U.S. patent application number 14/717232 was filed with the patent office on 2015-09-24 for abuse-deterrent pharmaceutical compositions of opioids and other drugs.
The applicant listed for this patent is Collegium Pharmaceutical, Inc.. Invention is credited to Stephen L. Buchwald, Alison B. Fleming, Jane Hirsh, Alexander M. Klibanov, Whe Yong Lo, Roman V. Rariy, Timothy M. Swager.
Application Number | 20150265596 14/717232 |
Document ID | / |
Family ID | 30119451 |
Filed Date | 2015-09-24 |
United States Patent
Application |
20150265596 |
Kind Code |
A1 |
Hirsh; Jane ; et
al. |
September 24, 2015 |
ABUSE-DETERRENT PHARMACEUTICAL COMPOSITIONS OF OPIOIDS AND OTHER
DRUGS
Abstract
An abuse-deterrent pharmaceutical composition has been developed
to reduce the likelihood of improper administration of drugs,
especially drugs such as opiods. In the preferred embodiment, a
drug is modified to increase its lipophilicity. In preferred
embodiments the modified drug is homogeneously dispersed within
microparticles composed of a material that is either slowly soluble
or not soluble in water. In some embodiments the drug containing
microparticles or drug particles are coated with one or more
coating layers, where at least one coating is water insoluble and
preferably organic solvent insoluble, but enzymatically degradable
by enzymes present in the human gastrointestinal tract. The
abuse-deterrent composition retards the release of drug, even if
the physical integrity of the formulation is compromised (for
example, by chopping with a blade or crushing) and the resulting
material is placed in water, snorted, or swallowed. However, when
administered as directed, the drug is slowly released from the
composition as the composition is broken down or dissolved
gradually within the GI tract by a combination of enzymatic
degradation, surfactant action of bile acids, and mechanical
erosion.
Inventors: |
Hirsh; Jane; (Wellesley,
MA) ; Klibanov; Alexander M.; (Newton, MA) ;
Swager; Timothy M.; (Newton, MA) ; Buchwald; Stephen
L.; (Newton, MA) ; Lo; Whe Yong; (Canton,
MA) ; Fleming; Alison B.; (Marshfield, MA) ;
Rariy; Roman V.; (Allston, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Collegium Pharmaceutical, Inc. |
Canton |
MA |
US |
|
|
Family ID: |
30119451 |
Appl. No.: |
14/717232 |
Filed: |
May 20, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13551455 |
Jul 17, 2012 |
9044398 |
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14717232 |
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12112993 |
Apr 30, 2008 |
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13551455 |
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10614866 |
Jul 7, 2003 |
7399488 |
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12112993 |
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60463518 |
Apr 15, 2003 |
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60463514 |
Apr 15, 2003 |
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60443226 |
Jan 28, 2003 |
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60436523 |
Dec 23, 2002 |
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60393876 |
Jul 5, 2002 |
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Current U.S.
Class: |
424/490 ;
514/282 |
Current CPC
Class: |
A61K 9/1694 20130101;
A61P 25/04 20180101; A61P 25/26 20180101; A61K 9/50 20130101; A61K
47/12 20130101; A61P 25/20 20180101; A61P 25/30 20180101; A61P
23/00 20180101; A61K 9/1617 20130101; A61K 9/1682 20130101; A61K
9/145 20130101; A61K 9/5052 20130101; A61P 25/36 20180101; A61P
25/24 20180101; A61K 9/5084 20130101; A61K 31/20 20130101; A61K
9/4858 20130101; A61K 31/485 20130101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 9/50 20060101 A61K009/50 |
Claims
1. An orally administerable abuse-deterrent pharmaceutical
composition comprising a therapeutically effective amount of a drug
prone to abuse selected from the group of compositions consisting
of (a) a composition comprising a therapeutically effective amount
of a lipophilic derivative of a drug prone to abuse, and (b) a
water-insoluble, preferably lipophilic, formulation comprising a
therapeutically effective amount of a drug prone to abuse.
2. The composition of claim 1 comprising a therapeutically
effective amount of a lipophilic derivative of a drug prone to
abuse in one or more pharmaceutically acceptable excipients.
3. The composition of claim 1, wherein the composition is a
controlled-release pharmaceutical composition.
4. The composition of claim 1, wherein the composition prevents the
immediate release of a substantial portion of incorporated drug
when the physical integrity of the composition is compromised and
the resulting material is exposed to an aqueous medium.
5. The composition of claim 4, wherein the portion of the drug
released immediately is less than 80% of the total amount of drug
incorporated into formulation.
6. The composition of claim 1, wherein the composition prevents the
immediate release of a substantial portion of incorporated drug
when the physical integrity of the composition is compromised and
the resulting material is exposed to a non-aqueous medium.
7. The composition of claim 6, wherein the portion of the drug
released immediately is less than 80% of the total amount of the
drug incorporated into the composition.
8. The composition of claim 1 wherein the drug prone to abuse is
selected from the group consisting of 1-phenylcyclohexylamine,
1-piperidinocyclohexanecarbonitrile, alfentanil,
alphacetylmethadol, alphaprodine, alprazolam, amobarbital,
amphetamine, anileridine, apomorphine, aprobarbital, barbital,
barbituric acid derivative, bemidone, benzoylecgonine,
benzphetamine, betacetylmethadol, betaprodine, bezitramide,
bromazepam, buprenorphine, butabarbital, butalbital, butorphanol,
carnazepam, cathine, chloral, chlordiazepoxide, clobazam,
clonazepam, clorazepate, clotiazepam, cloxazolam, cocaine, codeine,
chlorphentermine, delorazepam, dexfenfluramine, dextromoramide,
dextropropoxyphen, dezocine, diazepam, diethylpropion, difenoxin,
dihydrocodeine, dihydromorphine, dioxaphentyl butyrate, dipanone,
diphenoxylate, diprenorphine, ecgonine, enadoline, eptazocine,
estazolam, ethoheptazine, ethyl loflazepate, ethylmorphine,
etorphine, femproponex, fencamfamin, fenfluramine, fentanyl,
fludiazepam, flunitrazepam, flurazeparn, glutethimide, halazepam,
haloxazolam, hexalgon, hydrocodone, hydromorphone, isomethadone,
hydrocodone, ketamine, ketazolam, ketobemidone, levanone,
levoalphacetylmethadol, levomethadone, levomethadyl acetate,
levomethorphan, levorphanol, lofentanil, loperamide, loprazolam,
lorazepam, lormetazepam, lysergic acid, lysergic acid amide,
mazindol, medazepam, mefenorex, meperidine, meptazinol, metazocine,
methadone, methamphetamine, methohexital, methotrimeprazine,
methyldihydromorphinone, methylphenidate, methylphenobarbital,
metopon, morphine, nabilone, nalbuphine, nalbupine, nalorphine,
narceine, nefopam, nicomorphine, nimetazeparm, nitrazepam,
nordiazepam, normethadone, normorphine, oxazepam, oxazolam,
oxycodone, oxymoiphone, pentazocine, pentobarbital, phenadoxone,
phenazocine, phencyclidine, phendimetrazine, phenmetrazine,
pheneridine, pirninodine, prodilidine, properidine, propoxyphene,
racemethorphan, racemorphan, racemoramide, remifentanil,
secobarbital, sufentanil, talbutal, thebaine, thiamylal,
thiopental, tramadol, trimeperidine, vinbarbital, allobarbitone,
alprazolam, amylobarbitone, aprobarbital, barbital, barbitone,
benzphetamine, brallobarbital, bromazepam, brotizolam, buspirone,
butalbital, butobarbitone, butorphanol, camazepam, captodiame,
carbromal, carfentanil, carpipramine, cathine, chloral, chloral
betaine, chloral hydrate, chloralose, chlordiazepoxide,
chlorhexadol, chlormethiazole edisylate, chlormezanone,
cinolazepam, clobazam, potassium clorazepate, clotiazepam,
cloxazolam, cyclobarbitone, delorazepam, dexfenfluramine, diazepam,
diethylpropion, difebarbamate, difenoxin, enciprazine, estazolam,
ethyl lotlazepate, etizolam, febarbamate, fencamfamin,
fenfluramine, fenproporex, fluanisone, fludiazepam, flunitraam,
flunitrazepam, flurazepam, flutoprazepam, gepirone, glutethimide,
halazepam, haloxazolam, hexobarbitone, ibomal, ipsapirone,
ketazolam, loprazolam mesylate, lorazepam, lormetazepam, mazindol,
mebutamate, medazepain, mefenorex, mephobarbital, meprobamate,
metaclazepam, methaqualone, methohexital, methylpentynol,
methylphenobarbital, midazolam, milazolam, morphine, nimetazeparn,
nitrazepam, nordiazepam, oxazepam, oxazolam, paraldehyde, pemoline,
pentabarbitone, pentazocine, pentobarbital, phencyclidine,
phenobarbital, phendimetrazine, phenmetrazine, phenprobamate,
phentermine, phenyacetone, pinazepam, pipradol, prazepam,
proxibarbal, quazepam, quinalbaritone, secobarbital,
secbutobarbitone, sibutramine, temazepam, tetrazepam, triazolam,
triclofos, zalepan, zaleplon, zolazepam, zolpidem, and
zopiclone.
9. The composition of claim 2, wherein the lipophilic derivative of
a drug is a free base or a free acid of the drug.
10. The composition of claim 2, wherein the lipophilic derivative
of a drug is a salt comprising the ionized drug and a lipophilic
counter-ion.
11. The composition of claim 2, wherein the lipophilic derivative
of a drug is a complex comprising one or more components selected
from the group consisting of drug molecules, metal cations, and
lipophilic counter-ions.
12. The composition of claim 2, wherein the lipophilic derivative
of a drug is a complex comprising one or more components selected
from the group consisting of drug molecules, metal cations, and
cyclodextrin molecules.
13. The composition of claim 2 wherein the drug is complexed with a
metal cation selected from the group consisting of zinc, calcium,
magnesium, bismuth and combinations thereof.
14. The composition of claim 11 wherein the drug is oxycodone, and
wherein the metal cation is selected from the group consisting of
zinc, calcium, magnesium, and bismuth and the lipophilic
counter-ion is selected from the group consisting of stearate,
oleate, palmitate, laurate and linoleate.
15. The composition of claim 2, wherein the lipophilic derivative
of a drug is a complex comprising the drug and a cyclodextrin.
16. The composition of claim 2, wherein the lipophilic derivative
of a drug is an ester or amide formed between the drug and a fatty
acid.
17. The composition of claim 1, wherein the drug is incorporated
into a plurality of individual microparticles comprising a material
that is either slowly soluble in water or water insoluble.
18. The composition of claim 17 wherein the microparticles comprise
a wax or wax-like material.
19. The composition of claim 17 wherein the microparticles comprise
a fat or a fatty substance.
20. The composition of claim 17 wherein the microparticles comprise
a material selected from the group consisting of naturally water
insoluble proteins, naturally water insoluble polysaccharides,
naturally water insoluble lipids and phospholipids, cross-linked
water soluble proteins, cross-linked water soluble polysaccharides,
cross-linked water soluble cyclodextrins and combinations
thereof.
21. The composition of claim 17 wherein the individual
microparticles are coated with one or more independent layers,
where at least one of the layers is water insoluble and is degraded
by enzymes of the human gastrointestinal tract.
22. The composition of claim 1 wherein the drug is in the form of
individual drug particles coated with one or more independent
layers where at least one of the layers is water insoluble and is
degraded by enzymes of the human gastrointestinal tract.
23. The composition of claim 21 wherein at least one of the layers
is water-insoluble, organic solvent-insoluble, and degradable by
enzymes present in the human gastrointestinal tract.
24. The composition of claim 21 comprising materials wherein a
combination of these materials is not soluble in water, organic
solvent, or any combination thereof.
25. The composition of claim 21 wherein the composition is not
completely soluble, and wherein the drug is not fully released in a
single solvent or enzyme solution.
26. The composition of claim 21 wherein the enzymatically
degradable layer(s) comprise a material selected from the group
consisting of naturally water insoluble proteins, naturally water
insoluble polysaccharides, naturally water insoluble lipids and
phospholipids, cross-linked proteins, cross-linked polysaccharides,
and combinations thereof.
27. The composition of claim 1 wherein the drug prone to abuse is
co-administered with a drug that has no appreciable abuse
potential.
28. The composition of claim 1 formulated for the drug to be
immediately released upon oral administration.
29. The composition of claim 1 wherein the drug prone to abuse is
oxycodone.
30. A method of manufacturing an abuse-resistant pharmaceutical
composition comprising homogeneously dispersing a therapeutically
effective amount of a drug prone to abuse, in one or more
pharmaceutically acceptable carrier(s), diluent(s), and/or
additives, to form an orally administerable abuse-deterrent
pharmaceutical composition comprising a therapeutically effective
amount of a drug prone to abuse selected from the group of
compositions consisting of (a) a composition comprising a
therapeutically effective amount of a lipophilic derivative of a
drug prone to abuse, and (b) a water-insoluble, preferably
lipophilic, formulation comprising a therapeutically effective
amount of a drug prone to abuse, as defined by any of claim 1.
31. The method of claim 30 further comprising formulating the
composition into a capsule or tablet.
32. A method of administering an abuse-resistant pharmaceutical
composition comprising orally administering to a patient in need
thereof an abuse-deterrent pharmaceutical composition comprising a
therapeutically effective amount of a drug prone to abuse selected
from the group of compositions consisting of (a) a composition
comprising a therapeutically effective amount of a lipophilic
derivative of a drug prone to abuse, and (b) a water-insoluble,
preferably lipophilic, formulation comprising a therapeutically
effective amount of a drug prone to abuse, as defined by any of
claim 1.
Description
[0001] This application claims priority to U.S. Ser. No. 60/393,876
filed Jul. 5, 2002 entitled "Abuse-Resistant Formulations of
Oxycontin and Other Drugs" by Alexander M. Klibanov, Stephen L.
Buchwald, Timothy M. Swager, and Whe-Yong Lo; U.S. Ser. No.
60/436,523 filed Dec. 23, 2002 by Alison B. Fleming, Roman V.
Rariy, Alexander M. Klibanov, Whe-Yong Lo, and Jane Hirsh; U.S.
Ser. No. 60/443,226 filed Jan. 28, 2003 by Jane Hirsh, Alison B.
Fleming, Alexander M. Klibanov, and Who-Yong Lo; U.S. Ser. No.
60/463,514 filed Apr. 15, 2003 by Jane C. Hirsh, Alison B. Fleming,
Roman V. Rariy, Stephen L. Buchwald, and Timothy M. Swager; and
U.S. Ser. No. 60/463,518 filed Apr. 15, 2003 by Jane C. Hirsh,
Alison B. Fleming and Roman V. Rariy.
BACKGROUND OF THE INVENTION
[0002] The present invention is generally in the field of
pharmaceutical compositions, and specifically relates to
compositions that are designed to reduce the potential for improper
administration of drugs that are subject to abuse.
[0003] Oxycodone, morphine, and other opiod analgesics are
successful and therapeutically useful medications, e.g., as pain
killers, when administered orally. Unfortunately, they also pose a
severe threat for willful abuse due to their ability to alter mood
and/or cause a sense of euphoria. Currently available sustained
release formulations of such drugs, which contain a relatively
large amount of drug meant to be released from the formulation over
an extended time period, are particularly attractive to abusers
since the sustained release action can be destroyed by crushing or
grinding the formulation. The resulting material (ie, the crushed
formulation) can no longer control the release of drug. Depending
on the drug, abusers can then (1) snort the material, (2) swallow
the material or (3) dissolve the material in water and subsequently
inject it intravenously. The dose of drug contained in the
formulation is thus absorbed immediately through the nasal or GI
mucosa (for snorting or swallowing, respectively) or is
administered in a bolus to the systemic circulation (for IV
injection). These abuse methods result in the rapid bioavailability
of relatively high doses of drug, giving the abuser a "high". Since
relatively simple methods (crushing, grinding, chewing and/or
dissolution in water) can be used to transform such formulations
into an abusable form, they provide virtually no deterrent to a
potential abuser.
[0004] For example, the FDA recently strengthened the warnings and
precautions sections in the labeling of OxyContin.RTM. (oxycodone
HCl controlled-release) Tablets, a narcotic drug approved for the
treatment of moderate to severe pain, because of continuing reports
of abuse and diversion. OxyContin.RTM. contains oxycodone HCl
(available in 10, 20, 40 and 80 mg strengths), an opioid agonist
with an addiction potential similar to that of morphine. Opioid
agonists are substances that act by attaching to specific proteins
called opioid receptors, which are found in the brain, spinal cord,
and gastrointestinal tract. When these drugs attach to certain
opioid receptors in the brain and spinal cord they can effectively
block the transmission of pain messages to the brain.
OxyContin.RTM. is supplied in a controlled-release dosage form and
is intended to provide up to 12 hours of relief from moderate to
severe pain. The warning specifically states that the tablet must
be taken whole and only by mouth. When the tablet is chewed or
crushed and its contents are swallowed, snorted into the nostrils
or dissolved and subsequently injected intravenously, the
controlled release mechanism is destroyed and a potentially lethal
dose of oxycodone becomes bioavailable.
[0005] In recent years, there have been numerous reports of
Oxycodone diversion and abuse in several states. For example, DEA's
Office of Diversion Control reported 700 OxyContin.RTM. thefts in
the US between January 2000 and June 2001. Some of these reported
cases have been associated with serious consequences including
death.
[0006] Oxycodone is a controlled substance in Schedule II of the
Controlled Substances Act (CSA), which is administered by the Drug
Enforcement Administration (DEA). Despite the fact that Schedule II
provides the maximum amount of control possible under the CSA for
approved drug products, in practice it is difficult for law
enforcement agencies to control the diversion or misuse of
legitimate prescriptions. Although abuse, misuse, and diversion are
potential problems for all opioids, including Oxycodone, opioids
are a very important part of the medical armamentarium for the
management of pain when used appropriately under the careful
supervision of a physician.
[0007] Currently available formulations for such drugs are designed
for oral administration but do not include mechanisms to prevent or
retard improper methods of administration such as chewing,
injection and snorting. This represents a serious problem given the
large number of legitimate prescriptions written in the US; for
example, the medical use of opiods within the US increased 400%
from 1996 to 2000. The problems with abuse are significant and
longstanding, and efforts to design new abuse-resistant or
abuse-deterrent formulations have been largely unsuccessful. U.S.
Pat. Nos. 3,980,766, 4,070,494 and 6,309,668 describe formulations
designed to prevent the injection of compositions meant for oral
administration. U.S. Pat. No. 3,980,766 describes the incorporation
of an ingestible solid which causes a rapid increase in viscosity
upon concentration of an aqueous solution thereof. U.S. Pat. No.
4,070,494 describes the incorporation of a non-toxic, water gelable
material in an amount sufficient to render the drug resistant to
aqueous extraction. U.S. Pat. No. 6,309,668 describes a tablet for
oral administration containing two or more layers comprising one or
more drugs and one or more gelling agents within separate layers of
the tablet. The resulting tablet forms a gel when combined with the
volume of water necessary to dissolve the drug; this formulation
thus reduces the extractability of the drug from the tablet. It
should be noted that although these compositions preclude abuse by
injections, this approach fails to prevent abuse by crushing and
swallowing or snorting the formulation, which are commonly reported
methods of abuse associated with OxyContin.RTM..
[0008] U.S. Pat. Nos. 3,773,955 and 3,966,940 describe formulations
containing a combination of opiod agonists and antagonists, in
which the antagonist does not block the therapeutic effect when the
admixture is administered orally, but which does not produce
analgesia, euphoria or physical dependence when administered
parenterally by an abuser. U.S. Pat. No. 4,457,933 describes a
method for decreasing both the oral and parenteral abuse potential
of strong analgetic agents by combining an analgesic dose of the
analgetic agent with an antagonist in specific, relatively narrow
ratios. U.S. Pat. Nos. 6,277,384, 6,375,957 and 6,475,494 describe
oral dosage forms including a combination of an orally active opiod
agonist and an orally active opiod antagonist in a ratio that, when
delivered orally, is analgesically effective but that is aversive
in a physically dependent subject. While such a formulation may be
successful in deterring abuse, it also has the potential to produce
adverse effects in legitimate patients.
[0009] It is therefore an object of the present invention to
provide a pharmaceutical composition that significantly reduces the
potential for improper administration or use of drugs but which,
when administered as directed, is capable of delivering a
therapeutically effective dose.
SUMMARY OF THE INVENTION
[0010] An abuse-deterrent pharmaceutical composition and the method
of making and using the composition have been developed. The
composition can be used to reduce the likelihood of improper
administration of drugs, especially drugs such as oxycodone. The
technology is useful for a number of other drugs where sustained
release oral delivery is desired, and there is the potential for
abuse if the drug dose is made immediately available for nasal , IV
or oral administration. In the preferred embodiment, the drug is
chemically modified to increase its lipophilicity. In other
embodiments, the formulation contains lipophilic or water-insoluble
materials or is made using a process which increases the
lipophilicity and/or water-insolubility of the composition.
[0011] The abuse-deterrent composition retards the release of drug,
even if the physical integrity of the dosage form is compromised
(for example, by chopping with a blade or crushing) and the
resulting material is placed in water, snorted, or swallowed. The
composition thus provides a deterrent to common methods of improper
administration including IV injection of drug dissolved in water
and nasal or oral administration of the crushed formulation since
drug will not be immediately released from the formulation.
However, when administered as directed, the drug is slowly released
(typically over a period of 4-18 hours) from the composition as the
composition is broken down or dissolved gradually within the GI
tract by a combination of enzymatic degradation, surfactant action
of bile acids, and mechanical erosion.
[0012] In some embodiments, the individual drug-containing
microparticles or drug particles are coated with one or more
independent coating layers. At least one of the coating materials
is water-insoluble and preferably organic solvent-insoluble, but
enzymatically degradable. The components of the resulting coated
microparticles are not mutually soluble in water, organic solvents,
or any combination thereof, so that in vitro degradation of the
formulation will require more than one step. Hence the drug is not
easily extractable from such a formulation by conventional chemical
means. In contrast, when administered to the gastrointestinal tract
via swallowing, the drug gradually will be released from the coated
microparticles as a consequence of enzymatic degradation,
surfactant action of bile acids and mechanical erosion within the
GI tract.
[0013] The pharmaceutical composition, when administered orally,
results in a desired drug release profile. Such a release profile
provides a therapeutic effect for an extended period of time,
typically from 6 to 24 hours. Additional compositions are provided
which achieve a small immediate dose that precedes the sustained
release of drug. The compositions disclosed herein may optionally
comprise a drug having no appreciable abuse potential.
BRIEF DESCRIPTION OF THE DRAWING
[0014] FIG. 1A is a structural schematic of zinc bis-oxycodone.
[0015] FIG. 1B is a structural schematic of zinc oxycodone
stearate.
[0016] FIG. 1C is a structural schematic of zinc oxycodone
di-stearate.
DETAILED DESCRIPTION OF THE INVENTION
[0017] Disclosed herein are an abuse-deterrent pharmaceutical
composition and the method of making and using the composition.
I. Compositions
[0018] As used herein, "composition" refers to the drug dosage unit
for administration to a patient. This may also be used in reference
solely to the active ingredient, or to the formulation containing
the active ingredient.
[0019] The currently available sustained release dosage forms
containing narcotic analgesics and other drugs are subject to
misuse, in part, because mechanical destruction of the dosage form
exposes the encapsulated drug and allows for immediate dissolution
of the drug into aqueous media. Two properties of the dosage form
that contribute to this outcome are (1) the ease with which drug is
exposed to the extraction media and (2) the high water solubility
of the drug salt form.
[0020] In the composition disclosed herein, one or both of these
properties are altered in order to achieve an abuse-deterrent
composition. Specifically, in the preferred embodiment, the drug is
modified to increase its lipophilicity and, in additional preferred
embodiments, is then homogeneously dispersed within a material that
is either slowly soluble or not soluble in water and subsequently
formulated into microparticles. The drug may be present in the form
of discrete particles or may be partially or fully dispersed in the
carrier material on a molecular level.
[0021] The terms "abuse-deterrent composition" or "abuse-deterrent
formulation" are used interchangeably herein to refer to
compositions that reduce the potential for improper administration
of drugs but that deliver a therapeutically effective dose when
administered as directed. Improper administration includes
tampering with the dosage form and/or administering the drug by any
route other than instructed. For example, for a tablet or capsule,
methods of tampering with the dosage :form may include, but are not
limited to, breaking, crushing, grinding, chewing and/or dissolving
the tablet or the contents of the capsule. For oral administration,
improper administration includes administering the drug by any
route other than via swallowing.
[0022] The abuse deterrent composition preferably comprises a drug
modified to increase its lipophilicity. In other preferred
embodiments, the drug is homogenously dispersed within
microparticles composed of a material that is either slowly soluble
in water or water insoluble. The compositions slow the release of
drug if the dosage form is chopped or crushed and the resulting
material is placed in water, snorted, or swallowed since most of
the drug will remain associated with or entrapped within portions
of the core material of the microparticles. In some embodiments the
drug containing microparticles or individual drug particles are
coated with one or more coating layers, where at least one coating
is water insoluble and preferably organic solvent insoluble, but
enzymatically degradable. The components of the resulting coated
microparticles are not mutually soluble in water, organic solvents,
or any combination thereof, such that no one solvent or enzyme
solution is capable of dissolving the formulation in its entirety
in vitro. It follows that extraction of the drug from the
formulation cannot be carried out in one step. However, when
administered as directed, the drug is slowly released from the
formulation since it is eroded within the environment of the
gastrointestinal tract.
[0023] A. Drugs to be Formulated
[0024] There are many drugs that it is desirable to deliver using
the compositions described herein. The Controlled Substances Act
(CSA), Title II of the Comprehensive Drug Abuse Prevention and
Control Act of 1970, places all substances that are regulated under
existing federal law into one of five schedules based upon the
substance's medicinal value, harmfulness, and potential for abuse
or addiction. Drugs that are preferred include those classified as
Schedule II, III, IV and V drugs. Drugs that are most preferable
include those, like oxycodone, that are currently formulated as
sustained or controlled release compositions, where drug release is
intended to occur over a prolonged period of time through the
gastrointestinal tract, and immediate or burst release, for
example, by inhalation or injection, is undesirable. As used
herein, drugs prone to abuse refer to controlled substance
specified as schedule II, II, IV and V drugs.
[0025] The terms "drug", "active agent", and "pharmacologically
active agent" are used interchangeably herein to refer to a
chemical compound that induces a desired pharmacological,
physiological effect. The terms also encompass pharmaceutically
acceptable derivatives of those active agents specifically
mentioned herein, including, but not limited to, salts, solvates,
hydrates, complexes with one or more molecules, prodrugs, active
metabolites, analogs, and the like. When the terms "active agent",
"pharmacologically active agent" and "drug" are used, or when a
particular drug, such as oxycodone, is identified, it is to be
understood as including the active agent per se as well as
pharmaceutically acceptable salts, solvates, hydrates, complexes
with one or more molecules, prodrugs, active metabolites, and
analogs.
[0026] Examples of preferred drugs include,
1-phenylcyclohexylamine,-piperidinocyclohexanecarbonitrile,
alfentanil, alphacetylmethadol, alphaprodine, alprazolam,
amobarbital, amphetamine, anileridine, apomorphine, aprobarbital,
barbital, barbituric acid derivative, bemidone, benzoylecgonine,
benzphetamine, betacetylmethadol, betaprodine, bezitramide,
bromazepam, buprenorphine, butabarbital, butalbital, butorphanol,
camazeparm, cathine, chloral, chlordiazepoxide, clobazam,
clonazepam, clorazepate, clotiazepam, cloxazolam, cocaine, codeine,
chlorphentermine, delorazepam, dexfenfluramine, dextromoramide,
dextropropoxyphen, dezocine, diazepam, diethylpropion, difenoxin,
dihydrocodeine, dihydromorphine, dioxaphentyl butyrate, dipanone,
diphenoxylate, diprenorphine, ecgonine, enadoline, eptazocine,
estazolam, ethoheptazine, ethyl loflazepate, ethylmorphine,
etorphine, femproponex, fencamfamin, fenfluramine, fentanyl,
fludiazepam, flunitrazepam, flurazepam, glutethimide, halazepam,
haloxazolam, hexalgon, hydrocodone, hydromorphone, isomethadone,
hydrocodone, ketamine, ketazolam, ketobemidone, levanone,
levoalphacetylmethadohl, levomethadone, levomethadyl acetate,
levomethorphan, levorphanol, lofentanil, loperamide, loprazolam,
lorazepam, lormetazepam, lysergic acid, lysergic acid amide,
mazindol, medazepam, mefenorex, meperidine, meptazinol, metazocine,
methadone, methamphetamine, methohexital, methotrimeprazine,
methyldihydromorphinone, methylphenidate, methylphenobarbital,
metopon, morphine, nabilone, nalbuphine, nalbupine, nalorphine,
narceine, nefopam, nicomorphine, nimetazepam, nitrazepam,
nordiazepam, normethadone, normorphine, oxazepam, oxazolam,
oxycodone, oxymorphone, pentazocine, pentobarbital, phenadoxone,
phenazocine, phencyclidine, phendimetrazine, phenmetrazine,
pheneridine, piminodine, prodilidine, properidine, propoxyphene,
racemethorphan, racemorphan, racemoramide, remifentanil,
secobarbital, sufentanil, talbutal, thebaine, thiamylal,
thiopental, tramadol, trimeperidine, and vinbarbital.
[0027] In addition to the compounds above, the following scheduled
drugs may be incorporated into the composition: allobarbitone,
alprazolam, amylobarbitone, aprobarbital, barbital, barbitone,
benzphetamine, brallobarbital, bromazepam, brotizolam, buspirone,
butalbital, butobarbitone, butorphanol, camazepam, eaptodiame,
carbromal, carfentanil, carpipramine, cathine, chloral, chloral
betaine, chloral hydrate, chloralose, chlordiazepoxide,
chlorhexadol, chlormethiazole edisylate, chlormezanone,
cinolazepam, clobazam, potassium clorazepate, clotiazepam,
cloxazolarn, cyclobarbitone, delorazepam, dexfenfluramine,
diazepam, diethylpropion, difebarbarnate, difenoxin, enciprazine,
estazolam, ethyl loflazepate, etizolam, febarbamate, fencamfamin,
fenfluramine, fenproporex, fluanisone, fludiazepam, flunitraam,
flunitrazepam, flurazepam, flutoprazepam, gepirone, glutethimide,
halazepam, haloxazolam, hexobarbitone, ibomal, ipsapirone,
ketazolam, loprazolam mesylate, lorazepam, lormetazepam, mazindol,
mebutamate, medazepam, mefenorex, mephobarbital, meprobamate,
metaclazepam, methaqualone, methohexital, methylpentynol,
methylphenobarbital, midazolam, milazolam, morphine, nimetazepam,
nitrazepam, nordiazepam, oxazepam, oxazolam, paraldehyde, pemoline,
pentabarbitone, pentazocine, pentobarbital, phencyclidine,
phenobarbital, phendimetrazine, phenmetrazine, phenprobamate,
phentermine, phenyacetone, pinazepam, pipradol, prazepam,
proxibarbal, quazepam, quinalbaritone, secobarbital,
secbutobarbitone, sibutramine, temazepam, tetrazeparn, triazolam,
triclofos, zalepan, zaleplon, zolazepam, zolpidem, and zopiclone.
Certain compounds described herein may exist in particular
geometric or stereoisomeric forms. The composition disclosed herein
contemplates all such compounds, including cis- and trans-isomers,
R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the
racemic mixtures thereof, compounds of different spacial
conformations, and other mixtures thereof, as falling within the
scope of the invention. Additional asymmetric carbon atoms may be
present in a substituent such as an alkyl group. All such isomers,
as well as mixtures thereof, are intended to be included in this
invention.
[0028] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines;
alkali or organic salts of acidic residues such as carboxylic
acids; and the like. The pharmaceutically acceptable salts include
the conventional non-toxic salts or the quaternary ammonium salts
of the parent compound formed, for example, from non-toxic
inorganic or organic acids. For example, such conventional
non-toxic salts include those derived from inorganic acids such as
hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric
and the like; and the salts prepared from organic acids such as
acetic, propionic, succinic, glycolic, stearic, lactic, inalic,
tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, sulfanilic,
2-acetoxybenzoic, fumaric, tolunesulfonic, methanesulfonic, ethane
disulfonic, oxalic, and isethionic.
[0029] The pharmaceutically acceptable salts of the compounds can
be synthesized from the parent compound, which contains a basic or
acidic moiety, by conventional chemical methods. Generally, such
salts can be prepared by reacting the free acid or base forms of
these compounds with a stoichiometric amount of the appropriate
base or acid in water or in an organic solvent, or in a mixture of
the two; generally, non-aqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are preferred. Lists of
suitable salts are found in Remington's Pharmaceutical Sciences,
20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000,
p. 704, the disclosure of which is hereby incorporated by
reference.
[0030] Optionally, the composition described herein can further
include a drug having no appreciable abuse potential.
[0031] B. Drug Solubility Modification
[0032] In preferred embodiments, the solubility characteristics of
a drug are altered prior to incorporation into the formulation.
Modification of the drug to produce a more lipophilic derivative
serves to reduce the water solubility of the drug and thus reduces
the aqueous extractability. Furthermore, if the drug is made more
lipophilic, it can be solubilized in a molten fatty substance or
wax like mixture, rather than physically dispersed in a particulate
form. Solubilization of drug enhances the abuse-deterrent
properties of microparticles formulated from the mixture as it is
difficult to extract drug from an intimately dispersed
composition.
[0033] The terms "lipophilic derivative" and "lipophililic drug
derivative", as used herein, refer to derivatives of the drug that
are less soluble in water than the most soluble salt of the drug.
The most soluble salt being selected from either drug alkaline
metal salts (for acidic drugs) or salts of the drug with inorganic
acids (for basic drugs). The examples of the latter include but are
not limited to hydrohalates, sulfates, and nitrates.
[0034] Some of the methods that can be used to alter the drug's
lipophilicity are outlined below. It is understood that two or more
approaches can be combined to achieve a desired solubility
profile.
[0035] Methods for Increasing Lipophilicity
[0036] In one embodiment, drug is made more lipophilic by
eliminating or reducing the overall charge of the drug molecule.
For example, for a basic drug, a water soluble salt (such as
hydrochloride, sulfate, or maleate) can be converted to a free base
using techniques known in the art. Correspondingly, in the case of
an acidic drug, a water soluble salt (such sodium, potassium, or
the like) can be converted to a free acid.
[0037] In another embodiment, the drug's lipophilicity is increased
by forming a salt between a drug molecule and a charged lipophilic
compound. In this case the lipophilicity of the resulting salt can
be manipulated by varying the lipophilicity of the counter-ion. In
general lipophilic acids or amines with chain lengths between
C.sub.5-C.sub.30 are lipophilic counter-ion candidates. Some
specific examples include, but are not limited to, linoleic acid,
octanoic acid, lauric acid, stearic acid, palmitic acid, oleic
acid, octyl amine, lauryl amine, stearyl amine, palmityl amine,
linoleyl amine, and oleyl amine. Other salts which may increase
lipophilicity and, hence, lipid solubility relative to the parent
drug compound include, but are not limited to, pectinate, tannate,
phytate, salicylate, saccharinate, acesulfamate, gallate, and
terephthalate salts.
[0038] In yet another embodiment the lipophilicity of the drug is
increased by forming a stable complex between a drug molecule
(either charged or uncharged) and a metal cation such as zinc,
magnesium, calcium, bismuth or the like. This complex may consist
of one or more drug molecules, one or more metal cations, and,
optionally, one or more lipophilic charged species. The
aforementioned charged lipophilic species are incorporated into the
complex if necessary to bring the charge of the final complex to
zero and increase its overall lipophilicity. In general lipophilic
acids or amines with chain lengths between C.sub.5-C.sub.30 are
lipophilic counter-ion candidates. Examples of such complexes for a
narcotic drug oxycodone are given in FIG. 1; a lipophilic drug
complex may be composed of one or two oxycodone molecules, one
Zn.sup.2+ cation, and one or two stearate anions. It is understood
by one skilled in the art that various metal cations as well as
lipophilic counter-ions can be used to form complexes with an
analogous structure, for example, oxymorphone.
[0039] In still a further embodiment, drug lipophilicity is
increased via complexation with poorly water-soluble cyclodextrin.
For example, ethylated beta-cyclodextrin has been shown to decrease
aqueous solubility of complexed drug molecules.
[0040] In another embodiment, a drug is covalently modified to
increase its lipophilicity. For example, a lipophilic compound can
be covalently attached to a drug molecule via an ester or amide
linkage. Such drug derivatives are cleaved in vivo, thus releasing
the parent compound.
[0041] C. Drug Containing Microparticles
[0042] In preferred embodiments, drugs are formulated with a
carrier material to form microparticles. As used herein, the term
"microparticle" refers to a composition comprising a drug dispersed
within a carrier material and "coated microparticle" refers to a
composition comprising a drug containing microparticle or a drug
particle coated with one or more coating layers of material.
Microparticles and coated microparticles have a size range of 10 to
3000 microns in diameter.
[0043] Within microparticles, drug is preferably homogeneously
dispersed in the form of fine particles within the carrier
material. More preferably, drug is partially solubilized in molten
carrier material or partially dissolved with the carrier material
in a mutual solvent during the formulation of the microparticles.
Most preferably, drug is completely solubilized in the molten
carrier material or completely dissolved with the carrier material
in a co-solvent during the formulation of the microparticles. This
is accomplished through the selection of materials and the manner
in which they are processed.
[0044] Carrier materials appropriate for the fabrication of drug
containing microparticles are either slowly soluble in water or
insoluble in water, but capable of degrading within the GI tract by
means including enzymatic degradation, surfactant action of bile
acids and mechanical erosion. As used herein, the term "slowly
soluble in water" refers to materials that are not dissolved in
water within a period of 30 minutes. Preferred examples include
fats, fatty substances, waxes, wax-like substances and mixtures
thereof. Suitable fats and fatty substances include fatty alcohols
(such as lauryl, myristyl stearyl, cetyl or cetostearyl alcohol),
fatty acids and derivatives, including but not limited to fatty
acid esters, fatty acid glycerides (mono-, di- and tri-glycerides),
and hydrogenated fats. Specific examples include, but are not
limited to hydrogenated vegetable oil, hydrogenated cottonseed oil,
hydrogenated castor oil, hydrogenated oils available under the
trade name Sterotex.RTM., stearic acid, cocoa butter, and stearyl
alcohol. Suitable waxes and wax-like materials include natural or
synthetic waxes, hydrocarbons, and normal waxes. Specific examples
of waxes include beeswax, glycowax, castor wax, carnauba wax,
paraffins and candelilla wax. As used herein, a wax-like material
is defined as any material which is normally solid at room
temperature and has a melting point of from about 30 to 300.degree.
C.
[0045] In some cases, it may be desirable to alter the rate of
water penetration into the hydrophobic drug containing
microparticles. To this end, rate-controlling (wicking) agents may
be formulated along with the fats or waxes listed above. Examples
of rate-controlling materials include certain starch derivatives
(eg, waxy maltodextrin and drum dried corn starch), cellulose
derivatives (eg, hydroxypropylmethylcellulose,
hydroxypropylcellulose, methylcellulose, and
carboxymethylcellulose), alginic acid, lactose and talc.
Additionally, a pharmaceutically acceptable surfactant (for
example, lecithin) may be added to facilitate the degradation of
such microparticles.
[0046] Proteins which are water insoluble, such as zein, are
preferred carrier materials for the formation of drug containing
microparticles. Additionally, proteins, polysaccharides and
combinations thereof which are water soluble can be formulated with
drug into microparticles and subsequently cross-linked to form an
insoluble network. For example, cyclodextrins can be complexed with
individual drug molecules and subsequently cross-linked.
[0047] Certain polymers may also be used as carrier materials in
the formulation of drug containing microparticles. Suitable
polymers include ethylcellulose and other natural or synthetic
cellulose derivatives. Polymers which are slowly soluble and form a
gel in an aqueous environment, such as hydroxypropyl
methylcellulose or polyethylene oxide may also be suitable as
carrier materials for drug containing microparticles.
[0048] Encapsulation or incorporation of drug into carrier
materials to produce drug containing microparticles can be achieved
through known pharmaceutical formulation techniques. To create a
composition that protects drug from exposure upon mechanical
disruption (eg, grinding, chewing, or chopping), the drug is
intimately dispersed within the carrier material. In the case of
formulation in fats, waxes or wax-like materials, the carrier
material is heated above its melting temperature and the drug is
added to form a mixture comprising drug particles suspended in the
carrier material, drug dissolved in the carrier material, or a
mixture thereof. Microparticles can be subsequently formulated
through several methods including, but not limited to, the
processes of congealing, extrusion, spray chilling or aqueous
dispersion. In a preferred process, wax is heated above its melting
temperature, drug is added, and the molten wax-drug mixture is
congealed under constant stirring as the mixture cools.
Alternatively, the molten wax-drug mixture can be extruded and
spheronized to form pellets or beads. Detailed descriptions of
these processes can be found in "Remington--The science and
practice of pharmacy", 20th Edition, Jennaro et. Al., (Phila,
Lippencott, Williams, and Wilkens, 2000).
[0049] For some carrier materials it may be desirable to use a
solvent evaporation technique to produce drug containing
microparticles. In this case drug and carrier material are
co-dissolved in a mutual solvent and microparticles can
subsequently be produced by several techniques including, but not
limited to, forming an emulsion in water or other appropriate
media, spray drying or by evaporating off the solvent from the bulk
solution and milling the resulting material.
[0050] In addition to modification of the drug itself, processing
conditions can be used to influence the dispersion of the drug
within water-insoluble or slowly water soluble material. For
example, in the case where the water in-soluble or slowly soluble
material is melted and drug is fully or partially dissolved under
stirring conditions, the temperature, agitation rate and time of
processing will influence the degree of dissolution achieved. More
specifically, a more homogenous dispersion may be achieved with a
higher temperature, faster stirring rate and longer processing
time. Ultrasound can also be applied to the molten mixture to
increase the degree of dispersion and/or the rate of dissolution of
the drug.
[0051] In some embodiments, drug in a particulate form is
homogeneously dispersed in a water-insoluble or slowly water
soluble material. To minimize the size of the drug particles within
the composition, the drug powder itself may be milled to generate
fine particles prior to formulation. The process of jet milling,
known in the pharmaceutical art, can be used for this purpose. In
some embodiments drug in a particulate form is homogeneously
dispersed in a wax or wax like substance by heating the wax or wax
like substance above its melting point and adding the drug
particles while stirring the mixture. In this case a
pharmaceutically acceptable surfactant may be added to the mixture
to facilitate the dispersion of the drug particles.
[0052] D. Coated Drug Containing Microparticles
[0053] In some embodiments, drug containing microparticles or drug
particles are encapsulated within at least one water-insoluble
enzymatically degradable material. In some instances the substrates
of digestive enzymes are naturally water-insoluble and can be
utilized in the formulation without further processing. Solid
esters of fatty acids, which are hydrolyzed by lipases, can be
spray coated onto microparticles or drug particles. Zein is an
example of a naturally water-insoluble protein. It can be coated
onto drug containing microparticles or drug particles by spray
coating or by wet granulation techniques. In addition to naturally
water-insoluble materials, some substrates of digestive enzymes can
be treated with cross-linking procedures, resulting in the
formation of non-soluble networks. Many methods of cross-linking
proteins, initiated by both chemical and physical means, have been
reported. One of the most common methods to obtain cross-linking is
the use of chemical cross-linking agents. Examples of chemical
cross-linking agents include aldehydes (gluteraldehyde and
formaldehyde), epoxy compounds, carbodiimides, and genipin. In
addition to these cross-linking agents, oxidized and native sugars
have been used to cross-link gelatin (Cortesi, R., et al.,
Biomaterials 19 (1998) 1641-1649). Cross-linking can also be
accomplished using enzymatic means; for example, transglutaminase
has been approved as a GRAS substance for cross-linking seafood
products. Finally, cross-linking can be initiated by physical means
such as thermal treatment, UV irradiation and gamma
irradiation.
[0054] To produce a coating layer of cross-linked protein
surrounding drug containing microparticles or drug particles, a
water soluble protein can be spray coated onto the microparticles
and subsequently cross-linked by the one of the methods described
above. Alternatively, drug containing microparticles can be
microencapsulated within protein by coacervation-phase separation
(for example, by the addition of salts) and subsequently
cross-linked. Some suitable proteins for this purpose include
gelatin, albumin, casein, and gluten.
[0055] Polysaccharides can also be cross-linked to form a
water-insoluble network. For many polysaccharides, this can be
accomplished by reaction with calcium salts or multivalent cations
which cross-link the main polymer chains. Pectin, alginate,
dextran, amylose and guar gum are subject to cross-linking in the
presence of multivalent cations. Complexes between oppositely
charged polysaccharides can also be formed; pectin and chitosan,
for example, can be complexed via electrostatic interactions.
Insoluble coatings can be formed on particles in this fashion. It
should be noted that in many cases polysaccharides are broken down
specifically by enzymes produced by bacteria within the colon.
[0056] In some cases a water-insoluble but enzymatically degradable
coating comprising both a protein and a polysaccharide can be
produced if the components are oppositely charged polyelectrolytes.
Under the proper temperature, pH, and concentrations, the two
polymers can interact through their opposite electrical charges and
form a water-insoluble complex. If a core particle is present at
the time the complex phase separates, it will be coated. For
example, gelatin and gum arabic can be coated onto a core particle
utilizing this process. Optionally, the complex can be made
irreversibly insoluble by subsequent cross-linking induced by
chemical or physical means.
[0057] E. Dosage Forms
[0058] There are a number of drug compositions that meet the abuse
deterrent criteria outlined above. In one embodiment a drug is
homogeneously dispersed, in a fine particulate form, within a
water-insoluble or slowly water soluble material and the mixture is
formulated into microparticles. In another embodiment a drug is
partially dissolved within a water-insoluble or slowly water
soluble material during the manufacturing process, for example, by
mixing at a temperature above the melting point of the carrier
material, and the mixture is formulated into microparticles. In yet
another embodiment a drug is fully dissolved within a
water-insoluble or slowly water soluble material during the
manufacturing process, for example, by mixing at a temperature
above the melting point of the carrier material, and the mixture is
formulated into microparticles. In still a further embodiment, the
drug containing microparticles, where the drug is homogeneously
dispersed in a particulate form, or has been partially or fully
dissolved within the carrier material during the manufacturing
process, are coated with one or more coatings to form coated
microparticles. In a further embodiment, drug particles are coated
directly with one or more coatings to form coated
microparticles.
[0059] The microparticles, coated microparticles, or a mixture
thereof are formed into a solid dosage form suitable for oral
administration. For example, microparticles or coated
microparticles can be incorporated into hard capsules, dispersed
within a soft gelatin capsule, or combined with appropriate
excipients and tableted by compression.
[0060] In some embodiments, the compositions are coated with an
enteric coating. Enteric coatings known in the art are applied
directly to the abuse-deterrent microparticle or coated
microparticle compositions or are applied to the surface of a
capsule or tablet comprising the abuse deterrent microparticle
and/or coated microparticle compositions. Enteric coatings known in
the art include, for example, acrylic polymers that are
commercially available under the trade name EUDRAG1T.RTM.,
cellulose acetate phthalate, hydroxypropylmethylcellulose
phthalate, polyvinyl acetate phthalate, shellac,
hydroxypropylmethylcellulose succinate, cellulose acetate
trimelliate or mixtures thereof.
[0061] Dosage forms can include one or more drugs. When the dosage
form includes two or more drugs they can be Scheduled drugs or can
be a combination of Scheduled and non-Scheduled drugs. The drugs
can be incorporated into separate microparticle compositions where
the Scheduled drugs are incorporated into abuse deterrent
microparticle compositions and the non-Scheduled drugs are
incorporated into abuse deterrent microparticle compositions,
sustained release compositions known in the art or immediate
release compositions known in the art. The compositions comprising
the different drugs are formulated into a single solid dosage form
suitable for oral administration, for example, they can be
incorporated into a gelatin capsule, or combined with appropriate
excipients and compressed into a tablet form. Examples of
non-scheduled drugs that may be included in dosage forms described
herein include, but are not limited to, aspirin, acetaminophen,
non-steroidal anti-inflammatory drugs, cyclooxygenase II
inhibitors, N-methyl-D-aspartate receptor antagonists, glycine
receptor antagonists, triptans, dextromethorphan, promethazine,
fiorinal, guaifenesin, butalbital, and caffeine.
[0062] An immediate release dose can be incorporated into the
formulation in several ways. Immediate release microparticles can
be made utilizing standard methodologies and formulated along with
abuse-deterrent microparticle and/or coated microparticle
compositions in a suitable oral dosage form. Alternatively, a
coating containing drug which is available for immediate release
can be placed on a tablet comprising abuse-deterrent microparticle
and/or coated microparticle compositions plus appropriate
excipients. Additionally, an immediate dose of drug can be
granulated or blended with rapidly dissolving excipients and
subsequently compressed (1) as one layer of bi-layer tablets in
which the abuse-deterrent microparticle and/or coated microparticle
compositions are compressed as the other layer, or (2) as the outer
layer of compression-coated tablets in which the abuse-deterrent
microparticle and/or coated microparticle compositions are
compressed as the inner core, or (3) into tablets in which
abuse-deterrent microparticle and/or coated microparticle
compositions are embedded.
[0063] In some embodiments, the immediate release portion of the
dosage form comprises a lipophilic drug derivative. For example,
salt derivatives or complexes that are insoluble at a neutral pH
but dissociate, thereby releasing the parent compound, at an acidic
pH are ideal for immediate release within the stomach. In the case
of oxycodone some salts that may exhibit this property include, but
are not limited to, the tannate, phthalate, salicylate, gallate,
pectinate, phytate, saccharinate, asesulfamate and terephthalate
salts. Complexes of drug with one or more metal ions and,
optionally, one or more lipophilic counter-ions (see, for example,
FIG. 1) may also be used for immediate drug release. Use of salts
or complexes in the immediate release portion of the dosage form
reduces the abuse potential of the immediate release dose if the
formulation is crushed and (1) snorted or (2) dissolved in water
since these salts will be poorly soluble under these conditions. It
is understood by the one of ordinary skill in the art that such
salts or complexes may also be used to formulate an immediate
release dosage form without a sustained release portion.
[0064] Additional mechanisms to reduce the potential for abuse can
also be incorporated during the process of formulating tablets. For
example, ingredients can be added to deter chewing or snorting of
the final formulation. For example, an intensely bitter substance
may deter chewing, while an intensely spicy ingredient, such as
capsaicin, may deter snorting. The addition of a colored dye, which
would stain the skin and mucosal surface of the nose following
snorting may also serve to reduce this practice.
[0065] Optional excipients present in the oral dosage form
comprising abuse deterrent microparticles or coated microparticles
include, but are not limited to diluents, binders, lubricants,
disintigrants, colorants, plasticizers and the like. Diluents, also
termed "fillers," are typically necessary to increase the bulk of a
solid dosage form so that a practical size is provided for
compression of tablets. Examples of diluents include cellulose, dry
starch, microcrystalline cellulose, dicalcium phosphate, calcium
sulfate, sodium chloride confectioner's sugar, compressible sugar,
dextrates, dextrin, dextrose, sucrose, mannitol, powdered
cellulose, sorbitol, and lactose. Binders are used to impart
cohesive qualities powdered materials and can include materials
such as starch, gelatin, sugars, natural and synthetic gums,
polyethylene glycol, ethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose, waxes and
polyvinyl pyrrolidone. Lubricants are used to facilitate tablet
manufacture; examples of lubricants include talc, magnesium
stearate, calcium stearate, hydrogenated vegetable oils stearic
acid, sodium stearyl fumarate, sodium benzoate, sodium acetate,
leucine, sodium oleate, sodium lauryl sulfate, magnesium lauryl
sulfate and polyethylene glycol. Disintegrants can be added to
pharmaceutical formulations in order to facilitate "breakup" or
disintegration after administration. Materials used for this
purpose include starches, clays, celluloses, aligns, gums, and
cross-linked polymers. A plasticizer may be included in coating
materials to alter their mechanical properties. Examples of
plasticizers include benzyl benzoate, chlorobutanol, dibutyl
sebacate, diethyl phthalate, glycerin, mineral oil, polyethylene
glycol, sorbitol, triacetin, triethyl citrate, glycerol, etc. In
addition to the additives above, coloring and flavoring agents may
also be incorporated into the composition.
[0066] Optionally, the composition disclosed herein comprises
materials wherein a combination of the materials is not soluble in
water, organic solvent, or any combination thereof.
II. Methods of Administration
[0067] It is assumed that upon oral ingestion of the intact
composition, drug is released as the formulation is gradually
broken down or dissolved within the GI tract by a combination of
enzymatic degradation, surfactant action of bile acids, and
mechanical erosion. This is a result of the unique ability of the
human digestive system to efficiently break down or solubilize a
variety of materials. The process within the GI tract that results
in the digestion of food and the absorption of nutrients is well
known. Following mastication within the mouth, food passes into the
stomach where it is mixed with digestive juices. This fluid
contains the proteolytic enzyme pepsin which, following activation
by the low pH within the stomach, begins the process of cleaving
ingested proteins into smaller peptide fragments. Food then enters
the small intestine in the form of macromolecular aggregates, where
it is digested into molecules near or in a form capable of being
absorbed. This digestion is accomplished through the action of
various enzymes which are produced in the pancreas and flow into
the upper portion of the large intestine, the duodenum. The enzymes
synthesized in the pancreas include proteases, amylases and
lipases; these enzymes are capable of breaking down proteins,
starches and fats, respectively. The digestion of fats is further
facilitated by the secretion of bile into the duodenum since bile
salts, which contain both hydrophobic and hydrophilic portions, are
capable of emulsifying lipids into minute droplets in order to
increase the surface area available for digestion by lipases. The
material which remains following passage through the small
intestine enters the large intestine. Bacteria capable of breaking
down carbohydrates not digested in the small intestine (such as
cellulose) are present in large numbers this region of the
digestive tract. Finally, in addition to microbial fermentation,
the large intestine functions to absorb water and electrolytes and
to form and store feces until they are excreted.
[0068] In addition to providing a deterrent to common methods of
abuse/diversion, the formulation can provide a sustained release of
drug over an extended time period. This is a natural consequence of
the fact that, in the present formulation, drug is slowly released
from a predominantly water-insoluble, hydrophobic matrix following
the degradation of the matrix. The barrier components are degraded,
for example, by enzymes, the surfactant action of bile acids and
mechanical erosion.
[0069] In some embodiments, an immediate release of drug is
achieved within the stomach in order to provide rapid therapeutic
onset.
[0070] The pharmaceutical drug composition is administered orally.
The appropriate dosage formulations can be obtained by calculation
of the pharmacokinetics of the formulation, then adjusting using
routine techniques to yield the appropriate drug levels based on
the approved dosage focus. Any suitable amount of drug containing
microparticles or coated microparticles can be included in the
final formulation. The selection of a suitable amount of drug
containing microparticles depends on the dosage desired and is
readily determined by those skilled in the art.
[0071] In addition to oral administration, some embodiments may
also be administered by other routes, including, but not limited
to, rectal and nasal administration. Some embodiments may also be
suitable for formulation as oral liquids.
[0072] The present composition and method of making and using the
composition will be further understood by reference to the
following non-limiting examples.
EXAMPLE 1
Preparation of Lipophilic Oxycodone Derivatives
[0073] A. Oxycodone Free Base
[0074] The free base of oxycodone was prepared from its
hydrochloride salt by the following method: Oxycodone hydrochloride
was dissolved in water and sodium carbonate was added in the amount
required to neutralize hydrochloric acid. Methylene chloride was
added in order to extract the formed oxycodone free base. The
obtained organic layer was dried over sodium sulfate and methylene
chloride was evaporated using rotary evaporator. The obtained
oxycodone free base was purified by crystallization.
[0075] B. Zinc-bis-oxycodone
[0076] Zinc bis-oxycodone can be obtained in anhydrous media by
reacting oxycodone free base with Zn(Et).sub.2
[0077] C. Zinc oxycodone stearate
[0078] Zinc oxycodone stearate can be obtained in anhydrous media
by reacting oxycodone free base with
Zn(Et)(C.sub.18H.sub.35O.sub.2)
[0079] D. Zinc oxycodone di-stearate
[0080] Zinc-oxycodone di-stearate can be obtained by co-melting
Zn(C.sub.18H.sub.35O.sub.2).sub.2 and oxycodone free base.
[0081] E. Oxycodone terephthalate
[0082] Oxycodone terephthalate is commercially available and can be
used without further processing
[0083] The structures of some representative oxycodone zinc
complexes are shown in FIGS. 1A, 1B and 1C.
EXAMPLE 2
Preparation of Drug Containing Microparticles
[0084] The free base, salts or complexes from Example 1 are added
to molten hydrogenated vegetable oil, mixed, extruded and
spheronized to form drug containing microparticles.
EXAMPLE 3
Preparation of Coated Drug Containing Microparticles
[0085] The drug-containing particles from Example 2 are spray
coated with zein in a fluidized bed apparatus.
EXAMPLE 4
Preparation of Capsules for Oral Administration
[0086] The drug containing microparticles from Example 2 and/or the
coated microparticles from Example 3 are incorporated into standard
gelatin capsules.
EXAMPLE 5
Preparation of Capsules for Oral Administration Containing a Dose
of Drug for Immediate Release
[0087] The drug containing microparticles from Example 2 and/or the
coated microparticles from Example 3 are combined with immediate
release drug particles, and incorporated into standard gelatin
capsules.
* * * * *