U.S. patent application number 15/814524 was filed with the patent office on 2018-03-15 for anti-overingestion dosage forms.
The applicant listed for this patent is BANNER LIFE SCIENCES LLC. Invention is credited to Tatyana Dyakonov, Nashwa El-Gendy, Justin R Hughey, Jason M Vaughn, Chue Hue Yang.
Application Number | 20180071278 15/814524 |
Document ID | / |
Family ID | 60674469 |
Filed Date | 2018-03-15 |
United States Patent
Application |
20180071278 |
Kind Code |
A1 |
Yang; Chue Hue ; et
al. |
March 15, 2018 |
ANTI-OVERINGESTION DOSAGE FORMS
Abstract
Described herein are abuse deterrent oral pharmaceutical
compositions, methods for making the same, and methods of
treatement using such compositions. In particular, oral
pharmaceutical compositions that mitigate the risk of overingestion
of one or more active pharmaceutical ingredients are described.
Inventors: |
Yang; Chue Hue; (Greensboro,
NC) ; Dyakonov; Tatyana; (Greensboro, NC) ;
El-Gendy; Nashwa; (Greensboro, NC) ; Vaughn; Jason
M; (Browns Summit, NC) ; Hughey; Justin R;
(Asheboro, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BANNER LIFE SCIENCES LLC |
High Point |
NC |
US |
|
|
Family ID: |
60674469 |
Appl. No.: |
15/814524 |
Filed: |
November 16, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15341143 |
Nov 2, 2016 |
9849125 |
|
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15814524 |
|
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62250284 |
Nov 3, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/485 20130101;
A61K 9/4891 20130101; A61K 9/4866 20130101; A61K 9/2027 20130101;
A61K 9/146 20130101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 9/00 20060101 A61K009/00; A61K 9/20 20060101
A61K009/20 |
Claims
1. An oral immediate release composition comprising: one or more
active pharmaceutical ingredients (API) and one or more strong
cation exchange resins capable of interacting with the API at a
mass ratio of about 1:2 to about 1:8; less than 1% of the API is
bound to the strong cation exchange resin prior to solvation; and
after solvation of two more doses of the composition simultaneously
or successively over about a 4-hour period, the strong cation
exchange resin adsorbs about 15% to about 70% by mass of the API
and impedes its absorption into a subject's systemic circulation,
lowering C.sub.max for the API by about 30% to about 50% as
compared to an equivalent dose of the API lacking a strong cation
exchange resin.
2. The composition of claim 1, wherein the mass ratio of API to
strong cation exchange resin is about 1:4.
3. The composition of claim 1, wherein the composition comprises a
dry powder.
4. The composition of claim 1, wherein the composition is
non-layered.
5. The method of claim 1, wherein the composition is encapsulated
in a capsule or formed as a tablet.
6. The composition of claim 1, wherein the composition futher
comprises one or more pharmaceutically acceptable excipients.
7. The composition of claim 1, wherein subjects administered the
composition exhibit one or more of the following pharmacokinetic
parameters: (a) a delayed T.sub.max for the API as compared to an
equivalent API dose lacking a strong cation exchange resin; (b) a
lower plasma AUC for the API as compared to an equivalent API dose
lacking a strong cation exchange resin; (c) an extended absorption
time for the API as compared to an equivalent API dose lacking a
strong cation exchange resin; or (d) an extended clearance time for
the API as compared to an equivalent API dose lacking a strong
cation exchange resin.
8. The composition of claim 1, wherein the composition comprises:
about 10% to about 30% by mass of API; and about 70% to 90% by mass
of a strong cation exchange resin.
9. The composition of claim 1, wherein the composition comprises:
about 20% by mass of API; and about 80% by mass of a strong cation
exchange resin.
10. The composition of claim 1, wherein the composition exhibits an
in vitro disintegration or dissolution rate comprising about 50%
disintegration or dissolution after about 1 minute to about 15
minutes in simulated gastric fluid comprising 34.2 mM NaCl and 0.1
N HCl, pH 1.2 using the USP basket method.
11. The composition of claim 1, wherein subjects administered the
composition exhibit a plasma AUC for the API of about 15% lower as
compared to an equivalent API dose lacking a strong cation exchange
resin.
12. The composition of claim 1, wherein the strong cation exchange
resin comprises polystyrene sulfonate or a salt thereof.
13. The composition of claim 1, wherein the API comprises
analgesics, anaesthetics, antimigraine drugs, antiepileptics,
anticholinergics, antipsychotics, anxiolytics, hypnotics,
sedatives, antidepressants, anti-dementia drugs, or combinations
thereof.
14. The composition of claim 1, wherein the API comprises an opioid
agonist.
15. The composition of claim 1, wherein the API comprises
hydrocodone, oxycodone, oxymorphone, hydromorphone, morphine,
codeine, salts thereof, or combinations thereof.
16. The composition of claim 1, wherein the API comprises
hydrocodone or a salt thereof.
17. A method for mitigating the risk of overingestion of an active
pharmaceutical ingredient (API), the method comprising
administering to a subject in need thereof one or more oral
immediate release compositions of claim 1.
18. A method for regulating the concentration of an active
pharmaceutical ingredient in a subject's systemic circulation, the
method comprising: administering to a subject one or more oral
immediate release compositions of claim 1.
19. The method of claim 15, further comprising: (a) acquiring a
bodily fluid from the subject; (b) measuring the concentration of
the API in the subject's circulation; and (c) according to the
measured API concentration and a desired optimal API therapeutic
concentration, either: (i) administering one or more doses of the
composition comprising the API and the strong cation exchange
resin; (ii) administering an equivalent dose of the API comprising
a composition lacking the strong cation exchange resin; or (iii)
administering either one or more doses of the composition
comprising the API and the strong cation exchange resin or
administering an equivalent dose of the API comprising a
composition lacking the strong cation exchange resin after a period
of about 30 min to about 12 hours.
20. The method of claim 19, where the bodily fluid is blood.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/341,143, which was filed on Nov. 2, 2016,
and which claims priority to U.S. Provisional Patent Application
No. 62/250,284, filed on Nov. 3, 2015, each of which are
incorporated by reference herein in their entirety.
TECHNICAL FIELD
[0002] Described herein are abuse deterrent oral pharmaceutical
compositions, methods for making the same, and methods of
treatement using such compositions. In particular, oral
pharmaceutical compositions that mitigate the risk of overingestion
of one or more active pharmaceutical ingredients 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] There remains a need for abuse deterrent pharmaceutical
compositions that comprise properties that mitigate the risk of
accidental or intentional overingestion. In particular, there is a
need for formulations that are resistant to active pharmaceutical
ingredient extraction and that inhibit the risk of
overingestion.
SUMMARY
[0007] One embodiment described herein is an oral immediate release
pharmaceutical composition comprising a dry mixture comprising one
or more active pharmaceutical ingredients (API), one or more
sequestering agents, and optionally, one or more pharmaceutically
acceptable excipients, where less than about 1% of the API is bound
to the sequestering agent. In one aspect, upon ingestion of at
least one dose by a subject, the sequestering agent adsorbs a
quantity of the API and impedes its absorption into the subject's
systemic circulation. In another aspect, the quantity of the API
adsorbed by the sequestering agent is about 0.5% to about 15%. In
another aspect, a greater quantity of API is adsorbed by the
sequestering agent when a plurality of doses of the composition are
simultaneously ingested or successively ingested over about a
4-hour period. In another aspect, the quantity of the API adsorbed
by the sequestering agent is about 15% to about 70%. In another
aspect, the plurality of doses is 2 or greater. In another aspect,
the plurality of doses is from 2 to 30. In another aspect, the
composition is capable of achieving one or more of the following
pharmacokinetic parameters: (a) a lower C.sub.max for the API as
compared to an equivalent API dose lacking a sequestering agent;
(b) a delayed T.sub.max for the API as compared to an equivalent
API dose lacking a sequestering agent; (c) a similar plasma AUC for
the API as compared to an equivalent API dose lacking a
sequestering agent; (d) an extended absorption time for the API as
compared to an equivalent API dose lacking a sequestering agent; or
(e) an extended clearance time for the API as compared to an
equivalent API dose lacking a sequestering agent. In another
aspect, the API to sequestering agent comprises a mass ratio of
about 1:2 to about 1:8. In another aspect, the API to sequestering
agent comprises a mass ratio of about 1:3 to about 1:5. In another
aspect, the API to sequestering agent comprises a mass ratio of
about 1:4. In another aspect, the API comprises an opioid. In
another aspect, the API comprises hydrocodone, oxycodone,
oxymorphone, hydromorphone, morphine, codeine, salts thereof, or
combinations thereof. In another aspect, the API comprises
hydrocodone bitartrate. In another aspect, the sequestering agent
comprises one or more ion exchange polymers. In another aspect, the
sequestering agent comprises one or more cation exhange polymers or
salts thereof. In another aspect, the sequestering agent comprises
a sulfonated styrene and divinylbenzene copolymer or a salt
thereof. In another aspect, the sequestering agent comprises
polystyrene sulfonate or a salt thereof. In another aspect, the
composition comprises a dry admixture of hydrocodone bitartrate and
sodium polystyrene sulfonate at a mass ratio of about 1:4. In
another aspect, the composition is non-layered. In another aspect,
the composition comprises: about 10% to about 30% API; and about70%
to 90% sequestering agent. In another aspect, the composition
comprises about 20% API; and about 80% sequestering agent. In
another aspect, the composition comprises about 20% hydrocodone
bitartrate; and about 80% polystyrene sulfonate or a salt thereof.
In another aspect, the composition is encapsulated in a capsule or
formed as a tablet. In another aspect, the composition exhibits an
in vitro disintegration or dissolution rate comprising about 50%
disintegration or dissolution after about 1 minute to about 15
minutes at pH 1.2.
[0008] Another embodiment described herein is an oral immediate
release pharmaceutical composition comprising a dry mixture of
hydrocodone or a salt thereof and polystyrene sulfonate or a salt
thereof in a mass ratio of about 1:2 to about 1:8, where less than
about 1% of the hydrocodone is bound to the polystyrene sulfonate.
In one aspect, upon ingestion of at least one dose by a subject,
the polystyrene sulfonate adsorbs a quantity of the hydrocodone and
impedes its absorption into the subject's systemic circulation. In
another aspect, the quantity of hydrocodone adsorbed by the
polystyrene sulfonate is about 0.5% to about 15%. In another
aspect, a greater quantity of hydrocodone is adsorbed by the
polystyrene sulfonate when a plurality of doses of the composition
are simultaneously ingested or successively ingested over about a
4-hour period. In another aspect, the quantity of hydrocodone
adsorbed by the polystyrene sulfonate is about 15% to about 70%. In
another aspect, the plurality of doses is 2 or greater. In another
aspect, the plurality of doses is from 2 to 30. In another aspect,
the composition is capable of achieving one or more of the
following pharmacokinetic parameters: (a) a lower C.sub.max for the
hydrocodone as compared to an equivalent hydrocodone dose lacking
polystyrene sulfonate t; (b) a delayed T.sub.max for hydrocodone as
compared to an equivalent hydrocodone dose lacking polystyrene
sulfonate; (c) a similar plasma AUC for hydrocodone as compared to
an equivalent hydrocodone dose lacking polystyrene sulfonate; (d)
an extended absorption time for hydrocodone as compared to an
equivalent hydrocodone dose lacking polystyrene sulfonate; or (e)
an extended clearance time for hydrocodone as compared to an
equivalent hydrocodone dose lacking polystyrene sulfonate. In
another aspect, the composition comprises a non-layered powder
suspension. In another aspect, the mass ratio of hydrocodone to
polystyrene sulfonate is about 1:4. In another aspect, the
composition exhibits an in vitro disintegration or dissolution rate
comprising about 50% disintegration or dissolution after about 1
minute to about 15 minutes at pH 1.2. Another aspect is a dosage
form comprising the foregoing composition described herein
encapsulated in a capsule or formed as a tablet.
[0009] Another embodiment described herein is a method for treating
pain while mitigating the risk of overingestion, the method
comprising administering to a subject in need thereof an oral
immediate release pharmaceutical composition comprising a dry
mixture of one or more active pharmaceutical ingredients (API), one
or more sequestering agents, and optionally, one or more
pharmaceutically acceptable excipients, where less than 1% of the
API is bound to the sequestering agent, and following ingestion of
at least one dose by a subject, the sequestering agent adsorbs a
quantity of the API and impedes its release into the subject's
systemic circulation. In one aspect, the API to sequestering agent
mass ratio is about 1:2 to about 1:8. In another aspect, the
quantity of the API adsorbed by the sequestering agent is about
0.5% to about 15%. In another aspect, a greater quantity of API is
adsorbed by the sequestering agent when a plurality of doses of the
composition are simultaneously ingested or successively ingested
over about a 4-hour period. In another aspect, the quantity of the
API adsorbed by the sequestering agent is about 15% to about 70%.
In another aspect, the plurality of doses is 2 or greater. In
another aspect, the plurality of doses is from 2 to 30. In another
aspect, the composition is capable of achieving one or more of the
following pharmacokinetic parameters: (a) a lower C.sub.max for the
API as compared to an equivalent API dose lacking a sequestering
agent; (b) a delayed T.sub.max for the API as compared to an
equivalent API dose lacking a sequestering agent; (c) a similar
plasma AUC for the API as compared to an equivalent API dose
lacking a sequestering agent; or (d) an extended clearance time for
the API as compared to an equivalent API dose lacking a
sequestering agent. In another aspect, the API comprises
hydrocodone, oxycodone, oxymorphone, hydromorphone, morphine,
codeine, salts thereof, or combinations thereof. In another aspect,
the sequestering agent comprises one or more ion exchange polymers.
In another aspect, the composition comprises a dry powder
suspension of hydrocodone bitartrate and sodium polystyrene
sulfonate at a mass ratio of about 1:4. In another aspect, the
composition is a non-layered. In another aspect, the composition
comprises about 10% to about 30% API; and about70% to 90%
sequestering agent. In another aspect, the composition comprises
about 20% API; and about 80% sequestering agent. In another aspect,
the composition comprises about 20% hydrocodone bitartrate; and
about 80% polystyrene sulfonate or a salt thereof. In another
aspect, the composition is encapsulated in a capsule or formed as a
tablet. In another aspect, the composition exhibits an in vitro
disintegration or dissolution rate comprising about 50%
disintegration or dissolution after about 1 minute to about 15
minutes at pH 1.2. In another aspect, the pain arises from one or
more of 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, granuloma annulare, trauma,
cancer, or a combination thereof.
[0010] Another embodiment described herein is method for mitigating
the risk of overingestion, the method comprising administering to a
subject in need thereof one or more oral immediate release
pharmaceutical compositions comprising one or more active
pharmaceutical ingredients (API), one or more sequestering agents,
and optionally, one or more pharmaceutically acceptable excipients,
where less than about 1% of the API is bound to the sequestering
agent, and following ingestion of at least one dose by a subject,
the sequestering agent adsorbs a quantity of the API and impedes
its release into the subject's systemic circulation. In one aspect,
the API to sequestering agent mass ratio is about 1:2 to about 1:8.
In another aspect, the quantity of the API adsorbed by the
sequestering agent is about 0.5% to about 15%. In another aspect, a
greater quantity of API is adsorbed by the sequestering agent when
a plurality of doses of the composition are simultaneously ingested
or successively ingested over about a 4-hour period. In another
aspect, the quantity of the API adsorbed by the sequestering agent
is about 15% to about 70%. In another aspect, the plurality of
doses is 2 or greater. In another aspect, the plurality of doses is
from 2 to 30. In another aspect, the composition is capable of
achieving one or more of the following pharmacokinetic parameters:
(a) a lower C.sub.max for the API as compared to an equivalent API
dose lacking a sequestering agent; (b) a delayed T.sub.max for the
API as compared to an equivalent API dose lacking a sequestering
agent; (c) a similar plasma AUC for the API as compared to an
equivalent API dose lacking a sequestering agent; or (d) an
extended clearance time for the API as compared to an equivalent
API dose lacking a sequestering agent. In another aspect, the API
comprises hydrocodone, oxycodone, oxymorphone, hydromorphone,
morphine, codeine, salts thereof, or combinations thereof. In
another aspect, the sequestering agent comprises one or more ion
exchange polymers. In another aspect, the composition comprises a
dry powder suspension of hydrocodone bitartrate and sodium
polystyrene sulfonate at a mass ratio of about 1:4. In another
aspect, the composition is a non-layered. In another aspect, the
composition comprises about 10% to about 30% API; and about 70% to
90% sequestering agent. In another aspect, the composition
comprises about 20% API; and about 80% sequestering agent. In
another aspect, the composition comprises about 20% hydrocodone
bitartrate; and about 80% polystyrene sulfonate or a salt thereof.
In another aspect, the composition is encapsulated in a capsule or
formed as a tablet. In another aspect, the composition exhibits an
in vitro disintegration or dissolution rate comprising about 50%
disintegration or dissolution after about 1 minute to about 15
minutes at pH 1.2.
[0011] Another embodiment described herein is a method for
manufacturing an overingestion-inhibiting pharmaceutical dosage
form, the method comprising (i) combining one or more active
pharmaceutical ingredients (API) with one or more sequestering
agents, and optionally one or more pharmaceutically acceptable
excipients to form a powder suspension; and (ii) forming a dosage
form from the powder suspension. In one aspect, less than about 1%
of the API is bound to the sequestering agent. In another aspect,
the API to sequestering agent mass ratio is about 1:2 to about 1:8.
Another aspect is a dosage form produced by the manufacturing
method described herein. In another aspect, the dosage form
comprises an API comprising an opioid or a salt thereof and the
sequestering agent comprises an ion exchange resin or a salt
thereof. In another aspect, the dosage form is a capsule or a
tablet. In another aspect, the dosage form exhibits an in vitro
disintegration or dissolution rate comprising about 50%
disintegration or dissolution after about 1 minute to about 15
minutes at pH 1.2.
[0012] Another embodiment described herein is a kit comprising one
or more dosage forms comprising one or more oral immediate release
pharmaceutical composition comprising one or more active
pharmaceutical ingredients (API), one or more sequestering agents,
and optionally, one or more pharmaceutically acceptable excipients,
wherein less than about 1% of the API is bound to the sequestering
agent, and following ingestion of at least one dose by a subject,
the sequestering agent adsorbs a quantity of the API and impedes
its release into systemic circulation; (b) one or more moisture
proof dispensing receptacles; and optionally (c) an insert
comprising instructions, prescribing information,
contraindications, or warnings.
[0013] Another embodiment described herein is a method for
regulating the concentration of an active pharmaceutical ingredient
in a subject's systemic circulation, the method comprising
administering to a subject one or more oral immediate release
pharmaceutical compositions comprising one or more active
pharmaceutical ingredients (API), one or more sequestering agents,
and optionally, one or more pharmaceutically acceptable excipients,
where less than about 1% of the API is bound to the sequestering
agent, and following ingestion of at least one dose by a subject,
the sequestering agent adsorbs a quantity of the API and impedes
its release into the subject's systemic circulation. In another
aspect, the API to sequestering agent mass ratio is about 1:2 to
about 1:8. In another aspect, the quantity of the API adsorbed by
the sequestering agent is about 0.5% to about 15%. In another
aspect, a greater quantity of API is adsorbed by the sequestering
agent when a plurality of doses of the composition are
simultaneously ingested or successively ingested over about a
4-hour period. In another aspect, the quantity of the API adsorbed
by the sequestering agent is about 15% to about 70%. In another
aspect, the plurality of doses is 2 or greater. In another aspect,
the plurality of doses is from 2 to 30. In another aspect, the
composition is capable of achieving one or more of the following
pharmacokinetic parameters: (a) a lower C.sub.max for the API as
compared to an equivalent API dose lacking a sequestering agent;
(b) a delayed T.sub.max for the API as compared to an equivalent
API dose lacking a sequestering agent; (c) a similar plasma AUC for
the API as compared to an equivalent API dose lacking a
sequestering agent; or (d) an extended clearance time for the API
as compared to an equivalent API dose lacking a sequestering agent.
In another aspect, the sequestering agent comprises one or more ion
exchange polymers. In another aspect, the composition is a
non-layered. In another aspect, the composition comprises about 10%
to about 30% API; and about 70% to 90% sequestering agent. In
another aspect, the composition comprises about 20% API; and about
80% sequestering agent. In another aspect, the composition is
encapsulated in a capsule or formed as a tablet. In another aspect,
the composition exhibits an in vitro disintegration or dissolution
rate comprising about 50% disintegration or dissolution after about
1 minute to about 15 minutes at pH 1.2. In another aspect, the
method further comprises: (a) acquiring a bodily fluid from the
subject; (b) measuring the concentration of the API in the
subject's circulation; and (c) according to the measured API
concentration and a desired optimal API therapeutic concentration,
either: (i) administering one or more doses of the composition
comprising the API and a sequestering agent; (ii) administering an
equivalent dose of the API comprising a composition lacking a
sequestering agent; or (iii) administering either one or more doses
of the composition comprising the API and a sequestering agent or
administering an equivalent dose of the API comprising a
composition lacking a sequestering agent after a period of about 30
min to about 12 hours.
[0014] Another embodiment described herein is a pharmaceutical
composition comprising an abuse deterrent controlled release
composition comprising one or more active pharmaceutical
ingredients that prevent over ingestion of abuse prone drugs. The
composition is structured to prevent extraction of the active
pharmaceutical ingredients. The composition formulations described
herein minimize the likelihood of tampering, "dose dumping," or the
extraction of active pharmaceutical ingredients from the
composition. Further, the composition is structured to reduce the
release of one or more active pharmaceutical ingredients when
multiple pharmaceutical compositions are ingested.
[0015] One embodiment described herein is an abuse deterrent oral
pharmaceutical composition comprising a tamper resistant controlled
release composition, wherein the tamper resistant controlled
release composition comprises a means for preventing the crushing,
grating, grinding, cutting, solvating, or dissolving of the tamper
resistant controlled release composition comprising one or more
active pharmaceutical ingredients. In one aspect, the abuse
deterrent oral pharmaceutical composition comprises a means for
preventing the over ingestion of one or more active pharmaceutical
ingredients when more than the recommended dosage is taken.
[0016] Another embodiment described herein is an anti-overingestion
abuse deterrent pharmaceutical composition comprising a soft
capsule shell composition comprising a first one or more ionically
charged polymers, wherein the soft capsule shell encapsulates a
composition comprising one or more active pharmaceutical
ingredients and a second one or more ionically charged polymers,
wherein the one or more active pharmaceutical ingredients is in a
pH responsive resinate complex with the second one or more
ionically charged polymers. In one aspect described herein, the
soft capsule shells described herein comprise two or more soft
capsule shell sub compositions that comprise a total soft capsule
shell composition, wherein the two or more soft capsule shell sub
compositions are spatially separated. In another aspect, the one or
more ionically charged polymers comprises at least two ionically
charged polymers. In another aspect, the total soft capsule shell
composition comprises a first soft capsule shell sub composition
and a second soft capsule shell sub composition. In another aspect,
the at least two ionically charged polymers comprise at least one
positively charged polymer and at least one negatively charged
polymer. In another aspect, each one of the at least two ionically
charged polymers are each in the at least two or more of the soft
capsule shell sub compositions. In another aspect, the first soft
capsule shell sub composition comprises about 1% to about 90% of
the total soft capsule shell composition. In another aspect, the
second soft capsule shell sub composition comprises about 1% to
about 90% of the total soft capsule shell composition. In another
aspect, the first soft capsule shell sub composition comprises a
positively charged polymer. In another aspect, the second soft
capsule shell sub composition comprises a negatively charged
polymer. In another aspect, the positively charged polymer
comprises a dimethylaminoethyl methacrylate copolymer. In another
aspect, the negatively charged polymer comprises a methacrylic acid
copolymer. In another aspect, the positively charged polymer
comprises about 1% to about 25% of at least one of the soft capsule
shell sub compositions. In another aspect, the negatively charged
polymer comprises about 1% to about 25% of at least one of the soft
capsule shell sub compositions. In another aspect, the soft capsule
shell further comprises one or more adhesive polymers. In another
aspect, the one or more adhesive polymers comprises polycarbophil,
xanthan gum, Carbopol.RTM. 1342P, Carbopol.RTM. 974P, chitosan,
Carbopol.RTM. 971P, hydroxypropylmethyl cellulose (e.g., Methocel
K100M or Methocel K15M), sodium carboxymethyl cellulose,
hydroxypropylmethyl cellulose (Methocel K15M), gelatin, or acacia
gum, or a combination thereof. In another aspect, the one or more
adhesive polymers comprises about 0.5%-20% of the soft capsule
shell. In another aspect, the soft capsule shell further comprises
one or more thermoresponsive polymers. In another aspect, the one
or more thermoresponsive polymers comprises
poly(N-isopropylacrylamide), amine terminated
poly(N-isopropylacrylamide), carboxylic acid terminated
poly(N-isopropylacrylamide),
poly(N-isopropylacrylamide-co-methacrylic acid), or
poly(N-isopropylacrylamide-co-methacrylic acid-co-octadecyl
acrylate), or a combination thereof. In another aspect, the soft
capsule shell composition further comprises one or more film
forming polymers, one or more plasticizers, a solvent, and
optionally, an alkaline neutralizing agent, an acidic neutralizing
agent, a coloring agent, a flavoring or a pharmaceutical excipient.
In another aspect, each of the soft capsule shell sub compositions
comprises: (a) about 20% to about 36% by weight of at least one
film-forming polymer; (b) about 1% to about 25% by weight of one or
more ionically charged polymers; (c) about 1% to about 20% by
weight of at least one plasticizer; (d) about 10% to about 40% by
weight of a solvent; (e) optionally about 1% to about 5% by weight
of at least one alkali-neutralizing agent; (f) optionally about 1%
to about 5% by weight of at least one acidic neutralizing agent;
(g) optionally about 1% to about 5% by weight of an opacifying
agent; and (h) optionally about 0.05% to about 1% by weight of at
least one coloring agent. In another aspect, at least one of the
soft capsule shell sub compositions comprises: (a) about 30% by
weight of at least one film-forming polymer; (b) about 10% by
weight of at least one negatively charged polymer; (c) about 20% by
weight of at least one plasticizer; (d) about 1% by weight of at
least one alkali-neutralizing agent; (e) about 37% by weight of a
solvent; and (f) optionally about 1.5% by weight of an opacifying
agent; and (g) optionally about 0.05% to about 1% by weight of at
least one coloring agent. In another aspect, at least one of the
soft capsule shell sub compositions comprises: (a) about 25% by
weight of at least one film-forming polymer; (b) about 12% by
weight of at least one positively charged polymer; (c) about 17% by
weight of at least one plasticizer; (d) about 1% by weight of at
least one acidic neutralizing agent; (e) about 44% by weight of a
solvent; and (f) optionally about 1.5% by weight of an opacifying
agent; and (g) optionally about 0.05% to about 1% by weight of at
least one coloring agent. In another aspect, the at least one soft
capsule shell sub composition comprises gelatin, acrylic
methacrylate copolymers, glycerol, triethyl citrate, ammonia,
water, and optionally titanium dioxide. In another aspect, the at
least one soft capsule shell sub composition comprises gelatin,
dimethylaminoethyl methacrylate copolymer, glycerol, hydrochloric
acid, water, and optionally titanium dioxide. In another aspect,
the composition comprises one or more active pharmaceutical
ingredients and one or more ionically charged polymers, wherein the
one or more active pharmaceutical ingredients is in a pH responsive
resinate complex with the one or more ionically charged polymers.
In another aspect, the pH responsive resinate complex comprises one
or more positively charged polymers or one or more negatively
charged polymers or a combination of positively or negatively
charged polymers thereof. In another aspect, the pH responsive
resinate complex comprises a cation exchange resin or an anion
exchange resin or a combination thereof. In another aspect, the
cation exchange resin or anion exchange resin comprises an average
particle size of about 1 .mu.m to about 500 .mu.m. In another
aspect, the cation exchange resin or anion exchange resin comprises
an ion exchange capacity of about 1 meq/g to about 6 meq/g. In
another aspect, the cation exchange resin comprises a weak cation
exchange resin or a strong cation exchange resin. In another
aspect, the cation exchange resin comprises a polymer based on
repeating alkyl or heteroalkyl units that may be optionally
crosslinked and comprise functional groups comprising a sodium
polystyrene sulfonate or a carboxylic acid group. In another
aspect, the cation exchange resin comprises Amberlite.TM. IRP 69 or
Amberlite.TM. IRP 88 or a combination thereof. In another aspect,
the anion exchange resin comprises a polymer based on repeating
branched or unbranched alkyl or heteroalkyl units that may be
optionally crosslinked comprising functional groups comprising a
primary amine or a quaternary ammonium. In another aspect, the one
or more active pharmaceutical ingredients is positively charged or
negatively charged and forms a complex with the cation exchange
resin or anion exchange resin based upon an intermolecular ionic
interaction with the one or more ionically charged polymers. In
another aspect, the one or more active pharmaceutical ingredients
is in complex with the resinate complex at a normal pH and
disassociates from the resinate complex at a pH range found in the
stomach. In another aspect, the composition further comprises one
or more adhesive polymers. In another aspect, the one or more
adhesive polymers comprises polycarbophil, xanthan gum,
Carbopol.RTM. 1342P, Carbopol.RTM. 974P, chitosan, Carbopol.RTM.
971P, hydroxypropylmethyl cellulose (e.g., Methocel K100M or
Methocel K15M), sodium carboxymethyl cellulose, hydroxypropylmethyl
cellulose (Methocel K15M), gelatin, or acacia gum, or a combination
thereof. In another aspect, the one or more adhesive polymers
comprises polycarbophil. In another aspect, the composition further
comprises: (a) a liquid lipid vehicle; (b) a semi solid lipid or
lipophilic vehicle; (c) at least one ionic hydrophilic polymer; (d)
at least one hydroscopic polymer; and (e) a suspension agent; and
(f) optionally a non-ionic surfactant; and (g) optionally a
pH-buffering agent In another aspect, the composition comprises:
(a) soybean oil; (b) polyethylene glycol glyceride ester; (c) bee's
wax; (d) polyvinylpyrrolidone or polyethylene oxide; (e) carbomer
polymer; (g) dimethylaminoethyl methacrylate copolymer; (g) fumed
silica; and (h) optionally a poloxamer non-ionic surfactant; and
(I) optionally N-methyl-D-glucamine. In another aspect, the
composition comprises: (a) about 45% to about 52% soybean oil; (b)
about 1.5% to about 5% Gelucire.RTM. 43/01; (c) about 1.8% to about
4% bee's wax; (d) about 2% to about 8% Kollidon.RTM. 90 F; (e)
about 0.5% to about 4% Carbopol.RTM. 971 A; (f) about 2% to about
8% EUDRAGIT.RTM. EPO; (g) about 0.5% to about 5% Aerosil 200; and
(h) optionally about 1% to about 10% Pluronic.RTM. F127; and (i)
optionally about 0.5% to about 6% N-methyl-D-glucamine. In another
aspect, the composition further comprises: (a) one or more
hydrophilic vehicles; (b) at least one carbomer polymers; (c) at
least one hydroscopic polymer; (c) at least one hydrophilic
polymer; (d) at least one ion exchange resin. In another aspect,
the composition comprises: (a) polyethylene glycol 600 (b)
polyethylene glycol 1000; (b) carbopol.RTM. 974P; (c)
polyvinylpyrrolidone; (c) hydroxypropylmethyl cellulose; and (d) at
least one cation exchange resin. In another aspect, the composition
comprises: (a) about 40% to about 70% polyethylene glycol 600 (b)
about 2% to about 15% polyethylene glycol 1000; (b) about 0.25% to
about 3% carbopol.RTM. 974P; (c) about 2% to about 20%
polyvinylpyrrolidone K90; (c) about 2% to about 20%
hydroxypropylmethyl cellulose K100M; and (d) about 1% to about 20%
of at least one cation exchange resins in complex with one or more
active pharmaceutical ingredients. In another aspect, the at least
one cation exchange resin comprises Amberlite.TM. IRP 69 or
Amberlite.TM. IRP 88 or a combination thereof. In another aspect,
the pharmaceutical composition further comprises a means for having
gastro-retentive properties. In another aspect, the means for
having gastro-retentive properties comprises a means for floating
the pharmaceutical composition in a gastric compartment. In another
aspect, the means for floating the pharmaceutical composition in a
gastric compartment comprises the inclusion of one or more of an
effervescent gas generating system, a colloidal gel barrier, porous
beads, a microporous membrane, or the inclusion of one or more
low-density excipients to the pharmaceutical composition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1. Illustration of the anti-overingestion properties of
the pharmaceutical compositions.
[0018] FIG. 2. Illustration of an exemplary anti-overingestion
pharmaceutical composition.
[0019] FIG. 3. In vitro drug release of an Amberlite.TM.
IRP69-dextromethorphan drug resinate at pH 1.5, pH 4.8, and pH 7.4
buffers USP Apparatus I.
[0020] FIG. 4. In vitro drug release of an Amberlite.TM.
IRP88-dextromethorphan drug resinate at pH 1.5, pH 4.8, and pH 7.4
buffers using USP Apparatus I.
[0021] FIG. 5. In vitro drug release of an Amberlite.TM. IRP88 or
Amberlite.TM. IRP69-dextromethorphan drug resinate in distilled
water using USP Apparatus I.
[0022] FIG. 6. In vitro drug release of an Amberlite.TM. IRP88 or
Amberlite.TM. IRP69-dextromethorphan drug resinate in boiling
distilled water.
[0023] FIG. 7. In vitro drug release of an Amberlite.TM. IRP88 or
Amberlite.TM. IRP69-dextromethorphan drug resinate in boiling
distilled water.
[0024] FIG. 8. In vitro drug release of an Amberlite.TM.
IRP69-dextromethorphan drug resinate in simulated gastric fluid, pH
1.2 using USP Apparatus I.
[0025] FIG. 9. In vitro drug release of an Amberlite.TM.
IRP88-dextromethorphan drug resinate in simulated gastric fluid, pH
1.2 using USP Apparatus I.
[0026] FIG. 10. In vitro drug release of an Amberlite.TM.
IRP69-dextromethorphan drug resinate when either 1, 5, or 10
capsules were dissolved together in 0.1 N HCl using USP Apparatus
II.
[0027] FIG. 11. In vitro drug release of dextromethorphan from
control hard capsule shells (without resinate) when either 1 or 10
capsules were dissolved together in 0.1 N HCl using USP Apparatus
II.
[0028] FIG. 12. In vitro drug release of an Amberlite.TM.
IRP88-dextromethorphan drug physical blend when either 1 or 10
capsules were dissolved together in 0.1 N HCl using USP Apparatus
II.
[0029] FIG. 13. In vitro drug release of an Amberlite.TM.
IRP69-dextromethorphan drug physical blend when either 1 or 10
capsules were dissolved together in 0.1 N HCl using USP Apparatus
II.
[0030] FIG. 14. In vitro drug release of an Amberlite.TM. IRP69- or
Amberlite.TM. IRP88-dextromethorphan drug resinate when either 1, 5
or 10 capsules were dissolved together in 0.1 N HCl using USP
Apparatus II with media renewal every 15 minutes.
[0031] FIG. 15. In vitro drug release of Amberlite.TM.
IRP88-dextromethorphan drug resinates in a hydrogel abuse deterrent
composition according to the composition of Table 14 (-PCP) and
Table 16 (+PCP) when either 1 or 5 capsules were dissolved together
according to the parameters of Table 12.
[0032] FIG. 16. In vitro drug release of Amberlite.TM.
IRP69-dextromethorphan drug resinates in a hydrogel abuse deterrent
composition according to the composition of Table 14 (-PCP) and
Table 16 (+PCP) when either 1 or 5 capsules were dissolved together
according to the parameters of Table 12.
[0033] FIG. 17. In vitro drug release of Amberlite.TM.
IRP69-dextromethorphan drug physical blend in a hydrogel abuse
deterrent composition according to the composition of Table 14 when
either 1 or 5 capsules were dissolved together or when 5 control
dextromethorphan API-only containing compositions were dissolved
according to the parameters of Table 12.
[0034] FIG. 18. Pharmacokinetic results from hydrocodone
formulations in male dogs. Average plasma concentration of
hydrocodone as a function of time for the Test and Control dosage
forms at shown in Tables 19-20.
[0035] FIG. 19. Pharmacokinetic results from hydrocodone
formulations in male dogs. (A) C.sub.max versus dose for 5 mg, 25
mg, and 50 mg doses. (B) C.sub.max/dose for the same data in A.
[0036] FIG. 20. Pharmacokinetic results from hydrocodone
formulations in male dogs. (A) AUC.sub.0-14 hr versus dose for 5
mg, 25 mg, and 50 mg doses. (B) AUC.sub.0-14 hr/dose for the same
data in A.
DETAILED DESCRIPTION
[0037] Described herein are abuse deterrent pharmaceutical
compositions that can abrogate oral overingestion of large
quantities of active pharmaceutical ingredients accidentally or
purposely imbibed by a subject. The pharmaceutical compositions
described herein provide abuse deterrent compositions and methods
for preparation thereof. The compositions can be solids or liquids
and delivered as tablets, hard capsules, soft capsules, or enteric
dosage forms.
[0038] 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. The term abuse deterrent
further encompasses the term "anti-overingestion."
[0039] The term "anti-overingestion" refers to the prevention or
mitigation of oral over ingesting greater than one dose of an
active pharmaceutical ingredient when multiple dosage forms are
taken simultaneously or in succession prior to gastric emptying, so
that high levels of the drug are systemically absorbed. As used
herein, anti-overingestion can mitigate both oral abuse of an
active pharmaceutical agent for its euphoric or dissociative
effects, or alternatively mitigate intentional or accidental
overdose that could lead to adverse health effects such as
depressed respiration, comma, cardiac arrest, or death.
[0040] 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.
[0041] 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.
[0042] The phrases "oral abuse" or "oral drug abuse" refer to the
intentional or accidental oral ingestion of greater than the
prescribed or recommended dose of an active pharmaceutical agent by
ingesting multiple dosage forms simultaneously or successively over
a period of time. Oral abuse as used herein is distinguished from
other abusive administration routes such as insufflation,
injection, or ingestion of an extracted or tampered active
pharmaceutical ingredient. Oral abuse is difficult to counteract or
prevent because abuse is predicated on multiple dosage forms being
ingested through the normal or appropriate route of
administration.
[0043] 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."
[0044] 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.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] 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.
[0049] The term "titration" as used herein refers to the
incremental increase in drug dosage to a level that provides the
optimal therapeutic effect.
[0050] 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."
[0051] The term "immediate release" as used herein refers to a
composition that releases an active ingredient over a short period
under physiological conditions or in an in vitro test.
[0052] The term "delayed" release" as used herein refers to a
composition that releases an active ingredient after a period of
time, for example minutes or hours, such that the active ingredient
is not released initially. A delayed release composition may
provide, for example, the release of a drug or active ingredient
from a dosage form, after a certain period, under physiological
conditions or in an in vitro test.
[0053] 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.
[0054] The terms "extended release" or "sustained 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 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 about 18 hours under physiological
conditions or in an in vitro assay.
[0055] 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.
[0056] 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.
[0057] The term "C.sub.min" 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.
[0058] The term "C.sub.avg" 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.
[0059] 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.
[0060] The term "AUC.sub.0.fwdarw..tau." as used herein refers to
area under the blood (plasma, serum, or whole blood) concentration
versus time curve from time zero to time tau (.tau.) 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.12 as used
herein refers to the area under the concentration versus time curve
from 0 to 12 hours.
[0061] The term "AUC.sub.0.fwdarw..varies." 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.
[0062] 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.
[0063] 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.
[0064] 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.
[0065] The term "substantially" as used herein means to a great or
significant extent, but not completely.
[0066] As used herein, all percentages (%) refer to weight (mass)
percent unless noted otherwise.
[0067] 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."
[0068] As used herein, "a" or "an" means one or more unless
otherwise specified.
[0069] 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 capsule shell and matrix is
structured to prevent extraction and over ingestion 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. Exemplary and non-limiting abuse deterrent matrices
useful in the pharmaceutical composition described herein may be
those found in PCT International Application No. PCT/US2015/024464
and in U.S. patent application Ser. No. 14/679,233, each of which
is incorporated by reference herein in their entirety. 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 composition
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
composition 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 is a soft or hard capsule
having one or more active pharmaceutical ingredients in a resinate
complex with one or more ion exchange resins described herein. In
one aspect described herein, the one or more active pharmaceutical
ingredients may be blended with one or more ion exchange resins
described herein.
[0078] In one embodiment described herein, an exemplary abuse
deterrent controlled release matrix has the composition of Table 1
and 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
pharmaceutically acceptable excipients.
TABLE-US-00001 TABLE 1 Exemplary Abuse Deterrent Controlled Release
Composition Component Exemplary Components Composition Range (%)
Lipid or lipophilic Liquid lipid vehicle (LLV) and/or Semisolid
31-92 vehicle(s) lipid vehicle (SLV): soybean oil, bee's wax (LLV:
25-60/SLV: 6-32) Non-ionic surfactant(s) Pluronic .RTM. F127,
poloxamer, Tween .RTM. 80, 1-15 Triton .TM. X Hygroscopic
polymer(s) Polyvinylpyrrolidone (copovidone), ethyl 1-10 cellulose,
hydroxyproply methylcellulose, polyethylene oxide Hydrophilic ionic
Carbopol, Eudragit .RTM., Ethylenediamine 2-20 polymer(s)
Suspension agent(s) Fumed silica, Aerosil .RTM. 0.5-5 pH buffering
agent(s) Triethanolamine, N-methyl-D-glucamine, 1-8 Tromethamine
Active pharmaceutical Oxycodone, Tapentadol, Amytal, 5-50
ingredient with Resin Dextromethorphan Exchange Resin Amberlite
.TM. IRP 69, Amberlite .TM. IRP 88,
TABLE-US-00002 TABLE 2 Exemplary Abuse Deterrent Controlled Release
Composition Composition Range Component Exemplary Components (%)
Hydrophilic vehicle Polyethylene glycol 400-1000 40-80 Hygroscopic
polymer Polyvinylpyrrolidone (copovidone), 0.5-10 polyethylene
oxide Hydrophilic polymer(s) Polyvinylpyrrolidone (copovidone),
1-10 ethyl cellulose, hydroxyproply methylcellulose (Methocel .TM.
K100M), polyethylene oxide Active pharmaceutical Oxycodone,
Tapentadol, Amytal 5-50 ingredient(s) Exchange Resin Amberlite .TM.
IRP 69, Amberlite .TM. IRP 88,
[0079] 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; 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. In another aspect, the
semisolid lipid or lipophilic vehicle comprises a mixture of bee's
wax and carnauba wax.
[0081] In one embodiment, the composition 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.
[0082] In another embodiment, the abuse deterrent composition
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
comprise 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 composition. 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 10 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).
[0083] In one embodiment, the composition comprises a hydrophilic
ionic polymer. In one embodiment, the hydrophilic polymers comprise
polyhydroxylalkylenediamine, dimethylaminoethyl methacrylate
copolymer, Poly(butyl methacrylate-co-(2-dimethylaminoethyl)
methacrylate-co-(2-dimethylaminoethyl) 1:2:1 (Eudragit.RTM. EPO);
sodium carboxy methylcellulose, carboxymethyl cellulose
ethylenediamine, sodium alginate, alginic acid, pectin, carbomers,
Carbopol.RTM. copolymers (polyacrylic acid polymers), such as
Carbopol.RTM. 934, Carbopol.RTM. 940, Carbopol.RTM. 941 or
Carbopol.RTM. 974P; a Pemulen.RTM. polymer; polycarbophil poly
galacturonic acid, polyglucoronic acid, chondroitic sulfate,
carrageenan, and acrylic methacrylate copolymers. In one aspect,
the hydrophilic polymer swells in aqueous media. In another aspect,
the hydrophilic polymers swell at a pH of about 4 to about 6. In
another embodiment, one or more hydrophilic ionic polymers form
ionic interactions. In another embodiment, the composition
comprises anionic polymers, cationic polymers, or mixtures thereof.
In another embodiment, a hydrophilic cationic polymer and a
hydrophilic anionic polymer are combined to form an ionic polymer
complex or network. In one aspect, the hydrophilic ionic polymer is
Carbopol.RTM. 971A. In another aspect, the hydrophilic ionic
polymer is Eudragit.RTM. EPO.
[0084] In another embodiment, the composition comprises a
hygroscopic polymer. In one embodiment, the hygroscopic polymers
include polyvinylpyrrolidone, copovidone,
hydroxypropylmethylcellulose, hydroxypropylcellulose, ethyl
cellulose, methylcellulose, and polyethylene oxide. Suitable
hygroscopic polymers include polyvinyl alcohol, a copolymer of
polyvinylpyrrolidone and polyvinyl acetate, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose,
hydroxymethyl cellulose, gelatin, polyethylene oxide, such as
POLYOX.TM. 100,000-600,000 MW, acacia, dextrin, starch,
polyhydroxyethylmethacrylate, a water-soluble non-ionic
polymethacrylate or copolymer thereof, a modified cellulose, a
modified polysaccharide, a non-ionic gum, or a non-ionic
polysaccharide. In one aspect, the hygroscopic polymer is
polyvinylpyrrolidone. In one aspect, the hygroscopic polymer
comprises Kollidon.RTM. 90 F. In one aspect, the hygroscopic
polymer comprises a cellulose polymer. In one aspect, the
hygroscopic polymer comprises hydroxypropylmethylcellulose (e.g.,
HPMC 4M). In another aspect, the hygroscopic polymer is a
polyethylene oxide polymer (e.g., POLYOX.TM. 100,000).
[0085] In another embodiment, the abuse deterrent composition
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 (M.sub.N, 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 600. In another
aspect, the hydrophilic vehicle comprises polyethylene glycol 1000.
In another aspect, the hydrophilic vehicle comprises polyethylene
glycol 600 and polyethylene glycol 1000.
[0086] In one embodiment described herein, the composition
comprises: (a) about 35% to about 70% by mass of one or more
flowability enhancers; (b) about 20% to about 50% by mass of one or
more release modifiers; and (c) about 1% to about 30% by mass of
one or more active pharmaceutical ingredients. In one aspect, the
composition further comprises: (d) about 0.05% to about 0.5% of one
or more antioxidants. In one aspect, the composition comprises: (a)
glyceryl monolinoleate; (b) polyethylene oxide; and (c) an opiod
such as oxycodone, hydrocodone, or salts thereof. In another
aspect, the composition further comprises: (d) butylated
hydroxytoluene (BHT); and (e) butylated hydroxyanisole (BHA). In
another aspect, the composition comprises: (a) about 50% to about
70% by mass of glyceryl monolinoleate; (b) about 25% to about 40%
by mass of polyethylene oxide; and (c) about 1% to about 20% by
mass of an opiod such as oxycodone, hydrocodone, or salts thereof.
In another aspect, the composition further comprises: (d) about
0.05% to about 0.4% by mass of BHA; and (e) about 0.05% to about
0.2% by mass of BHT. In another aspect, the composition comprises:
(a) about 55% to about 65% by mass of glyceryl monolinoleate; (b)
about 30% to about 35% by mass of polyethylene oxide; and (c) about
1% to about 15% by mass of an opiod such as oxycodone, hydrocodone,
or salts thereof. In another aspect, the composition further
comprises: (d) about 0.1% to about 0.4% by mass of BHA; and (e)
about 0.05% to about 0.1% by mass of BHT. In another aspect, the
composition comprises: (a) about 50% to about 70% by mass of
glyceryl monolinoleate; (b) about 25% to about 40% by mass of
polyethylene oxide; (c) about 0.1% to about 0.4% by mass of BHA;
(d) about 0.05% to about 0.1% by mass of BHT; and (e) about 1% to
about 20% of by mass of an opiod such as oxycodone, hydrocodone, or
salts thereof.
[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.
[0088] In another embodiment, the abuse-deterrent composition
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.
[0089] In another embodiment, the abuse deterrent composition 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.
[0090] 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.
[0091] In one embodiment, the pharmaceutical composition may
comprise an active pharmaceutical ingredient in complex with an
ion-exchange resin. Suitable ion exchange resins described herein
are water-insoluble and comprise a pharmacologically inert organic
and/or inorganic matrix containing covalently bound functional
groups that are ionic or capable of being ionized under appropriate
pH conditions. The organic composition may be synthetic (e.g.,
polymers or copolymers of acrylic acid, methacrylic acid,
sulfonated styrene, sulfonated divinylbenzene), or partially
synthetic (e.g., modified cellulose and dextrans). The inorganic
composition preferably comprises silica gel modified by the
addition of ionic groups. Covalently bound ionic groups may be
strongly acidic (e.g., sulfonic acid, phosphoric acid), weakly
acidic (e.g., carboxylic acid), strongly basic (e.g., primary
amine), weakly basic (e.g. quaternary ammonium), or a combination
of acidic and basic groups. In one aspect, the ion exchange resin
is a sulfonated styrene and divinylbenzene copolymer such as
polystyrene sulfonate or a salt thereof (e.g., Amberlite
IRP-69).
[0092] Exemplary ion-exchangers suitable for use in ion-exchange
chromatography and for such applications as deionization of water
are suitable for use in the compositions described herein. Suitable
ion exchange resins are also sold under the trade names
Amberlite.TM. and Dowex.TM.. Both regularly and irregularly shaped
particles may be used as resins. Regularly shaped particles are
those particles that substantially conform to geometric shapes,
such as spherical, elliptical, cylindrical and the like.
Irregularly shaped ion-exchange resins of this type are exemplified
by Amberlite.TM. IRP-69, which consists of irregularly-shaped
particles with a size range of 47 microns to 149 microns. Such
ion-exchangers are described by H. F. Walton in "Principles of Ion
Exchange" (pp. 312-343) and "Techniques and Applications of
Ion-Exchange Chromatography" (pp. 344-361) in Chromatography. (E.
Heftmann, editor), Van Nostrand Reinhold Company, New York (1975)
and in U.S. Patent Application Publication No 2014/0127300, each of
which is incorporated herein by reference for its teachings of ion
exchange resins thereof. Further non-limiting ion-exchangers are
shown in Table 3.
TABLE-US-00003 TABLE 3 Exemplary Cation and Anion Exchange Resins
Polymer Exchanger type Amberlite IRP 69 Strong Cation Amberlite
200/200C Strong Cation DOWEX .TM. 50WX8H Strong Cation DOWEX .TM.
88 Strong Cation Purolite .RTM. C100HMR Strong Cation Purolite
.RTM. C100NaMR Strong Cation Purolite .RTM. C100CaMR Strong Cation
Lewatit K .RTM. 1481 Strong Cation Lewasorb .RTM. SW 12 Strong
Cation Amberlite .TM. IRP 64 Weak Cation Amberlite .TM. IRP 88 Weak
Cation Purolite .RTM. C 115 K MR Weak Cation Purolite .RTM. C 115 H
MR Weak Cation Purolite .RTM. C 108DR Weak Cation Lewatit .RTM. CNP
105 Weak Cation PolyAMPs Other Polyvinylsulfonic acid Other
(+derivatives) Polyvinylphosphonic acid Other (+derivatives) Poly
acrylic acid (+derivatives) Other
[0093] Binding of the active pharmaceutical ingredients to the
resins described herein may be accomplished using methods known in
the art. For example, the general reactions may be used for a basic
drug these are: (a) resin (e.g., Na.sup.+-form) and an ionic salt
form of the drug being bound; (b) resin (e.g., Na.sup.--form) plus
free base form of drug.
[0094] Analogous binding reactions can be carried out for binding
an acidic drug an anion exchange resin. These are: (a) resin (e.g.,
Cl.sup.- form) plus the salt form of acidic drug to be bound; (b)
resin (e.g., Cl.sup.- form) plus the free acid form of the drug to
be bound; (c) resin (e.g., OH.sup.--form) plus salt form of drug to
be bound; and (d) resin (e.g., OH.sup.--form) plus free acid form
of drug to be bound.
[0095] This binding may be performed, for example, as a batch or
column process, as is known in the art. The drug-resin complexes
described herein may be prepared by a batch process that is based
on reaction the exemplary reactions described herein. The drug to
be loaded on the ion exchange resin may be dissolved in an aqueous
medium or in a solvent miscible with water to make a solution. The
drug-containing solution is then placed in a slurry of the resin or
a column loaded with resin. The drug-resin resinate complex thus
formed is collected by filtration and washed with deionized or
purified water to ensure removal of any unbound drug.
[0096] In one embodiment described herein, the amount of drug
loaded onto the resin to form a resinate ranges from about 1% to
about 80%, including each integer within the specified range. In
one aspect, the amount of drug loaded onto the resin ranges from
about 10% to about 60%, including each integer within the specified
range. In another aspect, the amount of drug loaded onto the resin
ranges from about 30% to about 50%, including each integer within
the specified range. In another aspect, the amount of drug loaded
onto the resin comprises about 50%. In another aspect, the amount
of drug loaded onto the resin comprises about 33%. In another
aspect, the amount of drug loaded onto the resin comprises about
25%. In another aspect, the amount of drug loaded onto the resin
comprises about 20%. In another aspect, the amount of drug loaded
onto the resin comprises about 17%. In another aspect, the amount
of drug loaded onto the resin comprises about 14%. In another
aspect, the amount of drug loaded onto the resin comprises about
12.5%. In another aspect, the amount of drug loaded onto the resin
comprises about 10%.
[0097] Another embodiment described herein is oral immediate
release pharmaceutical composition comprising one or more active
pharmaceutical ingredients, one or more sequestering agents, and
optionally, one or more pharmaceutically acceptable excipients,
wherein the active pharmaceutical ingredients is not pre-bound to
the sequestering agent in the dosage form. In one aspect, the
quantity of active pharmaceutical ingredients (API) bound to the
sequestering agent in the composition prior to ingestion and
solvation is about 0.001% to about 1% including each integer within
the specified range. In one aspect the amount of API pre-bound to
the sequestering agent prior to ingestion is less than about:
0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, about
0.5%, or about 1%. In one aspect the amount of API bound to the
sequestering agent in the composition prior to ingestion is less
than about 1%. In one aspect, the pharmaceutical composition is a
dry powder admixture of one or more sequestering agents and one or
more APIs and optionally one or more pharmaceutically acceptable
excipients. In another aspect, the composition is a tablet,
compressed tablet, or capsule. In these compositions effectively
none of the API is boud to the sequestering agent. Dry powers of
the API and sequestering agent and any excipients are merely
combined, homogenized, and the dosage form produced. The particles
of the sequestering agent are incapable of effectively interacting
with the molecules of API in the solid state of the composition (as
compared to a solution-state binding interaction). Upon ingestion
of the composition by a subject, both the sequestering agent and
API rapidly dissolve in the gastric fluid and ingested liquid(s) in
the stomach. The sequestering agent is then capable of adsorbing a
quantity of the API in situ (in the stomach) and impedes or delays
absorption of the bound API into systemic circulation.
[0098] In one embodiment, the quantity of the API adsorbed by the
sequestering agent after ingestion of a single dose of the
composition is about 0.5% to about 15%, including each integer
within the specified range. In one aspect, the quantity of the API
adsorbed by the sequestering agent after ingestion of a single dose
of the composition is about 0.5%, about 1%, about 2.5%, about 5%,
about 7.5%, about 10%, about 12%, about 15%, about 20%, about 25%,
or about 30%. In aspect, the quantity of the API adsorbed by the
sequestering agent after ingestion of a single dose of the
composition is about 0.5% to about 15%.
[0099] In another embodiment, when a plurality of doses of the
composition are simultaneously ingested or successively ingested
over about a 4-hour period, the greater quantities of sequestering
agent adsorb greater quantities of the API in situ and impede or
delay absorption of the bound API into systemic circulation.
Typical gastric emptying for a human is about 4 hours. As
additional doses of the composition are ingested and solvated in
the stomach, greater quantities of sequestering agent are available
to adsorb the API. The principles of mass action and equilibrium
binding dictate the adsorption and subsequent release of the API
from the sequestering agent. The quantity of the API adsorbed by
the sequestering agent when one or more doses of the composition is
about 0.5% to about 80%, including each integer within the
specified range. In one aspect the quantity of the API adsorbed by
the sequestering agent is about 1%, about 2%, 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%, or about 80%. In one aspect, the quantity of the API
adsorbed by the sequestering agent is about 15% to about 70%.
[0100] In one embodiment, the sequestering agent is capable of
adsorbing API when a single dose of the composition is administered
and the extent bound depends on the molar ratio of the sequestering
agent's binding sites to API. In another aspect, when a plurality
of doses of the composition is ingested simultaneously, nearly
simultaneously, or in succession over a period of time prior to the
onset of gastric emptying (ca. 4 hours), the greater quantities of
sequestering agent present in the stomach are capable of binding
greater quantities of the API and consequently delay or retard
absorption of the API into the systemic circulation. A plurality of
doses can comprise 2 or more dosage forms. In one aspect, a
plurality of doses comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, or greater than 20 doses. Without
being bound by any theory, the composition described herein reduces
the C.sub.max observed by delaying, retarding, or impeding the
absorption of the API into systemic circulation and can also delay
T.sub.max. The AUC observed is proportional to the total dose of
API, but the absorption time is extended because the API is more
slowly absorbed into systemic circulation as the equilibrium shifts
from sequestering agent-bound API to free API that can be absorbed.
Clearance time is also extended because the absorption rate
constant and elimination rate constant are both reduced. The
composition mitigates accidental or intentional overingestion by
precluding a bolus concentration of API available for absorption
that can lead to toxic C.sub.max levels and consequent
physiological effects such as depressed respiration, coma, cardiac
arrest, or death.
[0101] Another embodiment described herein is a composition or a
method for reducing the C.sub.max of an API. In one aspect the
composition comprises an oral immediate release pharmaceutical
composition comprising one or more active pharmaceutical
ingredients, one or more sequestering agents, and optionally, one
or more pharmaceutically acceptable excipients, wherein the active
pharmaceutical ingredient is not bound to the sequestering agent in
the dosage form. Another aspect is a method for maintaining a
specific C.sub.max of an API within a therapeutic concentration
window or below a maximum concentration comprising administering to
a subject one or more oral immediate release pharmaceutical
compositions comprising one or more active pharmaceutical
ingredients (API), optionally, one or more sequestering agents, and
optionally, one or more pharmaceutically acceptable excipients,
where less than about 1% of the API is bound to the sequestering
agent, and following ingestion of at least one dose by a subject,
the sequestering agent adsorbs a quantity of the API and impedes
its release into the subject's systemic circulation. In one aspect,
the C.sub.max of an API in a composition comprising a sequestering
agent is about 10% to about 50% less than an equivalent dose of the
API in a composition lacking a sequestering agent including each
integer within the specified percentage range. In one aspect, the
API's C.sub.max is about 30% less; about 25% less, or about 50%
less when a composition comprising a sequestering agent is
administered than an equivalent dose of the API in a composition
lacking a sequestering agent.
[0102] Another embodiment described herein is a composition or a
method for maintaining a specific concentration of an API within a
therapeutic concentration window. In one aspect the composition
comprises an oral immediate release pharmaceutical composition
comprising one or more active pharmaceutical ingredients, one or
more sequestering agents, and optionally, one or more
pharmaceutically acceptable excipients, wherein the active
pharmaceutical ingredient is not bound to the sequestering agent in
the dosage form. Another aspect is a method for maintaining a
specific concentration of an API within a therapeutic concentration
window comprising administering to a subject one or more oral
immediate release pharmaceutical compositions comprising one or
more active pharmaceutical ingredients (API), optionally, one or
more sequestering agents, and optionally, one or more
pharmaceutically acceptable excipients, where less than about 1% of
the API is bound to the sequestering agent, and following ingestion
of at least one dose by a subject, the sequestering agent adsorbs a
quantity of the API and impedes its release into the subject's
systemic circulation. In another aspect, the method comprises
acquiring a bodily fluid from the subject; measuring the
concentration of the API in the subject's circulation; and
according to the measured API concentration and a desired optimal
API therapeutic concentration, either administering one or more
doses of the composition comprising the API and a sequestering
agent; administering an equivalent dose of the API comprising a
composition lacking a sequestering agent; or administering either
one or more doses of the composition comprising the API and a
sequestering agent or administering an equivalent dose of the API
comprising a composition lacking a sequestering agent after a
period of about 30 min to about 12 hours, including all integers
within the specified time range. In one aspect, doses of the API
with a sequestering agent can be titrated against equivalent does
of the same API without a sequestering agent to achieve the optimum
API therapeutic plasma concentration window.
[0103] In another embodiment described herein, the drug and a
sequestering agent, such as a resin, are combined with each other
in the dry state (a dry admixture) so that the drug is not bound to
the resin. Upon ingestion, the resin and drug are solvated and the
solvated resin is capable of binding a portion of the solvated
drug. In one embodiment, the quantity (mass) of resin is a multiple
of the quantity (mass) of drug comprising a range from 1:1 to 20:1,
including all ratios within the specified range. In some
embodiments the quantity (mass) of resin is a multiple of the
quantity (mass) of drug, such as: 2:1, 3:1, 4:1, 5:1, 6:1, 7:1,
8:1, 9:1, or 10:1. In another embodiment, the quantity (mass) of
resin is equal to the quantity (mass) of drug (1:1). An equal
quantity of resin and drug by mass does not necessarily saturate
the resin because the polymeric resin has many binding sites per
polymer. The moles of binding sites or milliequivalents per gram of
sequestering agent can be determined by the capacity of the
resin.
[0104] In another embodiment described herein, the abuse deterrent
compositions described herein can prevent extraction of an active
pharmaceutical ingredient through the additional means of crushing,
grating, grinding, or cutting dosage forms comprising the
pharmaceutical compositions described herein. In another embodiment
described herein, the abuse deterrent composition also prevents the
overingestion of one or more active pharmaceutical ingredients
described herein.
[0105] In one embodiment, the composition comprises any one of the
compositions of Tables 13-17 or 19.
[0106] In another embodiment, the one or more active pharmaceutical
ingredient comprises from about 1% to about 50% of the total
composition 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
composition mass, including all integers within the specified
range. In one aspect, the active pharmaceutical ingredient
comprises about 5% of the total composition mass. In one aspect,
the active pharmaceutical ingredient comprises about 7% of the
total composition mass. In one aspect, the active pharmaceutical
ingredient comprises about 10.5% of the total composition mass. In
one aspect, the active pharmaceutical ingredient comprises about
20% of the total composition mass. In one aspect, the active
pharmaceutical ingredient comprises about 25% of the total
composition mass.
[0107] In another embodiment, the ratio of active pharmaceutical
ingredient to the total composition 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 the total composition 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 composition is about 1:100. In another aspect, the ratio of
active pharmaceutical ingredient to the total composition is about
1:10. In another aspect, the ratio of active pharmaceutical
ingredient to the total composition is about 1:7.5. In another
aspect, the ratio of active pharmaceutical ingredient to the total
composition is about 1:5. In another aspect, the ratio of active
pharmaceutical ingredient to the total composition is about 1:3. In
another aspect, the ratio of active pharmaceutical ingredient to
the total composition is about 1:2.
[0108] In another embodiment, the ratio of active pharmaceutical
ingredient to the resin or resinate ranges from about 1:50 to about
10:1, including all iterations of ratios within the specified
range. In another embodiment, the ratio of active pharmaceutical
ingredient to the resin or resinate ranges from about 1:5 to about
1:1, including all iterations of ratios within the specified range.
In one aspect, the ratio of active pharmaceutical ingredient to the
resin or resinate is about 1:50. In another aspect, the ratio of
active pharmaceutical ingredient to the resin or resinate is about
1:10. In another aspect, the ratio of active pharmaceutical
ingredient to the resin or resinate is about 1:5. In another
aspect, the ratio of active pharmaceutical ingredient to the resin
or resinate is about 1:2. In another aspect, the ratio of active
pharmaceutical ingredient to the resin or resinate is about 1:1. In
another aspect, the ratio of active pharmaceutical ingredient to
the resin or resinate is about 2:1. In another aspect, the ratio of
active pharmaceutical ingredient to the resin or resinate is about
3:1. In another aspect, the ratio of active pharmaceutical
ingredient to the resin or resinate is about 4:1.
[0109] In one embodiment, the composition contains an active
pharmaceutical ingredient in a suspended, form, soluble form,
insoluble form, or combinations thereof. In another embodiment, the
composition 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.
[0110] In one embodiment, the composition 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.
[0111] 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.
[0112] 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.
[0113] 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.
[0114] 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.
[0115] 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.
[0116] 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.
[0117] 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.
[0118] 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.
[0119] 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.
[0120] 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.
[0121] 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.
[0122] 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.
[0123] 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.
[0124] 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.
[0125] 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.
[0126] 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-I
(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.
[0127] 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.
[0128] Other examples of active drug substances suitable for use in
the pharmaceutical compositions described herein include anabolic
steroids, cannabis, cocaine, or diazepam.
[0129] In another embodiment, the active drug substance comprises
the therapeutic classes including non-steroidal anti-inflammatory
substances or antirheumatic active drug substances.
[0130] 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.
[0131] 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.
[0132] 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.
[0133] 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.
[0134] 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.
[0135] In other embodiment, the active drug substance comprises
amfetamine, dexamfetamine, lisdexamfetamine, metamfetamine,
methylphenidate, dexmethylphenidate, or combinations thereof.
[0136] 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.
[0137] 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.
[0138] 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.
[0139] 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.
[0140] 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.
[0141] In another embodiment, the pharmaceutical compositions
described herein may comprise pharmaceutically acceptable salts of
any of the above mentioned active drug substances.
[0142] 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.
[0143] 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.
[0144] In another embodiment, the active pharmaceutical ingredient
may be in any of its crystalline, polymorphous, semi-crystalline,
amorphous or polyamorphous forms or mixtures thereof.
[0145] 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.
[0146] 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.
[0147] In one embodiment described herein, the pharmaceutical
composition comprises soft capsule shell comprising a matrix
comprising an active pharmaceutical ingredient.
[0148] In one embodiment described herein, the 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 colorings,
flavorings, or excipients.
TABLE-US-00004 TABLE 4 Exemplary soft gelatin capsule composition
Weight Exemplary Percentage Component Component (%) 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%
[0149] 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.
[0150] 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.
[0151] In one embodiment, the enteric soft capsule shell has the
exemplary composition shown in Table 5.
TABLE-US-00005 TABLE 5 Exemplary Soft Capsule Shell Composition
Percent weight Component (%) 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%
[0152] 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.
[0153] 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.
[0154] In one embodiment, the weight percentage range of
film-forming polymer of the soft capsule described herein is about
20% to about 45%, including all integers within the specified
range. In one aspect, the film-forming polymer weight percentage is
about 20%. In one aspect, the film-forming polymer weight
percentage is about 25%. In one aspect, the film-forming polymer
weight percentage is about 30%. In one aspect, the film-forming
polymer weight percentage is about 35%. In one aspect, the
film-forming polymer weight percentage is about 38%. In another
aspect, the film-forming polymer weight percentage is about 42%. In
another aspect, the film-forming polymer weight percentage is about
44%.
[0155] 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%.
[0156] 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.
[0157] 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.
[0158] 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
(.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).
[0159] 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 an 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 an 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 an 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.
[0160] In another embodiment described herein, the pharmaceutical
composition comprises an enteric soft capsule shell comprising a
matrix fill comprising an active pharmaceutical ingredient.
[0161] 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.
[0162] 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.
[0163] 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.
[0164] 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.
[0165] 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.
[0166] 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.
[0167] In one embodiment, an enteric soft capsule shell has the
composition of Table 6, 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-00006 TABLE 6 Exemplary Enteric Soft Capsule Shell
Composition Composition Range Component Exemplary Component (%)
Film-forming polymer Gelatin 20-36 Enteric, acid insoluble polymer
Methacrylic Acid Copolymer 8-20 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
[0168] 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.
[0169] 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.
[0170] 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%.
[0171] 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%.
[0172] 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.
[0173] 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).
[0174] 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).
[0175] 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).
[0176] 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.1.73).
[0177] 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).
[0178] 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.
[0179] 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%.
[0180] In one embodiment, the enteric soft capsule shell has the
exemplary composition shown in Table 7.
TABLE-US-00007 TABLE 7 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%
[0181] 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.
[0182] 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.
[0183] 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.
[0184] 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.
[0185] 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; 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 same thicknesses, capsule types and sizes as
described herein for soft capsules can also be used for enteric
soft capsules.
[0186] 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. Pat. 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).
[0187] 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.
[0188] In another embodiment, the capsule shell may be a soft
capsule shell that comprises multiple charges. The charges may be
spatially separated so that a first portion of the capsule shell
has one or more charges and a second portion of the capsule shell
has one or more charges. In some embodiments described herein, the
ionic charges result from charged polymers included in the capsule
shell. Thus, in some aspects, the capsule may comprise a portion
that has a positive charge and a second portion that has a negative
charge.
[0189] In one embodiment, the positive soft capsule shell comprises
a type gelatin A; dimethylaminoethyl methacrylate copolymer;
glycerol; HCl, water and optionally polyethylene oxide; an
opacifier, colorant, flavoring, or other pharmaceutical excipient.
Type A gelatins useful for the charged soft capsule shells
described herein has approximately 80 millimoles of free carboxyl
groups per 100 g of protein with an isoelectric point (PI) of about
7.0-9.0. Exemplary and non-limiting polymers for use in the
positive charged soft capsule shells described herein are shown in
Table 8.
[0190] In one embodiment, the negative soft capsule shell comprises
a type gelatin B; methacrylic acid coploymer; glycerol; ammonium
hydroxide, HCl, water and optionally polyethylene oxide; an
opacifier, colorant, flavoring, or other pharmaceutical excipient.
Type B gelatins useful for the charged soft capsule shells
described herein has approximately 100-115 millimoles of free
carboxyl groups per 100 g of protein with an isoelectric point (PI)
of about 4.7-5.2. Exemplary and non-limiting polymers for use in
the positive charged soft capsule shells described herein are shown
in Table 9.
TABLE-US-00008 TABLE 8 Exemplary Polymers Useful for Positive Soft
Capsule Shell Compositions EX 1 EX 2 EX 3 Gelatin (Type A) Gelatin
(Type A) Gelatin (Type A) Iso Elec. Pt. 8.9 (From Nitta)
Dimethylaminoethyl Dimethylaminoethyl Dimethylaminoethyl
Methacrylate Copolymer Methacrylate Copolymer Methacrylate
(EUDRAGIT .RTM. EPO) (EUDRAGIT .RTM. EPO) Copolymer (EUDRAGIT .RTM.
EPO) Glycerol Glycerol Glycerol HCl HCl HCl Water Water Water
Polyethylene oxide
TABLE-US-00009 TABLE 9 Exemplary Polymers Useful for Negative Soft
Capsule Shell Compositions EX 4 EX 5 EX 6 Gelatin (Type B) Gelatin
(Type B) Gelatin (Type B) Iso Elec. Pt. 4 (From Nitta) Methacrylic
Acid Methacrylic Acid Iota-carrageenan Coploymer Coploymer
(EUDRAGIT .RTM. L100) (EUDRAGIT .RTM. L100) Glycerol Glycerol
Glycerol Ammonium Hydroxide Ammonium Hydroxide Water 0.1N HCl 0.1N
HCl Water 1% Polyethylene oxide Water
[0191] In another embodiment the multiple charged soft capsule
shell may be a dual charged capsule shell. As described herein, the
dual charged soft capsule shell may comprise a first portion that
is positively charged and a second portion that is negatively
charged. The positive portion of the soft capsule shell may be
prepared by forming a positive gel mass ribbon composition.
Likewise, the negative portion of the soft capsule shell may be
prepared by forming a negative gel mass ribbon composition. The two
ribbon compositions may then be combined using standard rotary die
encapsulation techniques to form a dual charged (positive and
negative) total soft capsule shell. This total soft capsule shell
may further encapsulate one or more active pharmaceutical
ingredients (e.g., drug-resinate) in an abuse deterrent matrix as
described herein. Exemplary and non-limiting dual charged soft
capsule shell gel mass ribbon compositions are provided in Table
10.
[0192] In another embodiment, a soft capsule shell may be further
coated with one or more charged film compositions according to
Tables 8-10. In one aspect, a charged soft capsule shell comprising
the composition of any one of Tables 8-10 may further be coated
with an additional film composition according to any one of Tables
8-10.
TABLE-US-00010 TABLE 10 Exemplary Dual Charged Soft Capsule Shell
Gel Mass Ribbon Compositions Positive Percentage Negative
Percentage Components (%) (%) Gelatin 20-35 20-35 Methacrylic Acid
Copolymer -- 5-20 (EUDRAGIT .RTM. L 100) Dimethylaminoethyl 4-22 --
Methacrylate Copolymer (EUDRAGIT .RTM. EPO) Glycerol 5-25 5-25
Triethyl citrate 0.5-3 HCl 0.5 -- Ammonium hydroxide -- 0.5-5
Titanium dioxide -- 0.5-5 Water 30-50 30-50 TOTAL 100 100
[0193] Another embodiment described herein is an oral
pharmaceutical composition comprising a solid dosage form such as a
powder or a compressed tablet. In one aspect, the composition is a
non-layered homogeneous powder suspension. In one aspect, the
composition comprises one or more active pharmaceutical ingredients
and one or more sequestering agents. In one aspect, the
sequestering agent comprise one or more ionizable polymers,
including cationic, anionic polymers, or zwitterionic polymers. In
one aspect, the sequestering agent is an ion exchange resin. In one
aspect the one or more active pharmaceutical ingredients and one or
more sequestering agents are not pre-bound (e.g., are not a
resinate complex). In one aspect, the composition comprises a
powder suspension of the active pharmaceutical ingredients, the
sequestering agents, and optionally, one or more pharmaceutically
acceptable excipients.
[0194] One embodiment described herein is an oral pharmaceutical
composition comprising (a) a solid dispersion of an active
pharmaceutical ingredient or a salt thereof as described herein;
(b) one or more sequestering agents; and (c) one or more
pharmaceutically acceptable excipients. In some embodiments, the
composition further comprises (d) one or more fillers (e) one or
more binders, (f) one or more disintegrants, or (g) one or more
lubricants. In one aspect, the filler comprises one or more of
lactose, lactose monohydrate, glucose, fructose, sucrose, sorbitol,
mannitol, dicalcium phosphate dihydrate, cellulose, ethyl
cellulose, methyl cellulose, microcrystalline cellulose,
crospovidone, or a combination thereof. In one aspect, the
disintegrant comprises one or more of crospovidone, croscarmellose
sodium, alginic acid, microcrystalline cellulose, polacrilin
potassium, sodium starch glycolate, starch, pregelatinized starch,
or a combination thereof. In one aspect, the lubricant comprises
one or more of magnesium stearate, calcium stearate, zinc stearate,
sodium stearyl fumarate, stearic acid, talc, glyceryl behenate, or
a combination thereof. In one aspect, the pharmaceutical
composition comprises one or more colorants, flavorings, binders,
glidants, coatings, or other pharmaceutically acceptable
excipients. In one aspect, the filler comprises microcrystalline
cellulose and lactose monohydrate; the disintegrant comprises
crospovidone; and the lubricant comprises magnesium stearate.
[0195] As described herein, the pharmaceutically acceptable
compositions comprise pharmaceutically acceptable excipients,
carriers, adjuvants, or vehicles, which, as used herein, includes
any and all solvents, diluents, or other liquid vehicle, dispersion
or suspension aids, surface active agents, isotonic agents,
thickening or emulsifying agents, preservatives, solid binders,
lubricants and the like, as suited to the particular dosage form
desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.
W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses
various carriers used in formulating pharmaceutically acceptable
compositions and known techniques for the preparation thereof.
Except insofar as any conventional carrier medium is incompatible
with the compounds described herein, such as by producing any
undesirable biological effect or otherwise interacting in a
deleterious manner with any other component(s) of the
pharmaceutically acceptable composition, its use is contemplated to
be within the scope of the embodiments described herein. Some
examples of materials which can serve as pharmaceutically
acceptable carriers include, but are not limited to, ion
exchangers, alumina, aluminum stearate, lecithin, serum proteins,
such as human serum albumin, buffer substances such as phosphates,
glycine, sorbic acid, or potassium sorbate, partial glyceride
mixtures of saturated vegetable fatty acids, water, salts or
electrolytes, such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such
as lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol or polyethylene glycol;
esters such as ethyl oleate and ethyl laurate; agar; buffering
agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator.
[0196] Another embodiment described herein comprises a
pharmaceutical composition comprising an active pharmaceutical
ingredient or a salt thereof as described herein, and one or more
pharmaceutically acceptable excipients.
[0197] Another embodiment described herein comprises a
pharmaceutical composition comprising a therapeutically effective
amount of an active pharmaceutical ingredient or a salt thereof as
described herein, and one or more pharmaceutically acceptable
carriers or vehicles.
[0198] The compositions described herein may be administered using
any amount and any route of administration effective for treating
or lessening the severity of pain or non-pain diseases described
herein. The exact amount of the active pharmaceutical active
ingredient(s) required will vary from subject to subject, depending
on the species, age, and general condition of the subject, the
severity of the infection, the particular agent, its mode of
administration, tolerance of the individual to the active
ingredient, and the like. The compositions described herein are
preferably formulated in dosage unit form for ease of
administration and uniformity of dosage. The expression "dosage
unit form" as used herein refers to a physically discrete unit of
agent appropriate for the subject to be treated. The total daily
usage of the compounds and compositions described herein will be
decided by the attending physician within the scope of sound
medical judgment. The specific effective dose level for any
particular subject or organism will depend upon a variety of
factors including the disorder being treated and the severity of
the disorder; the activity of the specific compound employed; the
specific composition employed; the age, body weight, general
health, sex and diet of the subject; the time of administration,
route of administration, and rate of excretion of the specific
compound employed; the duration of the treatment; drugs used in
combination or coincidental with the specific compound employed,
and like factors well known in the medical arts.
[0199] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient including but not limited to:
(a) fillers or extenders such as starches, lactose, sucrose,
glucose, mannitol, and silicic acid, (b) binders such as, for
example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as
glycerol, (d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, (e) solution retarding agents such
as paraffin, (f) absorption accelerators such as quaternary
ammonium compounds, g) wetting agents such as, for example, cetyl
alcohol and glycerol monostearate, (h) absorbents such as kaolin
and bentonite clay, and (i) lubricants such as talc, calcium
stearate, magnesium stearate, solid polyethylene glycols, sodium
lauryl sulfate, and mixtures thereof. In the case of capsules,
tablets and pills, the dosage form may also comprise buffering
agents.
[0200] As used herein, a "disintegrant" is an excipient that
hydrates a pharmaceutical composition and aids in tablet
dispersion. Examples of disintegrants include crospovidone, sodium
croscarmellose, alginic acid, microcrystalline cellulose,
polacrilin potassium, sodium starch glycolate, starch,
pregelatinized starch, or combinations thereof.
[0201] As used herein, a "filler" is an excipient that adds
bulkiness to a pharmaceutical composition. Examples of fillers
include lactose, lactose monohydrate, glucose, fructose, sucrose,
sorbitol, mannitol, dicalcium phosphate dihydrate, cellulose, ethyl
cellulose, methyl cellulose, microcrystalline cellulose,
crospovidone, or a combination thereof.
[0202] As used herein, a "binder" is an excipient that imparts a
pharmaceutical composition with enhanced cohesion or tensile
strength (e.g., hardness). Examples of binders include dibasic
calcium phosphate, sucrose, corn (maize) starch, microcrystalline
cellulose, and modified cellulose (e.g., hydroxymethyl
cellulose).
[0203] As used herein, a "lubricant" is an excipient that is added
to pharmaceutical compositions that are pressed into tablets. The
lubricant aids in compaction of granules into tablets and ejection
of a tablet of a pharmaceutical composition from a die press.
Examples of lubricants include magnesium stearate, calcium
stearate, zinc stearate, sodium stearyl fumarate, stearic acid,
talc, glyceryl behenate, or a combination thereof.
[0204] As used herein, a "glidant" is an excipient that imparts a
pharmaceutical composition with enhanced flow properties. Examples
of glidants include colloidal silica or talc.
[0205] As used herein, a "surfactant" is an excipient that imparts
pharmaceutical compositions with enhanced solubility and/or
wetability. Examples of surfactants include sodium lauryl sulfate
(SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan
mono-oleate (e.g., Tween.TM.), or a combination thereof.
[0206] As used herein, a "colorant" is an excipient that imparts a
pharmaceutical composition with a desired color. Examples of
colorants include commercially available pigments such as FD&C
coloring agents, titanium dioxide, iron oxide, or combinations
thereof.
[0207] As used herein, a "flavoring" is an excipient that imparts a
flavor or taste masking property to a pharmaceutical composition.
Examples of flavorings include anethole, benzaldehyde, ethyl
vanillin, menthol, methyl salicylate, monosodium glutamate, orange
flower oil, peppermint, peppermint oil, peppermint spirit, rose
oil, stronger rose water, thymol, tolu balsam tincture, vanilla,
vanilla tincture, vanillin, or combinations thereof.
[0208] As used herein a "coating agent" makes the dosage from
smoother and easier to swallow, controls the release rate of the
active ingredient, and makes the dosage from more resistant to the
environment (extending its shelf life), or enhances the dosage
form's appearance Examples of coating agents include sodium
carboxymethylcellulose, cellulose acetate, cellulose acetate
phthalate, ethylcellulose, gelatin, pharmaceutical glaze,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
hydroxypropyl methylcellulose phthalate, methacrylic acid
copolymer, methylcellulose, polyvinyl acetate phthalate, shellac,
sucrose, titanium dioxide, carnauba wax, microcrystalline wax,
zein, or combinations thereof.
[0209] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions that can be used include
polymeric substances and waxes. Solid compositions of a similar
type may also be employed as fillers in soft and hard-filled
gelatin capsules using such excipients as lactose or milk sugar as
well as high molecular weight polyethylene glycols and the
like.
[0210] Another embodiment described herein is a kit for dispensing
the oral pharmaceutical dosage form produced by any of the
compositions or the methods described herein comprising: (a) at
least one dosage form comprising one or more active pharmaceutical
ingredients or salts thereof as described herein; (b) at least one
moisture proof dispensing receptacle comprising blister or strip
packs, an aluminum blister, a 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; and optionally (c) an insert comprising
instructions, prescribing information, or warnings for an active
pharmaceutical ingredient comprised by the pharmaceutical
composition; or (d) directions for administration or any
contraindications. In one aspect described herein, the kit is
useful for treating pain or a medical condition according to any of
the methods described herein.
[0211] One embodiment described herein, is a pharmaceutical
composition 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.
[0212] 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 dog. 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).
[0213] In one embodiment, the dosage may be administered to a human
in need of management of moderate to severe chronic pain or
neuropathic pain, when a continuous, persistent (around-the-clock)
opioid analgesic is needed for an extended period of time.
[0214] 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.
[0215] 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.
[0216] In one embodiment, the abuse deterrent oral composition
described herein, comprises one or more active pharmaceutical
ingredients in an amount of about 1 mg, about 2, mg, about 3 mg,
about 4 mg, 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, about 510 mg, about 520 mg, about 530 mg,
about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580
mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about
630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg,
about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720
mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about
770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg,
about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860
mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about
910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg,
about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000
mg, or even more. Multiples of any of the forgoing quantities can
be dispensed to achieve the therapeutic effect.
[0217] In another embodiment, the compositions described herein,
comprise 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. Multiples of any
of the forgoing quantities can be dispensed to achieve the
therapeutic effect.
[0218] In one embodiment described herein, the compositions
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 33%. 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 17%. In one aspect, the drug load is about 15%. In one
aspect, the drug load is about 12%. In one embodiment, the drug
load is about 50%.
[0219] 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.
[0220] 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.
[0221] 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.
[0222] 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.
[0223] 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.
[0224] 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.
[0225] 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.
[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 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.
[0227] 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.
[0228] 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.
[0229] In another embodiment, the abuse deterrent pharmaceutical
composition comprising an abuse deterrent composition 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.
[0230] 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 FIGS. 3-17.
[0231] 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.
[0232] 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 FIGS. 3-17.
[0233] Another embodiment described herein is a method for treating
an individual having pain, with a pharmaceutical composition
described herein comprising an abuse deterrent composition
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.
[0234] Another embodiment described herein is a method for treating
an individual having pain, with a pharmaceutical composition
described herein comprising an abuse deterrent composition
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..varies. 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
oxycodone, wherein subjects administered a single dosage exhibit a
mean plasma oxycodone AUC.sub.0.fwdarw..varies. 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..varies. 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..varies. 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..varies. of about 1000 hmg/L.
[0235] Another embodiment described herein is a method for treating
an individual having pain, with a pharmaceutical composition
described herein comprising an abuse deterrent composition
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 T.sub.max 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.
[0236] Another embodiment described herein is a method for treating
an individual having pain, with a pharmaceutical composition
described herein comprising an abuse deterrent composition
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.
[0237] Another embodiment described herein is a method for treating
an individual having pain, with a pharmaceutical composition
described herein comprising an abuse deterrent composition
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..varies. 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..varies. 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..varies. 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..varies. 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..varies. of about 1600 hmg/L.
[0238] Another embodiment described herein is a method for treating
an individual having pain, with a pharmaceutical composition
described herein comprising an abuse deterrent composition
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.
[0239] 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; OIC), 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.
[0240] 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.
[0241] 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.
[0242] 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.
[0243] 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.
[0244] 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.
[0245] 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.
[0246] 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.
[0247] 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.
[0248] 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.
[0249] 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 oxycodone and about 20 mg of naloxone, wherein subjects
administered a single dosage exhibit a mean plasma oxycodone
AUC.sub.0.fwdarw..varies. of about 400 hmg/L to about 600 hmg/L and
a mean plasma naloxone AUC.sub.0.fwdarw..varies. 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 T.sub.max of about 1 hr to about 5 hrs and a naloxone
T.sub.max of about 0.5 hr to about 3 hrs.
[0250] 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.
[0251] 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.
[0252] 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.
[0253] 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.
[0254] 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.
[0255] 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.
[0256] 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.
[0257] 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.
[0258] In another embodiment, 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.
[0259] In another embodiment, 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.
[0260] 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. 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.
[0261] 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.
[0262] 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. 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 OIC) as
described herein.
[0263] 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.
[0264] 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.
[0265] 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 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 withdrawl symptoms, diarrhea, nausea,
reduced euphoria or a mixture or combination thereof.
[0266] 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 the 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, contraindications, warnings, or other appropriate
information.
[0267] It will be apparent to one of ordinary skill in the relevant
art that suitable modifications and adaptations to the
compositions, formulations, methods, processes, 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 exemplary
compositions and formulations described herein may omit any
component, substitute any component disclosed herein, or include
any component disclosed elsewhere herein. The ratios of the mass of
any component of any of the compositions or 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. Should the
meaning of any terms in any of the patents or publications
incorporated by reference conflict with the meaning of the terms
used in this disclosure, the meanings of the terms or phrases in
this disclosure are controlling. Furthermore, the foregoing
discussion discloses and describes merely exemplary embodiments.
All patents and publications cited herein are incorporated by
reference herein for the specific teachings thereof.
EXAMPLES
Example 1
[0268] Pharmaceutical compositions as described herein for
preventing the over ingestion of active pharmaceutical ingredients
are illustrated in FIGS. 1 and 2.
[0269] FIG. 1 represents the anti-over ingestion properties of the
pharmaceutical compositions described herein. As shown, when one
capsule (2) is ingested into the stomach (1) a controlled release
(e.g., an immediate release) of all of the one or more active
pharmaceutical ingredients (3) occurs. However, when multiple of
the capsules (2) are ingested into the stomach (1), a clumping of
the capsules (4) occurs, which inhibits the release of the one or
more active pharmaceutical ingredients (3), effectively preventing
over ingestion of the active pharmaceutical ingredient.
[0270] FIG. 2 is a pharmaceutical composition contemplated herein.
In one embodiment described herein, the pharmaceutical composition
may be a soft or hard capsule shell containing one or more multiple
ionic polymers (5; 6) encapsulating one or more active
pharmaceutical ingredients (3). In another embodiment described
herein, the soft or hard capsule shell may not have any ionic
polymers. As shown, a positive polymer (5) may be used in at least
a portion of the soft capsule shell and a negative polymer (6) may
be used in at least a portion of the soft capsule shell in those
compositions containing multiple ionic polymers. The active
pharmaceutical ingredient (3) (e.g., an abuse prone drug;
oxycodone) may further be in a polyelectrolyte complex. In some
aspects described herein, this polyelectrolyte complex is a cation
or anion exchange complex, which further inhibits the release of
the active pharmaceutical ingredient (3) when multiple dosage forms
are dissolved in proximity of each other. The cation or anion
exchange complex may comprise a positive cation or a negative anion
exchanger. An exemplary positive cation exchanger polymer with
carboxylic acid groups (8) is shown.
[0271] The pharmaceutical composition described herein may further
comprise an abuse deterrent matrix (7), which prevents the
crushing, grating, grinding, cutting, solvating, or dissolving of
one or more active pharmaceutical ingredients. An additional means
(9) for obtaining gastroretentive properties to the pharmaceutical
composition may be included in the matrix fill or alternatively in
the capsule shell (not illustrated). Exemplary and non-limiting
means for gastroretentive properties known in the art may comprise
one or more of an effervescent gas generating system, a colloidal
gel barrier, porous beads, a microporous membrane, or the inclusion
of one or more low-density excipients.
Example 2
[0272] Weak and strong cation exchange resins and a bound surrogate
drug (dextromethorphan) were evaluated for use in an abuse
deterrent composition. Biochemically similar opioids contemplated
herein will demonstrate similar behaviors and release kinetics. The
first resin used was strongly acidic and is based on polystyrene
sulfonate (Amberlite.TM. IRP69) and a weakly acidic resin that is
based on carboxylic acid functional groups (Amberlite.TM. IRP88).
Drug-resinates were prepared according to the following process: a
solution of drug in deionized water was mixed with an ion-exchange
resin. Typically, a 1:1 ratio of resin to drug was used. The
resinate complex was then separated from the remaining solution by
filtration or centrifugation and the resulting resinate was washed
several times with DI water and dried in a vacuum. Several batches
of resinates of dextromethorphan with Amberlite.TM. IRP88 or
Amberlite.TM. IRP69 were prepared and encapsulated in a hard
capsule.
[0273] The in vitro drug release from drug-resinates was assessed
in simulated gastrointestinal fluid mediums and in medias having
different pH values. The in vitro drug release from drug-resinates
at pH: 1.5, 4.8 and 7.4 was assessed using the USP basket method
(APP I) at 100 rpm in 900 mL of media. The drug release profile
with either a drug load of 41 mg from Amberlite.TM. IRP69 and
Amberlite.TM. IRP88 is shown in FIGS. 3 and 4, respectively.
[0274] The in vitro drug release from drug-resinate was assessed in
DI water to demonstrate that the observed drug release from FIGS. 3
and 4 is resulting from the exchange of bound drug ions by ions
normally present in body fluids. This test was carried out using
the basket method (APP I) at 100 rpm in 900 mL with a
dextromethorphan Amberlite.TM. IRP69 or Amberlite.TM. IRP88
resinate as shown in FIG. 5. The drug release in DI water is
negligible suggesting that drug release occurs only in the presence
of ions in the media. Drug release in boiling DI water and in
boiling tap water was also negligible as shown in FIGS. 6 and
7.
[0275] Dissolution experiments for 200 mg dextromethorphan
Amberlite.TM. IRP69 or Amberlite.TM. IRP88 resinates were also
performed in simulated gastric fluid without pepsin. A stock
solution was made with 2 g of NaCl in 7 mL of HCl and DI water to
make 1000 mL of SGF at pH 1.2. The release profiles of
dextromethorphan from two-piece hard shell capsules containing 200
mg of the dextromethorphan-resinate complexes are shown in FIGS. 8
and 9. These data show a pronounced effect of ion concentration on
the release of dextromethorphan from Amberlite.TM. IRP69 (FIG. 8),
while there is almost no difference in release between 100% SGF and
5% SGF from the weaker Amberlite.TM. IRP88 (FIG. 9).
[0276] Overingestion or taking of more than the prescribed amount
of pharmaceuticals is a common method of abuse. To test the
anti-over ingestion properties of the pharmaceutical composition,
multiple capsules were combined in a single reaction vessel and
percentage of API released was measured. The Amberlite.TM. IRP69
composition was tested based upon its demonstrated ion-specific
release profile. The in vitro dissolutions studies of
dextromethorphan from Amberlite.TM. IRP69 from multiple capsules
(1, 5, and 10) were carried out in 0.1 HCl with each 200 mg capsule
containing 40 mg of the drug. As shown in FIG. 10, the amount of
the drug released from 1 capsule was about 40 mg. Surprisingly,
however, the amount of drug release was significantly lower than
expected for multiple capsules dissolved simultaneously; 5 capsules
released only 120 mg (theoretical amount should be about 200 mg)
and 10 capsules released about 150 mg (theoretical amount should be
about 400 mg). This result suggests that there is a ceiling effect
for the dissolution of multiple capsules at once and suggests an
alternative mechanism for preventing the overingestion of abuse
prone active agents (e.g., oxycodone).
[0277] An additional experiment was performed to support the
concept that the ceiling effect was not caused by solubility/sink
limitation, but rather by retention by sequestering. As shown in
FIG. 11, a single capsule without resin having 40 mg of
dextromethorphan or 10 capsules without resin comprising a total
amount of 400 mg of dextromethorphan had a dose proportional
release. This result suggests that the observed ceiling effect is
not restricted by any solubility or sink limitation, but rather
imparted by the presence of a sequestering effect of the resin.
[0278] Next, the possibility to gain the same sequestering effect
using physical blend of drug with resin instead of drug resinate
complex was explored. The results presented in FIGS. 12 and 13 show
that the release of dextromethorphan in the presence of
Amberlite.TM. IRP69 is significantly lower compared to those
obtained in the presence of Amberlite.TM. IRP88. This effect is
more pronounced for 10 capsules containing 10-fold dose of
Amberlite.TM. IRP69 in the same vessel as compared to 1 capsule per
vessel. These findings are consistent with the results obtained
with the dextromethorphan-Amberlite.TM. IRP69-resinate results.
[0279] The dissolution of hard capsules having a
dextromethorphan-Amberlite.TM. IRP69-resinate and percent release
of dextromethorphan was measured with media replacement every 15
minutes for 1, 5, and 10 capsules. As shown in FIG. 14, the percent
release for 1, 5, and 10 capsules is very similar with and without
media replacement with a small percent release delta at 120 minutes
(.DELTA..sub.120) (Table 11).
TABLE-US-00011 TABLE 11 Delta between dextromethorphan-Amberlite
.TM. IRP69-resinate with/without media replacement No. Capsules
.DELTA..sub.120 (mg) 1 4.3 15 20.1 10 33
Example 3
[0280] Next, the release of dextromethorphan from a drug-resinate
or drug-physical blend complexes in abuse deterrent matrices were
prepared and tested. These matrices were tested in the in vitro-in
vivo relationship (IVIVR) dissolution method as shown in Table
12.
TABLE-US-00012 TABLE 12 In Vitro-In Vivo Relationship Testing
Parameters Apparatus USP Apparatus III Agitation rate 30 dips per
minute (DPM) Temperature 37.0 .+-. 0.5.degree. C. Media volume 250
mL Media 2 hours FaSSGF; 10 hours FaSSIF Pull volume 2 mL Profiled
sampling times 1, 2, 4, 8, and 12 hours
[0281] An abuse deterrent composition as shown in Table 13 was
prepared by the following method. First, the specified amount of
PEG 400 and Methocel.TM. A4M was dispensed in a beaker and let it
hydrated for about an hour. Next the specified amount of soybean
oil was heated to about 140.degree. C. and the specified amount of
Ethocel.TM. (20 cP) was added and mixed until a clear solution was
obtained. The oil/ Ethocel.TM. (20 cP) mixture was cooled to about
90.degree. C. and the specified amount of carnauba wax and yellow
bees wax was added and mixed until dissolved and the resulting
solution was cooled to room temperature. The PEG 400 and
Methocel.TM. A4M mixture was then added to the oil and wax mixture
to obtain a uniform mix. This mixture was then homogenized for
approximately 5 minutes until a smooth final fill mixture was
obtained. A total of 4 g of dextromethorphan/Amberlite.TM. IRP88
resinate was added to 20 g of composition as shown in Table 13.
TABLE-US-00013 TABLE 13 Exemplary Abuse Deterrent Controlled
Release Composition Components Mass (mg/capsule) Percentage (%)
Soybean Oil 546 65 Ethocel .TM. (4 cP) 14 1.7 Carnauba Wax 17.5 2.0
Bee's Wax 17.5 2.0 Methocel .TM. A4M 52.5 6.3 Polyethylene Glycol
400 52.5 6.3 Dextromethorphan/resinate 140 16.7 TOTAL 840 100
Example 4
[0282] Several abuse deterrent hydrogel formulations based on an
abuse deterrent composition with a dextromethorphan/resinate
complex were developed as shown in Tables 14-17. These compositions
were then filled in a hard shell capsule for further dissolution
testing using the dissolution apparatus III with the parameters
shown in Table 12. The composition shown in Table 14 was
supplemented with the adhesive polymer 5% polycarbophil
(composition of Table 16) and about 50 mg dextromethorphan was
complexed with about 50 mg of Amberlite.TM. IRP88 (1:1 ratio) as a
resinate and tested by the same parameters. As shown in FIG. 15, a
modest decrease in drug release was observed after 5 capsules were
dissolved together in matrices containing PCP; the theoretical
release is about 250 mg and 217 mg release was actually
observed.
[0283] The release of dextromethorphan from the composition
according to Table 14 comprising 75 mg of Amberlite.TM. IRP69 and
25 mg of dextromethorphan in a resinate was tested. The addition of
Polycarbophil according to the composition of Table 16 was added as
an adhesive polymer to the Amberlite.TM. IRP69-dextromethorphan
resinate to determine if the addition of polycarbophil promotes
additional over ingestion ceiling effects in these compositions. As
shown in FIG. 16, the dissolution of 1 capsule resulted in about 25
mg of dissolved dextromethorphan and the dissolution of 5 capsules
resulted in the dissolution of 70-76 mg of dextromethorphan. There
was a modest decrease in drug release with the addition of
polycarbophil.
[0284] Next, the Amberlite.TM. IRP69-dextromethorphan blends with
25 mg of dextromethorphan and 75 mg of Amberlite.TM. IRP69 were
tested. As shown in FIG. 17, these physical blends demonstrated a
markedly decreased release rate for both 1 capsule and 5 capsules
compared to the resinate blends shown in FIG. 16.
TABLE-US-00014 TABLE 14 Exemplary Abuse Deterrent Controlled
Release Composition Components Mass (mg/capsule) Percentage (%)
Polyethylene Glycol 400 662.5 66.3 Polyethylene Glycol 1000 92.5
9.3 PVP K90 12.5 1.3 Carbopol .RTM. 974P 12.5 1.3 HPMC K100M 120 12
Dextromethorphan/resinate 100 10 TOTAL 1000 100
TABLE-US-00015 TABLE 15 Exemplary Abuse Deterrent Controlled
Release Composition Components Mass (mg/capsule) Percentage (%)
Polyethylene Glycol 400 463 60.2 Polyethylene Glycol 1000 64.8 8.4
PVP K90 8.8 1.1 Carbopol .RTM. 974P 8.8 1.1 HPMC K100M 84 10.9
Dextromethorphan/resinate 140 18.2 TOTAL 770 100
TABLE-US-00016 TABLE 16 Exemplary Abuse Deterrent Controlled
Release Composition Components Mass (mg/capsule) Percentage (%)
Polyethylene Glycol 400 629 62.95 Polyethylene Glycol 1000 88 8.8
PVP K90 12 1.2 Carbopol .RTM. 974P 12 1.2 HPMC K100M 114 11.4
Polycarbophil 50 5 Dextromethorphan/resinate 95 9.5 TOTAL 1050
100
TABLE-US-00017 TABLE 17 Exemplary Abuse Deterrent Controlled
Release Composition Components Mass (mg/capsule) Percentage (%)
Polyethylene Glycol 400 461.7 57 Polyethylene Glycol 1000 64.8 8
PVP K90 9.7 1.2 Carbopol .RTM. 974P 9.7 1.2 HPMC K100M 84.2 10.4
Polycarbophil 40.5 5 Dextromethorphan/resinate 140.1 17.3 TOTAL 810
100
Example 5
[0285] Exemplary soft capsules shells for encapsulating an abuse
deterrent composition described herein, which in some aspects
function to further limit the over ingestion of abuse prone drugs
were designed. These soft capsule shells prevent over ingestion by
promoting clumping of the one or more dosage forms, which limits
drug dissolution out of the matrices described herein. These soft
capsules have multiple charged ionic polymers that may be either
integrated within the capsule gel mass or coated on a formed soft
capsule. As described below, a soft gelatin capsule was generated
and approximately half of the soft capsule shell was coated with a
coating composition that comprises a negative polymer and the other
half was coated with a coating composition that comprises a
positive polymer as shown in Table 18.
TABLE-US-00018 TABLE 18 Exemplary Dual Charged Soft Capsule Shell
Coatings Positive Negative Coating Percentage Coating Percentage
Components (%) (%) Gelatin 26 29.2 Methacrylic Acid Copolymer --
11.2 (EUDRAGIT .RTM. L 100) Dimethylaminoethyl 12 -- Methacrylate
Copolymer (EUDRAGIT .RTM. EPO) Glycerol 16.5 18 Triethyl citrate
1.3 HCl 0.5 -- Ammonium hydroxide -- 1.7 Titanium dioxide -- 1.5
Water 44.2 37.1 TOTAL 100 100
Example 6
[0286] An exemplary anti-overingestion formulation was prepared by
combining a 1:4 mass ratio of dry hydrocodone bitartrate and dry
sodium polystyrene sulfonate IRP69 resin (e.g., Amberlite.TM.
IRP69) and blending to form a powder suspension (Table 19). The
resulting powder was filled into size 4 hard shell capsules to
provide a dosage form comprising 5 mg hydrocodone bitartrate. This
formulation provides an immediate release non-resin bound
pharmaceutical composition.
TABLE-US-00019 TABLE 19 Anti-Overingestion Formulation Weight
Percent Component Mass (mg) (%) Hydrocodone Bitartrate 5 20% Sodium
polystyrene sulfonate 20 80% IRP69* TOTAL 25 mg 100% API: Resin
Ratio 1:4 *AMBERLITE .TM. IRP69 USP, sulfonated copolymer of
stryene and divinylbenzene, pharmaceutical grade strong cation
exchange resin; size 4 hard capsule
[0287] A control composition comprising only the active
pharmaceutical ingredient was also prepared (Table 20). Each hard
capsule dosage form provides 5 mg of hydrocodone bitartrate.
TABLE-US-00020 TABLE 20 Anti-Overingestion Control Component Mass
(mg) Weight Percent (%) Hydrocodone Bitartrate 5 100% TOTAL 5 mg
100% Size 4 hard capsule
Example 7
[0288] Analytical analyses were performed on the composition shown
in Table 19 and a control composition lacking the sodium
polystyrene sulfonate IRP69 shown in Table 20.
TABLE-US-00021 TABLE 21 Analytical Analysis of Anti-Overingestion
Formulation Test/Methods Acceptable limits Results Test Sample
(Table 19) hydrocodone bitartrate immediate release capsules with
sodium polystyrene sulfonate IRP69, 5 mg API Physical Description
Two pice hard shell capsule, no Pass printing; tan powder
Identification Retention time of sample is Pass (HPLC; PD16-275)
between 0.98 and 1.02 relative to average retention time of
standard hydrocodone bitartrate Assay (PD16-275) Report results
99.9% Control Sample (Table 20) hydrocodone bitartrate immediate
release capsules, 5 mg API Physical Description Two pice hard shell
capsule, no Pass printing; white powder Identification Retention
time of sample is Pass (HPLC; PD16-275) between 0.98 and 1.02
relative to average retention time of standard hydrocodone
bitartrate Assay (PD16-275) Report results 99.9%
Example 8
Pharmacokinetic Crossover Study of Two Orally Administered
Hydrocodone Formulations in Beagle Dogs
[0289] A pharmacokinetic study was conducted using the formulations
shown in Table 19 comprising 5 mg hydrocodone bitartrate and 20 mg
of Amberlite.TM. IRP69. Control samples contained 5 mg hydrocodone
bitartrate (no resin; Table 20).
[0290] A total of six male beagle dogs were assigned to the study.
The same animals were used for each phase, with a minimum 3-day
washout period between dosing in each phase. For each phase, all
animals were fasted for at least eight hours prior to dosing and
through the first four hours of blood sample collection, (food was
returned 30 minutes following collection of the last blood sample
at the 4-hour collection interval). The total fasting time did not
exceed 24 hours.
[0291] For each phase, one animal per group (Groups 1-6) received
an oral capsule dose of the appropriate Test formulation or Control
formulation as outlined in Tables 22-23. Animals were dosed in a
latin-square design, with each animal receiving each of six
treatments once in a rotating fashion, as outlined below. For each
dose, at approximately 30 minutes (.+-.5 minutes) prior to test
article administration, each animal received 25 mg of naltrexone
(one half of a 50 mg tablet) to block the opioid effects of the
test article. In addition, naloxone (0.02-0.04 mg/kg, IV) was
available as a rescue medication, if opiate overdose effects (e.g.,
respiratory depression) were noted following test article
administration.
[0292] Blood samples, 0.5 mL/sample, were collected in K.sub.2EDTA
vacutainers from the jugular vein at the following times: predose
(0) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12 and
14-hours postdose. All blood samples were placed on wet ice
following collection until centrifuging and plasma was isolated.
Plasma samples were analyzed for the concentration of test article
over the applicable range (e.g., 1 ng/mL to 1,000 ng/mL) using a
HPLC mass spectrometry (HPLC MS/MS) method.
[0293] All animals were observed at least twice a day for
morbidity, mortality, injury, and availability of food and water.
Any animals in poor health were identified for further monitoring
and possible euthanasia. For each dose, body weights were measured
and recorded on the day of dosing or the day prior to dosing. A
detailed clinical examination for each animal was performed pretest
and relevant observations were recorded.
[0294] A model independent method was used to determine C.sub.max,
T.sub.max and AUC values for the test article from
concentration-time data in the Test species. Based on the data,
appropriate parameters were estimated including: C.sub.max/Dose,
AUC.sub.Tlast, AUC.sub.0-.tau., AUC/Dose, and Control Ratio (at
each dose level tested)=AUC.sub.Test/AUC.sub.Control.
[0295] Results are shown in Tables 24-25.
TABLE-US-00022 TABLE 22 Study Design Parameters Dose Dose Level
Dose Amount Collection Groups Treatment Number Route (mg/animal)
(capsule/animal) Interval 1-6 Test 1 Oral 5, 25, or 50 1, 5, or 10
Blood.sup..dagger. Hydrocodone- animal/ Capsule* mg as capsules as
Resin or group specified specified Hydrocodone Control *All animals
were pretreated with a single oral tablet 25 mg dose of naltrexone
prior to test article administration in each phase. All capsules
had 5 mg hydrocodone bitartrate per capsule. .sup..dagger.Blood
samples were collected predose (0) and at 0.25, 0.5, 0.75, 1, 1.25,
1.5, 2, 3, 4, 6, 8, 10, 12 and 14-hours postdose.
TABLE-US-00023 TABLE 23 Dosing Protocol (male beagle dogs)
Treatment Phase 1 Phase 2 Phase 3 Phase 4 Phase 5 Phase 6 Dose Dose
Dose Dose Dose Dose Grp (mg) Qant..sup.# (mg) Qant..sup.# (mg)
Qant..sup.# (mg) Qant..sup.# (mg) Qant..sup.# (mg) Qant..sup.# 1 5
T.sup.a 1 25 T 5 50 T 10 5 C 1 25 C 5 50 C 10 2 25 T 5 50 T 10 5 C
1 25 C 5 50 C 10 5 T 1 3 50 T 10 5 T 1 25 C 5 50 C 10 5 T 1 25 T 5
4 5 C.sup.b 1 25 C 5 50 C 10 5 T 1 25 T 5 50 T 10 5 25 C 5 50 C 10
5 T 1 25 T 5 50 T 10 5 C 1 6 50 C 10 5 C 1 25 T 5 50 T 10 5 C 1 25
C 5 .sup.aT = Test dosage form containing 20 mg Amberlite .TM.
IRP69 resin and 5 mg of hydrocodone bitartrate per capsule. .sup.bC
= Control dosage form containing 5 mg of hydrocodone bitartrate per
capsule. .sup.#Number of capsules administered per animal; all
capsules contain 5 mg of hydrocodone bitartrate per capsule.
[0296] Table 24 shows the average hydrocodone plasma concentration
as a function of time for the Test and Control compositions at 5
mg, 25 mg, and 50 mg doses. These data are plotted in FIG. 18.
TABLE-US-00024 TABLE 24 Average Plasma Hydrocodone Concentrations
for Test and Control Doses in Male Dogs Time Test Control (h) 5 mg
25 mg 50 mg 5 mg 25 mg 50 mg 0.0 0.5 0.0 0.4 0.3 0.4 0.7 0.25 1.2
2.4 1.6 5.6 11.6 34.4 0.5 2.9 14.0 17.1 11.8 88.2 152.6 0.75 5.9
57.7 39.8 23.6 91.5 174.1 1.0 12.2 58.3 68.7 17.7 99.1 150.7 1.25
13.1 95.2 93.0 26.6 106.9 175.9 1.5 18.6 98.6 145.1 23.4 90.4 187.3
2.0 20.8 77.7 150.0 19.7 72.2 162.0 3.0 12.1 47.2 91.0 10.1 38.9
77.4 4.0 5.7 25.7 60.0 5.6 24.6 48.6 6.0 1.7 10.9 24.8 1.8 7.4 14.2
8.0 0.8 5.4 11.9 0.8 3.0 7.6 10.0 0.6 3.3 7.7 0.2 1.8 4.1 12.0 0.4
2.3 6.3 0.5 1.3 3.2 14.0 0.6 1.6 5.4 0.3 0.6 2.2
TABLE-US-00025 TABLE 25 Pharmacokinetic Parameters Following a
Single Oral Administration of 5, 25, or 50 mg Hydrocodone and Resin
(T) or Hydrocodone Control (C) to Male Beagle Dogs AUC.sub.0-14 hr/
C.sub.max/dose Dose Test: C.sub.max (ng/ T.sub.max T.sub.last
AUC.sub.Tlast AUC.sub.0-14 hr (hr * ng/ Control Treatmt Stat
(ng/mL) mL/mg) (hr).sup.a (hr).sup.a (hr ng/mL) (hr ng/mL) mL/mg)
Ratio.sup.b 5 mg T N 6 6 6 6 6 6 6 6 Mean 26.3 5.25 NA 6 57.1 59.6
11.9 0.953 SD 6.53 1.31 (1-2) (4-14) 19.7 18.5 3.69 0.567 CV % 24.9
24.9 NA NA 34.6 30.9 30.9 59.5 25 mg T N 6 6 6 6 6 6 6 6 Mean 105
4.21 NA NA 282 283 11.3 1.01 SD 29.4 1.18 (0.75- (10- 67.7 67.7
2.71 0.313 1.5) 14) CV % 27.9 27.9 NA NA 24.0 23.9 23.9 31.1 50 mg
T N 6 6 6 6 6 6 6 5 Mean 178 3.57 1.5 14 510 510 10.2 0.834 SD 71.5
1.43 (1-2) (14- 182 182 3.63 0.168 14) CV % 40.1 40.1 NA NA 35.7
35.7 35.7 20.1 5 mg C N 6 6 6 6 6 6 6 NA Mean 36.2 7.24 NA 6 68.5
70.3 14.1 NA SD 14.0 2.81 (0.75-2) (4-14) 20.3 19.7 3.95 NA CV %
38.8 38.8 NA NA 29.7 28.1 28.1 NA 25 mg C N 6 6 6 6 6 6 6 NA Mean
150 6.01 1 NA 290 291 11.6 NA SD 41.1 1.64 (0.5-2) (8-14) 58.3 57.6
2.31 NA CV % 27.3 27.3 NA NA 20.1 19.8 19.8 NA 50 mg C N 5 5 5 5 5
5 5 NA Mean 300 6.00 1.5 14 591 592 11.8 NA SD 163 3.26 (0.5-2)
(12- 111 110 2.20 NA 14) CV % 54.4 54.4 NA NA 18.7 18.6 18.6 NA NA:
Not applicable. .sup.aMedian (minimum-maximum), median value only
reported if actual collection interval. .sup.bTest: Control Ratio =
AUC.sub.0-14hr Test/AUC.sub.0-14 hr Control.
[0297] Results are shown in FIGS. 18-19.
TABLE-US-00026 TABLE 26 Individual Pharmacokinetic Parameters
Following a Single Oral Administration of 5, 25, or 50 mg
Hydrocodone and Resin (T) or Hydrocodone Control (C) to Male Beagle
Dogs AUC.sub.0-14 hr/ Dose Test: C.sub.max C.sub.max/dose T.sub.max
T.sub.last AUC.sub.Tlast AUC.sub.0-14 hr (hr * ng/ Control Treat.
Gender Subject (ng/mL) (ng/mL/mg) (hr).sup.a (hr) (hr ng/mL) (hr
ng/mL) mL/mg).sup.a Ratio.sup.a 5 mg T 101 18.5 3.70 2 6 40.1 41.8
8.36 0.658 102 37.4 7.48 1 8 62.7 64.1 12.8 1.18 103 27.0 5.40 1.5
14 91.2 91.2 18.2 2.00 104 22.8 4.56 1 6 60.3 62.1 12.4 0.627 25 mg
T 105 28.8 5.76 2 4 51.6 58.0 11.6 0.747 106 23.1 4.62 2 4 36.5
40.7 8.13 0.494 101 107 4.28 1.5 12 279 281 11.2 0.787 102 108 4.32
0.75 12 294 295 11.8 1.09 50 mg T 103 91.0 3.64 1 14 264 264 10.6
1.29 104 145 5.80 1.5 14 399 399 16.0 1.43 105 122 4.88 1.25 10 269
270 10.8 0.763 106 57.9 2.32 1.5 14 189 189 7.56 0.673 5 mg C 101
23.5 4.70 2 6 62.2 63.5 12.7 0.783 102 43.2 8.64 1.25 4 49.6 54.1
10.8 0.895 103 24.5 4.90 1.5 6 44.3 45.5 9.10 0.673 104 33.1 6.62 1
8 97.6 99.0 19.8 1.10 25 mg C 105 60.9 12.2 0.75 4 75.0 77.6 15.5
NA 106 32.0 6.40 0.75 14 82.4 82.4 16.5 0.723 101 168 6.72 0.5 14
357 357 14.3 0.658 102 85.0 3.40 2 12 267 270 10.8 1.18 50 mg C 103
124 4.96 1.25 8 202 204 8.17 2.00 104 203 8.12 0.5 8 277 279 11.1
0.627 105 152 6.08 1.5 10 353 354 14.2 0.747 106 170 6.80 0.75 14
281 281 11.3 0.494 NA: Not applicable. .sup.aTest: Control Ratio =
AUC.sub.0-14 hr Test/AUC.sub.0-14 hr Control
[0298] Table 27 shows the difference (absolute value) and
percentage difference for C.sub.max AUC.sub.0-14 hr between the
Test and Control data shown in Table 24
TABLE-US-00027 TABLE 27 Differences between Test and Control
Pharmacokinetic Parameters at Each Dose Dose C.sub.max Test
C.sub.max Control Difference % Difference 5 mg 26.3 36.2 9.9 31.7%
25 mg 105 150 45 35.3% 50 mg 178 300 122 51.1% Dose AUC.sub.0-14
Test AUC.sub.0-14 Control Difference % Difference 5 mg 59.6 70.3
10.7 16.5% 25 mg 283 291 8 2.8% 50 mg 510 592 82 14.9%
* * * * *
References