U.S. patent application number 15/714137 was filed with the patent office on 2018-01-11 for immediate release, abuse deterrent pharmaceutical compositions.
The applicant listed for this patent is Mallinckrodt LLC. Invention is credited to Sunil K. Battu, Eric A. Burge, Thomas A. Diezi, Clifford J. Herman, Jae Han Park, Siva N. Raman.
Application Number | 20180008532 15/714137 |
Document ID | / |
Family ID | 48227563 |
Filed Date | 2018-01-11 |
United States Patent
Application |
20180008532 |
Kind Code |
A1 |
Raman; Siva N. ; et
al. |
January 11, 2018 |
IMMEDIATE RELEASE, ABUSE DETERRENT PHARMACEUTICAL COMPOSITIONS
Abstract
The present disclosure provides pharmaceutical compositions and
processes for making solid dosage form pharmaceutical compositions
that provide immediate release of active ingredients and have abuse
deterrent properties. The pharmaceutical compositions provided
herein comprise at least one pharmaceutically active ingredient, at
least one low molecular weight hydrophilic polymer, at least one
high molecular weight hydrophilic polymer, and an effervescent
system.
Inventors: |
Raman; Siva N.; (St. Louis,
MO) ; Park; Jae Han; (Olivette, MO) ; Diezi;
Thomas A.; (Webster Groves, MO) ; Herman; Clifford
J.; (St. Louis, MO) ; Battu; Sunil K.;
(Manchester, MO) ; Burge; Eric A.; (Collinsville,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Mallinckrodt LLC |
Hazelwood |
MO |
US |
|
|
Family ID: |
48227563 |
Appl. No.: |
15/714137 |
Filed: |
September 25, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13865286 |
Apr 18, 2013 |
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15714137 |
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|
61625926 |
Apr 18, 2012 |
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61792478 |
Mar 15, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/485 20130101;
A61K 9/0007 20130101; A61K 31/485 20130101; A61P 25/36 20180101;
A61K 2300/00 20130101; A61K 45/06 20130101; A61K 9/2031
20130101 |
International
Class: |
A61K 9/46 20060101
A61K009/46; A61K 9/20 20060101 A61K009/20; A61K 31/485 20060101
A61K031/485; A61K 45/06 20060101 A61K045/06 |
Claims
1. A solid dosage form comprising at least one active
pharmaceutical ingredient (API) or a pharmaceutically acceptable
salt thereof, at least one low molecular weight hydrophilic
polymer, at least one high molecular weight hydrophilic polymer,
and an effervescent system, wherein the at least one low molecular
weight hydrophilic polymer has an average molecular weight of no
more than 200,000 Daltons, the at least one high molecular weight
hydrophilic polymer has an average molecular weight of at least
400,000 Daltons, and the solid dosage form has been heated at a
temperature from about 50.degree. C. to about 80.degree. C. to
plasticize and/or cure at least one of the low or high molecular
weight hydrophilic polymers.
2. The solid dosage form of claim 1, wherein the at least one low
molecular weight hydrophilic polymer is chosen from a polyalkylene
oxide, a cellulose ether, a polyalkylene glycol, a poloxamer, or
combination thereof; and the at least one low molecular weight
hydrophilic polymer is present in an amount from about 5% to about
50% by weight of the solid dosage form.
3. The solid dosage form of claim 1, wherein the at least one high
molecular weight hydrophilic polymer is chosen from a polyalkylene
oxide, a cellulose ether, a polysaccharide, or combination thereof;
and the at least one high molecular weight hydrophilic polymer is
present in an amount from about 0.1% to about 30% by weight of the
solid dosage form.
4. The solid dosage form of claim 1, wherein the effervescent
system comprises an a) acid component chosen from an organic acid,
an inorganic acid, or combination thereof and b) a base component
chosen from an alkali metal bicarbonate, an alkaline earth metal
bicarbonate, an alkali metal carbonate, an organic carbonate, or
combination thereof; and the effervescent system is present in an
amount from about 20% to about 90% by weight of the solid dosage
form.
5. The solid dosage form of claim 1, wherein the at least one API
is an opioid or a combination of an opioid and a non-opioid
analgesic, and the opioid is chosen from oxycodone, oxymorphone,
hydrocodone, hydromorphone, codeine, or morphine.
6. The solid dosage form of claim 1, wherein the solid dosage form
further comprising a film coating.
7. The solid dosage form of claim 1, wherein the solid dosage form
has a hardness of at least about 15 kiloponds.
8. The solid dosage form of claim 1, wherein the solid dosage form
breaks into a plurality of particles having an average diameter of
greater than about 250 microns when crushed, ground, or
pulverized.
9. The solid dosage form of claim 1, wherein the solid dosage form
forms a viscous mixture or gel when in contact with about 3 mL to
about 10 mL of an aqueous solvent.
10. The solid dosage form of claim 1, wherein the solid dosage form
releases at least about 80% of the at least one API within about 30
minutes when measured using an USP-approved in vitro release
procedure.
11. The solid dosage form of claim 1, wherein the at least one low
molecular weight hydrophilic polymer is chosen from polyethylene
oxide, hydroxypropylmethyl cellulose, sodium carboxymethyl
cellulose, polyethylene glycol, a Poloxamer, or combination
thereof; the at least one high molecular weight hydrophilic polymer
is chosen from polyethylene oxide, xanthan gum, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, or combination thereof;
the effervescent system comprises a) an acid component chosen from
an organic acid, an inorganic acid, or combination thereof and b) a
base component chosen from an alkali metal bicarbonate, an alkaline
earth metal bicarbonate, an alkali metal carbonate, an organic
carbonate, or combination thereof; and the at least one API is an
opioid chosen from oxycodone, oxymorphone, hydrocodone,
hydromorphone, codeine, or morphine.
12. The solid dosage form of claim 11, wherein the at least one low
molecular weight hydrophilic polymer is present an amount from
about 15% to about 35% by weight of the solid dosage form; wherein
the at least one high molecular weight hydrophilic polymer is
present an amount from about 1% to about 55% by weight of the solid
dosage form; and the effervescent system is present in an amount
from about 50% to about 70% by weight of the solid dosage form.
13. The solid dosage form of claim 12, wherein the solid dosage
form has a hardness of at least about 20 kiloponds; and the solid
dosage form releases at least about 80% of the at least one API
within about 30 minutes when measured using an USP-approved in
vitro release procedure.
14. A process for preparing a solid dosage form, the process
comprising: a. forming a mixture comprising at least one active
pharmaceutical ingredient (API) or a pharmaceutically acceptable
salt thereof, at least one low molecular weight hydrophilic
polymer, at least one high molecular weight hydrophilic polymer,
and an effervescent system, wherein the at least one low molecular
weight hydrophilic polymer has an average molecular weight of no
more than 200,000 Daltons, and the at least one high molecular
weight hydrophilic polymer has an average molecular weight of at
least 400,000 Daltons; b. forming the mixture into a solid dosage
unit; and c. heating the solid dosage unit at a temperature of less
than about 90.degree. C. to yield the solid dosage form.
15. The process of claim 14, further comprising coating the solid
dosage unit at step (b) or the solid dosage form at step (c) with a
film coating.
16. The process of claim 14, wherein the at least one API is an
opioid or a combination of an opioid and a non-opioid analgesic;
and the opioid is chosen from oxycodone, oxymorphone, hydrocodone,
hydromorphone, codeine, or morphine.
17. The process of claim 14, wherein the at least one low molecular
weight hydrophilic polymer is chosen from a polyalkylene oxide, a
cellulose ether, a polyalkylene glycol, a poloxamer, or combination
thereof; and the at least one low molecular weight hydrophilic
polymer is present in an amount from about 5% to about 50% by
weight of the solid dosage form.
18. The process of claim 14, wherein the at least one high
molecular weight hydrophilic polymer is chosen from a polyalkylene
oxide, a cellulose ether, a polysaccharide, or combination thereof;
and the at least one high molecular weight hydrophilic polymer is
present in an amount from about 0.1% to about 30% by weight of the
solid dosage form.
19. The process of claim 14, wherein the effervescent system
comprises a) an acid component chosen from an organic acid, an
inorganic acid, or combination thereof and b) a base component
chosen from an alkali metal bicarbonate, an alkaline earth metal
bicarbonate, an alkali metal carbonate, an organic carbonate, or
combination thereof; and the effervescent system is present in an
amount from about 20% to about 90% by weight of the solid dosage
form.
20. The process of claim 15, wherein the mixture formed in step (a)
further comprises a lubricant that is present in an amount from
about 0.1% to about 2% by weight of the solid dosage form.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
application Ser. No. 13/865,286, filed Apr. 18, 2013, which claims
the benefit of U.S. Provisional Application No. 61/625,926 filed
Apr. 18, 2012, and U.S. Provisional Application No. 61/792,478
filed Mar. 15, 2013, the disclosure of each is hereby incorporated
by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present disclosure generally relates to pharmaceutical
compositions that provide immediate release of active ingredients
and have abuse deterrent properties.
BACKGROUND OF THE INVENTION
[0003] Abuse of prescription drugs (particularly opioids) has
become a serious societal problem. Such abuse places an enormous
economic burden on society due to increased health care, work
place, and criminal justice costs. Several routes of administration
are commonly attempted by abusers. For example, the oral solid
dosage form may be crushed or pulverized into a powder and
administered intranasally (i.e., snorted) or dissolved in a
suitable solvent (e.g., water) and administered parenterally (i.e.,
injected intravenously).
[0004] Attempts have been made to diminish the abuse of opioid
solid dosage forms. One approach has been to include in the dosage
form an opioid antagonist that is not orally active but will
substantially block the analgesic effects of the opioid if one
attempts to dissolve the opioid and administer it parenterally.
Another approach has been to include gel-forming high molecular
weight polymers that confer plasticity to the dosage form rendering
them difficult to crush and pulverize into a powder. These high
molecular weight polymers, however, retard the release of the
active ingredient from the dosage forms, making them unsuitable for
immediate release formulations.
[0005] Thus, there is a need for oral solid dosage forms that
provide immediate release of the active ingredient yet are
resistant to abuse.
SUMMARY OF THE INVENTION
[0006] Among the various aspects of the present disclosure is the
provision of a pharmaceutical composition comprising at least one
active pharmaceutical ingredient (API) or a pharmaceutically
acceptable salt thereof, at least one low molecular weight
hydrophilic polymer, at least one high molecular weight hydrophilic
polymer, and an effervescent system. The pharmaceutical composition
provides immediate release of the API and is abuse deterrent.
[0007] A further aspect of the present disclosure provides a
process for preparing a solid dosage form. The process comprises
forming a mixture comprising at least one low molecular weight
hydrophilic polymer, at least one high molecular weight hydrophilic
polymer, and an effervescent system. The process further comprises
forming the mixture into a solid dosage unit, and heating the solid
dosage unit to yield the solid dosage form.
[0008] Other aspects and iterations of the disclosure are described
in more detail below.
BRIEF DESCRIPTION OF THE FIGURES
[0009] FIG. 1A presents SEM image of L-(+)-tartaric acid particles.
FIG. 1B presents SEM image of L-(+)-tartaric acid particles coated
with Pluronic F127. FIG. 1C presents SEM image of Pluronic
F127-coated L-(+)-tartaric acid particles blended with talc.
[0010] FIG. 2A and FIG. 2B show the surface of Pluronic F127-coated
tartaric acid particles blended with talc. Elemental mapping shows
that the majority of the surface is covered with talc, with limited
Pluronic F127-coated surface visible.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The present disclosure provides pharmaceutical compositions
and processes for making solid dosage pharmaceutical compositions
that provide rapid release of the active ingredients and have abuse
deterrent properties. In particular, the pharmaceutical
compositions comprise a combination of low and high molecular
weight hydrophilic polymers and an effervescent system comprising
an acid component and a base component. It was unexpectedly
discovered that the combination of low and high molecular weight
hydrophilic polymers and the effervescent system makes the
compositions resistant to crushing into fine powders and/or
extracting with suitable solvents, while still providing immediate
release of the active ingredients.
(I) Pharmaceutical Compositions
[0012] One aspect of the present disclosure provides abuse
deterrent pharmaceutical compositions that provide immediate
release of the active pharmaceutical ingredients. Detailed below
are the components of the composition, dosage forms of the
composition, release characteristics of the composition, and abuse
deterrent properties of the composition.
(a) Components of the Pharmaceutical Composition
[0013] The pharmaceutical compositions disclosed herein comprise at
least one low molecular weight hydrophilic polymer, at least one
high molecular weight hydrophilic polymer, and an effervescent
system. The combination of hydrophilic polymers of different
molecular sizes and the effervescent system yields a functional
abuse deterrent, immediate release composition.
[0014] (i) Hydrophilic Polymers
[0015] The pharmaceutical compositions disclosed herein comprise
hydrophilic polymers of different molecular weights. The term
"hydrophilic polymer" refers to a polymer with affinity for water
such that it readily absorbs and/or dissolves in water or an
aqueous solution. Hydrophilic polymers may be soluble in water or
an aqueous solution and/or swellable in water or an aqueous
solution. Polymers that swell in water or an aqueous solution may
be termed gelling polymers.
[0016] A variety of hydrophilic polymers are suitable for use in
the pharmaceutical compositions. The hydrophilic polymer may be
natural, semi-synthetic, or synthetic. In some embodiments, the
hydrophilic polymer may be a polyalkylene oxide such as
polyethylene oxide (PEO), polypropylene oxide, combinations
thereof, or copolymers thereof. In other embodiments, the
hydrophilic polymer may be a cellulose ether, which is a cellulose
derivative in which the hydrogen atoms of hydroxyl groups are
replaced with alkyl groups. Non-limiting examples of suitable
cellulose ethers include hydroxypropyl cellulose (HPC),
hydroxypropylmethyl cellulose (HPMC), carboxymethyl cellulose
(CMC), methyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl
cellulose, and the like. In still other embodiments, the
hydrophilic polymer may be a polyalkylene glycol such as
polyethylene glycol (PEG) (e.g., PEG 1000, PEG 2000, PEG 4000, PEG
6000, PEG 8000, PEG 10,000, PEG 20,000, PEG 30,000), derivatives
thereof, combinations thereof, and copolymers thereof. In further
embodiments, the hydrophilic polymer may be a Poloxamer, which is a
difunctional, tri-block copolymer of ethylene oxide and
polyproplylene oxide (available under the tradenames KOLLIPHOR.TM.
or PLURONIC.RTM.). Available Poloxamers include Poloxamers 101,
105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215,
217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335,
338, 401, 402, 403, and 407, wherein the first two digits
multiplied by 100 give the approximate molecular mass and the last
digit multiplied by 10 gives the percentage of the polyoxyethylene
oxide content. In one embodiment, the hydrophilic polymer may be
Poloxamer 407. In still other embodiments, the hydrophilic polymer
may be a polysaccharide. Suitable polysaccharides include, without
limit, celluloses, starches, pectins, chitins, gums (i.e.,
polysaccharides derived from plants or microbes), combinations
thereof, and derivatives thereof. Non-limiting examples of suitable
gums include xanthan gum, acacia gum, diutan gum, gellan gum, guar
gum, fenugreek gum, locust bean gum, pullulan, welan gum, or
combinations thereof. In additional embodiments, the hydrophilic
polymer may be a polycarboxylic acid such as polyacrylic acid,
polyacrylic acid-co-acrylamide, polymethacrylate, polyhydroxyethyl
methacrylate, combinations, or copolymers thereof. In other
embodiments, the hydrophilic polymer may be a polyamine such as
polyethyleneimine, polyvinylamine, or the like. In further
embodiments, the hydrophilic polymer may be a polypeptide such as
gelatin, albumin, polylysine, soy protein, and so forth. In still
further embodiments, the hydrophilic polymer may be a polyolefinic
alcohol (such as polyvinyl alcohol), or a polyvinyl lactam (such
as, e.g., polyvinylpyrrolidone, polyvinyl caprolactam, and the
like). The hydrophilic polymer also may be a combination or a
copolymer of any of the foregoing.
[0017] (ii) Low molecular weight hydrophilic polymer
[0018] The pharmaceutical composition comprises at least one low
molecular weight hydrophilic polymer. As used herein, the term "low
molecular weight polymer" refers to a polymer having an average
molecular weight of no more than about 200,000 Da. In various
embodiments, the average molecular weight of the low molecular
weight polymer may range from about 200,000 to about 175,000 Da,
from about 175,000 to about 150,000 Da, from about 150,000 to about
125,000 Da, from about 125,000 to about 100,000 Da, from about
100,000 to about 75,000 Da, from about 75,000 to about 50,000 Da,
from about 50,000 to about 25,000 Da, or from about 25,000 to about
1000 Da. In some embodiments, the pharmaceutical composition may
comprise a hydrophilic polymer having an average molecular weight
of about 100,000 Da or less. In other embodiments, the
pharmaceutical composition may comprise a hydrophilic polymer
having an average molecular weight of about 30,000 Da or less. In
further embodiments, the pharmaceutical composition may comprise a
hydrophilic polymer having an average molecular weight of about
10,000 Da or less.
[0019] In one embodiment, the pharmaceutical composition comprises
one hydrophilic polymer having an average molecular weight of no
more than about 200,000 Da. In another embodiment, the
pharmaceutical composition comprises two hydrophilic polymers, the
average molecular weight of each being no more than about 200,000
Da. In still another embodiment, the pharmaceutical composition
comprises three hydrophilic polymers, the average molecular weight
of each being no more than about 200,000 Da. In a further
embodiment, the pharmaceutical composition comprises four
hydrophilic polymers, the average molecular weight of each being no
more than about 200,000 Da. In yet another embodiment, the
pharmaceutical composition comprises five hydrophilic polymers, the
average molecular weight of each being no more than about 200,000
Da. Examples of suitable hydrophilic polymers are detailed above in
section (I)(a)(i).
[0020] In one embodiment, the pharmaceutical composition comprises
polyethylene oxide having an average molecular weight of about
100,000 Da. In another embodiment, the pharmaceutical composition
comprises hydroxypropylmethyl cellulose having an average molecular
weight of about 100,000 Da. In still another embodiment, the
pharmaceutical composition comprises (sodium) carboxymethyl
cellulose having an average molecular weight of about 90,000 Da or
less. In a further embodiment, the pharmaceutical composition
comprises polyethylene glycol having an average molecular weight of
about 20,000 Da or less. In yet another embodiment, the
pharmaceutical composition comprises a Poloxamer having an average
molecular weight of about 10,000 Da or less. In further
embodiments, the pharmaceutical composition comprises two or more
of the specific above-cited polymers.
[0021] The amount of the low molecular weight hydrophilic polymer
present in the pharmaceutical composition can and will vary
depending upon the desired properties of the composition, as well
as the identity and amounts of other components present in the
composition. In general, the amount of the low molecular weight
hydrophilic polymer present may range from about 5% to about 50% by
weight of the pharmaceutical composition. In various embodiments,
the amount of the low molecular weight hydrophilic polymer present
in the composition may range from about 5% to about 10%, from about
10% to about 15%, from about 15% to about 20%, from about 20% to
about 25%, from about 25% to about 30%, from about 30% to about
40%, or from about 40% to about 50% by weight of the pharmaceutical
composition. In one embodiment, the amount of the low molecular
weight polymer present in the composition may range from about 10%
to about 40% by weight of the pharmaceutical composition. In an
exemplary embodiment, the amount of the low molecular weight
polymer present may range from about 20% to about 35% by weight of
the pharmaceutical composition.
[0022] (iii) High molecular weight hydrophilic polymer
[0023] The pharmaceutical composition disclosed herein also
comprises at least one high molecular weight hydrophilic polymer. A
"high molecular weight polymer," as used herein, refers to a
polymer having an average molecular weight of at least about
400,000 Da. In general, the average molecular weight of the high
molecular weight polymer may range from about 400,000 to about
15,000,000 Da. For example, the high molecular weight polymer may
have an average molecular weight that ranges from about 400,000 to
about 600,000 Da, from about 600,000 to about 800,000 Da, from
about 800,000 to 1,000,000 Da, from about 1,000,000 to about
4,000,000 Da, from about 4,000,000 to about 8,000,000 Da, from
about 8,000,000 to about 12,000,000 Da, or from about 12,000,000 to
about 15,000,000 Da. In some embodiments, the pharmaceutical
composition may comprise a hydrophilic polymer having an average
molecular weight of at least about 4,000,000 Da. In other
embodiments, the pharmaceutical composition may comprise a
hydrophilic polymer having an average molecular weight of at least
about 1,000,000 Da. In further embodiments, the pharmaceutical
composition may comprise a hydrophilic polymer having an average
molecular weight of at least about 800,000 Da.
[0024] In one embodiment, the pharmaceutical composition comprises
one hydrophilic polymer having an average molecular weight of at
least about 400,000 Da. In another embodiment, the pharmaceutical
composition comprises two hydrophilic polymers, the average
molecular weight of each being at least about 400,000 Da. In still
another embodiment, the pharmaceutical composition comprises three
hydrophilic polymers, the average molecular weight of each being at
least about 400,000 Da. In a further embodiment, the pharmaceutical
composition comprises four hydrophilic polymers, the average
molecular weight of each being at least about 400,000 Da. Examples
of suitable hydrophilic polymers are detailed above in section
(I)(a)(i).
[0025] In one embodiment, the pharmaceutical composition comprises
polyethylene oxide having an average molecular weight of at least
about 1,000,000 Da. In another embodiment, the pharmaceutical
composition comprises polyethylene oxide having an average
molecular weight of about 4,000,000 Da. In a further embodiment,
the pharmaceutical composition comprises xanthan gum having an
average molecular weight of at least about 1,000,000 Da. In still
another embodiment, the pharmaceutical composition comprises
hydroxypropyl cellulose having an average molecular weight of at
least about 800,000 Da. In further embodiments, the pharmaceutical
composition comprises two or more of the specific above-cited
polymers.
[0026] The amount of the high molecular weight hydrophilic polymer
present in the pharmaceutical composition can and will vary
depending upon the desired properties of the composition, as well
as the identity and amounts of other components present in the
composition. In general, the amount of the high molecular weight
polymer present in the composition may range from about 0.1% to
about 30% by weight of the composition. In various embodiments, the
amount of the high molecular weight polymer present in the
composition may range from about 0.1% to about 0.3%, from about
0.3% to about 1%, from about 1% to about 3%, from about 3% to about
10%, or from about 10% to about 30% by weight of the pharmaceutical
composition. In one embodiment, the amount of the high molecular
weight hydrophilic polymer present in the composition may range
from about 1% to about 15% by weight of the pharmaceutical
composition. In an exemplary embodiment, the amount of the high
molecular weight hydrophilic polymer present in the composition may
range from about 2% to about 10% by weight of the pharmaceutical
composition.
[0027] (iv) Effervescent System
[0028] The pharmaceutical compositions disclosed herein also
comprise an effervescent system. As used herein, an "effervescent
system" refers to a system generally comprising an acid component
and a base component, wherein the system liberates carbon dioxide
upon contact with an aqueous solution. Without being bound by any
particular theory, it is believed that the effervescent system
facilitates rapid dissolution of the API from a composition
comprising the combination of low and high molecular weight
hydrophilic polymers.
[0029] The acid component of the effervescent system may be an
organic acid, an inorganic acid, or a combination thereof.
Non-limiting examples of suitable acids include adipic acid,
ascorbic acid, benzoic acid, citric acid, fumaric acid, glutaric
acid, lactic acid, lauric acid, malic acid, maleic acid, malonic
acid, oxalic acid, phthalic acid, sorbic acid, succinic acid,
tartaric acid, ammonium phosphate, potassium bitartrate, potassium
phosphate, dipotassium phosphate, disodium pyrophosphate, sodium
acid pyrophosphate, sodium phosphate, disodium phosphate, and
combinations thereof. In exemplary embodiments, the acid component
of the effervescent system may be an organic acid. In one exemplary
embodiment, the acid component may be tartaric acid. In other
embodiments, the acid component of the effervescent system may be
an inorganic acid.
[0030] In some embodiments, the acid component of the effervescent
system may be co-processed with a polyalkylene glycol or a
Poloxamer. Suitable polyalkylene glycols and Poloxamers are
detailed above in section (I)(a)(i). The acid and the polyalkylene
glycol/Poloxamer may be co-processed by a variety of means
including, without limit, hot melt granulation, fluidized hot melt
granulation, hot melt mixing, wet granulation, liquid spray mixing,
and the like. The amount of polyalkylene glycol/Poloxamer
co-processed with the acid can and will vary. In general, the
weight to weight ratio of the acid to the polyalkylene
glycol/Poloxamer may range from about 1:0.01 to about 1:0.5.
[0031] The base component of the effervescent system may be a
bicarbonate, a carbonate, or a combination thereof. In various
embodiments, the base component may be an alkali metal bicarbonate,
an alkaline earth metal bicarbonate, an alkali metal carbonate, an
organic carbonate, or combinations thereof. Non-limiting examples
of suitable bases include ammonium bicarbonate, calcium
bicarbonate, lithium bicarbonate, magnesium bicarbonate, potassium
bicarbonate, sodium bicarbonate, arginine carbonate, ammonium
carbonate, calcium carbonate, lysine carbonate, potassium magnesium
carbonate, sodium carbonate, sodium glycine carbonate, sodium
sesquicarbonate, zinc carbonate, and combinations thereof. In
exemplary embodiments, the base component of the effervescent
system may be an alkali metal bicarbonate. In one exemplary
embodiment, the base component may be sodium bicarbonate. In
another exemplary embodiment, the base component may be
heat-treated sodium bicarbonate (for example EfferSoda.RTM.
12).
[0032] The mole to mole ratio of the acid component to the base
component in the effervescent system may also vary depending, for
example, upon the identity of the acid and the base components. In
general, the mole to mole ratio of the acid component to the base
component in the effervescent system may range from about 1:0.2 to
about 1:5. For example, the mole to mole ratio of the acid
component to the base component in the effervescent system may be
about 1:0.2, about 1:0.25, about 1:0.33, about 1:0.5, about 1:1,
about 1:2, about 1:3, about 1:4, about 1:5 or any ratio in between.
In one exemplary embodiment, the mole to mole ratio of the acid
component to the base component in the effervescent system may
range from about 1:1 to about 1:3. In another exemplary embodiment,
the mole to mole ratio of the acid component to the base component
in the effervescent system may be about 1:2.
[0033] The amount of the effervescent system present in the
composition can and will vary depending upon the identity of the
other components and the desired properties of the composition. In
general, the amount of the effervescent system present in the
composition may range from about 20% to about 90% by weight of the
composition. In various embodiments, the amount of the effervescent
system present in the composition may be from about 20% to about
30%, from about 30% to about 40%, from about 40% to about 50%, from
about 50% to about 60%, from about 60% to about 70%, from about 70%
to about 80%, or from about 80% to about 90% by weight of the
pharmaceutical composition. In certain embodiments, the amount of
the effervescent system present in the composition may range from
about 40% to about 80% by weight of the pharmaceutical composition.
In one exemplary embodiment, the amount of the effervescent system
present in the composition may range from about 50% to about 70% by
weight of the pharmaceutical composition.
[0034] (v) API
[0035] The pharmaceutical composition disclosed herein comprises at
least one API or salt thereof. Suitable APIs include, without
limit, opioid analgesic agents (e.g., adulmine, alfentanil,
allocryptopine, allylprodine, alphaprodine, anileridine, aporphine,
benzylmorphine, berberine, bicuculine, bicucine, bezitramide,
buprenorphine, bulbocaprine, butorphanol, clonitazene, codeine,
desomorphine, dextromoramide, dezocine, diampromide, diamorphone,
dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,
dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,
ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,
fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,
isomethadone, ketobemidone, levorphanol, levophenacylmorphan,
lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,
morphine, myrophine, narceine, nicomorphine, norlevorphanol,
normethadone, nalorphine, nalbuphene, normorphine, norpipanone,
opium, oxycodone, oxymorphone, papaveretum, pentazocine,
phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,
piritramide, propheptazine, promedol, properidine, propoxyphene,
sufentanil, tapentadol, tilidine, and tramadol); non-opioid
analgesic agents (e.g., acetylsalicylic acid, acetaminophen,
paracetamol, ibuprofen, ketoprofen, indomethacin, diflunisol,
naproxen, ketorolac, dichlophenac, tolmetin, sulindac, phenacetin,
piroxicam, and mefamanic acid); anti-inflammatory agents (e.g.,
glucocorticoids such as alclometasone, fluocinonide,
methylprednisolone, triamcinolone and dexamethasone; non-steroidal
anti-inflammatory agents such as celecoxib, deracoxib, ketoprofen,
lumiracoxib, meloxicam, parecoxib, rofecoxib, and valdecoxib);
antitussive agents (e.g., dextromethorphan, codeine, hydrocodone,
caramiphen, carbetapentane, and dextromethorphan); antipyretic
agents (e.g., acetylsalicylic acid and acetaminophen); antibiotic
agents (e.g., aminoglycosides such as, amikacin, gentamicin,
kanamycin, neomycin, netilmicin, streptomycin, and tobramycin;
carbecephem such as loracarbef; carbapenems such as certapenem,
imipenem, and meropenem; cephalosporins such as cefadroxil
cefazolin, cephalexin, cefaclor, cefamandole, cephalexin,
cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren,
cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten,
ceftizoxime, and ceftriaxone; macrolides such as azithromycin,
clarithromycin, dirithromycin, erythromycin, and troleandomycin;
monobactam; penicillins such as amoxicillin, ampicillin,
carbenicillin, cloxacillin, dicloxacillin, nafcillin, oxacillin,
penicillin G, penicillin V, piperacillin, and ticarcillin;
polypeptides such as bacitracin, colistin, and polymyxin B;
quinolones such as ciprofloxacin, enoxacin, gatifloxacin,
levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin,
and trovafloxacin; sulfonamides such as mafenide, sulfacetamide,
sulfamethizole, sulfasalazine, sulfisoxazole, and
trimethoprim-sulfamethoxazole; tetracyclines such as
demeclocycline, doxycycline, minocycline, and oxytetracycline);
antimicrobial agents (e.g., ketoconazole, amoxicillin, cephalexin,
miconazole, econazole, acyclovir, and nelfinavir); antiviral agents
(e.g., acyclovir, gangciclovir, oseltamivir, and relenza); steroids
(e.g., estradiol, testosterone, cortisol, aldosterone, prednisone,
and cortisone); amphetamine stimulant agents (e.g., amphetamine and
amphetamine-like drugs); non-amphetamine stimulant agents (e.g.,
methylphenidate, nicotine, and caffeine); laxative agents (e.g.,
bisacodyl, casanthranol, senna, and castor oil); anti-nausea agents
(e.g., dolasetron, granisetron, ondansetron, tropisetron,
meclizine, and cyclizine); anorexic agents (e.g., fenfluramine,
dexfenfluramine, mazindol, phentermine, and aminorex);
antihistaminic agents (e.g., phencarol, cetirizine, cinnarizine,
ethamidindole, azatadine, brompheniramine, hydroxyzine, and
chlorpheniramine); antiasthmatic agents (e.g., zileuton,
montelukast, omalizumab, fluticasone, and zafirlukast);
antidiuretic agents (e.g., desmopressin, vasopressin, and
lypressin); antimigraine agents (e.g., naratriptan, frovatriptan,
eletriptan, dihydroergotamine, zolmitriptan, almotriptan, and
sumatriptan); antispasmodic agents (e.g., dicyclomine, hyoscyamine,
and peppermint oil); antidiabetic agents (e.g., methformin,
acarbose, miglitol, pioglitazone, rosiglitazone, nateglinide,
repaglinide, mitiglinide, saxagliptin, sitagliptine, vildagliptin,
acetohexamide, chlorpropamide, gliclazide, glimepiride, glipizide,
glyburide, tolazamide, and tolbutamide); respiratory agents (e.g.,
albuterol, ephedrine, metaproterenol, and terbutaline);
sympathomimetic agents (e.g., pseudoephedrine, phenylephrine,
phenylpropanolamine, epinephrine, norepinephrine, dopamine, and
ephedrine); H2 blocking agents (e.g., cimetidine, famotidine,
nizatidine, and ranitidine); antihyperlipidemic agents (e.g.,
clofibrate, cholestyramine, colestipol, fluvastatin, atorvastatin,
genfibrozil, lovastatin, niacin, pravastatin, fenofibrate,
colesevelam, and simvastatin); antihypercholesterol agents (e.g.,
lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,
cholestyramine, colestipol, colesevelam, nicotinic acid,
gemfibrozil, and ezetimibe); cardiotonic agents (e.g., digitalis,
ubidecarenone, and dopamine); vasodilating agents (e.g.,
nitroglycerin, captopril, dihydralazine, diltiazem, and isosorbide
dinitrate); vasoconstricting agents (e.g., dihydroergotoxine and
dihydroergotamine); anticoagulants (e.g., warfarin, heparin, and
Factor Xa inhibitors); sedative agents (e.g., amobarbital,
pentobarbital, secobarbital, clomethiazole, diphenhydramine
hydrochloride, and alprazolam); hypnotic agents (e.g., zaleplon,
zolpidem, eszopiclone, zopiclone, chloral hydrate, and
clomethiazole); anticonvulsant agents (e.g., lamitrogene,
oxycarbamezine, phenytoin, mephenytoin, ethosuximide,
methsuccimide, carbamazepine, valproic acid, gabapentin,
topiramate, felbamate, and phenobarbital); muscle relaxing agents
(e.g., baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine,
dantrolene sodium, metaxalone, orphenadrine, pancuronium bromide,
and tizanidine); antipsychotic agents (e.g., phenothiazine,
chlorpromazine, fluphenazine, perphenazine, prochlorperazine,
thioridazine, trifluoperazine, haloperidol, droperidol, pimozide,
clozapine, olanzapine, risperidone, quetiapine, ziprasidone,
melperone, and paliperidone); antianxiolitic agents (e.g.,
lorazepam, alprazolam, clonazepam, diazepam, buspirone,
meprobamate, and flunitrazepam); antihyperactive agents (e.g.,
methylphenidate, amphetamine, and dextroamphetamine);
antihypertensive agents (e.g., alpha-methyldopa, chlortalidone,
reserpine, syrosingopine, rescinnamine, prazosin, phentolamine,
felodipine, propanolol, pindolol, labetalol, clonidine, captopril,
enalapril, and lisonopril); anti-neoplasia agents (e.g., taxol,
actinomycin, bleomycin A2, mitomycin C, daunorubicin, doxorubicin,
epirubicin, idarubicin, and mitoxantrone); soporific agents (e.g.,
zolpidem tartrate, eszopiclone, ramelteon, and zaleplon);
tranquilizer agents (e.g., alprazolam, clonazepam, diazepam,
flunitrazepam, lorazepam, triazolam, chlorpromazine, fluphenazine,
haloperidol, loxapine succinate, perphenazine, prochlorperazine,
thiothixene, and trifluoperazine); decongestant agents (e.g.,
ephedrine, phenylephrine, naphazoline, and tetrahydrozoline); beta
blockers (e.g., levobunolol, pindolol, timolol maleate, bisoprolol,
carvedilol, and butoxamine); alpha blockers (e.g., doxazosin,
prazosin, phenoxybenzamine, phentolamine, tamsulosin, alfuzosin,
and terazosin); non-steroidal hormones (e.g., corticotropin,
vasopressin, oxytocin, insulin, oxendolone, thyroid hormone, and
adrenal hormone); erectile disfunction improvement agents; herbal
agents (e.g., glycyrrhiza, aloe, garlic, nigella sativa, rauwolfia,
St John's wort, and valerian); enzymes (e.g., lipase, protease,
amylase, lactase, lysozyme, and urokinase); humoral agents (e.g.,
prostaglandins, natural and synthetic, for example, PGE1,
PGE2alpha, PGF2alpha, and the PGE1 analog misoprostol); psychic
energizers (e.g., 3-(2-aminopropy)indole and
3-(2-aminobutyl)indole); nutritional agents; essential fatty acids;
non-essential fatty acids; vitamins; minerals; and combinations
thereof.
[0036] Any of the above-mentioned APIs may be incorporated in the
composition described herein in any suitable form, such as, for
example, as a pharmaceutically acceptable salt, uncharged or
charged molecule, molecular complex, solvate or hydrate, prodrug,
and, if relevant, isomer, enantiomer, racemic mixture, and/or
mixtures thereof. Furthermore, the API may be in any of its
crystalline, semi-crystalline, amorphous, or polymorphous
forms.
[0037] In one embodiment, the API present in the pharmaceutical
composition may have a potential for abuse. For example, the API
may be an opioid analgesic agent, a stimulant agent, a sedative
agent, a hypnotic agent, an antianxiolitic agent, or a muscle
relaxing agent.
[0038] In another embodiment, the API present in the pharmaceutical
composition may be a combination of an opioid analgesic and a
non-opioid analgesic. Suitable opioid and non-opioid analgesics are
listed above.
[0039] In a preferred embodiment, the API in the pharmaceutical
composition may be an opioid analgesic. Exemplary opioid analgesics
include oxycodone, oxymorphone, hydrocodone, hydromorphone,
codeine, and morphine. In one exemplary embodiment, the API may be
oxycodone hydrochloride. In another exemplary embodiment, the API
may be oxymorphone hydrochloride.
[0040] The amount of the API in the pharmaceutical composition can
and will vary depending upon the active agent. In embodiments in
which the API is an opioid analgesic, the amount of opioid in the
composition may range from about 2 mg to about 160 mg. In various
embodiments, the amount of opioid in the pharmaceutical composition
may range from about 2 mg to about 10 mg, from about 10 mg to about
40 mg, from about 40 mg to about 80 mg, or from about 80 mg to
about 160 mg. In certain embodiments, the amount of opioid in the
pharmaceutical composition may be about 5 mg, 7.5 mg, 10 mg, 12.5
mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg,
35 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 100 mg,
120 mg, 140 mg, or 160 mg.
[0041] In embodiments in which the opioid is oxycodone
hydrochloride, the total amount of oxycodone hydrochloride present
in the pharmaceutical composition may range from about 2 mg to
about 80 mg. In certain embodiments, the amount of oxycodone
hydrochloride in the pharmaceutical composition may range from
about 2 mg to about 10 mg, from about 10 mg to about 30 mg, or from
about 30 mg to about 80 mg. In exemplary embodiments, the amount of
oxycodone hydrochloride present in the pharmaceutical composition
may be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30
mg, about 40 mg, about 60 mg, or about 80 mg.
[0042] In embodiments in which the opioid is oxymorphone
hydrochloride, the total amount of oxymorphone hydrochloride
present in the pharmaceutical composition may range from about 2 mg
to about 80 mg. In certain embodiments, the amount of oxymorphone
hydrochloride present in the pharmaceutical composition may range
from about 2 mg to about 10 mg, from about 10 mg to about 30 mg, or
from about 30 mg to about 80 mg. In preferred embodiments, the
amount of oxymorphone hydrochloride present in the pharmaceutical
composition may be about 5 mg, about 10 mg, about 20 mg, about 30
mg, or about 40 mg.
[0043] (vi) Lubricant
[0044] The pharmaceutical composition disclosed herein may also
comprise a lubricant. Non-limiting examples of suitable lubricants
include metal stearate such as magnesium stearate, calcium
stearate, zinc stearate, colloidal silicon dioxide, hydrogenated
vegetable oils, sterotex, polyoxyethylene monostearate,
polyethylene glycol, sodium stearyl fumarate, sodium benzoate,
sodium lauryl sulfate, magnesium lauryl sulfate, light mineral oil,
and combinations thereof. In exemplary embodiments, the lubricant
may be a metal stearate. In one exemplary embodiment, the lubricant
may be magnesium stearate.
[0045] The amount of lubricant present in the pharmaceutical
composition can and will vary depending upon the identities and
amounts of other components in the composition. In general, the
amount of lubricant present in the composition may range from about
0.1% to about 3% by weight of the pharmaceutical composition. In
various embodiments, the amount of lubricant present in the
composition may range from about 0.1% to about 0.3%, from about 0.3
to about 1%, or from about 1% to about 3% by weight of the
composition. In exemplary embodiments, the amount of lubricant
present in the composition may range from about 0.0.1% to about 2%
by weight of the pharmaceutical composition. In one exemplary
embodiment, the amount of lubricant present in the composition may
range from about 0.3% to about 1% by weight of the pharmaceutical
composition.
[0046] (vii) Optional Excipients
[0047] In various embodiments, the pharmaceutical compositions
disclosed herein may further comprise at least one additional
pharmaceutically acceptable excipient. Non-limiting examples of
suitable excipients include clay minerals, binders, fillers,
diluents, antioxidants, chelating agents, flavoring agents,
coloring agents, taste masking agents, and combinations
thereof.
[0048] In one embodiment, the excipient may be a clay mineral. A
clay mineral refers to a hydrated aluminum phyllosilicate or a
hydrated magnesium silicate comprising small insoluble particles.
Mixing a clay mineral with a suitable solvent forms a colloidal
dispersion of small particles that do not sediment. Non-limiting
examples of suitable clay minerals include talc, bentonites,
kaolinites, nontronites, montmorillonites, pyrophyllites,
saponites, sauconites, vermiculites, and combinations thereof. In
one iteration, the clay mineral may be powdered talc or micronized
talc.
[0049] In a further embodiment, the excipient may be a binder.
Suitable binders include, but are not limited to, starches,
pregelatinized starches, gelatin, polyvinylpyrolidone, cellulose,
methylcellulose, sodium carboxymethylcellulose, ethylcellulose,
polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18
fatty acid alcohol, polyethylene glycol, polyols, saccharides,
oligosaccharides, polypeptides, peptides, and combinations
thereof.
[0050] In another embodiment, the excipient may be a filler.
Suitable fillers include carbohydrates, inorganic compounds, and
polyvinylpyrrolidone. In some embodiments, the filler may be
calcium sulfate, calcium phosphate, calcium silicate,
microcrystalline cellulose, starch, modified starches, lactose,
sucrose, mannitol, sorbitol, or combinations thereof.
[0051] In another embodiment, the excipient may include a diluent.
Non-limiting examples of diluents suitable for use include
pharmaceutically acceptable saccharides such as sucrose, dextrose,
lactose, microcrystalline cellulose, fructose, xylitol, and
sorbitol; polyhydric alcohols; starches; pre-manufactured direct
compression diluents; and mixtures of any of the foregoing.
[0052] In yet another embodiment, the excipient may be an
antioxidant. Suitable antioxidants include, without limit, ascorbyl
palmitate, butylated hydroxyanisole, a mixture of 2 and 3
tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodium
isoascorbate, dihydroguaretic acid, potassium sorbate, sodium
bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate,
vitamin E, 4-chloro-2,6-ditertiarybutylphenol, alphatocopherol,
propylgallate, and combinations thereof.
[0053] In an alternate embodiment, the excipient may be a chelating
agent. Non-limiting examples of suitable chelating agents include
ethylenediamine tetracetic acid (EDTA) and its salts,
N-(hydroxy-ethyl)ethylenediaminetriacetic acid, nitrilotriacetic
acid (NIA), ethylene-bis(oxyethylene-nitrilo)tetraacetic acid,
1,4,7, 10-tetraazacyclodo-decane-N,N',N'',N'''-tetraacetic acid,
1,4,7,10-tetraaza-cyclododecane-N, N',N''-triacetic acid,
1,4,7-tris(carboxymethyl)-10-(2'-hydroxypropyl)-1,4,7,
10-tetraazocyclodecane, 1,4,7-triazacyclonane-N,N',N''-triacetic
acid, 1,4,8, 11
-tetraazacyclotetra-decane-N,N',N'',N'''-tetraacetic acid;
diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine,
bis(aminoethanethiol)carboxylic acid,
triethylenetetraamine-hexaacetic acid,
1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid, and combinations
thereof.
[0054] In a further embodiment, the excipient may be a flavoring
agent. Flavoring agents may be chosen from synthetic flavor oils
and flavoring aromatics and/or natural oils, extracts from plants,
leaves, flowers, fruits, and combinations thereof.
[0055] In still another embodiment, the excipient may be a coloring
agent. Suitable color additives include food, drug and cosmetic
colors (FD&C), drug and cosmetic colors (D&C), or external
drug and cosmetic colors (Ext. D&C).
[0056] In yet another embodiment, the excipient may be a
taste-masking agent. Taste-masking materials include cellulose
ethers; polyethylene glycols; polyvinyl alcohol; polyvinyl alcohol
and polyethylene glycol copolymers; monoglycerides or
triglycerides; acrylic polymers; mixtures of acrylic polymers with
cellulose ethers; cellulose acetate phthalate; and combinations
thereof.
[0057] The amount of the one or more additional excipients in the
composition can and will vary depending upon the identity of the
excipient and the identities and amounts of the other components of
the composition.
[0058] (viii) Optional Film Coating
[0059] In some embodiments, the pharmaceutical composition may
further comprise an optional film coating. Typically, the film
coating comprises at least one hydrophilic polymer and the coating
does not affect the immediate release or tamper resistant
properties of the composition. The film coating may provide
moisture protection, enhanced appearance, increased mechanical
integrity, improved swallowability, improved taste, and/or masking
of odors.
[0060] Film coatings are well known in the art, e.g., they are
commercially available under the tradename OPADRY.RTM.. Typically,
a film coating comprises at least one hydrophilic polymer and at
least one plasticizer. Non-limiting examples of suitable polymers
include hydroxypropylmethy cellulose, hydroxypropyl cellulose,
hydroxypropyl ethylcellulose, ethylcellulose, methylcellulose,
cellulose acetate phthalate, microcrystalline cellulose and
carrageenan, acrylic polymers, polyvinyl alcohol, anionic and
cationic polymers of methacrylic acid, copolymers of methacrylates,
copolymers of acrylates and methacrylates, copolymers of
ethacrylate and methylmethacrylate, polyvinylacetate phthalate, and
shellac. Examples of suitable plasticizers include, without limit,
triethyl citrate (TEC), acetyltriethyl citrate (ATEC), acetyl
tri-n-butyl citrate (ATBC), dibutyl sebacate, diethyl phthalate,
and triacetin. The film coating may optionally comprise additional
agents such as a coloring agent, a filler, a flavoring agent, a
taste-masking agent, a surfactant, an anti-tacking agent, and/or an
anti-foaming agent. Suitable examples of these agents are well
known in the art and/or are detailed above.
[0061] (ix) Exemplary Embodiments
[0062] In exemplary embodiments, the pharmaceutical composition
comprises from about 20% to about 35% by weight of a low molecular
weight hydrophilic polymer having an average molecular weight of no
more than about 200,000 Da; the low molecular weight comprising
polyethylene oxide, hydroxypropylmethyl cellulose, and sodium
carboxymethyl cellulose; about 2% to about 10% by weight of a high
molecular weight hydrophilic polymer having an average molecular
weight of at least about 400,000 Da; the high molecular weight
polymer comprising polyethylene oxide and xanthan gum; about 50% to
about 70% by weight of an effervescent system comprising an acid
component and a base component; and an API chosen from oxycodone,
oxymorphone, hydrocodone, hydromorphone, codeine, and morphine.
(b) Dosage Forms
[0063] The physical form of the pharmaceutical composition
disclosed herein can and will vary. In general, the pharmaceutical
composition is a solid dosage form. The solid dosage form may be
one of various solid dosage units. Non-limiting examples of
suitable solid dosage units include tablets, compacts, pellets,
caplets, pills, and capsules. Such dosage units may be prepared
using conventional methods known to those in the field of
pharmaceutical formulation and described in the pertinent texts,
e.g., in Gennaro, A. R., editor. "Remington: The Science &
Practice of Pharmacy", 21st ed., Williams & Williams, and in
the "Physician's Desk Reference", 2006, Thomson Healthcare. In
general, the solid dosage form is formulated for oral
administration.
[0064] In certain embodiments, the solid dosage unit may be a
tablet. Non-limiting types of tablets include coated tablets,
uncoated tablets, compressed tablets, compacted tablets, molded
tablets, layered tablets, bilayer tablets, extruded tablets,
multiparticle tablets, monolithic tablets, and matrix tablets. In
exemplary embodiments, the pharmaceutical composition may be a
solid dosage form comprising a tablet.
[0065] In embodiments in which the solid dosage form is a tablet,
the tablet generally has a friability of no greater than about
1.0%. In certain embodiments, the tablet may have a friability of
less than about 1.0%, less than about 0.5%, less than about 0.3%,
less than about 0.2%, less than about 0.1%, less than about 0.05%,
or less than about 0.01%. In exemplary embodiments, the tablet has
a friability of zero.
(c) In Vitro Release Properties of the Composition
[0066] The solid dosage pharmaceutical composition disclosed herein
is formulated such that the API in the composition is released
rapidly. Thus, the composition is termed an immediate release
composition. As used herein, "immediate release" generally refers
to an average release of at least 70% of the API within 45 minutes
in water. Unlike many immediate release compositions, the
pharmaceutical composition disclosed herein comprises a blend of
high molecular weight and low molecular weight hydrophilic
polymers. The disclosed composition, however, also comprises an
effervescent system that facilitates dissolution and rapid release
of the API.
[0067] The in vitro dissolution of the API from the composition
disclosed herein may be measured using an USP-approved release
procedure. For example, dissolution may be measured using an USP
Type 2 paddle apparatus, at a paddle speed of 50 rpm or 100 rpm,
and a constant temperature of 37.+-.0.5.degree. C. The dissolution
procedure may be performed in the presence of 500 mL, 900 mL, or
1,000 mL of a suitable dissolution medium (e.g., having a pH from
1.0 to 6.8). Non-limiting examples of suitable dissolution media
include water, phosphate buffer (pH 6.8), acetate buffer (pH 4.5),
and 0.1 N HCl.
[0068] The pharmaceutical compositions disclosed herein provide
immediate release of the API. In some embodiments, the
pharmaceutical composition may have an average release of about
50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the API
within 45 minutes. In other embodiments, the pharmaceutical
composition may have an average release of about 50%, 55%, 60%,
65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the API within 30
minutes.
(d) Abuse Deterrent Properties of the Composition
[0069] The solid dosage pharmaceutical compositions disclosed
herein also have abuse deterrent features. The blend of hydrophilic
polymers and the effervescent system imparts sufficient mechanical
integrity (i.e., strength, hardness, etc.) to the solid dosage form
such that it is resistant to crushing, grinding, cutting, or
pulverizing to form a powder comprising small particles.
Additionally, because some of the hydrophilic polymers of the
composition are gelling polymers, contact with a small volume of a
suitable solvent leads to the formation of a viscous mixture or
gel.
[0070] The mechanical integrity of the solid dosage pharmaceutical
composition may be assessed by measuring the hardness or crushing
strength of the solid dosage form. Hardness of the solid dosage
form may be measured using any of numerous hardness testers, which
are well known in the art. In general, the solid dosage composition
has a hardness or crushing strength of at least 10 kilopond (kp).
In various embodiments, the solid dosage composition may have a
hardness or crushing strength ranging from about 10 kp to about 20
kp, from about 20 kp to about 30 kp, from about 30 kp to about 40
kp, or more than about 40 kp. In certain embodiments, the hardness
or crushing strength of solid dosage composition is less than about
50 kp.
[0071] The mechanical integrity of the solid dosage pharmaceutical
composition also may be assessed by measuring the particle size
distribution after crushing, grinding, or pulverizing the
composition in a suitable apparatus for a specified period of time.
The solid dosage composition may be crushed, ground, or pulverized
in a high-shear mill, a ball mill, a co-mill, pill crusher, a
tablet grinder, a coffee grinder, a blender, a hammer, or another
apparatus to reduce particle size. In embodiments in which the
solid dosage composition is subjected to 6 minutes of milling in a
high shear mill to form particles, more than 20%, 30%, 40%, 50%,
60%, 70%, 80%, 90%, or 95% of the particles have an average
diameter of at least about 250 microns. In embodiments in which the
solid dosage composition is placed between two metal (i.e.,
aluminum) pans or two pieces of aluminum foil and struck ten times
with a hammer, more than 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or
95% of the particles have an average diameter of at least about 250
microns. Because the pharmaceutical composition disclosed herein is
resistant to forming a fine powder by crushing, grinding or
pulverizing, it deters abuse by inhalation.
[0072] Additionally, the pharmaceutical composition disclosed
herein, whether whole, flattened, broken, crushed, or pulverized,
forms a viscous mixture or gel when in contact with a small volume
of a suitable solvent. The volume may be about 3 mL, 5 mL, or 10
mL. Suitable solvents include water, alcohols such as ethanol,
acids such as acetic acid, fruit juice, and mixtures of any of the
foregoing. The viscosity of the gel prevents the material from
being drawn through an injection syringe needle. Consequently, the
pharmaceutical compositions are resistant to abuse by extraction,
filtering, and/or injection.
(II) Processes for Preparing Solid Dosage Pharmaceutical
Compositions
[0073] Another aspect of the disclosure encompasses processes for
preparing solid dosage forms of the pharmaceutical compositions
disclosed herein. The processes comprise: (a) forming a mixture
comprising at least one low molecular weight hydrophilic polymer,
at least one high molecular weight hydrophilic polymer, and an
effervescent system; (b) forming the mixture into a solid dosage
unit; and (c) heating the solid dosage unit to form the solid
dosage form. The solid dosage form optionally may be coated with a
film coating.
(a) Forming a Mixture
[0074] The first step of the process comprises forming a mixture
comprising the components of the pharmaceutical composition, which
are detailed above in section (I)(a). The mixture comprises at
least one hydrophilic polymer having an average molecular weight of
no more than about 200,000 Da, at least one hydrophilic polymer
having an average molecular weight of at least about 400,000 Da, an
effervescent system comprising an acid component and a base
component, and a lubricant. In general, the mixture further
comprises at one API or a pharmaceutically acceptable salt thereof.
The components may be combined in any order or may be premixed in
various combinations before being combined together. For example,
in one embodiment the acid component of the effervescent system may
be co-processed with a polyalkylene glycol or Poloxamer prior to
being mixed with the rest of the components. In another embodiment,
the API may be combined with some of the components before being
combined with the rest of the components. Thus, a variety of
ordered mixing schemes are possible.
[0075] The mixture comprising the components of the composition may
be formed by mixing, roller mixing, drum mixing, shear mixing, dry
blending, chopping, milling, roller milling, granulating, dry
granulating (e.g., slugging or roller compacting), wet granulating
(e.g., fluid bed granulating, high shear granulating), and other
mixing techniques known in the art.
(b) Forming a Solid Dosage Unit
[0076] The process further comprises forming the mixture from step
(a) into a solid dosage unit. Suitable solid dosage units are
described above in section (I)(b). Means of forming solid dosage
units are well known in the art. In exemplary embodiments, the
solid dosage unit may be a tablet. The tablet may be a compression
tablet, a molded tablet, a compacted tablet, or a pressed tablet.
In an exemplary embodiment, the tablet may be formed by direct
compression. The shape of the tablet may vary. Non-limiting tablet
shapes include round, oval, rectangular, and triangular. The size
and mass of the tablet may vary. In various embodiments, the mass
of the tablet may be range from about 100 mg to about 1000 mg. In
exemplary embodiments, the mass of the tablet may range from about
300 mg to about 500 mg.
(c) Heating the Solid Dosage Unit
[0077] The process further comprises heating the solid dosage unit.
This heating step dries and cures the solid dosage form, wherein
the cured solid dosage form may have improved properties or
characteristics relative to an uncured solid dosage unit (see
Examples 1, 6-8, and 10 below). For example, the heating step may
remove water from the solid dosage form, thereby protecting the
effervescent system from premature effervescence. Additionally, the
heating step may plasticize some of the polymers, thereby leading
to increased resistance to crushing/pulverization and to more rapid
release of the API.
[0078] In general, the heating step occurs at a temperature of less
than about 90.degree. C. In various embodiments, the solid dosage
unit may be heated at a temperature from about 30.degree. C. to
about 35.degree. C., from about 35.degree. C. to about 40.degree.
C., from about 40.degree. C. to about 45.degree. C., from about
45.degree. C. to about 50.degree. C., from about 50.degree. C. to
about 55.degree. C., from about 55.degree. C. to about 60.degree.
C., from about 60.degree. C. to about 65.degree. C., from about
65.degree. C. to about 70.degree. C., from about 70.degree. C. to
about 75.degree. C., from about 75.degree. C. to about 80.degree.
C., from about 80.degree. C. to about 85.degree. C., or from about
85.degree. C. to about 90.degree. C. In exemplary embodiments, the
heating temperature may range from about 50.degree. C. to about
80.degree. C.
[0079] The duration of the heating step can and will vary depending
upon the components of the composition and the heating temperature.
The duration of the heating step may range from about 10 minutes to
about 10 hours. In general, the higher the temperature, the shorter
the duration of time for the heating step. In an exemplary
embodiment, the solid dosage unit may be heated to a temperature
from about 65.degree. C. to about 75.degree. C. for a period of
time ranging from about 1 hour to about 2 hours.
(d) Optionally Coating the Solid Dosage Form
[0080] The solid dosage form may be coated with a film coating.
Suitable film coatings are detailed above in section (I)(a)(viii).
In general, the solid dosage form may be coated with a film coating
after the heating step.
DEFINITIONS
[0081] When introducing components of the embodiments described
herein, the articles "a", "an", "the" and "said" are intended to
mean that there are one or more of the elements. The terms
"comprising", "including" and "having" are intended to be inclusive
and mean that there may be additional components other than the
listed components.
[0082] If the components described herein have asymmetric centers,
all chiral, diastereomeric, racemic forms and all geometric
isomeric forms of a structure are intended, unless the specific
stereochemistry or isomeric form is specifically indicated.
[0083] Having described the invention in detail, it will be
apparent that modifications and variations are possible without
departing from the scope of the invention defined in the appended
claims.
EXAMPLES
[0084] The following examples are included to illustrate, but not
to limit the claimed pharmaceutical compositions and processes for
making them.
Example 1
Immediate Release Formulation
[0085] Table 1 describes the formulation made in this example. The
batch size was 1000 g. All the ingredients were first sieved
through a US Standard 30 mesh screen. An 8-qt V-blender was charged
with all the ingredients except the lubricant and blended for 15
minutes. Magnesium stearate was then added and blended for 3
minutes. Round tablets (diameter: 0.3125'') were made from the
blend using a Manesty Beta press. The tablets were cured by heating
in an air oven for 2 hours. Two curing temperatures were tried
(.about.65.degree. C. and .about.80.degree. C.).
TABLE-US-00001 TABLE 1 Composition of formulation made in Example
1. Component Mg/tablet % weight Oxycodone hydrochloride 15.7 8.49
L-(+) Tartaric acid 37.6 20.32 Sodium bicarbonate 42.2 22.81 Polyox
100 K (WSR N-10) 38.0 20.54 Polyox 4 Million (WSR 301NF) 19.5 10.54
Klucel HXF 19.0 10.27 Talc 10.0 5.41 Pluronic F127 2.0 1.08
Magnesium stearate 1.0 0.54 Total 185.0 100.00
[0086] The cured tablets were evaluated for hardness and
dissolution. Hardness was determined using a hardness tester. The
dissolution parameters were: USP Apparatus Type 2 (paddles) at 50
rpm. The temperature was 37.degree..+-.0.5.degree. C. The
dissolution medium was 500 mL water. At specified times, samples
were withdrawn from the dissolution tester and analyzed for
oxycodone hydrochloride by an HPLC method. The percent of oxycodone
released was calculated based on the amount in the formulation. The
data are reported in Table 2.
TABLE-US-00002 TABLE 2 Properties of tablets made per Example 1.
Cured at Cured at 65.degree. C. 80.degree. C. Uncured for 2 hours
for 2 hours Mean Hardness (kp) 5.4 kp 17.6 kp 13.0 kp % of
oxycodone HCl 77.1 99.9 93.5 release at 30 minutes
Example 2
Formulations with Varying Polymer Ratios
[0087] This example gives formulations consisting of oxycodone
hydrochloride, tartaric acid, sodium bicarbonate, Polyox N-10
(molecular weight 100,000), Polyox 301NF (molecular weight 4
million), Klucel HXF, and magnesium stearate. In order to determine
the optimal ratio of the polymers, formulations were prepared in
which the amounts of oxycodone hydrochloride, tartaric acid, sodium
bicarbonate, and magnesium stearate were kept constant and the
amounts of the other three ingredients were varied. Table 3
presents the generic formula and Table 4 gives the specific ratios
of the polymers for each formulation.
[0088] The batch size was 10-15 g. The required amounts were
weighed individually, placed in a plastic bag, and mixed manually
for about 5 minutes. Tablets were made by weighing the required
amount, filling the die of a single-station Carver press, and
compressing it at the desired force. The tablets were placed in
aluminum pans and cured for 2 hours at .about.65.degree. C. in an
air oven. After curing, the tablets were allowed to come to room
temperature and characterized by dissolution in water. Samples were
removed at 30 minutes and analyzed by HPLC for oxycodone
hydrochloride. The percentage of oxycodone hydrochloride released
from the formulation was determined.
TABLE-US-00003 TABLE 3 Composition of formulation made in Example
2. Component Mg/tablet Oxycodone hydrochloride 15.73 L-(+) Tartaric
acid 37.74 Sodium bicarbonate 42.37 Polyox 100 K (WSR N-10) x
Polyox 4 Million (WSR 301NF) y Klucel HXF z Magnesium stearate 0.92
Total 185.01 Note: For values of x, y, and z consult Table 4. The
sum of x, y, and z was 88.25 mg.
TABLE-US-00004 TABLE 4 Composition and properties of tablets made
in Example 2 Formulation details (relative ratios) Polyox Polyox
Klucel % Oxycodone 100 K 4 Million HXF released at 30 min ID (x)
(y) (z) Uncured Cured EFF37-1 58.83 14.71 14.71 82.4 85.1 EFF37-2
14.71 14.71 58.83 60.5 57.9 EFF37-3 44.12 44.12 0.0 39.9 51.3
EFF37-4 0.0 0.0 88.25 79.2 80.7 EFF37-5 0.0 44.12 44.12 8.6 10.0
EFF37-6 88.25 0.0 0.0 60.0 57.9 EFF37-7 14.71 58.83 14.71 8.7 9.6
EFF37-8 29.42 29.41 29.42 47.9 52.7 EFF37-9 0.0 88.25 0.0 8.7 9.2
EFF37-10 44.12 0.0 44.12 79.1 84.0
[0089] The data in Table 4 show that, in a few formulations, curing
increased the release of oxycodone hydrochloride (API). A number of
the formulations had unexpected results. For example, formulation
EFF37-10, which contained Polyox 100K and Klucel (molecular weight:
.about.1 million) had greater release than formulation EFF37-6,
which contained only Polyox 100K (molecular weight: 100,000).
Moreover, formulation EFF37-1, which contained all three polymers,
had higher release than formulation EFF37-6, which contained only
Polyox 100K.
Example 3
Formulations Comprising Different Grades of Klucel
[0090] To determine whether other grades of Klucel could be used in
place of Klucel HXF, formulations were prepared that contained
Klucel MXF, Klucel GXF, or Klucel EXF. The formulations were
prepared as described above in Example 2 by keeping constant the
amounts of oxycodone hydrochloride, tartaric acid, sodium
bicarbonate, and magnesium stearate while varying the other
ingredients. In some formulations talc and/or Pluronic F127 were
also included. Table 5 presents the relative ratios of the polymers
and additional components, as well as the release of oxycodone from
the formulations.
TABLE-US-00005 TABLE 5 Composition and properties of tablets made
per Example 3. Formulation details (relative ratios) % Oxycodone
Polyox Polyox Klucel released 100K 4 Million type Pluronic at 30
min ID (x) (y) (z) F127 Talc Uncured Cured EFF38-1 14.71 14.71 HXF
0.0 0.0 48.8 49.9 (58.83) EFF38-2 14.71 14.71 MXF 0.0 0.0 50.6 56.6
(58.83) EFF38-3 14.71 14.71 GXF 0.0 0.0 30.1 36.1 (58.83) EFF38-4
14.71 14.71 EXF 0.0 0.0 42.7 36.2 (58.83) EFF38-5 14.71 14.71 HXF
0.0 10.00 53.6 71.3 (48.83) EFF38-6 14.71 14.71 HXF 2.00 10.00 67.2
88.0 (46.83) Note: x, y, and z have the same connotations as in
Table 3.
[0091] The dissolution results showed that dissolution was lower in
formulations containing Klucel GXF or Klucel EXF (EFF-38-3 and
EFF38-4). This was unexpected because the molecular weights of GXF
and EXF grades are less than those of HXF or MXF. It was also found
that inclusion of talc or both talc and Pluronic increased the
amount of API released (compare formulations EFF38-5 and EFF38-6
with EFF38-1). The increased release imparted by talc and Pluronic
was especially noticeable in the cured tablets.
Example 4
Formulations Containing Other Low MW Polymers
[0092] To determine whether other low molecular weight polymers
could substitute for Polyox 100K, formulations were prepared that
contained polyethylene glycol (PEG 8000) or Pluronic F127 in place
of Polyox 100K. The formulations were prepared and tested as in
Example 2. Some formulations included talc. Table 6 details the
formulations, as well as the release of oxycodone from the
formulations.
TABLE-US-00006 TABLE 6 Composition and properties of tablets made
per Example 4. Formulation Details (relative ratios) Polyox Low MW
4 Klucel % Oxycodone released Polymer Million HXF at 30 min ID (x)
(y) (z) Talc Uncured Cured EFF39-1 Polyox 100K 14.71 58.83 0.0 44.3
31.4 14.71 EFF39-2 PEG 8000 14.71 58.83 0.0 76.7 80.9 14.71 EFF39-3
Pluronic F127 14.71 58.83 0.0 62.3 68.0 14.71 EFF39-4 Pluronic F127
14.71 48.83 10.00 80.2 75.0 14.71 EFF39-5 Pluronic F127 31.77 31.77
10.00 11.1 14.8 14.71 Note: x, y, and z have the same connotations
as in Table 3
[0093] The data in Table 6 show that PEG 8000 can give dissolution
properties similar to Polyox 100K, but not Pluronic F127. It was
discovered, however, that inclusion of talc along with Pluronic
F127 increased the amount of release (see formulation EFF39-4).
Example 5
Formulations Comprising Acid Co-Processed with Kolliphor
[0094] Formulations comprising the acid and base components of an
effervescent system are susceptible to premature effervescence
under conditions of high humidity. Such formulations may have a
reduced shelf-life and decreased stability. The following example
details a method for processing the tartaric acid with Kolliphor
P407 (Pluronic F127) to reduce the moisture sensitivity and lower
the likelihood of premature effervescence. Tartaric acid was placed
with Kolliphor P407 in a high-shear granulator fitted with a 25 L
bowl. The ratio of tartaric acid to Kolliphor P407 was 18.1/1.0
(w/w). With continued mixing, the temperature was raised to
65.degree. C. After the hot-melt process was complete, the bowl was
cooled to room temperature and sieved through a 20 Mesh sieve
screen. The material going through the screen was used to formulate
the blend shown in Table 7.
[0095] The blend in Table 7 had a batch size of 2700 g and was made
as follows. Tartaric acid co-processed with Kolliphor was mixed for
5 minutes with micronized talc in a 4-qt V-blender. This mixture
was then blended for 15 minutes with the other ingredients except
magnesium stearate in an 8-qt V-blender. The magnesium stearate was
then added to the blender and mixed for 3 minutes. It should be
noted that EfferSoda.RTM. 12 is heat-treated sodium bicarbonate
with a thin layer of sodium carbonate on its surface. The final
blend was compressed in a rotary tablet press (Manesty Beta press)
to produce round tablets. The tablets were then cured for 2 hours
at 60-65.degree. C. in a pan coater.
TABLE-US-00007 TABLE 7 Composition of the formulation made in
Example 5. Component Mg/tab % wt Oxycodone HCl 15.00 5.00 Tartaric
Acid co-processed with Kolliphor P407 94.34 31.45 EfferSoda .RTM.
12 105.66 35.22 Polyox N10 LEO (100K) 37.56 12.52 Polyox WSR 301 NF
LEO (4 Million) 19.13 6.38 Klucel HF 19.13 6.38 Micronized Talc
(Pharma M) 7.56 2.52 Magnesium stearate 1.62 0.54 Total 300.00
100.01
[0096] The hardness of the tablets before curing was 5.5 kp which
increased to 14.4 kp at the end of the curing process. Dissolution
of the oxycodone hydrochloride was 91.7% at 30 minutes.
Example 6
Formulations Comprising Additional Hydrophilic Polymers
[0097] It is possible to include other hydrophilic polymers in the
formulation cited in Example 5. Table 8 gives two formulations
(24-1 and 24-2), each having a batch size of 2700 g. Both
formulations used tartaric acid co-processed with Kolliphor as
described in Example 5. Formulation 24-1 contained sodium
carboxymethylcellulose and xanthan gum rather than Klucel HF.
Formulation 24-2 contained sodium carboxymethylcellulose, xanthan
gum, and Klucel HF. The blending, compression, and curing processes
were as outlined in Example 5. Curing was effected by heating the
tablets for 2 hours at 70-75.degree. C.
TABLE-US-00008 TABLE 8 Composition of the formulations made in
Example 6. Formulation 24-1 Formulation 24-2 Component Mg/tablet %
wt Mg/tablet % wt Oxycodone Hydrochloride 15.7 3.68 15.7 3.68
Tartaric Acid co-processed 141.5 33.30 132.1 31.08 with Kolliphor
P407 EfferSoda .RTM. 12 158.5 37.29 147.9 34.81 Polyox N10 LEO
(100K) 52.0 12.24 52.0 12.24 Polyox WSR 301 NF LEO 15.0 3.53 15.0
3.53 (4 Mil) Carboxymethyl cellulose, 20.0 4.71 20.0 4.71 sodium
Klucel HF 0.0 0.0 20.0 4.71 Xanthan gum 10.6 2.48 10.6 2.48
Micronized Talc 10.1 2.39 10.1 2.39 Magnesium stearate 1.6 0.38 1.6
0.38 Total 425.0 100.00 425.0 100.01
[0098] Hardness and dissolution data for the tablets are given in
Table 9. These data show that formulations containing additional
hydrophilic polymers retained good tablet hardness and excellent
oxycodone release.
TABLE-US-00009 TABLE 9 Hardness and dissolution data for the
tablets made per Example 6. Formulation 24-2 Formulation 24-1
Uncured Cured Uncured Cured Mean hardness (kp) ~5 17.6 ~5 18.7
Dissolution in water 10 minutes 45.1 78.7 53.7 94.0 20 minutes 69.9
99.4 81.2 100.6
Example 7
Formulations Comprising Acid and Kolliphor with or without
Co-Processing
[0099] This example details the properties of two formulations
(31-1 and 33-1). Formulation (31-1) was made with tartaric acid
co-processed with Kolliphor while formulation 33-1 used tartaric
acid and Kolliphor as received without co-processing. All the other
components were the same as evident from Table 10. The batch size
was .about.6 kg and utilized a 16-qt V-blender, a rotary tablet
press. Curing was performed at 70-75.degree. C. in a pan coater.
Both formulations were compressed to give oval tablets. Formulation
details are given in Table 10 and the dissolution data are shown in
Table 11.
TABLE-US-00010 TABLE 10 Composition of the formulations made in
Example 7. Formulation Formulation 31-1 33-1 Component Mg/tab % wt
Mg/tab % wt Oxycodone Hydrochloride 15.7 3.53 15.7 3.53 Tartaric
acid co-processed with 127.4 29.98 0.0 0.0 Kolliphor P407
L-(+)-Tartaric Acid 0.0 0.0 120.73 28.41 Kolliphor P407 0.0 0.0
6.67 1.57 EfferSod .RTM. 12 142.6 33.55 142.6 33.55 Polyox N10 LEO
(100K) 52.7 12.40 52.7 12.40 Polyox WSR 301 NF LEO (4 Mil) 15.0
3.53 15.0 3.53 Carboxymethyl cellulose, sodium 20.0 4.71 20.0 4.71
Hydroxypropylmethyl cellulose 30.0 7.06 30.0 7.06 Xanthan gum 10.6
2.49 10.6 2.49 Micronized Talc 10.1 2.38 10.1 2.38 Magnesium
stearate 1.6 0.38 1.6 0.38 Total 425.0 100.01 425.0 100.01
TABLE-US-00011 TABLE 11 Properties of tablets made per Example 7.
Formulation Formulation 31-1 33-1 Mean hardness (kp) before curing
6.1 8.1 Mean hardness (kp) after curing 23.7 26.8 % Oxycodone
released in water from cured 93.6 93.8 tablets at 15 minutes Abuse
deterrence test: Milling for 6 minutes % Particles >250 microns
post milling 73.22 91.89 Abuse deterrence test: Hammering %
Particles >250 microns post-hammering 87.38 93.9
[0100] Table 11 also gives results from two types of tests to
determine the abuse deterrence characteristics of cured tablets. In
the milling test, the tablets were ground for 6 minutes in a
high-shear mill. Sieve analysis was performed on the resulting
chunky product and the percent of coarse particles with size
>250 microns was determined. In the hammering test, the tablets
were placed between two aluminum pans and struck 10 times with a
hammer. The resulting product was crushed between fingers. The
particles size was then determined and the percent >250 microns
was reported. Higher values from these tests were taken as
indicators of abuse deterrence. This example revealed that
formulation 33-1 had improved abuse deterrent properties.
Example 8
Formulations with and without Kolliphor and/or Talc
[0101] In this example, four formulations (33-1, 33-2, 33-3, and
33-4) were evaluated in which Kolliphor and/or talc were removed in
some formulations. Table 12 gives the compositions in mg/tablet.
The tartaric acid and Kolliphor were used as received without
co-processing. The batches were .about.1 kg in size and were made
using a 4-qt blender. Oval tablets were made using a rotary tablet
press and cured in a pan coater for 2 hours at .about.72.degree. C.
The cured tablets were coated in a pan coater with Opadry coating
materials marketed by Colorcon, Inc. The tablets were tested for
hardness and dissolution. Comparing formulations 33-1 with 33-2,
33-3, and 33-4, it is clear that good dissolution characteristics
may be achieved without Kolliphor and/or talc in the
formulation.
TABLE-US-00012 TABLE 12 Compositions and properties of tablets made
in Example 8. Formulations 33-1 33-2 33-3 33-4 Mg/tab Mg/tab Mg/tab
Mg/tab Component Oxycodone Hydrochloride 15.7 15.7 15.7 15.7
L-(+)-Tartaric Acid 120.73 120.73 120.73 120.73 Kolliphor P407 6.67
0.0 7.17 0.0 Micronized Talc 10.1 10.6 0.0 0.0 EfferSoda .RTM. 12
142.6 142.6 142.6 142.6 Polyox N10 LEO (100K) 52.7 54.5 55.9 58.7
Polyox WSR 301 NF LEO (4 Mil) 15.0 15.7 16.1 16.9 Carboxymethyl
cellulose, sodium 20.0 21.0 21.5 22.6 Hydroxypropylmethyl cellulose
30.0 31.4 32.2 33.9 Xanthan gum 10.6 11.1 11.4 12 Magnesium
stearate 1.6 1.7 1.7 1.8 Total 425.0 425.0 425.0 425.0 Properties
Hardness of Uncured tablets (kp) 8.12 8.32 9.9 13.2 Hardness of
Cured tablets (kp) 26.8 23.4 18.4 28.4 Hardness of Coated tablets
(kp) 28.0 25.8 19.8 30.7 % Oxycodone released in water 93.8 93.6
95.1 90.2 at 15 minutes
Example 9
Further Formulation Modifications
[0102] Formulations in this example (37-7, 37-8, 37-9, and 37-10)
were made in batch sizes of .about.25 g by blending the components
in plastic bags. The tartaric acid and Kolliphor were used as
received without co-processing. Oval tablets were made using a
single station press and cured in an air oven at .about.70.degree.
C. for 2 hours. The cured tablets were evaluated by hardness and
hammering. The results are summarized in Table 13. The performance
of Kolliphor and PEG 3350 was comparable (Formulations 37-8 and
37-9). Formulation containing neither Kolliphor nor PEG 3350 also
performed well (37-10). Formulations 37-8 and 37-7 differed in
their content of Polyox 100K. Higher level of Polyox 100K in the
formulation (37-7) gave better crush resistance as seen from the
particle size data.
TABLE-US-00013 TABLE 13 Compositions and properties of tablets made
in Example 9. Formulations 37-7 37-8 37-9 37-10 Mg/tab Mg/tab
Mg/tab Mg/tab Component Oxycodone Hydrochloride 31.3 31.3 31.3 31.3
L-(+)-Tartaric Acid 126.0 131.5 131.5 132.9 Kolliphor P407,
Micronized 2.9 2.9 0.0 0.0 Polyethylene glycol (PEG 3350) 0.0 0.0
2.9 0.0 EfferSoda .RTM. 12 148.9 155.3 155.3 156.9 Polyox N10 LEO
(100K) 98.7 86.9 86.9 86.9 Polyox WSR 301 NF LEO (4M) 14.7 14.7
14.7 14.7 Sodium carboxymethyl cellulose 20.0 20.0 20.0 20.0
Methocel K100M CR 30.0 30.0 30.0 30.0 Xanthan gum 10.6 10.6 10.6
10.6 Magnesium stearate 1.9 1.9 1.9 1.9 Total 485.0 485.0 485.0
485.0 Abuse Deterrent Properties Mean hardness (kp) 27.5 24.1 23.3
23.2 % Particles >250 microns post- 94.2 91.1 94.5 92.7
hammering
Example 10
Additional Formulation Modifications
[0103] Formulations in this example were made using tartaric acid
and PEG 3350 as received. The compositions are presented in Table
14. The batch size was 100 g. The blends were made in plastic bags
and the tablets with a single station press. The tablets were cured
in an oven at .about.70.degree. C. for 2 hours. The tablets were
evaluated for oxycodone release and by abuse deterrence tests (see
Table 14 for data).
TABLE-US-00014 TABLE 14 Compositions and properties of tablets made
in Example 10. Formulations 44-1 44-5 44-6 44-7 44-8 44-9 44-10 %
wt % wt % wt % wt % wt % wt % wt Component Oxycodone HCl 6.41 6.41
9.24 8.66 7.33 7.15 8.07 L-(+)-Tartaric Acid 25.94 0.0 37.38 0.0
29.64 28.92 32.63 KH.sub.2PO.sub.4 0 25.94 0.0 0.0 0.0 0.0 0.0
EfferSoda .RTM. 12 30.62 30.62 0.0 41.34 34.99 34.14 38.52 PEG 3350
0.60 0.60 0.86 0.81 0.68 0.67 0.75 Polyox N10 LEO 20.52 20.52 29.57
27.70 23.44 11.38 0.0 (100K) Polyox WSR 301 NF 3.03 3.03 4.37 4.09
3.46 3.38 3.81 LEO (4 Million) Sodium 4.12 4.12 5.94 5.57 0.0 4.60
5.19 carboxymethyl cellulose Methocel K100M 6.19 6.19 8.92 8.35 0.0
6.90 7.78 CR Xanthan gum 2.19 2.19 3.15 2.95 0.0 2.44 2.75
Magnesium stearate 0.39 0.39 0.56 0.53 0.45 0.44 0.49 Total (%) 100
100 100 100 100 100 100 Tablet weight (mg) 485 485 344 366 408 431
376 Properties % drug released in water in 20 minutes Uncured
tablets 81.9 97.7 11.7 1.8 99.2 72.0 23.5 Cured tablets 95.8 90.5
13.8 2.3 100.5 91.7 23.7 Abuse Deterrence test (milling) %
Particles >250 68.5 47.9 85.9 44.2 72.2 55.8 9.3 microns post-
milling
[0104] The following conclusions were made from the data in Table
14: (i) Decreasing the level of PEO100K decreased dissolution in
uncured tablets in spite of increasing effervescent agents (compare
44-9 and 44-1); (ii) Removing the gel-forming polymers increased
dissolution (44-8); (iii) Removing the low molecular weight POLYOX
(PEO 100K) decreased dissolution (44-10) and curing in this case
did not increase dissolution; (iv) Data for formulations 44-6 and
44-7 show that both acid AND base components are necessary to
achieve good dissolution, and (v) Tartaric acid, an organic acid
may be substituted with an inorganic acid (Formulations 44-1 and
44-5).
* * * * *