U.S. patent application number 15/004461 was filed with the patent office on 2016-10-27 for misuse preventative, controlled release formulation.
The applicant listed for this patent is Paladin Labs (Barbados) Inc., Paladin Labs Europe Limited, Paladin Labs Inc.. Invention is credited to Ali Bichara, Frederic Duffayet, Ali El-Jammal, Sonia Gervais, Jean-Michel Ndong, Miloud Rahmouni, Shams Rustom, Vinayak Sant, Damon Smith.
Application Number | 20160310432 15/004461 |
Document ID | / |
Family ID | 42268221 |
Filed Date | 2016-10-27 |
United States Patent
Application |
20160310432 |
Kind Code |
A1 |
Rahmouni; Miloud ; et
al. |
October 27, 2016 |
MISUSE PREVENTATIVE, CONTROLLED RELEASE FORMULATION
Abstract
Disclosed is a misuse preventative, controlled release
composition in the form of a multilayered oral dosage form. A first
layer contains a plurality of controlled release microparticles
having a pharmaceutically active agent (for example, an opioid
analgesic) disposed therein. The second layer, which can be
adjacent the first layer comprises a pharmaceutically active agent
that can be the same or different from the pharmaceutically active
agent in the microparticles in the first layer. The composition
further comprises a superabsorbent material (for example,
polycarbophil) disposed within the first layer, the second layer,
or both the first layer and the second layer. When intact, the
pharmaceutically active agent is released from the second layer
faster than the pharmaceutically active agent in the first layer.
When crushed, either intentionally or accidentally, and exposed to
an aqueous medium, the superabsorbent material present swells to
encapsulate the microparticles, which remain substantially intact
thereby retarding the release of the pharmaceutically active agent
from the composition. Also disclosed is a method of using the
misuse preventative, controlled release composition to deliver at
least one pharmaceutically active agent to a mammal, for example, a
human, in need thereof.
Inventors: |
Rahmouni; Miloud;
(Pierrefonds, CA) ; Gervais; Sonia; (Laval,
CA) ; Sant; Vinayak; (Pittsburgh, PA) ; Smith;
Damon; (Saint-Laurent, CA) ; Duffayet; Frederic;
(Montreal, CA) ; Rustom; Shams; (Saint-Laurent,
CA) ; El-Jammal; Ali; (Beaconsfield, CA) ;
Ndong; Jean-Michel; (Repentigny, CA) ; Bichara;
Ali; (Ste-Therese, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Paladin Labs Inc.
Paladin Labs (Barbados) Inc.
Paladin Labs Europe Limited |
Montreal
Hastings
Dublin |
|
CA
BB
IE |
|
|
Family ID: |
42268221 |
Appl. No.: |
15/004461 |
Filed: |
January 22, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14560933 |
Dec 4, 2014 |
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15004461 |
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14195833 |
Mar 3, 2014 |
8927013 |
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14560933 |
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13919499 |
Jun 17, 2013 |
8685447 |
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14195833 |
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12639664 |
Dec 16, 2009 |
8486449 |
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13919499 |
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61138092 |
Dec 16, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2077 20130101;
A61K 9/1652 20130101; A61K 9/1635 20130101; A61K 9/2866 20130101;
A61K 31/485 20130101; A61K 9/0053 20130101; A61K 9/1623 20130101;
A61K 9/2009 20130101; A61K 9/209 20130101; A61K 9/2081 20130101;
A61K 9/28 20130101; A61K 9/205 20130101; A61K 9/2013 20130101; A61K
9/2018 20130101; A61K 9/2027 20130101; A61K 9/2054 20130101; A61K
9/2086 20130101; A61K 31/167 20130101; A61K 9/1611 20130101 |
International
Class: |
A61K 9/24 20060101
A61K009/24; A61K 9/20 20060101 A61K009/20; A61K 31/167 20060101
A61K031/167; A61K 9/00 20060101 A61K009/00; A61K 31/485 20060101
A61K031/485 |
Claims
1. A solid composition for oral administration of at least one
pharmaceutically active agent, comprising: (a) a first layer
comprising a first population of controlled release microparticles
having a pharmaceutically active agent disposed therein; (b) a
second layer comprising a pharmaceutically active agent disposed
therein; and (c) a superabsorbent material disposed within the
first layer, the second layer, or both the first layer and the
second layer, wherein the composition, (i) when intact and exposed
to an aqueous environment, the pharmaceutically active agent
disposed in the second layer is initially released at a faster rate
than the pharmaceutically active agent disposed in the first layer,
and (ii) when crushed and exposed to an aqueous environment, the
superabsorbent material swells to create a hard gel that traps the
microparticles, whereupon the hard gel, the microparticles or both
the hard gel and microparticles provide controlled release of at
least the pharmaceutically active agent disposed within the
microparticles.
2. The composition of claim 1, wherein the superabsorbent material
is disposed within the first layer.
3. The composition of claim 1, wherein the superabsorbent material
is disposed within the second layer.
4. A solid composition for oral administration of at least one
pharmaceutically active agent, comprising: (a) a first layer
comprising a superabsorbent material and first population of
controlled release microparticles having a pharmaceutically active
agent disposed therein; (b) a second layer comprising a
pharmaceutically active agent disposed therein, wherein the
composition, (i) when intact and exposed to an aqueous environment,
the pharmaceutically active agent disposed in the second layer is
initially released at a faster rate than the pharmaceutically
active agent disposed in the first layer, and (ii) when crushed and
exposed to an aqueous environment, the superabsorbent material
swells to create a hard gel that traps the microparticles,
whereupon the hard gel, the microparticles or both the hard gel and
microparticles provide controlled release of at least the
pharmaceutically active agent disposed within the
microparticles.
5. The composition of claim 1, wherein the pharmaceutically active
agent disposed in the second layer is present in a second
population of controlled release microparticles.
6. The composition of claim 1, wherein the pharmaceutically active
agent present in the first layer and the pharmaceutically active
agent present in the second layer are the same.
7. The composition of claim 1, wherein the pharmaceutically active
agent present in first layer and the pharmaceutically active agent
present in the second layer are different.
8. The composition of claim 1, wherein the first layer is adjacent
the second layer.
9. The composition of claim 8, wherein the composition is a
bilayer.
10. The composition of claim 1, wherein a third layer is disposed
between the first layer and the second layer.
11. The composition of claim 1, wherein the pharmaceutically active
agent present in the first layer is released over a period of at
least 6 hours.
12. The composition of claim 1, wherein the pharmaceutically active
agent present in the first layer is released over a period of at
least 12 hours.
13. The composition of claim 12, wherein the pharmaceutically
active agent present in the first layer is released over a period
of at least 24 hours.
14. The composition of claim 1, wherein the superabsorbent material
is a polysaccharide derivative selected from the group consisting
of a starch graft copolymer, a cross-linked carboxymethylcellulose
derivative, a cross-linked hydroxypropyl distarch phosphate, a
hydrolyzed starch-acrylonitrile graft copolymer and a neutralized
starch-acrylic acid graft copolymer.
15. The composition of claim 1, wherein the superabsorbent material
is a polymer selected from the group consisting of polyacrylic
acid, polyacrylamido methylpropane sulfonic acid, polyvinyl acetic
acid, polyvinyl phosphonic acid, polyvinyl sulfonic acid,
isobutylene-maleic anhydride copolymer, carboxymethyl cellulose,
alginic acid, carrageenan, polyaspartic acid, polyglutamic acid,
polyvinyl amine, polydiallyl dimethyl ammonium hydroxide,
polyacrylamidopropyl trimethyl ammonium hydroxide, polyamino
propanol vinyl ether, polyallylamine, chitosan, polylysine,
polyglutamine, polycarbophil, polycarbophilic calcium,
polymethacrylic acid, polyacrylic acid, and mixtures thereof.
16. The composition of claim 1, wherein the superabsorbent material
constitutes from about 1% to about 70% (w/w) of the first layer or
the second layer.
17. The composition of claim 16, wherein the superabsorbent
material constitutes from about 2% to about 50% (w/w) of the first
layer or the second layer.
18. The composition of claim 1, wherein the first layer, the second
layer, or both the first and second layers further comprise a
controlled release agent.
19. The composition of claim 18, wherein the controlled release
agent is selected from the group consisting of acetate succinate, a
polyvinyl derivative, polyethylene oxide, polyacrylic acid,
modified starch, cross-linked high amylose starch, hydroxypropyl
starch, hydroxypropyl methylcellulose phthalate, cellulose,
microcrystalline cellulose, carboxymethylethyl cellulose, cellulose
acetate, methylcellulose, ethylcellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, cellulose phthalate, cellulose
acetate, cellulose acetate phthalate, cellulose acetate propionate,
cellulose acetate succinate, cellulose acetate butyrate, cellulose
acetate trimellitate, poloxamer, povidone, alginic acid, sodium
alginate, polyethylene glycol, polyethylene glycol alginate, gums,
polymethacrylate, a copolymer of methacrylic acid and ethyl
acrylate, a copolymer of polymethyl vinyl ether and malonic acid
anhydride, a copolymer of polymethyl vinyl ether and malonic acid
or the ethyl-, isopropyl-, n-butylesters thereof, zein, and
mixtures of any of the foregoing.
20. The composition of claim 1, wherein the first layer, the second
layer or both the first and second layers further comprise a
diluent, a lubricant, a glidant, or a mixture thereof.
21-66. (canceled)
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of and priority to
co-pending U.S. Provisional Patent Application Ser. No. 61/138,092,
filed Dec. 16, 2008, the entire contents of which are incorporated
by reference herein.
FIELD OF THE INVENTION
[0002] The present invention relates generally to a controlled
release formulation for the delivery of at least one
pharmaceutically active agent, and more specifically, the invention
relates to a misuse preventative, controlled release formulation,
which maintains its controlled release properties for at least one
pharmaceutically active agent even when bisected or crushed, and
exposed to various media.
BACKGROUND OF THE INVENTION
[0003] Although significant developments have been made in the
field of drug delivery, concerns remain for drugs (for example,
opioid analgesics) that are subject to abuse. Furthermore, the
number of legitimate patients misusing such drugs, either
deliberately or accidentally, represents a serious medical problem.
In particular, patient risk can be heightened when controlled
release formulations are used because larger amounts of the
pharmaceutically active agent are typically incorporated into these
formulations to facilitate reduced dosing frequency. However, while
controlled release formulations offer greater convenience and often
an improved adverse event profile, serious problems can occur if
the control release mechanism is compromised in any way, for
example, by accidental chewing or grinding of, or other damage to
the tablet, or co-ingestion with alcohol. Under these scenarios,
immediate release of the pharmaceutically active agent followed by
the rapid absorption of up to a total daily dose of the
pharmaceutical agent can have potentially fatal consequences.
[0004] While a number of approaches have been tried to address the
abuse and misuse of certain drugs, including, for example, the use
of deterrent formulations, agonist/antagonist formulations, and
prodrug formulations, the commercialization of these approaches has
been limited to date.
[0005] Deterrent formulations are formulations that contain a
noxious substance, such as, capsaicin, an emetic, or niacin. The
objective is to prevent deliberate abuse by inflicting a painful or
otherwise unpleasant reaction should the formulation be crushed or
otherwise damaged prior to ingestion. For example, U.S. Patent
Publication Nos. 2003/0068370, 2003/0068392, and 2007/0020188
describe incorporation of aversive agents (e.g., a bitter agent, an
irritant, or an emetic agent) into a dosage containing an opioid
analgesic. The aversive agents discourage an abuser from tampering
with the dosage form and thereafter inhaling or injecting the
tampered dosage. The potential risk of such additives to the
legitimate user who accidentally damages the tablet is not
addressed by such formulations.
[0006] Antagonist formulations contain inhibitors (antagonists) of
the therapeutic drug. When the formulation is crushed, the
inhibitors are intended to prohibit or reverse the action of the
pharmaceutically active agent, thereby reducing or eliminating any
benefit for non-medical use. For example, naloxone is combined with
pentazocine (Talwin.RTM., sold by Sanofi-Winthrop) to deter
parenteral abuse of pentazocine. Naloxone is intended to block the
binding of pentazocine to opioid receptors. Similarly, naloxone has
been added to a buprenorphine-containing formulation
(Temgesic.RTM., sold by Reckitt & Colman). In addition,
naltrexone, an opioid receptor antagonist, has been added to a
morphine-containing formulation (Embeda.RTM., sold by King
Pharmaceuticals, Inc.). It is understood, however, that this
approach, can expose legitimate patients to unnecessary drugs, and
can potentially inhibit effective therapy because the inhibitors
may be released during normal passage through the gastrointestinal
tract. These formulations also assume that effective inhibition can
be achieved (i.e., that the bioavailability, pharmacokinetics and
relative affinities of the agonist and antagonist can be matched so
as to elicit effective inhibition in the intended recipient). U.S.
Pat. Nos. 3,773,955 and 3,966,940, for example, describe
formulations containing combinations of opioid agonists and
antagonists, in which the antagonist does not block the therapeutic
effect when the mixture is administered orally but blocks
analgesia, euphoria or physical dependence when administered
parenterally in crushed form by an abuser.
[0007] Prodrug formulations rely on in vivo metabolic conversion of
the prodrug into the active drug by enzymes found, for example, in
the gastrointestinal tract. While these formulations may prevent
euphoria via intravenous or nasal administration of the drug, they
do not address the problems associated with potential intoxication
(for example, alcohol intoxication) post oral administration.
[0008] Because of such limitations with existing technologies,
there exists an ongoing need for misuse preventative, controlled
release formulations that can reduce the risk of intentional abuse
and accidental misuse of formulations containing a pharmaceutically
active agent.
SUMMARY OF THE INVENTION
[0009] The invention is based, in part, upon the discovery that it
is possible to create a drug delivery platform where the
compositions are oral dosage forms that permit the controlled
release of at least one pharmaceutically active agent disposed
within the formulation even after being sectioned (for example,
bisected) or crushed. The platform is particularly useful for the
administration of pharmaceutically active agents that are capable
of misuse (either deliberate or accidental but in either case
causing harm), abuse and/or that have a narrow therapeutic index.
Agents capable of harmful misuse or abuse, include, for example,
analgesics (for example, opioid analgesics), hypnotic agents,
anxiolytic agents, central nervous system (CNS), and respiratory
stimulating agents. Examples of narrow therapeutic index drugs
include theophylline, lithium carbonate, and digoxin.
[0010] In one aspect, the invention provides a solid composition
(oral dosage form) for the oral administration of at least one
pharmaceutically active agent. The composition comprises (a) a
first layer comprising a first population of controlled release
microparticles having at least one pharmaceutically active agent
disposed therein; (b) a second layer comprising a pharmaceutically
active agent disposed therein; and (c) a superabsorbent material
disposed within the first layer, the second layer, or both the
first layer and the second layer. In another aspect, the invention
provides a solid composition (oral dosage form) for the oral
administration of at least one pharmaceutically active agent. The
composition comprises (a) a first layer comprising a superabsorbent
material and a first population of controlled release
microparticles having at least one pharmaceutically active agent
disposed therein; and (b) a second layer comprising a
pharmaceutically active agent disposed therein.
[0011] In each of the foregoing aspects, when the composition is
exposed intact to an aqueous environment, the pharmaceutically
active agent disposed in the second layer is initially released at
a faster rate than the pharmaceutically active agent disposed in
the first layer. At least one pharmaceutically active agent is
released from the intact formulation over a prolonged period of
time (for example, for at least 6 hours, at least 8 hours, at least
12 hours, at least 18 hours, or at least 24 hours). In certain
embodiments, at least 50%, preferably 60%, more preferably 70%, and
even more preferably 80% of at least one pharmaceutically active
agent is prevented from being released substantially immediately
(for example, within 30 minutes) from the intact formulation.
[0012] In addition, when the composition is crushed and exposed to
an aqueous environment, the superabsorbent material swells to
create a hard, rigid gel that traps the microparticles, which
remain substantially intact. As a result, and in addition to the
controlled release properties provided by the microparticles
themselves, the hard gel depending upon its composition, may
provide controlled release of at least one pharmaceutically active
agent disposed therein. Depending upon the mode of abuse, the
compositions of the invention create an unpleasant experience for
the abuser, make it difficult to extract the pharmaceutically
active agent, and/or prevent dose dumping. For example, when
crushed and snorted up a nostril, the superabsorbent material
produces a hard gel that creates an unpleasant experience.
Furthermore, if crushed and exposed to an extraction media, the
superabsorbant material can absorb all of the extraction media. The
resulting gel can be difficult to push through the needle of a
syringe. Furthermore, when crushed and administered, the
microparticles, or a combination of the microparticles and the gel,
maintain controlled release of the pharmaceutically active agent
and reduce or eliminate the potential for dose dumping. In certain
embodiments, at least 50%, preferably 60%, more preferably 70%, and
even more preferably 80% of at least one pharmaceutically active
agent is prevented from being released substantially immediately
(for example, within 30 minutes) from the formulation. As a result,
the compositions of the invention prevent dose dumping in water,
alcohol (for example, ethanol), and other media of various pH even
if the formulations have been broken or crushed.
[0013] The pharmaceutically active agent present in the first layer
and the pharmaceutically active agent present in the second layer
can be the same. Alternatively, they can be different so that a
first pharmaceutically active agent is present in the
microparticles in the first layer and a second, different
pharmaceutically active agent is present in the second layer.
Furthermore, the first layer can further comprise another
pharmaceutically active agent, which can be in free form or present
within microparticles. Furthermore, the pharmaceutically active
agent disposed in the second layer optionally can be present in a
second population of controlled release microparticles.
[0014] The composition is multilayered and can comprise two, three,
four or more different layers. In one embodiment, the first layer
is adjacent the second layer. As such, the two layers can form a
bilayer composition. In another embodiment, the composition
comprises a third layer, that can be adjacent the first layer,
adjacent the second layer, or is disposed between the first layer
and the second layer.
[0015] At least one pharmaceutically active agent present in the
second layer is initially (for example, within the first 15 minutes
or within the first 30 minutes after exposure to an aqueous
environment) released at a faster rate than the pharmaceutically
active agent in the first layer. This can be achieved via a number
of approaches. For example, the pharmaceutically active agent in
the first layer is disposed in controlled release microparticles
whereas the pharmaceutically active agent in the second layer is
not present within or otherwise associated with controlled release
microparticles. Furthermore, the first layer can comprise a first
controlled release matrix whereas the second layer can comprise an
immediate release matrix. Alternatively, the first layer can
comprise a first controlled release matrix whereas the second layer
comprises a second, different controlled release matrix, wherein
the first controlled release matrix has slower release kinetics
than the second controlled release matrix. It is understand that a
particular dosage form will vary depending upon the
pharmaceutically active agent or agents to be delivered and the
release profile desired for each pharmaceutically active agent.
[0016] A variety of superabsorbent materials can be used in the
practice of the invention. The superabsorbent material can be
polymeric, which can include, for example, polysaccharides,
polysaccharide derivatives, and synthetic polymers. Exemplary
polymers include, for example, a starch graft copolymer, a
cross-linked carboxymethylcellulose derivative, a cross-linked
hydroxypropyl distarch phosphate, a hydrolyzed starch-acrylonitrile
graft copolymer and a neutralized starch-acrylic acid graft
copolymer, polyacrylic acid, polyacrylamido methylpropane sulfonic
acid, polyvinyl acetic acid, polyvinyl phosphonic acid, polyvinyl
sulfonic acid, isobutylene-maleic anhydride copolymer,
carboxymethyl cellulose, alginic acid, carrageenan, polyaspartic
acid, polyglutamic acid, polyvinyl amine, polydiallyl dimethyl
ammonium hydroxide, polyacrylamidopropyl trimethyl ammonium
hydroxide, polyamino propanol vinyl ether, polyallylamine,
chitosan, polylysine, polyglutamine, polycarbophil, polycarbophilic
calcium, polymethacrylic acid, polyacrylic acid, and mixtures
thereof. In a preferred embodiment, the superabsorbent material is
polycarbophil.
[0017] The superabsorbent material can constitute from about 1% to
about 70% (w/w) of the layer in which it is present (e.g., the
first layer, the second layer, or both the first and second layers
or the optional third layer) or from about 4% to about 50% (w/w) of
the layer in which it is present (e.g., the first layer, the second
layer, or both the first and second layers or the optional third
layer).
[0018] As discussed above, the first layer, the second layer, or
both the first and second layers may further comprise a controlled
release agent. Exemplary controlled release agents include, for
example, acetate succinate, a polyvinyl derivative, polyethylene
oxide, polyacrylic acid, modified starch, cross-linked high amylose
starch, hydroxypropyl starch, hydroxypropyl methylcellulose
phthalate, cellulose, microcrystalline cellulose,
carboxymethylethyl cellulose, cellulose acetate, methylcellulose,
ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl
cellulose, cellulose phthalate, cellulose acetate, cellulose
acetate phthalate, cellulose acetate propionate, cellulose acetate
succinate, cellulose acetate butyrate, cellulose acetate
trimellitate, poloxamer, povidone, alginic acid, sodium alginate,
polyethylene glycol, polyethylene glycol alginate, gums (for
example, xanthan gums), polymethacrylate, a copolymer of
methacrylic acid and ethyl acrylate, a copolymer of polymethyl
vinyl ether and malonic acid anhydride, a copolymer of polymethyl
vinyl ether and malonic acid or the ethyl-, isopropyl-,
n-butylesters thereof, zein, and mixtures of any of the foregoing.
Furthermore, the first layer, the second layer or both the first
and second layers can further comprise a diluent, a lubricant, a
glidant, or a mixture thereof. The second layer can further
comprise a disintegrant. Disintegrants preferably are omitted from
the first layer, because when intact compositions are exposed to an
aqueous environment, disintegrants in the first layer may cause the
first layer to break apart thereby permitting the superabsorbent
material to prematurely swell and create a hard gel.
[0019] It is understood that the composition can further comprise a
coating that encapsulates the first layer and the second layer. The
coating can be a non-functional (aesthetic coating) or can be a
functional coating. Exemplary functional coatings include a
controlled released coating, (for example, a delayed release
coating, such as an enteric coating), a moisture barrier, or a
taste masking film. The controlled release coating can include a
controlled release agent and/or can be a controlled release film
coating.
[0020] The controlled release microparticles present in the first
layer and optionally present in the second layer can comprise a
controlled release agent (for example, cross-linked high amylose
starch sold under the Tradename CONTRAMID.RTM. from Labopharm,
Inc., Laval, Canada) that controls the release of the
pharmaceutically active agent disposed therein and/or a controlled
release coating or film. The microparticles have an average
diameter in the range from about 1 .mu.m to about 1000 .mu.m. The
microparticles, due to their small size and high radius of
curvature, resist crushing if the formulation is crushed, for
example, with a conventional pill crusher or between spoons or in a
pestle and mortar. In one embodiment, the microparticles have an
average diameter in the range from about of 200 .mu.m to about 900
.mu.m, or from about 300 .mu.m to about 800 .mu.m. The
microparticles under certain circumstances have an average diameter
of about 700 .mu.m. In another embodiment, the controlled release
microparticles have an average diameter in the range of from about
1 .mu.m to about 400 .mu.m, from about 5 .mu.m to about 300 .mu.m,
or from about 10 .mu.m to about 200 .mu.m. The microparticles can
have an average diameter of about 100 The controlled release
microparticles included in the first layer and optionally in the
second layer can be coated with one or more controlled release
films.
[0021] The compositions of the invention have certain properties.
For example, in certain embodiments, when the composition is
crushed and exposed to 900 mL of water in a U.S.P. Type I Apparatus
with stirring at 100 rpm for 30 minutes at 37.degree. C., less than
about 50% by weight or optionally less than about 25% by weight of
the pharmaceutically active agent originally present in the
composition before it was crushed broken is released into the
water. Alternatively or in addition, when the composition is
crushed and exposed to 900 mL of an aqueous solution containing 60%
(v/v) ethanol in a U.S.P. Type 1 Apparatus with stirring at 100 rpm
for 30 minutes at 37.degree. C., less than about 50% by weight or
optionally less than about 25% by weight of the pharmaceutically
active agent originally present in the composition before it was
broken is released into the aqueous solution.
[0022] It is understood that the oral dosage forms of the invention
can be in the form of a capsule, caplet, pill, or a compressed
tablet.
[0023] In another aspect, the invention provides a method of
providing controlled release of a pharmaceutically active agent to
a mammal, for example, a human. The method comprises orally
administering to an individual in need of the pharmaceutically
active agent one or more of the controlled release compositions
described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] The foregoing and other objects, features and advantages of
the invention will become apparent from the following description
of preferred embodiments, as illustrated in the accompanying
drawings. Like referenced elements identify common features in the
corresponding drawings. The drawings are not necessarily to scale,
with emphasis instead being placed on illustrating the principles
of the present invention, in which:
[0025] FIG. 1 shows a schematic representation of exemplary misuse
preventative, controlled release compositions. In FIGS. 1A and 1B,
the compositions are uncoated bilayers; in FIGS. 1C and 1D, the
compositions are coated bilayers. In FIGS. 1A and 1C, controlled
release microparticles containing a pharmaceutically active agent
are disposed within a first layer (FIGS. 1A and 1C), and a
pharmaceutically active agent, which can be the same or different,
is disposed within a second layer of the bilayer composition. In
FIGS. 1B and 1D, the second layer of the bilayer compositions also
comprise microparticles containing a pharmaceutically active agent,
which can be the same as or different to the pharmaceutically
active agent in the microparticles disposed within the first
layer.
[0026] FIG. 2 shows a schematic representation of exemplary misuse
preventative, controlled release formulations which are similar to
those presented in FIGS. 1C and 1D, except the coatings are
functional coatings, for example, a controlled release coating
achievable by one or more of the following--a controlled release
film, a controlled release agent, and controlled release
microparticles. In FIG. 2A, controlled release microparticles
containing a pharmaceutically active agent are disposed within the
first layer, and in FIG. 2B the controlled release microparticles
are present within both the first layer and the second layer.
[0027] FIGS. 3A and 3B are graphs showing the in vitro dissolution
profile of oxycodone HCl (FIG. 3A) and acetaminophen (FIG. 3B) from
an intact, exemplary controlled release formulation of the
invention in a U.S.P. Type III Apparatus. FIG. 3A shows the release
profile of oxycodone HCl in potassium phosphate buffer at pH 6.8
for 12 hours (-.DELTA.-), 0.1M hydrochloric acid at pH 1.2 for 12
hours (- -), 0.1M hydrochloric acid at pH 1.2 for 1 hour followed
by potassium phosphate buffer pH 6.8 for 11 hours (-.box-solid.-),
and 40% ethanol (--). FIG. 3B shows the release profile of
acetaminophen in potassium phosphate buffer at pH 6.8 for 12 hours
(-.DELTA.-), 0.1M hydrochloric acid at pH 1.2 for 12 hours (- -),
0.1M hydrochloric acid at pH 1.2 for 1 hour followed by potassium
phosphate buffer at pH 6.8 for 11 hours (-.box-solid.-), and 40%
ethanol (--).
[0028] FIGS. 4A and 4B are graphs showing the in vitro dissolution
profile of oxycodone HCl from half tablets (FIG. 4A) and quarter
tablets (FIG. 4B) of three lots of an exemplary controlled release
formulation of the invention in a U.S.P. Type I Apparatus in
potassium phosphate buffer at pH 6.8.
[0029] FIGS. 5A and 5B are graphs showing the in vitro dissolution
profile of acetaminophen from half tablets (FIG. 5A) and quarter
tablets (FIG. 5B) of three lots of an exemplary controlled release
formulation of the invention in a U.S.P. Type I Apparatus in
potassium phosphate buffer at pH 6.8.
[0030] FIGS. 6A and 6B are graphs showing the in vitro dissolution
profile of oxycodone HCl (FIG. 6A) and acetaminophen (FIG. 6B) from
a crushed, exemplary controlled release formulation of the
invention in a U.S.P. Type I Apparatus. FIG. 6A shows the release
profile of oxycodone HCl in acidified potassium phosphate aqueous
solution at pH 3.0 (-.quadrature.-), potassium phosphate buffer at
pH 6.8 (-.tangle-solidup.-), basified potassium phosphate aqueous
solution at pH 10.0 (-.diamond.-), water (- -), 20% ethanol
(-.gradient.-), and 40% ethanol (-.diamond-solid.-). FIG. 6B shows
the release profile of acetaminophen in acidified potassium
phosphate aqueous solution at pH 3.0 (-.quadrature.-), potassium
phosphate buffer pH 6.8 (-.tangle-solidup.-), basified potassium
phosphate aqueous solution at pH 10.0 (-.diamond.-), and water (-
-).
[0031] FIGS. 7A and 7B are graphs showing the in vitro dissolution
profile of oxycodone HCl (FIG. 7A) and acetaminophen (FIG. 7B) from
an intact, exemplary controlled release formulation of the
invention in a U.S.P. Type III Apparatus. FIG. 7A shows the release
profile of oxycodone HCl in 0.1M hydrochloric acid at pH 1.2 for 12
hours (- -), potassium phosphate buffer pH 6.8 for 12 hours
(-.DELTA.-), and 0.1M hydrochloric acid at pH 1.2 for 1 hour
followed by potassium phosphate buffer pH 6.8 for 11 hours
(-.box-solid.-). FIG. 7B shows the release profile of acetaminophen
in 0.1M hydrochloric acid at pH 1.2 for 12 hours (- -), potassium
phosphate buffer pH 6.8 for 12 hours (-.DELTA.-), and 0.1M
hydrochloric acid at pH 1.2 for 1 hour followed by potassium
phosphate buffer pH 6.8 for 11 hours (-.box-solid.-).
[0032] FIGS. 8A and 8B are graphs showing the in vitro dissolution
profile of oxycodone HCl (FIG. 8A) and acetaminophen (FIG. 8B) from
a crushed, exemplary controlled release formulation of the
invention in a U.S.P. Type I Apparatus. FIG. 8A shows the release
profile of oxycodone HCl in potassium phosphate buffer pH 6.8
(-.DELTA.-), and 0.1M hydrochloric acid at pH 1.2 (- -). FIG. 8B
shows the release profile of acetaminophen in potassium phosphate
buffer pH 6.8 (-.DELTA.-), and 0.1M hydrochloric acid at pH 1.2 (-
-).
[0033] FIG. 9 is a graph showing the in vitro dissolution profile
of a coated bilayer embodiment containing 20 mg oxycodone HCl/650
mg acetaminophen, where the release of oxycodone was measured in a
U.S.P. Type III Apparatus at 100 rpm for twelve hours in 0.1M
hydrochloric acid at pH 1.2 for 1 hour and then in potassium
phosphate buffer pH 6.8 for 11 hours.
[0034] FIGS. 10A and 10B are graphs showing the in vitro
dissolution profile of oxycodone HCl (FIG. 10A) and acetaminophen
(FIG. 10B) from an intact, exemplary controlled release formulation
of the invention in a U.S.P. Type III Apparatus. FIG. 10A shows the
release profile of oxycodone HCl in potassium phosphate buffer pH
6.8 (- -). FIG. 10B shows the release profile of acetaminophen in
potassium phosphate buffer pH 6.8 (- -).
[0035] FIGS. 11A and 11B are graphs showing the in vitro
dissolution profile of oxycodone HCl (FIG. 11A) and acetaminophen
(FIG. 11B) from a crushed, exemplary controlled release formulation
of the invention in a U.S.P. Type I Apparatus. FIG. 11A shows the
release profile of oxycodone HCl in potassium phosphate buffer pH
6.8 (- -), and FIG. 11B shows the release profile of acetaminophen
in potassium phosphate buffer pH 6.8 (- -).
[0036] FIG. 12 is a graph showing the in vitro dissolution profile
of methylphenidate from four intact, exemplary controlled release
formulations of the invention in a U.S.P. Type II Apparatus in
acidified water, pH 3.5.
[0037] FIGS. 13A and 13B are graphs showing the in vitro
dissolution profile of oxycodone HCl (FIG. 13A) and acetaminophen
(FIG. 13B) from three intact exemplary controlled release
formulations of the invention in a U.S.P. Type III Apparatus in
phosphate buffer, pH 6.8.
[0038] FIGS. 14A and 14B are graphs showing the in vitro
dissolution profiles of oxycodone HCl (FIG. 14A) and acetaminophen
(FIG. 14B) from uncoated crushed exemplary controlled release
formulations of the invention as measured in a U.S.P. Type I
Apparatus in potassium phosphate buffer pH 1.2 (- -), pH 6.8
(-.quadrature.-), and pH 10 (--), in water (-.tangle-solidup.-),
and in 40% ethanol (-.diamond-solid.-).
[0039] FIGS. 15A and 15B are graphs showing the in vitro
dissolution profiles of oxycodone HCl (FIG. 15A) and acetaminophen
(FIG. 15B) from whole and bisected exemplary controlled release
formulations of the invention as measured in a U.S.P. Type III
Apparatus. FIG. 15A shows the release profiles of oxycodone HCl in
whole tablets in phosphate buffer pH 6.8 (-.box-solid.-), whole
tablets in 40% ethanol (-.diamond-solid.-), bisected tablets in
phosphate buffer pH 6.8 (- -), and bisected tablets in 40% ethanol
(-.DELTA.-). FIG. 15B shows the release profiles of acetaminophen
in whole tablets in phosphate buffer pH 6.8 (-.box-solid.-), whole
tablets in 40% ethanol (-.diamond-solid.-), bisected tablets in
phosphate buffer pH 6.8 (- -), and bisected tablets in 40% ethanol
(-.DELTA.-).
[0040] FIG. 16 is a graph showing the in vitro dissolution profiles
of oxycodone HCl (- -) and acetaminophen (-.largecircle.-) from
intact exemplary controlled release formulations of the invention
as measured in a U.S.P. Type III Apparatus for 1 hour in acid
medium, pH 1.2, followed by 11 hours in phosphate buffer, pH
6.8.
[0041] FIG. 17 is a graph showing the in vitro dissolution profiles
of oxycodone HCl (- -) and acetaminophen (-.largecircle.-) from
crushed exemplary controlled release formulations of the invention
as measured in a U.S.P. Type I Apparatus in deionized water.
DETAILED DESCRIPTION OF THE INVENTION
[0042] The invention is based, in part, upon the discovery that it
is possible to produce a controlled release platform that renders
pharmaceutical compositions less susceptible to intentional abuse
and accidental misuse than other controlled release compositions,
while being free from noxious additives, active ingredient
antagonists, prodrugs and the like. The formulations maintain their
controlled release properties when bisected (broken in half) as can
occur when a patient or care-giver breaks a tablet in half to make
the tablet easier to swallow. Even when crushed, the compositions
of the invention prevent dose dumping because the microparticles
contained within the composition remain substantially intact and
retain their controlled release properties. The crushed
formulations cannot easily be administered intravenously via a
syringe because of hard gel formation, and if crushed and
administered nasally, they swell causing an unpleasant
sensation.
[0043] In one aspect, the invention provides a controlled release
multilayer composition comprising: (a) a first layer comprising a
first population of controlled release microparticles having a
pharmaceutically active agent disposed therein; (b) a second layer
comprising a pharmaceutically active agent disposed therein; and
(c) a superabsorbent material (e.g., polycarbophil) disposed within
the first layer, the second layer, or both the first layer and the
second layer. In another aspect, the invention provides a
controlled release multilayer composition comprising: (a) a first
layer comprising a superabsorbent material (for example,
polycarbophil) and a plurality of controlled release microparticles
having at least one pharmaceutically active agent disposed therein.
The second layer comprises a pharmaceutically active agent that can
be the same as or different from the pharmaceutically active agent
present in the microparticles of the first layer. In each aspect of
the invention, the first and second layers can be encapsulated with
either a non-functional coating or a functional coating. When the
compositions are crushed, the microparticles remain substantially
intact and control the release of the pharmaceutically active agent
disposed therein and prevent dose dumping. As used herein, the term
"dose dumping" is understood to mean an uncontrolled release of a
pharmaceutically active agent where at least 80% of the
pharmaceutically active agent in the formulation is released within
30 minutes (a specification that can be used to characterize a
formulation as an immediate release formulation).
[0044] FIGS. 1 and 2 show certain embodiments of the oral dosage
formulation of the invention. Each exemplary formulation contains a
bilayer composition 10 having a first layer 20 and a second layer
30. In each formulation, the first layer contains a plurality of
controlled release microparticles 40 that comprise a
pharmaceutically active agent. The second layer of each formulation
contains a second pharmaceutically active agent 50, which can be
the same or different as the pharmaceutically active agent present
in the microparticles in the first layer. Either the first layer,
the second layer, or both the first and second layers can contain a
superabsorbent material. In FIGS. 1B and 1D, the second layer also
contains controlled release microparticles 40', which may be the
same as or different from microparticles 40 disposed in the first
layer 10. In the embodiments shown in FIGS. 1A and 1B, the bilayer
is not coated; however, in the embodiments shown in FIGS. 1C and
1D, the bilayers are encapsulated in a coat, for example, a
non-functional (aesthetic) coat. The embodiments depicted in FIGS.
2A and 2B are similar to those depicted in FIGS. 1C and 1D except
coating 60 is a functional coating. As shown, the coating is a
controlled release coating that is defined by a controlled release
film, or is a coating containing a controlled release agent and/or
controlled release microparticles 40'', which can be the same as or
different from the controlled release microparticles 40 disposed in
first layer 20 or the optional controlled release microparticles
40' disposed in second layer 30. In each of the embodiments shown
in FIGS. 1 and 2, the microparticles control the release of the
active ingredient irrespective of whether the tablet is intact or
compromised (for example, by bisection or crushing). Furthermore,
it is understood that the principles depicted in each of the
figures can be present in multilayered dosage forms that contain
more than two layers.
[0045] In one embodiment, first layer 20 is a controlled release
layer in which the microparticles 40 enable a controlled release of
the pharmaceutically active agent from the formulation over a
prolonged period of time. Layer 20 can also comprise or define a
controlled release matrix. The superabsorbant material, which can
be disposed in layer 20, layer 30, or both layers 20 and 30 may
also slow release of the pharmaceutically active agent, with
minimal swelling upon contact with aqueous media. However, when the
composition is crushed, a greater surface area of the
superabsorbant material is exposed so that it swells rapidly to
form a hard gel upon contact with an aqueous solvent.
[0046] In one embodiment, second layer 30 is an immediate release
layer which allows for rapid disintegration and release of the
second pharmaceutically active agent 50. Agent 50 may be the same
as or different from agent 40. The second layer can also contain
microparticles 40', which would provide delayed release of the
pharmaceutically active agent disposed therein relative to the
release of agent 50. In another embodiment, composition 10 may have
a coating 60 that contains microparticles 40''.
[0047] Under normal use, the compressed multilayered composition 10
has a hardness in the range of, for example, from about 100 N to
about 500 N, such that the superabsorbent material in first layer
20, second layer 30, or both first and second layers 20 and 30 is
prevented from absorbing aqueous solvent. As a result, the
composition, even when combined with an aqueous solvent maintains
sufficient integrity so that the majority of the superabsorbent
material is prevented from swelling and disrupting the integrity of
the multilayered composition. Furthermore, the resulting hardness
renders the composition difficult to crush. When combined with an
aqueous solvent, the solvent gradually permeates into both first
layer 20 and second layer 30, and the pharmaceutically active agent
present in second layer 30 is initially released faster than the
pharmaceutically active agent present in the microparticles in
first layer 20. As used herein, the term "initially released"
refers to the release of at least one pharmaceutically active agent
within 15 minutes or within 30 minutes after the composition has
been exposed to an aqueous solvent. However, when crushed and
exposed to an aqueous solvent, the superabsorbent material swells
to form a rigid gel that encapsulates the microparticles. It is
understood that the microparticles are a primary mechanism for
controlling the release of the pharmaceutically active agent
disposed therein. However, the hard, rigid gel that forms around
the microparticles, along with other ingredients of the
composition, can also impart controlled release properties in
addition to those provided by the microparticles.
[0048] It is contemplated that the compositions described herein
can be used for the delivery of one or more (for example, two,
three, four or more) pharmaceutically active agents. With respect
to all the embodiments depicted in FIGS. 1 and 2, it is understood,
for example, that microparticles 40 in first layer 20 can contain
the same pharmaceutically active agent as the pharmaceutically
active agent 50 present in second layer 30. As a result, such a
bilayer composition permits the creation of a desired release
profile, for example, with a fast initial release from second layer
30 followed by a slower subsequent release from first layer 20.
Alternatively, the pharmaceutically active agent present in the
microparticles 40 in the first layer may be different from free
pharmaceutically active agent 50 in the second layer. For example,
the pharmaceutically active agent in microparticles 40 in the first
layer can be oxycodone whereas free pharmaceutically active agent
50 in second layer 30 can be acetaminophen. Furthermore, it is
understood that the same pharmaceutically active agent in the
second layer (for example, acetaminophen) can also be present in
the free form (i.e., not included in or associated with
microparticles) in the first layer. Such an example is depicted in
Examples 1 and 2, wherein the microparticles in the first layer
contain oxycodone, and acetaminophen is present in free form in
both the first layer and the second layer.
[0049] In addition, it is contemplated that in the bilayer depicted
in FIGS. 1 and 2, first layer 20 can contain or define a controlled
release matrix, whereas second layer 30 can define an immediate
release matrix. Alternatively, first layer 20 and second layer 30
can both contain or define two different controlled release
matrices. Furthermore, the compositions can further contain a
non-functional or aesthetic coating (see, FIGS. 1C and 1D) or a
functional coating (see, FIGS. 2A and 2B). It is understood,
however, that the compositions can vary depending upon what
pharmaceutically active agent or agents are to be released and what
release profiles are desired for each agent.
[0050] In the case of an intact composition, when exposed to an
aqueous environment (for example, a solution containing at least
10% (v/v) water), the pharmaceutically active agent disposed in the
second layer is initially released (for example, within 15 minutes
or within 30 minutes after exposure to an aqueous solvent) at a
faster rate than the pharmaceutically active agent disposed in the
first layer. At least one pharmaceutically active agent is released
from the intact formulation over a prolonged period of time (for
example, for at least 6 hours, at least 8 hours, at least 12 hours,
at least 18 hours, or at least 24 hours). In certain embodiments,
at least 50%, preferably 60%, more preferably 70%, and even more
preferably 80% of at least one pharmaceutically active agent is
prevented from being released substantially immediately (for
example, within 30 minutes) from the intact composition when
exposed to an extraction medium, for example, water, aqueous
solutions ranging in pH from 1.2 to 6.8, and different ethanolic
media (for example, water containing 20% ethanol, 40% ethanol, 60%
ethanol, or 80% ethanol and 100% ethanol).
[0051] When the oral dosage form of the invention is bisected, for
example, axially bisected, as can happen when a patient breaks a
tablet in half to make it easier to swallow, the first and/or
second layers become compromised to expose more superabsorbent
material. However, based on the hardness of the first layer, only a
small amount of the superabsorbent material swells and the
resulting portions of the bisected tablet maintain their integrity.
As a result, the bisected portions of the compositions of the
invention have a release profile of the pharmaceutically active
agent substantially the same as the intact composition. These
principles are demonstrated, for example, in Example 1 and FIGS.
3-5 where the superabsorbent material is disposed within the first
layer. Furthermore, even when bisected, the formulations of the
invention permit the release of the pharmaceutically active agent
over at least 6 hours, at least 12 hours, at least 18 hours, or
over at least 24 hours. In certain embodiments, at least 50%,
preferably 60%, more preferably 70%, and even more preferably 80%
of at least one pharmaceutically active agent is prevented from
being released substantially immediately (for example, within 30
minutes) from the formulation when exposed to an extraction medium,
for example, water, aqueous solutions ranging in pH from 1.2 to
6.8, and different ethanolic media (for example, water containing
20% ethanol, 40% ethanol, 60% ethanol, or 80% ethanol and 100%
ethanol).
[0052] When the oral dosage form of the invention is crushed (for
example, with a commercially available pill crusher to break
formulation into at least 10 particles or more) and then exposed to
an aqueous environment, the superabsorbent material swells rapidly
(for example, within about 30 seconds) to create a hard gel that
traps the microparticles. Based in part upon their small size (high
radius of curvature), the microparticles resist the crushing
process and remain substantially intact. The hard gel provides an
unpleasant experience if the crushed composition is snorted up a
nostril and gel formation occurs within the nostril. This process
has the advantage that the nasal secretions needed for absorption
of the active ingredient into the blood-stream are absorbed by the
superabsorbent material preventing intoxication via this route.
Similarly, if the composition is crushed and exposed to an aqueous
environment to extract the pharmaceutically active agent, the
superabsorbant material in the core can absorb the extraction
medium leaving little or no extraction medium to administer. In
addition, the hard gel that is formed during this process cannot be
drawn or pushed though a syringe needle.
[0053] In the case of compositions that have a controlled release
coating, the coatings may be compromised by crushing. However the
microparticles still permit the controlled release of the
pharmaceutically active agent and prevent the pharmaceutically
active agent from being released substantially immediately from the
formulation (i.e., the microparticles provide controlled release of
the pharmaceutically active agent) and the gel forms to entrap the
microparticles. For example, at least 50%, preferably 60%, more
preferably 70%, and even more preferably 80% of at least one
pharmaceutically active agent is prevented from being released
substantially immediately (for example, within 30 minutes) from the
formulation (see, FIG. 6A, which is discussed in Example 1). As a
result, the compositions of the invention prevent dose dumping in
water, 20% ethanol, 40% ethanol, and 60% ethanol even if the
formulations have been broken or crushed.
[0054] In certain embodiments, the compositions of the invention,
when crushed and exposed to 900 mL of water in a U.S.P. Type I
Apparatus with stirring at 100 rpm for 30 minutes at 37.degree. C.,
less than about 50%, less than about 45%, less than about 40%, less
than about 35%, less than about 30%, less than about 25%, or less
than about 20% by weight of at least one pharmaceutically active
agent originally present in the formulation before it was crushed
is released into the water. In certain other embodiments, when the
formulation of the invention is crushed and exposed to 900 mL of an
aqueous solution containing 60% (v/v) ethanol in a U.S.P. Type I
Apparatus with stirring at 100 rpm for 30 minutes at 37.degree. C.,
less than about 50%, less than about 45%, less than about 40%, less
than about 35%, less than about 30%, less than about 25%, or less
than about 20% by weight of at least one pharmaceutically active
agent originally present in the formulation before it was broken is
released into the aqueous solution.
[0055] Each of the components of the formulation of the invention
are discussed in the following sections.
[0056] A. Considerations for a Multilayer Component
[0057] It is understood that the multilayer can include two, three,
four or more different layers. In one embodiment, the multilayer is
a bilayer, where the first layer and the second layer are adjacent
one another. In another embodiment, the compositions can comprise a
third layer, which can be located adjacent the first layer,
adjacent the second layer, or disposed between the first and second
layers.
[0058] The first layer comprises a first population of controlled
release microparticles having at least one pharmaceutically active
agent disposed therein. The second layer comprises a
pharmaceutically active agent disposed therein, which can be the
same as or different from the pharmaceutically active agent in the
microparticles disposed in the first layer. The first layer, the
second layer, both the first and second layers, or an optional
third layer can comprise a superabsorbent material. The
pharmaceutically active agent disposed in the second layer is
initially released at a faster rate than the pharmaceutically
active agent disposed within the microparticles in the first layer.
This can be achieved in a number of different ways, which include
having at least one pharmaceutically active agent in the
microparticles in the first layer but not the second layer. In
addition, the first layer can comprise a controlled release agent
or define a controlled release matrix whereas the second layer can
define an immediate release matrix. Alternatively, the first layer
and the second layers can both comprise a controlled release agent
or define a controlled release matrix, but the compositions of each
can be chosen so that pharmaceutically active agents are initially
released from the second layer at a faster rate than from the first
layer.
[0059] The term "superabsorbent material," as used herein is
understood to mean any material that absorbs solvent, for example,
1 gram of material absorbs at least 30 mL, more preferably 50 mL of
solvent, which, upon absorption of the solvent, swells to produce a
hydrated gel (hydrogel). In general, useful superabsorbent
materials, when exposed to an aqueous medium (for example, water),
absorb in excess of 10-15 times, such as at least greater than 30
times, more preferably 50 times, of water based on its own weight.
In certain embodiments, the superabsorbent material is a
polymer.
[0060] Superabsorbent materials can be manufactured from
polysaccharide derivatives or cross-linked polyelectrolytes.
Polysaccharide superabsorbents include, but are not limited to, a
starch graft copolymer, a crosslinked carboxymethylcellulose
derivative, a hydrolyzed starch-acrylonitrile graft copolymer and a
neutralized starch-acrylic acid graft copolymer. Cross-linked
polyelectrolytes can contain functional groups such as carboxyl,
sulfonate, sulphate, sulfite, phosphate, amine, imine, amide,
quaternary ammonium or a mixture thereof. Examples of
polyelectrolyte polymers include, but are not limited to, salts or
partial salts of polyacrylic acid, polyacrylamido methylpropane
sulfonic acid, polyvinyl acetic acid, polyvinyl phosphonic acid,
polyvinyl sulfonic acid, an isobutylene-maleic anhydride copolymer,
carboxymethyl cellulose, alginic acid, carrageenan, polyaspartic
acid, polyglutamic acid, polyvinyl amine, polydiallyl dimethyl
ammonium hydroxide, polyacrylamidopropyl trimethyl ammonium
hydroxide, polyamino propanol vinyl ether, polyallylamine,
chitosan, polylysine, polyglutamine and copolymers or mixtures
thereof.
[0061] Exemplary superabsorbent materials can include a polymer
selected from the group consisting of polycarbophil,
polycarbophilic calcium, polymethacrylic acid, polyacrylic acid,
and mixtures thereof. Polycarbophil is a superabsorbent polymer
that is capable of absorbing and retaining large quantities of
water. Polycarbophil is a high molecular weight acrylic acid
polymer cross-linked with divinyl glycol, and is sold under the
tradename, NOVEON.RTM. AA-1, by Lubrizol Corporation OH, USA. It is
understood that 1 gram of polycarbophil can absorb about 62 grams
of water. Polycarbophil is stable and does not undergo hydrolysis
or oxidation under normal conditions. Calcium salts of
polycarbophil (polycarbophilic calcium) can be used and are
available commercially under the tradename NOVEON.RTM. CA-1 or CA-2
from Lubrizol Corporation OH, USA. Other exemplary superabsorbent
materials include, for example, Carbopol.RTM. 71G, Carbopol.RTM.
971P, Carbopol.RTM. 974 available from Lubrizol Corporation, OH,
USA.
[0062] The superabsorbent material provides two functions. First,
when the composition containing the superabsorbent material (for
example, polycarbophil) is crushed and combined with solvent (for
example, water) for parenteral injection, the superabsorbent
material rapidly absorbs water, swells and forms a hard gel thus
preventing injection. In addition, depending upon the amount of
solvent added, all of the solvent may be absorbed leaving no
residual solvent that can be administered. Second, if the
composition is crushed and snorted into a nostril the
superabsorbent material absorbs the liquid in the nostril causing
the superabsorbent material to swell. Not only does the swelling
cause discomfort but also prevents the drug disposed within the
formulation from being rapidly released (for example, within less
than 30 minutes).
[0063] In general, the proportion of the superabsorbent material in
the first layer varies from about 1% (w/w) to about 70% (w/w) of
the first layer, more preferably from about 2% (w/w) to about 50%
(w/w) of the first layer. Furthermore, the superabsorbent material
in the first layer varies from about 3% (w/w) to about 20% (w/w) of
the final intact composition, more preferably from about 4% (w/w)
to about 14% (w/w) of the final intact composition, more preferably
from about 4% (w/w) to about 10% (w/w) of the final intact
formulation.
[0064] Compositions of exemplary controlled release microparticles
and methods for their manufacture are described in Section C below.
In addition to the superabsorbent material and the microparticles,
the first layer optionally further comprises or defines a
controlled release matrix. In addition, depending up the
circumstances, the second layer optionally further comprises or
defines either an immediate release matrix or a controlled release
matrix.
[0065] It is understood that materials that can be used to create a
suitable controlled release matrix include, for example, acetyl
succinate, a polyvinyl derivative (for example, polyvinyl alcohol,
polyvinyl acetate, polyvinyl acetate phthalate, a copolymer of
vinyl acetate and vinyl pyrrolidone, a copolymer of vinyl acetate
and crotonic acid, polyvinylpyrollidone), polyethylene oxide,
polyacrylic acid, polysaccharides (for example, modified starch,
cross-linked high amylose starch, hydroxypropyl starch,
hydroxypropyl methylcellulose phthalate, cellulose and cellulose
derivatives (for example, microcrystalline cellulose,
carboxymethylethyl cellulose, cellulose acetate, methylcellulose,
ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl
cellulose, cellulose phthalate, cellulose acetate, cellulose
acetate phthalate, cellulose acetate propionate, cellulose acetate
succinate, cellulose acetate butyrate, cellulose acetate
trimellitate), poloxamer, povidone, alginic acid, sodium alginate,
polyethylene glycol, polyethylene glycol alginate, gums (for
example, xanthan gum), polymethacrylates (including, for example, a
copolymer of methacrylic acid and methyl-methacrylate, and a
copolymer of methacrylic acid and ethyl acrylate), a copolymer of
polymethyl vinyl ether and malonic acid anhydride, a copolymer of
polymethyl vinyl ether and malonic acid or the ethyl-, isopropyl-,
n-butylesters thereof, zein, and mixtures of the foregoing.
[0066] It is understood that materials that can be used to create
an immediate release matrix include, for example, microcrystalline
cellulose, calcium phosphates (monobasic, dibasic and or tribasic),
saccharides such as lactose, sucrose, dextrins, superdisintegrants
such as croscarmalose sodium, sodium starch glycolate, and
crospovidone.
[0067] In addition, the first layer and the second layer can
comprise other excipients and manufacturing aids including, for
example, one or more of, a diluent (for example, microcrystalline
cellulose, lactose, dicalcium phosphate, sucrose), a lubricant (for
example, sodium stearyl fumarate, magnesium stearate, calcium
stearate, stearic acid, hydrogenated vegetable oils), a glidant
(for example, colloidal silicon dioxide and talc), a dye (for
example, iron oxide), and a filler (for example, lactose,
pregelatinized starch, dextrin, maltose, calcium phosphates
(monobasic, dibasic and/or tribasic), microcrystalline starch).
[0068] In addition, the second layer optionally includes a
disintegrant to facilitate disintegration of the second layer. The
disintegrants, however, typically are not included in the first
layer so as to minimize the risk that the first layer disintegrates
upon exposure to an aqueous media to expose the bulk of the
superabsorbent material. It is preferred that the first layer
remain intact when exposed to an aqueous environment. Useful
disintegrants include, for example, crospovidone, sodium starch
glycolate, sodium alginate, and croscarmellose.
[0069] B. Considerations for the Coat
[0070] It is understood that the multilayered composition as
described in Section A can further comprise a coat (for example, a
non-functional (aesthetic) coating as shown in FIGS. 1C and 1D or a
functional coating (for example, a controlled release coat as shown
in FIGS. 2A and 2B)). Under normal use, the coat still provides a
rigid net-like structure that encapsulates the multilayer and can
help minimize the swelling of the superabsorbent material.
[0071] Exemplary non-functional coatings include, for example, an
aqueous based shellac dispersion MARCOAT 125.RTM. from Innovative
Material Technologies, an aqueous dispersion of ethyl cellulose
AQUACOAT.RTM. from FMC Biopolymers, methacrylic acid/ethyl acrylate
copolymers KOLLICOAT.RTM. from BASF, hydroxypropylcellulose
KLUCEL.RTM. from Aqualon, modified peas starch based aqueous film
coating system LYCOAT.RTM. from Roquette, hydroxypropyl
methylcellulose acetate succinate AQOAT.RTM. (HPMCAS) from
Shin-Etsu, and OPADRY.RTM., OPADRY TM.RTM., OPADRY FX.RTM.,
OPALUX.RTM., OPAGLOS.RTM., Ethocel.RTM. 10, 45, 100 cps (ethyl
cellulose) all from Colorcon (PA, USA)
[0072] It is understood, however, that the coating can be a
functional coating. In other words, the coating provides a function
beyond aesthetics, which can include, for example, controlled
release (such as delayed release) of an agent disposed within the
composition, a moisture barrier, and a taste masking film.
[0073] The controlled release coatings can resist the release of
drug as the pH of the extraction media varies (for example, when
the formulations are combined with conventional carbonated
beverages). Furthermore, the controlled release coatings can resist
the release of drug in the presence of alcohol in the extraction
media even at levels that exceed the alcohol content of alcoholic
beverages.
[0074] In certain embodiments, the controlled release coating
comprises a controlled release agent. Alternatively, or in
addition, the coat is a controlled release film. Exemplary
controlled release agents and film-coatings can be selected from
the group consisting of acetyl succinate, a polyvinyl derivative
(for example, polyvinyl alcohol, polyvinyl acetate, polyvinyl
acetate phthalate, a copolymer of vinyl acetate and vinyl
pyrrolidone, a copolymer of vinyl acetate and crotonic acid,
polyvinylpyrollidone), polyethylene oxide, polyacrylic acid,
polysaccharides (for example, modified starch, cross-linked high
amylose starch, hydroxypropyl starch, hydroxypropyl methylcellulose
phthalate, cellulose and cellulose derivatives (for example,
microcrystalline cellulose, carboxymethylethyl cellulose, cellulose
acetate, methylcellulose, ethylcellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, cellulose phthalate, cellulose
acetate, cellulose acetate phthalate, cellulose acetate propionate,
cellulose acetate succinate, cellulose acetate butyrate, cellulose
acetate trimellitate)), poloxamer, povidone, alginic acid, sodium
alginate, polyethylene glycol, polyethylene glycol alginate, gums
(for example, xanthan gum), polymethacrylates (including, for
example, a copolymer of methacrylic acid and methyl-methacrylate,
and a copolymer of methacrylic acid and ethyl acrylate), a
copolymer of methacrylic acid and ethyl acrylate, a copolymer of
polymethyl vinyl ether and malonic acid anhydride, a copolymer of
polymethyl vinyl ether and malonic acid or the ethyl-, isopropyl-,
n-butylesters thereof, zein, and mixtures of the foregoing.
[0075] Further examples of controlled release film-coating polymers
include, but are not limited to, methylcellulose, ethylcellulose
(for example, Aquacoat.RTM. type from FMC Corp.),
methylhydroxyethylcellulose, methylhydroxypropylcellulose (for
example, Pharmacoat.RTM. type from Shin Etsu Corp.),
ethylhydroxyethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, carboxymethylcellulose or
methylcarboxymethylcellulose, acrylic polymers, polyvinylacetates,
polyvinyl chlorides, polymethylmetacrylates or a terpolymer of
vinylchloride, vinylalcohol and vinylacetate,
hydroxypropylmethylcellulose phthalate (for example, HP type from
Shin Etsu), hydroxypropylmethylcellulose acetate succinate (for
example, Aqoat from Shin Etsu), cellulose acetate phthalate (for
example, Aquacoat CPD from FMC Corp. or C-A-P NF from Eastman
Chemical), polyvinyl acetate phthalate (for example, Sureteric from
Colorcon), carboxymethylethylcellulose, and co-polymerized
methacrylic acid/methacrylic acid methyl esters (for example,
Eudragit from Degussa/Evonik Industries or Kollicoat from BASF or
Acryl-Eze from Colorcon or Eastacryl from Eastman Chemical).
[0076] For example, Kollidon.RTM. SR (a powder consisting of
polyvinyl acetate (8 parts, w/w) and polyvinyl pyrrolidone (2
parts, w/w)) can be used in combination with xanthan gum.
Kollidon.RTM. SR is available from BASF, ON, Canada. Alternatively,
the coat can be, for example, Eudragit.RTM. L30D 55, available from
Degussa/Evonik Industries, NJ, USA. Furthermore, it is understood
that, depending upon the release kinetics desired, the same
controlled release agents and coatings can be disposed within or
can coat the microparticles described below in Section C.
[0077] Exemplary moisture barriers include, for example, Opadry.TM.
Aqueous Moisture Barrier (AMB), high performance Opadry II
(Colorcon, PA, USA).
[0078] Exemplary taste masking films include, for example,
Opadry.TM. (Colorcon, PA, USA).
[0079] In addition, the coating can comprise one or more of a
viscosity increasing agent (for example, xanthan gum, polyethylene
oxide, polyvinylpyrollidone, cellulose and sucrose derivatives), a
lubricant (for example, sodium stearyl fumarate, magnesium stearate
and stearic acid), a glidant (for example, colloidal silicon
dioxide and talc), and a dye (for example, iron oxide). In
addition, the coating can comprise a plasticizer. Examples of
plasticizers include, but are not limited to, cetanol, triacetin,
citric acid esters, phthalic acid esters, dibutyl succinate,
acetylated monoglyceride, acetyltributyl, acetyltributyl citrate,
acetyltriethyl citrate, benzyl benzoate, calcium stearate, castor
oil, chlorebutanol, colloidal silica dioxide, dibutyl phthalate,
dibutyl sebacate, diethyl oxalate, diethyl malate, diethyl maleate,
diethyl malonate, diethyl fumarate, diethyl phthalate, diethyl
sebacate, diethyl succinate, dimethylphthalate, dioctyl phthalate,
glycerin, glyceroltributyrate, glyceroltriacetate, glyceryl
behanate, glyceryl monostearate, hydrogenated vegetable oil,
lecithin, leucine, magnesium silicate, magnesium stearate,
polyethylene glycol, propylene, glycol, polysorbate, silicone,
stearic acid, talc, titanium dioxide, triacetin, tributyl citrate,
triethyl citrate, zinc stearate, PEG (polyethylene glycol), and the
like.
[0080] In addition, the coat can comprise controlled release
microparticles containing a pharmaceutically active agent of
interest. Compositions of exemplary controlled release
microparticles and methods for their manufacture are described in
the following section.
[0081] C. Considerations for the Controlled Release
Microparticles
[0082] As shown in FIGS. 1 and 2, the compositions of the invention
comprise controlled release microparticles disposed within at least
one layer of the multilayered composition (see, FIGS. 1A, 1C and
2A), two layers of the multilayered composition (see, FIGS. 1B, 1D
and 2B), or within the controlled release coating (see, FIGS. 2A
and 2B).
[0083] The controlled release microparticles contain a
pharmaceutically active agent and facilitate the controlled release
of the pharmaceutically active agent disposed therein. Depending
upon the configuration chosen, the formulations can release the
pharmaceutically active agent over a prolonged period of time, for
example, at least 6 hours, at least 8 hours, at least 12 hours, at
least 18 hours, or at least 24 hours.
[0084] Although the controlled release particles may take a variety
of forms, they have a number of features in common, which include
(i) they have controlled release properties and (ii) they are of a
size that makes them hard to crush even when the formulations are
crushed with a conventional pill crusher or the like. The
microparticles may have a core and a coat, where either or both
provide controlled release properties.
[0085] The core of the microparticles can comprise the
pharmaceutically active agent and a variety of excipients, which
include, for example, one or more of, a spheronizing agent, a
plasticizer, and a controlled release agent. Exemplary spheronizing
agents include, for example, microcrystalline cellulose, ethyl
cellulose, low substituted hydroxypropylcellulose and dicalcium
phosphate dihydrate. Microcrystalline cellulose is preferred and is
available commercially under the tradename Avicel.RTM. PH101 from
FMC BioPolymer, DE, USA. Microcrystalline cellulose forms a plastic
and cohesive mass upon wetting, which is desirable for the
successful production of spherical granules. Microcrystalline
cellulose is considered to aid the spheronization process by
absorbing water like a molecular sponge and helps in the binding
and lubrication of the moistened powder mass during extrusion.
During the spheronization process, moisture trapped in the
microcrystalline cellulose microfibrils adds plasticity to the
extrudate and helps convert short round extrudates obtained by
extrusion into spherical pellets. Different grades of
microcrystalline cellulose are commercially available, and a
preferred grade suitable for extrusion-spheronization is
Avicel.RTM. PH 101, because of its small particle size, low packing
density and high water retentive capacity.
[0086] In addition, the core of the microparticles can contain a
plasticizer. Exemplary plasticizers include, for example,
Plasacryl.RTM. available from IMTech, PA, USA, and triethyl citrate
available from Morflex, NC, USA.
[0087] In addition, the core of the microparticles optionally can
contain a controlled release agent that controls the release of the
pharmaceutically active agent. Exemplary controlled release agents
can be selected from the group consisting of starch, starch
derivatives, cellulose derivatives, xanthan gum, polyethylene
glycol, polyvinyl acetate, polyvinyl alcohol, and mixtures thereof.
In a preferred embodiment, the controlled release excipient
includes a starch derivative that is a cross-linked high amylose
starch, which provides the controlled release of the
pharmaceutically active agent for at least 12 hours, for at least
18 hours, or for at least 24 hours. The cross-linked high amylose
starch can be cross-linked with phosphorus oxychloride and/or can
contain hydroxypropyl side chains. In certain embodiments, a
suitable controlled release agent is commercially available from
Labopharm, Inc., Laval, Canada, under the trademark CONTRAMID.RTM..
The synthesis of the CONTRAMID.RTM. excipient is described in U.S.
Pat. No. 6,607,748.
[0088] The core of the microparticles containing a pharmaceutically
active agent can be prepared by a variety of methods, including,
for example, wet granulation and extrusion-spheronization. During
wet granulation, microparticles are prepared using, for example, a
fluid bed rotor granulator. The wet granulation process comprises,
for example, (i) wetting the powder to form wet granules; (ii)
exposing the wet granules to tumbling or spheronization, and (iii)
drying the resulting product. Alternatively, the pellets can be
produced by extrusion-spheronization, which has the advantage of
being highly reproducible, easy to scale up, cost effective, and
produces substantially perfect spherical microparticles.
Extrusion-spheronization comprises, for example, (i) wetting the
powder blend with an aqueous or organic solution generally
containing a binder to form a wet homogeneous mass suitable for wet
extrusion, (ii) extruding the wet mass to form cylindrical
extrudates of uniform shape and size, and (iii) spheronizing the
wet extrudates using a spheronizer, where, for example, a fast
spinning disc, breaks the extrudates into smaller microparticles
and rounds them to form spheres.
[0089] The cores of the microparticles can be coated with a
controlled-release coating that is sufficiently flexible to be
deformed under compression during tablet formation without
undergoing fracture. Suitable controlled release agents are
described in the previous section. In one embodiment, the
controlled release coating comprises polymethacrylate (e.g.,
Eudragit.RTM. RS, available from Degussa/Evonik Industries, NJ,
USA). Eudragit.RTM. RS30D grade, which is particularly useful, is
an aqueous dispersion (30% w/w) of a polymeric mixture of ethyl
acrylate, methyl methacrylate, and trimethylammonioethyl
methacrylate at a ratio of 1:2:0.1 (w/w). The Eudragit.RTM. RS
grade is designed to form water-insoluble film coats for sustained
release formulations. The Eudragit.RTM. RS grade forms a highly
flexible film coat with low permeability. Another useful coating
material includes Eudagrit.RTM. RL30D 55, available from
Degussa/Evonik Industries, NJ, USA. Another controlled release
coating comprises ethyl cellulose sold under the tradename
Surelease.RTM.. Another controlled release coating includes
Kollicoat.RTM. SR, available from BASF Fine Chemicals. In one
approach, the core of the microparticles is coated using a fluid
bed coater equipped with a bottom spray.
[0090] The resulting particles, depending upon their composition
and method of fabrication have an average diameter in the range of
from about 1 .mu.m to about 1000 .mu.m. In certain embodiments, the
microparticles have an average diameter of from about of 200 .mu.m
to about 900 .mu.m, or from about 300 .mu.m to about 800 .mu.m. In
certain embodiments, the resulting microparticles have an average
diameter of about 700 .mu.m. In certain other embodiments the
microparticles have an average diameter of from about 1 .mu.m to
about 400 .mu.m, from about 5 .mu.m to about 300 .mu.m, or from
about 10 .mu.m to about 200 .mu.m. In certain embodiments, the
resulting microparticles have an average diameter of about 100
.mu.m.
[0091] D. Pharmaceutically Active Agents
[0092] It is understood that the compositions described herein can
be used for the delivery of one or more pharmaceutically active
agents. In certain embodiments, the controlled release
microparticles can contain one or more pharmaceutically active
agents. In addition, it is understood that the compositions of the
invention can contain a number of different microparticles, with
one population of microparticles containing one pharmaceutically
active agent and another population of microparticles containing a
second, different pharmaceutically active agent. Furthermore, it is
understood that one or more of the pharmaceutically active agents
can be present in microparticles whereas one or more other
pharmaceutically active agents can be present in a free form within
the composition (i.e., not disposed in or associated with a
microparticle).
[0093] Many pharmaceutically active agents can benefit from being
delivered using the formulations described herein. The Controlled
Substances Act (CSA), Title II of the Comprehensive Drug Abuse
Prevention and Control Act of 1970, places all substances that are
regulated under existing Federal Law into one of five schedules
based upon the substance's medicinal value, harmfulness, and
potential for abuse or addiction. The formulations of the invention
are preferably used to deliver those drugs classified as Schedule
II, III, IV and V drugs. Similarly, although any drug in which
there is a benefit in having controlled release of the drug can be
incorporated into formulations of the invention, the formulations
described herein are particularly useful in the delivery of, for
example, CNS and respiratory stimulant agents, analgesics (for
example, opioid analgesics), hypnotic agents, anxiolytic agents,
and agents with a narrow therapeutic index. For purposes of this
invention, pharmaceutically active agents are intended to encompass
salts, esters, and the prodrugs of the pharmaceutically active
agents.
[0094] Exemplary opioid analgesics include, for example,
alfentanil, buprenorphine, butorphanol, carefentanil, codeine,
dezocine, diacetylmorphine, dihydrocodeine, dihydromorphine,
diprenorphine, etorphine, fentanyl, hydrocodone, hydromorphone,
.beta.-hydroxy-3-methylfentanyl, levo .alpha.-acetylmethadol,
levorphanol, lofentanil, meperidine, methadone, morphine,
nalbuphine, oxycodone, oxymorphone, pentazocine, pethidine,
propoxyphene, remifentanil, sufentanil, tilidine, tramadol
hydrochloride, or a mixture thereof.
[0095] In certain embodiments containing an opioid analgesic, the
solid composition can further include acetaminophen as a second,
different pharmaceutically active agent. Depending upon the desired
properties of the composition, the acetaminophen can be included in
the first layer, the second layer, or both the first and second
layers. In certain formulations, the acetaminophen is not included
within the microparticles as it is believed that, for certain
users, the rapid release of acetaminophen may serve as an
additional deterrent to crushing the compositions because
acetaminophen is generally known to have toxicity at high
concentrations.
[0096] Exemplary hypnotics include, for example, benzodiazepines
and non-benzodiazepines. Exemplary benzodiazepines include, but are
not limited to, alprazolam, diazepam, flurazepam, loprazolam,
mexazolam, nitrazepam, and the like. Exemplary non-benzodiazepines
include, but are not limited to, barbiturates (for example,
butobarbitone, phenobarbitone, or amylobarbitone) chlormethiazole,
eszopiclone, ramelteon, zaleplon, zopiclone, zolpidem, and the
like.
[0097] Exemplary anxiolytic agents include, but are not limited to,
amphetamine, buspirone, barbiturates, benzodiazepines (for example,
alprazolan, bromazepam, brotizolam, camazepam, chlordiazepoxide,
clobazam, clonazepam, desalkylflurazepam, diazepam, flunitrazepam,
flurazepam, lorazepam, lometazepam, medazepam, metaclazepam,
midazolam, nitrazepam, nordazepam, oxazepam, pentylenetetrazole,
prazepam, temazepam, tetrazepam, and triazolam) and the like.
[0098] Exemplary CNS and respiratory stimulatory agents include,
but are not limited to xanthines (for example, caffeine and
theophylline), amphetamines (for example, amphetamine,
benzphetamine hydrochloride, dextroamphetamine, dextroamphetamine
sulfate, levamphetamine, levamphetamine hydrochloride,
methamphetamine, and methamphetamine hydrochloride), and
miscellaneous stimulants such as methylphenidate, methylphenidate
hydrochloride, modafinil, pemoline, sibutramine, and sibutramine
hydrochloride.
[0099] Pharmaceutically active agents with a narrow therapeutic
index include, for example, amiodarone, amphotericin, cabamazepine,
clozapine, digoxin, disopyramide, lithium carbonate, minoxidil,
phenytoin, primidone, procainamide, quinidine, theophylline,
valproic acid, and warfarin.
[0100] It will be appreciated that the amount of the
pharmaceutically active agent present in the abuse-resistant
formulation depends upon the therapeutic dose required in
conventional tablets. In generally, each pharmaceutically active
agent is present in an amount ranging from about 0.5 mg to about
900 mg by weight, from about 1 mg to about 700 mg by weight, from
about 1 mg to about 600 mg by weight, from about 1 mg to about 500
mg, from about 1 mg to about 400 mg, from about 1 mg to about 300
mg, from about 1 mg to about 200 mg, and from about 10 mg to about
200 mg. It is understood, however, that the actual dosage will
depend upon the particular pharmaceutically active ingredient and
its proposed use.
[0101] It is understood that the intact compositions described
herein can be produced using techniques known to those in the
formulary arts. An exemplary protocol for producing controlled
release tablets is described in Example 1. It is understood,
however, that other approaches can be used to make formulations of
the invention.
[0102] In certain embodiment, the formulations have a hardness in
the range of from about 100 N to about 500 N, or from about 150 N
to about 400N, or from about 200 N to about 400N, or from about 300
N to about 400 N. In certain embodiments, the formulations have a
hardness from about 130 N to about 280 N, from about 130 N to about
210 N, from about 130 N to about 195 N, from about 150 N to about
250 N, from about 150 N to about 200 N, from about 150 N to about
180 N, from about 160N to about 195 N, from about 160 N to about
180 N, from about 180 N to about 230 N, from about 200 N to about
250 N, from about 200 N to about 260 N, from about 205 N to about
280 N, from about 210 to about 250 N, or from about 210 N to about
230 N.
[0103] In certain embodiments, for example, an oral dosage form
containing oxycodone and acetaminophen can have a hardness within
one or more of the ranges set forth above.
[0104] The composition, when made, can be used to administer a
pharmaceutically active agent to a mammal, for example, a human, in
need of the pharmaceutically active agent (for example, an opioid
analgesic for pain management). It is understood that the exact
dosage will vary depending on the symptoms, age, body weight,
severity of the disease to be treated and can be optimized through
routine experimentation known to those of skill in the art.
EXAMPLES
[0105] Practice of the invention will be more fully understood from
the foregoing examples, which are presented herein for illustrative
purposes only, and should not be construed as limiting the
invention in any way.
Example 1
Exemplary Oxycodone HCl/Acetaminophen Tablet
[0106] This Example describes an exemplary misuse preventative
tablet and how it can be made. The composition comprises a mixture
of acetaminophen (650 mg) and oxycodone HCl (25 mg). Oxycodone is a
drug used for the treatment of moderate to moderately severe pain,
which is capable of being abused and for which over exposure via
misuse can lead to harmful side effects. The tablet has a bilayer
core with a non-functional (aesthetic) coating. In this Example,
the superabsorbent material is disposed within the controlled
release layer. The formulation of the tablet is set forth in Table
1, and the manufacture of each of the components for the
formulation appear in the following sections of this Example.
TABLE-US-00001 TABLE 1 Tablet Composition Ingredients (Mg) (%)
First layer (controlled release) Oxycodone (as oxycodone
microparticles) 173.79 24.72 COMPAP .RTM. (which includes
acetaminophen) 433.33 61.64 Carbopol 71 G 42.02 5.98 Xanthan gum 80
mesh 42.02 5.98 Colloidal silicon dioxide (Cab O sil) 2.95 0.42
Sodium stearyl fumarate (Pruv) 8.86 1.26 Total 703.00 100.00 Second
layer (rapid release) COMPAP .RTM. (which includes acetaminophen)
288.89 89.72 Microcrystalline Cellulose PH102 19.77 6.14
Croscaramellose sodium AcDiSol 6.70 2.08 Colloidal silicon dioxide
(Cab O sil) 1.68 0.52 Sodium stearyl fumarate (Pruv) 4.83 1.50
FD&C Yellow #6 0.13 0.04 Total 322.00 100.00
[0107] Throughout the examples, COMPAP.RTM. (Mallinckrodt, Inc.) is
a compressible composition that comprises an admixture of
acetaminophen and pre-gelatinized starch, where the percentage of
acetaminophen in the composition can vary slightly depending upon
the batch of COMPAP.RTM.. To compensate for this variability, the
amount of COMPAP.RTM. is varied in the blend of excipients to be
compressed. Corresponding changes are made to the amount of
microcrystaline cellulose in order to maintain tablet weight. In
addition, the amount of oxycodone or other active ingredient
contained within the microparticles can vary, so the amount of
microparticles may be adjusted to keep the drug content
constant.
A. Manufacture of Oxycodone Microparticles
[0108] The microparticles were produced by mixing the components
set forth in Table 2 (except for the Eudragit NE 30D and Talc). The
resulting mixture was subjected to extrusion and spheronization,
and the resulting microparticles were coated with the Eudragit NE
30D and talc in a fluid bed coater equipped with a bottom spray.
The core of the tablet was a bilayer. The oxycodone containing
microparticles were incorporated in the slow release layer of the
bilayer whereas the acetaminophen, as COMPAP.RTM. which was in free
form and not incorporated into microparticles, was present in both
the rapid release layer and the slow release layer.
TABLE-US-00002 TABLE 2 Ingredients Mg/tablet % Composition
Oxycodone HCl 20.0 11.51 Cellulose microcrystalline (Avicel PH101)
37.3 21.49 Contramid .RTM. excipient 2.7 1.53 Lactose monohydrate
73.4 42.22 Eudragit NE 30D 20.0 11.51 Talc 20.0 11.51 Colloidal
silicon dioxide 0.4 0.23 Total 173.8 100.00
B. Manufacture of the Bilayer
[0109] The composition of the first layer (controlled release
layer) containing COMPAP.RTM. and the oxycodone containing
microparticles, and the composition of the second layer containing
COMPAP.RTM. (which includes acetaminophen) are shown in Table 1.
The bilayer was prepared by mixing the components of each layer and
then compressing the materials in a tablet press to form a tablet
having a hardness of about 210 N.
C. Aesthetic Coat
[0110] The bilayer tablet was coated with an aesthetic coat using
the Opaglos ingredients set forth in Table 3 using a pan coating
machine to form the final coated tablet.
TABLE-US-00003 TABLE 3 Ingredients Mg/tablet % tablet Opaglos II
Gray 30.75 3.0 Opaglos II Clear 10.25 1.0
[0111] The in vitro release properties of the resulting tablets
were measured in a U.S.P. Type III Apparatus in potassium phosphate
buffer at pH 6.8 for 12 hours, 0.1M hydrochloric acid at pH 1.2 for
12 hours, 0.1M hydrochloric acid at pH 1.2 for 1 hour followed by
potassium phosphate buffer at pH 6.8 for 11 hours, and in 40%
ethanol. As shown in FIG. 3A, the release profiles for oxycodone
were substantially the same across the pH range tested. In
addition, as shown in FIG. 3B, the release properties for
acetaminophen were substantially the same across the pH range
tested.
[0112] The in vitro release properties of three lots of tablets
were measured in a U.S.P. Type I Apparatus in potassium phosphate
buffer at pH 6.8. The effect of halving or quartering the tablets
on the release of oxycodone is shown in FIGS. 4A (half tablet) and
4B (quarter tablet). The effect of halving or quartering the
tablets on the release of acetaminophen is shown in FIGS. 5A (half
tablet) and 5B (quarter tablet). The partial tablets maintained a
controlled release for 12 hours, with no evidence of dose
dumping.
[0113] Crushed tablets were prepared using a conventional pill
crusher. The in vitro release properties of the crushed tablets
were measured in a U.S.P. Type I Apparatus under a variety of
conditions. FIG. 6A illustrates the release kinetics of oxycodone
in basified potassium phosphate aqueous solution at pH 10.0,
potassium phosphate buffer at pH 6.8 and acidified potassium
phosphate aqueous solution at pH 3.0, water, water containing 20%
ethanol and water containing 40% ethanol. Controlled release of
oxycodone was maintained under all conditions with no evidence of
dose dumping. FIG. 6B illustrates the release kinetics of
acetaminophen, which is less controlled than that of oxycodone. The
increased release allows for deterrence of injecting or snorting
the crushed powder, which is potentially hepatotoxic. Complete
sequestration of acetaminophen after crushing would not allow for
such deterrence.
[0114] When exposed to water, a crushed tablet rapidly formed a
gel, for example, within 21 seconds. Crushed tablets were exposed
to the 10 mL of the liquids shown in Table 4. The resulting
mixtures were agitated in a mechanical shaker for 120 minutes, then
allowed to stand for 15 minutes to determine whether any separation
of gel and liquid occurred.
TABLE-US-00004 TABLE 4 Oxycodone Acetaminophen Liquid % released* %
released* Tap Water Thick gel Thick gel Ethanol (40% (v/v)) Thick
gel Thick gel Acidic Media (pH 3.0) Thick gel Thick gel Basic Media
(pH 10.0) Thick gel Thick gel
[0115] As illustrated in Table 4, a thick gel formed when the
aqueous solvent contained 40% ethanol or had a pH in the range from
3 to 10. Because the gel did not separate into a solid and
supernatant, no liquid was available for analysis to determine the
amount of oxycodone or acetaminophen that may have eluted from the
composition.*
[0116] In order to simulate the effect of intravenous or nasal
administration of a crushed tablet, a tablet was crushed and mixed
with 2 mL of tap water or water containing 40% ethanol as shown in
Table 5. A hard gel formed in both cases. To extract liquid from
the hard gel for analysis, a cotton wool filter was placed on the
tip of a syringe and a small amount of liquid was extracted under
heavy suction. The extracts were analyzed for oxycodone and
acetaminophen content.
TABLE-US-00005 TABLE 5 Extract Liquid % Oxycodone % Acetaminophen
Water 0.0 0.14 Ethanol (40% v/v) 0.0 0.12
[0117] The results show that no oxycodone was detected in the
extracts, while a negligible amount of acetaminophen was present in
both water and 40% ethanol.
[0118] To determine the amount of active ingredient release upon
gel disruption, crushed tablets were added to either 100 mL of
water, acidified potassium phosphate aqueous solution buffer pH
3.0, or water containing 40% ethanol. The resulting gels were
disrupted by vigorous stirring for 1 minute. The mixtures were
assayed for oxycodone and acetaminophen content at 15, 30, and 60
seconds as shown in Table 6.
TABLE-US-00006 TABLE 6 % Oxycodone content % Acetaminophen content
15 30 60 15 30 60 Extract Liquid sec sec sec sec sec sec Water 0.8
1.7 2.1 30.9 42.1 49.2 Ethanol (40% v/v) 2.0 2.7 4.1 29.9 44.1 52.4
Acidic Media 2.0 3.5 5.3 48.2 52.1 68.4 (pH 3.0)
[0119] The results show a rapid release of acetaminophen, which
could deter potential intravenous or nasal administration because
high doses of acetaminophen are known to be hepatotoxic. Unlike
acetaminophen, oxycodone is present as microparticles in the tablet
formulation such that release of oxycodone following crushing was
minimal.
Example 2
Exemplary Oxycodone HCl/Acetaminophen Tablet
[0120] This Example describes the manufacture and testing of a
twice-a-day tablet containing oxycodone HCl (20 mg) and
acetaminophen (650 mg). The bilayer tablet contains microparticles
containing oxycodone HCl and Contramid.RTM., and coated with an
enteric coating. The resulting bilayer, however, was encapsulated
with a non functional (aesthetic) coat. The superabsorbent material
was disposed in the slow release layer.
[0121] The formulation of the tablet is set forth in Table 7, and
the manufacture of each of the components for the formulation
appear in the following sections of this Example.
TABLE-US-00007 TABLE 7 Tablet Composition Ingredients (Mg) (%)
First Layer (Slow Release) Oxycodone microparticles (coated at
198.4 26.40 10% Eudrait NE + 15% enteric coating) COMPAP .RTM.
(which includes acetaminophen) 469.44 62.46 Carbopol 71 G 36 4.79
Xanthan gum 80 mesh 36 4.79 Colloidal silicon dioxide (Cab O sil)
2.97 0.40 Sodium stearyl fumarate (Pruv) 8.83 1.17 Total 751.64 100
Second layer (Fast Release) COMPAP .RTM. (which includes
acetaminophen) 252.77 88.42 Microcrystalline Cellulose PH102 19.76
6.91 Croscaramellose sodium AcDiSol 6.7 2.34 Colloidal silicon
dioxide (Cab O sil) 1.68 0.59 Sodium stearyl fumarate (Pruv) 4.83
1.69 FD&C Yellow #6 0.13 0.05 Total 285.87 100
A. Manufacture of Oxycodone Microparticles
[0122] The microparticles were produced by mixing the first four
components set forth in Table 8. The resulting mixture was
subjected to extrusion and spheronization, and the resulting
microparticles were coated with the remaining four excipients
(Eudragit NE30D, talc, Eudragit L30D-55, triethyl citrate) in a
fluid bed coater equipped with a bottom spray. Microparticles
coated with a Eudragit L30D-55 coat withstand dissolution at low
pH, such as pH 1-3, and prevent the release of oxycodone. The
coating dissolves at higher pH, but its mechanical removal is
minimal when the tablet is crushed. The coating prevents the
release of oxycodone at low pH in both intact and crushed
tablets.
[0123] The core of the tablet was a bilayer. The oxycodone
containing microparticles were incorporated in the slow release
layer of the bilayer whereas the acetaminophen, as COMPAP.RTM.
which was in free form and not incorporated into microparticles,
was present in both the rapid release layer and the slow release
layer.
TABLE-US-00008 TABLE 8 Ingredients Mg/tablet % Composition
Oxycodone HCl 20.0 10.08 Cellulose microcrystalline (Avicel PH101)
37.3 18.82 Contramid .RTM. 2.7 1.34 Lactose monohydrate 73.3 36.96
Eudragit NE30D 13.3 6.72 Talc 25.3 12.77 Eudragit L30D-55 24.0 12.1
Triethyl citrate 2.4 1.21 Total 198.4 100.00
B. Manufacture of Bilayer
[0124] The composition of the first layer (controlled release
layer) containing COMPAP.RTM. and the oxycodone containing
microparticles, and the composition of the second layer containing
acetaminophen are shown in Table 7. The bilayer was prepared by
mixing the components of each layer and then compressing the
materials in a tablet press to form a tablet having a hardness of
about 230 N.
C. Aesthetic Coating
[0125] The resulting bilayer then was coated with the Opaglos
ingredients set forth in Table 9 by using a pan coating machine to
form the final coated tablet.
TABLE-US-00009 TABLE 9 Ingredients Mg/tablet % tablet Opaglos II
Green 31.12 3.0 Opaglos II Clear 10.38 1.0
[0126] The in vitro release properties of the resulting tablets
were measured in a U.S.P. Type I Apparatus in acid pH 1.2 for 12
hours, phosphate buffer pH 6.8 for 12 hours, and acid pH 1.2 for 1
hour, followed by phosphate buffer pH 6.8 for 11 hours. The release
kinetics were measured on intact tablets. As shown in FIG. 7A, the
release profiles for oxycodone demonstrate the delay in release for
at least 1 hour at low pH. As shown in FIG. 7B, a rapid release of
acetaminophen was observed. Release kinetics similar to Example 1
were observed for half and quarter tablets (data not shown).
[0127] The in vitro release properties of the resulting tablets
were measured in a U.S.P. Type I Apparatus in acid pH 1.2 for 1
hour and phosphate buffer pH 6.8 for 1 hour for crushed tablets. As
shown in FIG. 8A, the release profiles for oxycodone demonstrate
the delay in release for at least 1 hour at low pH. As shown in
FIG. 8B, a more rapid release of acetaminophen was observed.
Example 3
Exemplary Oxycodone HCl/Acetaminophen Tablet
[0128] This Example describes the manufacture and testing of a
tablet (BID) containing oxycodone HCl (20 mg) and acetaminophen
(650 mg). The tablet comprises a bilayer core surrounded by an
enteric, controlled release coating (namely, Eudragit L30D55). The
microparticles, however, did not have a controlled release coating.
The superabsorbent material is disposed in the slow release
layer.
[0129] The microparticles were produced by mixing the components
set forth in Table 10 (except for the Eudragit NE 30D and Talc).
The resulting mixture was subjected to extrusion and
spheronization, and the resulting microparticles were coated with
the Eudragit NE 30D and talc in a fluid bed coater equipped with a
bottom spray.
TABLE-US-00010 TABLE 10 Ingredients Mg/tablet % Composition
Oxycodone HCl 20.0 11.51 Cellulose microcrystalline (Avicel PH101)
37.3 21.49 Contramid .RTM. 2.7 1.53 Lactose monohydrate 73.4 42.22
Eudragit NE 30D 20.0 11.51 Talc 20.0 11.51 SiO.sub.2 0.4 0.23 Total
173.8 100.00
[0130] The composition of the core, which was a bilayer, is set
forth in Table 11. The oxycodone containing microparticles were
incorporated in the slow release layer of the bilayer whereas the
acetaminophen, as COMPAP.RTM. which was in free form and not
incorporated into microparticles, was present in both the rapid
release layer and the slow release layer.
TABLE-US-00011 TABLE 11 Tablet Composition Ingredients (Mg) (%)
First layer (slow release) Oxycodone (provided as oxycodone 173.79
24.72 microparticles) COMPAP .RTM. (which includes acetaminophen)
433.33 61.64 Carbopol 71 G 42.02 5.98 Xanthan gum 80 mesh 42.02
5.98 Colloidal silicon dioxide (Cab O sil) 2.95 0.42 Sodium stearyl
fumarate (Pruv) 8.86 1.26 Total 703.00 100.00 Second layer (rapid
release) COMPAP .RTM. (which includes acetaminophen) 288.89 89.72
Microcrystalline Cellulose PH102 19.77 6.14 Croscaramellose sodium
AcDiSol 6.70 2.08 Colloidal silicon dioxide (Cab O sil) 1.68 0.52
Sodium stearyl fumarate (Pruv) 4.83 1.50 FD&C Yellow #6 0.13
0.04 Total 322.00 100.00
[0131] The bilayer core was prepared by mixing the components of
each layer and then compressing the materials in a tablet press.
The bilayer tablets had a hardness in the range of 190 to 230
Newtons. The resulting bilayer core was then coated with Eudragit
L30D 55 by using a pan coating machine. The resulting coating
contained 82 mg of Eudragit L30D 55, which accounted for 8% of the
weight of the tablet.
[0132] The in vitro release kinetics of the resulting tablet were
measured in a U.S.P. Type III Apparatus at 20 dpm after incubation
in 0.1 M hydrochloric acid at pH 1.2 for 1 hour followed by
incubation in phosphate buffer pH 6.8 for 11 hours. The results
shown in FIG. 9 indicate that no oxycodone was released from the
tablet when incubated in 0.1 M hydrochloric acid, but the oxycodone
was released in a controlled manner when the buffer was changed to
phosphate buffer pH 6.8 after 1 hour.
Example 4
Exemplary Oxycodone HCl/Acetaminophen Tablet
[0133] This Example describes the manufacture and testing of a
tablet (BID) containing oxycodone HCl (20 mg) and acetaminophen
(650 mg). The tablet comprises a bilayer core, where the
superabsorbent material (Carbopol 71G) and lipids (Compritol 888
ATO) are present in the controlled release layer. The lipids are
designed to swell at low pH thereby minimizing release of oxycodone
HCl. The composition of the bilayer core is set forth in Table 12,
and the manufacture of each of the components for the formulation
appear in the following sections of this Example.
TABLE-US-00012 TABLE 12 Tablet Composition Ingredients (Mg) (%)
Rapid Release Layer COMPAP .RTM. (which includes acetaminophen)
288.90 89.72 Microcrystalline Cellulose PH102 19.76 6.14
Croscaramellose sodium AcDiSol 6.70 2.08 Colloidal silicon dioxide
(Cab O sil) 1.68 0.52 Sodium stearyl fumarate (Pruv) 4.83 1.50
FD&C Yellow #6 0.13 0.04 Total 322.00 100.00 Slow Release Layer
Oxycodone microparticles 148.58 17.38 COMPAP .RTM. (which includes
acetaminophen) 433.42 50.70 Carbopol 71 G 90.00 10.53 Compritol 888
ATO 171.00 20.00 Colloidal silicon dioxide (Cab O sil) 2.96 0.35
Sodium stearyl fumarate (Pruv) 8.83 1.03 Total 854.79 100.00
A. Manufacture of Oxycodone Microparticles
[0134] The microparticles were produced by mixing the components
set forth in Table 13 (except for the Eudragit NE 30D and Talc).
The resulting mixture was subjected to extrusion and
spheronization, and the resulting microparticles were coated with
the Eudragit NE 30D and talc in a fluid bed coater equipped with a
bottom spray.
TABLE-US-00013 TABLE 13 Ingredients Mg/batch % Composition
Oxycodone HCl 124.8 12.48 Cellulose microcrystalline (Avicel PH101)
232.9 23.29 Contramid .RTM. excipient 16.6 1.66 Lactose monohydrate
457.4 45.74 Eudragit NE 30D 83.2 8.32 Talc 83.2 8.32 SiO.sub.2 2.0
0.20 Total 1000 100.00
B. Manufacture of Bilayer
[0135] The core of the tablet was a bilayer. The oxycodone
containing microparticles were incorporated in the slow release
layer of the bilayer whereas the acetaminophen, as COMPAP.RTM.,
which was in free form and not incorporated into microparticles,
was present in both the rapid release layer and the slow release
layer.
[0136] The composition of the first layer (controlled release
layer) containing COMPAP.RTM. (containing acetaminophen) and the
oxycodone containing microparticles, and the composition of the
second layer containing COMPAP.RTM. are shown in Table 12. The
bilayer was prepared by mixing the components of each layer and
then compressing the materials in a tablet press (Manesty, UK) to
form a tablet having a hardness of about 150 N.
C. Aesthetic Coating
[0137] The resulting bilayer was coated with an aesthetic coating
using the Opaglos ingredients set forth in Table 14 by using a pan
coating machine to provide the final coated tablet.
TABLE-US-00014 TABLE 14 Ingredients Mg/tablet % Composition Opaglos
II Gray 30.75 3.0 Opaglos II Clear 10.25 1.0
[0138] The in vitro release properties of the resulting tablets
were measured in a U.S.P. Type III Apparatus in phosphate buffer pH
6.8. The release kinetics were measured on intact tablets. As shown
in FIG. 10A, the release profile of oxycodone in tablets comprising
Compritol in the controlled release layer was comparable to tablets
having an enteric coat on the oxycodone microparticles, such as the
data at pH 6.8 for intact tablets in Example 2 under similar
conditions (FIG. 7A). Likewise, the release kinetics for
acetaminophen shown in FIG. 10B were similar to that of Example 2
(FIG. 7B).
[0139] The in vitro release properties of the resulting tablets,
when crushed, were measured in a U.S.P. Type I Apparatus in acid at
pH 1.2. As shown in FIG. 11A, the release profile of oxycodone in
tablets comprising Compritol showed a greater release of oxycodone
than the crushed tablets of the Example 2 formulation (FIG. 8A)
under the same conditions. However, no dose dumping of oxycodone
was observed. In comparison to Example 2 for acetaminophen release
from crushed tablets (FIG. 8B), acetaminophen was not released as
fast from the Compritol containing crushed tablets (FIG. 11B).
Example 5
Exemplary Controlled Release Methylphenidate Formulation
[0140] This Example describes the manufacture and testing of a
tablet containing methylphenidate in a 12 hour controlled release
bilayer formulation. While the tablet is uncoated, an aesthetic or
functional (such as enteric) coat can be applied. The
superabsorbent material is disposed within the slow release layer.
The formulation of the tablet is set forth in Table 15, and the
manufacture of each of the components for the formulation appear in
the following sections of this Example.
TABLE-US-00015 TABLE 15 Lot 1 Lot 2 Lot 3 Lot 4 Ingredients %
Mg/tab % Mg/tab % Mg/tab % Mg/tab Fast release layer compositions
Film coated methylphenidate 27.31 27.31 27.31 27.31 27.31 27.31
27.31 27.31 microparticles Avicel PH 102 69.17 69.17 69.17 69.17
69.17 69.17 69.17 69.17 Croscarmellose (Ac-Di-Sol) 2.00 2.00 2.00
2.00 2.00 2.00 2.00 2.00 Colloidal silicon dioxide 0.5 0.5 0.5 0.5
0.5 0.5 0.5 0.5 Sodium stearyl fumarate 1.00 1.00 1.00 1.00 1.00
1.00 1.00 1.00 Total Core 100.0 100.0 100.0 100.0 100.0 100.0 100.0
100.0 Slow release layer compositions Film coated methylphenidate
44.22 154.8 44.22 154.8 44.22 154.8 44.22 154.8 microparticles
Avicel PH 102 -- -- -- -- -- -- -- -- Carbopol 71G 13.57 47.5 13.57
47.5 13.57 47.5 20.35 71.24 Xanthan gum 13.57 47.5 0 0 0 0 0 0
Kollidon SR 13.57 47.5 13.57 47.5 20.35 71.24 20.35 71.24 Plasdone
S-630 13.57 47.5 27.14 95.0 20.35 71.24 13.57 47.5 Colloidal
silicon dioxide 0.50 1.8 0.50 1.8 0.50 1.8 0.50 1.8 Sodium stearyl
fumarate 1.00 3.5 1.00 3.5 1.00 3.5 1.00 3.5 Total coat 100.0 350.0
100.0 350.0 100.0 350.0 100.0 350.0 Total tablet weight 450.0 450.0
450.0 450.0
A. Manufacture of Methylphenidate Microparticles
[0141] Microparticles of methylphenidate having the composition set
forth in Table 16 were formulated using an extrusion
microspheronization process.
TABLE-US-00016 TABLE 16 Ingredients % Composition Methylphenidate
hydrochloride 29.66 MCC Avicel PH 101 55.09 Eudragit RS30D .RTM. +
Plasacryl .RTM. + Triethyl citrate 15.25 Total 100.00
[0142] The methylphenidate hydrochloride and MCC Avicel PH 101 were
mixed in a mixer for 3 minutes under low shear conditions. The dry
blend then was wetted under agitation in the same mixer by
gradually adding water until a homogeneous wet mass suitable for
extrusion was produced. The wet mass then was extruded at a
constant speed (45 rpm) using a Laboratory Multigranulator extruder
model MG-55 from LCI, Inc., NC, USA equipped with a dome die having
a 0.6 mm diameter hole and a fixed extrusion gap. The extrudates
then were spheronized at a constant speed (1800 rpm) using a
Marumerzier Model QJ-230T from LCI, Inc., NC, USA. The wet
microparticles were dried at 45.degree. C. in a fluid bed (Glatt,
GPGC-1) until a moisture content of about 2% was achieved. The
resulting microparticles then were coated via fluidized bed coating
using a coating solution containing Eudragit RS30D.RTM., a film
that resists crushing, but is not an enteric coating.
B. Manufacture of the Bilayer
[0143] The composition of the first layer (fast release layer)
containing the methylphenidate microparticles (fast release) and
the second layer (slow release layer) containing the
methylphenidate microparticles (controlled release) are shown in
Table 15. The bilayer was prepared by mixing the components of each
layer and then compressing the materials using a tablet press to
form a tablet having a hardness of about 250 N.
[0144] Four lots of tablets were assayed for their in vitro release
properties of methylphenidate in a U.S.P. Type II Apparatus in
acidified water, pH 3.5. The release kinetics were measured on
intact tablets. As shown in FIG. 12, no dose dumping was observed.
Approximately 15% methylphenidate was released during the first
hour followed by a quasi-zero order release kinetics of
methylphenidate up to 12 hours.
Example 6
Exemplary Oxycodone HCl/Acetaminophen Tablets
[0145] This Example illustrates the preparation of a bilayer tablet
containing oxycodone HCl (20 mg) and acetaminophen (650 mg). One
layer is a rapid release layer which contains acetaminophen, and
the other layer is a slow release layer which includes oxycodone
HCl microparticles and acetaminophen. In this Example, the
superabsorbent material is disposed within the rapid release
layer.
[0146] The formulation of the complete tablet is set forth in Table
17.
TABLE-US-00017 TABLE 17 Ingredients Mg/Tablet %/Tablet Oxycodone
HCl (as Oxycodone HCl 20.0 1.76 microparticles - theoretical
content = 9.29%) COMPAP .RTM. (which includes acetaminophen) 722.22
63.69 Microcrystalline cellulose PH101 37.32 3.29 Contramid .RTM.
bulk powder 2.67 0.24 Lactose monohydrate (Spray Dry) # 315 73.31
6.46 Eudragit NE30D 19.99 1.76 Talc Suprafino H 32.99 2.91 Eudragit
L30D-55 25.99 2.29 Triethyl citrate 2.60 0.23 Mannitol 34.79 3.07
Microcrystalline Cellulose PH102 21.80 1.92 Croscarmellose sodium
AcDiSol 6.70 0.59 Carbomer homopolymer Type A carbomer 941 34.79
3.07 (granular) FD&C Yellow #6 Aluminium Lake (35-42) 0.13 0.01
Xanthan gum 80 mesh 80.00 7.05 Colloidal Silicon Dioxide 5.08 0.45
Sodium stearyl fumarate 13.66 1.20 Total 1134.03 100%
A. Manufacture of the Rapid Release Layer
[0147] COMPAP.RTM. and the ingredients of the rapid release layer
given in Table 18 were blended in a V-blender and set aside for a
later stage of the tablet preparation.
TABLE-US-00018 TABLE 18 Tablet Composition Ingredients (Mg) (%)
COMPAP .RTM. (which includes acetaminophen) 252.78 75.30 Mannitol
34.79 10.36 Carbopol 71 G 34.79 10.36 Croscarmellose sodium AcDiSol
6.70 2.00 Colloidal silicon dioxide (Cab O sil) 1.68 0.5 Sodium
stearyl fumarate (Pruv) 4.83 1.44 FD&C Yellow #6 Aluminum Lake
(35-42) 0.13 0.04 Total 335.70 100.00
B. Manufacture of Oxycodone HCl Microparticles
[0148] A wet mass of the first four ingredients (including
oxycodone HCl) given in Table 19 was extruded, spheronized, dried,
and sieved to give uncoated microparticles. The microparticles then
were coated with a polymer solution of Eudragit NE30D and talc,
followed by coating with a polymer solution of Eudragit L30D-55,
triethyl citrate, and talc. The coated microparticles were then
mixed with colloidal silicon dioxide and cured in an oven for 18
hours at 40.degree. C.
TABLE-US-00019 TABLE 19 Microsphere Ingredients Composition (%)
Oxycodone HCl 9.29 Cellulose microcrystalline (Avicel PH101) 17.34
Contramid .RTM. 1.24 Lactose monohydrate 34.05 Eudragit NE30D 9.29
Talc 15.32 Eudragit L30D-55 12.07 Triethyl citrate 1.21 Colloidal
silicon dioxide 0.20 Total 100%
C. Manufacture of the Slow Release Layer
[0149] The oxycodone HCl microparticles and the ingredients of the
slow release layer given in Table 20 were blended in a
V-blender.
TABLE-US-00020 TABLE 20 Tablet Composition Ingredients (Mg) (%)
Oxycodone HCl microparticles (9.29% 215.29 26.97 theoretical)
COMPAP .RTM. (which includes acetaminophen) 469.44 58.80 Xanthan
gum 80 mesh 80.00 10.02 Microcrystalline cellulose PH102 21.80 2.73
Colloidal silicon dioxide (Cab O sil) 2.97 0.37 Sodium stearyl
fumarate (Pruv) 8.83 1.11 Total 798.33 100.00
D. Manufacture of the Tablet
[0150] The blended rapid release layer and the blended slow release
layer were compressed on a rotary bilayer Picolla 11-station press
to provide caplet shaped tablets. The characteristics of the
tablets obtained are summarized in Table 21.
TABLE-US-00021 TABLE 21 Tablet Characteristics Typical Value Weight
(mg) 1134 Shape Caplet Length .times. width .times. thickness (mm)
18.5 .times. 9.3 .times. 7.6 Hardness (N) 180
[0151] The in vitro release kinetics of the resulting uncoated
tablet were measured in a U.S.P. Type III Apparatus at 20 dpm in
250 mL of phosphate buffer, pH 6.8. The release kinetics were
measured on three batches of intact tablets for 12 hours. As shown
in FIGS. 13A and 13B, the release profiles for oxycodone HCl and
acetaminophen, respectively, were substantially the same across the
three samples.
[0152] The in vitro release kinetics of oxycodone HCl from uncoated
crushed tablets were measured in a U.S.P. Type I Apparatus in
potassium phosphate aqueous solutions at pH 1.2, 6.8, and 10, in
water, and in 40% ethanol as shown in FIG. 14A. Less than 10% of
the oxycodone HCl was released in the various media. The in vitro
release kinetics of acetaminophen from uncoated crushed tablets
were measured in a U.S.P. Type I Apparatus, in potassium phosphate
aqueous solutions at pH 1.2, 6.8, and 10, in water, and in 40%
ethanol as shown in FIG. 14B. Less than 50% of the acetaminophen
was released in one hour in aqueous solution at pH 1.2, and less
than 20% of the acetaminophen was released at one hour in the other
media.
[0153] The in vitro release kinetics of oxycodone HCl and
acetaminophen from whole and bisected (half) tablets were measured
in a U.S.P. Type III Apparatus, 20 dpm, in 250 mL of potassium
phosphate buffer, pH 6.8. The in vitro release kinetics of
oxycodone HCl and acetaminophen from bisected (half) tablets were
also measured in a U.S.P. Type III Apparatus in 40% ethanol. The
effect of bisecting the tablets on the release of oxycodone is
shown in FIG. 15A, which depicts release profiles for whole and
half tablets. The effect of bisecting the tablets on the release of
acetaminophen is shown in FIG. 15B, which depicts release profiles
for whole and half tablets. The half tablet and the full tablet in
general displayed similar release characteristics. The release of
oxycodone and acetaminophen was slower in 40% ethanol from whole
tablets than from bisected tablets.
[0154] The misuse prevention properties of the crushed uncoated
tablets were determined by simple extraction into tap water, 40%
ethanol, and potassium phosphate aqueous solutions at pH 1.2, 6.8,
and 10. The results are given in Table 22. Oxycodone release was
well controlled in all media, while an increase in acetaminophen
release was observed at buffer pH 1.2 and 6.8.
TABLE-US-00022 TABLE 22 Oxycodone HCl Acetaminophen 15 sec 30 sec
60 sec 15 sec 30 sec 60 sec Tests (%) (%) (%) (%) (%) (%) Tap Water
0.4 0.7 0.8 22.1 33.1 24.4 Ethanol (40%) 1.6 1.6 1.7 17.6 15.5 13.3
Buffer pH 1.2 1.4 2.3 1.3 32.4 45.3 43.8 Buffer pH 6.8 2.2 6.2 2.1
33.3 48.4 40.8 Buffer pH 10.0 0.5 0.7 0.6 21.2 26.4 28.0
Example 7
Exemplary Oxycodone HCl/Acetaminophen Tablets
[0155] This Example illustrates the preparation of a bilayer tablet
containing oxycodone HCl (20 mg) and acetaminophen (650 mg). One
layer is a rapid release layer which contains acetaminophen, and
the other layer is a slow release layer which contains oxycodone
HCl microparticles and acetaminophen. The superabsorbent material
is disposed within the slow release layer. The formulation of the
tablet is set forth in Table 23.
TABLE-US-00023 TABLE 23 Tablet Composition Ingredients (Mg) (%)
Second Layer (Rapid Release) COMPAP .RTM. (which includes
acetaminophen) 252.8 88.4 Microcrystalline Cellulose PH 102 19.8
6.9 Sodium Croscarmellose 6.7 2.4 Colloidal Silicon Dioxide 1.7 0.6
Sodium stearyl fumarate (Pruv .RTM.) 4.8 1.7 FD&C Yellow #6
Aluminum Lake (35-42) 0.1 0.05 Total 285.9 100.0 First Layer (Slow
Release) Oxycodone microparticles 214.8 25.8 COMPAP .RTM. (which
includes acetaminophen) 469.4 56.4 Microcrystalline Cellulose PH
102 20.0 2.4 Carbopol .RTM. 71G 38.5 4.6 Kollidon SR 57.8 7.0 HPMC
K100M 19.3 2.3 Colloidal Silicon Dioxide 3.0 0.4 Sodium stearyl
fumarate (Pruv .RTM.) 8.8 1.1 Total 831.7 100.0
A. Manufacture of the Rapid Release Layer
[0156] COMPAP.RTM. and the ingredients of the rapid release layer
given in Table 23 were blended in a V-blender and set aside for a
later stage of the tablet preparation.
B. Manufacture of the Slow Release Layer
[0157] Oxycodone HCl microparticles were prepared according to the
procedure of Example 6. The microparticles and the ingredients of
the slow release layer given in Table 23 were blended in a
V-blender.
C. Manufacture of the Tablet
[0158] The blended rapid release layer and the blended slow release
layer were compressed on a rotary bilayer Picolla 11-station press
to provide caplet shaped tablets. The characteristics of the
tablets obtained are summarized in Table 24.
TABLE-US-00024 TABLE 24 Tablet Characteristics Typical Value Weight
(mg) 1117.6 Shape Caplet Length .times. width .times. thickness
(mm) 18.5 .times. 9.3 .times. 7.2 Hardness (N) 250
[0159] The in vitro release kinetics of oxycodone HCl and
acetaminophen for the resulting intact bilayer tablets were
measured in a U.S.P. Type III Apparatus for 1 hour in acid medium,
pH 1.2, followed by 11 hours in phosphate buffer, pH 6.8. The
results are summarized in FIG. 16, which show that drug release for
acetaminophen is faster than the release of oxycodone.
[0160] The in vitro release kinetics of oxycodone HCl and
acetaminophen for the resulting crushed bilayer tablets were
measured in a U.S.P. Type I Apparatus in 900 mL of deionized water
at 100 rpm for 60 hours. The results are summarized in FIG. 17,
which show that the drug release for oxycodone is much slower than
the release of acetaminophen.
INCORPORATION BY REFERENCE
[0161] The entire disclosure of each of the patent and scientific
documents referred to herein is incorporated by reference for all
purposes.
EQUIVALENTS
[0162] Although the present invention has been illustrated by means
of preferred embodiments thereof, it is understood that the
invention intends to cover broad aspects thereof without departing
from the spirit and scope of the invention as defined in the
appended claims.
* * * * *