthalate; alkyl and aryl phosphates, such as for
example, tributyl phosphate, trioctyl phosphate, tricresyl
phosphate, trioctyl phosphate, tricresyl phosphate and triphenyl
phosphate; alkyl citrate and citrates esters such as tributyl
citrate, triethyl citrate, and acetyl triethyl citrate; alkyl
adipates, such as for example, dioctyl adipate, diethyl adipate and
di(2-methoxyethyl)adipate; dialkyl tartrates, such as for example,
diethyl tartrates and dibutyl tartrate; alkyl sebacates, such as
for example, diethyl sebacate, dipropyl sebacate and dinonyl
sebacate; alkyl succinates, such as for example, diethyl succinate
and dibutyl succinate; alkyl glycolates, alkyl glycerolates, glycol
esters and glycerol esters, such as for example, glycerol
diacetate, glycerol triacetate, glycerol monolactate diacetate,
methyl phthalyl ethyl glycolate, butyl phthalyl butyl glycolate,
ethylene glycol diacetate, ethylene glycol dibutyrate, triethylene
glycol diacetate, triethylene glycol dibutyrate, triethylene glycol
dipropionate and mixtures thereof. Other plasticizers include
camphor, N-ethyl (o- and p-toulene)sulfonamide, chlorinated
biphenyl, benzophenone, N-cyclohexyl-p-toluene sulfonamide,
substituted epoxides and mixtures thereof.
[0569] The at least one means for forcibly dispensing the bupropion
hydrobromide salt from the core of certain embodiments of the
osmotic dosage form can be located such that it is approximately
centrally located within the core of the osmotic dosage form and is
surrounded by a layer comprising the bupropion hydrobromide salt.
Alternatively, the core of the osmotic dosage form comprises at
least two layers in which the first layer comprises the bupropion
salt, osmagent and/or osmopolymer and optionally at least one
pharmaceutically acceptable excipient adjacent to a second layer
comprising the means for forcibly dispensing the bupropion
hydrobromide salt. Alternatively, the core of the osmotic dosage
form comprises a multilayered structure in which the layer
comprising the bupropion hydrobromide salt is sandwiched between
two layers of the means for forcibly dispensing the bupropion
hydrobromide salt from the osmotic dosage form.
Combinations
[0570] The present invention also contemplates combinations of the
bupropion hydrobromide salt with at least one other drug. For
example, a composition is provided which comprises a first
component of bupropion hydrobromide, and a second component of at
least one other drug, wherein the two components are each present
in an amount effective in the treatment of a condition. The present
invention further provides a method for treating a condition,
comprising administering to a patient an effective amount of a
first component of bupropion hydrobromide in combination with an
effective amount of at least one other drug. The skilled artisan
will know or can determine by known methods which drug combinations
are acceptable. Types of drugs that can be selected as the second
drug include by way of example other depressants, anti-anxiety
agents, steroidal and non-steroidal inflammatories, SSRIs,
serotonin receptor agonists, anti-migraine agents, anti-pain
agents, anti-emetics, drugs for treating abuse such as nicotine,
appetite modulators, anti-virals, vasodilators, and anti-pain
agents. For example, the other drug can be an antidepressant
selected from: monoamine oxidase (MAO) inhibitor, tricyclic
antidepressant, serotonin reuptake inhibitor, selective
norepinephrine reuptake inhibitors (SNRIs), aminoketones, serotonin
antagonists, dopamine reuptake inhibitors, dual reuptake
inhibitors, norepinephrine enhancers, serotonin activity enhancers,
dopamine activity enhancers, and combinations thereof. Examples of
other drugs that can be combined with bupropion hydrobromide
include citalopram, escitalopram, venlafaxine, clozapine,
melperone, amperozide, iloperidone, risperidone, quetiapene,
olanzapine, ziprasidone, aripiprazole, reboxetine, VIAGRA.RTM.,
sertraline, paroxetine, fluoxetine, gabapentin, valproic acid,
amitriptyline, lofepramine, fluvoxamine, imipramine, mirtazapine,
nefazodone, nortriptyline, SAM-E, buspirone, and combinations
thereof. In at least one embodiment, a combination of bupropion
hydrobromide and citalopram is provided. In at least one other
embodiment, a combination of bupropion hydrobromide and
escitalopram is provided. In at least one other embodiment a
combination of bupropion hydrobromide and venlafaxine is provided.
In at least one other embodiment a combination of bupropion
hydrobromide and quetiapene is provided.
[0571] In certain embodiments combination products can be made by
providing an overcoat that contains at least one other drug. For
example, certain embodiments can include a core that comprises
bupropion hydrobromide, wherein the core is substantially
surrounded by a controlled release coat, which in turn is
substantially surrounded by an overcoat that contains at least one
other drug. In certain embodiments the overcoat provides an
immediate release of the other drug. In addition to the other drug,
the overcoat can include at least one low viscosity hydrophilic
polymer. The low-viscosity polymer provides for the immediate
release of the other drug from the overcoat. In at least one
embodiment, the low-viscosity polymer used in the overcoat is
hydroxypropyl methylcellulose (HPMC). The overcoat can also include
a lubricant such as talc. For example, such embodiments can provide
an immediate release of at least one other drug from the overcoat
in a first phase of drug release, and then a subsequent controlled
release of the bupropion hydrobromide from the controlled release
coated core in a second phase of drug release.
[0572] In addition, combinations of microparticles of the invention
each with a different functional coating can be combined together
in a dosage form. For example, by combining a first group of
uncoated, taste-masked or enteric coated microparticles with a
second group of delayed or sustained release coated microparticles,
a pulsatile drug release profile or chronotherapeutic profile can
be achieved. (e.g. see U.S. Pat. No. 5,260,068, U.S. Pat. No.
6,270,805, U.S. Pat. No. 6,926,909, US2002/0098232, US2004/0197405,
U.S. Pat. No. 6,635,284, or U.S. Pat. No. 6,228,398).
[0573] In other embodiments, the combination can comprise at least
2 different microparticles. For example, the combination can
include one group of microparticles that provide for a controlled
release of bupropion hydrobromide, and a second group of
microparticles that provide for an immediate release of the other
drug. The microparticles can be combined in a capsule
formulation.
[0574] While only specific combinations of the various features and
components of the present invention have been discussed herein, it
will be apparent to those of skill in the art that desired subsets
of the disclosed features and components and/or alternative
combinations of these features and components can be utilized as
desired.
[0575] As will be seen from the non-limiting examples described
below, the coatings of the invention are quite versatile. For
example, the length and time for the lagtime can be controlled by
the rate of hydration and the thickness of the controlled release
coat. It is possible to regulate the rate of hydration and
permeability of the controlled release coat so that the desired
controlled release profile can be achieved. There is no general
preferred controlled release coat thickness, as this will depend on
the controlled release profile desired. Other parameters in
combination with the thickness of the controlled release coat
include varying the concentrations of one or more of the
ingredients of the controlled release coat composition, varying the
curing temperature and length of time for curing the coated tablet
microparticles, and in certain embodiments, varying the level of
osmotic agent. The skilled artisan will know which parameters or
combination of parameters to change for a desired controlled
release profile.
Stability Studies
[0576] The enhanced stability of the bupropion hydrobromide salt
and compositions containing the bupropion hydrobromide salt, in
particular when compared to the bupropion hydrochloride salt and
compositions containing the bupropion hydrochloride salt
respectively, is evident from degradation studies performed on the
active pharmaceutical ingredient (API), alone, in the presence of
excipients and in the form of tablets (e.g. extended release
tablets). The results are described in greater detail in the
examples below and for example in U.S. Pat. No. 7,241,805, the
contents of which are incorporated herein by reference.
[0577] A comparison of the stability of several bupropion salts,
including the hydrobromide, hydrochloride, maleate, tosylate,
fumarate, succinate, tartrate and citrate salts, was performed by
placing these salts in both open and closed vials in a stability
chamber kept at about 40 degrees C. and about 75% relative humidity
for various periods of time (e.g. 10 days, 13 days, 14 days, 20
days, 24 days, or 32 days). The stability of the salts was
evaluated based on the formation of the main degradation products
as determined by HPLC analysis and the % potency (or assay) of the
API, after specific time periods in the stability chamber. The
effect of the addition of solvents, such as water, ethanol and
isopropyl alcohol, was also studied.
[0578] The results unexpectedly show that after various periods of
time the hydrobromide salt of bupropion, on average, showed the
least amount of degradation products, particularly when compared to
the hydrochloride salt. Accordingly the bupropion hydrobromide salt
showed greater stability than the hydrochloride salt.
[0579] Further stability tests were performed by directly comparing
bupropion hydrobromide and bupropion hydrochloride salts in forced
degradation studies. These studies were performed in closed bottles
in a stability chamber kept at about 40 degrees C. and about 75%
relative humidity. At specified times, the material in the bottles
was analyzed for the presence of degradation products and % potency
(% assay). It was unexpectedly found that the amount of impurities
was generally lower and the % potency was generally higher for the
bupropion hydrobromide salt when compared to the bupropion
hydrochloride salt.
[0580] Forced degradation studies were also performed on bupropion
hydrobromide and bupropion hydrochloride API's in the presence of
standard excipients used in pharmaceutical formulations. The amount
of the main degradation products was observed at about 24 and about
48 hours after treatment at about 55.degree. C., at about
55.degree. C. and 100% relative humidity, and at about 105.degree.
C. Once again, it was unexpectedly found that the bupropion
hydrobromide salt showed the lowest amount of degradation (as
determined by the formation of bupropion degradation impurities)
under these conditions.
[0581] The stability of the tablet formulations of bupropion
hydrobromide and bupropion hydrochloride salts was also compared.
With both salts, a single coated tablet having a controlled release
coat (e.g. ETHOCEL.RTM. or "EC" coat), as well as a double-coated
tablet (with a controlled release coat and a moisture barrier coat)
were evaluated. The tablets were placed individually on an open
dish, and exposed to the accelerated conditions of about 40.degree.
C. and about 75% relative humidity in a stability chamber. After 13
days and 20 days, the samples were assayed and impurity analysis
was performed. For the single coated bupropion hydrochloride
tablets, the main degradation impurities 3-CBZ and 852U77 were
about 0.12% and about 0.38% respectively, whereas, for the
bupropion hydrobromide tablets, these values were about 0.07% and
about 0.49% respectively. The other degradation impurities and the
total unknowns were very similar for both products; however, the
assay value for the hydrobromide product was higher than the
hydrochloride. The difference in the assay and the impurity levels
were more significant in the double coated tablets products. For
the same period of the study the assay of the bupropion
hydrochloride was lower (about 95.5% compared to about 98.6% for
bupropion hydrobromide) and the level of the degradation and total
unknowns were higher (3-CBZ: about 0.28%; 852U77: about 1.23%;
827U76: about 0.10%; and total about 1.73%) than the bupropion
hydrobromide (3-CBZ: about 0.12%, 852U77: about 0.41%, 827U76:
about 0.05%; and total about 0.75%).
[0582] The stability studies performed herein have demonstrated the
unexpected enhanced stability of bupropion hydrobromide, in
particular when compared to bupropion hydrochloride. This enhanced
stability is seen with the API form alone, the API form plus
excipients, and the extended release and enhanced absorption
tablets. The enhanced stability of pharmaceutical formulations
comprising bupropion hydrobromide will provide enhanced shelf life
and an ability to withstand storage at higher temperatures and
humidity levels when compared with bupropion hydrochloride
formulations.
Additional Embodiments
[0583] Further embodiments of the invention described herein and
enabled by the present description include the following:
[0584] Certain embodiments include bupropion hydrobromide and
3'-chloro-2-bromo-propiophenone. 3'-chloro-2-bromo-propiophenone is
an impurity associated with the preparation of bupropion
hydrobromide. In certain embodiments,
3'-chloro-2-bromo-propiophenone is present in an amount that is
non-genotoxic; or in an amount that would result in a daily
exposure of not more than ("NMT") about 1.5 .mu.g/day in the drug
product. Certain embodiments contain less than about 1.5 .mu.g of
3'-chloro-2-bromo-propiophenone. For example in certain embodiments
the 3'-chloro-2-bromo-propiophenone impurity is present in an
amount of less than about 1.5 .mu.g, 1.4 .mu.g, 1.3 .mu.g, 1.2
.mu.g, 1.1 .mu.g, 1.0 .mu.g, 0.9 .mu.g, 0.8 .mu.g, 0.6 .mu.g, 0.5
.mu.g, 0.4 .mu.g, 0.3 .mu.g, 0.2 .mu.g, 0.1 .mu.g, 0.09 .mu.g, 0.08
.mu.g, 0.07 .mu.g, 0.06 .mu.g, 0.05 .mu.g, 0.04 .mu.g, 0.03 .mu.g,
0.02 .mu.g, or 0.01 .mu.g, including all values and subranges
therebetween. In at least one embodiment the
3'-chloro-2-bromo-propiophenone impurity is present in undetectable
amounts wherein the limit of detection is 1.0 .mu.g, or 1 ppm.
[0585] In certain embodiments the 3-chlorobenzoic acid degradation
product is limited in the drug product to about 0.7% or less. In at
least one embodiment the 3-chlorobenzoic acid degradation product
is limited in the composition to about 0.5% or less. In at least
one further embodiment the 3-chlorobenzoic acid degradation product
is limited in the composition to about 0.3% or less.
[0586] In certain embodiments the moisture content in the drug
product is limited to not more than about 2.0%. In certain
embodiments the moisture content is limited to not more than about
2.0% after a storage time of about 1 minute when stored in a closed
container using a Karl Fischer apparatus and UPS Method 1. For
example in certain embodiments the moisture content after a storage
time of about 1 minute when stored in a closed container using a
Karl Fischer apparatus, and USP Method 1, is less than about 2.0%,
1.9%, 1.8%, 1.7%, 1.6%, 1.5% 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%,
0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%, including all
values and subranges therebetween.
[0587] In another embodiment there is a tablet comprising (i) a
core and (ii) a controlled release coat, said core comprising:
[0588] (a) bupropion HBr;
[0589] (b) binder (e.g. polyvinyl alcohol); and
[0590] (c) lubricant (e.g. glyceryl behenate--Compritol.RTM.
888);
[0591] said controlled release coat (e.g., "SMARTCOAT")
comprising:
[0592] (d) water-insoluble water-permeable film-forming polymer
(e.g. ethyl cellulose grade PR 100);
[0593] (e) plasticizer (e.g. polyethylene glycol 4000, dibutyl
sebacate, or a mixture thereof);
[0594] (f) water-soluble polymer (e.g.
polyvinylpyrrolidone--Povidone.RTM. USP);
[0595] wherein in the controlled release coat the ratio of
(d):(e):(f)=from about 3:1:4 to about 5:1:2; or from about 7:2:6 to
about 19:5:18; or about 13:4:12; or about 13:6:16;
[0596] the tablet optionally further comprising a moisture barrier
coat;
[0597] said optional moisture barrier coat comprising:
[0598] (g) enteric polymer (e.g. an acrylic polymer such as
methacrylic acid copolymer type C-Eudragit.RTM. L30 D-55);
[0599] (h) permeation enhancer (e.g. silicon dioxide--Syloid.RTM.
244FP); and
[0600] (i) plasticizer (optional)--(e.g. mixture of triethyl
citrate and polyethylene glycol 4000-Carbowax.RTM. 4000).
[0601] In another embodiment there is a once-daily modified release
pharmaceutical composition comprising 522 mg of bupropion
hydrobromide, said composition providing an in-vivo plasma profile
selected from:
[0602] Mean Tmax of from about 2 hours to about 7 hours;
[0603] Mean Cmaxof from about 113 ng/ml to about 239 ng/ml;
[0604] Mean Cmin of from about 18 ng/ml to about 44 ng/ml; and
[0605] Mean AUC0-t of from about 1236 ng-hr/ml to about 2224
ng-hr/ml.
[0606] In another embodiment there is a once-daily modified release
pharmaceutical composition comprising 348 mg of bupropion
hydrobromide, said composition providing an in-vivo plasma profile
selected from:
[0607] Mean Tmax of from about 2 hours to about 7 hours;
[0608] Mean Cmaxof from about 96 ng/ml to about 172 ng/ml;
[0609] Mean Cmin of from about 17 ng/ml to about 36 ng/ml; and
[0610] Mean AUC0-t of from about 1063 ng-hr/ml to about 1755
ng-hr/ml.
[0611] In another embodiment there is a once-daily modified release
pharmaceutical composition comprising bupropion hydrobromide, said
composition providing a mean Tmax of from about 2 hours to about 7
hours.
[0612] In another embodiment there is a once-daily modified release
pharmaceutical composition comprising bupropion hydrobromide, said
composition providing a mean Tmax that is substantially equivalent
to that of a once-daily modified release pharmaceutical composition
comprising bupropion hydrochloride.
[0613] In another embodiment there is a once-daily modified release
pharmaceutical composition comprising bupropion hydrobromide, said
composition providing a mean Tmax that is from about 80% to about
125% of that of a once-daily modified release pharmaceutical
composition comprising bupropion hydrochloride.
[0614] In another embodiment there is a once-daily modified release
pharmaceutical composition comprising bupropion hydrobromide, said
composition providing a mean Cmaxthat is substantially equivalent
to that of a once-daily modified release pharmaceutical composition
comprising bupropion hydrochloride.
[0615] In another embodiment there is a once-daily modified release
pharmaceutical composition comprising bupropion hydrobromide, said
composition providing a mean Cmaxthat is from about 80% to about
125% of that of a once-daily modified release pharmaceutical
composition comprising bupropion hydrochloride.
[0616] In another embodiment there is a once-daily modified release
pharmaceutical composition comprising bupropion hydrobromide, said
composition providing a mean Cmin that is substantially equivalent
to that of a once-daily modified release pharmaceutical composition
comprising bupropion hydrochloride.
[0617] In another embodiment there is a once-daily modified release
pharmaceutical composition comprising bupropion hydrobromide, said
composition providing a mean Cmin that is from about 80% to about
125% of that of a once-daily modified release pharmaceutical
composition comprising bupropion hydrochloride.
[0618] In another embodiment there is a once-daily modified release
pharmaceutical composition comprising bupropion hydrobromide, said
composition providing a mean AUC0-t that is substantially
equivalent to that of a once-daily modified release pharmaceutical
composition comprising bupropion hydrochloride.
[0619] In another embodiment there is a once-daily modified release
pharmaceutical composition comprising bupropion hydrobromide, said
composition providing a mean AUC0-t that is from about 80% to about
125% of that of a once-daily modified release pharmaceutical
composition comprising bupropion hydrochloride.
[0620] In another embodiment there is a modified release
pharmaceutical composition comprising:
[0621] a core comprising a therapeutically effective amount of
bupropion hydrobromide; and
[0622] a controlled release polymeric coat comprising a
water-insoluble polymer and a water-soluble polymer;
[0623] wherein said coat surrounds at least a part of said core;
and
[0624] wherein the amount of bupropion hydrobromide released at a
time point from about 0 hours to about 16 hours, in the presence of
at least 5% ethanol, using USP Apparatus I at 75 rpm and
37.+-.0.5.degree. C., is less than the amount of bupropion
hydrobromide released at the same time point in 0.1 N HCl using USP
Apparatus I at 75 rpm and 37.+-.0.5.degree. C.
[0625] In another embodiment there is a modified release
pharmaceutical composition comprising:
[0626] a core comprising a therapeutically effective amount of
bupropion hydrobromide; and
[0627] a controlled release polymeric coat comprising a
water-insoluble polymer and a water-soluble polymer;
[0628] wherein said coat surrounds at least a part of said core;
and
[0629] wherein the amount of bupropion hydrobromide released at a
time point from about 0 hours to about 16 hours, in the presence of
at least 5% ethanol, using USP Apparatus I at 75 rpm and
37.+-.0.5.degree. C., is less than about 125% of the amount of
bupropion hydrobromide released at the same time point in 0.1 N HCl
using USP Apparatus I at 75 rpm and 37.+-.0.5.degree. C.
[0630] In another embodiment there is a modified release
pharmaceutical composition comprising:
[0631] a core comprising a therapeutically effective amount of
bupropion hydrobromide; and
[0632] a controlled release polymeric coat comprising a
water-insoluble polymer and a water-soluble polymer;
[0633] wherein said coat at least partially surrounds said core;
and
[0634] wherein dose dumping does not occur in the presence of 0.1 N
HCl with 40% EtOH.
[0635] In another embodiment there is a method of reducing dose
dumping comprising administering to a subject a modified release
pharmaceutical composition comprising:
[0636] a core comprising a therapeutically effective amount of
bupropion hydrobromide; and
[0637] a controlled release polymeric coat comprising a
water-insoluble polymer and a water-soluble polymer;
[0638] wherein said coat at least partially surrounds said
core.
[0639] In another embodiment there is a pharmaceutical composition
comprising 522 mg of bupropion hydrobromide, said composition
providing an in-vivo plasma profile selected from:
[0640] Mean Tmax of from about 2 hours to about 7 hours;
[0641] Mean Cmaxof from about 115 ng/ml to about 235 ng/ml;
[0642] Mean Cmin of from about 20 ng/ml to about 40 ng/ml; and
[0643] Mean AUC0-24 hr of from about 1240 ng-hr/ml to about 2220
ng-hr/ml.
[0644] In another embodiment there is a pharmaceutical composition
comprising 522 mg of bupropion hydrobromide, said composition
providing an in-vivo plasma profile selected from:
[0645] Mean Tmax of about 4 hours;
[0646] Mean Cmaxof less than about 200 ng/ml; and
[0647] Mean AUC0-24 hr of more than about 2000 ng-hr/ml.
[0648] In another embodiment there is a once-daily modified release
pharmaceutical composition comprising bupropion hydrobromide, said
composition providing a mean Tmax that is substantially equivalent
to that of the same once-daily modified release pharmaceutical
composition comprising bupropion hydrochloride instead of bupropion
hydrobromide.
[0649] In another embodiment there is a once-daily modified release
pharmaceutical composition comprising bupropion hydrobromide, said
composition providing a mean Tmax that is from about 80% to about
125% of that of the same once-daily modified release pharmaceutical
composition comprising bupropion hydrochloride instead of bupropion
hydrobromide.
[0650] In another embodiment there is a modified release tablet
comprising
[0651] (i) a core comprising
[0652] (a) a therapeutically effective amount of bupropion
hydrobromide;
[0653] (b) a binder; and
[0654] (c) a lubricant; and
[0655] (ii) a control-releasing polymeric coat at least partially
surrounding said core;
[0656] wherein said modified release tablet provides for the
controlled release of said bupropion hydrobromide from said
modified release tablet over a period of about 24 hours; and
wherein said modified release tablet has improved stability when
compared to an otherwise similar or identical modified release
tablet comprising an equivalent molar amount of bupropion
hydrochloride instead of bupropion hydrobromide, when each are
stored for at least about 12 months at about 25.degree. C. and at
about 60% relative humidity.
[0657] In another embodiment there is a modified release bupropion
hydrobromide tablet suitable for oral administration comprising
[0658] (i) a core comprising
[0659] (a) a therapeutically effective amount of bupropion
hydrobromide;
[0660] (b) a binder; and
[0661] (c) a lubricant;
[0662] (ii) a controlled release polymeric coat which at least
partially surrounds said core; and
[0663] (iii) a degradation product chosen from 3-chlorobenzoic
acid, 827U76, 20U78, 852U77, and mixtures thereof;
[0664] wherein said modified release bupropion hydrobromide tablet
contains less of said degradation product as compared to an
otherwise similar or identical modified release tablet containing
an equivalent molar amount of bupropion hydrochloride instead of
bupropion hydrobromide;
[0665] when the modified release bupropion hydrobromide tablet and
the otherwise similar or identical modified release tablet
containing bupropion hydrochloride are each are stored for at least
about 12 months at 25.degree. C. and 60% relative humidity after
tablet formulation.
[0666] In another embodiment there is a modified release tablet
comprising:
[0667] a therapeutically effective amount of bupropion
hydrobromide;
[0668] wherein at about 12 months after formulation of said
modified release tablet, at about 37.+-.0.5.degree. C., from about
0% to 40% of said bupropion hydrobromide is released after 2 hours;
from about 40% to about 75% of said bupropion hydrobromide is
released after 4 hours; not less than about 75% of said bupropion
hydrobromide is released after 8 hours; and not less than about 85%
of said bupropion hydrobromide is released after 16 hours, in 900
ml of 0.1 N HCl using USP Type 1 apparatus with a rotational speed
of 75 rpm.
[0669] In another embodiment there is a modified release
pharmaceutical composition comprising:
[0670] (i) a core comprising a therapeutically effective amount of
bupropion hydrobromide; and
[0671] (ii) a controlled release polymeric coat comprising a
water-insoluble polymer and a water-soluble polymer;
[0672] wherein said coat at least partially surrounds said core;
and
[0673] wherein said composition is resistant to alcohol-induced
dose dumping.
[0674] In another embodiment there is a modified release
pharmaceutical composition comprising:
[0675] (i) a core comprising a therapeutically effective amount of
bupropion hydrobromide; and
[0676] (ii) a controlled release polymeric coat comprising a
water-insoluble polymer and a water-soluble polymer;
[0677] wherein said coat at least partially surrounds said core;
and
[0678] wherein the rate of release of bupropion hydrobromide in
dissolution media containing alcohol is slower than the rate of
release of bupropion hydrobromide in dissolution media not
containing alcohol.
[0679] In another embodiment there is a modified release
pharmaceutical composition comprising:
[0680] (i) a core comprising a therapeutically effective amount of
bupropion hydrobromide; and
[0681] (ii) a controlled release polymeric coat comprising a
water-insoluble polymer and a water-soluble polymer;
[0682] wherein said coat at least partially surrounds said core;
and
[0683] wherein the amount of bupropion hydrobromide released at a
time point from about 0 hours to about 16 hours, in dissolution
media comprising about 40% EtOH and 60% 0.1N HCl, using USP
Apparatus Type 1 at 75 rpm, is not more than the amount of
bupropion hydrobromide released at the same time point in
dissolution media comprising about 100% 0.1N HCl using USP
Apparatus Type 1 at 75 rpm.
[0684] In another embodiment there is a modified release
pharmaceutical composition comprising:
[0685] (i) a core comprising a therapeutically effective amount of
bupropion hydrobromide; and
[0686] (ii) a controlled release polymeric coat comprising a
water-insoluble polymer and a water-soluble polymer;
[0687] wherein said coat at least partially surrounds said core;
and
[0688] wherein the amount of bupropion hydrobromide released at a
time point from about 0 minutes to about 120 minutes, in
dissolution media comprising about 40% EtOH and 60% 0.1N HCl, using
USP Apparatus Type 1 at 75 rpm, is not more than the amount of
bupropion hydrobromide released at the same time point in
dissolution media comprising about 100% 0.1N HCl using USP
Apparatus Type 1 at 75 rpm.
[0689] In another embodiment there is a method of resisting
alcohol-induced dose dumping of bupropion hydrobromide comprising
administering to a subject a modified release pharmaceutical
composition, said composition comprising:
[0690] (i) a core comprising a therapeutically effective amount of
bupropion hydrobromide; and
[0691] (ii) a controlled release polymeric coat comprising a
water-insoluble polymer and a water-soluble polymer;
[0692] wherein said coat at least partially surrounds said
core.
[0693] In another embodiment there is a method of treating a
subject at risk of alcohol-induced dose dumping of bupropion
hydrobromide and in need of bupropion treatment, the method
comprising administering to a subject a modified release
pharmaceutical composition, said composition comprising:
[0694] (i) a core comprising a therapeutically effective amount of
bupropion hydrobromide; and
[0695] (ii) a controlled release polymeric coat comprising a
water-insoluble polymer and a water-soluble polymer;
[0696] wherein said coat at least partially surrounds said
core.
[0697] In another embodiment there is a composition comprising
bupropion hydrobromide and 3'-chloro-2-bromo-propiophenone.
[0698] In another embodiment there is a composition comprising
bupropion hydrobromide and less than about 1.5 .mu.g of
3'-chloro-2-bromo-propiophenone.
[0699] In another embodiment there is a composition comprising
bupropion hydrobromide and less than about 1.0 .mu.g of
3'-chloro-2-bromo-propiophenone.
[0700] In another embodiment there is a modified release
composition comprising bupropion hydrobromide wherein the moisture
content is not more than about 2.0% in said composition after a
storage time of about 1 minute, when stored in a closed container
using a Karl Fischer apparatus, USP Method 1.
[0701] In another embodiment there is a composition comprising
bupropion hydrobromide and at least one pharmaceutically acceptable
excipient, wherein the amount of bupropion hydrobromide is chosen
from 174 mg, 348 mg and 522 mg.
[0702] In another embodiment there is a modified release tablet
comprising bupropion hydrobromide and at least one pharmaceutically
acceptable excipient, wherein the amount of bupropion hydrobromide
is chosen from 174 mg, 348 mg and 522 mg.
[0703] In another embodiment there is a modified release tablet
comprising bupropion hydrobromide and at least one pharmaceutically
acceptable excipient, wherein the amount of bupropion hydrobromide
is chosen from 174 mg, 348 mg and 522 mg; and wherein the bupropion
hydrobromide is contained within a core of the tablet further
comprising a controlled release coating over the core.
[0704] In another embodiment there is a composition comprising at
least bupropion hydrobromide in the concentration specified in one
of A, B, and C in the following Table admixed with one or more
additional components listed in A, B and C in the following
Table:
TABLE-US-00012 Component A B C Bupropion Hydrobromide 174 mg 348 mg
522 mg Polyvinyl Alcohol 5.8 mg 11.6 mg 22.5 mg Glyceryl Behenate
5.8 mg 11.6 mg 22.5 mg Target Core Tablet Weight 185.6 mg 371.2 mg
567 mg (mg) Ethylcellulose 100, NF 15.4 mg 16.4 mg 18.13 mg
Povidone (K-90) 9.5 mg 10.2 mg 21.87 mg Polyethylene Glycol, 4000
3.4 mg 3.7 mg 5.33 mg Dibutyl Sebacate (DBS) 1.7 mg 1.8 mg 2.67 mg
Target Coating Weight Gain +30 mg +32 mg +48 mg (mg) Carnauba Wax
Trace Trace N/A Amount Amount Denatured Ethyl Alcohol, 200
Evaporated Evaporated Evaporated proof Off Off Off Ethyl Alcohol,
190 proof Evaporated Evaporated Evaporated Off Off Off Purified
Water Evaporated Evaporated Evaporated Off Off Off Opacode R Black
Ink Trace Trace Trace Amount Amount Amount Isopropyl Alcohol, 99%
None None None Final Printed Tablet Weight 216 mg 403 mg 615 mg
(mg)
[0705] In another embodiment there is a composition comprising at
least about 522 mg of bupropion hydrobromide and at least one
pharmaceutically acceptable excipient. In other aspects of this
embodiment the composition is in tablet form. In other aspects of
this embodiment the composition is a modified release formulation.
In other aspects of this embodiment the composition is in tablet
form and the bupropion hydrobromide is contained within a core of
the tablet further comprising a coating over the core. In other
aspects of this embodiment the coating is a controlled release
coating.
[0706] In at least one embodiment the bupropion hydrobromide 174 mg
tablet composition releases bupropion hydrobromide in a first
dissolution medium consisting of ethanol (5%-40%) and 0.1N HCl, at
a rate that is less than or equal to about 1.1 times the rate of
release of bupropion hydrobromide from the identical bupropion
hydrobromide 174 mg tablet composition in a second dissolution
medium consisting of 0.1N HCl (100%), measured over a time period
of at least from 0 to 2 hours, measured using a USP Apparatus I at
75 rpm and at 37.degree. C. See for example U.S. patent application
Ser. No. 11/930,644 (Pub. No. 2008-0274181), the contents of which
are incorporated herein by reference. In at least one embodiment
the bupropion hydrobromide 174 mg tablet composition releases
bupropion hydrobromide in a first dissolution medium consisting of
ethanol (40%) and 0.1N HCl, at a rate that is less than the rate of
release of bupropion hydrobromide from the identical bupropion
hydrobromide 174 mg tablet composition in a second dissolution
medium consisting of 0.1N HCl (100%), measured over a time period
of at least from 0 to 24 hours, measured using a USP Apparatus I at
75 rpm and at 37.degree. C.
[0707] In at least one embodiment the bupropion hydrobromide 174 mg
tablet composition releases bupropion hydrobromide in a first
dissolution medium consisting of ethanol (5%-40%) and 0.1N HCl at a
rate that is less than or equal to about 1.1 times the rate of
release of bupropion hydrobromide from the identical bupropion
hydrobromide 174 mg tablet composition in a second dissolution
medium consisting of 0.1N HCl (100%), measured over a time period
of at least from 0 to 2 hours, measured using a USP Apparatus I at
75 rpm and at 37.degree. C.
[0708] In at least one embodiment the bupropion hydrobromide 348 mg
tablet composition releases bupropion hydrobromide in a first
dissolution medium consisting of ethanol (5%-40%) and 0.1N HCl at a
rate that is less than or equal to about 1.1 times the rate of
release of bupropion hydrobromide from the identical bupropion
hydrobromide 348 mg tablet composition in a second dissolution
medium consisting of 0.1N HCl (100%), measured over a time period
of at least from 0 to 2 hours, measured using a USP Apparatus I at
75 rpm and at 37.degree. C.
[0709] In at least one embodiment the bupropion hydrobromide 522 mg
tablet composition releases bupropion hydrobromide in a first
dissolution medium consisting of ethanol (40%) and 0.1N HCl (60%)
at a rate that is less than the rate of release of bupropion
hydrobromide from the identical bupropion hydrobromide 522 mg
tablet composition in a second dissolution medium consisting of
0.1N HCl (100%), measured over a time period of at least from 0 to
16 hours, measured using a USP Apparatus I at 75 rpm and at
37.degree. C.
[0710] In at least one embodiment the bupropion hydrobromide 522 mg
tablet composition releases bupropion hydrobromide in a first
dissolution medium consisting of ethanol (5%-40%) and 0.1N HCl, at
a rate that is less than or equal to the rate of release of
bupropion hydrobromide from the identical bupropion hydrobromide
522 mg tablet composition in a second dissolution medium consisting
of 0.1N HCl (100%), measured over a time period of at least from 0
to 2 hours, measured using a USP Apparatus I at 75 rpm and at
37.degree. C.
[0711] In at least one embodiment a bupropion hydrobromide 174 mg
tablet composition releases bupropion hydrobromide in a first
dissolution medium consisting of ethanol (40%) and 0.1N HCl (60%),
at a rate that is less than the rate of release of bupropion
hydrobromide from the identical bupropion hydrobromide 174 mg
tablet composition in a second dissolution medium consisting of
0.1N HCl (100%), measured over a time period of at least from 0 to
24 hours, measured using a USP Apparatus I at 75 rpm and at
37.degree. C. In at least one embodiment a bupropion hydrobromide
174 mg tablet releases bupropion hydrobromide in a dissolution
medium consisting of ethanol (40%) and 0.1N HCl (60%), at a rate
that is less than the rate of release of bupropion hydrochloride
from a bupropion hydrochlroide 150 mg tablet having the identical
polymeric controlled release coat composition used in the bupropion
hydrobromide 174 mg tablet, in the identical dissolution medium
consisting of ethanol (40%) and 0.1N HCl (60%), measured over a
time period of at least from 0 to 16 hours, measured using a USP
Apparatus I at 75 rpm and at 37.degree. C.
[0712] In at least one embodiment a bupropion hydrobromide 174 mg
tablet composition releases bupropion hydrobromide in a first
dissolution medium consisting of ethanol (40%) and 0.1N HCl (60%),
at a rate that is less than the rate of release of bupropion
hydrobromide from the identical bupropion hydrobromide 174 mg
tablet composition in a second dissolution medium consisting of
0.1N HCl (100%), measured over a time period of at least from 0 to
2 hours, measured using a USP Apparatus I at 75 rpm and at
37.degree. C. In at least one embodiment a bupropion hydrobromide
174 mg tablet releases bupropion hydrobromide in a dissolution
medium consisting of ethanol (40%) and 0.1N HCl (60%), at a rate
that is less than the rate of release of bupropion hydrochloride
from a bupropion hydrochlroide 150 mg tablet having the identical
polymeric controlled release coat composition used in the bupropion
hydrobromide 174 mg tablet, in the identical dissolution medium
consisting of ethanol (40%) and 0.1N HCl (60%), measured over a
time period of at least from 0 to 2 hours, measured using a USP
Apparatus I at 75 rpm and at 37.degree. C.
[0713] The examples below are non-limiting and are representative
of various aspects of certain embodiments of the present
invention.
Examples
Example 1
Preparation of Bupropion HBr Salt
[0714] Bupropion HBr salt was prepared according to the method
shown in Scheme 1:
##STR00003##
[0715] (a) Bromination and Condensation Reactions
[0716] 3-Chloro-propiophenone starting material was brominated in
methylene chloride by dropping bromine under controlled conditions.
On reaction completion the mother liquor was worked up and then the
second reaction was executed by transferring the bromoderivative
solution onto the tert-butylamine. The second substitution reaction
(the tert-butylamine amino-group substitutes the bromine atom)
forms the final bupropion molecule. After work up of the mother
liquor, a bupropion toluene solution was obtained. The solvent was
evaporated and bupropion was dissolved in isopropanol. From the
isopropanol solution, the hydrobromide was precipitated with
hydrogen bromide gas. On precipitation completion, the product was
centrifuged, washed with isopropanol and dried under vacuum. On
dryer discharge approval it was discharged in Kraft drums within
double polyethylene bags.
[0717] In the last finishing step, the above intermediate was
sieved to obtain the Final Release which was packed in Kraft drums
within double polyethylene bags.
[0718] Elemental analysis of the bupropion HBr was carried out
using a Fisons Elemental Analyser EA 1108. The results were
consistent with the molecular formula of bupropion HBr.
Example 2
Bupropion HBr Extended Release (XL) Tablets
[0719] The aim of this example was to describe the development of
bupropion HBr XL (174 and 348 mg). Granulation, tabletting and
coating procedures are all described thoroughly in this example.
In-vitro testing was conducted on the cores, the ethylcellulose
coated cores and the final coated tablets in order to determine
which formulation gave the desired results. From their structural
formulae, it is observable that the difference between bupropion
HCl and bupropion HBr is the salt. This, of course, results in a
different molecular weight. However, these differences were taken
into account in the present study, and modifications were made in
order to obtain in-vitro correlation results to the bupropion HCl
using dissolution studies.
[0720] It was previously observed that when 150 mg of bupropion HCl
was tested for its release of bupropion, the base value that was
released was 130 mg. However, when 150 mg of bupropion HBr was
tested, the base value released was only 112 mg. Thus, the amount
of bupropion HBr had to be increased in order to increase the base
value from 112 mg to 130 mg, which was the target. Studies showed
that 174 mg of bupropion HBr gave a base value release of 130 mg
and is therefore why 174 mg was used as opposed to 150 mg bupropion
HBr.
Bupropion HBr XL--Granulation Process
[0721] A summary of the manufacturing process used for the
preparation of bupropion HBr XL tablets is shown in FIG. 1.
[0722] The following materials were used in the granulation of the
immediate release core of the bupropion HBr EA tablets: bupropion
HBr, polyvinyl alcohol (PVA) and purified water. Once granulated,
lubricant (COMPRITOL.RTM. 888) was added to complete the
formulation. Each Trial was divided into 5 parts. The percentage of
API in each formulation was 93.75%; the percentage of PVA in each
formulation was 3.125%. A summary of the breakdown of each trial
per part is described in Table 1.
[0723] The PVA was dissolved into the purified water using a
magnetic stirrer and a clear colourless solution was made.
[0724] The NIRO Fluid Bed was used to granulate the bupropion HBr
Granules with the PVA solution in a process known as wet massing.
FIG. 2 shows a summary of the granulation procedure.
[0725] The Bupropion HBr was loaded into the fluid bed and
granulation was initiated. The specifications that were used as
guidelines are listed in Table 2.
[0726] Loss on Drying was determined after each granulation using
the Moisture Analyzer. A 1 g sample was taken and loaded into the
moisture analyzer. The sample ran for 5 minutes at a temperature of
105.degree. C.
[0727] Upon completion of each batch part's granulation, the five
parts were combined together. They were hand screened using Mesh
No. 14 (1.4 mm) and any oversized granulation was passed through
the Comil fitted with a 2 mm screen.
[0728] COMPRITOL.RTM. 888 was used as a lubricant in the
formulation. The screened bupropion HBr granules and the
COMPRITOL.RTM. 888 were loaded into the V-blender and were blended
for 5 minutes. The COMPRITOL.RTM. 888 made up 3.125% of the
formulation. The final granule batch size is described in Table
3.
Bupropion HBr XL--Tabletting Process
[0729] The Beta Press was used to compress the Bupropion HBr
tablets. Depending on the dose of the tablet, 174 mg or 348 mg,
different tooling sets were used. The 7 mm punches were used to
compress the 174 mg tablets and 9 mm and 10 mm punches were used to
compress the 348 mg tablets. Tooling was polished prior to each
run.
[0730] The tablet weights were determined as being 185.6 mg for the
174 mg dose tablets and 371.2 mg for the 348 mg dose tablets. These
adjustments to tablet weight were made in order to compensate for
the fact that bupropion HBr was being used in place of bupropion
HCl.
[0731] The individual tablet weights had a control limit of .+-.5%,
and the average tablet weight had a control limit of .+-.3% (using
ten tablets).
[0732] A hardness tester was used to determine the load required to
diametrically break the tablets (crushing strength) into two equal
halves. A predetermined range set the specifications for hardness,
which was 6.0-12.0 SC for both the 174 mg and 348 mg tablets.
[0733] Friability was determined using tablets that equaled a
weight of 6.5 g in a friability tester for 4 minutes at 25 rpm.
Tablets were de-dusted before and after testing. A weight loss of
less than 0.8% was used as the criteria in order to accept or
reject a batch.
[0734] Table 4 summarizes the specifications of the tablet press
set-up. All the specifications were kept within the range and at
the setting that was assigned, throughout all of the batches.
[0735] Table 5 summarizes the specifications that were kept
constant throughout the compression of all the batches.
[0736] The flow chart shown in FIG. 2 describes the steps that led
up to and including the tabletting process. FIG. 3 shows a summary
of the tabletting procedure.
Bupropion HBr XL--Coating Process
[0737] A summary of the coating process used for the coating of the
Bupropion HBr XL tablets is shown in FIG. 4. The first coat is an
ethylcellulose (e.g. ETHOCEL.RTM.) coat that controls the release,
which is followed by a final coat that acts as a moisture
barrier.
[0738] For the ethylcellulose coating and final coating of the
Bupropion HBr XL tablets, the 15 inches O'Hara Labcoat II System
was used. An attached spraying nozzle and a propeller mixer were
also used.
[0739] Several ethylcellulose coating solutions were developed and
used to coat the Bupropion HBr tablets. The ethylcellulose coating
layer was placed on the tablets containing one of the formulations
listed in Table 6.
[0740] In formulation 1, ethyl Alcohol 95% and IPA 99% were
combined together in a stainless steel container. While stirring,
PEG 4000 was added and allowed to dissolve. Once dissolved,
ethylcellulose (e.g. ETHOCEL.RTM.) was added and left to stir for
30 minutes. Then, Povidone was added to the solution and was mixed
for an overnight period (15-20 hours).
[0741] In formulation 2, PEG4000 was placed into a beaker with the
Dibutyl Sebacate and was stirred until it dissolved. Ethyl Alcohol
95% was added accordingly in order to allow the PEG 4000 to
completely dissolve. In a separate stainless steel container, the
remaining Ethyl Alcohol 95% was placed and, while being stirred,
ethylcellulose was added and stirred for 30 minutes. Following
that, Povidone was added and allowed to stir for an overnight
period (15-20 hours).
[0742] In formulation 3, Ethyl Alcohol 95% was placed in a
stainless steel container. While stirring, PEG 4000 was added and
allowed to dissolve. Once dissolved, ethylcellulose was added and
left to stir for 30 minutes. Then, Povidone was added to the
solution and was mixed for an overnight period (15-20 hours).
[0743] Two Final coating solutions were developed and used to coat
the Bupropion HBr tablets after they had been first coated with the
ethylcellulose coat.
[0744] One of the following formulations shown in Table 7 was used
to coat the tablets with a final coat.
[0745] In Formulation A, the purified water was placed in a glass
beaker and Chroma-Tone DEB 5156-CLE was added and allowed to mix
for 15 minutes. The EUDRAGIT.RTM. was passed through a Mesh screen
(no. 60) prior to use. Following this, the EUDRAGIT.RTM. was added
to the beaker and was stirred for 15 more minutes.
[0746] In Formulation B, part 1 of the Purified Water was placed
into a glass beaker and PEG 4000 was added to it and allowed to mix
until it was completely dissolved (5 minutes). The Triethyl Citrate
was then added and left to mix for another 5 minutes. Once
dissolved, the solution was then added to the EUDRAGIT.RTM.
Suspension and left to stir for 45 minutes. The EUDRAGIT.RTM. was
passed through a Mesh screen (no. 60) prior to use. In a separate
beaker, part 2 of the purified water was added to the SYLOID.RTM.
244FP and mixed until it was completely dissolved (10 minutes).
Finally the SYLOID.RTM. Suspension was added to the EUDRAGIT.RTM.
Suspension and left to stir for another 10 minutes.
[0747] Table 8 summarizes the specifications that were monitored in
the ethylcellulose coating process and their ranges.
[0748] Table 9 summarizes the specifications that were monitored in
the final coating process and their ranges.
In-Vitro Studies on the Bupropion HBr Cores
[0749] Dissolution was performed on the Bupropion HBr cores, on the
different weight gains of ethylcellulose coated cores and on the
different weight gains of final coated tablets. USP-1 method was
used to conduct these studies. The dissolution test was performed
using 900 mL of 0.1N HCl and at a speed of 75 rpm. Samples were
taken at every hour for 16 hours. The dissolution profiles were
obtained by plotting the cumulative percent of API dissolved
against sampling time points. Sink conditions were maintained
throughout all the experiments.
[0750] On several trials, USP-3 method was used to conduct the
dissolution studies. These dissolution tests were performed for 16
hours total with the following breakdown: 2 hours using 900 mL of
Simulated Gastric Fluid (SGF) at pH 1.2 with 0.5% of Sodium Lauryl
Sulfate (SLS), followed by 2 hours in 900 mL of Acetate Buffer at a
pH of 4.5, followed by 12 hours in 900 mL of Phosphate Buffer
Simulated Intestinal Fluid (SIF) at a pH of 6.8. These results were
plotted with the in-vivo data and the Bupropion HCI data in order
for a comparison to be made.
Study on Batch BUP-HBr-XL-009-5
[0751] The formulation was granulated using NIRO Fluid Bed. After
granulation was completed, the batch was screened and then prior to
compression the lubricant (COMPRITOL.RTM. 888) was added. The final
blend was compressed into 348 mg tablets using the Beta press with
9 mm and 10 mm standard, round, concave tooling. Table 10 describes
the amounts of each material in the granulation of the 348 mg
tablets. A first compression run was done to produce tablets with
different hardness values so as to determine the effects of
hardness, if any, on the dissolution (FIG. 5). Dissolution was
conducted on the 348 mg cores in order to determine their release
(FIG. 6).
[0752] The granulation results show that the average granulation
time is 2.0 hours and the average LOD % is 0.345%. Tables 11 and 12
summarize the theoretical and actual values of the parameters that
were monitored in the compression process using the 9 mm and 10 mm
tooling, respectively.
[0753] In order to determine the tablet hardness for this study,
tablets of different hardness values were compressed and
dissolution was conducted on them to see the difference.
[0754] Tablets with a hardness of 4 kp, 6-7 kp and 9-10 kp were
compressed and the dissolution profiles of each were shown in FIG.
5. It was observed that there was no significant difference between
the three different hardness ranges.
[0755] The dissolution profiles of the 348 mg (FIG. 6) and 174 mg
cores (FIG. 7) showed that the cores were releasing approximately
100 percent of API in an hour.
[0756] Dissolution of the 10 mm, 348 mg cores was done also in
order to see if these tablets released faster when compared to the
9 mm cores due to their larger surface area (FIG. 7).
[0757] When the dissolution results of the 9 mm and 10 mm cores
were compared (FIG. 8), the mm cores showed no difference from the
9 mm cores. Thus, the 10 mm cores were no longer manufactured or
used in this study.
Study on Batch BUP-HBr-XL-021-5
[0758] The Formulation was granulated using NIRO Fluid Bed. The
final blend was compressed into 174 mg tablets using the Beta press
with 7 mm standard, round, concave, stainless steel tooling. Table
13 describes the amounts of each material in the granulation of the
174 mg tablets. It was noted that the 348 and the 174 mg tablets
had the same composition and amounts of each material; the only
variation was the tablet weight, which was adjusted at the
compression stage. Dissolution was conducted on the 174 mg cores in
order to see their release (FIG. 9).
[0759] The granulation results show that the granulation time is 2
hours 6 minutes and the average LOD % is 0.26%. Table 14 summarizes
the theoretical and actual values of the parameters that were
monitored in the compression process using the 7 mm tooling.
[0760] The dissolution profile of the 174 mg (FIG. 9) showed that
the cores were releasing approximately 100 percent of API in an
hour.
Study on Batch BUP-HBr-XL-348 mg-013-5
[0761] Using 348 mg tablets, an ethylcellulose (e.g. ETHOCEL.RTM.
or "EC") coating followed by a Final coating, were sprayed onto the
tablets using the O'Hara Labcoat II Coating Equipment. The
materials used in the ethylcellulose coating, their percent
contribution to the total solution, the amounts of each in the
batch and the percentage of the solids in the solution were all
listed in Table 15.
[0762] The parameters are as follows: Spray Rate: 13 g/min; Pan
Speed: 12.0 rpm; Inlet Air: 50.degree. C.; Product Temperature:
35.degree. C..+-.5.degree. C.; and Supply Air Flow: 200 CFW.
[0763] It took 2 hours and 25 minutes to coat the tablets with a
weight gain of 32 mg. Tablet weights were taken and recorded in
Table 16 at 28 mg, 30 mg, 32 mg, and 34 mg weight gains. The
dissolution profile (FIG. 10) shows that the tablets with the 34 mg
weight gain of ethylcellulose coating released Bupropion HBr the
slowest when compared to the others and that the tablets with the
28 mg weight gain released Bupropion HBr the fastest when compared
to the other weight gains.
[0764] The materials used in the final coating, their percent
contribution to the total solution, the amounts of each in the
batch, the amount of solid contribution in grams and the percentage
of the solids in the solution were all listed in Table 17.
[0765] The parameters are as follows: Spray Rate: 6 g/min; Pan
Speed: 12.0 rpm; Inlet Air: 40.degree. C.; Product Temperature:
35.degree. C..+-.5.degree. C.; and Supply Air Flow: 200 CFW.
[0766] After this trial run, Chroma-Tone was no longer used due to
the formulation problems it caused. First, it limited the
composition of the formulation due to its inflexibility, as
SYLOID.RTM., PEG and Triethyl Citrate ratios could not be varied.
Second, the solution foamed and coagulated, which in turn caused
the process for making the coating solution to be changed from the
original so that it did not re-coagulate. Chroma-Tone can, however,
still be considered an option for the formulation but different
grades and mixtures would need to be used and made in order to
accommodate the Bupropion HBr XL tablets.
[0767] It took 31 minutes to add a 7 mg weight gain of the final
coating solution to the tablets. Tablet weights were taken and
recorded in Table 18 at 4 mg, 5 mg, 6 mg and 7 mg weight gains.
[0768] The dissolution profile (FIG. 11) shows that the tablets
with the 7 mg weight gain of Final coating released the slowest
when compared to the other two weight gains (5 mg and 6 mg weight
gains).
Study on Batch BUP-HBr-XL-348 mg-018-5
[0769] Using 348 mg tablets, an ethylcellulose coating followed by
a final coating, were sprayed onto the tablets using the O'Hara
Labcoat II Coating Equipment.
[0770] The materials used in the ethylcellulose (e.g. ETHOCEL.RTM.)
coating, their percent contribution to the total solution, the
amounts of each in the batch and the percentage of the solids in
the solution were all listed in Table 19.
[0771] The parameters are as follows: Spray Rate: 13 g/min; Pan
Speed: 12.0 rpm; Inlet Air: 50.degree. C.; Product Temperature:
35.degree. C..+-.5.degree. C.; and Supply Air Flow: 200 CFW.
[0772] The coating process of this trial took 2 hours and 13
minutes to obtain a 32 mg weight gain. Tablet weights were taken
and recorded in Table 20 at 26 mg, 28 mg, 30 mg, and 32 mg weight
gains.
[0773] FIG. 12 shows that the tablets with the 30 mg and 32 mg
weight gain of ethylcellulose coating solution released at almost
the same rate. The tablets with the 32 mg weight gain released
slower than the tablets with the 30 mg weight gain in the first 5
hours of dissolution. After 6 hours, the tablets with the 32 mg
weight gain released slightly faster than those with a 30 mg weight
gain. The f2 similarity factor confirmed that the release rate of
both weight gains was similar (91.32%).
[0774] The materials used in the final coating, their percent
contribution to the total solution, the amounts of each in the
batch, the amount of solid contribution in grams and the percentage
of the solids in the solution were all listed in Table 21.
[0775] The parameters are as follows: Spray Rate: 6 g/min; Pan
Speed: 12.0 rpm; Inlet Air: 40.degree. C.; Product Temperature:
35.degree. C..+-.5.degree. C.; and Supply Air Flow: 200 CFW.
[0776] It took 41 minutes to add a 7 mg weight gain of the final
coating solution to the tablets. Tablet weights were taken and
recorded in Table 22 at 4 mg, 5 mg, 6 mg, and 7 mg weight
gains.
[0777] FIG. 13 shows the release profile of the tablets with the 7
mg weight gain of Final coating.
Study on Batch BUP-HBr-XL-174 mg-022-5
[0778] Using 174 mg tablets, an ethylcellulose coating followed by
a final coating, were sprayed onto the tablets using the O'Hara
Labcoat II Coating Equipment.
[0779] The materials used in the ethylcellulose (e.g. ETHOCEL.RTM.)
coating, their percent contribution to the total solution, the
amounts of each in the batch and the percentage of the solids in
the solution were all listed in Table 23.
[0780] The parameters are as follows: Spray Rate: 13 g/min; Pan
Speed: 12.0 rpm; Inlet Air: 50.degree. C.; Product Temperature:
35.degree. C..+-.5.degree. C.; and Supply Air Flow: 200 CFW.
[0781] It took 4 hours and 30 minutes to add a 30 mg weight gain of
the ethylcellulose coating solution to the tablets. Tablet weights
were taken at 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 29 mg, and 30 mg
weight gains and were recorded in Table 24.
[0782] FIG. 14 shows the % dissolved of each of the samples with
different weight gains of ethylcellulose coating (22 mg, 24 mg, 28
mg and 30 mg weight gains). From the graph, it was evident that the
tablets with the 30 mg weight gain of ethylcellulose coating
released slower than the other weight gains. When the release rates
of the tablets with the 30 mg and the 28 mg weight gains were
compared, there was only a slight difference noticed in the
release. The f2 similarity factor confirmed the similarity of the
two releases (92.34%).
[0783] The materials used in the final coating, their percent
contribution to the total solution, the amounts of each in the
batch, the amount of solid contribution in grams and the percentage
of the solids in the solution were all listed in Table 25.
[0784] The parameters are as follows: Spray Rate: 6 g/min; Pan
Speed: 12.0 rpm; Inlet Air: 40.degree. C.; Product Temperature:
35.degree. C..+-.5.degree. C.; and Supply Air Flow: 200 CFW.
[0785] It took 1 hour and 26 minutes to add a 7 mg weight gain of
the final coating solution to the tablets. Tablet weights were
taken and recorded in Table 26 at 4 mg, 5 mg, 6 mg, and 7 mg weight
gains.
[0786] The dissolution profile (FIG. 15) shows that the tablets
with the 7 mg weight gain of final coating released the slowest, in
comparison to the 5 mg and the 6 mg weight gains.
Study on Batch BUP-HBr-XL-348 mg-023-5
[0787] Using 348 mg tablets, an ethylcellulose coating was sprayed
onto the tablets using the O'Hara Labcoat II Coating Equipment.
[0788] The materials used in the ethylcellulose (e.g. ETHOCEL.RTM.)
coating, their percent contribution to the total solution, the
amounts of each in the batch and the percentage of the solids in
the solution were all listed in Table 27.
[0789] The parameters are as follows: Spray Rate: 13 g/min; Pan
Speed: 12.0 rpm; Inlet Air: 50.degree. C.; Product Temperature:
35.degree. C..+-.5.degree. C.; and Supply Air Flow: 200 CFW.
[0790] It took 2 hours and 16 minutes to add a 32 mg weight gain of
the ethylcellulose coating solution to the tablets. Tablet weights
were taken at 26 mg, 28 mg, 30 mg, and 32 mg weight gains and were
recorded in Table 28.
[0791] The dissolution profile (FIG. 16) shows that the tablets
with the 32 mg weight gain of ethylcellulose coating, when compared
to the tablets with the 26 mg, 28 mg and the 30 mg weight gain of
ethylcellulose coating, released at the slowest rate.
Study on Batch BUP-HBr-XL-348 mg-025-5
[0792] Using 348 mg tablets, an ethylcellulose coating followed by
a final coating, were sprayed onto the tablets using the O'Hara
Labcoat II Coating Equipment.
[0793] The materials used in the ethylcellulose (e.g. ETHOCEL.RTM.
or EC) coating, their percent contribution to the total solution,
the amounts of each in the batch and the percentage of the solids
in the solution were all listed in Table 29.
[0794] The parameters are as follows: Spray Rate: 13 g/min; Pan
Speed: 12.0 rpm; Inlet Air: 50.degree. C.; Product Temperature:
35.degree. C..+-.5.degree. C.; and Supply Air Flow: 200 CFW.
[0795] It took 2 hours and 13 minutes to add a 32 mg weight gain of
the ethylcellulose coating solution to the tablets. Tablet weights
were taken at 26 mg, 28 mg, 30 mg, and 32 mg weight gains and were
recorded in Table 30.
[0796] The dissolution profile (FIG. 17) shows that the tablets
with the 32 mg weight gain of ethylcellulose coating when compared
to those with 26 mg weight gain released slower in the beginning
and then faster after 7 hours. When comparing the tablets with 32
mg weight gain of ethylcellulose coating to those with 30 mg weight
gain of ethylcellulose coating, the tablets with the 32 mg weight
gain released slower up until 10 hours. The 12 similarity factor
showed that the release of the tablets with the 30 mg and 32 mg
weight gains were in fact similar (93.72%).
[0797] The materials used in the final coating, their percent
contribution to the total solution, the amounts of each in the
batch, the amount of solid contribution in grams and the percentage
of the solids in the solution were all listed in Table 31.
[0798] The parameters are as follows: Spray Rate: 6 g/min; Pan
Speed: 12.0 rpm; Inlet Air: 40.degree. C.; Product Temperature:
35.degree. C..+-.5.degree. C.; and Supply Air Flow: 200 CFW.
[0799] The coating solution was altered for this batch by changing
the percentage of solid from each of the solid components in the
solution. The percentage of EUDRAGIT.RTM. solid contribution was
decreased from 65% to 56.5%. The percentage of SYLOID.RTM.,
CARBOWAX.RTM. and Triethyl Citrate were increased from 25%, 6.65%
and 3.39% to 30%, 9% and 4.5%, respectively.
[0800] It took 40 minutes to add a 7 mg weight gain of the final
coating solution to the tablets.
[0801] Tablet weights were taken and recorded (Table 32) at 4 mg, 5
mg, 6 mg, and 7 mg weight gains. The dissolution profile (FIG. 18)
shows that the tablets with the 7 mg weight gains released the
slowest of the three samples tested. However, f2 calculation showed
that the tablets with the 6 mg weight gain released similarly to
those with the 7 mg weight gain of Final coating (93.33%).
Study on Batch BUP-HBr-XL-348 mg-026-5
[0802] Using 348 mg tablets, an ethylcellulose coating was sprayed
onto the tablets using the O'Hara Labcoat II Coating Equipment.
[0803] The materials used in the ethylcellulose (e.g. ETHOCEL.RTM.
or EC) coating, their percent contribution to the total solution,
the amounts of each in the batch and the percentage of the solids
in the solution were all listed in Table 33.
[0804] The parameters are as follows: Spray Rate: 13 g/min; Pan
Speed: 12.0 rpm; Inlet Air: 50.degree. C.; Product Temperature:
35.degree. C..+-.5.degree. C.; and Supply Air Flow: 200 CFW.
[0805] It took 2 hours and 11 minutes to add a 32 mg weight gain of
the ethylcellulose coating solution to the tablets. Tablet weights
were taken at 26 mg, 28 mg, 30 mg, and 32 mg weight gains and were
recorded in Table 34.
[0806] The dissolution profile (FIG. 19) shows that the tablets
with the 32 mg weight gain of ethylcellulose coating released the
slowest when compared to the other three samples with lower weight
gains of ethylcellulose coating (26 mg, 28 mg and 30 mg).
Study on Batch BUP-HBr-XL-174 mg-027-5
[0807] Using 174 mg tablets, an ethylcellulose coating followed by
a final coating, were sprayed onto the tablets using the O'Hara
Labcoat II Coating Equipment.
[0808] The materials used in the ethylcellulose (e.g. ETHOCEL.RTM.
or EC) coating, their percent contribution to the total solution,
the amounts of each in the batch and the percentage of the solids
in the solution were all listed in Table 35.
[0809] The parameters are as follows: Spray Rate: 13 g/min; Pan
Speed: 12.0 rpm; Inlet Air: 50.degree. C.; Product Temperature:
35.degree. C..+-.5.degree. C.; and Supply Air Flow: 200 CFW.
[0810] It took 3 hours and 29 minutes to add a 32 mg weight gain of
the ethylcellulose coating solution to the tablets. Tablet weights
were taken at 22 mg, 24 mg, and 26 mg weight gains and were
recorded in Table 36.
[0811] The dissolution profile (FIG. 20) shows that the tablets
with the 26 mg weight gain of ethylcellulose coating released the
slowest of the three samples tested.
[0812] The materials used in the final coating, their percent
contribution to the total solution, the amounts in each in the
batch, the amount of solid contribution in grams and the percentage
of the solids in the solution were all listed in Table 37.
[0813] The parameters are as follows: Spray Rate: 6 g/min; Pan
Speed: 12.0 rpm; Inlet Air: 40.degree. C.; Product Temperature:
35.degree. C..+-.5.degree. C.; and Supply Air Flow: 200 CFW.
[0814] It took 1 hour and 17 minutes to add a 7 mg weight gain of
the final coating solution to the tablets. Tablet weights were
taken and recorded in Table 38 at 4 mg, 5 mg, 6 mg, and 7 mg weight
gains.
[0815] The dissolution profile (FIG. 21) shows that the tablets
with the 7 mg weight gain of final coating initially released
slower that the tablets with 4 mg, 5 mg and 6 mg weight gains.
However, at approximately 12 hours, all 4 samples were releasing
similarly.
Example 3
Preparation and Stability Study of Bupropion HBr Polymorphs I, II
and III Bupropion Hydrobromide Polymorphic Forms I, II and III were
Prepared in the Following Manner and their Stability was Studied
Under the Conditions Described Below
Form I:
[0816] A 250 ml flask equipped with overhead stirrer and gas inlet
was charged with 34 g of bupropion base and 138 ml of isopropanol.
The solution was maintained under stirring while 13 g of gaseous
HBr was introduced through the gas inlet in a time of 20' while the
internal temperature of the mixture raises from 25.degree. C. to
40.degree. C. During the gas addition a heavy white precipitate
formed. At the end of the gas addition the temperature of the
mixture was raised to reflux (80.degree. C.), to get complete
solution of the suspended solid. The temperature was then lowered
to 25.degree. C. in 1 hour and further lowered to 0-5.degree. C. in
1 additional hour. The precipitate obtained was filtered and washed
with 20 ml of cold isopropanol. The discharged wet solid was dried
under vacuum (30 mmHg) in a static drier at 50.degree. C. for 16
hours. 34 g of bupropion hydrobromide form I were obtained.
[0817] Samples of bupropion hydrobromide form I were subjected to
the conditions for the accelerated stability study and the shelf
life stability study as described for example in U.S. Pat. No.
7,241,805 (eg. see examples 10 and 11), the contents of which are
incorporated herein by reference. PXRD studies carried out after 3
months and 6 months for each sample gave the same results. The PXRD
profile of one of the samples of form I after 6 months in the
accelerated stability condition is provided in FIG. 24.
Form II:
[0818] 10 g of bupropion hydrobromide form I were dissolved in a
mixture of 170 ml of acetone and 7 ml of water. The mixture was
brought to reflux with dissolution of the solid. The solution was
then cooled to room temperature. After one night the precipitate
formed was filtered and dried at 40.degree. C. under vacuum (30
mmHg) for 12 hours. 2.4 g of bupropion hydrobromide form II were
obtained. A sample of the product was prepared for an accelerated
stability test, in ICH (International Conference on Harmonisation
of Technical Requirements for Registration of Pharmaceuticals for
Human Use) conditions (40.degree. C./75% R.H.), by sealing the
product in polyethylene bags, which in turn were placed in
aluminium bags containing silica and sealed and placed in the
stability chamber in ICH conditions (40.degree. C./75% R.H.). The
crystalline form was checked after maintaining the product under
these conditions for 1 month. The PXRD profile shown in FIG. 27
shows that the compound is still in form II. This demonstrates the
stability of crystal form II under these conditions.
Form III:
[0819] 20 g of bupropion hydrobromide form 1 and 96 ml of absolute
ethanol were placed in a 250 ml flask. The mixture was brought to
reflux obtaining complete dissolution of the solid. The solution
was then cooled to room temperature without stirring and left in
these conditions for 18 hours. The resulting crystalline solid was
then filtered and dried under vacuum (30 mmHg) at 50.degree. C. for
4 hours. 11.2 g of bupropion hydrobromide form III were obtained. A
sample of the product was prepared for stability testing by sealing
the product in polyethylene bags, which in turn were placed in
aluminium bags containing silica and sealed, and placed in the
stability chamber in ICH conditions (40.degree. C./75% R.H.). The
crystalline form was checked after maintaining the product in these
conditions for 1 month. The PXRD profile shown in FIG. 30
demonstrates that the product is not stable in this form under
these conditions, as the majority of the product changed to form
II.
Example 4
Preparation of Bupropion HBr Polymorphs IV, V, VI and VII, and
Amorphous Bupropion HBr
[0820] Bupropion Hydrobromide Polymorphic Forms IV, V, VI and VII
and Amorphous Form were Prepared in the Following Manner:
Form IV:
[0821] 50 mg of bupropion hydrobromide form I is dissolved in 4 ml
of chloroform, with stirring, and filtered on a Whatman filter
(0.45 micron). The solution obtained is left to evaporate at room
temperature until the solvent has evaporated completely. In this
way we obtain a wet solid crystalline residue comprising bupropion
hydrobromide in form IV. The PXRD, DSC, TGA and IR profiles of this
crystalline form are shown respectively in FIGS. 31, 32, 33 and 34.
The sample is then dried to constant weight and the PXRD, DSC, TGA
and IR analyses are repeated, obtaining profiles identical to those
obtained on the sample prior to drying.
Form V:
[0822] 100 mg of bupropion hydrobromide form I is suspended in 2 ml
of 1,4-dioxan and stirred at room temperature for seven days. The
suspension obtained is then filtered on Whatman filter paper and
discharged wet from the filter. In this way we obtain a wet
crystalline solid residue comprising bupropion hydrobromide in form
V. The PXRD, DSC, TGA and IR profiles of this crystalline form are
shown respectively in FIGS. 35, 36, 37 and 38. The sample is then
dried to constant weight and the PXRD, DSC, TGA and IR analyses are
repeated, obtaining profiles identical to those obtained on the
sample prior to drying.
[0823] In another preparation of form V, a mixture of 50 mg of
bupropion hydrobromide form I and 50 mg of bupropion hydrobromide
form II is suspended in 2 ml of 1,4-dioxan and stirred at room
temperature for seven days. The suspension obtained is then
filtered on Whatman filter paper and discharged wet from the
filter. In this way we obtain a wet crystalline solid residue
comprising bupropion hydrobromide in form V. The PXRD, DSC, TGA and
IR profiles of the wet product and product after drying are
identical to those shown respectively in FIGS. 35, 36, 37 and
38.
Form VI:
[0824] 2 g of bupropion hydrobromide form I is suspended in 15 ml
of 1-propanol and refluxed, observing dissolution of the solid. The
solution obtained is then cooled at a rate of 0.45.degree. C./min
to a temperature of 20.degree. C. The solid obtained is then
filtered, obtaining bupropion hydrobromide form VI. The PXRD, DSC,
TGA and IR profiles of this crystalline form are shown respectively
in FIGS. 39, 40, 41 and 42. The sample is then dried to constant
weight and the PXRD, DSC, TGA and IR analyses are repeated,
obtaining profiles identical to those obtained on the sample prior
to drying.
Form VII:
[0825] 50 mg of bupropion hydrobromide form I is dissolved in 4 ml
of dimethylformamide (DMF), with stirring, and is filtered on a
Whatman filter (0.45 micron). The solution obtained is left to
evaporate at 60.degree. C. until the solvent has evaporated
completely. As a result, we obtain a wet solid crystalline residue
comprising bupropion hydrobromide in form VII. The PXRD, DSC, TGA
and IR profiles of this crystalline form are shown in FIGS. 43, 44,
45 and 46 respectively. The sample is then dried to constant weight
and the PXRD, DSC, TGA and IR analyses are repeated, obtaining
profiles identical to those obtained on the sample before
drying.
Amorphous Form:
[0826] 5 g of bupropion hydrobromide form I is dissolved at room
temperature in 195 ml of deionized water. The solution is loaded in
a 1-liter flask and frozen by immersion of the flask in rotation in
a rotary evaporator, on a bath of isopropanol and dry ice
maintained at a temperature of -50.degree. C. The freezing process
is continued for two hours, then the flask is mounted in
lyophilization apparatus and submitted to lyophilization in the
following conditions:
[0827] Apparatus: CHRIST Alpha 1-4 LSC
[0828] Coil conditioning temperature: -30.degree. C.
[0829] Pump conditioning pressure: atmospheric.
[0830] Condenser temperature during drying: -50.degree. C.
[0831] Residual pressure during drying: 0.02 mbar
[0832] Drying time: 18 hours.
[0833] At the end of the process, a solid is discharged from the
flask and is analyzed by X-ray diffraction. The profile obtained is
shown in FIG. 47; it is the typical PXRD profile of an amorphous
solid.
[0834] In another preparation of bupropion hydrobromide in
amorphous form, a sample of bupropion hydrobromide form I is
dissolved in 4 ml of p-xylene, with stirring. After about one hour
in these conditions, the solution is filtered on Whatman paper
(0.45 micron) and the solution obtained is left to evaporate until
the solvent has been removed. The resultant solid is analyzed by
PXRD, giving the profile shown in FIG. 48. It can be seen from the
PXRD profile that the product is obtained in amorphous form.
Example 5
Polymorph Screening
[0835] Solvent Screening:
[0836] We analyzed the powder sample obtained by recrystallization
from different solvents chosen on the basis of the following
parameters: (i) dielectric constants; (ii) boiling point (BP);
(iii) melting point (MP); and (iv) solubility of sample. See Table
40 for solvents used during the experiments.
Qualitative Solubility Screening:
[0837] Bupropion hydrobromide (50 mg) was introduced in 4 mL of
solvent under stirring for about 1 hour at room temperature. See
Table 41 for the qualitative solubility data.
Room Temperature Recrystallization:
[0838] Bupropion hydrobromide (50 mg) was dissolved in 4 mL of
solvent under stirring, after about 1 hour the solution was
filtered with a Whatman filter (0.45 .mu.m) and left to evaporate
at room temperature (RT). The solutions were evaporated at RT for 3
days, in some cases for 1 week. Four different crystal forms were
identified: Form I, Form IV, Form VII and an amorphous phase. See
Table 42 for the recrystallization results (experiments of
evaporation of Bupropion Hydrobromide at room temperature).
Low Temperature Recrystallization:
[0839] Bupropion hydrobromide (50 mg) was dissolved in 4 mL of
solvent under stirring, after about 1 hour the solution was
filtered with a Whatman filter (0.45 .mu.m) and left to evaporate
at 4.degree. C. for 1-2 weeks. See Table 43 for the
recrystallization results (experiments of evaporation of bupropion
hydrobromide at low temperature).
High Temperature Recrystallization:
[0840] Bupropion hydrobromide (50 mg) was dissolved in 4 mL of
solvent under stirring, after about 1 hour the solution was
filtered with a Whatman filter (0.45 .mu.m) and left to evaporate
at 60.degree. C. for 2-3 days. See Table 44 for the
recrystallization results (experiments of evaporation of bupropion
hydrobromide at high temperature).
Low Pressure Recrystallization:
[0841] Bupropion hydrobromide (50 mg) was dissolved in 4 mL of
solvent under stirring, after about 1 hour the solution was
filtered with a Whatman filter (0.45 .mu.m) and left to evaporate
at low pressure for 1-2 days. See Table 45 for the
recrystallization results (experiments of evaporation of bupropion
hydrobromide at low pressure).
Example 6
Slurries
Slurries of Form 1-7 Days
[0842] Slurry experiments of Form I were performed at room
temperature to verify if Form I is the thermodynamic crystal form.
0.050 g of Form I was suspended in 2 ml of solvent and stirred for
1 week. The sample was filtered and analyzed by X-ray diffraction.
In the large majority of the experiments, Form I converts into Form
II. As such, Form II is the thermodynamic stable form of bupropion
hydrobromide. By 1,4-Dioxane, a new crystal form was obtained named
Form V. See Table 46 for the Form I slurries results (7 days).
[0843] Further slurry experiments of Form I were performed at room
temperature using 0.5 g of powder in 10 mL of solvent to confirm
the results obtained even in large scale. With both Ethyl Acetate
and p-Xylene as solvents, Form I was found to convert into Form
II.
Slurries of Form I--30 Days
[0844] 0.050 g of Form I were suspended in 2 ml of solvent and
stirred at room temperature for 4 weeks (30 days). The sample was
filtered and analyzed by X-ray diffraction. By 1,4-Dioxane, Form V
was obtained. By tetrahydrofuran, Form II and Form VII were
obtained. In all other experiments, Form I converts to Form II;
showing that Form II is the thermodynamic stable form of bupropion
hydrobromide. See Table 47 for the Form I slurries results (30
days).
Slurries of Form I Mixed with Form II--7 Days
[0845] Slurry experiments of mixtures of Form I and Form II were
performed at room temperature to verify their thermodynamic
stability. 0.040 g of Form I+0.040 g of Form II were suspended in 4
ml of solvent and stirred for 1 week (7 days). The samples were
filtered and analyzed by X-ray diffraction. By 1,4-Dioxane, Form V
was obtained. In all other experiments, Form I converts to Form II;
showing that Form II is the thermodynamic stable form of bupropion
hydrobromide. See Table 48 for the Form I+Form II slurries results
(7 days).
Slurries of Form II Mixed with Form III--7 Days
[0846] Slurry experiments of mixtures of Form II and Form III were
performed at room temperature to verify their thermodynamic
stability. 0.040 g of Form II+0.040 g of Form III were suspended in
4 ml of solvent and stirred for 1 week (7 days). The samples were
filtered and analyzed by X-ray diffraction. By 1,4-Dioxane, Form V
was obtained. In all other experiments, Form III converts to Form
II; showing that Form II is the thermodynamic stable form of
bupropion hydrobromide. See Table 49 for the Form II+Form III
slurries results (7 days).
Slurries of Form II Mixed with Form IV--7 Days
[0847] Slurry experiments of mixtures of Form II and Form IV were
performed at room temperature to verify their thermodynamic
stability. 0.040 g of Form II+0.040 g of Form IV were suspended in
4 ml of solvent and stirred for 1 week (7 days). The samples were
filtered and analyzed by X-ray diffraction. By 1,4-Dioxane, Form V
was obtained. In all other experiments, Form IV converts to Form
II; showing that Form II is the thermodynamic stable form of
bupropion hydrobromide. See Table 50 for the Form II+Form IV
slurries results (7 days).
Slurries of Form II Mixed with Form V--7 Days
[0848] Slurry experiments of mixtures of Form II and Form V were
performed at room temperature to verify their thermodynamic
stability. 0.040 g of Form II+0.040 g of Form V were suspended in 4
ml of solvent and stirred for 1 week (7 days). The samples were
filtered and analyzed by X-ray diffraction. By 1,4-Dioxane, Form V
was obtained. In all other experiments, Form V converts to Form II;
showing that Form II is the thermodynamic stable form of bupropion
hydrobromide. See Table 51 for the Form II+Form V slurries results
(7 days).
Slurries of Form II Mixed with Form VI--7 Days
[0849] Slurry experiments of mixtures of Form II and Form VI were
performed at room temperature to verify their thermodynamic
stability. 0.040 g of Form II+0.040 g of Form VI were suspended in
4 ml of solvent and stirred for 1 week (7 days). The samples were
filtered and analyzed by X-ray diffraction. By 1,4-Dioxane, Form V
was obtained. In all other experiments, Form VI converts to Form
II; showing that Form II is the thermodynamic stable form of
bupropion hydrobromide. See Table 52 for the Form II+Form VI
slurries results (7 days).
Slurries of Form II Mixed with Form VII--7 Days
[0850] Slurry experiments of mixtures of Form II and Form VII were
performed at room temperature to verify their thermodynamic
stability. 0.040 g of Form II+0.040 g of Form VII were suspended in
4 ml of solvent and stirred for 1 week (7 days). The samples were
filtered and analyzed by X-ray diffraction. By 1,4-Dioxane, Form V
was obtained. In all other experiments, Form VII converts to Form
II; showing that Form II is the thermodynamic stable form of
bupropion hydrobromide. See Table 53 for the Form II+Form VII
slurries results (7 days).
Example 7
Slurries in 2-Propanol
Slurries of Form I at Room Temperature.
[0851] 0.050 g of Form I were suspended in 4 ml of solvent and
stirred at room temperature. for 1 week (7 days). The sample was
filtered and analyzed by X-ray diffraction. By 2-propanol, Form I
converted to Form II at room temperature.
Slurries of Mixture Form I and Form II at Room Temperature.
[0852] 0.040 g of Form I+0.040 g of Form II were suspended in 4 ml
of solvent and stirred at room temperature for 1 week (7 days). The
sample was filtered and analyzed by X-ray diffraction experiments.
By 2-propanol, Form I converted to Form II at room temperature. The
final result was that Form II was obtained.
Slurries of Form II at Room Temperature.
[0853] 0.050 g of Form II were suspended in 4 ml of solvent and
stirred at room temperature for 1 week (7 days). The sample was
filtered and analyzed by X-ray diffraction experiments. The final
result was that by 2-propanol, Form II was obtained.
Slurries of Form I at 50.degree. C.
[0854] 0.050 g of Form I were suspended in 4 ml of solvent and
stirred at 50.degree. C. for 1 Week (7 days). The sample was
filtered and analyzed by X-ray diffraction experiments. By
2-propanol, Form I converted to Form II at 50.degree. C.
Slurries of Mixture Form I and Form II at 50.degree. C.
[0855] 0.040 g of Form I+0.040 g of Form II were suspended in 4 ml
of solvent and stirred at 50.degree. C. for 1 week (7 days). The
sample was filtered and analyzed by X-ray diffraction experiments.
By 2-propanol, Form I converted to Form II at 50.degree. C. The
final result was that Form II was obtained.
Slurries of Mixture Form I and Form II at 80.degree. C.
[0856] Form I+Form II were suspended in solvent and stirred at
80.degree. C. for 14 hours. The sample was filtered and analyzed by
X-ray diffraction experiments. By 2-propanol, Form I remained as
Form I, whereas Form II converted to Form I after this assay at
80.degree. C. Slurry in 2-propanol at 80.degree. C. is an atypical
experiment because if we consider the boiling point of the solvent,
it could be defined as a combination between a slurry and
precipitation experiment. Form I was obtained during the
precipitation from supersaturated solution by 2-propanol. However
the high temperature and the reflux produce the energetic
conditions needed by the stable crystal form (Form II) to convert
to the metastable crystal form (Form I).
Example 8
Precipitation
Precipitation by Anti-Solvent Addition
[0857] Bupropion hydrobromide was dissolved at room temperature in
the solvent in which the sample showed high solubility, ethyl
acetate was chosen as antisolvent. The samples were filtered and
analyzed by X-ray diffraction. Form I converts into Form II using
chloroform, and also with benzyl alcohol. The other experiments
yield only Form I. See Table 54 for Form I precipitation results by
anti-solvent addition.
Precipitation from Oversaturated Solution
[0858] Bupropion hydrobromide Form I was dissolved at 100.degree.
C. in solvent to obtain the oversaturated solution. The cooling
rate applied was 0.45.degree. C./min. The samples were filtered and
analyzed by X-ray diffraction. Form I converts into Form VI using
1-Propanol, and into Form V using 1,4-Dioxane. The other
experiments yield only Form I. See Table 55 for Form I
precipitation results by oversaturated solution.
Precipitation from 2-Propanol
[0859] Bupropion hydrobromide Form I was dissolved in 2-propanol at
100.degree. C. to obtain oversaturated solution. The cooling rate
applied was 0.45.degree. C./min. The experiment was repeated to
verify the reproducibility of the crystal form obtained. The
samples were filtered and analyzed by X-ray diffraction. The
precipitation experiments yielded only Form I.
Example 9
Stability Tests on Bupropion Hydrobromide Polymorphs
[0860] Stability tests were performed on bupropion hydrobromide
Form I, Form II, Form III, Form IV, Form V and Form VI. The powders
were stored in a controlled atmosphere (85% R.H.) at 40.degree. C.
Form I and Form II were stored for 7 and 30 days respectively,
while the other forms were stored only for 30 days. The sample was
positioned on the sample-holder which was introduced, without any
cover, into the humidity chamber at 40.degree. C. The layer of the
sample on the sample-holder was about 0.5 cm. The experiments after
7 and 30 days evidenced that Form I and II did not show
modification in their XRD pattern, and remained as Form I and Form
II respectively. Form III, Form IV and Form V converted into Form I
after 30 days, while Form VI converted into a mixture of Form
I+Form II after 30 days.
[0861] In addition, stability tests were performed on bupropion
hydrobromide Form VII. Form VII was stored for 28 days at
25.degree. C., 75% R.H. The XRD pattern did not show modification,
and as such, Form VII was evidenced to be stable after 28 days.
Example 10
Characterization
[0862] PXRD, DSC, TGA and IR analyses were obtained for Bupropion
Hydrobromide Polymorph Form I, Form II, Form III, Form IV, Form V,
Form VI, and Form VII. PXRD analyses were obtained for the
amorphous form. With respect to the PXRD analyses, the Peak List is
shown for Form I, Form II, Form III, Form IV, Form V, Form VI, Form
VII and the amorphous form in Table 56, Table 57, Table 58, Table
59, Table 60, Table 61, Table 62 and Table 63 respectively. Table
64 shows the TGA and DSC summary for Form I, Form II, Form III,
Form IV, Form V, Form VI, and Form VII.
TABLE-US-00013 TABLE 1 Each trial's contents and amounts of each
material per part Amount (g) Materials Part 1 Part 2 Part 3 Part 4
Part 5 Bupropion HBr 2062.5 2062.5 2062.5 2062.5 2062.5 PVA 68.75
68.75 68.75 68.75 68.75 Purified Water 1452.5 1452.5 1452.5 1452.5
1452.5
TABLE-US-00014 TABLE 2 Summary of specifications for granulation
procedure. Specification Range Target Fan Speed Slow Slow Air
Volume (CMH) 60-65 65 Exhaust Temperature (.degree. C.) 35-45 40
Supply Temperature (.degree. C.) 60-65 65 Product Temperature
(.degree. C.) 35-55 45 Atomizing Air Pressure (Bar/psi) 35 35 Pump
Speed (rpm) 18 18 Liquid Flow Rate (g/min) 13 13 Bed Dew Point
(MMWC) 0 0 Filter Dew Point (MMWC 100-300 200
TABLE-US-00015 TABLE 3 The amount of lubricant in the final
formulation was 343.75 g, which was 3.125% of the total. Materials
Amount (g) Part 1 2131.25 Part 2 2131.25 Part 3 2131.25 Part 4
2131.25 Part 5 2131.25 COMPRITOL .RTM. 888 343.75 Total 11000.0
TABLE-US-00016 TABLE 4 Summary of Specifications for Tablet Press
Set-up. Parameters Settings/Ranges Pre-Compression Thickness (mm) 2
Control Thickness (mm) 1.5 Fill Thickness (mm) 7-8 Overload
Pressure (Tons) 1.5-2.0 Tablets per minute 450-500 Feeder Speed 1-2
Feeder Control Auto
TABLE-US-00017 TABLE 5 Summary of specifications for compression
Specification for Specification for Parameters 174 mg Tablet 348 mg
Tablet Individual Tablet 185.6 .+-. 5% 371.2 .+-. 5% Weight (mg)
(176.3 mg-194.9 mg) (352.6 mg-389.8 mg) Average Tablet 185.6 .+-.
3% 371.2 .+-. 3% Weight (mg) (180.0 mg-191.2 mg) (360.1 mg-382.3
mg) Tablet Hardness (SC) 6.0-12.0 6.0-12.0 Tablet Thickness (mm)
5.0-6.0 4.5-5.0 Friability (%) <0.8 <0.8
TABLE-US-00018 TABLE 6 Formulations used as the ethylcellulose
(e.g. ETHOCEL .RTM. or EC) coating on the 174 mg and 348 mg
Bupropion HBr cores. FORMULATION 1 FORMULATION 2 FORMULATION 3
ETHOCEL .RTM. (Ethyl ETHOCEL .RTM. (Ethyl ETHOCEL .RTM. (Ethyl
Cellulose) Cellulose) Cellulose) Standard Standard Standard 100
Premium 100 Premium 100 Premium Povidone USP Povidone USP Povidone
USP (KOLLIDON .RTM. 90F) (KOLLIDON .RTM. 90F) (KOLLIDON .RTM. 90F)
Polyethylene Polyethylene Polyethylene Glycol 4000 Glycol 4000
Glycol 4000 Ethyl Alcohol Dibutyl Sebacate Ethyl Alcohol 95% USP
Ethyl Alcohol 95% USP Isopropyl Alcohol 95% USP (IPA)
TABLE-US-00019 TABLE 7 Formulations used as the Final Coats on the
174 mg and 348 mg Bupropion HBr tablets. FORMULATION A FORMULATION
B EUDRAGIT .RTM. L30D-55 EUDRAGIT .RTM. L30D-55 Chroma-Tone DEB
5156-CLE SYLOID .RTM. 244FP Purified Water Polyethylene Glycol 4000
Triethyl Citrate Purified Water
TABLE-US-00020 TABLE 8 Summary of Specifications that were kept
constant in the ethylcellulose coating Process. Operational Process
Parameters Ranges Target Inlet Temperature for coating (.degree.
C.) SV: 40 .+-. 5 40 PV: 40 .+-. 5 Inlet Temperature for Drying
(.degree. C.) 30-35 35 Exhaust Temperature 30 .+-. 10 30 Product
Temperature 25-35 28 .DELTA.P Differential Pressure (W C)
(-0.1)-(-0.12) -0.10 Supply Air Flow (CFM) 200 .+-. 50 200 Pan
Speed (rpm) 2.5-12 5.0 Atomizing Air (psi) 35-40 35 Pattern Air
(psi) 20-30 25 Spray Rate (g/min) 5-15 6.0
TABLE-US-00021 TABLE 9 Summary of Specifications that were kept
constant in the Final coating Process. Operational Process
Parameters Ranges Target Inlet Temperature for coating (.degree.
C.) SV: 50 .+-. 5 50 PV: 50 .+-. 5 Inlet Temperature for Drying
(.degree. C.) 40 .+-. 5 40 Exhaust Temperature 35 .+-. 5 38 Product
Temperature 35 .+-. 2 35 .DELTA.P Differential Pressure (W C)
(-0.1)-(-0.12) -0.10 Supply Air Flow (CFM) 200 .+-. 50 200 Pan
Speed (rpm) 2.5-15 12.0 Atomizing Air (psi) 25-35 35 Pattern Air
(psi) 20-30 25 Spray Rate (g/min) 5-15 13.0
TABLE-US-00022 TABLE 10 Materials used in one part of the batch,
the percentage of each constituent, the amount per tablet and the
amount per batch, for BUP-HBr-XL-009-5 Materials % mg/tablet Batch
Quantity (g) Bupropion HBr 93.75 348.00 1993.75 PVA 3.125 11.60
68.75 COMPRITOL .RTM. 888 3.125 11.60 68.75 Total 100.00 371.2 mg
2131.25
TABLE-US-00023 TABLE 11 Results obtained using 9 mm tooling for
batch BUP-HBr-XL-009-5. Parameters Theoretical Actual Average
Individual Tablet Weight 371.2 mg 371.5 mg Average Hardness
6.0-12.0 SC 10.77 SC Average Thickness 5.0-6.0 mm 5.60 mm
Friability <0.8% 0%
TABLE-US-00024 TABLE 12 Results obtained using 10 mm tooling for
batch BUP-HBr-XL-009-5. Parameters Theoretical Actual Average
Individual Tablet Weight 371.2 mg 366.5 mg Average Hardness
6.0-12.0 SC 7.50 SC Average Thickness 5.0-6.0 mm 4.97 mm Friability
<0.8% 0%
TABLE-US-00025 TABLE 13 Materials used in one part of the batch,
the percentage of each constituent, the amount per tablet and the
amount per batch for batch BUP-HBr-XL-021-5. Materials % mg/tablet
Batch Quantity (g) Bupropion HBr 93.75 174.00 1993.75 PVA 3.125
5.80 68.75 COMPRITOL .RTM. 888 3.125 5.80 68.75 Total 100.00 185.60
2131.25
TABLE-US-00026 TABLE 14 Results obtained using 7 mm tooling for
batch BUP-HBr-XL-021-5. Parameters Theoretical Actual Average
Individual Tablet Weight 185.6 mg 186.8 mg Average Hardness
6.0-12.0 SC 9.23 SC Average Thickness 4.5-5.0 mm 4.70 mm Friability
<0.8% 0%
TABLE-US-00027 TABLE 15 Materials used in the ethylcellulose
coating and their quantities for batch BUP-HBr-XL-348-013-5. %
Contri- bution Batch % of to Total Quantity Solids in Materials
Solution (g) Solution ETHOCEL .RTM. (Ethyl Cellulose) 3.60 77.44*
38.74 Standard 100 Premium Povidone USP (KOLLIDON .RTM. 90F) 4.600
99.22* 49.64 PEG 4000 1.07 23.23* 11.62 Ethyl Alcohol 95% USP 86.44
1859.50 N/A Isopropyl Alcohol 99% USP 4.54 97.87 N/A Total 100.00
2151.00 100.00 *Total solid component of the formulation included
77.44 g of ethylcellulose (e.g. ETHOCEL .RTM.), 99.22 g of Povidone
and 23.23 g of PEG 4000, which gave a total solid amount of 199.89
g. The solid component of the formulation made up 9% of the total
solution and the remaining 91% was made up of liquid.
TABLE-US-00028 TABLE 16 Theoretical and Actual Tablet weights at 28
mg, 30 mg, 32 mg and 34 mg weight gains for batch
BUP-HBr-XL-348-013-5. Weight Gain (mg) Theoretical Weight (mg)
Actual Weight (mg) 28.0 400.0 401.3 30.0 402.0 402.6 32.0 404.0
404.5 34.0 406.0 406.8
TABLE-US-00029 TABLE 17 Materials used in the Final coating and
their quantities for batch BUP-HBr-XL-348-013-5. % Contri- bution
Batch Amount % of to Total Quantity of Solid Solids in Materials
Solution (g) (g) Solution EUDRAGIT .RTM. 22.73 104.8 31.44 65.00*
L30 D-55 Chroma-Tone DEB 3.66 16.90 16.90 35.00** 5156-CLE Purified
Water (1) 21.78 100.40 N/A N/A Purified Water (2) 51.89 239.20 N/A
N/A Total 100.00 460.95 48.34*** 100.00 *The percentage of EUDRAGIT
.RTM., solid, that contributed to the total amount of solid was
65%. **The percentage of Chroma-Tone, solid, that contributed to
the total amount of solid was 35%. ***The Total amount of solid
(48.34 g) was 10.5% of the total solution.
TABLE-US-00030 TABLE 18 Theoretical and Actual Tablet weights at 4
mg, 5 mg, 6 mg and 7 mg weight gains. Weight Gain (mg) Theoretical
Weight (mg) Actual Weight (mg) 4.0 410.0 410.5 5.0 411.0 410.8 6.0
412.0 412.4 7.0 413.0 413.9
TABLE-US-00031 TABLE 19 Materials used in the ethylcellulose
coating and their quantities for batch BUP-HBr-XL-348mg-018-5. %
Contribution Batch % of to Total Quantity Solids in Materials
Solution (g) Solution* ETHOCEL .RTM. (ethylcellulose) 3.42 73.57
38.00 Standard 100 Premium Povidone USP 4.41 94.86 49.00 (KOLLIDON
.RTM. 90F) PEG 4000 1.17 25.17 13.00 Ethyl Alcohol 95% USP 86.45
1859.53 N/A Isopropyl Alcohol 99% USP 4.55 97.87 N/A Total 100.00
2151.00 100.00 *Total solid included 73.57 g of ethylcellulose
94.86 g of Povidone and 25.17 g of PEG 4000.This gave a total of
193.6 g total solid amount.
TABLE-US-00032 TABLE 20 Theoretical and Actual Tablet weights at 26
mg, 28 mg, 30 mg, and 32 mg weight gains for batch
BUP-HBr-XL-348mg-018-5. Weight Gain (mg) Theoretical Weight (mg)
Actual Weight (mg) 26.0 398.0 397.7 28.0 400.0 399.5 30.0 402.0
401.5 32.0 404.0 404.0
TABLE-US-00033 TABLE 21 Materials used in the Final coating and
their quantities for batch BUP-HBr-XL-348mg-018-5. % Contribution
Batch Amount of % of to Total Quantity Solid Solids in Materials
Solution (g) (g) Solution EUDRAGIT .RTM. 22.75 104.86 31.46 65.00*
L30D D-55 SYLOID .RTM. 244FP 2.62 12.08 12.08 25.00** CARBOWAX
.RTM. 0.70 3.22 3.22 6.65** 4000 Triethyl Citrate 0.36 1.64 1.64
3.39** Purified Water (1) 33.84 156.00 N/A N/A Purified Water (2)
39.73 183.15 N/A N/A Total 100.00 460.95 48.40*** 100.00 *The
percentage of EUDRAGIT .RTM., solid, that contributed to the total
amount of solid was 65%. **The percentage of SYLOID .RTM., CARBOWAX
.RTM. 4000 and Triethyl Citrate that contributed to the total
amount of solid was 25%, 6.65% and 3.39%, respectively. This gave a
total of 35%. ***The total amount of solid (48.4 g) was 10.5% of
the total solution.
TABLE-US-00034 TABLE 22 Theoretical and Actual Tablet weights at 4
mg, 5 mg, 6 mg, and 7 mg weight gains for batch
BUP-HBr-XL-348mg-018-5. Weight Gain (mg) Theoretical Weight (mg)
Actual Weight (mg) 4.0 408.0 408.5 5.0 409.0 409.3 6.0 410.0 410.7
7.0 411.0 411.1
TABLE-US-00035 TABLE 23 Materials used in the ethylcellulose
coating and their quantities for batch BUP-HBr-XL-174mg-022-5. %
Contribution Batch % of Solids to Total Quantity in Materials
Solution (g) Solution* ETHOCEL .RTM. (ethylcellulose) 3.60 116.12
40.00 Standard 100 Premium Povidone USP 4.32 139.34 48.00 (KOLLIDON
.RTM. 90F) PEG 4000 1.08 34.84 12.00 Ethyl Alcohol 95% USP 86.45
2788.54 N/A Isopropyl Alcohol 99% USP 4.55 146.76 N/A Total 100.00
3225.60 100.00 *Total Solid included 116.12 g of ETHOCEL .RTM.,
139.34 g of Povidone and 34.84 g of PEG 4000. This gave a total
solid amount of 290.3 g.
TABLE-US-00036 TABLE 24 Theoretical and Actual Tablet weights at 20
mg, 22 mg, 24 mg, 26 mg, 28 mg, 29 mg, and 30 mg weight gains for
batch BUP-HBr-XL-174mg-022-5. Weight Gain (mg) Theoretical Weight
(mg) Actual Weight (mg) 20.0 206.0 206.1 22.0 208.0 207.8 24.0
210.0 210.2 26.0 212.0 211.5 28.0 214.0 213.7 29.0 215.0 214.9 30.0
216.0 216.5
TABLE-US-00037 TABLE 25 Materials used in the Final coating and
their quantities for batch BUP-HBr-XL-174mg-022-5. % Contribution
Batch Amount of to Total Quantity Solid % of Solids Materials
Solution (g) (g) in Solution EUDRAGIT .RTM. 22.75 104.86 31.46
65.0* L30D D-55 SYLOID .RTM. 244FP 2.62 12.08 12.08 25.0** CARBOWAX
.RTM. 0.70 3.22 3.22 6.65** 4000 Triethyl Citrate 0.36 1.64 1.64
3.39** Purified Water (1) 33.84 156.00 N/A N/A Purified Water (2)
39.73 183.15 N/A N/A Total 100.00 460.95 48.40*** 100.00 *The
percentage of EUDRAGIT .RTM., solid, that contributed to the total
amount of solid was 65%. **The percentage of SYLOID .RTM., CARBOWAX
.RTM. 4000 and Triethyl Citrate that contributed to the total
amount of solid was 25%, 6.65% and 3.39%, respectively. This gave a
total of 35%. ***The Total amount of solid (48.4 g) was 10.5% of
the total solution.
TABLE-US-00038 TABLE 26 Theoretical and Actual Tablet weights at 4
mg, 5 mg, 6 mg, and 7 mg weight gains for batch
BUP-HBr-XL-174mg-022-5. Weight Gain (mg) Theoretical Weight (mg)
Actual Weight (mg) 4.0 219.0 219.4 5.0 220.0 220.2 6.0 221.0 221.2
7.0 222.0 223.0
TABLE-US-00039 TABLE 27 Materials used in the ethylcellulose
coating and their quantities for batch BUP-HBr-XL-348mg-023-5. %
Contribution Batch % of to Total Quantity Solids in Materials
Solution (g) Solution* ETHOCEL .RTM. (ethylcellulose) 3.69 79.37
42.71 Standard 100 Premium Povidone USP 3.69 79.37 42.71 (KOLLIDON
.RTM. 90F) PEG 4000 1.26 27.11 14.58 Dibutyl Sebacate, NF 0.36 7.75
N/A Ethyl Alcohol 95% USP 91.00 1957.4 N/A Total 100.00 2151.00
100.00 *Total Solid includes 79.37 g of ETHOCEL .RTM., 79.37 g of
Povidone, 27.11 g of PEG 4000 and 7.75 g of Dibutyl Sebacate. This
gave a total solid amount of 193.6 g.
TABLE-US-00040 TABLE 28 Theoretical and Actual Tablet weights at 26
mg, 28 mg, 30 mg, and 32 mg weight gains for batch
BUP-HBr-XL-348mg-023-5. Weight Gain (mg) Theoretical Weight (mg)
Actual Weight (mg) 26.0 398.0 399.3 28.0 400.0 401.0 30.0 402.0
401.7 32.0 404.0 402.7
TABLE-US-00041 TABLE 29 Materials used in the ethylcellulose
coating and their quantities for batch BUP-HBr-XL-348mg-025-5. %
Contribution Batch % of to Total Quantity Solids in Materials
Solution (g) Solution* ETHOCEL .RTM. (ethylcellulose) 3.69 79.40
41.00 Standard 100 Premium Povidone USP 3.78 81.30 42.00 (KOLLIDON
.RTM. 90F) PEG 4000 1.53 32.90 17.00 Ethyl Alcohol 95% USP 91.00
1957.40 N/A Total 100.00 2151.00 100.00 *Total Solid included 79.40
g of ETHOCEL .RTM., 81.30 g of Povidone and 32.90 g of PEG 4000.
This gave a total solid amount of 193.6 g.
TABLE-US-00042 TABLE 30 Theoretical and Actual Tablet weights at 26
mg, 28 mg, 30 mg, and 32 mg weight gains for batch
BUP-HBr-XL-348mg-025-5. Weight Gain (mg) Theoretical Weight (mg)
Actual Weight (mg) 26.0 398.0 397.8 28.0 400.0 400.6 30.0 402.0
401.4 32.0 404.0 402.2
TABLE-US-00043 TABLE 31 Materials used in the Final coating and
their quantities for batch BUP-HBr-XL-348mg-025-5. % Contribution
Amount of % of to Total Batch Solid Solids in Materials Solution
Quantity (g) (g) Solution EUDRAGIT .RTM. 19.77 91.13 27.34 56.50*
L30D D-55 SYLOID .RTM. 244FP 3.15 14.52 14.52 30.00** CARBOWAX
.RTM. 0.95 4.36 4.36 9.00** 4000 Triethyl Citrate 0.47 2.17 2.17
4.50** Purified Water (1) 21.70 100.00 N/A N/A Purified Water (2)
53.96 248.77 N/A N/A Total 100.00 460.95 48.39*** 100.00 *The
percentage of EUDRAGIT .RTM., solid, that contributed to the total
amount of solid was 65%. **The percentage of SYLOID .RTM., CARBOWAX
.RTM. 4000 and Triethyl Citrate that contributed to the total
amount of solid was 30%, 9% and 4.5%, respectively. This gave a
total of 43.5%. ***The Total amount of solid (48.39 g) was 10.5% of
the total solution.
TABLE-US-00044 TABLE 32 Theoretical and Actual Tablet weights at 4
mg, 5 mg, 6 mg, and 7 mg weight gains for batch
BUP-HBr-XL-348mg-025-5. Weight Gain (mg) Theoretical Weight (mg)
Actual Weight (mg) 4.0 408.0 408.3 5.0 409.0 408.8 6.0 410.0 409.5
7.0 411.0 411.1
TABLE-US-00045 TABLE 33 Materials used in the ethylcellulose
coating and their quantities for batch BUP-HBr-XL-348mg-026-5. %
Contribution Batch % of to Total Quantity Solids Materials Solution
(g) Solution* ETHOCEL .RTM. (ethylcellulose) 3.69 79.37 41.00
Standard 100 Premium Povidone USP 3.69 79.37 41.00 (KOLLIDON .RTM.
90F) PEG 4000 0.36 7.75 4.00 Dibutyl Sebacate, NF 1.26 27.11 14.00
Ethyl Alcohol 95% USP 91.00 1957.4 N/A Total 100.00 2151.00 100.00
*Total Solid included 79.37 g of ETHOCEL .RTM., 79.37 g of
Povidone, 7.75 g of PEG 4000 and 27.11 g of Dibutyl Sebacate. This
gave a total solid amount of 193.6 g.
TABLE-US-00046 TABLE 34 Theoretical and Actual Tablet weights at 26
mg, 28 mg, 30 mg, and 32 mg weight gains for batch BUP-HBr-XL-348
mg-026-5. Weight Gain (mg) Theoretical Weight (mg) Actual Weight
(mg) 26.0 398.0 398.8 28.0 400.0 400.5 30.0 402.0 402.5 32.0 404.0
403.6
TABLE-US-00047 TABLE 35 Materials used in the ethylcellulose
coating and their quantities for batch BUP-HBr-XL-174 mg-027-5. %
Contri- bution Batch % of to Total Quantity Solid in Materials
Solution (g) Solution* ETHOCEL .RTM. (ethylcellulose) 3.69 138.87
41.00 Standard 100 Premium Povidone USP (KOLLIDON .RTM. 90F) 3.78
142.25 42.00 PEG 4000 1.53 57.58 17.00 Ethyl Alcohol 95% USP 91.00
3424.63 N/A Total 100.00 3763.33 100.00 *Total Solid included
138.87 g of ETHOCEL .RTM., 142.25 g of Povidone and 57.58 g of PEG
4000. This gave a total solid amount of 338.7 g.
TABLE-US-00048 TABLE 36 Theoretical and Actual Tablet weights at 22
mg, 24 mg, and 26 mg weight gains for batch BUP-HBr-XL-174
mg-027-5. Weight Gain (mg) Theoretical Weight (mg) Actual Weight
(mg) 22.0 208.0 207.7 24.0 210.0 210.8 26.0 212.0 212.4
TABLE-US-00049 TABLE 37 Materials used in the Final coating and
their quantities for batch BUP-HBr-XL-174 mg-027-5. % Contri-
bution Batch Amount % of to Total Quantity of Solid Solids in
Materials Solution (g) (g) Solution EUDRAGIT .RTM. 19.77 182.27
54.68 56.5* L30D D-55 SYLOID .RTM. 244FP 3.15 29.03 29.03 30.0**
CARBOWAX .RTM. 4000 0.95 8.71 8.71 9.0** Triethyl Citrate 0.47 4.35
4.35 4.5** Purified Water (1) 21.70 200.00 N/A N/A Purified Water
(2) 53.98 497.26 N/A N/A Total 100.00 921.62 96.77*** 100.00 *The
percentage of EUDRAGIT .RTM., solid, that contributed to the total
amount of solid was 56.5%. **The percentage of SYLOID .RTM.,
CARBOWAX .RTM. 4000 and Triethyl Citrate that contributed to the
total amount of solid was 30.0%, 9.0% and 4.5%, respectively. This
gave a total of 43.5%. ***The Total amount of solid (9.77 g) was
10.5% of the total solution.
TABLE-US-00050 TABLE 38 Theoretical and Actual Tablet weights at 4
mg, 5 mg, 6 mg, and 7 mg weight gains for batch BUP-HBr-XL-174
mg-027-5. Weight Gain (mg) Theoretical Weight (mg) Actual Weight
(mg) 4.0 216.0 216.6 5.0 217.0 217.6 6.0 218.0 217.8 7.0 219.0
219.8
TABLE-US-00051 TABLE 39 Bupropion Hydrobromide Polymorphs Cosolvent
Yield K.F. Trial Solvent (voll.) (voll.) (%) Form (%) Notes 085 IPA
+ HBr gas I 0.07 Standard procedure 097 Water 2 / 72 I 0.06 098A
Methanol 2.4 / II 0.13 098B Acetone 17 water 0.7 24 II 0.16 099
Ethanol / 56 III 0.12 abs. 4.8 100 IPA 15.1 / 77 I 0.11 102 AcOi-Pr
20 MeOH 3.6 26 I 0.25 108 Acetonitrile 20 / 70 I 0.14 109 Dichloro-
/ 25 II 0.21 methane 30 110 Water 2 HBr 48% 1 83 I 0.12 111 IPA 6
HBr 48% 1 69 I 0.32 112 MTBE 10 MeOH 3 67 I 0.18 113 Toluene 10
MeOH 1.25 40 II 0.39 114 DMC 10 MeOH 1.75 67 II 0.17 115 t-BuOH 20
Water 0.55 74 I 0.15 116 Form I in rotavapor I 0.45 100.degree. C.
24 h 117 IPA 10 Water 0.125 88 I 0.32 118 Toluene 10 MeOH 1.15 99 I
0.16 119 IPA 8 MeOH 1.32 83 I 0.47 120 Sec-BuOH 25 / 89 I 0.13 122
Water 8 / I 1.3 Spray dried
TABLE-US-00052 TABLE 40 Solvents used during the polymorph
screening experiments Solvent ID MP .degree. C. BP .degree. C.
Polarity (.epsilon.) Diethyl Ether DEE -116 35 4.34 Dichloromethane
DCM -97 40 9.08 Acetone ACT -94 56 20.7 Chloroform CHF -63 61 4.81
Methanol MET -98 65 33 n-Hexane NHX -95 69 2.02 Ethyl Acetate ETA
-84 75 6.02 Ethanol ETH -114 78 24.3 1,2-Dimethoxy Ethane DMX -58
82 7.2 Water H20 0 100 78.54 Nitromethane NMT -29 101 35.9
1,4-Dioxane DIX 11 101 2.21 Acetonitrile ACN -48 82 36.6 p-Xylene
PXY 13 138 2.27 2-Methoxy Ethanol 2MX -85 124 -- 1-Butanol 1BT -90
116 17.8 DMSO DMS 17 189 47.2 DMF DMF -61 153 38.3 1-Propanol 1PR
-127 97 20.1 Ethyl Formate EFM -80 54 7.1 t-Butyl Methyl Ether BME
-109 55 -- Methyl Acetate MAC -98 56.9 6.7 Tetrahydrofuran THF -108
65 7.52 Iso-Propyl Ether IPE -85 68 3.9 Methyl Ethyl Ketone MEK -87
80 18.5 Cyclohexane CHX 5 81 2.02 2-Propanol 2PR -90 82 18.3
Tert-Butanol TBT 24 83 12.5 Isopropyl Acetate IPA -73 89 -- Propyl
Acetate PAC -95 97 6.3 (.+-.) 2-Butanol 2BT -115 98 18.7
3-Pentanone 3PN -39 100 17.3 2-Methyl-1-Propanol MPR -108 108 --
Toluene TOL -93 110 2.38 Diethyl Carbonate DEC -43 126 --
Mesitylene MST -45 164 3.4 Benzonitrile BNT -13 188 26 Benzyl
Alcohol ABZ -13 203 13 Ethyl Benzoate EBZ -34 212 6
TABLE-US-00053 TABLE 41 Qualitative Solubility Solubility at
Solubility at Solvent Room Temp (RT) High Temp (HT) 1,2-Dimethoxy
Ethane Low Low 1-Butanol High -- 1-Propanol High -- 2-Methoxy
Ethanol High -- Acetone Low Low Acetonitrile High -- Chloroform
High -- Dichloromethane High -- Diethyl Ether Low Low Dioxane Low
High Dimethil sulfoxyde High -- Ethanol High -- Ethyl Acetate Low
Low Methanol High -- n-Hexane Low Low Nitromethane High -- p-Xylene
Low Low Water High -- (.+-.) 2-Butanol Low High
1-Methyl-2-Pyrrolidone High -- 1-Octanol Low Low
2-Methyl-1-Propanol High -- 2-Propanol High -- 3-Pentanone Low Low
4-Methyl-2-Pentanone Low Low Benzonitrile Low Low Benzyl Alcohol
High -- Cyclohexane Low Low Diethyl Carbonate Low Low Dimethyl
Formamide High -- Ethyl Benzoate Low Low Ethyl Formate Low Low
Isopropyl Acetate Low Low Iso-Propyl-Ether Low Low Mesitylene Low
Low Methyl Benzoate Low Low Methyl Ethyl Ketone Low Low
Methyl-Cyclohexan Low Low n-Hexan Low Low Nitrobenezene Low Low
Propyl Acetate Low Low t-Butyl Methyl Ether Low Low Tert-Butanol
Low Low Tetrahydrofuran Low Low Toluene Low Low Low: a large amount
of solid remains in suspension. Med: solid is not totally solved.
High: clear solution without solid suspended.
TABLE-US-00054 TABLE 42 Recrystallization Results Evaporation of
Bupropion Hydrobromide at Room Temperature Solvent
Recrystallization Result (Form) Acetonitrile Form I Acetone Form I
Chloroform Form IV Dichloromethane Form I 1,4-Dioxane Form I Ethyl
Acetate Form I Ethanol Form I Water Form I Methanol Form I
Nitromethane Form I p-Xylene Amorphous (.+-.)2-Butanol Form II
2-Methyl-1-Propanol Form I 2-Propanol Form I 3-Pentanone Form II
4-Methyl-2-Pentanone Form I Benzonitrile Form VII Diethyl Carbonate
Form I Dimethyl Formamide Form I Ethyl Formate Form I Isopropyl
Acetate Form I Mesitylene Amorphous Methyl Benzoate Form VII Methyl
Ethyl Ketone Form I Propyl Acetate Form I Tert-Butanol Form I
Tetrahydrofuran Form I
TABLE-US-00055 TABLE 43 Recrystallization Results Evaporation of
Bupropion Hydrobromide at Low Temperature (4.degree. C.) Solvent
Recrystallization Result (Form) Acetonitrile Form I Acetone Form I
Chloroform Form I Dichloromethane Form I 1,4-Dioxane Form I Ethyl
Acetate Form I Ethanol Form I Water Form I Methanol Form I
Nitromethane Form I p-Xylene Amorphous 2-Propanol Form I
3-Pentanone Form II Ethyl Formate Form I Isopropyl Acetate Form I
Methyl Ethyl Ketone Form I Propyl Acetate Form I Tetrahydrofuran
Form I
TABLE-US-00056 TABLE 44 Recrystallization Results Evaporation of
Bupropion Hydrobromide at High Temperature (60.degree. C.) Solvent
Recrystallization Result (Form) 1-Butanol Form I 1-Propanol Form I
2-Methoxy Ethanol Form I Acetonitrile Form I 1,4-Dioxane Form I
DMSO Form I 1,2-Dimethoxy Ethane Form I Water Form I Nitromethane
Form I p-Xylene Amorphous Methyl Ethyl Ketone Form I 2-Propanol
Form I Tert-Butanol Form I Isopropyl Acetate Form I Propyl Acetate
Form I (.+-.)2-Butanol Form I 3-Pentanone Form I
2-Methyl-1-Propanol Form I Diethyl Carbonate Form I Dimethyl
Formamide Form VII Benzonitrile Form VII Nitrobenzene Form I + VII
Ethyl Benzoate Form VII
TABLE-US-00057 TABLE 45 Recrystallization Results Evaporation of
Bupropion Hydrobromide at Low Pressure Solvent Recrystallization
Result (Form) Dichloromethane Form I Ethyl Formate Form I 2-Methoxy
Ethanol Form I Methyl Acetate Form I Chloroform Form I Methanol
Form I Ethanol Form I Methyl Ethyl Ketone Form I 2-Propanol Form I
Acetonitrile Form I Isopropyl Acetate Form I 1-Propanol Form I
Water Form I Ethyl Acetate Form I + VI 1,2-Dimetoxy Ethane Form I
Tert-Butanol Form I Propyl Acetate Form I (.+-.)2-Butanol Form
I
TABLE-US-00058 TABLE 46 Form I Slurries Results - 7 days At Room
Temperature Solvent Slurry Result Ethyl acetate Form II n-Hexan
Form II p-Xylene Form II 1,2-Dimethoxy Ethane Form II Acetone Form
II Diethyl ether Form II 1,4-Dioxane Form V 1-Octanol Form II
3-Pentanone Form II 4-Methyl-2-Pentanone Form II Benzonitrile Form
II + VII Cyclohexane Form I Diethyl Carbonate Form II Ethyl
Benzoate Form II Ethyl Formate Form II Isopropyl Acetate Form II
Iso-Propyl Ether Form II Mesitylene Form II Methyl Benzoate Form II
Methyl Ethyl Ketone Form II Methyl-Cyclohexane Form I Nitrobenzene
Form II Propyl Acetate Form II t-Butyl Methyl Ether Form II
Tert-Butanol Form II Tetrahydrofuran Form II Toluene Form II
TABLE-US-00059 TABLE 47 Form I Slurries Results - 30 days At Room
Temperature Solvent Slurry Result Ethyl acetate Form II n-Hexan
Form II p-Xylene Form II 1-Octanol Form II Acetone Form II t-Butyl
Methyl Ether Form II Toluene Form II 4-Methyl-2-Pentanone Form II
Methyl-Cyclohexane Form II Methyl Ethyl Ketone Form II Methyl
Benzoate Form II Cyclohexane Form II Ethyl Formate Form II
Isopropyl Acetate Form II Ethyl Acetate Form II Iso-Propyl Ether
Form II Diethyl Carbonate Form II Diethyl Ether Form II
1,2-Dimethoxy Ethane Form II 1,4-Dioxane Form V Tetrahydrofuran
Form II + VII
TABLE-US-00060 TABLE 48 Form I + Form II Slurries Results - 7 days
At Room Temperature Solvent Slurry Result Ethyl acetate Form II
n-Hexan Form II p-Xylene Form II 1,2-Dimethoxy Ethane Form II
Acetone Form II Diethyl Ether Form II 1,4-Dioxane Form V
TABLE-US-00061 TABLE 49 Form II + Form III Slurries Results - 7
days At Room Temperature Solvent Slurry Result Ethyl acetate Form
II n-Hexan Form II p-Xylene Form II 1,2-Dimethoxy Ethane Form II
Acetone Form II Diethyl Ether Form II 1,4-Dioxane Form V
TABLE-US-00062 TABLE 50 Form II + Form IV Slurries Results - 7 days
At Room Temperature Solvent Slurry Result Ethyl acetate Form II
n-Hexan Form II p-Xylene Form II 1,2-Dimethoxy Ethane Form II
Acetone Form II Diethyl Ether Form II 1,4-Dioxane Form V
TABLE-US-00063 TABLE 51 Form II + Form V Slurries Results - 7 days
At Room Temperature Solvent Slurry Result Ethyl acetate Form II
n-Hexan Form II p-Xylene Form II 1,2-Dimethoxy Ethane Form II
Acetone Form II Diethyl Ether Form II 1,4-Dioxane Form V
TABLE-US-00064 TABLE 52 Form II + Form VI Slurries Results - 7 days
At Room Temperature Solvent Slurry Result Ethyl acetate Form II
n-Hexan Form II p-Xylene Form II 1,2-Dimethoxy Ethane Form II
Acetone Form II Diethyl Ether Form II 1,4-Dioxane Form V
TABLE-US-00065 TABLE 53 Form II + Form VII Slurries Results - 7
days At Room Temperature Solvent Slurry Result Ethyl acetate Form
II n-Hexan Form II p-Xylene Form II 1,2-Dimethoxy Ethane Form II
Acetone Form II Diethyl Ether Form II 1,4-Dioxane Form V
TABLE-US-00066 TABLE 54 Form I Precipitation Results By
Anti-Solvent (Ethyl Acetate) addition at Room Temperature Solvent
Precipitation Result Dichloromethane Form I 1-Butanol Form I
1-Propanol Form I 2-Methoxy Ethanol Form I Dimethylformamide Form I
Chloroform Form II Ethanol Form I Methanol Form I
1-Methyl-2-Pyrrolidone Form I 2-Methyl-1-Propanol Form I 2-Propanol
Form I Benzyl Alcohol Form II
TABLE-US-00067 TABLE 55 Form I Precipitation Results By
Oversaturated Solution at 100.degree. C. Solvent Precipitation
Result Water Form I Nitromethane Form I p-Xylene Form I 1-Butanol
Form I 1-Propanol Form VI 2-Methoxy Ethanol Form I Dimethyl
sulfoxyde Form I Dimethyl formamide Form I 1,4-Dioxane Form V
2-Methyl-1-Propanol Form I 1-Methyl-2-Pyrrolidone Form I
(.+-.)2-Butanol Form I
TABLE-US-00068 TABLE 56 Form I Characterization Peak List: Pos.
Height FWHM d-spacing Rel. Int. [.degree.2Th.] [cts] [.degree.2Th.]
[.ANG.] [%] 6.6956 441.99 0.1171 13.20171 6.25 12.5142 1078.18
0.0669 7.07347 15.24 13.8338 495.49 0.0836 6.40157 7.01 14.1418
494.24 0.0836 6.26283 6.99 14.7981 708.72 0.1004 5.98651 10.02
18.7980 129.44 0.1338 4.72073 1.83 19.6003 959.53 0.0836 4.52928
13.57 21.2026 258.33 0.0669 4.19048 3.65 22.9330 604.92 0.1004
3.87806 8.55 23.6006 223.99 0.1171 3.76985 3.17 23.9869 597.98
0.1338 3.71000 8.45 24.3037 347.66 0.1004 3.66236 4.92 24.7629
271.46 0.2676 3.59547 3.84 25.5127 530.63 0.0669 3.49147 7.50
26.1117 7073.02 0.1338 3.41273 100.00 26.8429 162.01 0.0502 3.32140
2.29 27.2174 261.03 0.0669 3.27654 3.69 27.5656 85.43 0.1004
3.23594 1.21 28.4838 255.21 0.1171 3.13368 3.61 28.9551 94.43
0.1338 3.08374 1.34 29.4381 462.52 0.0836 3.03423 6.54 30.6366
159.60 0.1338 2.91821 2.26 31.5518 511.29 0.0669 2.83562 7.23
32.3505 143.17 0.1004 2.76741 2.02 32.7014 2460.48 0.1020 2.73625
34.79 32.7926 1562.72 0.0612 2.73564 22.09 33.8601 103.38 0.1224
2.64522 1.46 34.5527 153.32 0.1632 2.59377 2.17 35.5727 437.91
0.0612 2.52170 6.19 37.0456 106.77 0.2448 2.42475 1.51 37.8227
51.80 0.2856 2.37669 0.73 38.7631 92.78 0.1632 2.32117 1.31
TABLE-US-00069 TABLE 57 Form II Characterization Peak List: Pos.
Height FWHM d-spacing Rel. Int. [.degree.2Th.] [cts] [.degree.2Th.]
[.ANG.] [%] 6.5301 1078.87 0.1171 13.53592 54.01 12.1839 56.28
0.2007 7.26445 2.82 13.0302 341.23 0.3011 6.79449 17.08 14.1804
144.73 0.1338 6.24587 7.24 15.9162 237.30 0.1171 5.56838 11.88
16.5218 194.05 0.2007 5.36561 9.71 18.0133 104.98 0.2007 4.92457
5.26 18.8275 105.92 0.2007 4.71341 5.30 19.2806 106.21 0.2342
4.60365 5.32 20.6685 123.77 0.1004 4.29754 6.20 21.6359 140.14
0.1004 4.10752 7.01 21.9490 600.59 0.1171 4.04962 30.06 23.1059
1727.56 0.1506 3.84943 86.48 24.1802 175.85 0.1338 3.68077 8.80
25.7472 1691.24 0.0612 3.45734 84.66 25.8320 1997.69 0.0502 3.44904
100.00 26.8343 428.10 0.1004 3.32245 21.43 27.1433 175.53 0.1338
3.28532 8.79 27.8691 210.21 0.1506 3.20139 10.52 28.8111 507.17
0.1171 3.09883 25.39 29.6743 86.27 0.1338 3.01062 4.32 30.0692
343.86 0.0836 2.97197 17.21 31.8185 276.39 0.1673 2.81246 13.84
32.4172 421.65 0.0669 2.76188 21.11 33.2620 194.88 0.1673 2.69364
9.76 34.0877 90.26 0.2007 2.63025 4.52 34.8735 115.88 0.1338
2.57277 5.80 38.0294 133.57 0.1673 2.36621 6.69 38.7493 332.79
0.0669 2.32389 16.66 39.1289 148.12 0.1338 2.30222 7.41
TABLE-US-00070 TABLE 58 Form III Characterization Peak List: Pos.
Height FWHM d-spacing Rel. Int. [.degree.2Th.] [cts] [.degree.2Th.]
[.ANG.] [%] 8.0596 279.60 0.0669 10.97017 14.71 12.2853 367.57
0.1004 7.20473 19.34 12.8315 58.26 0.2007 6.89923 3.07 13.2434
71.14 0.1338 6.68559 3.74 15.2149 203.50 0.1171 5.82344 10.71
15.6269 312.41 0.1004 5.67081 16.44 16.0036 698.13 0.1004 5.53819
36.73 18.0692 1900.51 0.0836 4.90946 100.00 19.6718 224.36 0.0836
4.51297 11.81 20.6861 27.67 0.4015 4.29392 1.46 21.3980 87.79
0.2007 4.15264 4.62 22.7526 276.24 0.0502 3.90839 14.54 23.4234
433.75 0.3346 3.79796 22.82 24.2420 612.88 0.0669 3.67154 32.25
25.1221 1338.52 0.0836 3.54487 70.43 25.4298 765.07 0.0502 3.50267
40.26 26.5814 122.23 0.1673 3.35348 6.43 28.0071 89.35 0.2676
3.18593 4.70 28.9857 194.62 0.3011 3.08056 10.24 29.6568 289.74
0.1673 3.01236 15.25 30.6470 164.56 0.1338 2.91724 8.66 31.5990
64.65 0.2676 2.83150 3.40 32.3908 215.03 0.1338 2.76407 11.31
33.1938 318.21 0.0669 2.69901 16.74 34.0570 126.02 0.2676 2.63255
6.63 34.8593 60.37 0.2007 2.57379 3.18 36.3049 160.14 0.1338
2.47455 8.43 37.2156 100.45 0.2676 2.41606 5.29
TABLE-US-00071 TABLE 59 Form IV Characterization Peak List: Pos.
Height FWHM d-spacing Rel. Int. [.degree.2Th.] [cts] [.degree.2Th.]
[.ANG.] [%] 4.2724 62.71 0.8029 20.68230 10.43 10.7161 108.51
0.1673 8.25595 18.04 12.0264 176.45 0.2007 7.35926 29.34 12.4816
210.22 0.1673 7.09184 34.95 14.1738 202.54 0.1673 6.24875 33.68
14.8827 252.70 0.1338 5.95267 42.01 16.2511 79.85 0.2676 5.45440
13.28 16.8644 150.41 0.2007 5.25738 25.01 17.1048 104.89 0.1004
5.18404 17.44 17.8687 303.47 0.1673 4.96408 50.46 18.7619 119.28
0.2342 4.72973 19.83 19.2392 97.51 0.2342 4.61345 16.21 20.0869
283.86 0.2342 4.42063 47.19 21.7601 248.87 0.1673 4.08436 41.38
22.8957 601.46 0.1004 3.88428 100.00 23.8771 324.04 0.1338 3.72681
53.88 24.4544 410.44 0.2342 3.64013 68.24 25.5250 477.75 0.2007
3.48982 79.43 25.9015 275.99 0.1004 3.43995 45.89 29.1312 52.91
0.4015 3.06550 8.80 30.5089 258.69 0.2007 2.93014 43.01 32.0377
76.71 0.4684 2.79372 12.75 32.5333 42.72 0.2676 2.75228 7.10
33.0116 63.93 0.2342 2.71349 10.63 34.3203 34.09 0.5353 2.61296
5.67 35.9170 107.99 0.2007 2.50038 17.95 37.7676 59.12 0.2676
2.38201 9.83 38.5403 42.22 0.4015 2.33601 7.02
TABLE-US-00072 TABLE 60 Form V Characterization Peak List: Pos.
Height FWHM d-spacing Rel. Int. [.degree.2Th.] [cts] [.degree.2Th.]
[.ANG.] [%] 7.4871 204.47 0.1004 11.80774 28.74 11.8387 410.79
0.1338 7.47548 57.73 12.1526 209.30 0.1338 7.28311 29.42 14.9302
611.31 0.2007 5.93382 85.92 15.1873 422.88 0.1171 5.83395 59.43
17.3545 711.51 0.1171 5.10998 100.00 17.6294 576.40 0.1338 5.03095
81.01 19.5302 48.43 0.2007 4.54538 6.81 20.8970 102.38 0.6022
4.25107 14.39 22.4834 278.31 0.3346 3.95457 39.11 23.0890 609.75
0.1673 3.85220 85.70 23.3165 586.83 0.1338 3.81512 82.48 23.9911
280.63 0.2676 3.70936 39.44 24.9295 418.94 0.2676 3.57182 58.88
25.4770 303.12 0.2676 3.49628 42.60 27.1047 244.42 0.1673 3.28991
34.35 27.2757 253.41 0.1004 3.26968 35.62 28.8668 449.81 0.1171
3.09297 63.22 29.1165 459.78 0.1171 3.06701 64.62 30.2032 224.45
0.3346 2.95910 31.55 31.2523 110.46 0.4015 2.86211 15.52 32.1235
138.52 0.4015 2.78645 19.47 33.0720 178.41 0.3011 2.70868 25.07
35.2183 65.08 0.2676 2.54837 9.15 35.7909 62.54 0.2676 2.50890 8.79
36.5174 66.19 0.2007 2.46064 9.30 37.1599 52.08 0.5353 2.41956
7.32
TABLE-US-00073 TABLE 61 Form VI Characterization Peak List: Pos.
Height FWHM d-spacing Rel. Int. [.degree.2Th.] [cts] [.degree.2Th.]
[.ANG.] [%] 7.8496 1580.05 0.0836 11.26324 67.30 11.8964 1854.21
0.0836 7.43939 78.98 12.6410 202.90 0.0836 7.00278 8.64 15.0380
777.82 0.0836 5.89152 33.13 15.2810 1173.32 0.0836 5.79841 49.98
15.5243 1225.24 0.0836 5.70807 52.19 16.1145 164.99 0.0669 5.50030
7.03 17.6095 2347.80 0.1004 5.03657 100.00 19.0798 169.45 0.1004
4.65165 7.22 19.3067 302.45 0.0836 4.59748 12.88 20.3324 103.42
0.1171 4.36782 4.40 21.1331 526.05 0.1004 4.20409 22.41 22.4375
700.44 0.1004 3.96257 29.83 22.9995 1347.34 0.1004 3.86699 57.39
23.3043 684.79 0.1004 3.81710 29.17 23.7841 1744.10 0.1171 3.74117
74.29 24.5054 230.40 0.1004 3.63266 9.81 24.7579 434.11 0.1004
3.59618 18.49 25.0253 1655.56 0.1171 3.55836 70.52 25.5033 344.02
0.1171 3.49274 14.65 26.0438 327.56 0.0669 3.42147 13.95 26.2753
170.54 0.1004 3.39185 7.26 26.6025 80.83 0.1338 3.35086 3.44
27.5096 292.81 0.1004 3.24241 12.47 28.1175 878.41 0.1171 3.17367
37.41 28.7048 251.20 0.0836 3.11006 10.70 29.0435 1318.15 0.1004
3.07456 56.14 29.4202 234.78 0.0836 3.03604 10.00 30.3099 340.86
0.0836 2.94892 14.52 30.9237 358.99 0.1338 2.89177 15.29 31.6783
193.78 0.1338 2.82459 8.25 32.0151 172.84 0.1338 2.79564 7.36
32.4820 165.13 0.1338 2.75651 7.03 32.8446 219.60 0.1673 2.72691
9.35 33.2526 169.79 0.1506 2.69437 7.23 33.7436 333.64 0.0669
2.65628 14.21 35.1498 145.85 0.1004 2.55317 6.21 35.4257 223.46
0.2342 2.53392 9.52 36.1195 160.13 0.1171 2.48682 6.82 36.6412
148.76 0.1004 2.45261 6.34 37.3742 134.83 0.1004 2.40617 5.74
38.9668 127.14 0.1004 2.31142 5.42
TABLE-US-00074 TABLE 62 Form VII Characterization Peak List: Pos.
Height FWHM d-spacing Rel. Int. [.degree.2Th.] [cts] [.degree.2Th.]
[.ANG.] [%] 9.8602 13202.67 0.0787 8.97058 64.80 13.8310 1102.79
0.0590 6.40286 5.41 18.6304 430.48 0.0590 4.76283 2.11 19.4724
20373.14 0.0590 4.55874 100.00 19.5919 19333.60 0.0590 4.53120
94.90 19.9962 629.82 0.0787 4.44048 3.09 20.2520 337.93 0.0590
4.38498 1.66 21.8775 1392.67 0.0590 4.06271 6.84 23.3213 545.78
0.0787 3.81436 2.68 24.0376 1305.06 0.0787 3.70229 6.41 25.9551
143.45 0.0984 3.43296 0.70 27.6781 626.31 0.0787 3.22304 3.07
28.1796 573.45 0.0787 3.16682 2.81 29.3112 8508.46 0.0720 3.04456
41.76 29.4207 10351.49 0.0394 3.03599 50.81 31.0133 836.93 0.0984
2.88362 4.11 32.6067 111.06 0.0984 2.74626 0.55 35.5593 84.45
0.1968 2.52471 0.41 36.8168 190.51 0.1771 2.44131 0.94 39.5031
2222.25 0.0590 2.28127 10.91
TABLE-US-00075 TABLE 63 Amorphouse Form Characterization Peak List:
Pos. Height FWHM d-spacing Rel. Int. [.degree.2Th.] [cts]
[.degree.2Th.] [.ANG.] [%] 14.2290 373.13 0.7673 6.21949 100.00
14.2645 186.57 0.7673 6.21949 50.00 17.1264 157.26 0.3914 5.17326
42.15 17.1692 78.63 0.3914 5.17326 21.07 18.7217 154.19 0.4789
4.73588 41.32 18.7686 77.09 0.4789 4.73588 20.66 21.8014 177.84
1.4698 4.07334 47.66 21.8563 88.92 1.4698 4.07334 23.83
TABLE-US-00076 TABLE 64 TGA - DSC Summary Polymorph DSC (onset
.degree. C.) TGA (mass change) Form I 236.81 -100.04% Form II
194.20 -- 236.65 -93.35% Form III 77.66 -6.06% 236.97 -85.54% Form
IV 149.89 -9.41% 233.14 83.89% Form V -- -4.58% 237.85 -90.5% Form
VI 235 -97.68% Form VII -- -6.58% -- -17.52% 268.7 -71.65%
* * * * *