U.S. patent application number 16/990259 was filed with the patent office on 2020-11-26 for abuse-deterrent compositions.
The applicant listed for this patent is PATHEON SOFTGELS INC.. Invention is credited to Tatyana Dyakonov, Aqeel A. FATMI, Saujanya Gosangari, Justin Hughey, George VAMVAKAS.
Application Number | 20200368169 16/990259 |
Document ID | / |
Family ID | 1000005006983 |
Filed Date | 2020-11-26 |
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United States Patent
Application |
20200368169 |
Kind Code |
A1 |
Gosangari; Saujanya ; et
al. |
November 26, 2020 |
ABUSE-DETERRENT COMPOSITIONS
Abstract
Described herein are abuse deterrent controlled release oral
pharmaceutical compositions comprising and methods for making the
same. In particular, an abuse deterrent controlled release oral
pharmaceutical composition comprising a soft capsule and an abuse
deterrent controlled release matrix comprising an active
pharmaceutical ingredient are described.
Inventors: |
Gosangari; Saujanya;
(Jamestown, NC) ; Hughey; Justin; (Asheboro,
NC) ; Dyakonov; Tatyana; (Greensboro, NC) ;
VAMVAKAS; George; (Greensboro, NC) ; FATMI; Aqeel
A.; (High Point, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PATHEON SOFTGELS INC. |
High Point |
NC |
US |
|
|
Family ID: |
1000005006983 |
Appl. No.: |
16/990259 |
Filed: |
August 11, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14877208 |
Oct 7, 2015 |
10772842 |
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16990259 |
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14679233 |
Apr 6, 2015 |
10772841 |
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14877208 |
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62101431 |
Jan 9, 2015 |
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61976237 |
Apr 7, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/137 20130101;
A61K 9/485 20130101; A61K 31/485 20130101; A61K 9/4866 20130101;
A61K 9/4875 20130101; A61K 9/4858 20130101; A61K 31/00
20130101 |
International
Class: |
A61K 9/48 20060101
A61K009/48; A61K 31/485 20060101 A61K031/485; A61K 31/137 20060101
A61K031/137; A61K 31/00 20060101 A61K031/00 |
Claims
1. An oral pharmaceutical composition comprising: a soft gelatin
capsule shell encapsulating a tamper resistant, homogenous,
viscous, yet flowable matrix consisting essentially of: (a)
hydrophobic matrix phase comprising: one or more lipophilic
vehicles consisting of about 25% to about 85% of the flowable
matrix mass; and optionally one or more semisolid lipids consisting
of 0% to about 10% of the flowable matrix; (b) a hydrophilic phase
comprising: one or more hydrophilic polymers consisting of about 8%
to about 50% of the flowable matrix mass; one or more hydrophilic
vehicles consisting of about 2% to about 60% of the flowable matrix
mass; and one or more organogelators consisting of about 0.5% to
about 25% of the flowable matrix mass; and (c) one or more active
pharmaceutical ingredients dissolved in the flowable matrix
consisting of about 1% to about 35% of the flowable matrix
mass.
2. The composition of claim 1, wherein the ratio of the hydrophobic
matrix phase to the hydrophilic matrix phase is about 0.7:1 to
about 10:1.
3. The composition of claim 1, wherein the lipophilic vehicle
comprises one or more of olive oil, soybean oil, sunflower oil,
canola oil, palmitoleic acid, oleic acid, myristoleic acid,
linoleic acid, arachidonic acid, paraffin oil, or mineral oil.
4. The composition of claim 1, wherein the semisolid lipid or
lipophilic vehicle comprises one or more of polyethylene glycol
glyceride ester, paraffin wax, carnauba wax, or bee's wax.
5. The composition of claim 1, wherein the semisolid lipid or
lipophilic vehicle comprises one or more of carnauba wax or bee's
wax.
6. The composition of claim 1, wherein the hydrophilic polymer
comprises or more of methylcellulose, hydroxypropylmethyl
cellulose, a mixture of hydroxypropylmethyl cellulose and
methylcellulose, polymethylmethacrylate, polyvinyl or
pyrrolidone.
7. The composition of claim 1, wherein the hydrophilic vehicle
comprises one or more of propylene glycol, or polyethylene glycols
having a molecular weight of about 200 to about 8,000.
8. The composition of claim 1, wherein the organogelator comprises
one or more of ethyl cellulose, 12-hydroxyoctadecanoic acid,
1,3:2,4-di-O-benzylidene-D-sorbitol, 2,3-bis-n-decyloxyanthracene,
alkyl perfluoroalkanamides, sorbitan monostearate.
10. The composition of claim 1, wherein composition further
comprises one or more antioxidants.
11. The composition of claim 10, wherein the antioxidant comprises
about 0.05% to about 0.5% of the total matrix mass.
12. The composition of claim 10, wherein the antioxidant comprises
one or more of alpha-tocopherol, beta-tocopherol, gamma-tocopherol,
delta-tocopherol, butylated hydroxytoluene (BHT), butylated
hydroxyanisole (BHA), citric acid, ascorbic acid, carnosic acid,
carnosol, rosmanol, epirosmanol, isorosmanol, methyl carnosate,
rosmarinic acid, eugenol, eugenyl acetate, clove bud extract,
methanolic extract, epigallocatechin gallate, epicatechin gallate,
epigallocatechin, or epicatechin.
13. The composition of claim 1, wherein the composition further
comprises one or more disintegrants.
14. The composition of claim 13, wherein the disintegrant comprises
about 0.01% to about 5% of the total matrix mass.
14. The composition of claim 12, wherein the disintegrant comprises
one or more of crospovidone, crosslinked sodium carboxymethyl
cellulose (croscarmellose sodium) carboxymethyl cellulose calcium,
cysteine HCl, sodium starch glycolate, cellulose, calcium silicate,
silicon dioxide, alginic acid, sodium alginate, citric acid,
microcrystalline cellulose, polyoxy stearate, sodium
croscarmellose, or sodium lauryl sulfate.
15. The composition of claim 1, wherein the ratio of the active
pharmaceutical ingredient percent mass to the flowable matrix
percent mass is about 1:100 to about 1:3.
16. The composition of claim 1, wherein the active pharmaceutical
ingredient comprises one or more of hydrocodone, morphine, morphine
analogues, or morphine antagonists, tapentadol, codeine, morphine,
methadone, fentanyl and analogs, hydrocodone hydrochloride,
hydrocodone bitartrate, hydromorphone, oxymorphone, oxycodone,
meperidine, propoxyphene, flunitrazepam, barbiturates, amytal,
nembutal, seconal, phenobarbital; benzodiazepines, zolpidem,
zaleplon, eszopiclone, amphetamines, or methylphenidate.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/877,208, filed on Oct. 7, 2015, which
claims priority to U.S. Provisional Patent Application No.
62/101,431, filed on Jan. 9, 2015; and is a continuation in part of
U.S. patent application Ser. No. 14/679,233 filed on Apr. 6, 2015,
which claims priority to U.S. Provisional Application No.
61/976,237, filed on Apr. 7, 2014; each of which is incorporated by
reference herein in its entirety.
TECHNICAL FIELD
[0002] Described herein are abuse deterrent controlled release oral
pharmaceutical compositions and methods for making the same. In
particular, an abuse deterrent controlled release oral
pharmaceutical composition comprising a soft capsule and an abuse
deterrent controlled release matrix comprising an active
pharmaceutical ingredient are described.
BACKGROUND
[0003] Increased attention has been drawn to the recreational use
and abuse of prescription pharmaceutical compositions. The abuse,
or non-medicinal use, of prescription pharmaceutical compositions
is an increasing problem. Accordingly, preventing the abuse of
prescription pharmaceuticals through the development of abuse
deterrent pharmaceutical compositions has become a high public
health priority for the U.S. Food and Drug Administration (FDA).
Prescription pharmaceutical compositions that are typically misused
or abused fall, primarily, into three groups: (1) opioids
prescribed for pain; (2) Central Nervous System (CNS) depressants
prescribed for anxiety or sleep problems; and (3) stimulants,
prescribed, for example, for attention deficit hyperactivity,
narcolepsy, or obesity.
[0004] Methods for abusing prescription pharmaceutical compositions
are varied and can include, for example, extraction, boiling,
melting, volatilization, physical tampering (e.g., grinding,
grating, crushing, etc.), or direct administration. For purposes of
abuse, methods of administering active drug substances obtained
from prescription pharmaceutical compositions or of the
pharmaceutical compositions themselves are similarly diverse and
include, for example, injection, smoking, snorting, swallowing,
sublingual or buccal administration, chewing, or administration as
an anal or vaginal suppository. Alcohol-induced "dose dumping,"
i.e., the rapid release of active pharmaceutical ingredients in the
presence of a solvent such as ethanol, is also an abuse concern and
safety issue. Other methods include rapid extraction under aqueous
boiling conditions.
[0005] There are a number of strategies for preventing the abuse of
pharmaceuticals. Physical and chemical barriers can prevent the
extraction of the drug or change the form of the drug making it
less likely to be abused. Combinations of agonists and antagonists
can be used, wherein the antagonist is only released upon product
manipulation or tampering. Another strategy is to use aversive
compounds that produce an unpleasant effect when the dosage form is
tampered with. In addition, prodrugs can be used, which are only
changed into the active form of the drug in the gastrointestinal
tract. The pharmaceutical industry is utilizing these strategies to
develop abuse-deterrent pharmaceutical compositions in order to
reduce the potential for misuse of prescription pharmaceutical
compositions.
[0006] Accordingly, there is a need for abuse deterrent
pharmaceutical compositions that have controlled release
properties. In particular, there is a need for formulations that
are resistant to active pharmaceutical ingredient extraction under
boiling conditions.
SUMMARY
[0007] Described herein are pharmaceutical compositions comprising
abuse deterrent controlled release matrices comprising active
pharmaceutical ingredients. The matrix is structured to prevent
extraction of the active pharmaceutical ingredients. The matrix
formulations described herein minimize the likelihood of tampering,
"dose dumping," or the extraction of active pharmaceutical
ingredients from the composition.
[0008] One embodiment described herein is an abuse deterrent oral
pharmaceutical composition comprising a tamper resistant controlled
release matrix, wherein the tamper resistant controlled release
matrix comprises a means for preventing the crushing, grating,
grinding, cutting, solvating, or dissolving of the tamper resistant
controlled release matrix comprising one or more active
pharmaceutical ingredients.
[0009] Another embodiment described herein is an abuse deterrent
oral pharmaceutical composition comprising a tamper resistant
controlled release matrix comprising: (a) at least one lipid or
lipophilic vehicle; (b) at least one organogelator; (c) at least
one hydrophilic polymer; (d) at least one hydrophilic vehicle; and
(e) at least one active pharmaceutical ingredient; wherein the
matrix is resistant to tampering and is encapsulated in a soft
capsule shell. In one aspect described herein, the tamper resistant
controlled release matrix further comprises at least one
antioxidant. In another aspect described herein, wherein the tamper
resistant controlled release matrix further comprises at least one
disintegrant. In another aspect described herein, the lipid or
lipophilic vehicle comprises about 30% to about 85% of the total
matrix mass. In another aspect described herein, the at least one
organogelator comprises from about 0.5% to about 25% of the total
matrix mass. In another aspect described herein, the at least one
hydrophilic polymer comprises about 1% to about 30% of the total
matrix mass. In another aspect described herein, the at least one
hydrophilic vehicle comprises about 2% to about 40% of the total
matrix mass. In another aspect described herein, the at least one
active pharmaceutical ingredient comprises about 1% to about 35% of
the total matrix mass. In another aspect described herein, the at
least one anti-oxidant comprises about 0.05% to about 0.5% of the
total matrix mass. In another aspect described herein, the at least
one disintegrant comprises about 0.01% to about 5% of the total
matrix mass. In another aspect described herein, the ratio of the
active pharmaceutical ingredient percent mass to the matrix percent
mass is about 1:100 to about 1:3. In another aspect described
herein, the lipid or lipophilic vehicle comprises at least one
liquid lipid or lipophilic vehicle and at least one semisolid lipid
or lipophilic vehicle. In another aspect described herein, the
lipid or lipophilic vehicle comprises at least one liquid lipid or
lipophilic vehicle and not a semisolid lipid or lipophilic vehicle.
In another aspect described herein, the liquid lipid or lipophilic
vehicle comprises: olive oil, sunflower oil, canola oil,
palmitoleic acid, oleic acid, myristoleic acid, linoleic acid,
arachidonic acid, paraffin oil, or mineral oil. In another aspect
described herein, the lipid or lipophilic vehicle comprises olive
oil or soybean oil. In another aspect described herein, the
semisolid lipid or lipophilic vehicle comprises one or more of:
polyethylene glycol glyceride ester, paraffin wax, carnauba wax, or
bee's wax. In another aspect described herein, the semisolid lipid
or lipophilic vehicle comprises a combination of carnauba wax and
bee's wax. In another aspect described herein, the lipid or
lipophilic vehicle comprises soybean oil and carnauba wax, soybean
oil and bee's wax, or soybean oil and a combination of carnauba wax
and bee's wax. In another aspect described herein, the
organogelator forms a gel at a temperature of about 90.degree. C.
to about 120.degree. C. In another aspect described herein, the
organogelator comprises one or more of: a mixture of simple alkanes
and hexadecane, 12-hydroxyoctadecanoic acid,
1,3:2,4-di-O-benzylidene-D-sorbitol, 2,3-bis-n-decyloxyanthracene,
alkyl perfluoroalkanamides, sorbitan monostearate, or ethyl
cellulose, or a combination thereof. In another aspect described
herein, the organogelator comprises ethyl cellulose. In another
aspect described herein, the ethyl cellulose comprises a viscosity
value of about 3 cP to about 350 cP. In another aspect described
herein, the ethyl cellulose comprises a viscosity value of about 4
cP to about 100 cP. In another aspect described herein, the ethyl
cellulose comprises a viscosity value of about 3 cP to about 20 cP.
In another aspect described herein, the hydrophilic polymer
comprises methylcellulose, hydroxypropylmethyl cellulose, a mixture
of hydroxypropylmethyl cellulose and methylcellulose,
polymethylmethacrylate, polyvinyl pyrrolidone, or a combination
thereof. In another aspect described herein, the hydrophilic
polymer comprises methylcellulose. In another aspect described
herein, the hydrophilic polymer comprises hydroxypropylmethyl
cellulose. In another aspect described herein, methylcellulose has
a viscosity value of about 50 to about 4,000 cP. In another aspect
described herein, hydroxypropylmethyl cellulose has a viscosity
value of about 50 to about 100,000 cP. In another aspect described
herein, the anti-oxidant comprises alpha-tocopherol,
beta-tocopherol, gamma-tocopherol, delta-tocopherol, butylated
hydroxytoluene (BHT), butylated hydroxyanisole (BHA), citric acid,
ascorbic acid, carnosic acid, carnosol, rosmanol, epirosmanol,
isorosmanol, methyl carnosate, rosmarinic acid, eugenol, eugenyl
acetate, clove bud extract, methanolic extract, epigallocatechin
gallate, epicatechin gallate, epigallocatechin, epicatechin, or a
combination thereof. In another aspect described herein, the
disintegrant comprises crospovidone, crosslinked sodium
carboxymethyl cellulose (croscarmellose sodium) carboxymethyl
cellulose calcium, cysteine HCl, sodium starch glycolate,
cellulose, calcium silicate, silicon dioxide, alginic acid, sodium
alginate, citric acid, microcrystalline cellulose, polyoxy
stearate, sodium croscarmellose, sodium lauryl sulfate, or a
combination thereof. In another aspect described herein, the active
pharmaceutical ingredient comprises at least one of: hydrocodone,
morphine, morphine analogues, or morphine antagonists, tapentadol,
codeine, morphine, methadone, fentanyl and analogs, hydrocodone
hydrochloride, hydrocodone bitartrate, hydromorphone, oxymorphone,
oxycodone, meperidine, propoxyphene, flunitrazepam, barbiturates,
amytal, nembutal, seconal, phenobarbital; benzodiazepines,
zolpidem, zaleplon, eszopiclone, amphetamines, methylphenidate, or
a combination thereof. In another aspect described herein, the
active pharmaceutical ingredient comprises hydrocodone or
oxycodone. In another aspect described herein, the active
pharmaceutical ingredient comprises hydrocodone or oxycodone and a
second active pharmaceutical ingredient that reduces the symptoms
of or onset of or prophylaxis of a bowel dysfunction due to acute
or chronic opioid use. In another aspect described herein, the
second active pharmaceutical ingredient comprises a laxative
comprising lubiprostone, linaclotide, lactulose, a heavy molecular
weight poly ethylene glycol (e.g., PEG 3350; Miralax.RTM.;
GlycoLax), sorbitol, calcium carbonate, potassium phosphate,
magnesium hydroxide, psyllium, glycerin, polycarbophil, or
docusate, a natural therapeutic or nutraceutical comprising
barberry, cascara sagrada, flax, or senna, a peripherally acting
mu-opioid receptor antagonist comprising methylnaltrexone,
naltrexone, naloxone, naloxegol, alvimopan, or a combination
thereof. In another aspect described herein, the peripherally
acting mu-opioid receptor antagonist comprises methylnaltrexone,
naltrexone, naloxone, naloxegol, alvimopan, or a combination
thereof. In another aspect described herein, the peripherally
acting mu-opioid receptor antagonist comprises naloxone, methyl
naltrexone, or naltrexone. In another aspect described herein, the
active pharmaceutical ingredient comprises naloxone and hydrocodone
or naloxone and oxycodone. In another aspect described herein, the
at least one active pharmaceutical ingredient comprises naltrexone
and hydrocodone or naltrexone and oxycodone.
[0010] In another embodiment described herein, the tamper resistant
controlled release matrix comprises: (a) soybean oil; (b) ethyl
cellulose; (c) carnauba wax; (d) bee's wax; (e) methylcellulose;
(f) polyethylene glycol; (g) hydrocodone or oxycodone; and
optionally: (h) microcrystalline cellulose; (i) BHT; and (j) BHA.
In one aspect, the tamper resistant controlled release matrix
comprises: (a) about 30% to about 70% soybean oil; (b) about 1% to
about 7% Ethocel.TM. 20 cP; (c) comprises about 0% to about 10%
bee's wax; (d) about 0% to about 10% carnauba wax; (e) about 1% to
about 8% Methocel.TM. A4M; (f) about 2% to about 40% polyethylene
glycol 400; (g) about 10.5% of hydrocodone or oxycodone; and
optionally: (h) about 0.25% BHT; and (i) about 0.1% BHA. In another
aspect described herein, the tamper resistant controlled release
matrix further comprises a peripherally acting mu-opioid receptor
antagonist comprising naloxone, methyl naltrexone, or naltrexone.
In another aspect described herein, the weight percentage ratio of
naloxone methyl naltrexone or naltrexone to hydrocodone or
oxycodone is about 15:1 to about 1:18. In another aspect described
herein, the weight percentage ratio of naloxone to hydrocodone or
oxycodone is about 1:2.
[0011] In another embodiment described herein, the tamper resistant
controlled release matrix comprises: (a) soybean oil; (b) ethyl
cellulose; (e) hydroxypropylmethyl cellulose; (f) polyethylene
glycol; (g) hydrocodone or oxycodone; and optionally (h) BHT; and
(i) BHA. In one aspect, the tamper resistant controlled release
matrix comprises: (a) about 30% to about 70% soybean oil; (b) about
1% to about 7% Ethocel.sup..TM. 20 cP; (c) comprises about 0% to
about 10% bee's wax; (d) about 0% to about 10% carnauba wax; (e)
about 1% to about 30% MethocelTM K100M; (f) about 2% to about 40%
polyethylene glycol 400; (g) about 10.5% of hydrocodone or
oxycodone; and optionally (h) about 0.25% BHT; and (i) about 0.1%
BHA. In another aspect described herein, the tamper resistant
controlled release matrix further comprises a peripherally acting
mu-opioid receptor antagonist comprising naloxone, methyl
naltrexone, or naltrexone. In another aspect described herein, the
weight percentage ratio of naloxone methyl naltrexone or naltrexone
to hydrocodone or oxycodone is about 15:1 to about 1:18. In another
aspect described herein, the weight percentage ratio of naloxone to
hydrocodone or oxycodone is about 1:2.
[0012] In another embodiment described herein, the soft capsule
shell comprises a film forming polymer, a plasticizer, a solvent,
optionally, an opacifying agent, a coloring agent, or a
pharmaceutical excipient. In another aspect described herein, the
soft capsule shell comprises: (a) about 25% to about 50% of at
least one film-forming polymer; (b) about 15% to about 25% of at
least one plasticizer; (c) about 20% to about 40% of a solvent; (d)
optionally, an opacifying agent, a coloring agent, a pharmaceutical
excipient, or combination thereof. In another aspect described
herein, the soft capsule shell comprises: (a) about 42% of at least
one film-forming polymer; (b) about 20% of at least one
plasticizer; (c) about 38% of a solvent; (d) optionally, about 0.7%
of an opacifying agent; and (e) optionally, about 0.1% at least one
coloring agent. In another aspect described herein, the soft
capsule shell comprises gelatin, glycerol, water, and optionally,
titanium oxide, and a coloring agent. In another aspect described
herein, the soft capsule shell comprises gelatin, glycerol, water,
and optionally, titanium oxide, and a coloring agent.
[0013] Another embodiment described herein is a method for making a
tamper resistent controlled release matrix dosage form comprising
the steps of: (a) heating one or more liquid lipophilic vehicles to
about 60.degree. C. and adding one or more organogelators until
completely dissolved to form a first clear gel mixture; (b)
hydrating one or more hydrophilic polymers (e.g., hydroxypropyl
methyl cellulose) with one or more hydrophilic vehicles (e.g.,
polyethylene glycol); (c) mixing one or more active pharmaceutical
ingredients with the mixture of step (b) to form a second uniform
mixture; and (d) adding the second uniform mixture of step (c) to
the first clear gel mixture of step (a) to form a final uniform
matrix composition. In one aspect, the tamper resistent controlled
release comprises: (a) soybean oil; (b) ethyl cellulose; (e)
hydroxypropylmethyl cellulose; (f) polyethylene glycol; and (g)
hydrocodone or oxycodone. In another aspect described herein, step
(a) further comprises adding one or more semi-solid lipid or
lipophilic vehicles or one or more disintegrants one or more
anti-oxidants or a combination thereof.
[0014] Another embodiment described herein is a method for
manufacturing a soft capsule shell and a tamper resistant
controlled release matrix comprising the steps of: (a) providing a
matrix comprising a tamper resistent controlled release matrix as
described herein made by the methods described herein; (b)
providing a soft capsule gel mass; (c) casting the soft capsule gel
mas into films using heat-controlled drums or surfaces; and (d)
forming a soft capsule comprising the matrix composition using
rotary die encapsulation technology.
[0015] Another embodiment described herein is a soft capsule
comprising a tamper resistant controlled release matrix produced by
the method described herein.
[0016] Another embodiment described herein is an enteric soft
capsule comprising a tamper resistant controlled release matrix
produced by the method described herein.
[0017] Another embodiment described herein is a tamper resistent
oral pharmaceutical composition comprising a tamper resistant
controlled release matrix comprising: (a) about 30% to about 70%
soybean oil; (b) about 1% to about 7% Ethocel.sup..TM. 20 cP; (c)
about 0% to about 7% bee's wax; (d) about 0% to about 7% carnauba
wax; (e) about 1% to about 8% MethocelTM A4M; (f) about 2% to about
40% polyethylene glycol 400; (g) about 10.5% of hydrocodone or
oxycodone; and optionally (h) about 0.25% BHT; and (i) about 0.1%
BHA; wherein the matrix is resistant to tampering and has
controlled release properties; the matrix being encapsulated in a
soft capsule shell comprising:(j) about 25% to about 50% gelatin;
(k) about 15% to about 25% glycerol; (l) about 20% to about 40%
water; and (m) optionally, an opacifying agent, a coloring agent, a
pharmaceutical excipient, or combination thereof. In one aspect,
the tamper resistent controlled release matrix further comprises a
peripherally acting mu-opioid receptor antagonist comprising
naloxone, methyl naltrexone, or naltrexone. In another aspect, the
weight percentage ratio of naloxone, methyl naltrexone or
naltrexone to hydrocodone or oxycodone is about 15:1 to about 1:18.
In another aspect, the weight percentage ratio of naloxone to
hydrocodone or oxycodone is about 1:2.
[0018] Another embodiment described herein is a tamper resistent
oral pharmaceutical composition comprising a tamper resistant
controlled release matrix comprising: (a) about 30% to about 70%
soybean oil; (b) about 1% to about 7% Ethocel.sup..TM. 20 cP; (c)
comprises about 0% to about 10% bee's wax; (d) about 0% to about
10% carnauba wax; (e) about 1% to about 30% Methocel.TM. K100M; (f)
about 2% to about 40% polyethylene glycol 400; (g) about 10.5% of
hydrocodone or oxycodone; and optionally (h) about 0.25% BHT; and
(i) about 0.1% BHA; wherein the matrix is resistant to tampering
and has controlled release properties; the matrix being
encapsulated in a soft capsule shell comprising: (j) about 25% to
about 50% gelatin; (k) about 15% to about 25% glycerol; (l) about
20% to about 40% water; and (m) optionally, an opacifying agent, a
coloring agent, a pharmaceutical excipient, or combination thereof.
In one aspect, the tamper resistent controlled release matrix
further comprises a peripherally acting mu-opioid receptor
antagonist comprising naloxone, methyl naltrexone, or naltrexone.
In another aspect, the weight percentage ratio of naloxone, methyl
naltrexone or naltrexone to hydrocodone or oxycodone is about 15:1
to about 1:18. In another aspect, the weight percentage ratio of
naloxone to hydrocodone or oxycodone is about 1:2.
[0019] Another embodiment described herein is a tamper resistent
oral pharmaceutical composition comprising a tamper resistant
controlled release matrix comprising: (a) about 30% to about 70%
soybean oil; (b) about 1% to about 7% Ethocel.sup..TM. 20 cP; (c)
about 0% to about 7% bee's wax; (d) about 0% to about 7% carnauba
wax; (e) about 1% to about 8% MethocelTM A4M; (f) about 2% to about
40% polyethylene glycol 400; (g) about 10.5% of hydrocodone or
oxycodone; (h) optionally, about 5.25% of naloxone; and optionally
(i) about 0.25% BHT; and (j) about 0.1% BHA; wherein the matrix is
resistant to tampering and has controlled release properties; the
matrix being encapsulated in a soft capsule shell comprising: (k)
about 25% to about 50% gelatin; (l) about 15% to about 25%
glycerol; (m) about 20% to about 40% water; and (n) optionally, an
opacifying agent, a coloring agent, a pharmaceutical excipient, or
combination thereof.
[0020] Another embodiment described herein is a tamper resistent
oral pharmaceutical composition comprising a tamper resistant
controlled release matrix comprising: (a) about 30% to about 70%
soybean oil; (b) about 1% to about 7% Ethocel.TM. 20 cP; (c) about
0% to about 7% bee's wax; (d) about 0% to about 7% carnauba wax;
(e) about 1% to about 30% Methocel.TM. K100M; (f) about 2% to about
40% polyethylene glycol 400; (g) about 10.5% of hydrocodone or
oxycodone; (h) optionally, about 5.25% of naloxone; and optionally
(i) about 0.25% BHT; and (j) about 0.1% BHA; wherein the matrix is
resistant to tampering and has controlled release properties; the
matrix being encapsulated in a soft capsule shell comprising: (k)
about 25% to about 50% gelatin; (l) about 15% to about 25%
glycerol; (m) about 20% to about 40% water; and (n) optionally, an
opacifying agent, a coloring agent, a pharmaceutical excipient, or
combination thereof.
[0021] Another embodiment described herein is a method for
treating, reducing the symptoms or onset of, or prophylaxis of pain
stemming from diabetic neuropathy, chronic arthritis,
osteoarthritis, rheumatoid arthritis, acute tendonitis, bursitis,
headaches, migraines, chronic neuropathies, shingles, premenstrual
symptoms, sports injuries, malignancy, radiculopathy,
sciatica/sciatic pain, sarcoidosis, necrobiosis, lipoidica or
granuloma annulare comprising administering to a subject in need
thereof a pharmaceutical composition as described herein. In one
aspect, the administration is sufficient to achieve a reduction of
pain relative to baseline in the subject without substantially
inducing one or more of opioid induced bowel disfunction (OIBD)
comprising constipation (opioid induced constipation; 010),
anorexia, nausea and vomiting, gastro-oesophageal reflux, delayed
digestion, abdominal pain, flatulence, bloating, hard stools,
incomplete evacuation, or straining during bowel movements.
[0022] Another embodiment described herein is a method for
delivering about a 10 mg to about a 80 mg dose of oxycodone or
about a 10 mg to about a 80 mg dose of hydrocodone comprising
administering to a subject a pharmaceutical composition comprising
oxycodone or hydrocodone and other pharmaceutically acceptable
excipients in a tamper resistent matrix in a soft gel capsule, the
method capable of achieving one or more of the following
pharmacokinetic parameters: (a) a mean plasma oxycodone T.sub.max
of about 1 hours to about 8 hours; (b) a mean plasma oxycodone
C.sub.max of about 10 ng/mL to about 150 ng/mL; (c) a mean plasma
oxycodone AUC.sub.0.fwdarw..infin. of about 100 hmg/L to about 1000
hmg/L; or (d) a mean plasma hydrocodone T.sub.max of about 3 hours
to about 8 hours; (e) a mean plasma hydrocodone C.sub.max of about
10 ng/mL to about 120 ng/mL; (f) a mean plasma hydrocodone
AUC.sub.0.fwdarw..infin. of about 100 hmg/L to about 1600 hmg/L. In
one aspect, the method further comprises delivering a dose of a
peripherally acting mu-opioid receptor antagonist comprising
naloxone, methyl naltrexone, or naltrexone. In another aspect, the
weight percentage ratio of naloxone methyl naltrexone or naltrexone
to hydrocodone or oxycodone is about 15:1 to about 1:18. In another
aspect, the weight percentage ratio of naloxone to hydrocodone or
oxycodone is about 1:2. In another aspect, the administration is
sufficient to achieve a reduction of pain relative to baseline in
the subject without substantially inducing one or more of opioid
induced bowel disfunction (OIBD) comprising constipation (opioid
induced constipation), anorexia, nausea and vomiting,
gastro-oesophageal reflux, delayed digestion, abdominal pain,
flatulence, bloating, hard stools, incomplete evacuation or
straining during bowel movements. In one aspect, the administration
provides an improvement of bowel function during pain therapy,
comprising an improvement of the mean bowel function score of at
least about 5, at least about 8, at least about 10, or at least
about 15 after steady state administration to human patients,
wherein the mean bowel function score is measured with a numerical
analog scale ranging from 0 to 100. In another aspect, the
pharmaceutical composition comprises a soft capsule. In another
aspect described herein, the pharmaceutical composition exhibits an
in vitro dissolution rate at pH 6.8, of about 50% after about 60
minutes to about 480 minutes. In another aspect described herein,
the pharmaceutical composition exhibits an in vitro dissolution
rate under boiling conditions of less than about 20% to about 80%
after about 5 minutes to about 120 minutes. In another aspect
described herein, the pharmaceutical composition exhibits an in
vitro dissolution rate in an aqueous alcohol solution or distilled
water of less than about 50% after about 280 minutes to about 1440
minutes.
[0023] Another embodiment described herein is a method for
retarding the extraction an active pharmaceutical ingredient from a
pharmaceutical composition by means of crushing, grating, grinding,
cutting, solvating, or dissolving the matrix comprising: providing
a pharmaceutical composition described herein, wherein the
composition is resistant to crushing, grating, grinding, cutting,
solvation, or dissolution. In one aspect described herein, the
pharmaceutical composition comprises a soft capsule as described
herein.
[0024] Another embodiment described herein is a kit for dispensing
the abuse deterrent oral pharmaceutical composition described
herein comprising: (a) at least one soft capsule comprising an
abuse deterrent controlled release matrix comprising an active
pharmaceutical ingredient; (b) at least one receptacle comprising a
tamper evident, moisture proof packaging that reduces the ability
of removing the oral pharmaceutical composition comprising blister
or strip packs, aluminum blister, transparent or opaque polymer
blister with pouch, polypropylene tubes, colored blister materials,
tubes, bottles, and bottles optionally containing a child-resistant
feature, optionally comprising a desiccant, such as a molecular
sieve or silica gel; (c) optionally, an insert comprising
instructions or prescribing information for the active
pharmaceutical ingredient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] The patent or application file contains at least one drawing
executed in color. Copies of this patent or patent application
publication with color drawing(s) will be provided by the Office
upon request and payment of the necessary fee.
[0026] FIG. 1. Representative images of abuse deterrent matrices.
FIG. 1A shows the hydrophilic phase; FIG. 1B shows the gelled
phase, and FIG. 1C shows the final mixture prior to
encapsulation.
[0027] FIG. 2. Release profile of hydrocodone and oxycodone from
the abuse deterrent matrix shown in Table 7 under boiling
conditions compared to a reference abuse deterrent matrix.
[0028] FIG. 3. Release profile of hydrocodone from the abuse
deterrent matrix shown in Table 7 compared to a reference abuse
deterrent matrix in a dissolution test using Apparatus III at 10
dips/min in a pH 6.8 buffer.
[0029] FIG. 4. Release profile of hydrocodone from the abuse
deterrent matrix shown in Table 7 compared to a reference abuse
deterrent matrix in a dissolution test using Apparatus I at 100 RPM
in 500 mL of a 40% solution of ethanol in 0.1 N HCl (pH 1.2).
[0030] FIG. 5. Comparison of release profiles of hydrocodone from
the abuse deterrent matrix shown in Table 7 with two different
reference abuse deterrent matrices in distilled water at different
temperatures and under agitation at 300 RPM.
[0031] FIG. 6. Comparison of release profiles of hydrocodone from
the abuse deterrent matrix shown in Table 7 to two different
reference abuse deterrent matrices in distilled water at different
times under agitation at 300 RPM.
[0032] FIG. 7. Release profile of hydrocodone from the abuse
deterrent matrix shown in Table 8 in a dissolution test using
Apparatus III at 10 dips/min in a 40% solution of ethanol in 0.1 N
HCl (pH 1.2) and a pH 6.8 buffer.
[0033] FIG. 8. Release profile of oxycodone from the abuse
deterrent matrix labelled F8 shown in Table 16 compared to a
reference abuse deterrent matrix in a dissolution test using
Apparatus III at 10 dips/min RPM in 250 mL of a pH 6.8 buffer.
[0034] FIG. 9. Release profile of oxycodone from the abuse
deterrent matrix labelled F8 shown in Table 16 compared to a
reference abuse deterrent matrix in a dissolution test using
Apparatus III at 10 dips/min RPM in a 40% solution of ethanol in
0.1 N HCl (pH 1.2).
[0035] FIG. 10. Release profile of oxycodone from the abuse
deterrent matrices labelled F12 and F13 shown in Table 16 under
boiling conditions compared to a reference abuse deterrent
matrix.
[0036] FIG. 11. Release profile of oxycodone from a test abuse
deterrent matrix shown in Table 9 in a dissolution test using
Apparatus III at 10 dips/min in a 40% solution of ethanol in 0.1 N
HCl (pH 1.2) and a pH 6.8 buffer compared to the release rate of a
reference abuse deterrent abuse deterrent matrix in a dissolution
test using Apparatus III at 10 dips/min in a pH 6.8 buffer.
[0037] FIG. 12. Release profile of oxycodone from the abuse
deterrent matrix shown in Table 9 under boiling conditions compared
to a reference abuse deterrent matrix.
[0038] FIG. 13. Release profile of oxycodone from the abuse
deterrent matrix shown in Table 10 under boiling conditions
compared to a reference abuse deterrent matrix.
[0039] FIG. 14. Release profile of oxycodone from the abuse
deterrent matrix shown in Table 12 without carnauba wax compared to
a reference abuse deterrent matrix.
[0040] FIG. 15. Release profile of oxycodone from the abuse
deterrent matrix shown in Table 13 with two different amounts of
oxycodone compared to a reference abuse deterrent matrix.
[0041] FIG. 16. Release profile of oxycodone from the abuse
deterrent matrix shown in Table 17 (F 14) compared to a reference
abuse deterrent matrix.
[0042] FIG. 17. Release profile of oxycodone under boiling
conditions from the abuse deterrent matrix shown in Table 17 (F 14)
compared to a reference abuse deterrent matrix.
DETAILED DESCRIPTION
[0043] Described herein are abuse deterrent controlled release
pharmaceutical compositions. The pharmaceutical compositions
described herein provide abuse deterrent matrices and methods for
preparation thereof. Also described herein are compositions and
methods for manufacturing soft capsules comprising abuse deterrent
controlled release pharmaceutical matrices. In some embodiments
described herein, the soft capsule is an enteric soft capsule.
[0044] The term "abuse deterrent," or "tamper resistant" as used
herein, refers to a pharmaceutical composition that is resistant to
tampering or accessing the active pharmaceutical ingredient for
recreational drug use or drug abuse.
[0045] The phrase "recreational drug use," as used herein, refers
to the voluntary use of an active pharmacetical agent or drug for a
non-medical purpose to induce an effect, such as pleasure,
satisfaction, euphoria, dissociation, or to enhance an
experience.
[0046] The term "drug abuse," as use herein, refers to the
habitual, compulsive, or recurrent use of an active pharmaceutical
agent or drug, often despite negative consequences.
[0047] The term "tampering," as used herein, refers to any kind of
actual or attempted physical manipulation or interference that may
result in particle size reduction of a pharmaceutical composition.
Tampering, as used herein also includes any actual or attempted
dissolution or extraction of active pharmaceutical ingredients
using solvents. Compositions that are resistant to physical
tampering are formulated in such a way that the composition cannot
readily reduced to a form that is suitable for abuse, such as, for
example, injection or snorting, because the tablet cannot easily be
ground, grated, dissolved, extracted, and the like at any
temperature. Examples of physical tampering include, but are not
limited to, crushing, grinding, grating, cutting, crisping, and
other methods of particle size reduction. Dissolution tampering
includes actual or attempted actions to dissolve or extract active
pharmaceutical ingredients using aqueous or organic solvents such
as water, ethanol, isopropanol, ethyl acetate, acetone, ether, or
the like, at any temperature including boiling. Tampering, as used
herein, includes "dose dumping."
[0048] The term "dose dumping" or "dumping" as used herein refers
to the rapid release of the entire amount or a significant fraction
of an active pharmaceutical ingredient or drug. Drug abusers often
intentionally pursue dumping of a drug from the dosage form.
[0049] The terms "drug", "active ingredient," "active
pharmaceutical ingredient," or "active pharmaceutical agent" as
used herein refer to an agent, active ingredient, compound, or
substance, compositions, or mixtures thereof, that provide a
pharmacological, often beneficial, effect. Reference to a specific
active ingredient includes, where appropriate, the active
ingredient and any of its pharmaceutically acceptable salts or
esters.
[0050] The terms "dosage" or "dose" denote any form of the active
ingredient formulation that contains an amount sufficient to
produce a therapeutic effect with a single administration. The
dosage form used herein is for oral administration. The preferred
oral dosage forms are soft capsules or enteric soft capsules.
[0051] The terms "active pharmaceutical ingredient load" or "drug
load" as used herein refers to the quantity (mass) of the active
pharmaceutical ingredient comprised in a single soft capsule
fill.
[0052] The term "formulation" or "composition" as used herein
refers to the active pharmaceutical ingredient or drug in
combination with pharmaceutically acceptable excipients. This
includes orally administrable formulations as well as formulations
administrable by other means.
[0053] The term "titration" as used herein refers to the
incremental increase in drug dosage to a level that provides the
optimal therapeutic effect.
[0054] The term "controlled release" as used herein refers to a
composition that does not immediately releases an active
ingredient. "Controlled relase" as used herein encompasses the
terms "modified release," "sustained release," "extended release,"
and "delayed release." The term "delayed release" as used herein
refers to a composition that releases an active ingredient
according to a desired profile over an extended period under
physiological conditions or in an in vitro test. By "extended
period" it is meant a continuous period of time of at least about
20 minutes, about 30 minutes, about 1 hour; about 2 hours; about 4
hours; about 6 hours; about 8 hours; about 10 hours; about 12
hours; about 14 hours; about 16 hours; about 18 hours; about 20
hours about 24 hours; or even longer.
[0055] The term "modified release" as used herein refers to a
composition that releases an active ingredient at a slower rate
than does an immediate release formulation under physiological
conditions or in an in vitro test.
[0056] The term "sustained" "release" as used herein refers to a
composition that releases an active ingredient over an extended
period of time, for example minutes, hours, or days, such that less
than all the active ingredient is released initially. A sustained
release rate may provide, for example, a release of a certain
specified amount of a drug or active ingredient from a dosage form,
over a certain period, under physiological conditions or in an in
vitro test.
[0057] The term "extended release" as used herein refers to a
composition that releases an active ingredient over an extended
period, such as of at least about 20 minutes, about 30 minutes,
about 1 hour; about 2 hours; about 4 hours; about 6 hours; about 8
hours; about 10 hours; about 12 hours; about 14 hours; about 16
hours; about 18 hours; about 20 hours about 24 hours; or even
longer; specifically over a period of at least 18 hours under
physiological conditions or in an in vitro assay.
[0058] As used herein, the phrase "abuse deterrent controlled
release" refers to a pharmaceutical composition comprising
components or a formulation that prevents liberation of the active
pharmaceutical ingredient(s) from the composition for potential
abuse or dose dumping and the composition provides controlled
release delivery of the active pharmaceutical ingredient upon
ingestion of the composition by a subject.
[0059] The term "C.sub.max " as used herein refers to the maximum
observed blood (plasma, serum, or whole blood) concentration or the
maximum blood concentration calculated or estimated from a
concentration to time curve, and is expressed in units of mg/L or
ng/mL, as applicable.
[0060] The term "C.sub.max" as used herein refers to the minimum
observed blood (plasma, serum, or whole blood) concentration or the
minimum blood concentration calculated or estimated from a
concentration to time curve, and is expressed in units of mg/L or
ng/mL, as applicable.
[0061] The term "C.sub.ave" as used herein refers to the blood
(plasma, serum, or whole blood) concentration of the drug within
the dosing interval, is calculated as AUC/dosing interval, and is
expressed in units of mg/L or ng/mL, as applicable.
[0062] The term "T.sub.max" as used herein refers to the time after
administration at which C.sub.max occurs, and is expressed in units
of hours (h) or minutes (min), as applicable.
[0063] The term "AUC.sub.0.fwdarw.t" as used herein refers to area
under the blood (plasma, serum, or whole blood) concentration
versus time curve from time zero to time tau (i) over a dosing
interval at steady state, where tau is the length of the dosing
interval, and is expressed in units of hmg/L or hng/mL, as
applicable. For example, the term AUC.sub.0.fwdarw..infin. as used
herein refers to the area under the concentration versus time curve
from 0 to 12 hours.
[0064] The term "AUC.sub.0.fwdarw..infin." as used herein refers to
the area under the blood (plasma, serum, or whole blood)
concentration versus time curve from time 0 hours to infinity, and
is expressed in units of hmg/L or hng/mL, as applicable. The term
"AUC.sub.overall" as used herein refers to the combined area under
the blood (plasma, serum, or whole blood) concentration versus time
curve, and is expressed in units of hmg/L (or hng/mL) for at least
one or more doses of the pharmaceutical compositions described
herein. In one aspect, the "AUC.sub.overall" refers to the combined
area under the blood concentration versus time curve for at least
two doses of the pharmaceutical compositions described herein.
[0065] The term "treating" refers to administering a therapy in an
amount, manner, or mode effective to improve a condition, symptom,
or parameter associated with a disorder.
[0066] The term "prophylaxis" refers to preventing or reducing the
progression of a disorder, either to a statistically significant
degree or to a degree detectable to one skilled in the art.
[0067] The term "substantially" as used herein means to a great or
significant extent, but not completely.
[0068] The term "about" as used herein refers to any values,
including both integers and fractional components that are within a
variation of up to .+-.10% of the value modified by the term
"about." For example, the phrase "about 50%" is equivalent to any
vale .apprxeq.50 .+-.10%, e.g., 44.6%, 45%, 46%, 47%, 48%, 49%,
49.5%, 50%, 50.3%, 51%, 52%, 53%, 54%, 55%, inter alia.
[0069] As used herein, "a" or "an" means one or more unless
otherwise specified. Terms such as "include," "including,"
"contain," "containing," "has," or "having," and the like, mean
"comprising."
[0070] The term "or" can be conjunctive or disjunctive.
[0071] Described herein are pharmaceutical compositions comprising
abuse deterrent controlled release matrices comprising active
pharmaceutical ingredients. The matrix is structured to prevent
extraction of the active pharmaceutical ingredients.
[0072] In one embodiment, the pharmaceutical composition described
herein comprises a soft capsule comprising an abuse deterrent
controlled release matrix comprising an active pharmaceutical
ingredient. In one embodiment, the active pharmaceutical ingredient
is an analgesic. In another embodiment, the active pharmaceutical
ingredient is an opioid analgesic.
[0073] In another embodiment, the soft capsule comprising a matrix
can provide controlled release properties. Such controlled release
matrix fills are described in International Patent Application
Publication No. WO 2005/009409 and WO 2006/096580, U.S. Patent
Application Publication Nos. US 2006/0115527 and US 2007/0053868,
and U.S. Pat. Nos. 8,293,270 and 8,333,989, each of which are
incorporated by reference herein for such teachings. In one aspect,
the soft capsule and matrix can be configured to provide controlled
release, extended release, sustained release, delayed release, or
combinations thereof.
[0074] In other embodiments, the pharmaceutical composition
described herein comprises abuse deterrent properties. These abuse
deterrent properties reduce the likelihood that the active
pharmaceutical ingredient can be extracted from the composition
through mechanisms, including but not limited to crushing, grating,
grinding, or cutting of the capsule to expose the matrix thereby
facilitating solvation or extraction of the active pharmaceutical
ingredient. In addition, the abuse deterrent properties reduce the
likelihood that the active pharmaceutical ingredient can be
extracted from the composition by dissolving or extracting in
ethanol solutions of about 1% to about 50%, dissolving in solutions
having pH values from about 1 to about 12, or dissolving in
household chemical compositions, including water, coffee, vinegar,
cola, milk, ethanol, isopropanol, acetone, ethyl acetate, or other
common solvents. In addition, the abuse deterrent properties
further reduce the likelihood that the active pharmaceutical
ingredient can be extracted by boiling in water or ethanol
solutions.
[0075] In other embodiments described herein, the matrix comprises
a lipid or lipophilic vehicle that provides a suspension or a
solution of the active pharmaceutical ingredient. In one aspect, a
soft capsule comprising an active pharmaceutical ingredient
provides controlled release of the active pharmaceutical
ingredient.
[0076] In other embodiments described herein, the pharmaceutical
composition provides matrix fills for the active pharmaceutical
ingredient, or derivatives thereof, based on lipids or lipophilic
materials. The matrices described herein have a hydrophobic
(lipophilic) surface in contact with a hydrophilic soft capsule
shell to minimize any potential shell-fill interactions, such as
when the soft capsules are filled with hydrophilic materials. In
one embodiment described herein are methods for manufacturing
matrix fills comprising an abuse deterrent controlled release
matrix comprising an active pharmaceutical ingredient in a soft
capsule in the form of a suspension, where part or all of the
active pharmaceutical ingredient is suspended within the matrix. In
one embodiment described herein is a soft capsule having a shell
and an abuse deterrent controlled release matrix fill, wherein the
matrix includes an active pharmaceutical ingredient suspended as
solid particles within the lipophilic vehicle.
[0077] In one embodiment described herein, an exemplary abuse
deterrent controlled release matrix has the composition of Table 1,
including all possible iterations of the specified ranges that
provide 100% for the total weight percentage, including or
excluding the optional colorings, flavorings, or pharmaceutically
acceptable excipients.
TABLE-US-00001 TABLE 1 Exemplary Abuse Deterrent Controlled Release
Matrix Composition Component Exemplary Components Composition Range
(%) Liquid lipophilic vehicle(s) Soybean oil 35-75 Semisolid lipid
vehicle Bee's wax, carnauba wax 0-7 Organogelator Ethyl cellulose
2-25 Hydrophilic Polymer Methyl cellulose, hydroxypropyl 2-25
methylcellulose, poly(ethylene) oxide Hydrophilic vehicle
Polyethylene glycol 2-20 Disintegrant Microcrystalline cellulose
0-5 Anti-oxidant BHT, BHA 0-0.5 Active pharmaceutical Oxycodone,
hydrocodone, tapentadol 1-35 ingredient(s)
[0078] In another embodiment, the lipid or lipophilic vehicle can
be a liquid lipophilic vehicle, a semisolid lipophilic vehicle, or
combinations thereof. Suitable lipid or lipophilic vehicles include
mineral oil; light mineral oil; natural oils (e.g., vegetable,
corn, canola, sunflower, soybean, olive, coconut, cocoa, peanut,
almond, cottonseed, persic, sesame, squalane, castor, cod liver,
etc) hydrogenated vegetable oil; partially hydrogenated oils; bee's
wax (beeswax); polyethoxylated bee's wax; paraffin; normal waxes;
medium chain medium chain monoglycerides, diglycerides and
triglycerides; higher aliphatic alcohols; higher aliphatic acids;
long chain fatty acids; saturated or unsaturated fatty acids;
hydrogenated fatty acids; fatty acid glycerides;
[0079] polyoxyethylated oleic glycerides; monoglycerides and
diglycerides; mono-, bi- or tri-substituted glycerides; glycerol
mono-oleate esters; glycerol mono-caprate; glyceryl monocaprylate;
propylene glycol dicaprylate; propylene glycol monolaurate;
glyceryl palmitostearate; glyceryl behenate; diethyleneglycol
palmitostearate; polyethyleneglycol stearate; polyoxyethyleneglycol
palmitostearate; glyceryl mono palmitostearate; cetyl palmitate;
polyethyleneglycol palmitostearate; dimethylpolysiloxane; mono- or
di-glyceryl behenate; fatty alcohols associated with polyethoxylate
fatty alcohols; cetyl alcohol; octyl dodecanol; myristyl alcohol;
isopropyl myristate, isopropyl palmitate, stearic acid, stearyl
alcohol, and others known in the art.
[0080] In one embodiment, the lipid or lipophilic vehicle comprises
both a liquid lipophilic vehicle and a semisolid lipophilic
vehicle. In one embodiment, the liquid lipid or lipophilic vehicle
can be olive oil, soybean oil, sunflower oil, canola oil,
palmitoleic acid, oleic acid, myristoleic acid, linoleic acid,
arachidonic acid, paraffin oil, or mineral oil. In another
embodiment, the semi-solid lipophilic vehicle can be a polyethylene
glycol glyceride ester, paraffin wax, carnauba wax, or bee's wax.
In another embodiment, the semi-solid lipophilic vehicle can be
Gelucire.RTM. 33/01, Gelucire.RTM. 37/02,Gelucire.RTM. 39/01,
Gelucire.RTM. 43/01, Gelucire.RTM. 44/14, Gelucire.RTM. 50/02,
Gelucire.RTM. 50/13, Gelucire.RTM. 53/10, or Gelucire.RTM. 62/02.
In another embodiment, the Gelucire.RTM. semisolid lipid vehicle
has a HLB value of about 1 and a melting point of about 43. In one
aspect, the liquid lipid or lipophilic vehicle is soybean oil. In
another aspect, the semisolid lipid or lipophilic vehicle comprises
a wax. In another aspect, the semisolid lipid or lipophilic vehicle
comprises bee's wax. In another aspect, the semisolid lipid or
lipophilic vehicle comprises carnauba wax.
[0081] In another aspect, the semisolid lipid or lipophilic vehicle
comprises a mixture of bee's wax and carnauba wax.
[0082] In one embodiment, the matrix comprises a surfactant. The
surfactant can have a hydrophilic/lipophilic balance (HLB) value
between about 1 and about 25 and a melting point between about
25.degree. C. and about 70.degree. C. The HLB characteristic of
surfactants can be determined in accordance with "Physical
Pharmacy: Physical Chemical Principles in the Pharmaceutical
Sciences," Fourth Edition, pp. 371-373, A. Martin, Ed., Lippincott
Williams & Wilkins, Philadelphia (1993). Suitable surfactants
include: glyceryl monocaprylate (e.g., Capmul.RTM. MCM),
Pluronic.RTM. 10R5, Pluronic.RTM. 17R2, Pluronic.RTM. 17R4,
Pluronic.RTM. 25R2, Pluronic.RTM. 25R4, Pluronic.RTM. 31R1,
Pluronic.RTM. F 108, Pluronic.RTM. F 108 NF, Pluronic.RTM. F 108,
Pluronic.RTM. F 108NF, Poloxamer 338, Pluronic.RTM. F 127,
Pluronic.RTM. F 127 NF, Pluronic.RTM. F 127 NF 500 BHT Prill,
Pluronic.RTM. F 127 NF Prill, Poloxamer 407, Pluronic.RTM. F 38,
Pluronic.RTM. F 38 Pastille, Pluronic.RTM. F 68, Pluronic.RTM. F 68
LF Pastille, Pluronic.RTM. F 68 NF, Pluronic.RTM. F 68 NF Prill,
Poloxamer 188, Pluronic.RTM. F 68 Pastille, Pluronic.RTM. F 77,
Pluronic.RTM. F 77 Micropastille, Pluronic.RTM. F 87, Pluronic.RTM.
F 87 NF, Pluronic.RTM. F 87 NF Prill, Poloxamer 237, Pluronic.RTM.
F 88, Pluronic.RTM. F 88 Pastille, Pluronic.RTM. F 98,
Pluronic.RTM. L 10, Pluronic.RTM. L 101, Pluronic.RTM. L 121,
Pluronic.RTM. L 31, Pluronic.RTM. L 35, Pluronic.RTM. L 43,
Pluronic.RTM. L 61, Pluronic.RTM. L 62, Pluronic.RTM. L 62 LF,
Pluronic.RTM. L 62D, Pluronic.RTM. L 64, Pluronic.RTM. L 81,
Pluronic.RTM. L 92, Pluronic.RTM. N 3, Pluronic.RTM. P 103,
Pluronic.RTM. P 104, Pluronic.RTM. P 105, Pluronic.RTM. P 123
Surfactant, Pluronic.RTM. P 65, Pluronic.RTM. P 84, Pluronic.RTM. P
85, Adogen.RTM. 464, Alkanol.RTM. 6112, Brij.RTM. 52, Brij.RTM. 93,
Brij.RTM. S2, Brij.RTM. S, Brij.RTM. 58, Brij.RTM. C10, Brij.RTM.
L4, Brij.RTM. O10, Brij.RTM. O10, BRIJ.RTM. O20, Brij.RTM. S10,
Brij.RTM. S20, ethylenediamine
tetrakis(ethoxylate-block-propoxylate) tetrol, ethylenediamine
tetrakis(ethoxylate-block-propoxylate) tetrol, ethylenediamine
tetrakis(propoxylate-block-ethoxylate) tetrol, IGEPAL.RTM. CA-210,
IGEPAL.RTM. CA-520, IGEPAL.RTM. CA-720, IGEPAL.RTM. CO-520,
IGEPAL.RTM. CO-630, IGEPAL.RTM. CO-720, IGEPAL.RTM. CO-890,
IGEPAL.RTM. DM-970, MERPOL.RTM. DA, MERPOL.RTM. HCS, MERPOL.RTM.
OJ, MERPOL.RTM. SE, MERPOL.RTM. SH, MERPOL.RTM. A, Poly(ethylene
glycol) sorbitan tetraoleate, poly(ethylene glycol) sorbitol
hexaoleate, poly(ethylene glycol) (12), poly(ethylene glycol) (18),
polyethylene-block-poly(ethylene glycol), sorbitan monopalmitate,
2,4,7,9-tetramethyl-5-decyne-4,7-diol ethoxylate, Nonidet.TM. P-40,
Triton.TM. N-101, Triton.TM. X-100, Triton.TM. X-114, Triton.TM.
X-405, TWEEN.RTM. 20, TWEEN.RTM. 40, TWEEN.RTM. 60, TWEEN.RTM. 85,
Zonyl.RTM. FS-300, or Zonyl.RTM. FSN. In one embodiment, the
surfactant comprises Pluronic.RTM. F127, Tween.RTM. 80, Span.RTM.
80, IGEPAL.RTM., Triton.TM. X-100, or Capmul.RTM. MCM.
[0083] In another embodiment, the abuse deterrent matrix comprises
one or more organogelator controlled release polymers. An organogel
is a cross-linked fibrous three-dimensional network. These types of
gels are formed in a liquid organic phase via the covalent
polymerization of monomers through reactive groups or aggregation
and self-assembly of monomers. The assembly of these monomers
occurs through extensive van der Waals forces, hydrogen bonding, or
dipole-dipole interactions, among others. At or near the gel-point,
the network is strong enough that the liquid solution is gel-like
with physical rheological properties. In general, organogelators
relying on hydrogen bonding are amino acids, amides, urea moieties,
and carbohydrates or carbohydrate derivatives. Covalent or
chemical-type organogelators typically are anthracene,
anthraquinone, or steroid-based molecules.
[0084] Potential suitable organogelators for the abuse deterrent
matrices described herein include but are not limited to the
simplest n-alkanes (C.sub.24-36), which function to gel other short
alkanes, such as hexadecane; substituted fatty acids (e.g.,
12-hydroxyoctadecanoic acid or 1, 3:2,4-di-O-benzylidene-D-sorbitol
(D-DBS), steroids and derivatives; anthryl derivatives (e.g.,
2,3-bis-n-decyloxyanthracene); macrocyclic gelators (e.g.,
calixarenes); aromatic linked steroidal groups; cyclodipeptides;
bisurea compounds; bisamides; bolaform amides; alkyl
perfluoroalkanamides; carbohydrate derivatives, cellulose
derivatives, such as ethyl cellulose;
[0085] perfluoroalkanes and carbon dioxide; methyl
2,6,-diisocyanatohexanoate and alkylamines; primary alkyl amines;
any light-responsive gelator; oxadiazole-based benzene;
1,3,5-tricarboxamide; cobalt (II) triazole complexes; and fatty
acid derivatives of L-alanine; sorbitan monostearate based
organogelators; metha methacrylate based organogels (e.g., mixtures
of Eudragit.RTM. and polyhydric alcohols); gelatin microemulsions;
lecithin based organogels; poloxamer and lecithin; or mixtures or
combinations thereof. Additional organogelators are described by
Murdan, Expert. Opin. Drug Deliv. 2(3): 489-505 (2005), which is
incorporated by reference herein for its specific teachings
thereof.
[0086] Gelation of organogels occurs at a certain temperature
depending on the polymer. Typically, the solution is heated, which
allows for the dissolution of the gelator polymer into an organic
liquid and subsequent gelation as temperature drops. The gel-point
temperature can be modified by the addition of different solvents
or surfactants.
[0087] A common method for extracting abuse prone drugs is by
boiling the composition. Thus, in some embodiments, the abuse
deterrent matrices described herein reduce the percentage of
released active pharmaceutical ingredient released during boiling
conditions. Without being bound by any theory, it is thought that
the extensive three dimensional network formed by the organogelator
polymers in the abuse deterrent controlled release matrices
described herein slows the release of active pharmaceutical
ingredients under boiling conditions. Thus, in some embodiments
described herein, suitable organogelator molecules for the
controlled release matrices described herein gel in boiling
temperatures from about 95.degree. C. to about 120.degree. C.
[0088] Most organogelators, including the principally used low
molecular weight organogelators, are thermoreversible and lose
their rheological properties upon extensive heat. Other
organogelators react with active pharmaceutical ingredients and
prevent the formation of a strong gel network or are water-soluble.
Thus, it was uniquely found that the ethyl ether derivative of
cellulose, ethyl cellulose, is water insoluble and forms an
excellent organogel at a boiling temperature of about 100.degree.
C. in a soft gelatin capsule comprising an active pharmaceutical
ingredient. Further, it was found that the gel strength and
gel-point temperature could be further customized by the level of
ethoxylation or with the addition of surfactants or different
molecular weight ethyl cellulose. Ethyl cellulose is available in a
variety of molecular weights denoted as a centipoise viscosity
value (cP), and useful ethyl cellulose polymers have a cP value of
about 3 cP to about 350 cP.
[0089] Thus, in another embodiment described herein, the abuse
deterrent matrix comprises one or more organogelators including but
not limited to ethylcellulose (e.g., Ethocel.TM.; Dow Chemical). In
one aspect, ethyl cellulose has viscosity of about 2 to about 100
cP. In another aspect, ethyl cellulose has a viscosity of about 4
cP, about 8 cP, about 12 cP, about 16 cP, about 20 cP, about 24 cP,
about 28 cP, about 32 cP, about 36 cP, about 40 cP, about 48 cP,
about 52 cP, about 56 cP, about 60 cP, about 64 cP, about 68 cP,
about 72 cP, about 76 cP, about 80 cP, about 84 cP, about 88 cP,
about 92 cP, about 96 cP, or about 100 cP. In another aspect, ethyl
cellulose has a cP of about 4. In another aspect, ethyl cellulose
has a viscosity of about 20 cP.
[0090] In another embodiment, the abuse deterrent matrix comprises
a disintegrant excipient. Disintegrants, useful in the abuse
deterrent matrices described herein, include any polymer, which
expands in acqueous solution, which causes a tablet or capsule to
burst and facilitate dissolution. Exemplary, non-limiting
disintegrants comprise crosslinked polyvinylpyrrolidone (e.g.,
crospovidone), crosslinked sodium carboxymethyl cellulose
(croscarmellose sodium) carboxymethyl cellulose calcium, cysteine
HCl, modified starches (e.g., sodium starch glycolate), cellulose,
calcium silicate, silicon dioxide, alginic acid, sodium alginate,
citric acid, microcrystalline cellulose, polyoxy stearate, sodium
croscarmellose, sodium lauryl sulfate, or a mixture or combination
thereof. In one aspect, the disintegrant comprises microcrystalline
cellulose.
[0091] In another embodiment, the abuse deterrent matrix comprises
one or more hydrophilic vehicles. Suitable, non-limiting
hydrophilic vehicles comprise hydro-alcohols including propylene
glycol, or polyethylene glycols of a molecular weight ranging from
about 200 to about 8,000 (MN, number average molecular weight) or a
mixture or combination thereof. In one aspect, the hydrophilic
vehicle comprises polyethylene glycol. In another aspect, the
hydrophilic vehicle comprises polyethylene glycol 400.
[0092] In another embodiment, the abuse deterrent matrix comprises
one or more hydrophilic polymers. Suitable, non-limiting
hydrophilic polymers comprise methylcellulose, hydroxypropylmethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
hydroxyethyl cellulose, hydroxymethyl cellulose,
polymethylmethacrylate, polyhydroxyethylmethacrylate, polyvinyl
pyrrolidone, polyvinylpyrrolidone, copovidone, polyethylene oxide
such as POLYOX.TM. 100,000-8,000,000 MW, polyvinyl alcohol, a
copolymer of polyvinylpyrrolidone and polyvinyl acetate, or
combinations thereof. In one aspect, the hydrophilic polymers
comprises one or more of Methocel.TM. K100 Premium LV CR, K4M
Premium CR, K15M Premium CR, K100 Premium CR, E4M Premium CR, E10M
Premium CR, or E4M Premium (Dow Chemical Co.); POLYOX.TM.,
CELLOSIZE.TM., or WALOCEL.TM. CRT. Without being bound by any
theory, it is thought that water coming into contact with the
hydrophilic polymer, such as methylcellulose or
hydroxypropylmethylcellulose, causes it to expand or swell and
further impede the release of active pharmaceutical ingredients
from the matrix. In one aspect, the hydrophilic polymer comprises
methylcellulose. In one aspect, the hydrophilic polymer comprises
hydroxypropylmethylcellulose. In another aspect, the hydrophilic
polymer comprises a viscosity of about 50 cP to about 100,000 cP.
In another aspect, hydrophilic polymer comprises a viscosity of
about 50 cP, about 100 cP, about 200 cP, about 300 cP, about 400
cP, about 500 cP, about 750 cP, about 1,000 cP, about 1,500 cP,
about 2,000 cP, about 2,500 cP, about 3,000 cP, about 3,500 cP,
about 4,000 cP, about 4,500 cP, about 5,000 cP, about 6,000 cP,
about 7,000 cP, about 8,000 cP, about 9,000 cP, or about 10,000 cP,
about 15,000 cP, about 20,000 cP, about 30,000 cP, about 40,000 cP,
about 50,000 cP, about 60,000 cP, about 70,000 cP, about 80,000 cP,
about 90,000 cP, about 100,000 cP, greater than 100,000 cP, or even
greater. In one aspect, methylcellulose has a viscosity of about
4,000 cP (e.g., Methocel.TM. A4M). In another aspect,
hydroxypropylmethylcellulose has a viscosity of about 100,000 cP
(e.g., Methocel.TM. K100M).
[0093] In another embodiment, the hydrophilic polymer may comprise
a high molecular weight polyethylene oxide. As described herein,
high molecular weight polyethylene oxide polymers have an
approximate molecular weight of at least about 100,000 to about
10,000,000 or greater. In one aspect, the hydrophilic polymer may
comprise a high molecular weight polyethylene oxide having a
molecular weight of about 600,000 to about 10,000,000, including
each integer within the specified range. In another aspect, the
hydrophilic polymer may comprise a high molecular weight
polyethylene oxide having a molecular weight of about 5,000,000 to
about 10,000,000, including each integer within the specified
range. In another aspect, the hydrophilic polymer may comprise a
high molecular weight polyethylene oxide having a molecular weight
of about 4,000,000 to about 7,000,000, including each integer
within the specified range. In another aspect, the hydrophilic
polymer may comprise a high molecular weight polyethylene oxide
having a molecular weight of about 600,000, about 700,000, about
800,000, about 900,000, about 1,000,000, about 2,000,000, about
3,000,000, about 4,000,000, about 5,000,000, about 6,000,000, about
7,000,000, about 8,000,000, about 9,000,000 or about 10,000,000. In
another aspect, the hydrophilic polymer may comprise a high
molecular weight polyethylene oxide having a molecular weight of
about 4,000,000. In another aspect, the hydrophilic polymer may
comprise a high molecular weight polyethylene oxide having a
molecular weight of about 5,000,000. In another aspect, the
hydrophilic polymer may comprise a high molecular weight
polyethylene oxide having a molecular weight of about
7,000,000.
[0094] The molecular weight measurements of hydrophilic polymers
may be approximated using rheological measurements using a
viscometer. For example, a hydrophilic polymer is considered to
have an approximate molecular weight of 600,000 when a 5% (by wt)
aqueous solution of polyethylene oxide using a Brookfield
viscometer Model RVF, spindle No. 2, at 2 rpm, at 25.degree. C.
shows a viscosity range of 30 to 50 mPa s (cP). A hydrophilic
polymer is considered to have an approximate molecular weight of
1,000,000 when a 2% (by wt) aqueous solution of A hydrophilic
polymer using a Brookfield viscometer Model RVF, spindle No. 1, at
10 rpm, at 25.degree. C. shows a viscosity range of 400 to 800 mPa
s (cP). A hydrophilic polymer is considered to have an approximate
molecular weight of 2,000,000 when a 2% (by wt) aqueous solution of
A hydrophilic polymer using a Brookfield viscometer Model RVF,
spindle No. 3, at 10 rpm, at 25.degree. C. shows a viscosity range
of 2000 to 4000 mPa s (cP). A hydrophilic polymer is considered to
have an approximate molecular weight of 4,000,000 when a 1% (by wt)
aqueous solution of A hydrophilic polymer using a Brookfield
viscometer Model RVF, spindle No. 2, at 2 rpm, at 25.degree. C.
shows a viscosity range of 1650 to 5500 mPa s (cP). A hydrophilic
polymer is considered to have an approximate molecular weight of
5,000,000 when a 1% (by wt) aqueous solution of A hydrophilic
polymer using a Brookfield viscometer Model RVF, spindle No. 2, at
2 rpm, at 25.degree. C. shows a viscosity range of 5500 to 7500 mPa
s (cP). A hydrophilic polymer is considered to have an approximate
molecular weight of 7,000,000 when a 1% (by wt) aqueous solution of
A hydrophilic polymer using a Brookfield viscometer Model RVF,
spindle No. 2, at 2 rpm, at 25.degree. C. shows a viscosity range
of 7500 to 10,000 mPa s (cP). A hydrophilic polymer is considered
to have an approximate molecular weight of 8,000,000 when a 1% (by
wt) aqueous solution of A hydrophilic polymer using a Brookfield
viscometer Model RVF, spindle No. 2, at 2 rpm, at 25.degree. C.
shows a viscosity range of 10,000 to 15,000 mPa s (cP).
[0095] In another embodiment, the one or more hydrophilic polymers
comprises from about 1% to about 50% of the matrix fill mass,
including all integers within the specified range. In one aspect,
the one or more hydrophilic polymer s comprises from about 1% to
about 30% of the matrix fill mass, including all integers within
the specified range. In another aspect, the one or more hydrophilic
polymers comprises from about 25% to about 40% of the matrix fill
mass, including all integers within the specified range. In another
aspect, the one or more hydrophilic polymers comprises from about
25% to about 35% of the matrix fill mass, including all integers
within the specified range. In another aspect, the one or more
hydrophilic polymers comprises about 20%, about 25%, about 30%,
about 35%, about 40%, about 45%, or about 50% of the matrix fill
mass.
[0096] In another embodiment, the abuse-deterrent matrix comprises
one or more antioxidants. Suitable antioxidants comprise
tocopherols (e.g., alpha-tocopherol, beta-tocopherol,
gamma-tocopherol, or delta-tocopherol), butylated hydroxytoluene
(BHT), butylated hydroxyanisole (BHA), citric acid, ascorbic acid,
phenolic diterpenes (e.g., carnosic acid, carnosol, rosmanol,
epirosmanol, isorosmanol, or methyl carnosate), rosmarinic acid,
eugenol, eugenyl acetate, clove bud extract, methanolic extract,
tea catechins (e.g., epigallocatechin gallate, epicatechin gallate,
epigallocatechin, or epicatechin), or combinations thereof.
[0097] In another embodiment, the abuse deterrent matrix can
include a hydrophilic internal phase and a lipid or lipophilic
external phase (water in oil) or a lipid or lipophilic internal
phase and a hydrophilic external phase (oil in water). The internal
phase can also be structured. A "structured" phase, as used herein,
means a solid, semisolid, or a gel whose shape is relatively stable
and does not usually aggregate to form a large globule. One or more
structured phases provide controlled drug release and stabilize the
physical state of the matrix. Without being bound to any theory, it
is believed that a structured matrix impedes solvation and/or
diffusion of the active pharmaceutical ingredient out of the matrix
after the capsule shell dissolves.
[0098] In another embodiment, the active pharmaceutical ingredient
can be dispersed in the internal phase as a suspension form. A
suspension as used herein means the API does not dissolve in one of
the phases and remains as a solid. In one embodiment, the active
pharmaceutical ingredient is dispersed or suspended in the internal
phase as a solid form.
[0099] In one embodiment described herein, the abuse deterrent
matrix may comprise one or more liquid lipophilic vehicles, one or
more semisolid lipid vehicles, one or more organogelators, one or
more hydrophilic polymers, one or more hydrophilic vehicles, one or
more anti-oxidants, one or more active pharmaceutical ingredients,
optionally one or more disintegrants, and optionally one or more
pharmaceutically acceptable excipients.
[0100] In one aspect, the combination of matrix fill components
prevents or reduces the likelihood of extraction of an active
pharmaceutical ingredient in aqueous or boiling conditions. Without
being bound by any theory, it is believed that the presence of the
components of the abuse deterrent matrix compositions described
herein function to inhibit drug release from the pharmaceutical
compositions described herein. In one aspect, a semi solid lipid
vehicle (e.g., bee's wax or carnauba wax) forms a highly viscous
structure and inhibits the release of active pharmaceutical
ingredients from the matrix fill in acqueous conditions. In another
aspect, the semi-solid lipid vehicle prevents release in an aqueous
solvent (e.g., pure water or a mixture of ethanol and water) at low
to middle ranges of temperatures (e.g., from about 20.degree. C. to
about 85.degree. C.). In one aspect, the presence of a hydrophilic
polymer (e.g., methylcellulose) is soluble in water demonstrating
controlled release swelling properties but is insoluble in ethanol,
which further helps reduce the release of an active pharmaceutical
ingredient in aqueous solutions of ethanol. In one aspect, the
organogelator prevents the release of active pharmaceutical
ingredients at boiling or near-boiling temperatures by forming a
three dimensional network, which prevents drug release at high
temperatures. In one aspect, the hydrophilic vehicle enhances the
release of active pharmaceutical ingredients in the stomach and
gastro intestinal tract. In one aspect, the one or more optional
disintegrants functions to swell and de-structure the matrix and
increase the release rate of the active pharmaceutical ingredient
in the stomach and gastrointestinal tract. Thus, the matrix
compositions described herein permit abuse deterrence by preventing
liberation of the active ingredient for injection or insufflation
and prevent solvation, dissolution, or extraction of the active
pharmaceutical ingredient by use of aqueous or organic solutions.
Furthermore, the matrix compositions also provide controlled
release delivery of the active pharmaceutical ingredient after
ingestion by a subject.
[0101] In another embodiment described herein, the abuse deterrent
matrix described herein prevents extraction of an active
pharmaceutical ingredient through the additional means of crushing,
grating, grinding, or cutting dosage forms comprising the
pharmaceutical compositions described herein.
[0102] In one aspect, increasing the weight percentage of semisolid
lipid vehicle, organogelator, and hydrophilic polymer in the matrix
fill increases the overall viscosity of the matrix fill solution
and decreases the release rate of an active pharmaceutical
ingredient in acqueous solvents and acqueous solvents in boiling
conditions. Conversely, in another aspect, decreasing the weight
percentage of semisolid lipid vehicle, organogelator, and
hydrophilic polymer decreases the overall viscosity of the matrix
fill solution and decreases the release rate of an active
pharmaceutical ingredient in acqueous solvents and acqueous
solvents in boiling conditions. Thus, the abuse deterrent matrices
described herein are compatible with a broad range of active
pharmaceutical ingredients and demonstrate abuse deterrent
properties.
[0103] In another embodiment, the lipid or lipophilic vehicle
comprises a liquid lipid or lipophilic vehicle, a semisolid lipid
or lipophilic vehicle, or combinations thereof. In one embodiment,
the total lipid or lipophilic vehicle comprises one or more liquid
lipid vehicles and one or more semi-solid lipid vehicles. In one
embodiment, the total lipid or lipophilic vehicle comprises about
25% to about 85% of the total matrix mass, including all integers
within the specified range. In some aspects, the total lipid or
lipophilic vehicle comprises about 25%, about 30%, about 35%, about
40%, about 45%, about 50%, about 55%, about 60%, about 65%, about
70%, about 75%, about 80%, or about 85% of the total matrix
mass.
[0104] In another embodiment, the total weight percentage of lipid
or lipophilic vehicle comprises about 45% to about 55% of the total
matrix mass, including all integers within the specified range. In
another embodiment, the total weight percentage of lipid or
lipophilic vehicle comprises about 50% to about 65% of the total
matrix mass, including all integers within the specified range. In
another embodiment, the total weight percentage of lipid or
lipophilic vehicle comprises about 60% to about 70% of the total
matrix mass, including all integers within the specified range. In
one aspect, the total weight percentage of lipid or lipophilic
vehicle comprises about 46% of the total matrix mass. In another
aspect, the total weight percentage of lipid or lipophilic vehicle
comprises about 50% of the total matrix mass. In one aspect, the
total weight percentage of lipid or lipophilic vehicle comprises
about 60% of the total matrix mass. In one aspect, the total weight
percentage of lipid or lipophilic vehicle comprises about 65% of
the total matrix mass. In another aspect, the total weight
percentage of lipid or lipophilic vehicle comprises about 68% of
the total matrix mass. In another aspect, the total lipid or
lipophilic vehicle comprises about 70% of the total matrix
mass.
[0105] In another embodiment, total weight percentage of the liquid
lipid or lipophilic vehicles comprises about 20% to about 85% of
the total matrix mass, including all integers within the specified
range. In some aspects, total weight percentage of liquid lipid or
lipophilic vehicles comprises about 20%, about 25%, about 30%,
about 35%, about 40%, about 45%, about 50%, about 55%, about 60%,
about 65%, about 70%, about 75%, or about 80% of the total matrix
mass. In one embodiment, the total weight percentage of liquid
lipid or lipophilic vehicle comprises from about 45% to about 55%
of the total matrix mass, including all integers within the
specified range. In one embodiment, the total weight percentage of
liquid lipid or lipophilic vehicle comprises from about 55% to
about 60% of the total matrix mass, including all integers within
the specified range. In one embodiment, the total weight percentage
of liquid lipid or lipophilic vehicle comprises from about 60% to
about 65% of the total matrix mass, including all integers within
the specified range. In one embodiment, the total weight percentage
of liquid lipid or lipophilic vehicle comprises from about 60% to
about 72% of the total matrix mass, including all integers within
the specified range. In one aspect, the total weight percentage of
liquid lipid or lipophilic vehicle comprises about 45% of the total
matrix mass. In another aspect, the total weight percentage of
liquid lipid or lipophilic vehicle comprises about 50% of the total
matrix mass. In another aspect, the total weight percentage of
liquid lipid or lipophilic vehicle comprises about 58% of the total
matrix mass. In another aspect, the total weight percentage of
liquid lipid or lipophilic vehicle comprises about 65% of the total
matrix mass. In another aspect, the total weight percentage of
liquid lipid or lipophilic vehicle comprises about 70% of the total
matrix mass.
[0106] In another embodiment, the total weight percentage of the
one or more semisolid lipid or lipophilic vehicles comprises from
about 0% to about 10% of the total matrix mass, including all
integers within the specified range. In another embodiment, the
total weight percentage of the one or more semisolid lipid or
lipophilic vehicles comprise from about 1.5% to about 5% of the
total matrix mass, including all integers within the specified
range. The total weight percentage of the one or more semisolid
lipid or lipophilic vehicles comprise about 1%, about 2%, about 3%,
about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or
about 10% of the total matrix mass. In one aspect, the total weight
percentage of semisolid lipid or lipophilic vehicle comprises about
1% of the total matrix mass. In one aspect, the total weight
percentage of semisolid lipid or lipophilic vehicle comprises about
2% of the total matrix mass. In one aspect, the total weight
percentage of semisolid lipid or lipophilic vehicle comprises about
3.5% of the total matrix mass. In one aspect, the total weight
percentage of semisolid lipid or lipophilic vehicle comprises about
4.5% of the total matrix mass. In one aspect, the total weight
percentage of semisolid lipid or lipophilic vehicle comprises about
6% of the total matrix mass. In one aspect, the total weight
percentage of semisolid lipid or lipophilic vehicle comprises about
7% of the total matrix mass. In one aspect, no (0%) semisolid lipid
or lipophilic vehicle is present in the composition.
[0107] In another embodiment, the total weight percentage of the
one or more organogelators comprises from about 2% to about 25% of
the total matrix mass, including all integers within the specified
range. In another embodiment, the one or more organogelators
comprise from about 3% to about 10% of the total matrix mass,
including all integers within the specified range. In another
embodiment, the one or more organogelators comprises from about 10%
to about 18% of the total matrix mass, including all integers
within the specified range. In one aspect, the one or more
organogelators comprise about 3.5% of the total matrix mass. In one
aspect, the one or more organogelators comprise about 5% of the
total matrix mass. In another aspect, the one or more
organogelators comprise about 7% of the total matrix mass. In
another aspect, the one or more organogelators comprise about 9% of
the total matrix mass. In another aspect, the one or more
organogelators comprise about 11% of the total matrix mass. In
another aspect, the one or more organogelators comprise about 13%
of the total matrix mass. In another aspect, the one or more
organogelators comprise about 25% of the total matrix mass. In one
aspect, the organogelators is a hydrophobic organogelator
controlled release polymer.
[0108] In another embodiment, the total weight percentage of the
one or more hydrophilic polymers comprises from about 1% to about
30% of the total matrix mass, including all integers within the
specified range. In another embodiment, the one or more hydrophilic
polymers comprises from about 2% to about 20% of the total matrix
mass, including all integers within the specified range. In another
embodiment, the one or more hydrophilic polymers comprises from
about 10% to about 15% of the total matrix mass, including all
integers within the specified range. In one aspect, the one or more
hydrophilic polymers comprise about 2.5% of the total matrix mass.
In another aspect, the one or more hydrophilic polymers comprise
about 5% of the total matrix mass. In another aspect, the one or
more hydrophilic polymers comprise about 7% of the total matrix
mass. In another aspect, the one or more hydrophilic polymers
comprise about 9% of the total matrix mass. In another aspect, the
one or more hydrophilic polymers comprise about 10.5% of the total
matrix mass. In another aspect, the one or more hydrophilic
polymers comprise about 12% of the total matrix mass. In another
aspect, the one or more hydrophilic polymers comprise about 14% of
the total matrix mass. In another aspect, the one or more
hydrophilic polymers comprise about 15% of the total matrix mass.
In another aspect, the one or more hydrophilic polymers comprise
about 20% of the total matrix mass. In another aspect, the one or
more hydrophilic polymers comprise about 25% of the total matrix
mass.
[0109] In another embodiment, the one or more hydrophilic vehicles
comprise from about 2% to about 60% of the total matrix mass,
including all integers within the specified range. In another
embodiment, the one or more hydrophilic vehicles comprise from
about 4% to about 11% of the total matrix mass, including all
integers within the specified range. In another embodiment, the one
or more hydrophilic vehicles comprise from about 12% to about 20%
of the total matrix mass, including all integers within the
specified range. In one aspect, the one or more hydrophilic
vehicles comprise about 4% of the total matrix mass. In another
aspect, the one or more hydrophilic vehicles comprise about 6% of
the total matrix mass. In another aspect, the one or more
hydrophilic vehicles comprise about 10% of the total matrix mass.
In another aspect, the one or more hydrophilic vehicles comprise
about 18% of the total matrix mass. In another aspect, the one or
more hydrophilic vehicles comprise about 20% of the total matrix
mass. In another aspect, the one or more hydrophilic vehicles
comprise about 22% of the total matrix mass. In another aspect, the
one or more hydrophilic vehicles comprise about 24% of the total
matrix mass. In another aspect, the one or more hydrophilic
vehicles comprise about 28% of the total matrix mass. In another
aspect, the one or more hydrophilic vehicles comprise about 36% of
the total matrix mass.
[0110] In another embodiment, the one or more disintegrant
excipients comprises from about 1% to about 5% of the total matrix
mass, including all integers within the specified range. In one
aspect, the one or more disintegrant excipients comprise about 1%
of the total matrix mass. In another aspect, the one or more
disintegrant excipients comprise about 1.5% of the total matrix
mass. In another aspect, the one or more disintegrant excipients
comprise about 2.5% of the total matrix mass.
[0111] In another embodiment, the matrix comprises one or more
surfactants. In another embodiment, the one or more surfactants
comprise from about 10% to about 20% of the total matrix mass,
including all integers within the specified range. In another
embodiment, the one or more surfactants comprise from about 2.5% to
about 10% of the total matrix mass, including all integers within
the specified range. In one aspect, the one or more surfactants
comprise about 5% of the total matrix mass. In another aspect, the
one or more surfactants comprise about 6.5% of the total matrix
mass. In another aspect, the one or more surfactants comprise about
8.5% of the total matrix mass. In one aspect, the one or more
surfactants comprise about 10% of the total matrix mass. In another
aspect, the one or more surfactants comprise about 15% of the total
matrix mass. In another aspect, the one or more surfactants
comprise about 10% of the total matrix mass. In another aspect, the
one or more surfactants comprise about 20% of the total matrix
mass.
[0112] In another embodiment, one or more antioxidants comprises
from about 0.1% to about 0.5% of the matrix mass, including all
integers within the specified range. In one aspect, the one or more
antioxidants comprise about 0.3% of the matrix mass. In another
aspect, the one or more antioxidants comprise about 0.4% of the
matrix mass.
[0113] In another embodiment, the total hydrophobic matrix (e.g.,
lipophilic vehicle and hydrophobic organogelator) comprises from
about 40% to about 85% of the total matrix mass, including all
integers within the specified range. In one aspect, the total
hydrophobic matrix comprises about 40% of the total matrix mass. In
one aspect, the total hydrophobic matrix comprises about 45% of the
total matrix mass. In one aspect, the total hydrophobic matrix
comprises about 50% of the total matrix mass. In one aspect, the
total hydrophobic matrix comprises about 55% of the total matrix
mass. In one aspect, the total hydrophobic matrix comprises about
60% of the total matrix mass. In another aspect, the total
hydrophobic matrix comprises about 65% of the total matrix mass. In
another aspect, the total hydrophobic matrix comprises about 70% of
the total matrix mass. In another aspect, the total hydrophobic
matrix comprises about 75% of the total matrix mass. In another
aspect, the total hydrophobic matrix comprises about 80% of the
total matrix mass.
[0114] In another embodiment, the total hydrophilic matrix (e.g.,
hydrophilic polymer and hydrophilic vehicle) comprises from about
15% to about 50% of the total matrix mass, including all integers
within the specified range. In one aspect, the total hydrophilic
matrix comprises about 15% of the total matrix mass. In another
aspect, the total hydrophilic matrix comprises about 20% of the
total matrix mass. In another aspect, the total hydrophilic matrix
comprises about 25% of the total matrix mass. In another aspect,
the total hydrophilic matrix comprises about 30% of the total
matrix mass. In another aspect, the total hydrophilic matrix
comprises about 35% of the total matrix mass. In another aspect,
the total hydrophilic matrix comprises about 40% of the total
matrix mass. In another aspect, the total hydrophilic matrix
comprises about 45% of the total matrix mass. In another aspect,
the total hydrophilic matrix comprises about 50% of the total
matrix mass.
[0115] In another embodiment, the total polymer weight percentage
(e.g., hydrophilic polymer and organogelator) comprises from about
8% to about 50% of the total matrix mass, including all integers
within the specified range. In one aspect, the total polymer
comprises about 8% of the total matrix mass. In another aspect, the
total polymer comprises about 10% of the total matrix mass. In
another aspect, the total polymer comprises about 12% of the total
matrix mass. In another aspect, the total polymer comprises about
15% of the total matrix mass. In another aspect, the total polymer
comprises about 18% of the total matrix mass. In another aspect,
the total polymer comprises about 20% of the total matrix mass. In
another aspect, the total polymer comprises about 25% of the total
matrix mass. In another aspect, the total polymer comprises about
30% of the total matrix mass. In another aspect, the total polymer
comprises about 35% of the total matrix mass. In another aspect,
the total polymer comprises about 40% of the total matrix mass. In
another aspect, the total polymer comprises about 50% of the total
matrix mass.
[0116] In one embodiment, the total lipid or lipophilic vehicle
comprises about 25% to about 85% of the total matrix mass,
including all integers within the specified range. In some aspects,
the total lipid or lipophilic vehicle comprises about 25%, about
30%, about 35%, about 40%, about 45%, about 50%, about 51%, about
52%, about 53%, about 54%, about 55%, about 60%, about 65%, about
70%, about 75%, about 80%, or about 85% of the total matrix
mass.
[0117] In another embodiment, the total lipid or lipophilic vehicle
comprises about 35% to about 55% of the total matrix mass,
including all integers within the specified range. In another
embodiment, the total lipid or lipophilic vehicle comprises about
50% to about 65% of the total matrix mass, including all integers
within the specified range. In another embodiment, the total lipid
or lipophilic vehicle comprises about 60% to about 70% of the total
matrix mass, including all integers within the specified range. In
one aspect, the total lipid or lipophilic vehicle comprises about
35% of the total matrix mass. In one aspect, the total lipid or
lipophilic vehicle comprises about 46% of the total matrix mass. In
another aspect, the total lipid or lipophilic vehicle comprises
about 50% of the total matrix mass. In one aspect, the total lipid
or lipophilic vehicle comprises about 60% of the total matrix mass.
In one aspect, the total lipid or lipophilic vehicle comprises
about 65% of the total matrix mass. In another aspect, the total
lipid or lipophilic vehicle comprises about 68% of the total matrix
mass. In another aspect, the total lipid or lipophilic vehicle
comprises about 70% of the total matrix mass.
[0118] In another embodiment, the total polymers (e.g.,
organogelator and hydrophilic polymer) comprise about 8% to about
50% of the total matrix mass, including all integers within the
specified range. In another embodiment, the total polymers comprise
about 8% to about 25% of the total matrix mass, including all
integers within the specified range. In another embodiment, the
total polymers comprise about 25% to about 35% of the total matrix
mass, including all integers within the specified range. In another
embodiment, the total polymers comprise about 35% to about 50% of
the total matrix mass, including all integers within the specified
range. In one aspect, the total polymers comprise about 8.5% of the
total matrix mass. In another aspect, the total polymers comprise
about 12% of the total matrix mass. In another aspect, the total
polymers comprise about 14% of the total matrix mass. In another
aspect, the total polymers comprise about 18% of the total matrix
mass. In another aspect, the total controlled release polymer
comprises about 22% of the total matrix mass. In another aspect,
the total polymers comprise about 30% of the total matrix mass. In
another aspect, the total polymers comprise about 50% of the total
matrix mass.
[0119] In another embodiment, the ratio of the liquid lipid vehicle
to semisolid lipid ranges from about 1.5:1 to about 40:1, including
all iterations of ratios within the specified range. In one
embodiment, the ratio of the lipid liquid to semisolid liquid
ranges from about 1.5:1 to about 10:1, including all iterations of
ratios within the specified range. In one embodiment, the ratio of
the lipid liquid to semisolid liquid ranges from about 10:1 to
about 20:1, including all iterations of ratios within the specified
range. In one embodiment, the ratio of the lipid liquid to
semisolid liquid ranges from about 20:1 to about 40:1, including
all iterations of ratios within the specified range. In one aspect,
the ratio of the lipid liquid to semisolid liquid is about 2:1. In
one aspect, the ratio of the lipid liquid to semisolid liquid is
about 5:1. In one aspect, the ratio of the lipid liquid to
semisolid liquid is about 8.5:1. In one aspect, the ratio of the
lipid liquid to semisolid liquid is about 15:1. In one aspect, the
ratio of the lipid liquid to semisolid liquid is about 12:1. In one
aspect, the ratio of the lipid liquid to semisolid liquid is about
18:1. In one aspect, the ratio of the lipid liquid to semisolid
liquid is about 20:1. In one aspect, the ratio of the lipid liquid
to semisolid liquid is about 35:1.
[0120] In another embodiment, the ratio of total hydrophobic matrix
(e.g., liquid lipophilic vehicle and organogelator or liquid
lipophilic vehicle, organogelator, and semi-solid lipophilic
vehicle) to the hydrophilic matrix (e.g., hydrophilic polymer,
hydrophilic vehicle) ranges from about 0.7:1 to about 10:1,
including all iterations of ratios within the specified range. In
one aspect, the ratio of total hydrophobic matrix to hydrophilic
matrix is about 0.7:1. In one aspect, the ratio of total
hydrophobic matrix to hydrophilic matrix is about 1.5:1. In one
aspect, the ratio of total hydrophobic matrix to hydrophilic matrix
is about 1.6:1. In one aspect, the ratio of total hydrophobic
matrix to hydrophilic matrix is about 1.8:1. In one aspect, the
ratio of total hydrophobic matrix to hydrophilic matrix is about
2:1. In one aspect, the ratio of total hydrophobic matrix to
hydrophilic matrix is about 3.5:1. In one aspect, the ratio of
total hydrophobic matrix to hydrophilic matrix is about 4.5:1. In
one aspect, the ratio of total hydrophobic matrix to hydrophilic
matrix is about 6.5:1. In one aspect, the ratio of total
hydrophobic matrix to hydrophilic matrix is about 9:1.
[0121] In another embodiment, the ratio of total lipophilic vehicle
to the total polymer ranges from about 0.5:1 to about 10:1,
including all iterations of ratios within the specified range. In
one aspect, the ratio of total lipophilic vehicle to total polymer
is about 1.5:1. In another aspect, the ratio of total lipophilic
vehicle to total polymer is about 2:1. In another aspect, the ratio
of total lipophilic vehicle to total polymer is about 3:1. In
another aspect, the ratio of total lipophilic vehicle to total
polymer is about 4:1. In another aspect, the ratio of total
lipophilic vehicle to total polymer is about 5:1. In another
aspect, the ratio of total lipophilic vehicle to total polymer is
about 6.5:1. In another aspect, the ratio of total lipophilic
vehicle to total polymer is about 7.5:1.
[0122] In another embodiment, the ratio of organogelator to
hydrophilic polymer ranges from about 0.05:1 to about 5:1,
including all iterations of ratios within the specified range. In
one aspect, the ratio of organogelator to hydrophilic polymer is
about 0.07:1. In another embodiment, the ratio of organogelator to
hydrophilic polymer ranges from about 0.2:1 to about 1:1, including
all iterations of ratios within the specified range. In one aspect,
the ratio of organogelator to hydrophilic polymer is about 0.5:1.
In another aspect, the ratio of organogelator to hydrophilic
polymer is about 0.7:1. In another aspect, the ratio of
organogelator to hydrophilic polymer is about 1:1. In another
aspect, the ratio of organogelator to hydrophilic polymer is about
1.3:1. In another aspect, the ratio of organogelator to hydrophilic
polymer is about 1.5:1. In another aspect, the ratio of
organogelator to hydrophilic polymer is about 2.0:1. In another
aspect, the ratio of organogelator to hydrophilic polymer is about
5:1. In another aspect, the ratio of organogelator to hydrophilic
polymer is about 0.2:1.
[0123] In one embodiment, the matrix comprises one or more liquid
lipid vehicles, one or more semi-solid lipid vehicles, one or more
organogelators, one or more hydrophilic polymers, one or more
hydrophilic vehicles, one or more disintegrants, one or
antioxidants and more active pharmaceutical ingredients. In one
embodiment, the matrix comprises any one of the compositions of
Tables 7-27.
[0124] In another embodiment, the one or more active pharmaceutical
ingredient comprises from about 1% to about 50% of the total matrix
mass, including all integers within the specified range. In another
embodiment, the one or more active pharmaceutical ingredient
comprises from about 1% to about 25% of the total matrix mass,
including all integers within the specified range. In one aspect,
the active pharmaceutical ingredient comprises about 5% of the
total matrix mass. In one aspect, the active pharmaceutical
ingredient comprises about 7% of the total matrix mass. In one
aspect, the active pharmaceutical ingredient comprises about 10.5%
of the total matrix mass. In one aspect, the active pharmaceutical
ingredient comprises about 20% of the total matrix mass. In one
aspect, the active pharmaceutical ingredient comprises about 25% of
the total matrix mass.
[0125] In another embodiment, the ratio of active pharmaceutical
ingredient to total hydrophobic matrix ranges from about 1:100 to
about 1:2, including all iterations of ratios within the specified
range. In another embodiment, the ratio of active pharmaceutical
ingredient to total hydrophobic matrix ranges from about 1:15 to
about 1:2, including all iterations of ratios within the specified
range. In one aspect, the ratio of active pharmaceutical ingredient
to total hydrophobic matrix is about 1:100. In another aspect, the
ratio of active pharmaceutical ingredient to total hydrophobic
matrix is about 1:10. In another aspect, the ratio of active
pharmaceutical ingredient to total hydrophobic matrix is about
1:7.5. In another aspect, the ratio of active pharmaceutical
ingredient to total hydrophobic matrix is about 1:5.5. In another
aspect, the ratio of active pharmaceutical ingredient to total
hydrophobic matrix is about 1:5. In another aspect, the ratio of
active pharmaceutical ingredient to total hydrophobic matrix is
about 1:3. In another aspect, the ratio of active pharmaceutical
ingredient to total hydrophobic matrix is about 1:2.
[0126] In another embodiment, the ratio of active pharmaceutical
ingredient to total hydrophilic matrix ranges from about 1:50 to
about 1:5:1, including all iterations of ratios within the
specified range. In another embodiment, the ratio of active
pharmaceutical ingredient to total hydrophilic matrix ranges from
about 1:10 to about 1.5:1, including all iterations of ratios
within the specified range. In one aspect, the ratio of active
pharmaceutical ingredient to total hydrophilic matrix is about
1:20. In another aspect, the ratio of active pharmaceutical
ingredient to total hydrophilic matrix is about 1:10. In another
aspect, the ratio of active pharmaceutical ingredient to total
hydrophilic matrix is about 1:7.5. In another aspect, the ratio of
active pharmaceutical ingredient to total hydrophilic matrix is
about 1:6.5. In another aspect, the ratio of active pharmaceutical
ingredient to total hydrophilic matrix is about 1:5.5. In another
aspect, the ratio of active pharmaceutical ingredient to total
hydrophilic matrix is about 1:4.5. In another aspect, the ratio of
active pharmaceutical ingredient to total hydrophilic matrix is
about 1:4. In another aspect, the ratio of active pharmaceutical
ingredient to total hydrophilic matrix is about 1:3.5. In another
aspect, the ratio of active pharmaceutical ingredient to total
hydrophilic matrix is about 1:2. In another aspect, the ratio of
active pharmaceutical ingredient to total hydrophilic matrix is
about 1:1.5. In another aspect, the ratio of active pharmaceutical
ingredient to total hydrophilic matrix is about 1.5:1.
[0127] In another embodiment, the ratio of active pharmaceutical
ingredient to the total matrix ranges from about 1:100 to about
1:2, including all iterations of ratios within the specified
range.
[0128] In another embodiment, the ratio of active pharmaceutical
ingredient to the total matrix ranges from about 1:15 to about 1:2,
including all iterations of ratios within the specified range. In
one aspect, the ratio of active pharmaceutical ingredient to the
total matrix is about 1:100. In another aspect, the ratio of active
pharmaceutical ingredient to the total matrix is about 1:10. In
another aspect, the ratio of active pharmaceutical ingredient to
the total matrix is about 1:7.5. In another aspect, the ratio of
active pharmaceutical ingredient to the total matrix is about 1:5.
In another aspect, the ratio of active pharmaceutical ingredient to
the total matrix is about 1:3. In another aspect, the ratio of
active pharmaceutical ingredient to the total matrix is about
1:2.
[0129] Another embodiment described herein is a method of
manufacturing an abuse deterrent pharmaceutical composition
described herein comprising one or more liquid lipophilic vehicles,
one or more organogelators, one or more hydrophilic polymers, one
or more hydrophilic vehicles, one or more anti-oxidants, one or
more active pharmaceutical ingredients, optionally one or more
semisolid lipid vehicles, optionally one or more disintegrants, and
optionally one or more pharmaceutically acceptable excipients. The
method comprises the steps of (a) heating a specified amount of one
or more liquid lipophilic vehicles to about 60.degree. C. and
adding one or more organogelators (e.g., ethyl cellulose) until
completely dissolved to form a first clear gel mixture; (b)
hydrating one or more hydrophilic polymers (e.g., hydroxypropyl
methyl cellulose) with one or more hydrophilic vehicles (e.g.,
polyethylene glycol); (c) mixing one or more active pharmaceutical
ingredients with the mixture of step (b) to form a second uniform
mixture; and (d) adding the second uniform mixture of step (c) to
the first clear gel mixture of step (a) to form a final uniform
matrix composition. The matrix compositions generated by the method
described above may then be encapsulated in a soft capsule shell
using standard rotary die encapsulation methods known in the art.
Other suitable non-limiting capsule shells for the abuse deterrent
matrices described herein comprise an enteric soft capsule shell, a
hard capsule shell, and an enteric hard capsule shell.
[0130] In some embodiments, further annealing processing steps may
be needed for matrix compositions comprising one or more semi-solid
vehicles (e.g., a wax). As described herein, annealing may be
carried out by heating a pharmaceutical composition comprising a
soft capsule shell encapsulating a matrix fill described herein
following encapsulation to form an annealed dosage form. In some
aspects, the pharmaceutical compositions may be annealed at a
temperature from about 50.degree. C. to about 90.degree. C. for
about 0.25 hours to about 5 hours, including all integers within
the specified ranges of temperature and time. In one aspect,
pharmaceutical compositions comprising a soft capsule shell
encapsulating a matrix fill as described herein may be annealed at
a temperature of about 70.degree. C. for about 1 hour.
[0131] In one embodiment, the matrix contains an active
pharmaceutical ingredient in a suspended, form, soluble form,
insoluble form, or combinations thereof. In another embodiment, the
matrix contains an active pharmaceutical ingredient useful for the
treatment of pain. In one embodiment, the active pharmaceutical
ingredient includes tapentadol, oxycodone, morphine, morphine
analogues, or morphine antagonists, codeine, morphine, methadone,
fentanyl and analogs, opioid pain relievers: oxycodone
hydrochloride, hydrocodone bitartrate hydromorphone, oxymorphone,
meperidine, propoxyphene, flunitrazepam, barbiturates, amytal,
nembutal, seconal, phenobarbital; benzodiazepines, zolpidem,
zaleplon, eszopiclone, amphetamines, or methylphenidate.
[0132] In one embodiment, the matrix comprises one or more active
pharmaceutical ingredients (API). In one aspect, the active
pharmaceutical ingredient is useful in treating pain. In one
aspect, the active pharmaceutical ingredient is tapentadol,
oxycodone, hydrocodone, or codeine. In one aspect, the active
pharmaceutical ingredient is oxycodone or hydrocodone.
[0133] Examples of specific active drug substances suitable for use
in the pharmaceutical compositions provided herein include:
anti-inflammatory and antirheumatic active drug substances, such
as, for example: butylpyrazolidine, phenylbutazone, mofebutazone,
oxyphenbutazone, clofezone, kebuzone, acetic acid derivatives and
related substances, indometacin, sulindac, tolmetin, zomepirac,
diclofenac, alclofenac, bumadizone, etodolac, lonazolac, fentiazac,
acemetacin, difenpiramide, oxametacin, proglumetacin, ketorolac,
aceclofenac, bufexamac, oxicam, piroxicam, tenoxicam, droxicam,
lornoxicam, meloxicam, methotrexate, propionic acid derivatives,
ibuprofen, naproxen, ketoprofen, fenoprofen, fenbufen,
benoxaprofen, suprofen, pirprofen, flurbiprofen, indoprofen,
tiaprofenic acid, oxaprozin, ibuproxam, dexibuprofen,
flunoxaprofen, alminoprofen, dexketoprofen, fenamates, mefenamic
acid, tolfenamic acid, flufenamic acid, meclofenamic acid, coxibs,
celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib,
lumiracoxib, nabumetone, niflumic acid, azapropazone, glucosamine,
benzydamine, glucosaminoglycan polysulfate, proquazone, orgotein,
nimesulide, feprazone, diacerein, morniflumate, tenidap, oxaceprol,
chondroitin sulfate, feprazone, dipyrocetyl, acetylsalicylic acid,
quinolines, oxycinchophen, gold preparations, sodium
aurothiomalate, sodium aurotiosulfate, auranofin, aurothioglucose,
aurotioprol, penicillamine or bucillamine.
[0134] In another embodiment, suitable active pharmaceutical
ingredients can comprise analgesics, such as, for example: opioids,
natural opium alkaloids, morphine, opium, hydromorphone,
nicomorphine, oxycodone, dihydrocodone, diamorphine, tapentadol,
papaveretum, papaveretum, codeine, phenylpiperidine derivatives,
ketobemidone, pethidine, fentanyl, diphenylpropylamine derivatives,
dextromoramide, piritramide, dextropropoxyphene, bezitramide,
methadone, benzomorphan derivatives, pentazocine, phenazocine,
oripavine derivatives, buprenorphine, morphinan derivatives,
butorphanol, nalbuphine, tilidine, tramadol, dezocine, salicylic
acid and derivatives, acetylsalicylic acid, aloxiprin, choline
salicylate, sodium salicylate, salicylamide, salsalate,
ethenzamide, morpholine salicylate, dipyrocetyl, benorilate,
diflunisal, potassium salicylate, guacetisal, carbasalate calcium,
imidazole salicylate, pyrazolones, phenazone, metamizole sodium,
aminophenazone, propyphenazone, nifenazone, anilides, paracetamol,
phenacetin, bucetin, propacetamol, other analgesics and
antipyretics, such as, for example: rimazolium, glafenine,
floctafenine, viminol, nefopam, flupirtine, or ziconotide.
[0135] In another embodiment, suitable active pharmaceutical
ingredients can comprise anaesthetics, such as, for example:
ethers, diethyl ether, vinyl ether, halogenated hydrocarbons,
halothane, chloroform, methoxyflurane, enflurane,
trichloroethylene, isoflurane, desflurane, sevoflurane,
barbiturates, methohexital, hexobarbital, thiopental,
narcobarbital, opioid anaesthetics, fentanyl, alfentanil,
sufentanil, phenoperidine, anileridine, remifentanil, other general
anaesthetics, such as, for example: droperidol, ketamine,
propanidid, alfaxalone, etomidate, propofol, hydroxybutyric acid,
nitrous oxide, esketamine, xenon, esters of aminobenzoic acid,
metabutethamine, procaine, tetracaine, chloroprocaine, benzocaine,
amides, bupivacaine, lidocaine, mepivacaine, prilocaine,
butanilicaine, cinchocaine, etidocaine, articaine, ropivacaine,
levobupivacaine, esters of benzoic acid, cocaine, other local
anaesthetics, such as, for example: ethyl chloride, dyclonine,
phenol, or capsaicin.
[0136] In another embodiment, suitable active pharmaceutical
ingredients can comprise antimigraine active drug substances, such
as, for example: ergot alkaloids, dihydroergotamine, ergotamine,
methysergide, lisuride, corticosteroid derivatives, flumedroxone,
selective serotonin (5HT.sup.1) agonists, sumatriptan, naratriptan,
zolmitriptan, rizatriptan, almotriptan, eletriptan, frovatriptan,
other antimigraine preparations, pizotifen, clonidine,
iprazochrome, dimetotiazine, or oxetorone.
[0137] In another embodiment, suitable active pharmaceutical
ingredients can comprise antiepileptic active drug substances, such
as, for example: barbiturates and derivatives, methylphenobarbital,
phenobarbital, primidone, barbexaclone, metharbital, hydantoin
derivatives, ethotoin, phenytoin, amino(diphenylhydantoin) valeric
acid, mephenytoin, fosphenytoin, oxazolidine derivatives,
paramethadione, trimethadione, ethadione, succinimide derivatives,
ethosuximide, phensuximide, mesuximide, benzodiazepine derivatives,
clonazepam, carboxamide derivatives, carbamazepine, oxcarbazepine,
rufinamide, fatty acid derivatives, valproic acid, valpromide,
aminobutyric acid, vigabatrin, progabide, tiagabine, other
antiepileptics, such as, for example: sultiame, phenacemide,
lamotrigine, felbamate, topiramate, gabapentin, pheneturide,
levetiracetam, zonisamide, pregabalin, stiripentol, lacosamide, or
beclamide.
[0138] In another embodiment, suitable active pharmaceutical
ingredients can comprise anticholinergic active drug substances,
such as, for example: tertiary amines, trihexyphenidyl, biperiden,
metixene, procyclidine, profenamine, dexetimide, phenglutarimide,
mazaticol, bornaprine, tropatepine, ethers chemically close to
antihistamines, etanautine, orphenadrine (chloride), ethers of
tropine or tropine derivatives, benzatropine, or
etybenzatropine.
[0139] In another embodiment, suitable active pharmaceutical
ingredients can comprise dopaminergic active drug substances, such
as, for example: dopa and dopa derivatives, levodopa, melevodopa,
etilevodopa, adamantane derivatives, amantadine, dopamine agonists,
bromocriptine, pergolide, dihydroergocryptine mesylate, ropinirole,
pramipexole, cabergoline, apomorphine, piribedil, rotigotine,
monoamine, oxidase B inhibitors, selegiline, rasagiline, other
dopaminergic agents, such as, for example: tolcapone, entacapone,
or budipine.
[0140] In another embodiment, suitable active pharmaceutical
ingredients can comprise antipsychotic active drug substances, such
as, for example: phenothiazines with aliphatic side-chain,
chlorpromazine, levomepromazine, promazine, acepromazine,
triflupromazine, cyamemazine, chlorproethazine, phenothiazines with
piperazine structure, dixyrazine, fluphenazine, perphenazine,
prochlorperazine, thiopropazate, trifluoperazine, acetophenazine,
thioproperazine, butaperazine, perazine, phenothiazines with
piperidine structure, periciazine, thioridazine, mesoridazine,
pipotiazine, butyrophenone derivatives, haloperidol, trifluperidol,
melperone, moperone, pipamperone, bromperidol, benperidol,
droperidol, fluanisone, indole derivatives, oxypertine, molindone,
sertindole, ziprasidone, thioxanthene derivatives, flupentixol,
clopenthixol, chlorprothixene, tiotixene, zuclopenthixol,
diphenylbutylpiperidine derivatives, fluspirilene, pimozide,
penfluridol, diazepines, oxazepines, thiazepines, loxapine,
clozapine, olanzapine, quetiapine, neuroleptics, tetrabenazine,
benzamides, sulpiride, sultopride, tiapride, remoxipride,
amisulpride, veralipride, levosulpiride, lithium, other
antipsychotics, such as, for example prothipendyl, risperidone,
clotiapine, mosapramine, zotepine, aripiprazole, or
paliperidone.
[0141] In another embodiment, suitable active pharmaceutical
ingredients can comprise anxiolytic active drug substances, such
as, for example: benzodiazepine derivatives, diazepam,
chlordiazepoxide, medazepam, oxazepam, potassium clorazepate,
lorazepam, adinazolam, bromazepam, clobazam, ketazolam, prazepam,
alprazolam, halazepam, pinazepam, camazepam, nordazepam,
fludiazepam, ethyl loflazepate, etizolam, clotiazepam, cloxazolam,
tofisopam, diphenylmethane derivatives, hydroxyzine, captodiame,
carbamates, meprobamate, emylcamate, mebutamate,
dibenzo-bicyclo-octadiene derivatives, benzoctamine,
azaspirodecanedione derivatives, buspirone, other anxiolytics, such
as, for example: mephenoxalone, gedocarnil, or etifoxine.
[0142] In another embodiment, suitable active pharmaceutical
ingredients can comprise hypnotic and sedative active drug
substances, such as, for example: barbiturates, pentobarbital,
amobarbital, butobarbital, barbital, aprobarbital, secobarbital,
talbutal, vinylbital, vinbarbital, cyclobarbital, heptabarbital,
reposal, methohexital, hexobarbital, thiopental, ethallobarbital,
allobarbital, proxibarbal, aldehydes and derivatives, chloral
hydrate, chloralodol, acetylglycinamide chloral hydrate,
dichloralphenazone, paraldehyde, benzodiazepine emepronium
derivatives, flurazepam, nitrazepam, flunitrazepam, estazolam,
triazolam, lormetazepam, temazepam, midazolam, brotizolam,
quazepam, loprazolam, doxefazepam, cinolazepam, piperidinedione
derivatives, glutethimide, methyprylon, pyrithyldione,
benzodiazepine related drugs, zopiclone, zolpidem, zaleplon,
ramelteon, other hypnotics and sedatives, such as, for example:
methaqualone, clomethiazole, bromisoval, carbromal, scopolamine,
propiomazine, triclofos, ethchlorvynol, valerian, hexapropymate,
bromides, apronal, valnoctamide, methylpentynol, niaprazine,
melatonin, dexmedetomidine, or dipiperonylaminoethanol.
[0143] In another embodiment, suitable active pharmaceutical
ingredients can comprise antidepressant active drug substances,
such as, for example: non-selective monoamine reuptake inhibitors,
desipramine, imipramine, imipramine oxide, clomipramine, opipramol,
trimipramine, lofepramine, dibenzepin, amitriptyline,
nortriptyline, protriptyline, doxepin, iprindole, melitracen,
butriptyline, dosulepin, amoxapine, dimetacrine, amineptine,
maprotiline, quinupramine, selective serotonin reuptake inhibitors,
zimeldine, fluoxetine, citalopram, paroxetine, sertraline,
alaproclate, fluvoxamine, etoperidone, escitalopram, monoamine
oxidase inhibitors, isocarboxazid, nialamide, phenelzine,
tranylcypromine, iproniazide, iproclozide, monoamine oxidase A
inhibitors, moclobemide, toloxatone, other antidepressants, such
as, for example: oxitriptan, tryptophan, mianserin, nomifensine,
trazodone, nefazodone, minaprine, bifemelane, viloxazine,
oxaflozane, mirtazapine, medifoxamine, tianeptine, pivagabine,
venlafaxine, milnacipran, reboxetine, gepirone, duloxetine,
agomelatine, desvenlafaxine, centrally acting sympathomimetics,
such as, for example: amfetamine, dexamfetamine, lisdexamfetamine,
metamfetamine, methylphenidate, dexmethylphenidate, pemoline,
fencamfamin, modafinil, fenozolone, atomoxetine, fenetylline,
xanthine derivatives, caffeine, propentofylline, other
psychostimulants and nootropics, such as, for example
meclofenoxate, pyritinol, piracetam, deanol, fipexide, citicoline,
oxiracetam, pirisudanol, linopirdine, nizofenone, aniracetam,
acetylcarnitine, idebenone, prolintane, pipradrol, pramiracetam,
adrafinil, or vinpocetine.
[0144] In another embodiment, suitable active pharmaceutical
ingredients can comprise anti-dementia active drug substances, such
as, for example: anticholinesterases, tacrine, donepezil,
rivastigmine, galantamine, other anti-dementia drugs, memantine, or
ginkgo biloba.
[0145] In another embodiment, suitable active pharmaceutical
ingredients can comprise other nervous system active drug
substances, such as, for example: parasympathomimetics,
anticholinesterases, neostigmine, pyridostigmine, distigmine,
ambenonium, choline esters, carbachol, bethanechol, and other
parasympathomimetics, such as, for example, pilocarpine, or choline
alfoscerate.
[0146] Active drug substances used in addictive disorders, such as,
for example: nicotine, bupropion, varenicline, disulfiram, calcium
carbimide, acamprosate, naltrexone, buprenorphine, methadone,
levacetylmethadol, lofexidine, betahistine, cinnarizine,
flunarizine, acetylleucine, gangliosides and ganglioside
derivatives, tirilazad, riluzole, xaliproden, hydroxybutyric acid,
or amifampridine.
[0147] In another embodiment, suitable active pharmaceutical
ingredients can comprise opium alkaloids and derivatives, such as,
for example: ethylmorphine, hydrocodone, codeine, opium alkaloids
with morphine, normethadone, noscapine, pholcodine,
dextromethorphan, thebacon, dimemorfan, acetyldihydrocodone,
benzonatate, benproperine, clobutinol, isoaminile, pentoxyverine,
oxolamine, oxeladin, clofedanol, pipazetate, bibenzonium bromide,
butamirate, fedrilate, zipeprol, dibunate, droxypropine,
prenoxdiazine, dropropizine, cloperastine, meprotixol, piperidione,
tipepidine, morclofone, nepinalone, levodropropizine, or
dimethoxanate.
[0148] In another embodiment, the active pharmaceutical ingredient
may be a substance with abuse potential that presents a safety
risk. Such active drug substance may include:
1-(1-phenylcyclohexyl)pyrrolidine,
1-(2-phenylethyl)-4-phenyl-4-acetoxypiperidine,
1-[1-(2-thienyl)-cyclohexylpiperidine,
1-[1-(2-thienyl)cyclohexyl]pyrrolidine,
1-methyl-4-phenyl-4-propionoxy-piperidine, 1-phenylcyclohexylamine,
1-piperidinocyclohexanecarbonitrile,
2,5-dimethoxy-4-ethylamphetamine, 2,5-dimethoxyamphetamine,
2C-B-(4-bromo-2,5-dimethoxypenethylamine), 2C-D
(2,5-dimethoxy-4-methylphenethylamine), 2C-1
(4-iodo-2,5-dimethoxy-phenethylamine), 2C-T-2
(2,5-dimethoxy-4-ethylthiophenethylamine), 2C-T-4
(2,5-dimethoxy-4-isopropyl thiophenethylamine), 2C-T-7
(2,5-dimethoxy-4-(n)-propylthiophenethylamine),
3,4-methylene-dioxymethamphetamine, 3,4,5-trimethoxyamphetamine,
3,4-methylenedioxyamphetamine,
3,4-methylenedioxy-N-ethylamphetamine, 3-methylfentanyl,
3-methylthiofentanyl, 4-brorno-2,5-dimethoxyamphetamine,
4-bromo-2,5-dimethoxyphenethylamine, 4-methoxyamphetamine,
4-methyl-2,5-dimethoxyamphetamine, 4-methylaminorex (cis isomer),
5-MeO-DIPT (5-methoxy-N,N-diisopropyltryptamine), 5-MeO-DMT
(5-methoxy-N,N-dimethyltryptamine),
5-methoxy-3,4-methylenedioxyamphetamine, acetorphine, acetorphine,
acetyl-alpha-methylfentanyl, acetyl-alpha-methylfentanyl,
acetyldihydrocodone, acetylmethadol, acetylmethadol, alfentanil,
allobarbital, allylprodine, alphacetylmethadol except
levo-alphacetylmethadol, alpha-ethyltryptamine, alphameprodine,
alphamethadol, alphamethadol, alpha-methylfentanyl,
alpha-methylthiofentanyl, alphaprodine, alprazolam, amfepramon,
amfetaminil, amineptin, aminorex, amobarbital, amphetamine,
dextroamphetamine, amilnitrite (all isomers of the amyl group),
anabolic steroids, anileridine, aprobarbital, barbital, barbituric
acid derivative, BDB (3,4-methylenedioxyphenyl)-2-butanamine),
benzethidin, benzethidine, benzoylecgonine, benzphetamine,
benzphetamine, benzylmethylcetone, benzylmorphine,
betacetylmethadol, beta-hydroxy-3-methylfentanyl,
beta-hydroxyfentanyl, betameprodine, betameprodine, betamethadol,
betaprodine, bezitramide, bezitramide, boldenone, brolamfetamine,
bromazepam, brotizolam, bufotenine, buprenorphine, butabarbital,
butalbital, butobarbital, butorphanol, BZP (A2)(1-benzylpiperazin),
camazepam, cannabis, carfentanil, catha edulis, cathine, cathinone,
chloral betaine, chloral hydrate, chlordiazepoxide, chlorhexadol,
chlorotestosterone (same as clostebol), chlorphentermine, clobazam,
clonazepam, clonitazene, clonitazene, clorazepate, clortermine,
clostebol, clotiazepam, cloxazolam, coca leaves, cocaine, codeine,
codeine and isoquinoline alkaloid, codeine methylbromide,
codeine-N-oxide, codoxime, cyclobarbital (hexemal NFN),
cyprenorphine, dehydrochlormethyltestosterone, delorazepam,
desomorphine, dexamfetamine, dexfenfluramine, dexmethylphenidate,
dextromoramide, dextropropoxyphene, diacetylmorphine, diampromide,
diazepam, dichloralphenazone, diethylpropion, diethylthiambutene,
diethyltryptamine, difenoxin, dihydrocodone, dihydroetorphine,
dihydromorphine, dihydrotestosterone, dimenoxadol, dimepheptanol,
dimethylthiambutene, dimethyltryptamine, dioxaphetyl butyrate,
diphenoxylate, dipipanone, diprenorphine, dronabinol, drostanolone,
drotebanol, ecgonine, estazolam, ethchlorvynol, ethinamate, ethyl
loflazepate, ethylestrenol, ethylmethylthiambutene, ethylmorphine,
ethylmorphine, eticyclidine, etilamfetamine, etonitazene,
etorphine, etoxeridine, etryptamine, fencamfamin, fenethylline,
fenetylline, fenfluramine, fenproporex, fentanyl, fludiazepam,
flunitrazepam, fluoxymesterone, flurazepam, formebolone, fungi and
spores of the species psilocybe semilanceata, furethidine, gamma
hydroxybutyric acid, glutethimide, halazepam, haloxazolam, heroine,
hydrocodone, hydrocodone & isoquinoline alkaloid,
hydromorphinol, hydromorphone, hydroxypethidine, ibogaine, isobutyl
nitrite, isomethadone, ketamine, ketazolam, ketobemidone,
levamfetamine, levo-alphacetylmethadol, levo-methamphetamine,
levomethorphan, levomoramide, levophenacylmorphan, levorphanol,
lisdexamfetamine, loprazolam, lorazepam, lormetazepam, lysergic
acid, lysergic acid amide, lysergic acid diethylamide, marijuana,
mazindol, MBDN
(N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine), mCPP
(1-(3-chlorphenyl)piperazine), mebutamate, mecloqualone, medazepam,
mefenorex, MeOPP (1-(4-methoxyphenyl)piperazine), meperidine,
meperidine intermediate, meprobamate, mescaline, mesocarb,
mesterolone, metamfetamine, metazocine, methadone, methadone
intermediate, methamphetamine, methandienone, methandrolone,
methandriol, methandrostenolone, methaqualone, methcathinone,
methenolone, methohexital, methyldesorphine, methyldihydromorphine,
methylphenidate, methylphenobarbital (mephobarbital),
methyltestosterone, methyprylone, metopone, mibolerone, midazolam,
modafinil, moramide-intermediate, morpheridine, morphine, morphine
methylbromide, morphine methylsulfonate, morphine-N-oxide,
myrophine, N,N-dimethylamphetamine, nabilone, nalorphine,
nandrolone, N-ethyl-1-phenylcyclohexylamine, N-ethyl-3-piperidyl
benzilate, N-ethylamphetamine,
N-hydroxy-3,4-methylenedioxyamphetamine, nicocodeine, nicocodine,
nicodicodine, nicomorphine, nimetazepam, nitrazepam,
N-methyl-3-piperidyl benzilate, noracymethadol, norcodeine,
nordiazepam, norethandrolone, norlevorphanol, normethadone,
normorphine, norpipanone, norpipanone, opium, oxandrolone,
oxazepam, oxazolam, oxycodone, oxymesterone, oxymetholone,
oxymorphone, para-fluorofentanyl, parahexyl, paraldehyde, pemoline,
pentazocine, pentobarbital, petrichloral, peyote, phenadoxone,
phenampromide, phenazocine, phencyclidine, phendimetrazine,
phenmetrazine, phenobarbital, phenomorphan, phenoperidine,
phentermine, phenylacetone, pholcodine, piminodine, pinazepam,
pipradrole, piritramide, PMMA (paramethyxymethyl amphetamine),
prazepam, proheptazine, properidine, propiram, psilocybine,
psilocine, pyrovalerone, quazepam, racemethorphane, racemoramide,
racemorphane, remifentanil, salvia divinorum, salvinorin A,
secobarbital, secobarbital, sibutramine, SPA, stanolone,
stanozolol, sufentanil, sulfondiethylmethane, sulfonethylmethane,
sulfonmethane, talbutal, temazepam, tenamfetamine, testolactone,
testosterone, tetrahydrocannabinols, tetrazepam, TFMPP
(1-(3-triflourmethylphenyl)piperazine), thebacon, thebaine,
thiamylal, thiofentanyl, thiopental, tiletamine and zolazepam in
combination, tilidine, trenbolone, triazolam, trimeperidine,
vinbarbital, zaleplon, zipeprol, zolpidem, or zopiclone.
[0149] Other suitable examples of active drug substances suitable
for use in the pharmaceutical compositions described herein
include, for example, alfentanil, allylprodine, alphaprodine,
anileridine, benzylmorphine, bezitramide, buprenorphine,
butorphanol, clonitazene, codeine, cyclazocine, desomorphine,
dextromoramide, dezocine, diampromide, dihydrocodone,
dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl,
heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,
dextropropoxyphene, ketobemidone, levallorphan, levorphanol,
levophenacylmorphan, lofentanil, meperidine, meptazinol,
metazocine, methadone, metopon, morphine, morphine 6-glucuronide,
morphine 3-glucuronide, myrophine, nalbuphine, narcine,
nicomorphine, norlevorphanol, normethadone, nalorphine,
normorphine, norpipanone, opium, oxycodone, oxycodeine,
oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,
phenazocine, phenoperidine, piminodine, piritramide, propheptazine,
promedol, properidine, propiram, propoxyphene, sufentanil,
tilidine, tramadol, thebaine, levo-alphacetylmethadol (LAAM),
remifentanil, carfentanyl, ohmefentanyl, MPPP, prodine, PEPAP,
levomethorphan, etorphine, lefetamine, loperamide, diphenoxylate,
or pethidine.
[0150] Other examples of active drug substances suitable for use in
the pharmaceutical compositions described herein include anabolic
steroids, cannabis, cocaine, or diazepam.
[0151] In another embodiment, the active drug substance comprises
the therapeutic classes including non-steroidal anti-inflammatory
substances or antirheumatic active drug substances.
[0152] In other embodiments, the active drug substance comprises
analgesics, opioids, antipyretics, anaesthetics, antimigraine
agents, antiepileptics, anti-parkinson agents, dopaminergic agents,
antipsychotics, anxiolytics, sedatives, antidepressants,
psychostimulants agents, dopamine, noradrenaline, nicotinic,
alfa-adrenergic, serotonin, H3 antagonists used for ADHD or
nootropics agents used in addictive disorders.
[0153] In other embodiments, the active drug substance comprises
therapeutic classes including anaesthetics, centrally acting
analgesics, sedative-hypnotics, anxiolytics, appetite suppressants,
decongestants, antitussives, antihistamines, antiemetics,
antidiarrheals, and drugs used to treat narcolepsy, or attention
deficit hyperactivity disorder.
[0154] In another embodiment, the active drug substance is
associated with abuse syndromes and the active drug substance may,
for example, be selected from opioids, CNS depressants, CNS
stimulants, cannabinoids, nicotine-like compounds, glutamate
antagonists, or N-methyl-D-aspartate (NMDA) antagonists.
[0155] In another embodiment, the active drug substance is an
analgesic. Examples of analgesics suitable for use in the
pharmaceutical compositions described herein include, for example,
opioids, natural opium alkaloids, morphine, opium, hydromorphone,
nicomorphine, oxycodone, dihydrocodone, diamorphine, tapentadol,
papaveretum, codeine, phenylpiperidine derivatives, ketobemidone,
pethidine, fentanyl, diphenylpropylamine derivatives,
dextromoramide, piritramide, dextropropoxyphene, bezitramide,
methadone, benzomorphan derivatives, pentazocine, phenazocine,
oripavine derivatives, buprenorphine, morphinan derivatives,
butorphanol, nalbuphine, tilidine, tramadol, dezocine, salicylic
acid and derivatives, acetylsalicylic acid, aloxiprin, choline
salicylate, sodium salicylate, salicylamide, salsalate,
ethenzamide, morpholine salicylate, dipyrocetyl, benorilate,
diflunisal, potassium salicylate, guacetisal, carbasalate calcium,
imidazole salicylate, pyrazolones, phenazone, metamizole sodium,
aminophenazone, propyphenazone, nifenazone, anilides, paracetamol,
phenacetin, bucetin, propacetamol, other analgesics and
antipyretics such as, for example, rimazolium, glafenine,
floctafenine, viminol, nefopam, flupirtine, or ziconotide.
[0156] In another embodiment, the active drug substance is an
opioid. Where an opioid is included as an active drug substance,
the opioid may comprise naturally occurring opioids, synthetic
opioids, or semisynthetic opioids.
[0157] In other embodiment, the active drug substance comprises
amfetamine, dexamfetamine, lisdexamfetamine, metamfetamine,
methylphenidate, dexmethylphenidate, or combinations thereof.
[0158] In another embodiment, the pharmaceutical compositions
disclosed herein includes an opioid, the opioid is selected from
buprenorphine, codeine, dextromoramide, dihydrocodone, fentanyl,
hydrocodone, hydromorphone, morphine, pentazocine, oxycodeine,
oxycodone, oxymorphone, norhydrocodone, noroxycodone,
morphine-6-glucuronode, tramadol, tapentadol, or
dihydromorphine.
[0159] Where an opioid is used as an active drug substance, the
opioid may be present in any of its crystalline, polymorphous,
semi-crystalline, and amorphous or polyamorphous forms.
Furthermore, in another embodiment, an opioid used as an active
drug substance may be present in one or more forms selected from
its crystalline, polymorphous, semi-crystalline, or amorphous or
polyamorphous forms.
[0160] Some embodiments of the pharmaceutical compositions
disclosed herein include an opioid as an active drug substance, the
active drug substance is selected from morphine, oxycodone,
hydrocodone, hydromorphone, norhydrocodone, oxymorphone,
noroxycodone, morphine-6-glucuronode and pharmaceutically
acceptable salts thereof, including oxycodone hydrochloride,
hydrocodone bitartrate, hydromorphone hydrochloride or morphine
sulphate pentahydrate.
[0161] In other embodiments, the pharmaceutical compositions as
described herein are suitable for use for water soluble as well as
slightly soluble or insoluble active drug substances.
[0162] In another embodiment, all of the above mentioned active
drug substances may also be in the form of pharmaceutically
acceptable salts, uncharged or charged molecules, molecular
complexes, solvates, or anhydrates thereof, and, if relevant,
single isomers, enantiomers, racemic mixtures, or mixtures
thereof.
[0163] In another embodiment, the pharmaceutical compositions
described herein may comprise pharmaceutically acceptable salts of
any of the above mentioned active drug substances.
[0164] In another embodiment, the active pharmaceutical ingredient
is hydrocodone or oxycodone or a pharmaceutically acceptable salt
form of either hydrocodone or oxycodone. Pharmaceutically
acceptable salts forms are those formed by contacting hydrocodone
or oxycodone free base with a suitable acid in a suitable solvent
under suitable conditions that will form a form of hydrocodone or
oxycodone acid addition salt. Suitable acids include hydrochloric
acid, camphorsulfonic acid, hydrobromic acid, sulfuric acid,
methanesulfonic acid, formic acid, acetic acid, oxalic acid,
succinic acid, tartaric acid, mandelic acid, malic acid, salicylic
acid, fumaric acid, lactic acid, citric acid, glutamic acid, and/or
aspartic acid.
[0165] The term "pharmaceutically acceptable salts" of an active
drug substance includes alkali metal salts such as, for example,
sodium or potassium salts, alkaline earth metal salts such as, for
example, calcium and magnesium salts, and salts with organic or
inorganic acid such as, for example, hydrochloric acid, hydrobromic
acid, nitric acid, sulfuric acid, phosphoric acid, citric acid,
formic acid, maleic acid, succinic acid, tartaric acid,
methanesulphonic acid, toluenesulphonic acid etc. In another
embodiment, pharmaceutically acceptable opioid salts can comprise
sulphate salts, hydrochloride salts, and bitartrate salts.
[0166] In another embodiment, the active pharmaceutical ingredient
may be in any of its crystalline, polymorphous, semi-crystalline,
amorphous or polyamorphous forms or mixtures thereof.
[0167] The concentration of the active drug substance in the
pharmaceutical composition for use according to the disclosure
depends on the specific active drug substance, the disease to be
treated, the condition of the patient, the age, and gender of the
patient, etc. The above-mentioned active drug substances may be
known active drug substances and a person skilled in the art will
be able to find information as to the dosage of each active drug
substance and, accordingly, will know how to determine the amount
of each active drug substance in the pharmaceutical
composition.
[0168] The active pharmaceutical ingredient may be a new chemical
entity for which the amount of information is limited. In such
cases, the dosage has to be evaluated based on available
preclinical and/or clinical data.
[0169] In one embodiment described herein, the pharmaceutical
composition comprises soft capsule shell comprising a matrix
comprising an active pharmaceutical ingredient.
[0170] In one embodiment described herein, the soft capsule shell
has the composition of Table 2, including all possible iterations
of the specified ranges that provide 100% for the total weight
percentage, including or excluding the optional colorings,
flavorings, or excipients.
TABLE-US-00002 TABLE 2 Exemplary soft gelatin capsule composition
Exemplary Weight Component Component Percentage (%) Film-forming
polymer Gelatin 20-36 (Gelatin) Plasticizer Glycerol 10-30 Solvent
Water 20-70 Opacifier (optional) Titanium dioxide 0.5-1.5 Coloring
agent (optional) Various 0.05-0.1 TOTAL 100%
[0171] Film-former polymers that are useful for creating soft
capsules are gelatin, hydroxypropylmethylcellulose (HPMC) or
carrageenan (e.g., iota carrageenan and kappa carrageenan). In one
aspect of the enteric soft capsule shell described herein, the
film-forming polymer is gelatin. In another aspect of the enteric
soft capsule shell described herein, the film-forming polymer is
carrageenan.
[0172] Plasticizers that are useful for creating soft capsules as
described herein are glycerol, sorbitol, polyethylene glycols, or
combinations thereof. The weight ratio between the film-forming
polymer, plasticizer, and solvent is adjusted so that the gel mass
is flowable and not too viscous, and can be made into soft capsules
using rotary die encapsulation methods. In one embodiment, the
enteric soft capsule shell has the exemplary composition shown in
Table 3.
TABLE-US-00003 TABLE 3 Exemplary Soft Capsule Shell Composition
Component Percent weight (%) Gelatin 43 Glycerol 20 Titanium
dioxide (optional) 0.7 Coloring agent (optional) 0.1 Water 36.2
TOTAL 100% Final pH ~4-7 Ratio total plasticizer to gelatin 20:43
(0.46:1) Water content in dried soft capsule shell: 8-15%
[0173] In one embodiment described herein, the soft capsule
comprises about 43% of at least one film-forming polymer; about 20%
of at least one plasticizer; about 36% water; optionally, about
0.7% titanium dioxide; and optionally, about 0.1% of at least one
coloring agent.
[0174] In one embodiment described herein, the enteric soft capsule
described herein comprises a composition of about 3% to about 10%
film forming polymer (e.g., a composition of carrageenan); about
10% to about 30% filler; about 10% to about 30% plasticizer; and
about 30% to about 70% solvent.
[0175] In one embodiment, the weight percentage range of
film-forming polymer of the soft capsule described herein is about
35% to about 45%, including all integers within the specified
range. In one aspect, the film-forming polymer weight percentage is
about 38%. In another aspect, the film-forming I polymer weight
percentage is about 42%. In another aspect, the film-forming
polymer weight percentage is about 44%.
[0176] In one embodiment, the weight percentage range of
film-forming polymer of the soft capsule described herein is about
3% to about 15%, including all integers within the specified range.
In one aspect, the film-forming polymer weight percentage is about
3%. In one aspect, the film-forming polymer weight percentage is
about 5%. In one aspect, the film-forming polymer weight percentage
is about 7%. In one aspect, the film-forming polymer weight
percentage is about 10%. In one aspect, the film-forming polymer
weight percentage is about 12%.
[0177] In one embodiment, the weight percentage range of
plasticizer is about 15% to about 22%, including all iterations of
integers with the specified range. In one aspect, the plasticizer
weight percentage is about 17%. In another aspect, the plasticizer
weight percentage is about 18.5%. In another aspect, the
plasticizer weight percentage is about 20%.
[0178] In one embodiment, the weight percentage ratio range of
plasticizer to film-forming polymer is about 0.33:1 to about
0.56:1, including all iterations of iterations of ratios with the
specified range. In one embodiment, the weight percentage ratio
range of plasticizer to film-forming polymer is about 0.38:1. In
one embodiment, the weight percentage ratio range of plasticizer to
film-forming polymer is about 0.42:1. In one embodiment, the weight
percentage ratio range of plasticizer to film-forming polymer is
about 0.46:1. In one embodiment, the weight percentage ratio range
of plasticizer to film-forming polymer is about 0.52:1.
[0179] In one aspect, soft capsules are made using a rotary die
apparatus as described in U.S. Pat. Nos. 5,459,983; 5,146,730; and
6,482,516, each of which are incorporated by reference herein for
such teachings.
[0180] Another embodiment described herein includes a process of
manufacturing soft capsules comprising the pharmaceutical
composition as described herein. The process includes preparing a
gel mass composition comprising a film-forming, water-soluble
polymer, an appropriate plasticizer, and solvent; casting the gel
mass into films or ribbons using heat-controlled drums or surfaces;
and manufacturing a soft capsule comprising a matrix fill using
rotary die technology. The thickness of the films or ribbons that
form the soft capsule shell is from about 0.010 inches (0.254 mm)
to about 0.050 inches (.apprxeq.1.27 mm), including all integers
within the specified range. The shell thickness can be about 0.010
inch (.apprxeq.0.254 mm), about 0.015 inch (.apprxeq.0.381 mm),
about 0.02 in (.apprxeq.0.508 mm), about 0.03 in (.apprxeq.0.762
mm), about 0.04 in (.apprxeq.1.02 mm), or about 0.05 in
(.apprxeq.1.27 mm). In one embodiment, the thickness is about 0.02
inches (.apprxeq.0.508 mm) to about 0.040 inches (.apprxeq.1.02
mm). In one embodiment, the shell thickness is about 0.028 inches
(.apprxeq.0.711 mm). In another embodiment, the shell thickness is
about 0.033 inches (.apprxeq.0.838 mm). In another embodiment, the
shell thickness is about 0.038 inches (.apprxeq.0.965 mm).
[0181] In one embodiment described herein, the soft capsule shell
described herein, encapsulates a matrix fill as described herein.
In another embodiment described herein, the soft capsule shell and
encapsulated matrix fill comprises a outer dimension from about 2
oval to about 30 oval including all iterations of capsule size
within the specified range (e.g., 2 oval, 3 oval, 4 oval, 5 oval, 6
oval, 7 oval, 8 oval, 10 oval, 12 oval, 16 oval, 20, or 30 oval).
In another embodiment described herein, the soft capsule shell and
encapsulated matrix fill comprises a outer dimension from about 2
round to about 28 round including all iterations of capsule size
within the specified range (e.g., 2 round, 3 round, 4 round, 5
round, 6 round, 7 round, 8 round, 10 round, 12 round, 16 round, 20
round or 28 round). In another embodiment described herein, the
soft capsule shell and encapsulated matrix fill comprises a outer
dimension from about 2 oblong to about 22 oblong including all
iterations of capsule size within the specified range (e.g., 2
oblong, 3 oblong, 4 oblong, 5 oblong, 6 oblong, 7 oblong, 8 oblong,
10 oblong, 11, oblong, 12 oblong, 14 oblong, 16 oblong, 20 oblong,
or 22 oblong). Dimension specifications of soft capsules and
tablets are known to those skilled in the art. See Remington's
Essentials of Pharmaceutics, Pharmaceutical Press Publishing
Company, London, UK, 1.sup.st Edition, 2013, which is incorporated
by reference herein for such teachings.
[0182] In another embodiment described herein, the pharmaceutical
composition comprises an enteric soft capsule shell comprising a
matrix fill comprising an active pharmaceutical ingredient.
[0183] Enteric soft capsules are described in International Patent
Application Publication No. WO 2004/030658; U.S. Patent Application
Publication No. US 2006/0165778; and U.S. Pat. No. 8,685,445, each
of which is incorporated by reference herein for such teachings.
The enteric soft capsule shell may comprise one or more film
forming polymers, one or more enteric acid-insoluble polymers, one
or more plasticizers, one or more alkali-neutralizing agents, one
or more solvents, optionally one or more colorants, and optionally
one or more flavorings or other conventionally accepted
pharmaceutical excipients or additives.
[0184] Film-former polymers that are useful for creating enteric
soft capsules are gelatin, hydroxypropylmethylcellulose (HPMC) or
carrageenan (e.g., iota carrageenan and kappa carrageenan). In one
aspect of the enteric soft capsule shell described herein, the
film-forming polymer is gelatin. In another aspect of the enteric
soft capsule shell described herein, the film-forming polymer is
carrageenan.
[0185] Examples of enteric, acid-insoluble polymers are acrylic and
methacrylate acid copolymers, cellulose acetate phthalate (CAP),
cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate
(HPMCP), algenic acid salts such as sodium or potassium alginate,
or shellac. Poly(methacylic acid-co-methyl methacrylate) anionic
copolymers based on methacrylic acid and methyl methacrylate are
particularly stable and are preferred in some embodiments.
Poly(meth)acrylates (methacrylic acid copolymer), available under
the trade name EUDRAGIT.RTM. (Evonik Industries AG, Essen,
Germany), are provided as powder or aqueous dispersions. In one
aspect, the methacrylic acid copolymer can be EUDRAGIT.RTM. L 30
D-55; EUDRAGIT.RTM. L 100-55; EUDRAGIT.RTM. L 100; EUDRAGIT.RTM. L
12.5; EUDRAGIT.RTM. S 100; EUDRAGIT.RTM. S 12.5; EUDRAGIT.RTM. FS
30 D; EUDRAGIT.RTM. E 100; EUDRAGIT.RTM. E 12.5; EUDRAGIT.RTM. E
PO; EUDRAGIT.RTM. RL 100; EUDRAGIT.RTM. RL PO; EUDRAGIT.RTM. RL 30
D; EUDRAGIT.RTM. RL 12.5; EUDRAGIT.RTM. RS 100; EUDRAGIT.RTM. RS
PO; EUDRAGIT.RTM. RS 30 D; EUDRAGIT.RTM. RS 12.5; EUDRAGIT.RTM. NE
30 D; EUDRAGIT.RTM. NE 40 D; EUDRAGIT.RTM. NM 30 D; or other
poly(meth)acrylate polymers. In one aspect, the enteric polymer is
EUDRAGIT.RTM. L 100, a methacrylic acid copolymer, Type A.
Acid-insoluble polymer specifications are detailed in the United
States Pharmacopoeia and in various monographs.
[0186] Plasticizers that are useful for creating enteric soft
capsules as described herein are glycerol, sorbitol, polyethylene
glycol, citric acid, citric acid esters, such as tri-ethyl citrate,
or combinations thereof. The weight ratio between the film-forming
polymer, the enteric acid-insoluble polymer, and plasticizer is
adjusted so that the gel mass is flowable and not too viscous, and
can be made into soft capsules using rotary die encapsulation
methods.
[0187] In one embodiment, enteric soft capsule shell compositions
can be made by dissolving the enteric acid-insoluble polymer in an
aqueous solution of an alkali neutralizing agent such as ammonia,
sodium hydroxide, potassium hydroxide, or liquid amines such as
tri-ethanol amine or ethylene diamine. The amount of alkali is
adjusted to give a final pH value of the gel mass less than or
equal to about pH 9.0. In one embodiment, the final pH does not
exceed 8.5. The volatile alkali neutralizing agent, ammonia is
preferred. The film-forming polymer can then be combined with the
plasticizer and solvent and then blended with the acid-insoluble
gel to make a final homogeneous mix in a heat-controlled vessel and
can be degassed by using vacuum. The fugitive ammonia evaporates
during degassing. Using the foregoing process, the alkali
concentrations do not require an additional step such as heating or
neutralizing with acid in order to neutralize the gel mass.
[0188] In another embodiment described herein, an enteric soft
capsule shell can be made by using an aqueous dispersion of the
acid-insoluble polymer by adding alkaline materials such as
ammonium, sodium, or potassium hydroxides, other alkalis, or a
combination thereof that will cause the enteric acid-insoluble
polymer to dissolve. The plasticizer-wetted, film-forming polymer
can then be mixed with the solution of the acid-insoluble polymer.
In one embodiment, enteric acid-insoluble polymers in the form of
salts of the above-mentioned bases or alkalis can be dissolved
directly in water and mixed with the plasticizer-wetted,
film-forming polymer.
[0189] In one embodiment, an enteric soft capsule shell has the
composition of Table 4, including all possible iterations of the
specified ranges that provide 100% for the total weight percentage,
including or excluding the optional, excipients, opacifiers,
colorants, and flavorings.
TABLE-US-00004 TABLE 4 Exemplary Enteric Soft Capsule Shell
Composition Composition Component Exemplary Component Range (%)
Film-forming polymer Gelatin 20-36 Enteric, acid insoluble
Methacrylic Acid 8-20 polymer Copolymer Plasticizer Glycerol,
Triethyl citrate 15-22 Alkali neutralizing agents NH.sub.4OH (30%),
NaOH 1-5 Solvent Water 20-40 Opacifier Titanium Dioxide 1-7.5
Colorant (optional) Various 0.05-1 Flavoring (optional) Various
0.05-2 Excipients (optional) Various 1-5
[0190] In one embodiment, an enteric soft capsule shell comprises a
composition of about 30% film forming polymer (e.g., gelatin);
about 10% enteric, acid insoluble polymer; about 20% plasticizer;
about 1% alkali neutralizing agent; and about 37% solvent.
[0191] In one embodiment described herein, the enteric soft capsule
described herein comprises a composition of about 3% film forming
polymer (e.g., a composition of carrageenan); about 10% enteric,
acid insoluble polymer; about 10% filler; about 10% plasticizer;
about 1% alkali neutralizing agent; about 2% sealant; and about 60%
solvent.
[0192] In one embodiment, the weight percentage range of total
polymer content (i.e., film forming polymer and enteric
acid-insoluble polymer) of the enteric soft capsule described
herein is about 30% to about 45%, including all integers within the
specified range. In another embodiment, the weight percentage range
of total polymer content (i.e., film forming polymer and enteric
acid-insoluble polymer) of the enteric soft capsule described
herein is about 9% to about 35%, including all integers within the
specified range. In one aspect, the total polymer weight percentage
is about 40%. In another aspect, the total polymer weight
percentage is about 42%. In another aspect, the total polymer
weight percentage is about 45%. In another aspect, the total
polymer weight percentage is about 38%. In another aspect, the
total polymer weight percentage is about 12%. In another aspect,
the total polymer weight percentage is about 16%.
[0193] In one embodiment, the weight percentage range of total
plasticizer is about 15% to about 22%, including all iterations of
integers with the specified range. In one aspect, the total
plasticizer weight percentage is about 19%. In another aspect, the
total plasticizer weight percentage is about 17.7%. In another
aspect, the total plasticizer weight percentage is about 18.9%. In
another aspect, the total plasticizer weight percentage is about
19.3%.
[0194] In one embodiment, the alkali neutralizing-agent is ammonia
(ammonium hydroxide; 30% w/v) that is added to comprise a weight
percentage of about 1 to about 5% of the total enteric soft capsule
composition. In one aspect, 30% w/v ammonia is added to comprise a
weight percentage of about 2%. In another aspect, 30% w/v ammonia
is added to a weight percentage of about 1.7%. In one aspect,
ammonia is added to provide a final pH of about 9 in the enteric
soft capsule composition. In another aspect, ammonia is added to
provide a final pH of about 8.5 in the enteric soft capsule
composition. In another aspect, after the capsules are filled and
dried, the ammonia concentration is substantially reduced, owing to
the fugitive nature of the volatile alkali. In one aspect,
practically all of the ammonia is evaporated except for ammonium
ions comprising salts with other moieties in the composition.
[0195] In one embodiment, the weight ratio range of film forming
polymer to enteric acid insoluble polymer (film forming: enteric)
is about 25:75 (.apprxeq.0.33) to about 40:60 (.apprxeq.0.67)
(i.e., .apprxeq.0.33-0.67), including all iterations of ratios
within the specified range. In one aspect, the ratio of film
forming polymer to enteric acid insoluble polymer is about 30:70
(.apprxeq.0.43). In another aspect, the ratio of film forming
polymer to enteric acid insoluble polymer is about 28:72
(.apprxeq.0.38).
[0196] In another embodiment described herein, the weight ratio
range of film forming polymer (i.e., total carrageenan composition)
to enteric acid insoluble polymer (film forming: enteric) in the
enteric soft gel composition is about 3:9 (.apprxeq.0.3) to about
4:3 (.apprxeq.1.3) (i.e., .apprxeq.0.3-1.3), including all ratios
within the specified range. In some aspects, the ratio of film
forming polymer to enteric acid insoluble polymer in the gel mass
is about 1:3 (.apprxeq.0.33), about 1:2.5 (.apprxeq.0.4), about 1:2
(.apprxeq.0.5), about 1:1.6 (.apprxeq.0.6), about 1:1.25
(.apprxeq.0.8), about 1:1 (.apprxeq.1), about 1.1:1 (.apprxeq.1.1),
about 1.21 (.apprxeq.1.2), or about 1.3:1 (.apprxeq.1.3). In one
aspect, the ratio of film forming polymer to enteric acid insoluble
polymer in the gel mass is about 1:2.5 (.apprxeq.0.4). In another
aspect, the ratio of film forming polymer to enteric acid insoluble
polymer is about 1:3 (.apprxeq.0.3).
[0197] In one embodiment, the weight ratio of total plasticizer to
film forming polymer is about 20:40 to 21:30 (i.e.,
.apprxeq.0.5-0.7), including all iterations of ratios within the
specified range. In one aspect, the weight ratio of total
plasticizer to film forming polymer is about 20:40 (.apprxeq.0.5).
In another aspect, the weight ratio of total plasticizer to film
forming polymer is about 21:30 (.apprxeq.0.7). In another aspect,
the weight ratio of total plasticizer to film forming polymer is
about 19:29 (.apprxeq.0.65). In another aspect, the weight ratio of
total plasticizer to film forming polymer is about 19.3:29.2
(.apprxeq.0.66).
[0198] In one embodiment, the weight ratio of total plasticizer to
enteric acid insoluble polymer is about 1:1 to about 2:1
(.apprxeq.1-2), including all iterations of ratios within the
specified range. In one aspect, the weight ratio of total
plasticizer to enteric acid insoluble polymer is about 11:10
(.apprxeq.1.1). In another aspect, the weight ratio of total
plasticizer to enteric acid insoluble polymer is about 14:10
(.apprxeq.1.4). In another aspect, the weight ratio of total
plasticizer to enteric acid insoluble polymer is about 17:10
(.apprxeq.1.7). In another aspect, the weight ratio of total
plasticizer to enteric acid insoluble polymer is about 20:10
(.apprxeq.2). In another aspect, the weight ratio of total
plasticizer to enteric acid insoluble polymer is about 19.3:11.2
(.apprxeq.01.73).
[0199] In one embodiment, the weight ratio range of total
plasticizer to total polymer (film forming and enteric acid
insoluble polymer) is about 18:45 to about 20:40 (i.e.,
.apprxeq.0.40-0.5), including all iterations of ratios within the
specified range. In one aspect, the weight ratio range of total
plasticizer to total polymer is about 18:45 (.apprxeq.0.40). In
another aspect, the weight ratio range of total plasticizer to
total polymer is about 19:40 (.apprxeq.0.475). In another aspect,
the weight ratio range of total plasticizer to total polymer is
about 20:40 (.apprxeq.0.5). In another aspect, the weight ratio
range of total plasticizer to total polymer is about 19.3:40.4
(.apprxeq.0.477).
[0200] In one embodiment, the solvent comprises about 20% to about
40% of the enteric soft capsule composition, including all integers
within the specified range. In one embodiment, the solvent is
water. The quantity of water in the composition varies depending on
the quantities of the other ingredients. For example, the quantity
of opacifier, colorant, flavoring, or other excipients can change
the percentage of water present the composition. In one embodiment,
the weight percentage of water is as much as suffices to bring the
total weight percentage to 100% (i.e., quantum sufficiat; q.s.). In
another embodiment, the water comprises about 20%, about 25%, about
30%, about 35%, or about 40% of the enteric soft capsule
composition. In another embodiment, water comprises about 35% to
about 40% of the enteric soft capsule composition. In one
embodiment, water comprises about 37% of the composition.
[0201] In one embodiment, the final moisture (water) content of the
enteric soft capsule is from about 8% to about 15%, including all
integers within the specified range. In another embodiment, the
moisture content is about 8% to about 12%, including all integers
within the specified range. In one aspect, the final moisture
content is about 8%. In one aspect, the final moisture content is
about 9%. In one aspect, the final moisture content is about 10%.
In one aspect, the final moisture content is about 11%. In another
aspect, the final moisture content is about 12%.
[0202] In one embodiment, the enteric soft capsule shell has the
exemplary composition shown in Table 5.
TABLE-US-00005 TABLE 5 Exemplary Enteric Soft Capsule Shell
Composition Component Percent weight Gelatin 29.2 Methacrylic Acid
Copolymer (EUDRAGIT .RTM. L 100) 11.2 Glycerol 18.0 Triethyl
citrate 1.3 Ammonium hydroxide 1.7 Titanium dioxide 1.5 Water 37.1
TOTAL 100% Final pH ~4-9 Total polymer % weight (gelatin + enteric)
40.4% Gelatin % wt of total polymer (gelatin + enteric) 72.4%
Enteric % wt of total polymer (gelatin + enteric) 27.6% Ratio of
Enteric to Gelatin 11.2:29.2 (0.38) Total plasticizer % weight
(glycerol + triethyl citrate) 19.3% Ratio of total plasticizer to
total polymer 19.3:40.4 (0.48) Ratio total plasticizer to gelatin
19.3:29.2 (0.66) Ratio total plasticizer to enteric 19.3:11.2
(1.73) Water content in dried enteric soft capsule: 8-15%
[0203] In one embodiment, the enteric soft capsule shell comprises
about 30% gelatin; about 10% poly(methyl) acrylate copolymer; about
18% glycerol; about 1% triethyl citrate; about 1.5% ammonia; about
37% water; and about 1.5% titanium dioxide.
[0204] One embodiment described herein provides an enteric
acid-insoluble polymer dispersed within the film-forming polymer
gel mass that provides the total soft gel composition with enteric
acid-insoluble properties, at relatively low concentrations of the
enteric acid-insoluble polymer (e.g., from about 8% to about 20% of
the total wet gel mass composition) and without the need of
excessive amounts of alkali, thus avoiding denaturation or
degradation of the film-forming polymer that can weaken the
integrity of the enteric soft capsule shell.
[0205] In some embodiments, the enteric soft capsule shell does not
dissolve or disintegrate in acids, such as 0.1 N hydrochloric acid
or simulated gastric fluid (ca. pH 1.2), despite the fact that the
majority of the shell ingredients (i.e., greater than 50%) normally
dissolve in, or are miscible with, acids. In some embodiments, the
enteric soft capsules made using the compositions described herein
remain intact in hydrochloric acid or simulated gastric fluid for
at least two hours and the capsules readily release their contents
upon shifting the pH of the solution to ca. 6.8, such as that of
simulated intestinal fluid. In one aspect, the enteric soft capsule
is resistant to dissolution at about pH 1.2 for at least about 2
hours. In another aspect, the enteric soft capsule begins
dissolution at pH of about 6.8 within about 10 min.
[0206] In another embodiment, the final enteric capsule composition
provides films of increased strength without substantially
compromising film elasticity. Moreover, films made from the enteric
soft capsule compositions as described herein can be sealed at
normal temperature range typically used for making traditional soft
gel capsules. In one aspect, enteric soft capsules are made using a
rotary die apparatus as described in U.S. Pat. Nos. 5,459,983;
5,146,730; and 6,482,516, each of which are incorporated by
reference herein for such teachings.
[0207] Another embodiment described herein includes a process of
manufacturing enteric soft capsules comprising the pharmaceutical
composition as described herein. The process includes preparing a
gel mass composition comprising a film-forming, water-soluble
polymer and an enteric acid-insoluble polymer and mixing with
appropriate plasticizers and solvent;
[0208] casting the gel mass into films or ribbons using
heat-controlled drums or surfaces; and manufacturing a soft capsule
comprising a matrix fill using rotary die technology. The thickness
of the films or ribbons that form the enteric capsule shell is from
about 0.010 inches (.apprxeq.0.254 mm) to about 0.050 inches
(.apprxeq.1.27 mm), including all integers within the specified
range. The shell thickness can be about 0.010 inch (.apprxeq.0.254
mm), about 0.015 inch (.apprxeq.0.381 mm), about 0.02 in
(.apprxeq.0.508 mm), about 0.03 in (.apprxeq.0.762 mm), about 0.04
in (.apprxeq.1.02 mm), or about 0.05 in (.apprxeq.1.27 mm). In one
embodiment, the thickness is about 0.02 inches (.apprxeq.0.508 mm)
to about 0.040 inches (.apprxeq.1.02 mm). In one embodiment, the
shell thickness is about 0.028 inches (.apprxeq.0.711 mm). In
another embodiment, the shell thickness is about 0.033 inches
(.apprxeq.0.838 mm). In another embodiment, the shell thickness is
about 0.038 inches (.apprxeq.0.965 mm).
[0209] In one embodiment described herein, the enteric soft capsule
shell described herein, encapsulates a matrix fill as described
herein. In another embodiment described herein, the enteric soft
capsule shell and encapsulated matrix fill comprises a outer
dimension from about 2 oval to about 30 oval, including all
iterations of capsule size within the specified range (e.g., 2
oval, 3 oval, 4 oval, 5 oval, 6 oval, 7 oval, 8 oval, 10 oval, 12
oval, 16 oval, 20, or 30 oval). In another embodiment described
herein, the enteric soft capsule shell and encapsulated matrix fill
comprises a outer dimension from about 2 round to about 28 round,
including all iterations of capsule size within the specified range
(e.g., 2 round, 3 round, 4 round, 5 round, 6 round, 7 round, 8
round, 10 round, 12 round, 16 round, 20 round or 28 round). In
another embodiment described herein, the enteric soft capsule shell
and encapsulated matrix fill comprises a outer dimension from about
2 oblong to about 22 oblong, including all iterations of capsule
size within the specified range (e.g., 2 oblong, 3 oblong, 4
oblong, 5 oblong, 6 oblong, 7 oblong, 8 oblong, 10 oblong, 11,
oblong, 12 oblong, 14 oblong, 16 oblong, 20 oblong, or 22 oblong).
Dimension specifications of soft capsules and tablets are known to
those skilled in the art. See Remington's Essentials of
Pharmaceutics, Pharmaceutical Press Publishing Company, London, UK,
1.sup.st Edition, 2013, which is incorporated by reference herein
for such teachings.
[0210] In another embodiment, the capsule is a soft capsule
comprising a film-forming polymer that is stable at higher
temperatures (e.g., about 50.degree. C. to about 80.degree. C.). An
exemplary film-forming polymer is carrageenan (e.g., kappa or iota
carrageenan). Exemplary, non-limiting soft capsules comprising
carrageenan are described in the International Patent Application
Publication No. WO 2003/061633; U.S. Patent Application Publication
No. US 2004/0052839; and U.S. Patent Nos. 6,949,256 and 7,887,838,
each of which is incorporated by reference herein for such
teachings. In one aspect, soft capsules comprising a film-forming
polymer stable at high temperatures allow for matrix fills having a
higher viscosity to be encapsulated minimizing the use of
additional plasticizers. The increased encapsulation temperature,
for example, from about 50.degree. C. to about 80.degree. C. allows
for a viscous matrix at a lower temperature to exhibit flowability
for encapsulation by the methods described herein (e.g., rotary die
encapsulation).
[0211] In another embodiment, the capsule shell is a hard capsule
shell. In one aspect, the hard capsule shell may comprise the abuse
deterrent matrices described herein. Any hard capsule shell, for
example hard capsule shells comprising gelatin, HPMC, or pullulan,
including hard capsule shells exhibiting enteric properties, maybe
used with the abuse deterrent matrix fills described herein. Hard
capsule shells are known in the art and are described by Kathpalia
et al., J. Adv. Pharm. Edu. & Res. 4(2): 165-177 (2014), which
is incorporated by reference herein for its specific teachings
thereof.
[0212] The pharmaceutical composition described herein can comprise
a soft capsule comprising a matrix fill that is liquid, semi-solid,
or solid. Capsules prepared as described herein can contain a
hydrophobic solution or suspension, such as vegetable oils or
shortening, or waxes, or combinations thereof. The matrix can be
formulated to prevent interaction with the capsule shell components
and release the pharmaceutical composition at a specified rate.
[0213] One embodiment described herein, is a pharmaceutical
composition comprising a matrix fill formulation comprising any of
the formulations shown in the Tables or Examples described herein.
Any of the components of the formulations shown in the Tables or
Examples can be increased, decreased, combined, recombined,
switched, or removed to provide for a formulation comprising about
100% by weight.
[0214] In another embodiment, the abuse deterrent pharmaceutical
composition described herein provides a dosage of an active
pharmaceutical ingredient described herein for administration to a
subject. The dosage form can be administered, for example, to a
subject, or a subject in need thereof. In one aspect, the subject
is a mammal, or a mammal in need thereof. In one aspect, the
subject is a human, or human in need thereof. In one aspect, the
human or human in need thereof is a medical patient. In one aspect,
the human subject is a child (.about.0-9 years old) or an
adolescent (.about.10-17 years old). In one aspect, the subject is
from 0 to 9 years of age. In another aspect, the human subject is
from 10 to 17 years of age. In another aspect, the human subject is
over 17 years of age. In another aspect, the human subject is an
adult (.gtoreq.18 years of age).
[0215] In one embodiment, the dosage may be administered to a human
in need of management of moderate to severe chronic pain and
neuropathic pain associated with diabetic peripheral neuropathy
(DPN), when a continuous, persistent (around-the-clock) opioid
analgesic is needed for an extended period of time.
[0216] The dosage form can be administered, for example, 1.times.,
2.times., 3.times., 4.times., 5.times., 6.times., or even more
times per day. One or more dosage form can be administered, for
example, for 1, 2, 3, 4, 5, 6, 7 days, or even longer. One or more
dosage forms can be administered, for example, for 1, 2, 3, 4
weeks, or even longer. One or more dosage forms can be
administered, for example, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12 months, 1 year, 2, years, 3 years, 4 years, 5 years, over 5
years, a decade, multiple decades, or even longer. One or more
dosage forms can be administered at a regular interval until the
subject or subject in need thereof, does not require treatment,
prophylaxis, or amelioration of any disease or condition, including
but not limited to, pain.
[0217] In one embodiment, the pharmaceutical composition described
herein is administered in multiple dosages simultaneously. For
example, two or more identical dosages are administered at one
time. In another embodiment, two or more different dosages are
administered at one time. Such dual or different simultaneous doses
can be used to provide an effective amount of the pharmaceutical
composition to a subject in need thereof.
[0218] In one embodiment, the abuse deterrent oral composition
described herein, comprises one or more active pharmaceutical
ingredients in an amount of about 5 mg, about 10 mg, about 15 mg,
about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg,
about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg,
about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,
about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115
mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about
140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg,
about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185
mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about
210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg,
about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255
mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about
280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg,
about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325
mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about
350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg,
about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395
mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about
420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg,
about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465
mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about
490 mg, about 495 mg, about 500 mg, or even more.
[0219] In another embodiment, the abuse deterrent oral composition
described herein, comprises one or more active pharmaceutical
ingredients in the range of about 20 mg to about 250 mg, about 30
mg to about 250 mg, about 40 mg to about 250 mg, about 50 mg to
about 250 mg, about 60 mg to about 250 mg, about 70 mg to about 250
mg, about 80 mg to about 250 mg, about 90 mg to about 250 mg, about
100 mg to about 250 mg, about 110 mg to about 250 mg, about 120 mg
to about 250 mg, about 130 mg to about 250 mg, about 140 mg to
about 250 mg, about 150 mg to about 250 mg, about 160 mg to about
250 mg, about 170 mg to about 250 mg, about 180 mg to about 250 mg,
about 190 mg to about 250 mg, about 200 mg to about 250 mg, about
210 mg to about 250 mg, about 220 mg to about 250 mg, about 230 mg
to about 250 mg, about 240 mg to about 250 mg; about 250 mg to
about 500 mg, about 260 mg to about 500 mg, about 270 mg to about
500 mg, about 280 mg to about 500 mg, about 290 mg to about 500 mg,
about 300 mg to about 500 mg, about 310 mg to about 500 mg, about
320 mg to about 500 mg, about 330 mg to about 500 mg, about 340 mg
to about 500 mg, about 350 mg to about 500 mg, about 360 mg to
about 500 mg, about 370 mg to about 500 mg, about 380 mg to about
500 mg, about 390 mg to about 500 mg, about 400 mg to about 500 mg,
about 410 mg to about 500 mg, about 420 mg to about 500 mg, about
430 mg to about 500 mg, about 440 mg to about 500 mg, about 450 mg
to about 500 mg, about 460 mg to about 500 mg, about 470 mg to
about 500 mg, about 480 mg to about 500 mg, or about 490 mg to
about 500 mg.
[0220] In one embodiment described herein, the abuse deterrent oral
composition described herein may comprise an active pharmaceutical
ingredient load (e.g., a drug load of one or more active
pharmaceutical ingredients) of about 1% to about 90%, including
each integer within the specified range. In one embodiment, the
drug load can comprise about 1%, about 2%, about 2.5%, about 5%,
about 10%, about 15%, about 20%, about 25%, about 30%, about 35%,
about 40%, about 45%, about 50%, about 55%, about 60%, about 65%,
about 70%, about 75%, about 80%, about 85%, about 90%, or even
higher. In one aspect, the drug load is about 5%. In one aspect,
the drug load is about 10%. In one aspect, the drug load is about
20%. In one aspect, the drug load is about 25%. In one aspect, the
drug load is about 30%. In one aspect, the drug load is about 35%.
In one aspect, the drug load is about 40%. In one aspect, the drug
load is about 50%. In one aspect, the drug load is about 60%. In
one aspect, the drug load is about 28%. In one aspect, the drug
load is about 32%. In one aspect, the drug load is about 44%. In
one embodiment, the drug load is about 48%.
[0221] In one embodiment, the active pharmaceutical ingredient is
oxycodone, hydrocodone or codeine, or a salt, ether, ester,
variant, or derivative thereof. In one embodiment, the active
pharmaceutical ingredient is oxycodone. In another embodiment, the
active pharmaceutical ingredient is hydrocodone. See Prescribing
Information for OxyContin.RTM. ER 04/2014 (Purdue Pharma LP;
available at www.purduepharma.com) and Zohydro.RTM. ER 01/2015
(Zogenix.RTM. Inc.; available at: www.zogenix.com), which are
incorporated by reference herein for such teachings.
[0222] In another embodiment, the active pharmaceutical ingredient
may comprise oxycodone, hydrocodone, or codeine and an additional
active pharmaceutical ingredient. In one aspect, the additional
active pharmaceutical ingredient prevents opioid abuse when an
excess of opioid is used. In another aspect, the additional active
pharmaceutical ingredient reduces or prevents opioid induced side
effects.
[0223] In one embodiment, the abuse deterrent oral composition
described herein comprises a dose of hydrocodone. In one aspect,
the dose of hydrocodone is about 5 mg. In one aspect, the dose of
hydrocodone is about 10 mg. In one aspect, the dose of hydrocodone
is about 20 mg. In another aspect, the dose of hydrocodone is about
30 mg. In another aspect, the dose of hydrocodone is about 40 mg.
In another aspect, the dose of hydrocodone is about 50 mg. In
another aspect, the dose of hydrocodone is about 60 mg. In another
aspect, the dose of hydrocodone is about 70 mg. In another aspect,
the dose of hydrocodone is about 80 mg. In another aspect, the dose
of hydrocodone is about 90 mg. In another aspect, the dose of
hydrocodone is about 100 mg. In another aspect, the dose of
hydrocodone is about 120 mg. In another aspect, the dose of
hydrocodone is about 140 mg. In another aspect, the dose of
hydrocodone is about 160 mg. In another aspect, the dose of
hydrocodone is about 180 mg. In another aspect, the dose of
hydrocodone is about 200 mg.
[0224] In one embodiment, the abuse deterrent oral composition
described herein comprises a dose of oxycodone. In one aspect, the
dose of oxycodone is about 5 mg. In another aspect, the dose of
oxycodone is about 10 mg. In another aspect, the dose of oxycodone
is about 15 mg. In another aspect, the dose of oxycodone is about
20 mg. In another aspect, the dose of oxycodone is about 30 mg. In
another aspect, the dose of oxycodone is about 40 mg. In another
aspect, the dose of oxycodone is about 50 mg. In another aspect,
the dose of oxycodone is about 60 mg. In another aspect, the dose
of oxycodone is about 70 mg. In another aspect, the dose of
oxycodone is about 80 mg. In another aspect, the dose of oxycodone
is about 100 mg. In another aspect, the dose of oxycodone is about
120 mg. In another aspect, the dose of oxycodone is about 140 mg.
In another aspect, the dose of oxycodone is about 160 mg. In
another aspect, the dose of oxycodone is about 180 mg. In another
aspect, the dose of oxycodone is about 200 mg.
[0225] In another embodiment, the total dosage of oxycodone or
hydrocodone administered in a 24-hour period is about 20 mg to
about 600 mg per 24-hour period. In one aspect, the total dosage of
oxycodone or hydrocodone administered in a 24-hour period is about
50 mg to about 250 mg per 24-hour period. The dosage can contain a
total amount of oxycodone or hydrocodone effective for treatment,
amelioration, prophylaxis, or reducing the onset of or symptoms of
pain.
[0226] In one embodiment, the recommended dosage is based upon the
condition of the subject in need thereof. The subject can comprise
a human or mammal in need thereof. In one aspect, the need is
defined as a painful condition or perception of pain. In one
embodiment, the initial dosage of hydrocodone is 10 mg to about 40
mg. In one aspect, an initial dose of about 10 mg to about 40 mg is
suitable for a subject that not tolerant of an opioid. In one
aspect, the initial dose is about 10 mg of hydrocodone. In another
aspect, the initial dose is about 20 mg of hydrocodone. In another
aspect, the initial dose is about 20 mg of hydrocodone. In another
aspect, the initial dose is about 30 mg of hydrocodone. In another
aspect, the initial dose is about 40 mg of hydrocodone. In another
aspect, the dose of hydrocodone may be maintained and given every 8
to 12 hours. In another aspect, the dose of hydrocodone may be
increased by about 10 mg to about 20 mg every 8 hrs to 12 hrs until
relief of a painful condition or the perception of pain occurs.
[0227] In another embodiment, the initial dosage of hydrocodone is
40 mg to about 80 mg. In one aspect, an initial dose of about 40 mg
to about 80 mg is suitable for a subject that has an opioid
tolerant phenotype. In one aspect, the initial dose is about 40 mg
of hydrocodone. In another aspect, the initial dose is about 50 mg
of hydrocodone. In another aspect, the initial dose is about 60 mg
of hydrocodone. In another aspect, the initial dose is about 70 mg
of hydrocodone. In another aspect, the initial dose is about 80 mg
of hydrocodone. In another aspect, the dose of hydrocodone may be
maintained and given every 8 to 12 hours. In another aspect, the
dose of hydrocodone may be increased by about 10 mg to about 20 mg
every 8 hrs to 12 hrs until relief of a painful condition or the
perception of pain occurs.
[0228] In one embodiment, the recommended dosage is based upon the
condition of the subject in need thereof. The subject can comprise
a human or mammal in need thereof. In one aspect, the need is
defined as a painful condition or perception of pain. In one
embodiment, the initial dosage of oxycodone is 10 mg to about 40
mg. In one aspect, an initial dose of about 10 mg to about 40 mg is
suitable for a subject that not tolerant of an opioid and a dose.
In one aspect, the initial dose is about 10 mg of oxycodone. In
another aspect, the initial dose is about 20 mg of oxycodone. In
another aspect, the initial dose is about 20 mg of oxycodone. In
another aspect, the initial dose is about 30 mg of oxycodone. In
another aspect, the initial dose is about 40 mg of oxycodone. In
another aspect, the dose of oxycodone may be maintained and given
every 8 to 12 hours. In another aspect, the dose of oxycodone may
be increased by about 10 mg to about 20 mg every 8 hrs to 12 hrs
until relief of a painful condition or the perception of pain
occurs.
[0229] In another embodiment, the initial dosage of oxycodone is 40
mg to about 160 mg. In one aspect, an initial dose of about 40 mg
to about 80 mg is suitable for a subject that has an opioid
tolerant phenotype. In one aspect, the initial dose is about 40 mg
of oxycodone. In another aspect, the initial dose is about 50 mg of
oxycodone. In another aspect, the initial dose is about 60 mg of
oxycodone. In another aspect, the initial dose is about 70 mg of
oxycodone. In another aspect, the initial dose is about 80 mg of
oxycodone. In another aspect, the initial dose is about 100 mg of
oxycodone. In another aspect, the initial dose is about 120 mg of
oxycodone. In another aspect, the initial dose is about 140 mg of
oxycodone. In another aspect, the initial dose is about 160 mg of
oxycodone. In another aspect, the dose of oxycodone may be
maintained and given every 8 to 12 hours. In another aspect, the
dose of oxycodone may be increased by about 10 mg to about 20 mg
every 8 hrs to 12 hrs until relief of a painful condition or the
perception of pain occurs.
[0230] Additional pain that the abuse deterrent pharmaceutical
composition described herein may be useful for the treatment of
pain stemming from including, but not limited to, chronic
arthritis, osteoarthritis, rheumatoid arthritis, acute tendonitis,
bursitis, headaches, migraines, chronic neuropathies, shingles,
premenstrual symptoms, sports injuries, malignancy, radiculopathy,
sciatica/sciatic pain, sarcoidosis, necrobiosis, lipoidica, or
granuloma annulare.
[0231] Another embodiment described herein is an abuse deterrent
pharmaceutical composition as described herein for administration
to a subject having pain, comprising a therapeutically effective
amount of one or more active pharmaceutical ingredients exhibiting
an in vitro dissolution rate at pH 6.8 comprising about 20% to
about 80% dissolution after about 60 minutes to about 720 minutes
including each integer within the specified ranges of dissolution
and time. In another aspect, the in vitro dissolution rate at pH
6.8 is about 50% after about 280 minutes to about 720 minutes,
including each integer with in the specified time range. In one
aspect, the in vitro dissolution rate at pH 6.8 is about 50% after
about 60 min, about 50% after about 70 min, about 50% after about
80 min, about 50% after about 90 min, about 50% after about 120
min, about 50% after about 150 min, about 50% after about 180 min,
about 50% after about 210 min, about 50% after about 240 min, about
50% after about 300 min, is about 50% after about 330 min, about
50% after about 360 min, is about 50% after about 390 min, about
50% after about 420 min, about 50% after about 480 min, about 50%
after about 540 min, about 50% after about 600 min, about 50% after
about 660 min, about 50% after about 720 min, about 50% after about
780 min, about 50% after about 840 min, about 50% after about 900
min, about 50% after about 960 min, or about 50% after 1080
min.
[0232] In another embodiment, the abuse deterrent pharmaceutical
composition comprising an abuse deterrent matrix as described
herein reduces the dissolution and extraction of an active
pharmaceutical ingredient. Suitable non-limiting examples of
extraction methods comprise incubating the abuse deterrent
pharmaceutical composition in boiling conditions, in aqueous
solutions of alcohol, and in distilled water. These methods may be
used in conjunction with additional means of agitating, for
example, with paddles, dipping, vigourous shaking, physical
manipulations, and the like.
[0233] In another embodiment, the abuse deterrent pharmaceutical
composition as described herein has an in vitro dissolution rate at
pH 6.8 of about 50% after about 240 to about 480 minutes. In
another aspect, the in vitro dissolution rate at pH 6.8 is about
50% after about 300 to about 480 minutes. In another aspect, the in
vitro dissolution rate at pH 6.8 is about 50% after about 320 to
about 420 minutes. In another aspect, the in vitro dissolution rate
at pH 6.8 is about 50% after about 300 to about 400 minutes. In
another aspect, the in vitro dissolution rate at pH 6.8 is about
50% after about 320 minutes. In another aspect, the in vitro
dissolution rate at pH 6.8 is about 50% after about 340 minutes. In
another aspect, the in vitro dissolution rate at pH 6.8 is about
50% after about 360 minutes. In another aspect, the in vitro
dissolution rate at pH 6.8 is about 50% after about 380 minutes. In
another aspect, the in vitro dissolution rate at pH 6.8 is about
50% after about 400 minutes. In another aspect, the in vitro
dissolution rate at pH 6.8 is about 50% after about 420 minutes. In
another aspect, the in vitro dissolution rate at pH 6.8 is about
50% after about 440 minutes. In another aspect, the in vitro
dissolution rate at pH 6.8 is about 50% after about 480 minutes. In
another aspect, the in vitro dissolution rate at pH 6.8 is about
50% after about 500 minutes. In another embodiment, the abuse
deterrent pharmaceutical composition as described herein has an in
vitro dissolution rate under boiling conditions in an aqueous media
(e.g., a temperature of about 90.degree. C. to about 120.degree.
C.) less than about 20% to about 80% after about 5 minutes to about
120 minutes including each integer within the specified ranges of
dissolution and time. In one aspect, the in vitro dissolution rate
of the controlled release pharmaceutical composition under boiling
conditions in an aqueous media is less than about 50% after about 5
minutes. In another aspect, the in vitro dissolution rate of the
controlled release pharmaceutical composition under boiling
conditions in an aqueous media is less than about 50% after about
10 minutes. In another aspect, the in vitro dissolution rate of the
controlled release pharmaceutical composition under boiling
conditions in an aqueous media is less than about 50% after about
20 minutes. In another aspect, the in vitro dissolution rate of the
controlled release pharmaceutical composition under boiling
conditions in an aqueous media is less than about 50% after about
30 minutes. In another aspect, the in vitro dissolution rate of the
controlled release pharmaceutical composition under boiling
conditions in an aqueous media is less than about 50% after about
40 minutes. In another aspect, the in vitro dissolution rate of the
controlled release pharmaceutical composition under boiling
conditions in an aqueous media is less than about 50% after about
50 minutes. In another aspect, the in vitro dissolution rate of the
controlled release pharmaceutical composition under boiling
conditions in an aqueous media is less than about 50% after about
60 minutes. In another aspect, the in vitro dissolution rate of the
controlled release pharmaceutical composition under boiling
conditions in an aqueous media is less than about 50% after about
120 minutes.
[0234] In another embodiment, the abuse deterrent controlled
release pharmaceutical composition as described herein has an in
vitro dissolution rate in an aqueous alcohol solution (e.g., an
aqueous solution of ethanol of 10% to 50% at a pH of about 1.2) of
less than about 20% to about 50% after about 30 minutes to about
280 minutes including each integer within the specified ranges of
dissolution and time. In another embodiment, the abuse deterrent
controlled release pharmaceutical composition as described herein
has an in vitro dissolution rate in an aqueous alcohol solution of
less than about 50% after about 280 minutes to about 1440 minutes
including each integer within the specified ranges of dissolution
and time. In one aspect, the in vitro dissolution rate of the
controlled release pharmaceutical composition in an aqueous alcohol
solution is less than about 50% after about 30 minutes. In another
aspect, the in vitro dissolution rate of the controlled release
pharmaceutical composition in an aqueous alcohol solution is less
than about 50% after about 45 minutes. In another aspect, the in
vitro dissolution rate of the controlled release pharmaceutical
composition in an aqueous alcohol solution is less than about 50%
after about 60 minutes. In another aspect, the in vitro dissolution
rate of the controlled release pharmaceutical composition in an
aqueous alcohol solution is less than about 50% after about 120
minutes. In another aspect, the in vitro dissolution rate of the
controlled release pharmaceutical composition in an aqueous alcohol
solution is less than about 50% after about 180 minutes. In another
aspect, the in vitro dissolution rate of the controlled release
pharmaceutical composition in an aqueous alcohol solution is less
than about 50% after about 360 minutes. In another aspect, the in
vitro dissolution rate of the controlled release pharmaceutical
composition in an aqueous alcohol solution is less than about 50%
after about 720 minutes. In another aspect, the in vitro
dissolution rate of the controlled release pharmaceutical
composition in an aqueous alcohol solution is less than about 50%
after about 960 minutes. In another aspect, the in vitro
dissolution rate of the controlled release pharmaceutical
composition in an aqueous alcohol solution is less than about 50%
after about 1440 minutes.
[0235] In another embodiment, the abuse deterrent controlled
release pharmaceutical composition as described herein has an in
vitro dissolution rate in distilled water of less than about 20% to
about 50% after about 30 minutes to about 280 minutes including
each integer within the specified ranges of dissolution and time.
In another embodiment, the abuse deterrent controlled release
pharmaceutical composition as described herein has an in vitro
dissolution rate in distilled water of less than about 50% after
about 280 minutes to about 1440 minutes including each integer
within the specified ranges of dissolution and time. In one aspect,
the in vitro dissolution rate of the controlled release
pharmaceutical composition in distilled water is less than about
50% after about 30 minutes. In another aspect, the in vitro
dissolution rate of the controlled release pharmaceutical
composition in distilled water is less than about 50% after about
45 minutes. In another aspect, the in vitro dissolution rate of the
controlled release pharmaceutical composition in distilled water is
less than about 50% after about 60 minutes. In another aspect, the
in vitro dissolution rate of the controlled release pharmaceutical
composition in distilled water is less than about 50% after about
120 minutes. In another aspect, the in vitro dissolution rate of
the controlled release pharmaceutical composition in distilled
water is less than about 50% after about 180 minutes. In another
aspect, the in vitro dissolution rate of the controlled release
pharmaceutical composition in distilled water is less than about
50% after about 360 minutes. In another aspect, the in vitro
dissolution rate of the controlled release pharmaceutical
composition in distilled water is less than about 50% after about
720 minutes. In another aspect, the in vitro dissolution rate of
the controlled release pharmaceutical composition in distilled
water is less than about 50% after about 960 minutes. In another
aspect, the in vitro dissolution rate of the controlled release
pharmaceutical composition in distilled water is less than about
50% after about 1440 minutes.
[0236] Another embodiment described herein is an abuse deterrent
pharmaceutical composition as described herein comprising a
therapeutically effective amount of one or more active
pharmaceutical ingredients for administration to a subject having
pain, exhibiting an in vitro dissolution rate at pH 6.8, of about
50% after about 60 minutes to about 480 minutes, an in vitro
dissolution rate under boiling conditions less than about 20% to
about 80% after about 5 minutes to about 120 minutes, and an in
vitro dissolution rate in an aqueous alcohol solution or distilled
water of less than about 50% after about 280 minutes to about 1440
minutes.
[0237] Another embodiment described herein is an abuse deterrent
pharmaceutical composition as described herein comprising a
therapeutically effective amount of one or more active
pharmaceutical ingredients for administration to a subject having
pain, exhibiting an in vitro dissolution rate as described herein
in any one of Drawings 2-17.
[0238] Another embodiment described herein is a method for orally
administering a dosage form of an abuse deterrent pharmaceutical
composition comprising an active pharmaceutical ingredient
described herein for the treatment, amelioration, prophylaxis, or
reducing the onset of or symptoms of pain.
[0239] Another embodiment described herein is a method for
treating, retarding the progression of, delaying the onset of,
prophylaxis of, amelioration of, or reducing the symptoms of pain,
comprising administering to a subject in need thereof an oral
pharmaceutical composition as described herein comprising a
therapeutically effective amount of one or more active
pharmaceutical ingredients for administration to a subject having
pain, wherein the pharmaceutical composition exhibits an in vitro
dissolution rate at pH 6.8, of about 50% after about 60 minutes to
about 480 minutes, an in vitro dissolution rate under boiling
conditions less than about 20% to about 80% after about 5 minutes
to about 120 minutes, and an in vitro dissolution rate in an
aqueous alcohol solution or distilled water of less than about 50%
after about 280 minutes to about 1440 minutes.
[0240] Another embodiment described herein is a method for
treating, retarding the progression of, delaying the onset of,
prophylaxis of, amelioration of, or reducing the symptoms of pain,
comprising administering to a subject in need thereof an oral
pharmaceutical composition as described herein comprising a
therapeutically effective amount of one or more active
pharmaceutical ingredients for administration to a subject having
pain, exhibiting an in vitro dissolution rate as described herein
in any one of Drawings 2-15.
[0241] Another embodiment described herein is a method for treating
an individual having pain, with a pharmaceutical composition
described herein comprising an abuse deterrent matrix described
herein comprising a dosage of about 10 mg of oxycodone to about 80
mg of oxycodone, wherein subjects administered a single dosage
exhibit a mean plasma oxycodone C.sub.max of about 10 ng/mL to
about 150 ng/mL, including each integer within the specified range.
In one aspect, the composition is provided in a dosage form
containing a total amount of about 10 mg of oxycodone, wherein
subjects administered a single dosage exhibit a mean plasma
oxycodone C.sub.max of about 10 ng/mL. In another aspect, the
composition is provided in a dosage form containing a total amount
of about 20 mg of oxycodone, wherein subjects administered a single
dosage exhibit a mean plasma oxycodone C.sub.max of about 20 ng/mL.
In another aspect, the composition is provided in a dosage form
containing a total amount of about 40 mg of oxycodone, wherein
subjects administered a single dosage exhibit a mean plasma
oxycodone C.sub.max of about 40 ng/mL. In another aspect, the
composition is provided in a dosage form containing a total amount
of about 80 mg of oxycodone, wherein subjects administered a single
dosage exhibit a mean plasma oxycodone C.sub.max of about 100
ng/mL.
[0242] Another embodiment described herein is a method for treating
an individual having pain, with a pharmaceutical composition
described herein comprising an abuse deterrent matrix described
herein comprising a dosage of about 10 mg of oxycodone to about 80
mg of oxycodone, wherein subjects administered a single dosage
exhibit a mean plasma oxycodone AUC.sub.0.fwdarw..infin. of about
100 hmg/L to about 1000 hmg/L, including each integer within the
specified range. In one aspect, the composition is provided in a
dosage form containing a total amount of about 10 mg of a
oxycodone, wherein subjects administered a single dosage exhibit a
mean plasma oxycodone AUC.sub.0.fwdarw..infin. of about 100 hmg/L.
In another aspect, the composition is provided in a dosage form
containing a total amount of about 20 mg of oxycodone, wherein
subjects administered a single dosage exhibit a mean plasma
oxycodone AUC.sub.0.fwdarw..infin. of about 200 hmg/L. In another
aspect, the composition is provided in a dosage form containing a
total amount of about 40 mg of oxycodone, wherein subjects
administered a single dosage exhibit a mean plasma oxycodone
AUC.sub.0.fwdarw..infin. of about 400 hmg/L. In another aspect, the
composition is provided in a dosage form containing a total amount
of about 80 mg of oxycodone, wherein subjects administered a single
dosage exhibit a mean plasma oxycodone AUC.sub.0.fwdarw..infin. of
about 1000 hmg/L.
[0243] Another embodiment described herein is a method for treating
an individual having pain, with a pharmaceutical composition
described herein comprising an abuse deterrent matrix described
herein comprising a dosage of about 10 mg of oxycodone to about 80
mg of oxycodone, wherein subjects administered a single dosage
exhibits a T.sub.max of about 1 hr to about 8 hrs, including each
integer within the specified range. In one aspect, the composition
is provided in a dosage form containing a total amount of about 10
mg to about 80 mg of oxycodone, wherein subjects administered a
single dosage exhibit a Tmax of about 1 hr, about 1.5 hrs, about 2
hrs, about 2.5 hrs, about 3 hrs, about 3.5 hrs, about 4 hrs, 4.5
hrs, 5 hrs, 5.5 hrs, 6 hrs, 6.5 hrs, 7 hrs, 7.5 hrs, or about 8
hrs.
[0244] Another embodiment described herein is a method for treating
an individual having pain, with a pharmaceutical composition
described herein comprising an abuse deterrent matrix described
herein comprising a dosage of about 10 mg of hydrocodone to about
80 mg of hydrocodone, wherein subjects administered a single dosage
exhibit a mean plasma hydrocodone C.sub.max of about 10 ng/mL to
about 120 ng/mL, including each integer within the specified range.
In one aspect, the composition is provided in a dosage form
containing a total amount of about 10 mg of a hydrocodone, wherein
subjects administered a single dosage exhibit a mean plasma
hydrocodone C.sub.max of about 20 ng/mL. In another aspect, the
composition is provided in a dosage form containing a total amount
of about 20 mg of hydrocodone, wherein subjects administered a
single dosage exhibit a mean plasma hydrocodone C.sub.max of about
30 ng/mL. In another aspect, the composition is provided in a
dosage form containing a total amount of about 30 mg of
hydrocodone, wherein subjects administered a single dosage exhibit
a mean plasma hydrocodone C.sub.max of about 40 ng/mL. In another
aspect, the composition is provided in a dosage form containing a
total amount of about 40 mg of hydrocodone, wherein subjects
administered a single dosage exhibit a mean plasma hydrocodone
C.sub.max of about 60 ng/mL. In another aspect, the composition is
provided in a dosage form containing a total amount of about 80 mg
of hydrocodone, wherein subjects administered a single dosage
exhibit a mean plasma hydrocodone C.sub.max of about 120 ng/mL.
[0245] Another embodiment described herein is a method for treating
an individual having pain, with a pharmaceutical composition
described herein comprising an abuse deterrent matrix described
herein comprising a dosage of about 10 mg of hydrocodone to about
80 mg of hydrocodone, wherein subjects administered a single dosage
exhibit a mean plasma hydrocodone AUC.sub.0.fwdarw..infin. of about
100 hmg/L to about 1600 hmg/L, including each integer within the
specified range. In one aspect, the composition is provided in a
dosage form containing a total amount of about 10 mg of a
hydrocodone, wherein subjects administered a single dosage exhibit
a mean plasma hydrocodone AUC.sub.0.fwdarw..infin. of about 150
hmg/L. In another aspect, the composition is provided in a dosage
form containing a total amount of about 20 mg of hydrocodone,
wherein subjects administered a single dosage exhibit a mean plasma
hydrocodone AUC.sub.0.fwdarw..infin. of about 400 hmg/L. In another
aspect, the composition is provided in a dosage form containing a
total amount of about 40 mg of hydrocodone, wherein subjects
administered a single dosage exhibit a mean plasma hydrocodone
AUC.sub.0.fwdarw..infin. of about 850 hmg/L. In another aspect, the
composition is provided in a dosage form containing a total amount
of about 80 mg of hydrocodone, wherein subjects administered a
single dosage exhibit a mean plasma hydrocodone
AUC.sub.0.fwdarw..infin. of about 1600 hmg/L.
[0246] Another embodiment described herein is a method for treating
an individual having pain, with a pharmaceutical composition
described herein comprising an abuse deterrent matrix described
herein comprising a dosage of about 10 mg of hydrocodone to about
80 mg of hydrocodone, wherein subjects administered a single dosage
exhibits a T.sub.max of about 3 hrs to about 8 hrs, including each
integer within the specified range. In one aspect, the composition
is provided in a dosage form containing a total amount of about 10
mg to about 80 mg of hydrocodone, wherein subjects administered a
single dosage exhibit a T.sub.max of about 3 hrs, about 4 hrs,
about 5 hrs, about 6 hrs, about 7 hrs, or about 8 hrs.
[0247] In another embodiment, the pharmaceutical compositions
described herein further comprise one or more active pharmaceutical
ingredient(s) suitable for treating, ameliorating, or
prophylactically treating a bowel dysfunction due to acute or
chronic opioid use, often referred to as opioid induced bowel
disfunction (OIBD). Symptoms of OIBD typically comprise
constipation (e.g., opioid induced constipation; 010), anorexia,
nausea and vomiting, gastro-oesophageal reflux, delayed digestion,
abdominal pain, flatulence, bloating, hard stools, incomplete
evacuation or straining during bowel movements. Alternative or
additional uses for the one or more active pharmaceutical
ingredient(s) described herein may be to treat, reduce, inhibit, or
prevent additional effects of acute or chronic opioid use
including, e.g., aberrant migration or proliferation of endothelial
cells (e.g., vascular endothelial cells), increased angiogenesis,
and increase in lethal factor production from opportunistic
infectious agents (e.g., Pseudomonas aeruginosa). Additional
advantageous uses of one or more active pharmaceutical
ingredient(s) include treatment of opioid-induced immune
suppression, inhibition of angiogenesis, inhibition of vascular
proliferation, treatment of pain, treatment of inflammatory
conditions such as inflammatory bowel syndrome, treatment of
infectious diseases and diseases of the musculoskeletal system such
as osteoporosis, arthritis, osteitis, periostitis, myopathies, and
treatment of autoimmune diseases, terminally ill patients receiving
opioid therapy such as an AIDS patient, a cancer patient, a
cardiovascular patient; subjects receiving opioid therapy for
maintenance of opioid withdrawal. In one aspect, the subject is a
subject using an opioid for chronic pain management. In another
aspect, the subject is a subject using an acutely using an opioid
for temporary pain management. In another aspect, the subject is a
terminally ill patient. In another aspect, the subject is a person
receiving opioid withdrawal maintenance therapy.
[0248] In another embodiment, suitable active pharmaceutical
ingredients for treating a symptom or condition of opioid use may
comprise a laxative such as lubiprostone, linaclotide, lactulose,
and a heavy molecular weight poly ethylene glycol (e.g., PEG 3350;
Miralax.RTM.; GlycoLax), sorbitol, calcium carbonate, potassium
phosphate, magnesium hydroxide, psyllium, glycerin, polycarbophil,
or docusate, or a mixture or combination thereof. In some aspects,
other suitable pharmaceutical ingredients may comprise a natural
therapeutic or nutraceutical comprising barberry, cascara sagrada,
flax, or senna or a mixture or combination thereof. In some further
aspects, suitable active pharmaceutical ingredients for the
treatment, amelioration, or prophylaxis of OIBD or OIC comprise a
peripherally acting mu-opioid receptor antagonist (PAMORA). In some
aspects, the PAMORA comprises methylnaltrexone, naltrexone,
naloxone, naloxegol, or alvimopan, or a mixture or combination
thereof.
[0249] It is understood that activation of mu-opiod receptors along
the gastro intestinal tract are responsible for decreased bowel
function and constipation. Thus, without being bound by any theory,
PAMORAs are useful for preventing symptoms of OIBD, and
specifically OIC, by inhibiting the action of the mu-opioid
receptor peripherally along the gastro-intestinal tract without
inhibiting the mu-opiod receptors of the central nervous system
(CNS). Therefore, a combination of an opioid agonist (e.g.,
oxycodone or hydrocodone) activates the CNS receptors and the
co-administration of a PAMORA inhibits the peripheral gut mu-opioid
receptors, which are believed to be responsible for the incurrence
of OIC.
[0250] In one embodiment, the pharmaceutical compositions described
herein comprise a dose of an opioid (e.g., oxycodone or
hydrocodone) and a dose of a PAMORA. In one aspect, the
pharmaceutical compositions described herein comprise a dose of an
opioid and a dose of a PAMORA comprising naloxone or a
pharmaceutically acceptable salt form thereof. In one aspect, the
pharmaceutical compositions described herein comprise a dose of an
opioid and a dose of a PAMORA comprising naltrexone or a
pharmaceutically acceptable salt form thereof. In another aspect,
the pharmaceutical compositions described herein comprise a dose of
an opioid and a dose of a PAMORA comprising methylnaltrexone or a
pharmaceutically acceptable salt form thereof. In another aspect,
the pharmaceutical compositions described herein comprise a dose of
an opioid and a dose of a PAMORA comprising naloxegol or a
pharmaceutically acceptable salt form thereof.
[0251] In one embodiment, the pharmaceutical composition described
herein comprises a dose of a PAMORA (e.g., naloxegol, naloxone,
methylnaltrexone, or naltrexone) and a dose of an opioid (e.g.,
hydrocodone or oxycodone). In one aspect, the dose of the PAMORA
ranges from about 50 mg to about 600 mg and the dose of the opioid
is from about 5 mg to about 150 mg, including every integer within
the specified ranges. In another aspect, the dose of the PAMORA
ranges from about 50 mg to about 550 mg and the dose of the opioid
is from about 5 mg to about 150 mg, including every integer within
the specified ranges. In another aspect, the dose of the PAMORA
ranges from about 5 mg to about 50 mg and the dose of the opioid is
from about 5 mg to about 100 mg, including every integer within the
specified ranges.
[0252] In another embodiment, the weight percentage ratio range of
PAMORA (e.g., naloxegol, naloxone, methylnaltrexone, or naltrexone)
to opioid (e.g., hydrocodone or oxycodone) in the pharmaceutical
composition described herein ranges from about 15:1 to about 1:18,
including each ratio within the specified range. In one aspect, the
weight percentage ratio range of PAMORA (e.g., naloxegol, naloxone,
methylnaltrexone, or naltrexone) to opioid is from about 13:1 to
about 1:1, including each ratio within the specified range. In
another aspect, the weight percentage ratio range of PAMORA (e.g.,
naloxegol, naloxone, methylnaltrexone, or naltrexone) to opioid is
from about 1:16 to about 1:1, including each ratio within the
specified range. In another aspect, the weight percentage ratio
range of PAMORA to opioid is about 1:16, about 1:15, about 1:14,
about 1:13, about 1:12, about 1:11, about 1:10, about 1:9, about
1:8, about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about
1:2, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about
6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about
12:1, about 13:1, about 14:1, or about 15:1.
[0253] In one embodiment, the pharmaceutical composition described
herein comprises a dose of naloxone and a dose of an opioid
comprising hydrocodone or oxycodone as described herein. In one
aspect, the dose of the naloxone ranges from about 2.5 mg to about
100 mg, including each integer within the specified range. In
another aspect, the dose of naloxone ranges from about 2.5 mg to
about 50 mg, including each integer within the specified range. In
another aspect, the dose of naloxone ranges from about 10 mg to
about 50 mg, including each integer within the specified range. In
another aspect, the dose of naloxone ranges from about 20 mg to
about 40 mg, including each integer within the specified range. In
another aspect, the dose of naloxone is about 2.5 mg, about 5 mg,
about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg,
about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,
about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,
about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100
mg.
[0254] In another embodiment, the weight percentage ratio range of
naloxone to opioid comprising hydrocodone or oxycodone in the
pharmaceutical composition described herein ranges from about 1:10
to about 5:1, including all iterations of ratios within the
specified range. In one aspect, the weight percentage ratio range
of naloxone to opioid comprising hydrocodone or oxycodone is from
about 1:5 to about 1:1, including all iterations of ratios within
the specified range. In another aspect, the weight percentage ratio
range of naloxone to opioid comprising hydrocodone or oxycodone is
from about 1:4 to about 1:2, including all iterations of ratios
within the specified range. In another aspect, the weight
percentage ratio range of naloxone to opioid comprising hydrocodone
or oxycodone is about 1:10, about 1:9, about 1:8, about 1:7, about
1:6, about 1:5, about 1:4, about 1:3, about 1:2, about 1:1, about
2:1, about 3:1, about 4:1, or about 5:1. In another aspect, the
weight percentage ratio range of naloxone to opioid comprising
hydrocodone or oxycodone is about 1:2.
[0255] In another embodiment, the pharmaceutical composition
described herein comprises a dose of about 5 mg of naloxone and a
dose of about 10 mg of oxycodone. In another embodiment, the
pharmaceutical composition described herein comprises a dose of
about 10 mg of naloxone and a dose of about 20 mg of oxycodone. In
another embodiment, the pharmaceutical composition described herein
comprises a dose of about 20 mg of naloxone and a dose of about 40
mg of oxycodone. In another embodiment, the pharmaceutical
composition described herein comprises a dose of about 40 mg of
naloxone and a dose of about 80 mg of oxycodone. In another
embodiment, the pharmaceutical composition described herein
comprises a dose of about 80 mg of naloxone and a dose of about 160
mg of oxycodone.
[0256] In another embodiment, the pharmaceutical composition
described herein comprises a dose of about 5 mg of naloxone and a
dose of about 10 mg of hydrocodone. In another embodiment, the
pharmaceutical composition described herein comprises a dose of
about 10 mg of naloxone and a dose of about 20 mg of hydrocodone.
In another embodiment, the pharmaceutical composition described
herein comprises a dose of about 20 mg of naloxone and a dose of
about 40 mg of hydrocodone. In another embodiment, the
pharmaceutical composition described herein comprises a dose of
about 40 mg of naloxone and a dose of about 80 mg of hydrocodone.
In another embodiment, the pharmaceutical composition described
herein comprises a dose of about 80 mg of naloxone and a dose of
about 160 mg of hydrocodone.
[0257] In another embodiment, the pharmaceutical composition
described herein comprises a dose of about 40 mg of oxycodone and a
dose of about 20 mg of naloxone. In one aspect, the composition is
provided in a dosage form containing a total amount of about 40 mg
of a oxycodone and about 20 mg of naloxone, wherein subjects
administered a single dosage exhibit a mean plasma oxycodone
AUC.sub.0.fwdarw..infin. of about 400 hmg/L to about 600 hmg/L and
a mean plasma naloxone AUC.sub.0.fwdarw..infin. of about 500 hmg/L
to about 600 hmg/L. In another aspect, the composition is provided
in a dosage form containing a total amount of about 40 mg of
oxycodone and about 20 mg of naloxone, wherein subjects
administered a single dosage exhibit a mean plasma oxycodone
C.sub.max of about 30 ng/mL to about 50 ng/mL and a mean plasma
naloxone C.sub.max of about 50 ng/mL to about 70 ng/mL. In another
aspect, the composition is provided in a dosage form containing a
total amount of about 40 mg of oxycodone and about 20 mg of
naloxone, wherein subjects administered a single dosage exhibit an
oxycodone Tmax of about 1 hr to about 5 hrs and a naloxone
T.sub.max of about 0.5 hr to about 3 hrs.
[0258] In one embodiment, the pharmaceutical composition described
herein comprises a dose of methylnaltrexone or naltrexone and a
dose of an opioid comprising hydrocodone or oxycodone as described
herein. In one aspect, the dose of the methylnaltrexone or
naltrexone ranges from about 2.5 mg to about 100 mg, including each
integer within the specified range. In another aspect, the dose of
methylnaltrexone or naltrexone ranges from about 50 mg to about 600
mg, including each integer within the specified range. In another
aspect, the dose of methylnaltrexone or naltrexone ranges from
about 100 mg to about 600 mg, including each integer within the
specified range. In another aspect, the dose of methylnaltrexone or
naltrexone ranges from about 300 mg to about 600 mg, including each
integer within the specified range. In another aspect, the dose of
methylnaltrexone or naltrexone ranges from about 400 mg to about
600 mg, including each integer within the specified range. In
another aspect, the dose of methylnaltrexone or naltrexone is about
50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about
175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg,
about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400
mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about
525 mg, or about 550 mg.
[0259] In another embodiment, the weight percentage ratio range of
methylnaltrexone or naltrexone to opioid comprising hydrocodone or
oxycodone in the pharmaceutical composition described herein ranges
from about 13:1 to about 1:1, including all iterations of ratios
within the specified range. In one aspect, the weight percentage
ratio range of methylnaltrexone or naltrexone to opioid comprising
hydrocodone or oxycodone is from about 10:1 to about 1:1, including
all iterations of ratios within the specified range. In another
aspect, the weight percentage ratio range of methylnaltrexone or
naltrexone to opioid comprising hydrocodone or oxycodone is from
about 5:1 to about 1:1, including all iterations of ratios within
the specified range. In another aspect, the weight percentage ratio
range of methylnaltrexone or naltrexone to opioid comprising
hydrocodone or oxycodone is about 1:1, about 2:1, about 3:1, about
4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about
10:1, about 11:1, about 12:1, or about 13:1.
[0260] In one embodiment, the pharmaceutical composition described
herein comprises a dose of naloxegol and a dose of an opioid
comprising hydrocodone or oxycodone as described herein. In one
aspect, the dose of the naloxegol ranges from about 2.5 mg to about
100 mg, including each integer within the specified range. In
another aspect, the dose of naloxegol ranges from about 2.5 mg to
about 50 mg, including each integer within the specified range. In
another aspect, the dose of naloxegol ranges from about 10 mg to
about 50 mg, including each integer within the specified range. In
another aspect, the dose of naloxegol ranges from about 20 mg to
about 40 mg, including each integer within the specified range. In
another aspect, the dose of naloxegol is about 2.5 mg, about 5 mg,
about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg,
about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,
about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,
about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100
mg.
[0261] In another embodiment, the weight percentage ratio range of
naloxegol to opioid comprising hydrocodone or oxycodone in the
pharmaceutical composition described herein ranges from about 1:10
to about 5:1, including all iterations of ratios within the
specified range. In one aspect, the weight percentage ratio range
of naloxegol to opioid comprising hydrocodone or oxycodone is from
about 1:5 to about 1:1, including all iterations of ratios within
the specified range. In another aspect, the weight percentage ratio
range of naloxegol to opioid comprising hydrocodone or oxycodone is
from about 1:4 to about 1:2, including all iterations of ratios
within the specified range. In another aspect, the weight
percentage ratio range of naloxegol to opioid comprising
hydrocodone or oxycodone is about 1:10, about 1:9, about 1:8, about
1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, about
1:1, about 2:1, about 3:1, about 4:1, or about 5:1. In another
aspect, the weight percentage ratio range of naloxegol to opioid
comprising hydrocodone or oxycodone is about 1:2.
[0262] Another embodiment described herein is a method for
treating, retarding the progression of, prophylaxis of, delaying
the onset of, ameliorating, or reducing the symptoms of pain
comprising the administration of a therapeutically effective amount
of one or more abuse deterrent pharmaceutical compositions
described herein to a subject with pain, wherein the administration
is sufficient to achieve a reduction pain relative to baseline in
the subject without substantially inducing one or more side effects
including, but not limited to, headache, vertigo, somnolence,
nausea, constipation, vomiting, xerostomia, fatigue, pruritus,
eructation, heartburn, abdominal discomfort, or loss of appetite.
Another embodiment described herein is a method for treating,
retarding the progression of, prophylaxis of, delaying the onset
of, ameliorating, or reducing the symptoms of pain comprising the
administration of a therapeutically effective amount of one or more
abuse deterrent pharmaceutical compositions described herein to a
subject with pain, wherein the administration is sufficient to
achieve a reduction pain relative to baseline in the subject
without substantially inducing one or more side effects including,
but not limited to, opioid use, such as, for example, opioid
induced bowel dysfunction, opioid induced constipation,
gastrointestinal dysfunction (e.g., inhibition of intestinal
motility, constipation, GI sphincter constriction), nausea, emesis
(vomiting), biliary spasm, colic, dysphoria, pruritus, urinary
retention, depression of respiration, papillary constriction,
cardiovascular effects, chest wall rigidity and cough suppression,
depression of stress response, and immune suppression associated
with use of narcotic analgesia, etc, or combinations thereof.
[0263] Another embodiment described herein is a method for
treating, retarding the progression of, prophylaxis of, delaying
the onset of, ameliorating, or reducing the symptoms of, irritable
bowel syndrome, colitis, post-operative or postpartum ileus, nausea
and/or vomiting, decreased gastric motility and emptying,
inhibition of the stomach, and small and/or large intestinal
propulsion, increased amplitude of non-propulsive segmental
contractions, constriction of sphincter of Oddi, increased anal
sphincter tone, impaired reflex relaxation with rectal distention,
diminished gastric, biliary, pancreatic or intestinal secretions,
increased absorption of water from bowel contents,
gastro-esophageal reflux, gastroparesis, cramping, bloating,
abdominal or epigastric pain and discomfort, constipation,
idiopathic constipation, post-operative gastrointestinal
dysfunction following abdominal surgery (e.g., colectomy (e.g.,
right hemicolectomy, left hemicolectomy, transverse hemicolectomy,
colectomy takedown, low anterior resection)), and delayed
absorption of orally administered medications or nutritive
substances comprising the administration of a therapeutically
effective amount of one or more abuse deterrent pharmaceutical
compositions described herein.
[0264] Another embodiment described herein is a method for
improving the quality of life of subjects receiving opioids, as
well as to reduce complications arising from chronic constipation,
such as hemorrhoids, appetite suppression, mucosal breakdown,
sepsis, colon cancer risk, and myocardial infarction comprising the
administration of a therapeutically effective amount of one or more
abuse deterrent pharmaceutical compositions described herein.
[0265] In another embodiment, a the pharmaceutical composition
described herein provides for a dosage form, which comprises an
opioid and a PAMORA as described in, which in terms of efficacy, is
ranked good or very good by more than 50% of patients, 60%, 70%,
80%, 90% or more of patients. In aspect, the dosage form is
provided which comprises an opioid and a PAMORA as described in,
which in terms of tolerability, is ranked good or very good by more
than 50% of patients, 60%, 70%, 80%, 90% or more of patients.
[0266] In another embodiment, a the pharmaceutical composition
described herein provides for a dosage form, which comprises an
opioid and a PAMORA as described in, which provides a reduction of
days with laxative intake by at least 10%, 20%, 30%, 40%, 50%, 60%,
70%, 80%, or even 90%. In one aspect, the dosage form completely
reduces the need for laxative to be taken independently.
[0267] In some embodiments, bowel function is assessed by observing
parameters that are associated with bowel function. In particular,
bowel function may be determined based on parameters selected from
ease or difficulty of defecation, feeling of incomplete bowel
evacuation, and/or personal judgment of patient regarding
constipation. Other parameters which may be observed alternatively
or in addition in order to assess the bowel function of a patient
include among other things stool frequency, stool consistency,
cramping, and painful laxation.
[0268] Bowel function may be assessed by measuring parameters,
which are associated with bowel function using numerical analog
scales (NAS) for these parameters because this may provide more
accurate results. This approach is particularly advantageous when
assessing the bowel function in patients receiving treatment with
analgesics, because analgesic efficacy of drugs is usually assessed
using a numeric analog scale.
[0269] In some embodiments, a pharmaceutical composition is
provided comprising an opioid and PAMORA as described herein to
provide an improvement of the bowel function characterized by an
improvement of the mean bowel function score of at least 5, at
least about 8, at least about 10 or at least about 15 after
administration at steady state or of a single dose to human
patients or healthy human subjects, wherein the mean bowel function
score is measured with a numerical analog scale ranging from 0 to
100.
[0270] In one embodiment, the bowel function is assessed by the
bowel function index (BFI), which is measured in patients. The mean
bowel function score may be determined by a method for assessing
bowel function in a patient comprising the steps of: providing the
patient with a numeric analog scale for at least one parameter,
which parameter is associated with bowel function; causing the
patient to indicate on the numeric analog scale the amount and/or
intensity of the parameter being experienced; and observing the
amount and/or intensity of the at least one parameter indicated on
the numeric analog scale in order to assess bowel function. In one
aspect the patient indicates the amount and/or intensity of
parameter being experienced during the last days or weeks, e.g.
during the last 1, 2, 3, 4, 5, 6, 7, 10, or 14 days. In another
aspect, the numerical analog scale on which the patient indicates
his/her subjective experience of the observed parameter may have
any size or form and may range from 0 or any other number to any
number, such as from 0 to 10 or from 0 to 50 or from 0 to 300 or
from 1 to 10.
[0271] In another embodiment, if more than one parameter is
observed, a mean bowel function may be obtained in form of a
numerical value. This numerical value is the mean of the parameters
observed, e.g., the three numeric analog scale values for ease or
difficulty of defecation, feeling of incomplete bowel evacuation
and judgment of constipation. The parameters, which are measures of
bowel function or which are associated with bowel function, may
comprise opioid induced bowel dysfunctions (OIBD or 010) as
described herein.
[0272] In another embodiment, bowel function may be determined
based on the following parameters: ease or difficulty of
defecation, for example during the last 7 days according to the
patient assessment, wherein 0 corresponds to no difficulties and
100 corresponds to severe difficulties; feeling of incomplete bowel
evacuation, for example during the last 7 days according to the
patient assessment, wherein 0 corresponds to no feeling of
incomplete bowel evacuation and 100 corresponds to very strong
feeling of incomplete bowel evacuation; personal judgment of
patient regarding constipation, for example during the last 7 days,
wherein 0 corresponds to no constipation at all and 100 corresponds
to very heavy constipation.
[0273] In another embodiment, bowel function may be assessed with
analogs scales as described in U.S. Pat. No. 6,258,042 and
International Patent Application Publication No. WO 2003/073937,
which may be adapted to devices or analog scales as described above
as would be understood by one of ordinary skill in the art. The
disclosures of these two references are hereby incorporated by
reference for such teachings.
[0274] In another embodiment, the pharmaceutical compositions
described herein further comprise one or more active pharmaceutical
ingredient(s), which prevent drug abuse by inhibiting the action or
effects of an opioid. In one aspect, the pharmaceutical composition
comprises an opioid (e.g., hydrocodone or oxycodone) and one or
more abuse deterrent aversive agents. The abuse deterrent aversive
agent may be any one of the a laxative such as lubiprostone,
linaclotide, lactulose, and a heavy molecular weight poly ethylene
glycol (e.g., PEG 3350; Miralax.RTM.; GlycoLax), sorbitol, calcium
carbonate, potassium phosphate, magnesium hydroxide, psyllium,
glycerin, polycarbophil, or docusate, or a mixture or combination
thereof. Further abuse deterrent aversive agents may comprise
methylnaltrexone, naltrexone, naloxone, naloxegol, or alvimopan, or
a mixture or combination thereof. The aversive effect of the abuse
deterrent aversive agent may include any unpleasant side effect
comprising inducing opioid withdraw! symptoms, diarrhea, nausea,
reduced euphoria or a mixture or combination thereof.
[0275] In another embodiment, the abuse deterrent pharmaceutical
composition described herein is contained and dispensed from a
tamper evident packaging. The term "tamper evident" or "tamper
resistant" refers to a packaging of any kind that readily displays
or allows for an individual to observe any physical interference or
manipulation of said packaging. The tamper evident packaging
provides reasonable evidence to consumers that tampering has
occurred. The tamper evident packaging additionally contains
appropriate labelling statements describing the features and
evidences of the tamper evident packaging. In one aspect, the
tamper evident packaging comprises: bottles, film wrappers, blister
or strip packs, bubble packs, heat shrink bands or wrappers, foil,
paper, or plastic pouches, container mouth inner seals, tape seals,
breakable caps, sealed metal tubes or plastic heat-sealed tubes,
sealed cartons, aerosol containers, cans including metal and
composite materials, or any combination thereof. The packaging may
also contain appropriate instructions for prescribing, instructions
for use, warnings, or other appropriate information.
[0276] It will be readily apparent to one of ordinary skill in the
relevant arts that suitable modifications and adaptations to the
compositions, methods, and applications described herein can be
made without departing from the scope of any embodiments or aspects
thereof. The compositions and methods provided are exemplary and
are not intended to limit the scope of any of the specified
embodiments. All of the various embodiments, aspects, and options
disclosed herein can be combined in any and all variations or
iterations. The scope of the compositions, formulations, methods,
and processes described herein include all actual or potential
combinations of embodiments, aspects, options, examples, and
preferences herein described. The ratios of the mass of any
component of any of the formulations disclosed herein to the mass
of any other component in the formulation or to the total mass of
the other components in the formulation are hereby disclosed as if
they were expressly disclosed. All patents and publications cited
herein are incorporated by reference herein for the specific
teachings thereof.
EXAMPLES
Example 1
[0277] Abuse deterrent matrices as described herein were prepared
using the composition shown in Tables 7-16. The composition was
prepared according to the method of Example 2 and encapsulated in a
soft capsule shell. Other suitable non-limiting capsule shells for
the abuse deterrent matrices described herein comprise an enteric
soft capsule shell, a hard capsule shell, and an enteric hard
capsule shell.
TABLE-US-00006 TABLE 7 Exemplary Abuse Deterrent Controlled Release
Matrix Composition Components Mass (mg/capsule) Percentage (%)
Soybean Oil 111.6 58.7 Ethocel .TM. (4 cP) 9 4.7 Carnauba Wax 1.8
0.9 Bee's Wax -- -- Methocel .TM. A4M 18 9.5 Polyethylene Glycol
400 36 18.9 Microcrystalline Cellulose 3.6 1.9 BHT -- -- BHA -- --
Hydrocodone 10 5.3 TOTAL 190 100
TABLE-US-00007 TABLE 8 Exemplary Abuse Deterrent Controlled Release
Matrix Composition Components Percentage (%) Soybean Oil 63.2
Ethocel .TM. (4 cP) 3.4 Carnauba Wax 3.4 Bee's Wax -- Methocel .TM.
A4M 11.5 Polyethylene Glycol 400 11.5 Microcrystalline Cellulose
1.2 BHT -- BHA -- Hydrocodone 5.6 TOTAL 100
TABLE-US-00008 TABLE 9 Exemplary Abuse Deterrent Controlled Release
Matrix Composition Components Mass (mg/capsule) Percentage (%)
Soybean Oil 266.6 66.6 Ethocel .TM. (4 cP) 14 3.5 Carnauba Wax 4 1
Bee's Wax 10 2.5 Methocel .TM. A4M 20 5 Polyethylene Glycol 400 40
10 Microcrystalline Cellulose 4 1 BHT 0.4 0.1 BHA 1 0.25 Oxycodone
40 10 TOTAL 400 100
TABLE-US-00009 TABLE 10 Exemplary Abuse Deterrent Controlled
Release Matrix Composition Components Mass (mg/capsule) Percentage
(%) Soybean Oil 244.6 60.9 Ethocel .TM. (20 cP) 12 3.0 Carnauba Wax
26 5.0 Bee's Wax 12 3.0 Methocel .TM. A4M 36 7.5 Polyethylene
Glycol 400 40 10 Microcrystalline Cellulose -- -- BHT 1 0.25 BHA
0.4 0.01 Oxycodone 42 10.4 TOTAL 402 100
TABLE-US-00010 TABLE 11 Exemplary Abuse Deterrent Controlled
Release Matrix Composition Components Mass (mg/capsule) Percentage
(%) Soybean Oil 244.6 60.9 Ethocel .TM. (20 cP) 12 3.0 Carnauba Wax
26 6.5 Bee's Wax -- -- Methocel .TM. A4M 36 9.0 Polyethylene Glycol
400 40 10 Microcrystalline Cellulose -- -- BHT 1 0.25 BHA 0.4 0.10
Oxycodone 42 10.4 TOTAL 402 100
TABLE-US-00011 TABLE 12 Exemplary Abuse Deterrent Controlled
Release Matrix Composition Components Mass (mg/capsule) Percentage
(%) Soybean Oil 270.28 67.57 Ethocel .TM. (20 cP) 8 2 Carnauba Wax
-- -- Bee's Wax 16 4 Methocel .TM. A4M 20 5 Polyethylene Glycol 400
40 10 Microcrystalline Cellulose 4 1 BHT 0.4 0.1 BHA 1.32 0.33
Oxycodone 40 10 TOTAL 400 100
TABLE-US-00012 TABLE 13 Exemplary Abuse Deterrent Controlled
Release Matrix Composition Mass Mass Percentage Components
(mg/capsule) (mg/capsule) (%) Soybean Oil 66.07 264.28 66.07
Ethocel .TM. (20 cP) 2.5 10 2.5 Carnauba Wax -- -- -- Bee's Wax 5
20 5 Methocel .TM. A4M 5 20 5 Polyethylene Glycol 400 10 40 10
Microcrystalline Cellulose 1 4 1 BHT 0.1 0.4 0.1 BHA 0.33 1.32 0.33
Oxycodone 10 40 10 TOTAL 100 400 100
TABLE-US-00013 TABLE 14 Exemplary Abuse Deterrent Controlled
Release Matrix Composition Components Mass (mg/capsule) Percentage
(%) Soybean Oil 244.6 60.9 Ethocel .TM. (20 cP) 12 3.0 Carnauba Wax
26 6.5 Bee's Wax -- -- Methocel .TM. A4M 36 9.0 Polyethylene Glycol
400 40 10 Microcrystalline Cellulose -- -- BHT 1 0.25 BHA 0.4 0.10
Oxycodone 42 10.4 TOTAL 402 100
TABLE-US-00014 TABLE 15 Exemplary Abuse Deterrent Controlled
Release Matrix Composition % Weight Components F1 F2 F3 F4 F5 F6 F7
Soybean Oil 69.3 71.4 64.4 51.3 63.7 46.2 64.9 Ethocel .TM. 9.9
13.0 11.7 10.3 11.5 10.3 9.1 Methocel .TM. -- 2.6 11.5 7.7 11.3
10.2 15.3 PEG 400 -- 6.5 5.9 10.3 5.8 5.1 4.6 MCC -- -- -- -- 2.0
2.6 1.6 PEO 5.0 -- -- -- -- -- -- Span .RTM. 60 1.0 -- -- -- -- --
-- Capmul .RTM. MCM -- -- -- 15.4 -- -- -- Di water 9.9 -- -- -- --
20.5 -- Hydrocodone 5.0 6.5 5.9 5.1 5.8 5.1 4.6 Total 100 100 100
100 100 100 100
TABLE-US-00015 TABLE 16 Exemplary Abuse Deterrent Controlled
Release Matrix Composition % Weight Components F8 F9 F10 F11 F12
F13 Soybean Oil 65.4 65.4 65.4 65.4 63.2 67.1 Ethocel .TM. (4cP)
3.5 3.5 3.5 3.5 6.8 3.4 Carnauba Wax 3.5 1.8 -- 1.8 3.4 3.4 Bee's
Wax -- 1.8 3.5 -- -- -- Methocel .TM. A4M 5.2 5.2 5.2 5.2 5.1 5.0
Polyethylene 10.5 10.5 10.5 10.5 10.1 10 Glycol 400
Microcrystalline 1.0 1.0 1.0 1.0 0.0 1.0 Cellulose BHT 0.3 0.3 0.3
0.3 0.3 0.1 BHA 0.1 0.1 0.1 0.1 0.1 -- Oxycodone 10.5 10.5 10.5
10.5 10.5 10 TOTAL 100 100 100 100 100 100
Example 2
[0278] An exemplary abuse deterrent controlled release matrix
composition as described herein comprises one or more liquid
lipophilic vehicles, one or more organogelators, one or more
hydrophilic polymers, one or more hydrophilic vehicles, one or more
active pharmaceutical ingredients, optionally one or more
semi-solid lipophilic vehicles, and optionally one or more
disintegrants, and optionally one or more anti-oxidants as
described in any one of Tables 7-27. An exemplary process for
preparing an abuse deterrent controlled release matrix includes
preparing a mixture comprising one or more liquid lipophilic
vehicles, one or more organogelators, one or more hydrophilic
polymers, one or more hydrophilic vehicles, one or more active
pharmaceutical ingredients, optionally one or more semi-solid
lipophilic vehicles, optionally one or more disintegrants, and
optionally one or more anti-oxidants by heating the mixture from
between 45.degree. C. and 80.degree. C. with stirring or agitation
in a suitable vessel. The process further comprises decreasing the
matrix mixture temperature to between about 25.degree. C. and about
45.degree. C. followed by a homogenization step, wherein the matrix
is homogenized to be substantially flowable. Prior to encapsulation
in a soft gel capsule described herein, the matrix is deaerated at
a temperature of about 25.degree. C. to about 45.degree. C. Prior
to encapsulation in a soft gel capsule comprising carrageenan as
described herein, the matrix is deaerated at a temperature of about
25.degree. C. to about 75.degree. C.
[0279] The abuse deterrent matrices as described are
multi-component and have a viscous yet flowable aspect as shown in
FIG. 1 A-C. FIG. 1A is the hydrophilic phase, B is a gelled phase,
and C is the final mixture prior to encapsulation.
[0280] Matrix compositions containing one or more semi-solid
lipophilic vehicles, such as a wax, may be further annealed by
heating a soft capsule encapsulating the abuse deterrent controlled
release matrix to a temperature of about 70.degree. C. for about
0.25 hours to about one hour.
[0281] The process for manufacturing a soft capsule comprising the
abuse deterrent matrices as described herein includes preparing a
gel mass for a soft capsule; casting the gel mass into films or
ribbons using heat-controlled drums or surfaces; and manufacturing
a soft capsule comprising a matrix fill using rotary die
technology. During this process, the abuse deterrent controlled
release matrix is injected in to the lumen as the soft capsule is
formed by rotary die encapsulation. The soft capsule can be a
typical soft capsule ("soft gel") or an enteric soft capsule.
Example 3
[0282] The dissolution and release profiles under different
dissolution conditions for pharmaceutical compositions comprising
the abuse deterrent matrix formulations described in Tables 7-16
and Tables 18-19 are shown in FIGS. 1-17.
[0283] The abuse deterrent controlled release matrix composition
shown in Table 7, generated by the methods described herein and
encapsulated in a soft gel capsule as described herein, was tested
for its release rate under boiling conditions. As shown in FIG. 2,
a test pharmaceutical composition comprising the abuse deterrent
matrix of Table 7 comprising hydrocodone demonstrated a much lower
release rate compared to a reference abuse deterrent pharmaceutical
composition comprising either tapentadol or hydrocodone and was on
par with reference abuse deterrent pharmaceutical compositions
comprising either tapentadol or hydrocodone.
[0284] As shown in FIG. 3, the test pharmaceutical composition
comprising the abuse deterrent matrix of Table 7 demonstrated a
better release rate of hydrocodone in a dissolution test (Apparatus
III at 10 dips/min) in 250 mL of a pH 6.8 buffer when compared to a
reference abuse deterrent pharmaceutical composition comprising
hydrocodone.
[0285] The test pharmaceutical composition comprising the abuse
deterrent matrix of Table 7 demonstrated a lower release rate of
hydrocodone in a dissolution test using Apparatus I at 100 RPM in
500 mL of a 40% solution of ethanol in 0.1 N HCl (pH 1.2) compared
to a reference abuse deterrent pharmaceutical composition (FIG.
4).
[0286] The test pharmaceutical composition comprising the abuse
deterrent matrix of Table 7 demonstrated a similar or lower release
rate of hydrocodone in distilled water under agitation at 300 RPM
at low temperatures of 4.degree. C. and 25.degree. C. when compared
to two different reference abuse deterrent pharmaceutical
compositions as shown in FIG. 5. Even lower release rates were
observed at temperatures of 60.degree. C. and 100.degree. C. (FIG.
5). In addition, the test pharmaceutical composition demonstrated
lower release rates in distilled water under agitation at 300 RPM
from 0.5 hrs to 2 hrs (FIG. 6).
[0287] A test pharmaceutical composition comprising the abuse
deterrent matrix of Table 8 hydrocodone had a similar release rate
up to two hours in a dissolution test (Apparatus III at 10
dips/min) in a 40% solution of ethanol in 0.1 N HCl (pH 1.2)
compared to a pH 6.8 buffer (FIG. 7).
[0288] The test pharmaceutical composition comprising the abuse
deterrent matrix labelled F8 in Table 16 demonstrated a lower but
comparable release rate of oxycodone in a dissolution test
(Apparatus III at 10 dips/min) in a simulated intestinal fluid
(SIF) buffer comprising 250 mL of a pH 6.8 buffer when compared to
a reference abuse deterrent pharmaceutical composition comprising
oxycodone (FIG. 8). However, as shown in FIG. 9, the test
pharmaceutical composition demonstrated a lower release rate when
compared to a reference abuse deterrent pharmaceutical composition
comprising oxycodone (Apparatus III at 10 dips/min) in a 40%
solution of ethanol in 0.1 N HCl (pH 1.2).
[0289] As further shown in FIG. 10, increasing the amount of
Ethocel.TM. between formulations F12 and F13 of Table 16 at a
higher viscosity (i.e., 20 cP) dramatically decreased the release
rate of oxycodone under boiling conditions.
[0290] The test pharmaceutical composition comprising the abuse
deterrent matrix of Table 9 comprising oxycodone had a similar
release rate up to two hours in a dissolution test (Apparatus III
at 10 dips/min) in a 40% solution of ethanol in 0.1 N HCl (pH 1.2)
compared to a pH 6.8 buffer (FIG. 11). As further shown in FIG. 11,
the test pharmaceutical composition demonstrated a comparable
release rate in a pH 6.8 buffer compared to a reference
pharmaceutical composition comprising oxycodone. The test
pharmaceutical composition further displayed a lower release rate
after about 15 minutes under boiling conditions in distilled water
compared to a reference pharmaceutical composition comprising
oxycodone (FIG. 12).
[0291] The test pharmaceutical composition comprising the abuse
deterrent matrix of Table 10 comprising oxycodone demonstrated a
lower release rate under boiling conditions compared to a reference
pharmaceutical composition comprising oxycodone (FIG. 13).
[0292] The percent release of oxycodone was determined by measuring
the amount of oxycodone released from the test and the reference
abuse deterrent composition according to F14 of Table 19 in
fasted-state simulated gastric fluid (FASSGF) at pH 1.2 for two
hours and in fasted-state simulated intestinal fluid (FASSIF) at pH
6.8 for two hours according to USP specifications using Apparatus
III at 30 dpm. As shown in FIG. 16 the test composition and
reference abuse deterrent formulation demonstrated a similar
percent release in FASSGF/FASSIF buffer. The composition F14 of
Table 19 was further tested under boiling conditions and
demonstrated a lower percent release after about 30 minutes
compared to a reference abuse deterrent formulation (FIG. 17).
[0293] It was determined that increasing the amount of soybean oil
of composition F14 of Table 19 and concomitantly decreasing the
amount of polyethylene glycol, such as composition F15 improved the
flowability of the composition for encapsulation feasability. This
composition, exemplified by F15 of Table 19 was tested and
demonstrated a comparable release profile both in FASSGF/FASSIF
buffers as well as under boiling conditions when compared to
composition F14 (data not shown).
Example 4
[0294] Differing compositions of wax were determined to affect the
release rate of oxycodone from the test pharmaceutical composition
comprising the abuse deterrent matrices shown in Tables 12-13. As
shown in FIG. 14, the test pharmaceutical composition of Table 13,
wherein carnauba wax was removed, demonstrated an increased release
rate of 40 mg of oxycodone from the matrix when compared to a
reference pharmaceutical composition comprising oxycodone. This,
for example, is in contrast to the composition of Table 9, which
comprises both carnauba wax and bee's wax and demonstrates a lower
release rate compared to the same reference pharmaceutical
composition comprising oxycodone (FIG. 13).
[0295] As shown in FIG. 15, the test pharmaceutical composition of
Table 13, wherein the amount of bee's wax was increased, led to a
decreased release rate of oxycodone compared to the reference
pharmaceutical composition comprising oxycodone only at a 40 mg
dose and not at the 10 mg dose, suggesting higher concentrations of
bee's wax or the addition of carnauba wax is also stabilizing to
the abuse deterrent matrix under higher boiling temperatures.
Example 5
[0296] Additional abuse deterrent matrices may comprise a range of
components as shown in Table 17. Additional abuse deterrent
matrices having the composition shown in Tables 18-19 were
prepared.
[0297] The compositions in Tables 18-19 were prepared by first
heating the specified amount of soybean oil to about 60.degree. C.
and adding ethyl cellulose (e.g., Ethocel.TM.) until it was
completely dissolved and formed a first clear gel mixture. Next,
the specified amounts of hydroxypropyl methylcellulose (e.g.,
Methocel.TM. K100M) was hydrated in the specified amount of
polyethylene glycol (e.g., PEG 400) for at least about an hour. The
active pharmaceutical ingredient oxycodone was then mixed with the
hydrated hydroxypropylmethyl cellulose mixture to form a uniform
blended mixture. Then the mixture containing oxycodone,
hydroxypropyl methylcellulose and polyethylene glycol was added to
the first mixture containing soybean oil and dissolved ethyl
cellulose. The matrix compositions generated by the method
described above was encapsulated in a soft capsule shell following
standard rotary die encapsulation techniques. The matrices
generated by the method described above are also suitable for other
capsule shells, such as enteric soft capsule shells, hard capsule
shells, and enteric hard capsule shells.
[0298] Further annealing processing steps may be needed for
compositions comprising one or more waxes. For example, a
composition comprising a soft capsule shell encapsulating the
composition F16 of Table 19 was annealed by heating the capsule and
matrix to about 70.degree. C. for about 1 hour. The example method
described above may be used to encapsulate any of the matrix
compositions described herein (e.g., Tables 7-27) with suitable
modification.
TABLE-US-00016 TABLE 17 Exemplary Abuse Deterrent Controlled
Release Matrix Composition Components Weight Percentage (%) Soybean
Oil 30-65 Ethocel .TM. 1-7 Hydroxypropylmethyl cellulose 8-22 Wax 1
0-10 Wax 2 0-10 Polyethylene glycol 8-40 Oxycodone; Hydrocodone
1-20 TOTAL 100
TABLE-US-00017 TABLE 18 Exemplary Abuse Deterrent Controlled
Release Matrix Composition Components Weight Percentage (%) Soybean
Oil 52 Ethocel .TM. (20 cP) 3.0 Methocel .TM. K100M 15 Polyethylene
Glycol 400 20 Oxycodone 10 TOTAL 100
TABLE-US-00018 TABLE 19 Exemplary Abuse Deterrent Controlled
Release Matrix Composition Weight Percentage (%) Components F14 F15
F16 Soybean Oil 36.0 51 51 Ethocel .TM. (20 cP) 3.0 2.7 0.8
Carnauba Wax 0.0 0.0 1.6 Bee's Wax 0.0 0.0 1.6 Methocel .TM. K100M
15.0 13.8 12.0 Polyethylene Glycol 400 36.0 23.0 24.0 BHT 0.1 0.1
0.1 BHA 0.1 0.1 0.1 Oxycodone 10.0 9.25 8.0 TOTAL 100 100 100
Example 6
[0299] Additional exemplary abuse deterrent matrix compositions
useful for producing abuse deterrent controlled release soft gel
capsules as described herein are shown in Tables 20-27. Composition
components are set forth by weight percentage of the total weight
of the matrix composition. Such compositions may be encapsulated in
soft capsules, enteric soft capsules, hard capsules or enteric hard
capsules.
TABLE-US-00019 TABLE 20 Exemplary Abuse Deterrent Controlled
Release Matrix Compositions Weight Percentage (%) Components EX 1
EX 2 EX 3 EX 4 EX 5 EX 6 Total Hydrophobic Matrix (HBM) 79.7 63.6
61.6 68.6 54.6 63.6 Total Hydrophilic Matrix (HPM) 19.4 16.4 16.4
16.4 44.4 16.4 Total Polymer (tP) 13.0 8.5 8.5 8.5 50.0 8.5 Total
Hydrophilic Vehicle (tHV) 11.0 11.0 11.0 11.0 19.0 11.0 Active
Pharmaceut. Ingredient (API) 1 10 10 15 1 20 Components and
Relational Ratios Ratio of HBM to HPM 4.1 3.9 3.8 4.2 1.2 3.9 Ratio
of Lipophilic Vehicle to tP 5.4 6.7 6.4 7.2 0.4 6.7 Ratio of
Organogelator to Hydrophilic 0.6 0.7 0.7 0.7 1.0 0.7 Polymer Ratio
of tHV to tP 0.8 1.3 1.3 1.3 0.4 1.3 Ratio of API to HBM 0.01 0.2
0.2 0.2 0.02 0.3 Ratio of API to HPM 0.1 0.6 0.6 0.9 0.02 1.2 Ratio
of API to Total Matrix 0.01 0.1 0.1 0.2 0.01 0.3
TABLE-US-00020 TABLE 21 Exemplary Abuse Deterrent Controlled
Release Matrix Compositions Weight Percentage (%) Components EX 7
EX 8 EX 9 EX 10 EX 11 EX 12 Total Hydrophobic Matrix (HBM) 66.1
39.6 58.6 72.9 67.4 51.6 Total Hydrophilic Matrix (HPM) 23.9 50.4
16.4 17.1 22.6 24.4 Total Polymer (tP) 22.0 33.0 8.5 9.0 9.5 8.5
Total Hydrophilic Vehicle (tHV) 3.5 25.0 11.0 13.7 16.7 11.0 Active
Pharmaceut. Ingredient (API) 10 10 25 10 10 10 Components and
Relational Ratios Ratio of HBM to HPM 2.8 0.8 3.6 4.3 3.0 2.1 Ratio
of Lipophilic Vehicle to CRP 2.4 0.6 6.1 6.7 6.0 5.2 Ratio of
Organogelator to Hydrophilic 0.1 0.3 0.7 2.0 0.7 0.7 Polymer Ratio
of tHV to tP 0.2 0.8 1.3 1.5 1.8 1.3 Ratio of API to HBM 0.2 0.3
0.4 0.1 0.1 0.2 Ratio of API to HPM 0.4 0.2 1.5 0.6 0.4 0.4 Ratio
of API to Total Matrix 0.1 0.1 0.3 0.1 0.1 0.1
TABLE-US-00021 TABLE 22 Exemplary Abuse Deterrent Controlled
Release Matrix Compositions Weight Percentage (%) Components EX 13
EX 14 EX 15 EX 16 EX 17 EX 18 Oil 70 56.6 54.6 61.6 20.1 56.6
Ethocel .TM. 5 3.5 3.5 3.5 25 3.5 Wax 1 1 1 1 1 7 1 Wax 2 3.7 2.5
2.5 2.5 2.5 2.5 Methocel .TM. 8 5 5 5 25 5 Polyethylene Glycol 10
10 10 10 18 10 Microcrystalline Cellulose 1 1 1 1 1 1 Plasticizer
-- -- 12 -- -- -- Surfactant -- 10 -- -- BHT 0.1 0.1 0.1 0.1 0.1
0.1 BHA 0.25 0.25 0.25 0.25 0.25 0.25 Active Pharmaceut.
Ingredient(s); 1 10 10 15 1 20 (e.g., hydrocodone, oxycodone,
naloxone, methylnaltrexone, naltrexone) TOTAL 100 100 100 100 100
100
TABLE-US-00022 TABLE 23 Exemplary Abuse Deterrent Controlled
Release Matrix Compositions Weight Percentage (%) Components EX 19
EX 20 EX 21 EX 22 EX 23 EX 24 Oil 10 10 25 10 10 10 Ethocel .TM.
52.6 19.6 51.6 60.4 56.9 44.6 Wax 1 2 8 3.5 6 4 3.5 Wax 2 4.5 5 1 2
2 1 Methocel .TM. 7 7 2.5 4.5 4.5 2.5 Polyethylene Glycol 20 25 5 3
5.5 5 Microcrystalline Cellulose 2 20 10 12 15 10 Plasticizer 1.5 5
1 1.7 1.7 1 Surfactant -- -- -- -- -- 14 BHT -- -- -- -- -- 8 BHA
0.1 0.1 0.1 0.1 0.1 0.1 Active Pharmaceut. Ingredient(s); 0.25 0.25
0.25 0.25 0.25 0.25 (e.g., hydrocodone, oxycodone, naloxone,
methylnaltrexone, naltrexone) TOTAL 100 100 100 100 100 100
TABLE-US-00023 TABLE 24 Exemplary Abuse Deterrent Controlled
Release Matrix Compositions Weight Percentage (%) Components EX 25
EX 26 EX 27 EX 28 EX 29 EX 30 Total Hydrophobic Matrix (HBM) 55 55
57 59.5 62 62.5 Total Hydrophilic Matrix (HPM) 35.4 25.4 33.4 30.9
28.4 27.9 Total Polymer (tP) 18.0 15.5 19.0 19.5 20.0 20.5 Total
Hydrophilic Vehicle (tHV) 20.0 12.5 16.0 12.5 13.0 9.5 Active
Pharmaceut. Ingredient (API) 10.0 20.0 10.0 10.0 10.0 10.0
Components and Relational Ratios Ratio of HBM to HPM 1.6 2.2 1.7
1.9 2.2 2.2 Ratio of Lipophilic Vehicle to CRP 2.9 3.4 2.9 3.0 2.6
2.9 Ratio of Organogelator to Hydrophilic 0.2 0.2 0.1 0.1 0.3 0.1
Polymer Ratio of tHV to tP 1.1 0.8 0.8 0.6 0.7 0.5 Ratio of API to
HBM 0.2 0.4 0.2 0.2 0.2 0.2 Ratio of API to HPM 0.3 0.8 0.3 0.3 0.4
0.4 Ratio of API to Total Matrix 0.1 0.2 0.1 0.1 0.1 0.1
TABLE-US-00024 TABLE 25 Exemplary Abuse Deterrent Controlled
Release Matrix Compositions Weight Percentage (%) Components EX 31
EX 32 EX 33 EX 34 EX 35 EX 36 Total Hydrophobic Matrix (HBM) 56.5
55 68.5 63 56.5 56 Total Hydrophilic Matrix (HPM) 33.9 30.4 30.9
32.4 33.9 34.4 Total Polymer (tP) 16.5 18.0 19.5 22.0 19.0 15.0
Total Hydrophilic Vehicle (tHV) 18.5 15.0 14.5 15.0 17.0 23.0
Active Pharmaceut. Ingredient (API) 10.0 15.0 1.0 5.0 10.0 10.0
Components and Relational Ratios Ratio of HBM to HPM 1.7 1.8 2.2
1.9 1.7 1.6 Ratio of Lipophilic Vehicle to CRP 2.7 2.9 3.3 2.6 2.8
3.5 Ratio of Organogelator to Hydrophilic 0.1 0.2 0.2 0.3 0.2 0.4
Polymer Ratio of tHV to tP 1.1 0.8 0.7 0.7 0.9 1.5 Ratio of API to
HBM 0.2 0.3 0.0 0.1 0.2 0.2 Ratio of API to HPM 0.3 0.5 0.0 0.2 0.3
0.3 Ratio of API to Total Matrix 0.1 0.2 0.0 0.1 0.1 0.1
TABLE-US-00025 TABLE 26 Exemplary Abuse Deterrent Controlled
Release Matrix Compositions Weight Percentage (%) Components EX 37
EX 38 EX 39 EX 40 EX 41 EX 42 Oil 52 52 55 58 52 60 Ethocel .TM. 3
3 2 1.5 5 2.5 Wax 1 0 0 0 0 5 0 Wax 2 0 0 0 0 0 0
Hydroxypropylmethyl cellulose 15 12.5 17 18 15 18 Polyethylene
Glycol 20 12.5 16 12.5 13 9.5 Opt. BHT 0.1 0.1 0.1 0.1 0.1 0.1 Opt.
BHA 0.25 0.25 0.25 0.25 0.25 0.25 Active Pharmaceut. Ingredient(s);
10 20 10 10 10 10 (e.g., hydrocodone, oxycodone, naloxone,
methylnaltrexone, naltrexone) TOTAL 100 100 100 100 100 100
TABLE-US-00026 TABLE 27 Exemplary Abuse Deterrent Controlled
Release Matrix Compositions Weight Percentage (%) Components EX 43
EX 44 EX 45 EX 46 EX 47 EX 48 Oil 45 52 65 58 54 52 Ethocel .TM.
1.5 3 3.5 5 2.5 4 Wax 1 5 0 0 0 0 0 Wax 2 5 0 0 0 0 0
Hydroxypropylmethyl cellulose 15 15 16 17 16.5 11 Polyethylene
Glycol 18.5 15 14.5 15 17 23 Opt. BHT 0.1 0.1 0.1 0.1 0.1 0.1 Opt.
BHA 0.25 0.25 0.25 0.25 0.25 0.25 Active Pharmaceut. Ingredient(s);
10 15 1 5 10 10 (e.g., hydrocodone, oxycodone, naloxone,
methylnaltrexone, naltrexone) TOTAL 100 100 100 100 100 100
* * * * *
References