U.S. patent application number 12/207702 was filed with the patent office on 2009-03-12 for orally adminstrable opioid formulations having extended duration of effect.
This patent application is currently assigned to Purdue Pharma L.P.. Invention is credited to Mark Chasin, Benjamin Oshlack, Frank Pedi, JR..
Application Number | 20090068269 12/207702 |
Document ID | / |
Family ID | 27557234 |
Filed Date | 2009-03-12 |
United States Patent
Application |
20090068269 |
Kind Code |
A1 |
Oshlack; Benjamin ; et
al. |
March 12, 2009 |
ORALLY ADMINSTRABLE OPIOID FORMULATIONS HAVING EXTENDED DURATION OF
EFFECT
Abstract
Sustained release oral solid dosage forms of opioid analgesics
are provided as multiparticulate systems which are bioavailable and
which provide effective blood levels of the opioid analgesic for at
least about 24 hours. A unit dose of the opioid analgesic contains
a plurality of substrates including the opioid analgesic in
sustained release form. The substrates have a diameter from about
0.1 mm to about 3 mm.
Inventors: |
Oshlack; Benjamin; (Boca
Raton, NY) ; Chasin; Mark; (Monroe, NJ) ;
Pedi, JR.; Frank; (Yorktown Heights, NY) |
Correspondence
Address: |
DARBY & DARBY P.C.
P.O. BOX 770, Church Street Station
New York
NY
10008-0770
US
|
Assignee: |
Purdue Pharma L.P.
Stamford
CT
|
Family ID: |
27557234 |
Appl. No.: |
12/207702 |
Filed: |
September 10, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10731678 |
Dec 8, 2003 |
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12207702 |
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10392586 |
Mar 20, 2003 |
7270831 |
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10731678 |
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09891882 |
Jun 26, 2001 |
6572885 |
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10392586 |
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09390719 |
Sep 7, 1999 |
6294195 |
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09891882 |
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08508246 |
Jul 27, 1995 |
5968551 |
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09390719 |
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08133503 |
Oct 7, 1993 |
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08508246 |
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08097558 |
Jul 27, 1993 |
5580578 |
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08133503 |
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07826084 |
Jan 27, 1992 |
5286493 |
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08097558 |
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08081618 |
Jun 23, 1993 |
5472712 |
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08133503 |
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08086248 |
Jul 1, 1993 |
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08081618 |
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07814111 |
Dec 24, 1991 |
5273760 |
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08086248 |
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Current U.S.
Class: |
424/484 ;
424/489; 514/282 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 9/2866 20130101; A61K 31/485 20130101; Y10S 514/951 20130101;
A61K 9/2013 20130101; A61K 9/5026 20130101; A61K 9/2077 20130101;
A61K 31/522 20130101; A61K 9/2095 20130101; A61K 9/1617 20130101;
A61K 9/1635 20130101; A61K 9/2081 20130101; A61K 9/2072 20130101;
A61P 43/00 20180101; A61K 9/2846 20130101; A61K 9/5047 20130101;
A61K 9/1623 20130101; A61K 9/5078 20130101 |
Class at
Publication: |
424/484 ;
514/282; 424/489 |
International
Class: |
A61K 9/10 20060101
A61K009/10; A61K 31/485 20060101 A61K031/485; A61K 9/14 20060101
A61K009/14 |
Claims
1-52. (canceled)
53: A sustained-release dosage form, comprising oxymorphone or a
salt, a hydrophilic polymer, an alkylcellulose, a binder, and a
diluent; wherein said dosage form provides a therapeutic effect for
about 12 hours or more.
54: The sustained-release dosage form of claim 53, wherein the
dosage form contains granules having a diameter from about 0.1 mm
to about 3 mm.
55: The sustained-release dosage form of claim 53, wherein the
alkylcellulose is ethylcellulose.
56: The sustained-release dosage form of claim 53, wherein the
dosage form is in the form of a tablet.
57: The sustained-release dosage form of claim 53, wherein the
dosage form is in the form of a capsule.
58: The sustained-release dosage form of claim 53, wherein the
dosage form is in the form of a matrix.
59: The sustained-release dosage form of claim 53, wherein the
dosage form provides a therapeutic effect for about 24 hours or
more.
60: A sustained-release dosage form, made by the process
comprising: (a) mixing oxymorphone salt with a hyrodrophilic
polymer, an alkylcellulose, a binder, and a diluent; (b) subjecting
the mixture to shear to form granules; and (c) incorporating the
granules into a dosage form; wherein said dosage form provides a
therapeutic effect for about 12 hours or more.
61: The process of claim 60, wherein the granules have a diameter
from about 0.1 mm to about 3 mm.
62: The process of claim 60, wherein step (c) comprises
incorporating the granules into a tablet.
63: The process of claim 60, wherein step (c) comprises
incorporating the granules into a capsule.
64: The process of claim 60, wherein the dosage form is a
matrix.
65: The process of claim 60, wherein the alkylcellulose is
ethylcellulose.
66: The process of claim 60, wherein the dosage form provides a
therapeutic effect for about 24 hours or more.
67: A process of making a sustained-release dosage form that
provides a therapeutic effect for about 12 hours or more, which
process comprises: (a) mixing oxymorphone salt with a hydrophilic
polymer, an alkylcellulose, a binder, and a diluent; (b) subjecting
the mixture to shear to form granules; and (c) incorporating the
granules into a dosage form.
68: The process of claim 67, wherein the granules have a diameter
from about 0.1 mm to about 3 mm.
69: The process of claim 67, wherein step (c) comprises
incorporating the granules into a tablet.
70: The process of claim 67, wherein step (c) comprises
incorporating the granules into a capsule.
71: The process of claim 67, wherein the dosage form is a
matrix.
72: The process of claim 67, wherein the alkylcellulose is
ethylcellulose.
73: The process of claim 67, wherein the dosage form provides a
therapeutic effect for about 24 hours or more.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation of U.S. patent application Ser. No.
10/731,678 filed Dec. 8, 2003 and now abandoned, which is a
continuation of application Ser. No. 10/392,586 filed Mar. 20, 2003
and now abandoned. Ser. No. 10/392,586 is a continuation of
application Ser. No. 09/891,882 filed Jun. 26, 2001 (now issued as
U.S. Pat. No. 6,572,885), which is a continuation of application
Ser. No. 09/390,719 filed Sep. 7, 1999 (now issued as U.S. Pat. No.
6,294,195), which is a continuation of application Ser. No.
08/508,246 filed Jul. 27, 1995 (now issued as U.S. Pat. No.
5,968,551), which is a continuation of application Ser. No.
08/133,503 filed Oct. 7, 1993 and now abandoned. Ser. No.
08/133,503 is a continuation-in-part of application Ser. No.
08/081,618 filed Jun. 23, 1993 (now issued as U.S. Pat. No.
5,472,712) and also a continuation-in-part of application Ser. No.
08/086,248 filed Jul. 1, 1993 and now abandoned. Ser. Nos.
08/081,618 and 08/086,248 are both continuations-in-part of
application Ser. No. 07/814,111 filed Dec. 24, 1991 and now issued
as U.S. Pat. No. 5,273,760. Prior application Ser. No. 08/508,246
is also a continuation-in-part of application Ser. No. 08/097,558
filed Jul. 27, 2993 (now issued as U.S. Pat. No. 5,580,578), which
is a continuation-in-part of application Ser. No. 07/826,084 filed
Jan. 27, 1992 (now issued as U.S. Pat. No. 5,286,493).
BACKGROUND OF THE INVENTION
[0002] The present invention relates to bioavailable
sustained-release pharmaceutical formulations of analgesic drugs,
in particular opioid analgesics, which provide an extended duration
of effect when orally administered.
[0003] It is known in the pharmaceutical art to prepare
compositions which provide for controlled (slow) release of
pharmacologically active substances contained in the compositions
after oral administration to humans and animals Such slow release
compositions are used to delay absorption of a medicament until it
has reached certain portions of the alimentary tract. Such
sustained-release of a medicament in the alimentary tract further
maintains a desired concentration of said medicament in the blood
stream for a longer duration than would occur if conventional rapid
release dosage forms are administered.
[0004] Slow release formulations known in the art include specially
coated pellets, coated tablets and capsules wherein the slow
release of the active medicament is brought about through selective
breakdown of the coating of the preparation or through compounding
with a special matrix to affect the release of a drug. Some slow
release formulations provide for related sequential release of a
single dose of an active compound at predetermined periods after
administration.
[0005] It is the intent of all sustained-release preparations to
provide a longer period of pharmacologic response after the
administration of the drug and is ordinarily experienced after the
administration of the rapid release dosage forms. Such longer
periods of response provide for many inherent therapeutic benefits
that are not achieved with corresponding short acting, immediate
release preparations. This is especially true in the treatment of
cancer patients or other patients in need of treatment for the
alleviation of moderate to severe pain, where blood levels of an
opioid analgesic medicament must be maintained at a therapeutically
effective level to provide pain relief. Unless conventional rapid
acting drug therapy is carefully administered at frequent intervals
to maintain effective steady state blood levels of the drug, peaks
and valleys in the blood level of the active drug occur because of
the rapid absorption, systemic excretion of the compound and
through metabolic inactivation, thereby producing special problems
in maintenance of analgesic efficacy.
[0006] The prior art teaching of the preparation and use of
compositions providing the sustained-release of an active compound
from a carrier is basically concerned with the release of the
active substance into the physiologic fluid of the alimentary
tract. However, it is generally recognized that the mere presence
of an active substance in the gastrointestinal fluids does not, by
itself, insure bioavailability.
[0007] In order to be absorbed, the active drug substance must be
in solution. The time required for a given proportion of an active
substance from a unit dosage form is determined as the proportion
of the amount of active drug substance released from a unit dosage
form over a specified time base by a test method conducted under
standardized conditions. The physiologic fluids of the
gastrointestinal tract are the media for determining dissolution
time. The present state of the art recognizes many satisfactory
test procedures to measure dissolution time for pharmaceutical
compositions, and these test procedures are described in official
compendia world wide.
[0008] Although there are many diverse factors which influence the
dissolution of drug substance from its carrier, the dissolution
time determined for a pharmacologically active substance from the
specific composition is relatively constant and reproducible. Among
the different factors affecting the dissolution time are the
surface area of the drug substance presented to the dissolution
solvent medium, the pH of the solution, the solubility of the
substance in the specific solvent medium, and the driving forces of
the saturation concentration of dissolved materials in the solvent
medium. Thus, the dissolution concentration of an active drug
substance is dynamically modified in its steady state as components
are removed from the dissolution medium through absorption across
the tissue site. Under physiologic conditions, the saturation level
of the dissolved materials is replenished from the dosage form
reserve to maintain a relatively uniform and constant dissolution
concentration in the solvent medium providing for a steady state
absorption.
[0009] The transport across a tissue absorption site of the
gastrointestinal tract is influenced by the Donnan osmotic
equilibrium forces on both sides of the membrane since the
direction of the driving force is the difference between the
concentrations of active substance on either side of the membrane,
i.e., the amount dissolved in the gastrointestinal fluids and the
amount present in the blood. Since the blood levels are constantly
being modified by dilution, circulatory changes, tissue storage,
metabolic conversion and systemic excretion, the flow of active
materials is directed from the gastrointestinal tract into the
blood stream.
[0010] Notwithstanding the diverse factors influencing both
dissolution and absorption of a drug substance, a strong
correlation has been established between the in-vitro dissolution
time determined for a dosage form and (in-vivo) bioavailability.
The dissolution time and the bioavailability determined for a
composition are two of the most significant fundamental
characteristics for consideration when evaluating sustained-release
compositions.
[0011] It has previously been known in the art that
sustained-release compositions of opioids or salts thereof could be
prepared in a suitable matrix. For example, in U.S. Pat. Nos.
4,990,341 and 4,844,909 (Goldie, et al.), both assigned to the
assignee of the present invention, describes hydromorphone
compositions wherein the dissolution rate in vitro of the dosage
form, when measured by the USP Paddle or Basket Method at 100 rpm
in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C.,
is between 12.5 and 42.5% (by wt) hydromorphone released after 1
hour, between 25 and 55% (by wt) released after 2 hours, between 45
and 75% (by wt) released after 4 hours and between 55 and 85% (by
wt) released after 6 hours, the in vitro release rate being
independent of pH between pH 1.6 and 7.2 and chosen such that the
peak plasma level of hydromorphone obtained in vivo occurs between
2 and 4 hours after administration of the dosage form. At least 12
hours of pain relief is obtained with the hydromorphone
formulations.
[0012] Once-a-day orally administrable dosage forms have previously
been developed in the art and are commercially available. However,
currently, there are no orally administered opioid formulations
commercially available which provide an extended duration of
effect, e.g., greater than about 12 hours. Examples of commercially
available once-a-day dosage forms include Dilacor.RTM. XR
(diltiazem hydroxide, extended-release capsules, available from
Rhone-Poulenc Rorer), Thorazine.RTM. Spanule.RTM. (chlorpromazine
HCl, extended-release capsules, available from SmithKline Beecham),
Theo-24.RTM. (theophylline, extended-release capsules, available
from Searle), TheoX.RTM. (theophylline, extended-release tablets,
available from Carnrick), Theo-dur.RTM. (theophylline,
extended-release tablets, available from Key), Theo-Sav.RTM.
(theophylline, extended-release tablets, available from Sauage),
Uniphyl.RTM. Unicontin.RTM. (theophylline, extended-release
tablets, available from Purdue Frederick), T-Phyl.RTM.
Unicontin.RTM. (theophylline, extended-release tablets, available
from Purdue Frederick), Tenuate Dospan.RTM. (diethylpropion HCl,
extended-release tablets, available from Marion Merrill Dow),
Tepanil.RTM. Ten-Tab.RTM. (diethylpropion HCl, extended-release
tablets, available from 3M Riker), Desoxyn.RTM. Gradumet.RTM.
(phenmetrazine HCl, extended-release tablets, available from
Abbott), Dexedrine.RTM. Spanule.RTM. (dextroamphetamine,
extended-release capsules, available from SmithKline Beecham),
Compazine.RTM. Spanule.RTM. (prochlorperazine maleate,
extended-release capsules, available from SmithKline Beecham),
Indocin.RTM. SR (indomethacin, extended-release capsules, available
from Merck), Betachron.RTM. (propranolol HCl, extended-release
capsules, available from Inwood), Inderal.RTM. LA (propranolol HCl,
extended-release capsules, available from Wyeth-Ayerst),
Inderide.RTM. LA (propranolol HCl and hydrochlorothiazide,
extended-release capsules from Wyeth-Ayerst), Procardia XL.RTM.
(nifedipine, extended-release tablets, available from Pfizer),
Mestinon.RTM. Timespan.RTM. (pyridostigmine Br, extended-release
tablets, available from ICN), Temaril.RTM. Spanule.RTM.
(trimeprazine tartrate, extended-release capsules, available from
Herbert), AL-R.RTM. 6 (chlorpheniramine maleate, extended-release
capsules, available from Saron), Chlor-Trimeton.RTM. Allergy
Repetabs.RTM. (chlorpheniramine maleate, extended-release tablets,
available from Schering-Plough), Adipost.RTM. (phendimetrazine
tartrate, extended-release capsules, available from Ascher),
Bontril.RTM. Slow-Release (phendimetrazine tartrate,
extended-release capsules, available from Carnrick),
Melfiat.RTM.-105 Unicelles.RTM. (phendimetrazine tartrate,
extended-release capsules, available from Solway), Prelu-2.RTM.
(phendimetrazine tartrate, extended-release capsules, available
from Boehringer Ingelheim), PT 105.RTM. (phendimetrazine tartrate,
extended-release capsules, available from Legere), Wehless.RTM.-105
Timecelles (phendimetrazine tartrate, extended-release capsules,
available from Hauck), Preludin.RTM. Endurets.RTM. (phenmetrazine
HCl, extended-release tablets, available from Boehringer
Ingelheim), Caffedrine (caffeine, extended-release capsules,
available from Thompson), Diamox.RTM. Sequels.RTM. (acetazolamide,
extended-release capsules, available from Storz), Verelan.RTM.
(verapamil HCl, extended-release capsules cont. pellets, available
from Wyeth-Ayerst), Calan.RTM. SR Caplets.RTM. (verapamil HCl,
extended-release tablets, available from Searle), Isoptin.RTM. SR
(verapamil HCl, extended-release tablets, available from Knoll),
Verapamil HCl Tablets (verapamil HCl, extended-release tablets,
available from GoldLine), and Artane.RTM. Sequels.RTM.
(trihexyphenidyl HCl, extended-release capsules, available from
Lederle).
[0013] There is a need in the art to develop drug formulations
which provide a duration of effect lasting longer than twelve hours
such as a drug that may be administered to a patient only once a
day. Many of the oral opioid analgesic formulations that are
currently available in the market must be administered every four
to six hours daily with a selected few formulated for less frequent
12 hour dosing.
[0014] Morphine, which is considered to be the prototypic opioid
analgesic, has been formulated into 12 hour controlled-release
formulations (i.e., MS Contin.RTM. tablets, commercially available
from Purdue Frederick Company).
[0015] An orally administrable opioid formulation which would
provide an extended duration of effect would be highly desirable.
Such an oral sustained-release formulation of an opioid analgesic
would provide effective steady-state blood levels (e.g., plasma
levels) of the drug when orally administered such that a duration
of effect greater than 12 hours, and more preferably, of about 24
hours or more, which formulation is bioavailable as well.
OBJECTS AND SUMMARY OF THE INVENTION
[0016] It is accordingly an object of the present invention to
provide an orally administered pharmaceutical dosage form of an
opioid analgesic that is suitable for once-a-day
administration.
[0017] Another object of the present invention is to provide a
sustained-release products which provides effective steady-state
blood levels in a human patient for greater than 12 hours,
preferably at least 24 hours, which products are bioavailable.
[0018] Still another object of the present invention is to provide
a method of treating a patient with an orally administrable dosage
form of an opioid analgesic which provides a desired analgesic
effect for a period of time greater than 12 hours, preferably for
at least 24 hours and which dosage form is bioavailable.
[0019] In accordance with the above objects and others which will
be apparent from the further reading of the specification and of
the appended claims, the present invention is related to the
surprising discovery that in order to provide a 24 hour dosage form
of an opioid analgesic, it is necessary to do so via a sustained
multiparticulate system. More particularly, the present invention
is related to the surprising discovery that while sustained-release
tablets and sustained-release multiparticulate systems containing
opioid analgesics may be prepared which provide an in-vitro
dissolution indicative of a 24 hour formulation, only
sustained-release multiparticulate systems of opioid analgesics are
bioavailable. This is true even when the sustained-release tablets
have an in-vitro dissolution profile which is virtually equivalent
to that provided by the multiparticulate system.
[0020] More particularly, the present invention relates to a
sustained-release oral analgesic dosage form for once-a-day
administration, comprising a unit dose of a plurality of inert
pharmaceutically acceptable substrates. The unit dose of the
substrates comprises an analgesically effective amount of an opioid
analgesic or a salt thereof. Each of said substrates having a
diameter from about 0.1 mm to about 3 mm. The unit dose is
bioavailable and provides effective blood levels of the opioid
analgesic for at least about 24 hours. The unit dose of the
substrates may be, for example, contained within a hard gelatin
capsule for oral administration.
[0021] In certain preferred embodiments of the present invention,
each of the substrates has a diameter from about 0.5 mm to about 2
mm (narrower range).
[0022] The present invention is further related to a bioavailable
sustained-release opioid analgesic dosage form for once-a-day oral
administration, comprising inert pharmaceutically acceptable beads
having a diameter from about 0.1 mm to about 3 mm coated with an
analgesically effective amount of an opioid analgesic or a salt
thereof. The beads further comprise a sustained-release overcoat
comprising an effective amount of a hydrophobic material selected
from the group consisting of (i) an acrylic polymer such as
copolymers of acrylic and methacrylic acid; (ii) an alkylcellulose
such as ethylcellulose; (iii) other commonly used retardant
coatings such as shellac, zein, and hydrophobic waxy-type products,
such as hydrogenated castor oil or hydrogenated vegetable oil, or
(iv) mixtures of any of groups (i)-(iii) to provide a
sustained-release of said opioid analgesic in aqueous solutions for
at least about 24 hours.
[0023] The present invention is further related to a method for
obtaining a bioavailable sustained-release opioid analgesic dosage
form for once-a-day oral administration, comprising preparing a
plurality of substrates comprising a unit dose of an oral analgesic
in a sustained-release form, each of which substrates having a
diameter from about 0.1 mm to about 3 mm. The substrates are
manufactured to provide an in-vitro dissolution indicative of a
once-a-day product.
[0024] The term "bioavailable" is defined for the purposes of the
present invention as the total amount of a drug substance that is
absorbed to be available to provide the desired therapeutic effect
after administration of a unit dosage form, as compared to the
known reference drug product, as commonly determined and accepted
by Governmental Regulatory Agencies, such as the United States
FDA.
[0025] The term "bioavailability" is defined for purposes of the
present invention as the extent to which the drug (e.g., opioid
analgesic) is absorbed from the unit dosage forms and becomes
available at the site of drug action.
[0026] The terms "sustained release" and "extended duration" are
defined for purposes of the present invention as the release of the
drug (e.g., opioid analgesic) at such a rate that blood (e.g.,
plasma) levels are maintained within the therapeutic range but
below toxic levels over a period of time greater than 12 hours,
more preferably for about 24 hours, or longer.
[0027] The term "substrate" is defined for the purposes of the
present invention as spheroids, beads, microspheres, seeds,
pellets, ion-exchange resin beads, and other multi-particulate
systems comprising the drug(s), which have a diameter from about
0.1 mm to about 3 mm, preferably between 0.5 mm and 2.0 mm.
[0028] The term "unit dose" is defined for purposes of the present
invention as the total amount of substrates needed to administer a
desired dose of drug (e.g., opioid analgesic) to a patient.
[0029] The sustained-release substrates of the present invention
permit release of the opioid (or salt) over a sustained period of
time in an aqueous medium. The term "aqueous medium" is defined for
purposes of the present invention as any pharmaceutically
acceptable dissolution medium, gastric fluid and/or intestinal
fluid.
BRIEF DESCRIPTION OF THE DRAWING
[0030] The following drawing is illustrative of an embodiment of
the invention and is not meant to limit the scope of the invention
as encompassed by the claims.
[0031] FIG. 1 is a graphical representation of the formulation
dissolution obtained for Examples 1-4.
DETAILED DESCRIPTION
[0032] The multiparticulate systems of the present invention may
incorporate one or more compounds known as opioid analgesics.
Opioid analgesic compounds which may be used in the present
invention include alfentanil, allylprodine, alphaprodine,
anileridine, benzylmorphine, bezitramide, buprenorphine,
butorphanol, clonitazene, codeine, cyclazocine, desomorphine,
dextromoramide, dezocine, diampromide, dihydrocodeine,
dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl,
heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,
ketobemidone, levallorphan, levorphanol, levophenacylmorphan,
lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,
morphine, myrophine, nalbuphine, narceine, nicomorphine,
norlevorphanol, normethadone, nalorphine, normorphine, norpipanone,
opium, oxycodone, oxymorphone, papavereturn, pentazocine,
phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,
piritramide, propheptazine, promedol, properidine, propiram,
propoxyphene, sufentanil, tramadol, tilidine, salts thereof,
mixtures of any of the foregoing, mixed mu-agonists/antagonists,
mu-antagonist combinations, and the like.
[0033] In certain preferred embodiments, the opioid analgesic is
selected from morphine, codeine, hydromorphone, hydrocodone,
oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, or
mixtures thereof.
[0034] In one preferred embodiment the sustained-release opioid
oral dosage form of the present invention includes hydromorphone as
the therapeutically active ingredient in an amount from about 4 to
about 64 mg hydromorphone hydrochloride. Alternatively, the dosage
form may contain molar equivalent amounts of other hydromorphone
salts or of the hydromorphone base. In other preferred embodiments
where the opioid analgesic is other than hydromorphone, the dosage
form contains an appropriate amount to provide a substantially
equivalent therapeutic effect. For example, when the opioid
analgesic comprises morphine, the sustained-release oral dosage
forms of the present invention include form about 5 mg to about 800
mg morphine, by weight. When the opioid analgesic comprises
oxycodone, the sustained-release oral dosage forms of the present
invention include from about 5 mg to about 400 mg oxycodone.
[0035] The sustained-release dosage forms of the present invention
generally achieve and maintain therapeutic levels substantially
without significant increases in the intensity and/or degree of
concurrent side effects, such as nausea, vomiting or drowsiness,
which are often associated with high blood levels of opioid
analgesics. There is also evidence to suggest that the use of the
present dosage forms leads to a reduced risk of drug addiction.
Furthermore, the sustained-release dosage forms of the present
invention preferably release the opioid analgesic at a rate that is
independent of pH, e.g., between pH 1.6 and 7.2. In other words,
the dosage forms of the present invention avoid "dose dumping" upon
oral administration.
[0036] In the present invention, the oral opioid analgesics have
been formulated to provide for an increased duration of analgesic
action allowing once-daily dosing. Surprisingly, these
formulations, at comparable daily dosages of conventional
immediate-release drug, are associated with a lower incidence in
severity of adverse drug reactions and can also be administered at
a lower daily dose than conventional oral medication while
maintaining pain control.
[0037] The substrates of the present invention may further include
one or more additional drugs which may or may not act
synergistically with the opioid analgesics of the present
invention. Examples of such additional drugs include non-steroidal
anti-inflammatory agents, including ibuprofen, diclofenac,
naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,
ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin,
pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,
tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,
tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,
clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic
acid, niflumic acid tolfenamic acid, diflurisal, flufenisal,
piroxicam, sudoxicam or isoxicam, and the like. Other suitable
additional drugs which may be included in the dosage forms of the
present invention include acetaminophen, aspirin, and other
non-opioid analgesics.
[0038] For example, if a second (non-opioid) drug is included in
the formulation, such drug may be included in controlled release
form or in immediate release form. The additional drug may be
incorporated into the controlled release matrix along with the
opioid; incorporated into the controlled release coating;
incorporated as a separated controlled release layer or immediate
release layer; or may be incorporated as a powder, granulation,
etc., in a gelatin capsule with the substrates of the present
invention.
[0039] The sustained-release preparations of the present invention
may be used in conjunction with any multiparticulate system, such
as beads, spheroids, microspheres, seeds, pellets, ion-exchange
resin beads, and other multi-particulate systems in order to obtain
a desired sustained-release of the therapeutically active agent.
Beads, granules, spheroids, or pellets, etc., prepared in
accordance with the present invention can be presented in a capsule
or in any other suitable unit dosage form.
[0040] When the substrates of the present invention are inert
pharmaceutical beads, the inert pharmaceutical beads may be from
about 8 mesh to about 50 mesh. In certain preferred embodiments,
the beads are, e.g., nu pariel 18/20 beads.
[0041] In certain preferred embodiments of the present invention,
the sustained-release opioid dosage forms comprise a plurality of
substrates comprising the active ingredient, which substrates are
coated with a sustained-release coating. The coating formulations
of the present invention should be capable of producing a strong,
continuous film that is smooth and elegant, capable of supporting
pigments and other coating additives, non-toxic, inert, and
tack-free.
[0042] In order to obtain a sustained-release of the opioid
sufficient to provide an analgesic effect for the extended
durations set forth in the present invention, the substrate
comprising the therapeutically active agent may be coated with a
sufficient amount of hydrophobic material to obtain a weight gain
level from about 2 to about 30 percent, although the overcoat may
be greater depending upon the physical properties of the particular
opioid analgesic compound utilized and the desired release rate,
among other things.
[0043] The solvent which is used for the hydrophobic material may
be any pharmaceutically acceptable solvent, including water,
methanol, ethanol, methylene chloride and mixtures thereof. It is
preferable however, that the coatings be based upon aqueous
dispersions of the hydrophobic material.
[0044] In certain preferred embodiments of the present invention,
the hydrophobic polymer comprising the sustained-release coating is
a pharmaceutically acceptable acrylic polymer, including but not
limited to acrylic acid and methacrylic acid copolymers,
methacrylic acid copolymers, methyl methacrylate copolymers,
ethoxyethyl methacrylates, cynaoethyl methacrylate, methyl
methacrylate, copolymers, methacrylic acid copolymers, methyl
methacrylate copolymers, methyl methacrylate copolymers, methyl
methacrylate copolymers, methacrylic acid copolymer, aminoalkyl
methacrylate copolymer, methacrylic acid copolymers, methyl
methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid,
methacrylic acid alkylamide copolymer, poly(methyl methacrylate),
poly(methacrylic acid) (anhydride), methyl methacrylate,
polymethacrylate, methyl methacrylate copolymer, poly(methyl
methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide,
aminoalkyl methacrylate copolymer, poly(methacrylic acid
anhydride), and glycidyl methacrylate copolymers.
[0045] In certain preferred embodiments, the acrylic polymer is
comprised of one or more ammonio methacrylate copolymers. Ammonio
methacrylate copolymers are well known in the art, and are
described in NF XVII as fully polymerized copolymers of acrylic and
methacrylic acid esters with a low content of quaternary ammonium
groups.
[0046] In one preferred embodiment, the acrylic coating is an
acrylic resin lacquers used in the form of an aqueous dispersion,
such as that which is commercially available from Rohm Pharma under
the Tradename Eudragit.RTM.. In further preferred embodiments, the
acrylic coating comprises a mixture of two acrylic resin lacquers
commercially available from Rohm Pharma under the Tradenames
Eudragit.RTM. RL 30 D and Eudragit.RTM. RS 30 D, respectively.
Eudragit.RTM. RL 30 D and Eudragit.RTM. RS 30 D 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 30 D and 1:40 in Eudragit.RTM. RS 30 D. The mean molecular
weight is about 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.
[0047] The Eudragit.RTM. RL/RS dispersions of the present invention
may be mixed together in any desired ratio in order to ultimately
obtain a sustained-release formulation having a desirable
dissolution profile. Desirable sustained-release formulations may
be obtained, for instance, from a retardant coating derived from
100% Eudragit.RTM. RL, 50% Eudragit.RTM. RL and 50% Eudragit.RTM.
RS, and 10% Eudragit.RTM. RL:Eudragit.RTM. 90% RS. Of course, one
skilled in the art will recognize that other acrylic polymers may
also be used, such as, for example, Eudragit.RTM. L.
[0048] In other preferred embodiments, the hydrophobic polymer
which may be used for coating the substrates of the present
invention is a hydrophobic cellulosic material such as
ethylcellulose. Those skilled in the art will appreciate that other
cellulosic polymers, including other alkyl cellulosic polymers, may
be substituted for part or all of the ethylcellulose included in
the hydrophobic polymer coatings of the present invention.
[0049] One commercially-available aqueous dispersion of
ethylcellulose is Aquacoat.RTM. (FMC Corp., Philadelphia, Pa.,
U.S.A.). Aquacoat.RTM. is 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, it is necessary
to intimately mix the Aquacoat.RTM. with a suitable plasticizer
prior to use.
[0050] Another aqueous dispersion of ethylcellulose is commercially
available as Surelease.RTM. (Colorcon, Inc., West Point, Pa.,
U.S.A.). This product is prepared by incorporating plasticizer into
the dispersion during the manufacturing process. A hot melt of a
polymer, plasticizer (dibutyl sebacate), and stabilizer (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.
[0051] In embodiments of the present invention where the coating
comprises an aqueous dispersion of a hydrophobic polymer, the
inclusion of an effective amount of a plasticizer in the aqueous
dispersion of hydrophobic polymer will further improve the physical
properties of the film. For example, because ethylcellulose has a
relatively high glass transition temperature and does not form
flexible films under normal coating conditions, it is necessary to
plasticize the ethylcellulose before using the same as a coating
material. Generally, the amount of plasticizer included in a
coating solution is based on the concentration of the film-former,
e.g., most often from about 1 to about 50 percent by weight of the
film-former. Concentration of the plasticizer, however, can only be
properly determined after careful experimentation with the
particular coating solution and method of application.
[0052] Examples of suitable plasticizers for ethylcellulose include
water insoluble plasticizers such as dibutyl sebacate, diethyl
phthalate, triethyl citrate, tibutyl citrate, and triacetin,
although it is possible that other water-insoluble plasticizers
(such as acetylated monoglycerides, phthalate esters, castor oil,
etc.) may be used. Triethyl citrate is especially preferred.
[0053] Examples of suitable plasticizers for the acrylic polymers
of the present invention include citric acid esters such as
triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and
possibly 1,2-propylene glycol, polyethylene glycols, propylene
glycol, diethyl phthalate, castor oil, and triacetin, although it
is possible that other water-insoluble plasticizers (such as
acetylated monoglycerides, phthalate esters, castor oil, etc.) may
be used. Triethyl citrate is especially preferred.
[0054] The sustained-release profile of the formulations of the
invention can be altered, for example, by varying the thickness of
the hydrophobic coating, changing the particular hydrophobic
material used, or altering the relative amounts of, e.g., different
acrylic resin lacquers, altering the manner in which the
plasticizer is added (e.g., when the sustained-release coating is
derived from an aqueous dispersion of hydrophobic polymer), by
varying the amount of plasticizer relative to hydrophobic polymer,
by the inclusion of additional ingredients or excipients, by
altering the method of manufacture, etc.
[0055] Sustained-release spheroids or beads, coated with a
therapeutically active agent are prepared, e.g. by dissolving the
opioid analgesic in water and then spraying the solution onto a
substrate, for example, nu pariel 18/20 beads, using a Wurster
insert. Optionally, additional ingredients are also added prior to
coating the beads in order to assist the hydromorphone binding to
the substrates, and/or to color the solution, etc. For example, a
product which includes hydroxypropyl methylcellulose, etc. with or
without colorant may be added to the solution and the solution
mixed (e.g., for about 1 hour) prior to application of the same
onto the beads. The resultant coated substrate, in this example
beads, may then be optionally overcoated with a barrier agent, to
separate the therapeutically active agent from the hydrophobic
sustained-release coating. An example of a suitable barrier agent
is one which comprises hydroxypropyl methylcellulose. However, any
film-former known in the art may be used. It is preferred that the
barrier agent does not affect the dissolution rate of the final
product.
[0056] The hydromorphone, HPMC protected (optional) beads may then
be overcoated with hydrophobic polymer, preferably with an
effective amount of plasticizer.
[0057] The coating solutions of the present invention may contain,
in addition to the film-former, plasticizer, and solvent system
(i.e., water), a colorant to provide elegance and product
distinction. Color may be added to the solution of the
therapeutically active agent instead, or in addition to the aqueous
dispersion of hydrophobic polymer.
[0058] The plasticized aqueous dispersion of hydrophobic polymer
may be applied onto the substrate comprising the therapeutically
active agent by spraying using any suitable spray equipment known
in the art. In a preferred method, a Wurster fluidized-bed system
is used in which an air jet, injected from underneath, fluidizes
the core material and effects drying while the acrylic polymer
coating is sprayed on. A sufficient amount of the aqueous
dispersion of hydrophobic polymer to obtain a predetermined
sustained-release of said therapeutically active agent when said
coated substrate is exposed to aqueous solutions, e.g. gastric
fluid, is preferably applied, taking into account the physically
characteristics of the therapeutically active agent, the manner of
incorporation of the plasticizer, etc. After coating with the
hydrophobic polymer, a further overcoat of a film-former, such as
Opadry.RTM., is optionally applied to the beads. This overcoat is
provided, if at all, in order to substantially reduce agglomeration
of the beads.
[0059] Next, the coated beads are cured in order to obtain a
stabilized release rate of the therapeutically active agent.
[0060] When the coating comprises an aqueous dispersion of
ethylcellulose, the coated substrate is preferably subjected to
curing at a temperature greater than the glass transition
temperature of the coating solution (i.e., ethylcellulose) and at a
relative humidity from about 60% to about 100%, until the curing
endpoint is reached, e.g., about 60.degree. C. and a relative
humidity from about 60% to about 100% for a time period from about
48 to about 72 hours.
[0061] In preferred embodiments of the present invention directed
to the acrylic coating, a stabilized product is obtained by
subjecting the coated substrate to oven curing at a temperature
above the Tg of the plasticized acrylic polymer for the required
time period, the optimum values for temperature and time for the
particular formulation being determined experimentally. In certain
embodiments of the present invention, the stabilized product is
obtained via an oven curing conducted at a temperature of about
45.degree. C. for a time period from about 24 to about 48 hours or
longer.
[0062] The release of the therapeutically active agent from the
sustained-release formulation of the present invention can be
further influenced, i.e., adjusted to a desired rate, by the
addition of one or more release-modifying agents, or by providing
one or more passageways through the coating. The ratio of
hydrophobic polymer to water soluble material is determined by,
among other factors, the release rate required and the solubility
characteristics of the materials selected.
[0063] The release-modifying agents which function as pore-formers
may be organic or inorganic, and include materials that can be
dissolved, extracted or leached from the coating in the environment
of use. The pore-formers may comprise one or more hydrophilic
polymers such as hydroxypropylmethylcellulose.
[0064] The sustained-release coatings of the present invention can
also include erosion-promoting agents such as starch and gums.
[0065] The sustained-release coatings of the present invention can
also 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.
[0066] The release-modifying agent may also comprise a
semi-permeable polymer.
[0067] In certain preferred embodiments, the release-modifying
agent is selected from hydroxypropylmethylcellulose, lactose, metal
stearates, and mixtures of any of the foregoing.
[0068] The sustained-release coatings of the present invention may
also include an exit means comprising at least one passageway,
orifice, or the like. The passageway may be formed by such methods
as those disclosed in U.S. Pat. Nos. 3,845,770; 3,916,889;
4,063,064; and 4,088,864 (all of which are hereby incorporated by
reference). The passageway can have any shape such as round,
triangular, square, elliptical, irregular, etc.
[0069] In other embodiments of the present invention, the present
invention may utilize a multiparticulate sustained-release matrix.
Suitable materials for inclusion in a sustained-release matrix
are
[0070] (a) Hydrophilic polymers, such as gums, cellulose ethers,
acrylic resins and protein derived materials. Of these polymers,
the cellulose ethers, especially hydroxyalkylcelluloses and
carboxyalkylcelluloses, are preferred. The oral dosage form may
contain between 1% and 80% (by weight) of at least one hydrophilic
or hydrophobic polymer.
[0071] (b) Digestible, long chain (C.sub.8C.sub.50, especially
C.sub.12-C.sub.40), substituted or unsubstituted hydrocarbons, such
as fatty acids, fatty alcohols, glyceryl esters of fatty acids,
mineral and vegetable oils and waxes. Hydrocarbons having a melting
point of between 25.degree. and 90.degree. C. are preferred. Of
these long chain hydrocarbon materials, fatty (aliphatic) alcohols
are preferred. The oral dosage form may contain up to 60% (by
weight) of at least one digestible, long chain hydrocarbon.
[0072] (c) Polyalkylene glycols. The oral dosage form may contain
up to 60% (by weight) of at least one polyalkylene glycol.
[0073] For example, a suitable matrix may be one which comprises at
least one water soluble hydroxyalkyl cellulose, at least one
C.sub.12-C.sub.36, preferably C.sub.14-C.sub.22, aliphatic alcohol
and, optionally, at least one polyalkylene glycol. The at least one
hydroxyalkyl cellulose is preferably a hydroxy (C.sub.1 to C.sub.6)
alkyl cellulose, such as hydroxypropylcellulose,
hydroxypropylmethylcellulose and, especially, hydroxyethyl
cellulose. The amount of the at least one hydroxyalkyl cellulose in
the present oral dosage form will be determined, inter alia, by the
precise rate of opioid release required. The at least one aliphatic
alcohol may be, for example, lauryl alcohol, myristyl alcohol or
stearyl alcohol. In certain preferred embodiments, the at least one
aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The
amount of the at least one aliphatic alcohol in the present oral
dosage form will be determined, as above, by the precise rate of
opioid release required. It will also depend on whether at least
one polyalkylene glycol is present in or absent from the oral
dosage form. In the absence of at least one polyalkylene glycol,
the oral dosage form preferably contains between 20% and 50% (by
wt) of the at least one aliphatic alcohol. When at least one
polyalkylene glycol is present in the oral dosage form, then the
combined weight of the at least one aliphatic alcohol and the at
least one polyalkylene glycol preferably constitutes between 20%
and 50% (by wt) of the total dosage.
[0074] In one embodiment, the ratio of, e.g., at least one
hydroxyalkyl cellulose or acrylic resin to at least one aliphatic
alcohol/polyalkylene glycol determines, to a considerable extent,
the release rate of the opioid from the formulation. A ratio of the
at least one hydroxyalkyl cellulose to at least one aliphatic
alcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred,
with a ratio of between 1:3 and 1:4 being particularly
preferred.
[0075] At least one polyalkylene glycol may be, for example,
polypropylene glycol or, preferably, polyethylene glycol. The
number average molecular weight of the at least one polyalkylene
glycol is preferred between 1000 and 15000 especially between 1500
and 12000.
[0076] Another suitable sustained-release matrix would comprise an
alkylcellulose (especially ethyl cellulose), a C.sub.12 to C.sub.36
aliphatic alcohol and, optionally, a polyalkylene glycol.
[0077] In addition to the above ingredients, a sustained-release
matrix may also contain suitable quantities of other materials,
e.g., diluents, lubricants, binders, granulating aids, colorants,
flavorants and glidants that are conventional in the pharmaceutical
art.
[0078] In order to facilitate the preparation of a solid,
sustained-release oral dosage form according to this invention
there is provided, in a further aspect of the present invention, a
process for the preparation of a solid, sustained-release oral
dosage form according to the present invention comprising
incorporating opioids or a salt thereof in a sustained-release
matrix. Incorporation in the matrix may be effected, for example,
by
[0079] (a) forming granules comprising at least one water soluble
hydroxyalkyl cellulose and opioid or an opioid salt, [0080] (b)
mixing the hydroxyalkyl cellulose containing granules with at least
one C.sub.12-C.sub.36 aliphatic alcohol, and
[0081] (c) optionally, compressing and shaping the granules.
[0082] Preferably, the granules are formed by wet granulating the
hydroxyalkyl cellulose/opioid with water. In a particularly
preferred embodiment of this process, the amount of water added
during the wet granulation step is preferably between 1.5 and 5
times, especially between 1.75 and 3.5 times, the dry weight of the
opioid.
[0083] In yet other alternative embodiments, a spheronizing agent,
together with the active ingredient can be spheronized to form
spheroids. Microcrystalline cellulose is preferred. A suitable
microcrystalline cellulose is, for example, the material sold as
Avicel PH 101 (Trade Mark, FMC Corporation). In such embodiments,
in addition to the active ingredient and spheronizing agent, the
spheroids may also contain a binder. Suitable binders, such as low
viscosity, water soluble polymers, will be well known to those
skilled in the pharmaceutical art. However, water soluble hydroxy
lower alkyl cellulose, such as hydroxy propyl cellulose, are
preferred. Additionally (or alternatively) the spheroids may
contain a water insoluble polymer, especially an acrylic polymer,
an acrylic copolymer, such as a methacrylic acid-ethyl acrylate
copolymer, or ethyl cellulose. In such embodiments, the
sustained-release coating will generally include a water insoluble
material such as (a) a wax, either alone or in admixture with a
fatty alcohol; or (b) shellac or zein.
[0084] The substrates of the present invention may also be prepared
via a melt pellitization technique. In such circumstance, the
opioid in finely divided form is combined with a binder (also in
particulate form) and other optional inert ingredients, and
thereafter the mixture is pelletized, e.g., by mechanically working
the mixture in a high shear mixer to form the pellets (granules,
spheres). Thereafter, the pellets (granules, spheres) may be sieved
in order to obtain pellets of the requisite size. The binder
material is preferably in particulate form and has a melting point
above about 40.degree. C. Suitable binder substances include, for
example, hydrogenated castor oil, hydrogenated vegetable oil, other
hydrogenated fats, fatty alcohols, fatty acid esters, fatty acid
glycerides, and the like.
[0085] In certain embodiments of the present invention, an
effective amount of opioid in immediate release form is included in
the unit dose comprising the substrates of the present invention.
The immediate release form of the opioid is included in an amount
which is effective to shorten the time to maximum concentration of
the opioid in the blood (e.g., plasma), such that the T.sub.max is
shortened to a time of, e.g., from about 2 to about 4 hours. This
causes the blood concentration curve to have an early peak rather
than the substantially flattened curves currently recommended by
those skilled in the art. It has been discovered that by including
such an effective amount of immediate release opioid in the unit
dose, the experience of relatively higher levels of pain in
patients is significantly reduced. In such embodiments, an
effective amount of the opioid in immediate release form may be
coated onto the substrates of the present invention. For example,
where the extended release opioid from the formulation is due to a
controlled release coating, the immediate release layer would be
overcoated on top of the controlled release coating. On the other
hand, the immediate release layer may be coated onto the surface of
substrates wherein the opioid is incorporated in a controlled
release matrix. Where a plurality of the sustained release
substrates comprising an effective unit dose of the opioid are
incorporated into a hard gelatin capsule, the immediate release
portion of the opioid dose may be incorporated into the gelatin
capsule via inclusion of the sufficient amount of immediate release
opioid as a powder or granulate within the capsule. Alternatively,
the gelatin capsule itself may be coated with an immediate release
layer of the opioid. One skilled in the art would recognize still
other alternative manners of incorporating the immediate release
opioid portion into the unit dose. Such alternatives are deemed to
be encompassed by the appended claims.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0086] The following examples illustrate various aspects of the
present invention. They are not to be construed to limit the claims
in any manner whatsoever.
EXAMPLE 1
Sustained-Release Beads With Ethylcellulose Coating
[0087] In Example 1, morphine sulfate sustained-release beads with
a 5% w/w sustained-release of ethylcellulose were prepared,
including 3% of HPMC as a pore-former in the coating.
[0088] Morphine sulfate beads are first manufactured using a rotor
processing technique. The formula of the morphine sulfate bead to
which the sustained-release coating is applied is set forth in
Table 1 below:
TABLE-US-00001 TABLE 1 Amt/Unit Ingredient (mg) Percent (%)
Morphine Sulfate Powder 30 mg 14.3% Lactose Hydrous Impalpable 42.5
mg 20.2% PVP 2.5 mg 1.2% Sugar Beads 18/20 125 mg 59.4% Purified
Water qs -- Opadry .RTM. Red YS-1-1841 10.5 mg 4.9% Total 210.5 mg
100.0%
[0089] The morphine sulphate beads were then overcoated with a
sustained-release coating. The formula for the sustained-release
coating is set forth in Table 2 below:
TABLE-US-00002 TABLE 2 Amt/Unit Ingredient (mg) Percent (%)
Morphine Sulfate Base Beads 210.5 mg 89.7% Aquacoat ECD 30 (solids)
10.2 mg 4.3% Methocel E5 Premium 0.3 mg 0.1% Triethyl Citrate 2.1
mg 0.9% Purified Water qs -- Opadry .RTM. Red YS-1-1841 11.7 mg
5.0% Purified Water qs -- Total 234.8 mg 100.0%
[0090] The sustained-release coating was manufactured as
follows:
[0091] The pore former Methocel E5 Premium (HPMC), is dispersed and
dissolved in purified water to yield a 2% w/w solution. An Aquacoat
dispersion is plasticized with triethyl citrate for approximately
30 minutes. After 30 minutes the HPMC dispersion is mixed into the
plasticized Aquacoat dispersion, and blended for an additional
15-30 minutes. A load of the morphine sulfate beads is charged into
a Uniglatt Wurster Insert equipped with a 1.2 mm fluid nozzle. The
beads are then filmcoated with the Aquacoat/HPMC dispersion (in a
ratio of 93:7) to a weight gain of 5%.
[0092] After completion of the coating process, the coated beads
are taken from the Wurster Insert to a tray and then cured in a
chamber at a temperature of 60.degree. C. and humidity of 80%
R.sup.H for 72 hours. Upon completion of the curing process, the
beads are dried to a LOD of 4% or less. The beads are then given a
final overcoating of Opadry.RTM. Red YS-1-1841 (15% w/w solution)
with the use of the Wurster Insert. The coated morphine sulfate
beads are then filled into hard gelatin capsules.
[0093] Dissolution testing were conducted on the finished products
via USP Apparatus II-(Paddle Method). The capsules were placed into
700 ml of simulated gastric fluid (without enzymes) for the first
hour at 100 rpm and 37.degree. C., and then placed into 900 ml of
simulated gastric fluid (without enzymes) after the first hour. The
results are set forth in Table 3 below:
TABLE-US-00003 TABLE 3 Percent Morphine Time Sulfate Dissolved 1
hour 18.4% 2 hours 28.4% 4 hours 46.7% 8 hours 73.1% 12 hours 86.0%
18 hours 95.0% 24 hours 99.0%
[0094] The dissolution testing as set forth in Table 3 indicates
that 100% of the morphine sulfate dissolved after 12 hours.
EXAMPLE 2
Sustained-Release Beads with Acrylic Polymer Coating
[0095] In example 2, morphine sulfate sustained-release beads with
a 5% w/w sustained-release Eudragit RS were prepared, including a
10% immediate release morphine sulfate overcoat.
[0096] Morphine sulfate beads are first manufactured using a rotor
processing technique. The formula of the morphine sulfate bead to
which the sustained-release coating is applied is set forth in
Table 4 below:
TABLE-US-00004 TABLE 4 Amt/Unit Ingredient (mg) Percent (%)
Morphine Sulfate Powder 30 mg 14.3% Lactose Hydrous Impalpable 42.5
mg 20.2% PVP 2.5 mg 1.2% Sugar Beads 18/20 125 mg 59.4% Purified
Water qs mg -- Opadry Red YS-1-1841 10.5 mg 4.9% Total 210.5 mg
100.0%
[0097] A sustained-release coating was then applied to the morphine
sulfate beads. The formula for the functional coating is set forth
in Table 5 below:
TABLE-US-00005 TABLE 5 Amt/Unit Ingredient (mg) Percent (%)
Morphine Base Beads 189.45 mg 86.7% Retardant Coating Eudragit RS
30D 9.5 mg 4.3% Triethyl Citrate 1.9 mg 0.9% Talc 3.8 mg 1.7%
Purified Water qs -- Overcoat Morphine Sulfate Powder 3.0 mg 1.4%
Opadry Red YS-1-1841 10.8 mg 5.0% Purified Water qs -- Total 218.45
mg 100.0%
[0098] The sustained-release coating is manufactured as
follows:
[0099] The Eudragit RS 30D is plasticized with triethyl citrate and
talc for approximately 30 minutes. A load of the morphine sulfate
beads is charged into a Wurster Insert of a Glatt equipped with a
1.2 mm spray nozzle and the beads are coated to a weight gain of
5%. The final protective Opadry dispersion overcoat is then applied
in the Wurster Insert. Upon completion the beads are cured for two
days in a dry oven of 45.degree. C. The cured beads were then
filled into gelatin capsules at a 30 mg strength.
[0100] Dissolution testing were conducted on the gelatin capsules
via U.S.P. Apparatus II (Paddle Method). The capsules were placed
into 700 ml of simulated gastric fluid (without enzymes) for the
first hour at 100 rpm and 37.degree. C., and then placed into 900
ml of simulated gastric fluid (without enzymes) after the first
hour. The results of the percent of morphine sulfate dissolved in
relation to time, are set forth in Table 6 below:
TABLE-US-00006 TABLE 6 Percent Morphine Time Sulfate Dissolved 1
hour 11.9% 2 hours 15.4% 4 hours 28.1% 8 hours 58.3% 12 hours 79.2%
18 hours 92.0% 24 hours 96.6%
[0101] The dissolution testing as set forth in Table 6 indicates
that 96.6% of the morphine sulfate dissolved after 24 hours.
EXAMPLE 3
High Load Sustained-Release Beads with Acrylic Polymer Coating
[0102] In certain circumstances, patients require higher doses of
morphine sulfate. However, if the low load beads of Examples 1 and
2 were filled to a weight equivalent to 60 mg or more, the capsules
would be relatively large, and difficult to swallow. Therefore, in
Example 3, beads with a higher loading of morphine sulfate were
produced with the use of the powder layering technique in the Glatt
Rotor Processor. The formulation of the high load beads, as well as
a comparison of the high load beads with the low load beads of
Examples 1 and 2, are set forth in Table 7 below:
TABLE-US-00007 TABLE 7 Low Load Bead High Load Bead (Examples 1
& 2) Percent Percent Ingredient mg/unit (%) mg/unit (%)
Morphine Sulfate 30.0 mg 63.3% 30.0 mg 14.3% Powder Lactose 6.0 mg
12.7% 42.5 mg 20.2% Povidone C-30 1.25 mg 2.6% 2.5 mg 1.2% Sugar
Beads 7.75 mg 16.4% 125.0 mg 59.4% Opadry 2.37 mg 5.0% 10.5 mg 4.9%
Purified Water qs -- qs -- Total 47.37 mg 100.0% 210.5 mg
100.0%
[0103] Since high load beads of Example 3 are different from the
low load beads of Examples 1 and 2, the sustained-release coating a
different acrylic polymer (i.e., Eudragit.RTM. RL, which is more
soluble than Eudragit.RTM. RS) is utilized, as well as extra HPMC
protective coat between the Eudragit layer and the morphine
immediate release layer to further enhance stability. The formula
of the sustained-release coating of Example 3 is set forth in Table
8 below:
TABLE-US-00008 TABLE 8 Amt/Unit Ingredient (mg) Percent (%)
Morphine (high load) base beads 42.63 mg 78.8% Retardant Coating
Eudragit RS 30D 2.1 mg 3.9% Eudragit RL 30D 0.05 mg 0.1% Triethyl
Citrate 0.45 mg 0.8% Talc 0.85 mg 1.6% Overcoatings Opadry Blue
YS-1-10542A 2.45 mg 4.5% Purified Water qs -- Morphine Sulfate
Powder 3.0 mg 5.5% Opadry Blue YS-1-10542A 2.55 mg 4.8% Purified
Water qs -- Total 54.08 mg 100.0%
[0104] The sustained-release and the immediate release coatings
were applied in the manner described in Example 2. The cured beads
were then filled into gelating capsules at a strength of 30 mg.
[0105] The capsules were then subjected to dissolution testing
applying the method described in Example 1. The results of
dissolution testing is set forth in Table 9 below:
TABLE-US-00009 TABLE 9 Percent Morphine Time Sulfate Dissolved 1
hour 11.7% 2 hours 12.1% 4 hours 22.0% 8 hours 45.3% 12 hours 63.7%
18 hours 81.8% 24 hours 92.5%
[0106] The dissolution testing as set forth in Table 9 indicates
that 92.5% of the morphine sulfate dissolved after 24 hours.
EXAMPLE 4
Sustained-Release Tablets
[0107] Controlled release morphine sulfate tablets were developed
with an in-vitro dissolution profile that would be suitable for
once-a-day administration. The formula of the morphine sulfate
tablets is set forth in Table 10 below.
TABLE-US-00010 TABLE 10 Amt/Unit Ingredient (mg) Percent (%)
Morphine Sulfate 60.0 mg 40.0% Lactose 36.1 mg 24.1% Povidone 6.0
mg 4.0% Eudragit RS 30D (solids) 12.0 mg 8.0% Triacetin 1.4 mg 0.9%
Cetostearyl alcohol 30.0 mg 20.0% Talc 3.0 mg 2.0% Magnesium
stearate 1.5 mg 1.0% Total 150.0 mg 100.0%
[0108] These tablets are manufactured in the following manner:
[0109] The morphine sulfate, lactose and povidone were added and
mixed in fluid bed granulator. The triacetin, a plasticizer was
mixed into the Eudragit RS 30D dispersion for about 30 minutes, and
then was sprayed onto the powders using a 1.2 mm nozzle in the
fluid bed. Once the spraying is completed, the granulate is
screened. The cetostearyl alcohol is then melted and mixed into the
granulation in a standard mixing bowl. The granulate is then
cooled, screened and lubricated with talc and magnesium stearate.
Tablets were then compressed at a weight of 150 mg.
[0110] Dissolution testing of these morphine sulfate tablets was
then conducted using the method described in Example 1. The results
of the dissolution testing of these tablets is set forth in Table
11 below:
TABLE-US-00011 TABLE 11 Percent Morphine Time Sulfate Dissolved 1
hour 20.9% 2 hours 29.3% 4 hours 40.8% 8 hours 59.9% 12 hours 69.7%
18 hours 82.9% 24 hours 90.5%
[0111] The results of dissolution of the morphine sulfate tablets
as set forth in Table 11 shows that 90.5% of the morphine sulfate
dissolved in 24 hours.
[0112] Examples 1, 2, 3 and 4 were plotted on a dissolution graph
(see FIG. 1) and it can be observed that the dissolution of the
morphine sulfate tablets of Example 4 are approximately the same as
the three bead examples. The release rate of the tablets of Example
4 lies with the dissolution of the bead products (Examples 1-3).
For reference purposes, the dissolution of MS Contin.RTM. 30 mg and
60 mg tablets were also plotted on FIG. 1. MS Contin.RTM. tablets
are well known morphine sustained-release tablets that are
commercially available from the Purdue Frederick Company for
twice-a-day administration.
EXAMPLE 5
In-Vivo Bioavailability Studies
[0113] The bead products of Examples 1, 2 and 3 were then studied
in separate human bioavailability studies at a dose of 30 mg. Each
study also used a 30 mg strength MS Contin.RTM. as a reference in a
cross-over design. The 60 mg tablet of Example 4 was compared to MS
Contin.RTM. 60 mg as a reference in a cross-over study. The results
of all four bioavailability studies are set forth in Tables 12-15
below. In Table 16, the in-vivo results of Example 4 are set forth
with the results adjusted to a 30 mg strength. In each of Tables
12-16, C.sub.max is expressed in ng/ml; T.sub.max is expressed in
hours; W.sub.50 represents the peak width at half height in hours;
and AUC represents the area under the curve (O to infinity),
expressed in ng-hr/ml.
TABLE-US-00012 TABLE 12 Beads - Example 1 C.sub.max T.sub.max W50
AUC % Bioavail. MS Contin .RTM. 13 2.3 5 103 (100) 30 mg Tablets
Experimental 5.9 5.6 11.5 101 98 Bead Formulation
TABLE-US-00013 TABLE 13 Beads - Example 2 C.sub.max T.sub.max W50
AUC % Bioavail. MS Contin .RTM. 13 2.2 5 99 (100) 30 mg Tablets
Experimental 5.4 5.9 17 107 108 Bead Formulation
TABLE-US-00014 TABLE 14 Beads - Example 3 C.sub.max T.sub.max W50
AUC % Bioavail. MS Contin .RTM. 11.8 2.8 5 114 (100) 30 mg Tablets
Experimental 3.8 10.1 47 125 110 Bead Formulation
TABLE-US-00015 TABLE 15 Tablets - Example 4 C.sub.max T.sub.max W50
AUC % Bioavail. MS Contin .RTM. 18.2 2.7 5.56 195.6 (100) 60 mg
Tablets Experimental 8.8 3.2 13.19 129.5 66 Tablet Formulation
TABLE-US-00016 TABLE 16 Example 4 - Adjusted to 30 mg Strength
C.sub.max T.sub.max W50 AUC % Bioavail. MS Contin .RTM. 9.1 2.7
5.56 97.8 (100) Experimental 4.4 3.2 13.19 64.8 66 Tablet
Formulation
[0114] From the bioavailability studies, it can be observed that
all three of the bead products of Examples 1, 2 and 3 exhibit
pharmacokinetic properties which would allow them to be suitable
for once-a-day administration. In other words, the bead products of
Examples 1-3 were all bioavailable (as determined by comparing the
AUC of the bead product to the AUC of the reference standard, MS
Contin.RTM.). However, the tablet products of Example 4 were
surprisingly not bioavailable despite the reduction of the peak
plasma concentration (C.sub.max) and the lengthening of the time to
reach peak plasma concentration (T.sub.max) and W-50 and even
though the dissolution studies show that the morphine sulfate was
released from the tablet products in-vitro over the same time
period as the bead products.
[0115] Therefore, it is surprising result that a bioavailable
once-a-day product was only produced when the sustained release
opioid was formulation as a multiparticulate system (in this
instance beads) as opposed to the sustained release tablet
formulation, which from all other indications would have been
expected to have substantially identical bioavailability.
[0116] The examples provided above are not meant to be exclusive.
Many other variations of the present invention would be obvious to
those skilled in the art, and are contemplated to be within the
scope of the appended claims.
* * * * *