U.S. patent application number 12/914478 was filed with the patent office on 2011-02-24 for mirtazapine solid dosage forms.
This patent application is currently assigned to WATSON LABORATORIES, INC.. Invention is credited to Salah U. Ahmed, Tahseen A. Chowdhury, Sudhir R. Gorukanti, Gandha V. Naringrekar.
Application Number | 20110046115 12/914478 |
Document ID | / |
Family ID | 43087247 |
Filed Date | 2011-02-24 |
United States Patent
Application |
20110046115 |
Kind Code |
A1 |
Ahmed; Salah U. ; et
al. |
February 24, 2011 |
Mirtazapine Solid Dosage Forms
Abstract
A non-effervescent, solid dosage form containing mirtazapine,
which is used to form mirtazapine pharmaceutical tablets. The
dosage form contains mirtazapine, a hydrophilic component, and at
least one lubricant. In some embodiments, the dosage forms contain
a salivating agent. Processes for producing mirtazapine orally
disintegrating tablets are also provided.
Inventors: |
Ahmed; Salah U.; (New City,
NY) ; Naringrekar; Gandha V.; (Princeton, NJ)
; Chowdhury; Tahseen A.; (Washington Township, NJ)
; Gorukanti; Sudhir R.; (Harriman, NY) |
Correspondence
Address: |
Florek & Endres PLLC
1156 Avenue of the Americas, Suite 600
New York
NY
10036
US
|
Assignee: |
WATSON LABORATORIES, INC.
Corona
CA
|
Family ID: |
43087247 |
Appl. No.: |
12/914478 |
Filed: |
October 28, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10902836 |
Aug 2, 2004 |
7838029 |
|
|
12914478 |
|
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|
60491279 |
Jul 31, 2003 |
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Current U.S.
Class: |
514/214.02 |
Current CPC
Class: |
A61K 9/0056 20130101;
A61K 9/2054 20130101; A61P 25/00 20180101; C07D 223/00
20130101 |
Class at
Publication: |
514/214.02 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61P 25/00 20060101 A61P025/00 |
Claims
1-41. (canceled)
42. A method of treating neurological disorders and diseases which
comprises administering a non-effervescent, orally disintegrating
mirtazapine tablet comprising: i) about 0.5% to about 10% of
mirtazapine; ii) about 35% to about 65% by weight of water-soluble
carbohydrate selected from the group consisting of mannitol,
xylitol, sorbitol, sucrose and combinations thereof; iii) about 15%
to about 35% by weight of a disintegrating agent selected from the
group consisting of crospovidone, croscarmelose sodium, sodium
starch glycolate and combinations thereof; iv) about 5% to about
15% by weight of microcrystalline cellulose; v) about 0.5% to about
4% by weight of at least one lubricant; vi) 0 to about 10% by
weight of a salivating agent; vii) optionally a coloring agent;
viii) optionally a flavoring agent; and ix) optionally a
sweetener.
43-51. (canceled)
52. The method of claim 42 wherein the tablet comprises 15 mg, 30
mg or 45 mg of mirtazapine and exhibits a hardness of about 1.5 kp
to about 3 kp, a hardness greater than 1.0 kp after exposure for 24
hours at 25.degree. C. and 60% relative humidity and greater than
about 0.8 kp after exposure for 60 minutes at 40.degree. C. and 75%
relative humidity.
53. The method according to claim 42 wherein the tablet
disintegrates in about 3 to about 8 seconds.
54. The method of claim 42 wherein the hardness of the tablet is
about 2 kp to about 3 kp.
55. The method of claim 42 wherein the tablet comprises: i) about
0.5% to about 10% by weight of mirtazapine; ii) about 35% to about
65% by weight of mannitol; iii) about 15% to about 35% by weight of
crospovidone; iv) about 5% to about 15% by weight of
microcrystalline cellulose; v) about 0.5% to about 4% by weight of
at least one lubricant; vi) 0 to about 10% by weight of a
salivating agent; vii) colloidal silicon dioxide; viii) optionally
a coloring agent; xi) optionally a flavoring agent; and x)
optionally a sweetener.
56. The method of claim 55 wherein the tablet comprises 15 mg, 30
mg or 45 mg of mirtazapine and exhibits a hardness of about 1.5 kp
to about 3 kp, a hardness greater than 1.0 kp after exposure for 24
hours at 25.degree. C. and 60% relative humidity and greater than
about 0.8 kp after exposure for 60 minutes at 40.degree. C. and 75%
relative humidity.
57. A method of treating neurological disorders and diseases which
comprises administering a non-effervescent, orally disintegrating
mirtazapine tablet prepared by a method consisting of: a) preparing
a dry mixture consisting of: i) about 0.5% to about 10% by weight
of mirtazapine; ii) about 35% to about 65% by weight of
water-soluble carbohydrate selected from the group consisting of
mannitol, xylitol, sorbitol, sucrose and combinations thereof; iii)
about 15% to about 35% by weight of a disintegrating agent selected
from the group consisting of crospovidone, croscarmelose sodium,
sodium starch glycolate and combinations thereof; iv) about 5 to
about 15% by weight of microcrystalline cellulose; v) about 0.5% to
about 4% by weight of at least one lubricant; vi) 0 to about 10% by
weight of a salivating agent; vii) optionally a coloring agent;
viii) optionally a flavoring agent; and ix) optionally a sweetener;
and b) compressing the dry mixture into 15 mg, 30 mg or 45 mg
mirtazapine tablets.
58. The method of claim 57 wherein the tablet exhibits a hardness
of about 1.5 kp to about 3 kp, a hardness greater than 1.0 kp after
exposure for 24 hours at 25.degree. C. and 60% relative humidity
and greater than about 0.8 kp after exposure for 60 minutes at
40.degree. C. and 75% relative humidity.
59. The method according to claim 57 wherein the tablet
disintegrates in about 3 to about 8 seconds.
60. The method of claim 57 wherein the hardness of the tablet is
about 2 kp to about 3 kp.
61. The method of claim 57 wherein the orally disintegrating
mirtazapine tablet is prepared by a method consisting of: a)
preparing a dry mixture consisting of: i) about 0.5% to about 10%
by weight of mirtazapine; ii) about 35% to about 65% by weight of
mannitol; iii) about 15% to about 35% by weight of crospovidone;
iv) about 5 to about 15% by weight of microcrystalline cellulose;
v) about 0.5% to about 4% by weight of at least one lubricant; vi)
0 to about 10% by weight of a salivating agent; vii) colloidal
silicon dioxide; viii) optionally a coloring agent; xi) optionally
a flavoring agent; and x) optionally a sweetener.
Description
[0001] The application claims the benefit of U.S. Provisional
Application No. 60/491,279, filed Jul. 31, 2003, which is herein
incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is generally related to solid dosage
forms of mirtazapine for the treatment of depression and other
neurological disorders and diseases.
[0004] 2. Related Art
[0005] Mirtazapine is the common name of the isomeric compound
1,2,3,4,10,14.beta.-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c]benzaze-
pine. The use of mirtazapine is well known for the treatment of
depression and the symptoms associated with depression including,
memory loss, changes in mood, insomnia, lethargy, increase or
decrease in weight, and anxiety.
[0006] Mirtazapine treats depression by antagonizing the adrenergic
5-HT2A, 5-HT3, and alpha 2 autoreceptors and alpha
2-heteroreceptors, and enhancing the release of norepinephrine and
5-HT1A-mediated serotonergic transmission. It is not known exactly
how mirtazapine accomplishes this function. It is also being
considered for the treatment of psychotic disorders and diseases
such as schizophrenia and movement disorders such as Parkinson's
tremors, as disclosed in U.S. Pat. No. 6,281,207. Mirtazapine can
be administered alone or with other pharmaceuticals such as
selective serotonin reuptake inhibitors (SSRIs), such as those
described in U.S. Pat. No. 5,977,099, or antipsychotic agents, such
as those described in U.S. Pat. No. 6,150,353.
[0007] Mirtazapine has been found to have limited drug interaction
and few side effects associated with many antidepressants such as
sexual dysfunction. The tetracylic compound is currently
manufactured through the methods described in U.S. Pat. No.
4,062,848, forming a racemic mixture of isomeric compounds.
[0008] Oral administration in the form of a conventional tablet,
pill or capsule constitutes the generally preferred route for
administration of pharmaceuticals, such as mirtazapine, since this
route is generally convenient and acceptable to patients.
Unfortunately such compositions may be associated with certain
disadvantages, particularly in the treatment of pediatric or
geriatric patients, who may dislike or have difficulty in
swallowing such compositions, or where administration of a
conventional tablet, pill or capsule is not feasible. It is highly
desirable, particularly in the treatment of acute conditions, that
pharmaceutical compositions have a rapid and consistent onset of
action combined with sustained activity and good
bioavailability.
[0009] Since a solid preparation such as an oral tablet requires
water for swallowing, a liquid dosage form is normally preferred
for the elderly, infants or patients who have difficulty in
swallowing. However, a liquid preparation has shortcomings
regarding difficulties in handling, especially in measuring an
accurate dosage, and that it is not suitable for drugs which are
unstable in a moist environment. Thus, an effort has been made to
develop a rapidly disintegrating tablet of drugs which can easily
disintegrate by the action of saliva.
[0010] For example, oral dosage forms have been developed including
effervescents which rapidly disintegrate in the mouth and provide
taste-masking. See Wehling et al., U.S. Pat. No. 5,178,878. These
dosage forms provide significant problems in terms of production,
storage, transport and during consumer usage. They are also
significantly more costly to produce than conventional tablets.
[0011] U.S. Pat. No. 5,178,878 discloses an effervescent tablet
which comprises microparticles of various active ingredients.
Effervescence is typically created by the formation of gas bubbles
upon a reaction of an alkali metal carbonate or carbonate source
with an acid or an acid source. The effervescence aids in the
complete disintegration of the tablet upon oral administration.
[0012] Mirtazapine is currently available in an effervescent oral
disintegrating tablet. However, effervescent tablets containing an
alkalizing agent are usually moisture sensitive, may be
incompatible with an acidic drug and require protection due to
their sensitivity to humidity. In addition, the manufacture of
effervescent tablets requires strict humidity controls.
[0013] Therefore, there is a need for an orally disintegrating
tablet of a pharmaceutical composition that does not require an
alkalizing agent such as a carbonate or bicarbonate; is compatible
with an acidic drug; is physically stable under humid conditions;
and is easier to manufacture.
SUMMARY OF THE INVENTION
[0014] In some embodiments, the invention provides a
non-effervescent, solid dosage form adapted for oral administration
to a mammal:
[0015] about 1 to about 60% by weight of mirtazapine;
[0016] about 1 to about 95% by weight of a hydrophilic component
selected from the group consisting of a water-soluble component, a
water-insoluble component, or combinations thereof, wherein the
water-soluble component is selected from the group consisting of
cellulose derivatives, polyol, water-soluble carbohydrate, a
component having a --CHOH group, hydroxypropyl cellulose, methyl
cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, a
component having a --CHCOOH group, tartaric acid, citric acid,
malic acid, succinic acid, sodium and potassium salts thereof, or
combinations thereof, wherein the water-soluble carbohydrate is
selected from the group consisting of mannitol, xylitol, sorbitol,
malitol, lacitol, erytritol, xylose, arabinose, pentose, galactose,
dextrose, inositol, sucrose, trehalose, or combinations thereof,
and wherein the water-insoluble component is selected from the
group consisting of microcrystalline cellulose, crospovidone,
croscarmelose sodium, sodium starch glycolate, AMBERLITE (Rohm and
Haas, Philadelphia, Pa.), calcium silicate, calcium trisilicate,
magnesium silicate, magnesium trisilicate, modified starches, or
combinations thereof;
[0017] up to about 5% by weight of at least one lubricant selected
from the group consisting of magnesium stearate, sodium stearyl
fumarate, calcium stearate, sodium stearate, stearic acid, talc,
hydrogenated vegetable oil, aluminum stearate, silica gel,
colloidal silicon dioxide, or combinations thereof;
[0018] wherein said dosage form does not rely upon effervescence
for disintegration of said dosage form;
[0019] wherein dissolution of said dosage form in a medium of 900
mL of 0.1 N HCl with a paddle speed of 50 rpm is greater than about
75% at five minutes; and
[0020] wherein the water-soluble and water-insoluble component are
provided in a weight ratio from about 20:80 to about 95:5.
[0021] In some embodiments, the solid dosage form further comprises
about 0.1 to about 30% by weight of at least one salivating agent
selected from the group consisting of mannitol, xylitol, tartaric
acid, citric acid, malic acid, fumaric acid, adipic acid, succinic
acid, sodium and potassium salts thereof, and combinations
thereof.
[0022] In some embodiments, the dosage form further comprises,
about 1 to about 50% of a first hydrophilic component selected from
a group consisting of cellulose derivatives, hydrophilic polymers,
polyvinyl pyrrolidone, and combinations thereof. In some
embodiments, the first hydrophilic component is selected from the
group consisting of microcrystalline cellulose, hydroxypropyl
cellulose, methyl cellulose, hydroxypropyl methyl cellulose,
polyvinyl pyrrolidone, and combinations thereof.
[0023] In some embodiments the dosage form comprises a component
having a negative heat of solution, the component selected from the
group consisting of mannitol, xylitol, sorbitol, sucrose, and
combinations thereof.
[0024] The solid dosage forms of the present invention do not rely
upon effervescence for release of the active agent since the
present dosage forms lack the base necessary for the
effervescent-causing reaction, i.e. the release of bicarbonate. In
some embodiments, the solid dosage forms of the present invention
have a have a dissolution of greater than 75% in five mins in a
medium of 900 mL of 0.1 N HCl with a paddle speed of 50 rpm. In
some embodiments, the solid dosage forms of the present invention
have a have a dissolution of greater than 95% in five mins in a
medium of 900 mL of 0.01 N HCl with a paddle speed of 50 rpm.
[0025] In some embodiments, the invention provides a process of
making a non-effervescent, solid dosage form adapted for oral
administration which comprises:
[0026] a) mixing about 1 to about 60% by weight of mirtazapine;
[0027] about 1 to about 95% by weight of a hydrophilic component
selected from the group consisting of a water-soluble component, a
water-insoluble component, or combinations thereof, wherein the
water-soluble component is selected from the group consisting of
cellulose derivatives, polyol, a component having a --CHOH group,
water-soluble carbohydrate, hydroxypropyl cellulose, methyl
cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, a
component having a --CHCOOH group, tartaric acid, citric acid,
malic acid, succinic acid, sodium and potassium salts thereof, and
combinations thereof, wherein the water-soluble carbohydrate is
selected from the group consisting of mannitol, xylitol, sorbitol,
malitol, lacitol, erytritol, xylose, arabinose, pentose, galactose,
dextrose, inositol, sucrose, trehalose, and combinations thereof,
and wherein the water-insoluble component is selected from the
group consisting of microcrystalline cellulose, crospovidone,
croscarmelose sodium, sodium starch glycolate, AMBERLITE, calcium
silicate, calcium trisilicate, magnesium silicate, magnesium
trisilicate, modified starches, and combinations thereof; and
[0028] up to about 5% by weight of at least one lubricant selected
from the group consisting of magnesium stearate, sodium stearyl
fumarate, calcium stearate, sodium stearate, stearic acid, talc,
hydrogenated vegetable oil, aluminum stearate, silica gel,
colloidal silicon dioxide, and combinations thereof in an agitator
to form a mixture;
[0029] b) followed by directly compressing the mixture to form a
pharmaceutical tablet,
[0030] wherein said tablet does not rely upon effervescence for
disintegration of said tablet, wherein dissolution of said dosage
form in a medium of 900 mL of 0.1 N HCl with a paddle speed of 50
rpm is greater than about 75% at five minutes, and wherein the
water-soluble and water-insoluble component are provided in a
weight ratio from about 20:80 to about 95:5.
[0031] In some embodiments, the process further comprises mixing,
about 1 to about 50% of a first hydrophilic component selected from
a group consisting of cellulose derivatives, hydrophilic polymers,
polyvinyl pyrrolidone, and combinations thereof. In some
embodiments, the first hydrophilic component is selected from the
group consisting of microcrystalline cellulose, hydroxypropyl
cellulose, methyl cellulose, hydroxypropyl methyl cellulose,
polyvinyl pyrrolidone, and combinations thereof.
[0032] Pharmaceutical tablets formed from this process are also
provided by the present invention. The solid dosage forms of the
present invention do not rely upon effervescence for release of the
active agent since the present dosage forms lack the base necessary
for the effervescent-causing reaction, i.e. the release of
bicarbonate. In some embodiments, the solid dosage forms of the
present invention have a have a dissolution of greater than 75% in
five mins in a medium of 900 mL of 0.1 N HCl with a paddle speed of
50 rpm. In some embodiments, the solid dosage forms of the present
invention have a have a dissolution of greater than 95% in five
mins in a medium of 900 mL of 0.01 N HCl with a paddle speed of 50
rpm.
[0033] In some embodiments, the invention provides a method of
treating neurological disorders and diseases including depression,
symptoms associated with depression including suicidal thoughts,
drowsiness, memory loss, anxiety, sleeplessness and others,
psychotic disorders and diseases such as schizophrenia and movement
disorders and diseases in a human which comprises administering the
solid dosage form of the present invention to a mammal in need
thereof.
[0034] Particularly, the present invention provides for mirtazapine
orally disintegrating tablets which do not rely upon effervescence
for release of the active agent. The non-effervescent, mirtazapine
tablets have various advantages over effervescent tablets. For
example, the present dosage form does not require an alkalizing
agent such as a carbonate or bicarbonate; a non-effervescent,
tablet is compatible with an acidic drug; the present
pharmaceutical tablet is more physically stable, less sensitive to
humidity, and thus are easier to package since they need not be
protected from moisture at all times; and the manufacture of the
present pharmaceutical tablets does not require the strict humidity
controls that effervescent tablets typically do.
[0035] In some embodiments, the hardness of the non-effervescent,
solid dosage forms is about 0.1 to about 5 kp. In some embodiments,
the hardness of the dosage forms is about 0.1 to about 3 kp. In
some embodiments, the hardness of the dosage forms is greater than
about 1.0 kp after exposure for 24 hours at 25.degree. C. and 60%
relative humidity, and is greater than about 0.8 kp after exposure
for 60 minutes at 40.degree. C. and 75% relative humidity.
[0036] In some embodiments the invention provides a
non-effervescent, solid dosage form, wherein the dosage form having
a first hardness being the dosage form inside a closed space,
wherein the dosage form having a second hardness being the dosage
form exposed to about 25.degree. C. and about 60% relative humidity
for about 24 hours, and wherein the second hardness is at least
about 50% of the first hardness. In some embodiments, the invention
provides, a non-effervescent, solid dosage form, wherein the dosage
form having a first hardness being the dosage form inside a closed
space, wherein the dosage form having a second hardness being the
dosage form exposed to about 40.degree. C. and about 75% relative
humidity for about 15 minutes, and wherein the second hardness is
at least about 50% of the first hardness.
[0037] Thus, an orally disintegrating tablet of a mirtazapine
pharmaceutical composition is provided which does not require an
alkalizing agent such as a carbonate or bicarbonate; is compatible
with an acidic drug; is physically stable under humid conditions;
and is easier to manufacture. The mirtazapine dosage form of the
present invention provides orally disintegrating tablets having a
high tolerance of humidity; maintain their physical integrity when
exposed to environmental conditions thus facilitating processing,
compressing and packaging; are more stable under harsh conditions;
and last longer when removed from packaging as compared to
reference mirtazapine tablets.
BRIEF DESCRIPTION OF THE FIGURES
[0038] FIG. 1 is a flow chart illustrating a dry-mixing process of
making some of the mirtazapine formulations according to the
present invention.
[0039] FIG. 2 is a dry-mixing process of making some of the
mirtazapine formulations of the present invention.
[0040] FIG. 3 is a graph showing the effect of temperature and
humidity on the 15 mg mirtazapine orally disintegrating tablets
provided in Table 8.
[0041] FIG. 4 is a graph showing the effect of temperature and
humidity on the 30 mg mirtazapine orally disintegrating tablets
provided in Table 8.
[0042] FIG. 5 is a graph showing the effect of temperature and
humidity on the 45 mg mirtazapine orally disintegrating tablets
provided in Table 8.
DETAILED DESCRIPTION OF THE INVENTION
[0043] Throughout the present document, all expressions of
percentage, ratio, and the like, will be in weight units unless
otherwise indicated.
[0044] The present invention contemplates solid oral dosage forms,
such as a pharmaceutical tablet containing mirtazapine. The dosage
forms of the present invention do not rely upon effervescence for
release of the active agent. The mirtazapine formulations
contemplated can employ a racemic mixture of mirtazapine or an
enantiomeric excess of, or a substantially pure enantiomer, i.e.,
R-mirtazapine and S-mirtazapine. See U.S. Pat. No. 4,062,848. As
will be appreciated by those skilled in the art, salts, hydrates,
solvates, and the like, could be employed in the present invention
to obtain the same beneficial effects as that provided by the base
form mirtazapine. Accordingly, as used herein, the term
"mirtazapine" contemplates all such forms, with a racemic mixture
of mirtazapine being preferred.
[0045] As used herein, the term "pharmaceutically effective" refers
to that amount of mirtazapine, which diminishes one or more
symptoms of the disease or disorder being treated. For example, a
pharmaceutically effective amount for the treatment of depression
refers to the amount which when administered diminishes one or more
symptoms of depression, such as insomnia or anxiety. The precise
therapeutic dosage of mirtazapine necessary to be pharmaceutically
active will vary with age, size, sex and condition of the subject,
the nature and severity of the disorder or disease to be treated,
and the like; thus, a precise pharmaceutically effective amount
cannot be specified in advance and will be determined by a
caregiver. However, appropriate amounts can be determined by
routine experimentation with animal models. In general terms, an
effective daily dose is about 5 to 50 milligrams (mg) per day per
human subject of mirtazapine. In some embodiments, an effective
daily dose is about 5 mg per day. In some embodiments, an effective
daily dose is about 10 mg per day. In some embodiments, an
effective daily dose is about 15 mg per day. In some embodiments,
an effective daily dose is about 30 mg per day. In some
embodiments, an effective daily dose is about 45 mg per day.
[0046] The term "tablet" as used herein is intended to encompass
compressed pharmaceutical dosage formulations of all shapes and
sizes, whether coated or uncoated.
[0047] As used herein, the term "excipient" refers to the additives
used to convert an active compound into a form suitable for its
intended purpose. For dosage forms of the present invention
suitable for administration to humans, the term "excipient" is
meant to include, but is not limited to, those ingredients
described in Remington: The Science and Practice of Pharmacy,
Lippincott Williams & Wilkins, 21.sup.st ed. (2004), which is
herein incorporated by reference in its entirety.
[0048] As used herein, the term "disintegration" refers to the loss
of integrity of the dosage forms of the invention to form granules
or aggregates or particles, as generally described in Remington:
The Science and Practice of Pharmacy, Lippincott Williams &
Wilkins, 21.sup.st ed. (2004).
[0049] As used herein, "dissolution" refers to the process by which
mirtazapine goes into solution from the solid dosage forms of the
invention.
[0050] As used herein, a "closed space" refers to the space within
a package or container such as a blister pack or foil-wrapped
package containing the solid dosage forms of the invention.
[0051] As used herein, "low humidity" refers to the conditions
provided by use of desiccated bags to control moisture or to
conditions inside a package such as a blister pack containing the
solid dosage forms of the invention.
[0052] In some embodiments, the invention provides a
non-effervescent, solid dosage form adapted for oral administration
to a mammal:
[0053] about 1 to about 60% by weight of mirtazapine;
[0054] about 1 to about 95% by weight of a hydrophilic component
selected from the group consisting of a water-soluble component, a
water-insoluble component, or combinations thereof, wherein the
water-soluble component is selected from the group consisting of
cellulose derivatives, polyol, water-soluble carbohydrate, a
component having a --CHOH group, hydroxypropyl cellulose, methyl
cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, a
component having a --CHCOOH group, tartaric acid, citric acid,
malic acid, succinic acid, sodium and potassium salts thereof, or
combinations thereof, wherein the water-soluble carbohydrate is
selected from the group consisting of mannitol, xylitol, sorbitol,
malitol, lacitol, erytritol, xylose, arabinose, pentose, galactose,
dextrose, inositol, sucrose, trehalose, or combinations thereof,
and wherein the water-insoluble component is selected from the
group consisting of microcrystalline cellulose, crospovidone,
croscarmelose sodium, sodium starch glycolate, AMBERLITE (Rohm and
Haas, Philadelphia, Pa.), calcium silicate, calcium trisilicate,
magnesium silicate, magnesium trisilicate, modified starches, or
combinations thereof;
[0055] up to about 5% by weight of at least one lubricant selected
from the group consisting of magnesium stearate, sodium stearyl
fumarate, calcium stearate, sodium stearate, stearic acid, talc,
hydrogenated vegetable oil, aluminum stearate, silica gel,
colloidal silicon dioxide, or combinations thereof;
[0056] wherein said dosage form does not rely upon effervescence
for disintegration of said dosage form;
[0057] wherein dissolution of said dosage form in a medium of 900
mL of 0.1 N HCl with a paddle speed of 50 rpm is greater than about
75% at five minutes; and
[0058] wherein the water-soluble and water-insoluble component are
provided in a weight ratio from about 20:80 to about 95:5. In some
embodiments, the dissolution of the dosage form in a medium of 900
mL of 0.01 N HCl with a paddle speed of 50 rpm is greater than
about 95% at five minutes.
[0059] In some embodiments, the dosage form further comprises about
0.1 to about 30% by weight of at least one salivating agent
selected from mannitol, tartaric acid, citric acid, malic acid,
fumaric acid, adipic acid, succinic acid, sodium and potassium
salts thereof, and combinations thereof.
[0060] In some embodiments, the dosage form further comprises,
about 1 to about 50% of a first hydrophilic component selected from
a group consisting of cellulose derivatives, hydrophilic polymers,
polyvinyl pyrrolidone, and combinations thereof. In some
embodiments, the first hydrophilic component is selected from the
group consisting of microcrystalline cellulose, hydroxypropyl
cellulose, methyl cellulose, hydroxypropyl methyl cellulose,
polyvinyl pyrrolidone, and combinations thereof.
[0061] The dosage forms of the present invention do not rely upon
effervescence for release of the active agent, need not contain an
alkalyzing agent, but can contain any other additives, colorings
and/or flavorings that are pharmaceutically acceptable. In some
embodiments, the dissolution rate of dosage forms of the present
invention, in a medium of 900 mL of 0.01 N HCl with a paddle speed
of 50 rpm, is greater than 95% at five minutes.
[0062] In some embodiments, the dosage form comprises about 0.5 to
about 40% mirtazapine, up to about 30% of at least one salivating
agent, about 5 to about 50% of a first hydrophilic component, about
10 to about 80% of a water-soluble carbohydrate, about 10 to about
50% of a disintegrating agent, and less than about 5% of at least
one lubricant.
[0063] In some embodiments, the dosage form comprises about 0.5 to
about 10% by weight of mirtazapine; up to about 10% by weight of at
least one salivating agent; about 5 to about 15% by weight of a
first hydrophilic component; about 35 to about 65% by weight of a
water-soluble carbohydrate; about 15 to about 35% by weight of a
disintegrating agent; and about 0.5 to about 4% by weight of at
least one lubricant.
[0064] In some embodiments, the dosage form comprises about 6%
mirtazapine, about 14.4% of one or more salivating agents, about 6%
of a first hydrophilic component, about 44% of a water-soluble
carbohydrate, about 24% of a disintegrating agent, and about 1.4%
of at least two lubricants.
[0065] The present invention contemplates the use of at least one
salivating agent source suitable for human consumption. Salivating
agents include organic compounds such as polyols and mild acids.
Examples of water-soluble carbohydrates and polyols which can be
used as salivating agents in the present invention are xylitol and
mannitol. Mild acids are used to adjust the pH, or acidity, of the
pharmaceutical composition and in some cases to provide flavoring.
A purpose of using a mild acid in the present composition is to
provide for a sour taste to stimulate saliva secretion, which helps
disintegrate the tablets. Acceptable mild acids are tartaric acid,
citric acid, malic acid, fumaric acid, adipic acid, succinic acid,
sodium and potassium salts thereof, and combinations thereof. Also
contemplated is the use of acid anhydrides and acid salts such as
sodium dihydrogen phosphate, disodium dihydrogen pyrophosphate,
acid citrate salts, and sodium acid sulfite. It is preferred that
either tartaric acid, citric acid, or both, or sodium or potassium
salts thereof, or combinations thereof are used in the present
formulation. Most preferred is a combination of tartaric acid, NF
and citric acid USP Anhydrous Powder.
[0066] Preferred water-soluble carbohydrates for use in the present
invention include but are not limited to mannitol, xylitol,
sorbitol, malitol, lacitol, erytritol, xylose, arabinose, pentose,
galactose, dextrose, inositol, sucrose, trehalose and mixtures
thereof, most preferably, mannitol USP available under the trade
name PARTECK M-200 (Merck KGaA, Darmstadt, Germany).
[0067] In some embodiments, the invention provides a solid dosage
form which further comprises a component having a negative heat of
solution selected from the group consisting of mannitol, xylitol,
sorbitol, sucrose, and combinations thereof.
[0068] The mirtazapine dosage form of the present invention neither
relies upon effervescence for release of the active agent nor aids
in its complete disintegration. Instead, the present invention
employs a disintegrating agent. Particularly useful disintegrating
agents are super-disintegrating agents such as crospovidone,
croscarmelose sodium, AMBERLITE (Rohm and Haas, Philadelphia, Pa.),
and sodium starch glycolate. The preferred disintegrating agent is
crospovidone, NF available under the trade name POLYPLASDONE XL
(ISP Technologies, Wayne, N.J.). Microcrystalline cellulose also
aids in disintegration by acting as a wicking agent. Wicking agents
take moisture from the ambient conditions and draws it into the
tablet to aid in dissolving the water soluble components. Types of
AMBERLITE (Rohm and Haas, Philadelphia, Pa.) resins for use in the
formulation include but are not limited to AMBERLITE IRP64,
AMBERLITE IRP69, AMBERLITE IRP88, and combinations thereof The
components of the present invention are sufficient for complete
disintegration without the use of effervescent agents. In some
embodiments, the dosage form further comprises an agent selected
from the group consisting of calcium silicate, magnesium silicate,
magnesium trisilicate, and combinations thereof. While not wishing
to be bound by a specific theory, it appears that the agent, such
as, calcium silicate, calcium trisilicate, magnesium trisilicate,
magnesium silicate, and combinations thereof, might act by
facilitating the disintegration action of the disintegrating agents
such as crospovidone. In some embodiments, the weight ratio of the
disintegrating agents such as crospovidone to that of agents such
as calcium silicate can range from 9:1 to 1:9.
[0069] The present invention contemplates the use of at least one
lubricant to assist in the removal of tablets from the dies during
tablet compression and to reduce the friction of particles. Common
hydrophobic lubricants suitable in the present formulation are:
magnesium stearate, sodium stearyl fumarate, calcium stearate,
sodium stearate, stearic acid, talc, hydrogenated vegetable oil,
aluminum stearate, silica gel, such as colloidal silicon dioxide,
and mixtures thereof The presence of at least one of the above
mentioned lubricants is contemplated in the present invention.
Preferred is a combination of magnesium stearate, NF and sodium
stearyl fumarate, NF. Sodium stearyl fumarate is commonly available
under the tradename PRUV (Penwest Pharmaceuticals Co., Patterson,
N.Y.).
[0070] In addition to the above mentioned ingredients, other
excipients can be added to the present composition. In particular,
coloring agents and flavoring agents can be added. Any coloring
suitable for oral ingestion, including natural synthetic coloring
such as F.D.& C. dyes, are appropriate in the present
invention. A natural or an artificial sweetener can be employed to
improve the taste of the tablet upon disintegration, such as
aspartame, sucralose, acesulfame potassium, sodium cyclamate,
saccharin and the like. In some embodiments, the sweetener is
aspartame. In addition, natural and artificial flavorings can be
added. The citrus flavorings, including but not limited to orange,
tangerine, lemon, lime, lemon-lime, citrus, and the like, are
particularly suited to combat the bitter taste of mirtazapine. In
some embodiments, orange flavor is preferred. In some embodiments,
strawberry flavor is preferred.
[0071] The pharmaceutical dosage forms of the present invention are
useful in the therapeutic treatment for patients suffering from
DSM-IV diagnosable disorders such as schizophrenia, Alzheimer's
Disease, autism, depression, benign forgetfulness, childhood
learning disorders, close head injury, and attention deficit
disorder. See U.S. Pat. No. 6,228,875. In addition, the mirtazapine
of the present invention can be used in treating movement disorders
such as Parkinsonian tremors, rubral tremors, post-traumatic
tremors, drug-induced tremors (e.g. induced by lithium or other
drug agents), cerebellar tremors associated with lesions of the
cerebellum or cerebellar outflow pathway, Tourette's syndrome
tremors and other peripheral neuropathy-associated tremors,
akathisias, asterixis, athetosis, choreaathetosis, tics,
chorea/choreaform movements, dystonias, spasticity, restless legs
syndrome, hyperkinetic movement disorders, hemiballismus,
myoclonus, tardive dyskinesia and other types of dyskinesia, and
sleep apnea disorders. See U.S. Pat. Nos. 6,281,207 and
6,303,595.
[0072] In addition, the mirtazapine dosage form can be used to
treat other mental disorders and diseases currently being treated
by antidepressants, such as, but not limited to, selective
serotonin reuptake inhibitors (SSRIs) such as depression (including
major depression (single episode, recurrent, melancholic),
atypical, dysthymia, subsyndromal, agitated, retarded, co-morbid
with cancer, diabetes, or post-myocardial infarction, involutional,
bipolar disorder, psychotic depression, endogenous, and reactive,
obsessive-compulsive disorder, bulimia. In addition, the
formulations can be used to treat people suffering from pain (given
alone or in combination with other pain relievers),
obsessive-compulsive personality disorder, post-traumatic stress
disorder, hypertension, atherosclerosis, anxiety, anorexia nervosa,
panic, social phobia, stuttering, sleep disorder, weight loss,
agoraphobia, improving memory, amnesia, smoking cessation, nicotine
withdrawal syndrome symptoms, disturbance of mood and/or appetite
associated with pre-menstrual syndrome, depressed mood and/or
carbohydrate craving associated with pre-menstrual syndrome,
disturbance of mood, disturbance of appetite or disturbances which
contribute to recidivism associated with nicotine withdrawal,
circadian rhythm disorder, borderline personality disorder,
hypochondriasis, pre-menstrual syndrome (PMS), late luteal phase
dysphoric disorder, pre-menstrual dysphoric disorder,
trichotillomania, symptoms following discontinuation of other
antidepressants, aggressive/intermittent explosive disorder,
compulsive gambling, compulsive spending, compulsive sex,
psychoactive substance abuse disorder, sexual disorder,
schizophrenia, premature ejaculation, or psychiatric symptoms such
as stress, worry, anger, rejection sensitivity, and lack of mental
or physical energy. See e.g., U.S. Pat. No. 6,150,353.
[0073] In some embodiments, the invention provides a process for
preparing a pharmaceutical tablet, the process comprising:
[0074] In some embodiments, the invention provides a process of
making a non-effervescent, solid dosage form adapted for oral
administration which comprises:
[0075] a) mixing about 1 to about 60% by weight of mirtazapine;
[0076] about 1 to about 95% by weight of a hydrophilic component
selected from the group consisting of a water-soluble component, a
water-insoluble component, or combinations thereof, wherein the
water-soluble component is selected from the group consisting of
cellulose derivatives, polyol, a component having a --CHOH group,
water-soluble carbohydrate, hydroxypropyl cellulose, methyl
cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone,
wherein the water-soluble carbohydrate is selected from the group
consisting of mannitol, xylitol, sorbitol, malitol, lacitol,
erytritol, xylose, arabinose, pentose, galactose, dextrose,
inositol, sucrose, trehalose, and combinations thereof, a component
having a --CHCOOH group, tartaric acid, citric acid, malic acid,
succinic acid, sodium and potassium salts thereof, and combinations
thereof, and wherein the water-insoluble component is selected from
the group consisting of microcrystalline cellulose, crospovidone,
croscarmelose sodium, sodium starch glycolate, AMBERLITE, calcium
silicate, calcium trisilicate, magnesium silicate, magnesium
trisilicate, modified starches, and combinations thereof; and
[0077] up to about 5% by weight of at least one lubricant selected
from the group consisting of magnesium stearate, sodium stearyl
fumarate, calcium stearate, sodium stearate, stearic acid, talc,
hydrogenated vegetable oil, aluminum stearate, silica gel,
colloidal silicon dioxide, and combinations thereof in an agitator
to form a mixture;
[0078] b) followed by directly compressing the mixture to form a
pharmaceutical tablet,
[0079] wherein said tablet does not rely upon effervescence for
disintegration of said tablet, wherein dissolution of said dosage
form in a medium of 900 mL of 0.1 N HCl with a paddle speed of 50
rpm is greater than about 75% at five minutes, and wherein the
water-soluble and water-insoluble component are provided in a
weight ratio from about 20:80 to about 95:5. In some embodiments,
the dissolution of the dosage form in a medium of 900 mL of 0.01 N
HCl with a paddle speed of 50 rpm is greater than about 95% at five
minutes.
[0080] In some embodiments, the process further comprises mixing,
about 1 to about 50% of a first hydrophilic component selected from
a group consisting of cellulose derivatives, hydrophilic polymers,
polyvinyl pyrrolidone, and combinations thereof. In some
embodiments, the first hydrophilic component is selected from the
group consisting of microcrystalline cellulose, hydroxypropyl
cellulose, methyl cellulose, hydroxypropyl methyl cellulose,
polyvinyl pyrrolidone, and combinations thereof.
[0081] The non-effervescent, solid dosage forms formed from the
present process have a hardness of from about 0.1 to about 5 kp. In
some embodiments, the hardness of the dosage forms can be 0.1 to
about 3 kp. In some embodiments, the hardness of the dosage forms
is greater than about 1.0 kp after exposure for 24 hours at
25.degree. C. and 60% relative humidity, and is greater than about
0.8 kp after exposure for 60 minutes at 40.degree. C. and 75%
relative humidity.
[0082] When the solid dosage forms of the invention such as the
tablets come off a tablet press, they are kept under low humidity
conditions by use of, e.g., desiccated bags to control the moisture
around the tablets. The tablets stored under desiccated conditions
are then packaged into blister packs under ambient controlled
conditions at temperatures of about 25.degree. C. and relative
humidity ranging from about 35% to about 60% relative humidity,
which results in a decrease in hardness of the tablet ranging from
about 0.1 to about 0.5 kp. While not wishing to be bound by any
specific theory, it is believed that because a low amount of air is
trapped inside a blister pack and around a packaged tablet, the
relative humidity of the atmosphere around a tablet inside a
blister pack is low. Moreover, the packaging materials used for
preparing the blister pack such as aluminum are impermeable to
moisture and maintain the conditions of low humidity around the
solid dosage forms for long periods of time.
[0083] When a user opens the package containing the solid dosage
form to consume the dosage form, then the dosage form is exposed to
conditions such as about 25.degree. C. and about 60% relative
humidity, or about 40.degree. C. and about 75% relative humidity,
or about 25.degree. C. and about 35% relative humidity, or other
ambient atmosphere, for periods of time whereby the hardness of the
solid dosage form decreases. However, the formulation of the dosage
form is such that even after exposure to conditions such as about
25.degree. C. and about 60% relative humidity for about 24 hours,
or about 40.degree. C. and about 75% relative humidity for about 15
min, or about 25.degree. C. and about 35% relative humidity for
about 24 hours, or about 25.degree. C. and about 35% relative
humidity for about 6 hours, or about 25.degree. C. and about 35%
relative humidity for about 1 hr, the hardness of the exposed
dosage form is at least about 50% of the hardness of the dosage
form when packed inside a package. This physical property of the
formulations of the invention whereby the dosage form retains its
hardness for a period of time after its removal from a package is
advantageous to users as patients do not have to consume the dosage
form as soon as they open a package. In some embodiments, the
package can be prepared under conditions including, but not limited
to low humidity, controlled temperature, low oxygen, inert
atmosphere, under nitrogen, in vacuum, and combinations
thereof.
[0084] In some embodiments, the invention provides, a
non-effervescent, solid dosage form, wherein the dosage form having
a first hardness being the dosage form inside a closed space,
wherein the dosage form having a second hardness being the dosage
form exposed to about 25.degree. C. and about 60% relative humidity
for about 24 hours, and wherein the second hardness is at least
about 50% of the first hardness. In some embodiments, the invention
provides a non-effervescent, solid dosage form, wherein the dosage
form having a first hardness being the dosage form inside a closed
space, wherein the dosage form having a second hardness being the
dosage form exposed to about 40.degree. C. and about 75% relative
humidity for about 15 minutes, and wherein the second hardness is
at least about 50% of the first hardness.
[0085] The disintegrating tablets must be made under generally
anhydrous conditions. To assist in the cohesion of dry ingredient,
it is helpful to include a hydrophilic component, which includes
water-soluble and water-insoluble components such as
microcrystalline cellulose, hydroxypropyl cellulose,
methylcellulose, hydroxypropyl methylcellulose, and polyvinyl
pyrrolidone. In some embodiments, the hydrophilic component is
microcrystalline cellulose, in particular, microcrystalline
cellulose NF available under the trade name AVICEL PH 101 (FMC
BioPolymer, Philadelphia, Pa.).
[0086] Some embodiments of the present invention are shown in Table
1.
TABLE-US-00001 TABLE 1 Mirtazapine Formulations Preferred More Most
Ingredient % (mg) Preferred/mg Preferred/mg Mirtazapine 6.0 1 to 60
1 to 30 1 to 10 Tartaric Acid 6.0 0 to 20 0 to 15 0 to 10
Microcrystalline 6.0 1 to 80 1 to 50 1 to 10 Cellulose Citric Acid
8.4 0 to 20 0 to 15 0 to 10 Aspartame 4.0 0.1 to 10 1 to 8 1 to 5
Orange Flavor 0.6 0 to 2.4 0 to 1.2 0 to 0.6 Mannitol 43.6 0 to 80
0 to 60 0 to 50 Crospovidone 24.0 3 to 50 5 to 40 10 to 30
Magnesium 0.6 0 to 5 0 to 3 0 to 1 Stearate Sodium Stearyl 0.8 0 to
5 0 to 3 0 to 1 Fumarate
[0087] A compressed tablet contemplated in the present invention
has a hardness of from about 0.1 to about 5 kiloponds (kp). In some
embodiments, the hardness of the tablets ranges from about 0.1 kp
to about 3 kp. In some embodiments, the hardness of the tablet is
about 2 kp.
[0088] FIG. 1 depicts a flow chart of a manufacturing process which
can be used to form pharmaceutical tablets of the pharmaceutical
composition of the present invention. Tartaric acid and
microcrystalline cellulose are mixed in an agitator; citric acid,
aspartame, orange flavoring, mirtazapine and mannitol are
subsequently added and mixed to form a mixture; crospovidone is
then transferred to the agitator and mixed in with the mixture
followed by subsequent additions of sodium stearyl fumarate and
magnesium stearate; the composition is mixed and the resultant
mixture is compressed to form mirtazapine pharmaceutical
tablets.
[0089] FIG. 2 depicts a flow chart of a dry mixing process to
prepare mirtazapine orally disintegrating tablets. Mannitol and
xylitol are mixed and passed through a screen, and then mixed in a
tumble blender, e.g., GEMCO 20 cubic feet (General Machine Company
of New Jersey Inc., Middlesex, N.J.). Mirtazapine and
microcrystalline cellulose are subsequently added to the tumble
blender and mixed. Crospovidone and polyvinyl pyrrolidone are added
to the mixture. Strawberry flavor, aspartame and colloidal silicon
dioxide are passed through a screen and then added to the tumble
blender and mixed with the above mixture, then passed through a
screen and then again transferred to a tumble blender. Sodium
stearyl fumarate and magnesium stearate are passed through a
screen, e.g. Russell Finex #30 (Russel Finex Inc., Pineville,
N.C.), and added to the tumble blender, mixed and then the blend is
compressed into tablets using a tablet press.
[0090] The disclosed mirtazapine dosage forms can be prepared as a
solid oral dosage forms, preferably as orally disintegrating
tablets, for medical administration. The preferred method of
administration is in the form of a non-effervescent, orally
disintegrating tablet compressed from a mixture of the dry
ingredients. In some embodiments, mirtazapine is in the form of
uncoated mirtazapine particles. The net weight of a compressed
tablet comprising the mirtazapine dosage form of the present
invention is from about 50 mg to about 1000 mg. Preferably, the
mirtazapine dosage form would be made commercially available in two
strengths, one about 250 mg and the other about 500 mg, each
containing proportional doses of mirtazapine.
[0091] It has been unexpectedly found that mirtazapine tablets
formed from the present pharmaceutical dosage form are physically
stable at humid conditions although they have similar dissolution
profiles to that of reference mirtazapine effervescent tablets.
[0092] Moreover, the mirtazapine tablets of the present invention
are easier to package because they are more physically stable, less
sensitive to moisture and are thus less fragile than reference
mirtazapine tablets.
[0093] While not wishing to be bound by a specific theory, it is
believed that upon oral administration to a patient, the dosage
forms of the invention undergo disintegration to form granules or
aggregates or fine particles, and subsequently most of the
mirtazapine is released into solution.
[0094] The following examples of processing conditions and
parameters are given for the purpose of illustrating the present
invention and shall not be construed as being limitations on the
scope or spirit of the invention.
Examples
Example 1
[0095] FIG. 1 is a flow chart describing the process for making the
mirtazapine formula of the present invention. Microcrystalline
cellulose and tartaric acid are combined in a 20 cubic foot GEMCO
blender (General Machine Company of New Jersey Inc., Middlesex,
N.J.) for seven minutes with the agitator off. The mixture is then
milled, e.g., through a FITZMILL (Fitzpatrick, South Plainfield,
N.J.) fitted with a 1522-033 screen and a hammer forward. The
mixture is then combined with citric acid, aspartame, orange
flavor, mirtazapine, and mannitol and mixed again in the GEMCO
blender (General Machine Company of New Jersey Inc., Middlesex,
N.J.) with the agitator off. After 15 minutes, crospovidone is
added and the mixture is blended for another 15 minutes. The
mixture is then screened through #20 mesh and mixed again for 18
minutes. Sodium stearyl fumarate is then added and the mixture is
mixed for seven more minutes. At which time, magnesium stearate,
which has been passed through a #30 mesh screen, is added, and the
mixing continues for a final seven minutes. The mixture is then
compressed into tablets on a tablet press, e.g., KIKUSUI (Kikusui
Tablet Press, Toms River, N.J.) using 13/32 inch flat-face bevel
edge (FFBE) tooling for forming 15 mg mirtazapine orally
disintegrating tablets, and 16/32 inch FFBE tooling for forming 30
mg mirtazapine orally disintegrating tablets.
Example 2
[0096] The procedure of Example 1 was used to make the following 15
mg mirtazapine orally disintegrating pharmaceutical tablet:
TABLE-US-00002 TABLE 2 15 mg mirtazapine orally disintegrating
tablet Milligrams/ Ingredient Tablet % Mirtazapine 15 mg 6.0
Tartaric Acid 15 mg 6.0 Microcrystalline Cellulose 15 mg 6.0 Citric
Acid 21 mg 8.4 Aspartame 10 mg 4.0 Orange Flavor 1.5 mg 0.6
Mannitol 109 mg 43.6 Crospovidone 60 mg 24.0 Magnesium Stearate 1.5
mg 0.6 Sodium Stearyl Fumarate 2 mg 0.8 Net Tablet weight 250 mg
100
Example 3
[0097] The procedure of Example 1 was also used to make the
following 30 mg mirtazapine orally disintegrating pharmaceutical
tablet:
TABLE-US-00003 TABLE 3 30 mg mirtazapine orally disintegrating
tablet Ingredient Milligrams/Tablet Mirtazapine 30 mg Tartaric Acid
30 mg Microcrystalline Cellulose 30 mg Citric Acid 42 mg Aspartame
20 mg Orange Flavor 3 mg Mannitol 218 mg Crospovidone 120 mg
Magnesium Stearate 3 mg Sodium Stearyl Fumarate 4 mg Net Tablet
weight 500 mg
Example 4
[0098] Table 4 depicts the comparative hardness (kp) for
mirtazapine tablets for the 15 and 30 mg dosage forms tablets of
Examples 2 and 3. The 15 mg and 30 mg tablets were determined to
have a hardness from about 2.6 to about 1.8 and from 2.7 kp to
about 1.7 kp, respectively, at 25.degree. C. and 60% relative
humidity (RH) when the tablets were exposed to the environment for
up to 24 hours. Table 4 shows that at control room temperature, the
hardness of the reference tablets decreased rapidly over a period
of time (i.e. the tablet breaks down and gets mushy).
TABLE-US-00004 TABLE 4 Comparative Hardness (Kp) data for
Mirtazapine Tablets, 15 and 30 mg Barr vs. Reference at 25.degree.
C./60% RH 15 mg 30 mg Time (Example 2), Reference 1, (Example 3),
Reference 2, (Hours) kp kp kp kp 0 2.6 1.8 2.7 1.6 2 1.2 0.6 1.2
0.5 6 1.2 0.3 1.2 0.3 24 1.2 0.3 1.2 Powder 48 1.8 0.5 1.7
Powder
[0099] Table 5 shows that the hardness of the 15 mg and 30 mg
dosage forms at 40.degree. C. and 75% RH ranged from about 2.8 kp
to about 0.8 kp and from about 2.7 kp to about 1.1 kp,
respectively, when the tablets were exposed to the environment for
up to one hour. Table 5 demonstrates that the physical integrity of
the 30 mg mirtazapine tablet of the present invention is maintained
under harsher conditions and is thus not spoiled. This physical
property of the tablet is advantageous to users of the tablet in
hot and humid climates.
TABLE-US-00005 TABLE 5 Comparative Hardness (Kp) data for 15 mg and
30 mg Mirtazapine Tablets vs. Reference at 40.degree. C./75% RH
Time Barr Reference Barr Reference (Hours) (15 mg), kp (15 mg), kp
(30 mg), kp (30 mg), kp 0 2.8 1.9 2.7 1.9 0.25 1.5 0.6 2.0 0.5 0.5
1.5 0.4 1.4 0.4 0.75 0.9 0.4 1.1 0.4 1.0 0.8 0.4 1.1 0.4
[0100] Table 6 depicts the dissolution profile for the 15 mg dosage
form, which was obtained in a dissolution medium of 900 mL of 0.01
N HCl with a paddle speed of 50 rpm. The table shows that about
100% of the 15 mg dosage form dissolves in five minutes.
TABLE-US-00006 TABLE 6 Comparative Dissolution Profile for 15 mg
Mirtazapine Orally Disintegrating Tablets Dissolution Medium: 0.01
N HCl 900 mL, 50 rpm, Paddle (Percent Dissolved) 15 mg Tablet Time
Reference 1 (Example 2) (mins) 0010300046 202411001R 0 0 0 5 97 101
10 103 101 20 103 101 30 103 101 45 103 101 60 103 101
[0101] Table 7 depicts the dissolution profile for a 30 mg dosage
form of the present invention which was obtained in a dissolution
medium of 900 mL of 0.01 N HCl with a paddle speed of 50 rpm. The
table shows that about 99% of the 30 mg dosage form dissolves in
five minutes.
TABLE-US-00007 TABLE 7 Comparative Dissolution Profile for
Mirtazapine Orally Disintegrating Tablets 30 mg Dissolution Medium:
0.01 N HCl 900 mL, 50 rpm, Paddle Dissolution Medium: 0.01 N HCl
900 mL, 50 rpm, Paddle (Percent Dissolved) 30 mg Tablet Time
Reference 1 (Example 3) (mins) 0010300046 202411001R 0 0 0 5 90 99
10 101 99 20 102 99 30 102 99 45 102 99
Example 5
[0102] Table 8 shows 15 mg, 30 mg and 45 mg mirtazapine orally
disintegrating tablet formulations prepared by the process shown in
FIG. 2.
TABLE-US-00008 TABLE 8 Mirtazapine orally disintegrating tablets 15
mg 30 mg 45 mg Tablet Tablet Tablet # INGREDIENT (mg) (mg) (mg) % 1
Mirtazapine 15.00 30.00 45.00 9.375 2 Microcrystalline cellulose,
10.00 20.00 30.00 6.25 NF (AVICEL PH101) 3 N-C NATURAL & 1.000
2.000 3.000 0.625 ARTIFICIAL ORANGE FLAVOR (POWDER) 4 Crospovidone,
NF 42.00 84.00 126.0 26.25 (POLYPLASDONE XL) 5 Mannitol, USP
(PARTECK 76.30 152.6 228.9 47.68 M200) 6 Colloidal Silicon Dioxide,
1.700 3.400 5.100 1.06 NF (CAB-O-SIL) 7 Magnesium stearate, NF
1.500 3.000 4.500 0.937 8 Sodium stearyl fumarate, NF 1.500 3.000
4.500 0.937 9 Xylitol (XYLISORB 300) 5.000 10.00 15.00 3.125 10
Aspartame, USP (NUTRA 6.000 12.00 18.00 3.75 SWEET powder) Total
160.0 320 480
[0103] Table 9 provides the disintegration time, friability and
tablet hardness (kp) for the 15 mg, 30 mg and 45 mg formulations
shown in Table 8. Friability, which is a measure of the crumbliness
of the tablet is also provided. As seen in Table 8, friability of
the tablets at a hardness lesser than about 1.5 kp is more than
2%.
TABLE-US-00009 TABLE 9 Disintegration time and friability Tablet
Hardness Disintegration time (sec) Friability (%) (kp) 15 mg 30 mg
45 mg 15 mg 30 mg 45 mg 0.5 3.3 5.2 6.33 100 100 100 1 4 5 6.4 100
100 100 1.5 4.7 6.7 6.7 0.1 60.6 100 2 5.7 6.3 5.7 <0.1 0.7 48
2.5 7.7 7.3 7 <0.1 0.7 18 3 -- 7.33 8 <0.1 0.1 2
[0104] Tables 10, 11 and 12 provide the effect of temperature and
moisture (also referred to as relative humidity or RH) on the
hardness of the 15 mg, 30 mg and 45 mg formulations provided in
Table 8. The results in Tables 10, 11 and 12 are graphically
depicted in FIGS. 3, 4 and 5. As seen in Table 10, the hardness of
15 mg tablets exposed to 22.degree. C./35% RH for 6 hr was about
64% of the hardness of the tablets exposed for 0 min, i.e., the
hardness of the tablet after exposure to 22.degree. C./35% RH for 6
hr was more than 50% of the hardness of the tablet exposed for 0
min. Further, the hardness of the 15 mg tablet exposed to
40.degree. C./75% RH for 15 min was about 57% of the hardness after
exposure for 0 min, i.e., the hardness of the tablet after exposure
to 40.degree. C./75% RH for 15 min was more than 50% of the
hardness of the unexposed 15 mg tablet.
[0105] Table 11 shows that the hardness of the 30 mg after exposure
to 22.degree. C./35% RH for 6 hr, or to 40.degree. C./75% RH for 15
min was more than 50% of the hardness of the 30 mg tablet exposed
for 0 min to either condition.
[0106] Table 12 shows that the hardness of the 45 mg after exposure
to 22.degree. C./35% RH for 6 hr, or to 40.degree. C./75% RH for 15
min was more than 50% of the hardness of the 45 mg tablet exposed
for 0 min to either condition.
TABLE-US-00010 TABLE 10 Effect of temperature/moisture on hardness
of the 15 mg formulation Hardness (kp) Time 15 mg Tablet 15 mg
Tablet 15 mg Tablet (min) 40.degree. C./75% RH 22.degree. C./35% RH
60.degree. C. 0 1.4 1.4 1.4 5 1.0 1.4 1.3 10 0.9 1.4 1.3 15 0.8 1.4
1.3 30 0.5 1.4 1.3 45 0.5 1.2 1.3 60 0.5 1.2 1.3 120 0.2 1.1 1.4
180 <0.1 0.9 1.3 240 <0.1 0.9 1.4 360 <0.1 0.9 1.4
TABLE-US-00011 TABLE 11 Effect of temperature/moisture on hardness
of the 30 mg formulation Hardness (kp) Time 30 mg Tablet 30 mg
Tablet 30 mg Tablet (min) 40.degree. C./75% RH 22.degree. C./35% RH
60.degree. C. 0 1.9 1.9 1.9 5 1.2 1.8 1.8 10 1.1 1.9 1.8 15 1.2 1.7
1.8 30 0.9 1.7 1.6 45 0.9 1.7 1.9 60 0.9 1.8 1.7 120 0.5 1.8 1.4
180 0.3 1.9 1.3 240 0.3 1.9 1.2 360 0.2 1.8 1.2
TABLE-US-00012 TABLE 12 Effect of temperature/moisture on hardness
of the 45 mg formulation Hardness (kp) Time 45 mg Tablet 45 mg
Tablet 45 mg Tablet (min) 40.degree. C./75% RH 22.degree. C./35% RH
60.degree. C. 0 1.9 1.9 1.9 5 1.6 1.9 1.9 10 1.2 1.9 1.9 15 1.4 1.8
1.9 30 1.2 1.8 1.9 45 0.9 1.9 1.7 60 0.8 1.9 1.7 120 0.7 1.9 1.8
180 0.4 2.1 1.6 240 0.4 2.1 1.4 360 0.3 2.0 1.3
Example 8
[0107] Table 13 shows 15 mg, 30 mg and 45 mg mirtazapine orally
disintegrating tablets containing calcium silicate, which were
prepared by the process shown in FIG. 2.
TABLE-US-00013 TABLE 13 Mirtazapine orally disintegrating tablets
containing calcium silicate 15 mg 30 mg 45 mg INGREDIENT Tablet
Tablet Tablet % 1 Mirtazapine 15.00 30.00 45.00 9.375 2
Microcrystalline cellulose, 10.00 20.00 30.00 6.25 NF (AVICEL
PH101) 3 N-C NATURAL & 1.000 2.000 3.000 0.625 ARTIFICIAL
ORANGE FLAVOR (POWDER) 4 Crospovidone, NF 21.00 42.00 63.00 13.125
(POLYPLASDONE XL) 5 Calcium Silicate (FM 1000) 21.00 42.00 63.00
13.125 6 Mannitol, USP (PARTECK 76.30 152.6 228.9 47.6 M200) 7
Colloidal Silicon Dioxide, 1.700 3.400 5.100 1.06 NF (CAB-O-SIL) 8
Magnesium stearate, NF 1.500 3.000 4.500 0.937 9 Sodium stearyl
fumarate, NF 1.500 3.000 4.500 0.937 10 Xylitol (XYLISORB 300)
5.000 10.00 15.00 3.125 11 Aspartame, USP (NUTRA 6.000 12.00 18.00
3.75 SWEET powder) Total 160.0 320.0 480.0 100
[0108] Table 14 provides the relationship between hardness of the
15 mg tablet of Table 10 and the disintegration time (DT).
TABLE-US-00014 TABLE 14 Tablet disintegration time vs. hardness
Tablet Hardness DT Friability (kp) (sec) (%) 0.5 3.6 100 1 3.3 100
1.5 4 5.3 2 3 0.1 2.5 4.8 <0.1 3 5.7 <0.1 4 6.3 <0.1 5 8.3
<0.1
[0109] One skilled in the art would understand that, despite the
full description provided herein, the present invention can be
performed within a wide and equivalent range of conditions,
formulations, and other parameters without affecting the scope of
the invention or any embodiment thereof. All patents and
publications cited herein are fully incorporated by reference
herein in their entirety.
* * * * *