U.S. patent application number 14/494148 was filed with the patent office on 2015-02-12 for abuse resistant forms of immediate release oxycodone, method of use and method of making.
The applicant listed for this patent is Inspirion Delivery Technologies, LLC. Invention is credited to Ray J. DiFalco, Manish S. SHAH.
Application Number | 20150044282 14/494148 |
Document ID | / |
Family ID | 40351440 |
Filed Date | 2015-02-12 |
United States Patent
Application |
20150044282 |
Kind Code |
A1 |
SHAH; Manish S. ; et
al. |
February 12, 2015 |
ABUSE RESISTANT FORMS OF IMMEDIATE RELEASE OXYCODONE, METHOD OF USE
AND METHOD OF MAKING
Abstract
An abuse resistant oral pharmaceutical composition, comprising:
a barrier layer, comprising a first polymer; a diffusion layer,
comprising a second polymer, substantially covering the barrier
layer, wherein the diffusion layer is bonded to the barrier layer
and comprises a drug that is substantially homogeneously
distributed within the second polymer and diffuses from the
diffusion layer within the gastrointestinal (GI) tract; and
optionally an expansion layer comprising an expandable polymer,
wherein the expansion layer is substantially covered by the barrier
layer. Methods of making the same and methods of using the same are
also provided.
Inventors: |
SHAH; Manish S.; (West
Caldwell, NJ) ; DiFalco; Ray J.; (Ridgewood,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Inspirion Delivery Technologies, LLC |
Valley Cottage |
NY |
US |
|
|
Family ID: |
40351440 |
Appl. No.: |
14/494148 |
Filed: |
September 23, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13408068 |
Feb 29, 2012 |
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14494148 |
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Current U.S.
Class: |
424/452 ;
424/465; 424/497; 514/282 |
Current CPC
Class: |
A61K 9/2018 20130101;
A61K 9/2031 20130101; A61K 9/4891 20130101; A61K 9/5031 20130101;
A61P 25/30 20180101; Y10T 156/10 20150115; A61P 25/00 20180101;
A61P 25/26 20180101; A61K 9/2086 20130101; A61K 9/1617 20130101;
A61P 29/00 20180101; A61K 47/38 20130101; A61K 9/2081 20130101;
A61K 9/2846 20130101; A61K 9/5078 20130101; A61K 31/138 20130101;
A61K 31/437 20130101; A61K 31/485 20130101; A61K 47/32 20130101;
A61K 9/4858 20130101; A61K 9/2013 20130101; A61K 9/28 20130101;
A61K 9/5042 20130101; A61K 47/34 20130101; A61K 9/16 20130101; A61K
9/1623 20130101; A61K 9/4808 20130101; A61K 9/1641 20130101; A61K
9/2054 20130101; A61K 9/2027 20130101; A61K 31/4458 20130101; A61K
9/1676 20130101; A61K 9/5047 20130101; A61K 9/1652 20130101; A61K
9/5026 20130101; A61K 9/209 20130101; A61K 9/4866 20130101; A61P
25/04 20180101; A61K 9/2886 20130101 |
Class at
Publication: |
424/452 ;
424/465; 424/497; 514/282 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 9/16 20060101 A61K009/16; A61K 9/48 20060101
A61K009/48; A61K 31/485 20060101 A61K031/485; A61K 9/28 20060101
A61K009/28 |
Claims
1. A method of treating pain in a patient in need thereof,
comprising orally administering to the patient an abuse resistant
pharmaceutical composition comprising an inner expansion layer that
does not contain any drug and comprises a hydrophilic expandable
polymer, a barrier layer that substantially covers the expansion
layer and comprises a first polymer that does not substantially
dissolve in the gastrointestinal (GI) tract, and a diffusion layer
that substantially covers and is bonded to the barrier layer and
comprises oxycodone or pharmaceutically acceptable salt thereof
substantially homogeneously distributed within a second polymer
selected from the group consisting of ethyl cellulose, quarternary
ammonium acrylic or methacrylic polymers, acrylic or methacrylic
polymers, acrylic or methacrylic copolymers, synthetic waxes,
natural waxes, cellulose acetate phthalate, hydroxypropyl
methylcellulose phthalate, polyvinyl acetate phthalate,
hydroxypropyl methylcellulose acetate succinate, shellac, cellulose
acetate trimellitate, and mixtures thereof, wherein the oxycodone
or pharmaceutically acceptable salt thereof diffuses from the
diffusion layer within the GI tract to treat pain, wherein the
pharmaceutical composition is configured such that when the
pharmaceutical composition is administered to a subject in an
intact form at least 90% of the total amount of oxycodone or
pharmaceutically acceptable salt thereof in the intact form is
released after 1 hour, wherein when the pharmaceutical composition
is physically compromised to produce particles having a particle
size between 8 mesh and 500 mesh and exposed to a liquid comprising
water and/or alcohol, the bond between the diffusion layer and the
barrier layer is substantially preserved and the expandable polymer
of the expansion layer absorbs at least a portion of the liquid and
expands and/or forms a gel, and wherein when the pharmaceutical
composition is physically compromised to produce particles having a
particle size between 8 mesh and 500 mesh and administered to a
subject no more than 75% of the total amount of oxycodone or
pharmaceutically acceptable salt thereof in the particles is
released after 1 hour.
2. The method of claim 1, wherein the oxycodone or pharmaceutically
acceptable salt thereof is present in an amount of about 5 mg to
about 400 mg.
3. The method of claim 1, wherein the oxycodone or pharmaceutically
acceptable salt thereof comprises oxycodone hydrochloride.
4. The method of claim 1, wherein the pharmaceutical composition in
the intact form releases at least 80% of the oxycodone or
pharmaceutically acceptable salt thereof in vitro after 1 hour, as
determined under the following conditions: USP Apparatus I (basket)
at 100 rpm in 900 mL aqueous buffer at pH 1.6 or 7.2 and 37.degree.
C.
5. The method of claim 1, wherein the pharmaceutical composition is
in a form selected from the group consisting of a tablet, a
capsule, a micro tablet, granules, pellets, a lozenge, a lollipop,
and a coated capsule.
6. The method of claim 1, wherein the pharmaceutical composition is
in a form of a tablet.
7. The method of claim 6, wherein the expansion layer has a
thickness of about 5 to 95% of the total thickness of the
tablet.
8. The method of claim 6, wherein the barrier layer has a thickness
of about 5 to 50% of the total thickness of the tablet.
9. The method of claim 6, wherein the diffusion layer has a
thickness of about 1 to 30% of the total thickness of the
tablet.
10. The method of claim 1, wherein the first polymer and the second
polymer are each independently selected from the group consisting
of acrylic polymers, methacrylic polymers, acrylic copolymers and
methacrylic copolymers.
11. The method of claim 1, wherein the first polymer and the second
polymer are independently selected from the group consisting of
ethyl acrylate, methyl methacrylate, and copolymers thereof.
12. A method of treating pain in a patient in need thereof,
comprising orally administering to the patient an abuse resistant
pharmaceutical composition comprising an inner expansion layer that
does not contain any drug and comprises a hydrophilic expandable
polymer, a barrier layer that substantially covers the expansion
layer and comprises a first polymer that does not substantially
dissolve in the gastrointestinal (GI) tract, and a diffusion layer
that substantially covers and is bonded to the barrier layer and
comprises oxycodone or pharmaceutically acceptable salt thereof
substantially homogeneously distributed within a second polymer
selected from the group consisting of ethyl cellulose, quarternary
ammonium acrylic or methacrylic polymers, acrylic or methacrylic
polymers, acrylic or methacrylic copolymers, synthetic waxes,
natural waxes, cellulose acetate phthalate, hydroxypropyl
methylcellulose phthalate, polyvinyl acetate phthalate,
hydroxypropyl methylcellulose acetate succinate, shellac, cellulose
acetate trimellitate, and mixtures thereof, wherein the oxycodone
or pharmaceutically acceptable salt thereof diffuses from the
diffusion layer within the GI tract to treat pain, wherein the
pharmaceutical composition is configured such that when the
pharmaceutical composition is physically compromised to produce
particles having a particle size between 8 mesh and 500 mesh and
exposed to a liquid comprising water and/or alcohol, the bond
between the diffusion layer and the barrier layer is substantially
preserved and the expandable polymer of the expansion layer absorbs
at least a portion of the liquid and expands and/or forms a gel,
and wherein when the pharmaceutical composition is physically
compromised to produce particles having a particle size between 8
mesh and 500 mesh and administered to a subject the maximum blood
concentration (Cmax) and/or area under the serum concentration
curve (AUC) of the oxycodone or pharmaceutically acceptable salt
thereof achieved in the subject after 2 hours is lower than the
Cmax and/or AUC achieved in the subject when the pharmaceutical
composition is administered in an intact form.
13. The method of claim 12, wherein the oxycodone or
pharmaceutically acceptable salt thereof is present in an amount of
about 5 mg to about 400 mg.
14. The method of claim 12, wherein the oxycodone or
pharmaceutically acceptable salt thereof comprises oxycodone
hydrochloride.
15. The method of claim 12, wherein the hydrophilic expandable
polymer is present in an amount of 5 to 90% by weight based on the
total weight of the dosage form.
16. The method of claim 12, wherein the pharmaceutical composition
is in a form selected from the group consisting of a tablet, a
capsule, a micro tablet, granules, pellets, a lozenge, a lollipop,
and a coated capsule.
17. The method of claim 12, wherein the pharmaceutical composition
is in a form of a tablet.
18. The method of claim 17, wherein the expansion layer has a
thickness of about 5 to 95% of the total thickness of the
tablet.
19. The method of claim 17, wherein the barrier layer has a
thickness of about 5 to 50% of the total thickness of the
tablet.
20. The method of claim 17, wherein the diffusion layer has a
thickness of about 1 to 30% of the total thickness of the
tablet.
21. The method of claim 12, wherein the first polymer and the
second polymer are each independently selected from the group
consisting of acrylic polymers, methacrylic polymers, acrylic
copolymers and methacrylic copolymers.
22. The method of claim 12, wherein the first polymer and the
second polymer are independently selected from the group consisting
of ethyl acrylate, methyl methacrylate, and copolymers thereof.
23. A method of treating pain in a patient in need thereof,
comprising orally administering to the patient an abuse resistant
pharmaceutical composition comprising an inner expansion layer that
does not contain any drug and comprises a hydrophilic expandable
polymer, a barrier layer that substantially covers the expansion
layer and comprises a first polymer that does not substantially
dissolve in the gastrointestinal (GI) tract, and a diffusion layer
that substantially covers and is bonded to the barrier layer and
comprises oxycodone or pharmaceutically acceptable salt thereof
substantially homogeneously distributed within a second polymer
selected from the group consisting of ethyl cellulose, quarternary
ammonium acrylic or methacrylic polymers, acrylic or methacrylic
polymers, acrylic or methacrylic copolymers, synthetic waxes,
natural waxes, cellulose acetate phthalate, hydroxypropyl
methylcellulose phthalate, polyvinyl acetate phthalate,
hydroxypropyl methylcellulose acetate succinate, shellac, cellulose
acetate trimellitate, and mixtures thereof, wherein the oxycodone
or pharmaceutically acceptable salt thereof diffuses from the
diffusion layer within the GI tract to treat pain, wherein the
pharmaceutical composition is configured such that when the
pharmaceutical composition is physically compromised to produce
particles having a particle size between 8 mesh and 500 mesh and
exposed to a liquid comprising water and/or alcohol, the bond
between the diffusion layer and the barrier layer is substantially
preserved and the expandable polymer of the expansion layer absorbs
at least a portion of the liquid and expands and/or forms a gel,
and wherein when the pharmaceutical composition is administered
with an alcohol, the rate of release of the oxycodone or
pharmaceutically acceptable salt thereof from the pharmaceutical
composition within 2 hours after administration is lower than the
rate of release of the oxycodone or pharmaceutically acceptable
salt thereof from the pharmaceutical composition without
alcohol.
24. The method of claim 23, wherein the oxycodone or
pharmaceutically acceptable salt thereof is present in an amount of
about 5 mg to about 400 mg.
25. The method of claim 23, wherein the oxycodone or
pharmaceutically acceptable salt thereof comprises oxycodone
hydrochloride.
26. The method of claim 23, wherein the pharmaceutical composition
is in a form selected from the group consisting of a tablet, a
capsule, a micro tablet, granules, pellets, a lozenge, a lollipop,
and a coated capsule.
27. The method of claim 23, wherein the pharmaceutical composition
is in a form of a tablet.
28. The method of claim 23, wherein the first polymer and the
second polymer are each independently selected from the group
consisting of acrylic polymers, methacrylic polymers, acrylic
copolymers and methacrylic copolymers.
29. The method of claim 23, wherein the first polymer and the
second polymer are independently selected from the group consisting
of ethyl acrylate, methyl methacrylate, and copolymers thereof.
30. The method of claim 23, wherein the rate of release is
determined by comparing the maximum blood concentration (Cmax)
and/or area under the serum concentration curve (AUC) of the
oxycodone or pharmaceutically acceptable salt thereof achieved in a
subject after administration of the pharmaceutical composition with
alcohol versus administration of the pharmaceutical composition
without alcohol.
Description
[0001] This application claims priority from U.S. Provisional
Application Ser. No. 60/955,584 filed Aug. 13, 2007, which is
incorporated herein by reference in its entirety.
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 medications and their use in a non-indicated or
non-prescribed manner. The present invention can comprise any drug,
especially medications that are subject to abuse. More
specifically, it pertains to pain medications, medications to
reduce or eliminate anxiety attack (psychotherapeutic drugs),
stimulants and sleeping pills. With these general type drugs there
is the potential of abuse that may result in drug overdose,
addiction, suboptimal efficacy, and/or death.
[0003] In particular, the present invention relates to an abuse
resistant composition (for, e.g., pain medication, anxiety attack
medication, sleeping medication or stimulants), having, but not
limited to, a diffusion layer and a barrier layer; use of such a
composition in a dosage form to treat diseases or conditions; and a
method of making an abuse deterrent composition having a diffusion
layer and a barrier layer. In some embodiments, the composition
also comprises an expansion layer.
[0004] 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. Opioid analgesics such as oxycodone, morphine, oxymorphone,
hydrocodone and hydromorphone are successful and therapeutically
useful pain medications. Unfortunately, they also pose a severe
threat for willful abuse due to their ability to alter mood and/or
cause a sense of euphoria (a "high"). Currently available sustained
release formulations of such drugs, which contain a relatively
large amount of drug substance 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 (i.e., the crushed formulation) can no longer control the
release of drug. Depending on the drug substance, abusers can then
(1) snort the material, (2) swallow the material or (3) dissolve
the material in water or alcohol 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).
[0005] These abuse methods result in the rapid bioavailability of
relatively high doses of drug contained in a single tablet or
capsule, giving the abuser a "high." The sense of euphoria, or
"high," is highly correlated with the peak serum concentration of
the drug substance (Cmax). Although such a high serum concentration
can be obtained from taking several immediate release or sustained
release tablets at once, abusers are deterred from doing so because
multiple tablets are harder to come by and, maybe more importantly,
the very high dose associated with taking several tablets at once
is associated with an severely increased risk of overdose
(typically a function of high serum levels of the drug substance
over prolonged periods of time; resulting in a high area under the
curve: the integral of the serum concentration over time, also
known by the acronym "AUC"). In order to reduce the risk of
overdose, the typical abuser will prefer to obtain a high peak
serum concentration from a single tablet or capsule. In the
scientific terminology of a pharmacologist, the typical abuser
appears to maximize Cmax while minimizing AUC, or alternatively, to
maximize the Cmax/AUC ratio.
[0006] In some cases, abusers consume alcohol with immediate and/or
extended release formulations to reach a "high" more quickly.
Abusers sometimes place the formulation in water or alcohol, in
order to extract the drug in an accelerated fashion. The
coadministration of these liquids is known to sometimes decrease
the time after drug administration in which the peak plasma
concentration and Cmax are reached. Sometimes abusers place the
formulation into other solvents such as freon, methylene chloride,
ethanol, and acetone, in order to extract the drug, which can then
be injected. Another technique used by abusers to extract drug from
a dosage form such as a tablet is wiping the coating off of the
tablet, crushing the tablet into a fine powder, placing the powder
into sterile water, and then drawing the liquid into a syringe. In
addition, the dosage form can be generally physically compromised
by crushing, grinding, and chewing.
[0007] Since relatively simple methods (crushing, grinding, chewing
and/or dissolution in water or alcohol) can be used to transform a
single extended release tablet or capsule formulation into an
abusable form, these conventional dosage forms provide virtually no
deterrent to a potential abuser.
[0008] 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, 80, and 160 mg strengths), an opioid
agonist with an addiction potential similar to that of morphine.
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 FDA 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 dangerous dose of
oxycodone becomes bioavailable, which is potentially lethal to
users of this product, in particular first time users.
[0009] 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 U.S. between January 2000 and June 2001. Some of these reported
cases have been associated with serious consequences, including
death.
[0010] 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. 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 U.S.; for example, the medical use of opioids within the
U.S. increased 400% from 1996 to 2000.
[0011] 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. No.
3,980,766 describes the incorporation of an ingestible solid which
causes a rapid increase in viscosity (gelling) 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, thus retarding the release of the drug substance. 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
examples in this patent all describe conventional immediate release
formulations and the resulting tablets form 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 may
preclude abuse by injections, this approach would fail to prevent
abuse by crushing and swallowing or snorting the formulation, which
are commonly reported methods of abuse associated with
OXYCONTIN.RTM..
[0012] 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
opioid agonist and an orally active opioid 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.
[0013] U.S. Patent Application Publication No. 2007/0066537
discloses an abuse resistant opioid wherein the opioid is bound to
niacin, biotin or peptide.
[0014] U.S. Patent Application Publication No. 2006/0104909
discloses a pharmaceutical composition comprising an opioid and a
tamper-resistant matrix comprising one or more tenacious
cross-linked polymers that are capable of bonding with the opioid
such that the opioid is substantially incapable of immediate
release from the polymer. A further preferred aspect uses a water
insoluble matrix material comprising a pH insensitive material such
as ethylcellulose, cellulose acetate, vinyl acetate/vinyl chloride
copolymers, acrylate/methacrylate copolymers, polyethylene oxide,
hydroxypropyl methylcellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, triglycerides, hydrogenated vegetable
oils, triglyceride polyalkoxyalkylesters, fats, waxes and water
insoluble partially-degraded proteins. The surface coating material
comprises a hydrophobic polymer such as a pharmaceutically
acceptable acrylic polymer such as acrylic acid and methacrylic
acid copolymers, methyl methacrylate copolymers, ethoxyethyl
methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate
copolymer, poly(acrylic acid), polymethacrylic acid, methacrylic
acid alkylamide copolymer, poly(methyl methacrylate),
poly(methacrylic acid anhydride), methyl methacrylate,
polymethacrylate, polyacrylamide and glycidyl methacrylate
copolymers. In certain preferred embodiments, the acrylic polymer
is comprised of one or more ammonio methacrylate copolymers Ammonio
methacrylate copolymers are well known in the art, and are
described in NF XVII as fully polymerized copolymers of acrylic and
methacrylic acid esters with a low content of quaternary ammonium
groups.
[0015] U.S. Patent Application Publication No. 2005/0281748
discloses an opioid bound to a lipid or fatty acid to produce an
abuse resistant drug.
[0016] It is 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. In particular, the present
invention addresses the need for a drug product which, compared to
conventional formulations, decreases the intensity, quality,
frequency and rate of occurrence of the "euphoria" effect which can
occur with improper administration.
SUMMARY OF THE INVENTION
[0017] The present invention relates to an abuse resistant oral
pharmaceutical composition, comprising: a barrier layer, comprising
a first polymer; and a diffusion layer, comprising a second
polymer, substantially covering the barrier layer, wherein the
diffusion layer is bonded to the barrier layer and comprises a drug
that is substantially homogeneously distributed within the second
polymer and diffuses from the diffusion layer within the
gastrointestinal (GI) tract. The pharmaceutical composition may
optionally comprise an expansion layer comprising an expandable
polymer and wherein the barrier layer substantially covers the
expansion layer.
[0018] The present invention also relates to an oral pharmaceutical
composition, comprising a drug in a pharmaceutically effective
amount, wherein the pharmaceutical composition in configured such
that when the pharmaceutical composition is administered in
physically compromised form to a subject, the rate of drug released
from the composition within a time period selected from the group
consisting of 2 hours, 4 hours, 8 hours and 16 hours is
substantially the same or lower than the rate of drug released when
the pharmaceutical composition is administered in an intact
form.
[0019] The present invention also relates to an oral pharmaceutical
composition, comprising a drug in a pharmaceutically effective
amount, wherein the pharmaceutical composition is configured such
that when the pharmaceutical composition is administered in
physically compromised form to a subject, the amount of drug
released from the composition within a time period selected from
the group consisting of 2 hours, 4 hours, 8 hours and 16 hours, is
substantially the same or lower, preferably less than 20%, more
preferably less than 30%, and most preferably less than 40%, than
the amount of drug released when the pharmaceutical composition is
administered in an intact form. In the context of this application,
the phrase "substantially the same" means within (+/-) 30%,
preferably within (+/-) 20%, and more preferably within (+/-)
10%.
[0020] The present invention also relates to an oral pharmaceutical
composition, comprising a drug in a pharmaceutically effective
amount, wherein the pharmaceutical composition in configured such
that when the pharmaceutical composition is contacted with an
alcohol or consumed with an alcohol, the rate of drug released from
the composition within a time period selected from the group
consisting of 2 hours, 4 hours, 8 hours and 16 hours, is
substantially the same or lower, preferably less than 40%, more
preferably less than 30%, and most preferably less than 20%, than
the rate of drug released when the pharmaceutical composition is
administered without an alcohol.
[0021] The present invention also relates to an oral pharmaceutical
composition, comprising a drug in a pharmaceutically effective
amount, wherein the pharmaceutical composition is configured such
that when the pharmaceutical composition is administered in an
intact form at least 50% of the amount of drug is released after 8
hours and when the pharmaceutical composition is administered in
physically compromised form no more than 40%, preferably no more
than 30%, of the amount of drug is released after 1 hour.
[0022] The present invention also relates to an oral pharmaceutical
composition, comprising a drug in a pharmaceutically effective
amount, wherein the pharmaceutical composition is configured such
that when the pharmaceutical composition is administered in an
intact form at least 90% of the amount of drug is released after 1
hour and when the pharmaceutical composition is administered in
physically compromised form no more than 75% of the amount of drug
is released after 1 hour.
[0023] The present invention also relates to a method of making an
abuse resistant oral pharmaceutical composition, comprising:
forming a barrier layer, wherein the barrier layer comprises a
first polymer; and applying a diffusion layer over the barrier
layer to substantially cover the barrier layer, wherein the
diffusion layer comprises a second polymer and a drug that is
homogeneously distributed within the second polymer; and bonding
the diffusion layer to the barrier layer, preferably by physical
bonding.
[0024] The present invention also relates to a method of making an
abuse resistant oral pharmaceutical composition, comprising:
forming an expansion layer comprising an expandable polymer;
applying a barrier layer over the expansion layer to substantially
cover the expansion layer, wherein the barrier layer comprises a
first polymer; and applying a diffusion layer over the barrier
layer to substantially cover the barrier layer, wherein the
diffusion layer comprises a second polymer and a drug that is
homogeneously distributed within the second polymer; and bonding
the diffusion layer to the barrier layer, preferably by physical
bonding. In some embodiments, the barrier layer can be applied onto
the expansion layer by spraying or dry coating.
[0025] The present invention also relates to a method of treating a
condition, comprising administering to a patient in need thereof
the pharmaceutical composition of the invention.
[0026] The present invention also relates to an oral pharmaceutical
composition, comprising a drug in a pharmaceutically effective
amount, wherein the pharmaceutical composition is configured such
that when the pharmaceutical composition is administered in
physically compromised form to a subject, the intensity of the
euphoria is substantially the same or lower than the intensity of
the euphoria achieved after administration of a physically
compromised bioequivalent composition not comprising means for
deterring abuse.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 is a graph of percent release rate versus time of a
tablet made according to Example 31 when taken properly (intact) as
compared to a ground form of the same tablet formulation.
[0028] FIG. 2 is a graph of percent release rate versus time of a
ground tablet of OXYCONTIN.RTM. versus a ground tablet of the
formulation of Example 31.
[0029] FIG. 3 is an in vivo simulation showing features of the
invention, prepared utilizing the Microsoft Excel software program.
Currently marketed immediate or extended release tablets would
exhibit Cmax-1 as shown after grinding the tablets and subsequently
snorting the ground powder. The same tablets when ingested intact
would show Cmax-2, as the rate of absorption will be delayed due to
physiological factors in the GI tract. A bioequivalent tablet
formulation of the invention would show the same profile as the
Cmax-2 curve. However, the tablets of the current invention when
ground and snorted would show the lower Cmax-3.
[0030] FIG. 4 is a graph of percent release rate versus time of a
tablet made according to Example 31 when taken properly (intact) as
compared to a "cut form" of the same tablet formulation.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0031] The concept behind the present invention of an abuse
resistant pharmaceutical composition is to provide the necessary
amount of a drug to the patient to accomplish the pharmaceutical
effect (such as pain relief), while decreasing the ability of a
potential abuser to alter the composition in order to experience a
"high" or to induce rapid death. Drugs which are typically abused,
and therefore are suitable for the present invention, include pain
medications, such as opioids, anxiety attack medications, sleeping
medication, and stimulants, among others.
[0032] The abuse deterrent composition of the invention can retard,
or at least not increase significantly, the release of the drug
substance from a dosage form when the physical integrity of the
dosage form containing the composition is compromised and the
resulting formulation is subsequently snorted, injected, or
swallowed. The composition is "physically compromised" when it is
in a form other than an intact form. This can be achieved by
various means such as by chewing, chopping, grinding, crushing, or
placing into solvents, such as those containing an alcohol (e.g.,
ethyl alcohol) and/or water. The composition of the invention thus
provides a deterrent to common methods of improper administration,
including intravenous injection of the drug dissolved in solvent,
and nasal or oral administration of the crushed formulation, as the
drug will not be immediately and rapidly released from the
formulation and as the actual amount of drug release can be
decreased as compared to an intact formulation. When administered
as directed, the drug substance is released more gradually from the
composition within the gastrointestinal (GI) tract, preferably by
dissolution and/or diffusion mechanisms.
[0033] According to one embodiment, the abuse resistant
pharmaceutical composition of the present invention comprises: a
barrier layer, comprising a first polymer; and a diffusion layer,
comprising a second polymer, substantially covering the barrier
layer, wherein the diffusion layer is bonded to the barrier layer
and comprises a drug that is substantially homogeneously
distributed within the second polymer and diffuses from the
diffusion layer within the gastrointestinal tract. The
pharmaceutical composition optionally comprises an expansion layer
comprising an expandable polymer. In embodiments wherein the
pharmaceutical composition comprises an expansion layer, the
barrier layer substantially covers the expansion layer.
[0034] The abuse deterrent composition of the invention can
comprise either or both extended release formulations, with a
typical in vivo or in vitro slow release of drug over a period of
about 6 to about 24 hours, preferably at least 80% of the drug
released at about 12 to about 24 hours, as well as immediate
release formulations, preferably with a release of at least 80%,
more preferably at least 90% and most preferably at least 95%, of
the drug in one hour, designed for oral administration.
[0035] The abuse resistant oral pharmaceutical composition can be
in any pharmaceutical dosage form, including, but not limited to a
tablet, a capsule, a micro tablet, granules, pellets, a lollipop, a
lozenge and a coated capsule. In preferred embodiments, the abuse
resistant oral pharmaceutical composition is in a tablet dosage
form.
[0036] In embodiments where the abuse resistant oral pharmaceutical
composition comprises the optional expansion layer, the expansion
layer is the innermost of the three layers of the drug composition.
The expansion layer is preferably an inert layer, which does not
contain any drug, and it comprises an expandable polymer. The
expansion layer preferably has a thickness of about 0.5 to 15 mm,
more preferably about 2 to 12 mm, and most preferably about 4 to 10
mm. The thickness of the expansion layer is preferably about 5 to
95%, more preferably about 40% to 95%, and most preferably about
50% to 90% of the thickness of the tablet.
[0037] In some embodiments, when the expandable polymer of the
optional expansion layer is exposed to liquids, preferably liquids
comprising water and/or an alcohol such as ethyl alcohol, the
expandable polymer absorbs the liquid, and preferably expands
and/or forms a gel. It is preferably a hydrophilic polymer, most
preferably a hydrophilic polymer that swells upon contact with
liquids and/or gels. In a preferred form, when the expansion layer
is exposed to a liquid after the abuse deterrent composition is
physically compromised and fragments of the composition containing
the expansion layer are formed, the expandable polymer absorbs at
least a portion of the liquid and forms a gel. Preferably the gel
further retards release of the drug from the diffusion layer.
Further, the increased viscosity may make it difficult for an
abuser to draw up the formulation into a syringe for injection. The
expansion layer preferably comprises a polymer present in the range
of 5 to 90% by weight, based on the total weight of the dosage
form.
[0038] Typical agents employed in the expansion layer include, but
are not limited to methylcellulose, sodium carboxymethylcellulose,
methylhydroxyethylcellulose, methylhydroxypropylcellulose, alginic
acid, polyacrylic acid, and tragacanth, or a combination of two or
more of these substances. Most preferred are hydroxypropyl
methylcellulose, which is sometimes marketed under the tradename
METHOCEL.RTM. and polyacrylic acid, which is sometimes marketed
under the tradename CARBOPOL.RTM..
[0039] The expansion layer may also include a disintegrant such as
croscarmellose sodium or sodium starch glycolate, to help assure
the expansion layer quickly disperses in a liquid. Additional
ingredients which may be present in the expansion layer include,
but are not limited to fillers, dyes, lubricants or water
permeation enhancers such as sodium chloride. The use of highly
soluble polymers, disintegrants or combinations thereof is
generally known in the pharmaceutical arts, and as would be
understood to one skilled in the art, any suitable highly soluble
polymer or disintegrant or equivalent substances may be used in
conjunction with the present invention and embodiments thereof.
[0040] The barrier layer is interior to the diffusion layer. In
some embodiments wherein the pharmaceutical composition comprises
an expansion layer, the expansion layer is the innermost of the
three layers and the barrier layer substantially covers the
expansion layer. Substantial covering of the expansion layer means
that more that 80%, more preferably more than 90%, and most
preferably more than 95% of the expansion layer is covered by the
barrier layer. 100% coverage is most suitable.
[0041] The barrier layer preferably has a thickness of about 0.1 to
2.5 mm, more preferably about 0.2 to 2.0 mm, and most preferably
about 0.5 to 1.5 mm. The thickness of the barrier layer is
preferably about 5 to 50%, more preferably about 8 to 30%, and most
preferably about 10 to 25% of the total thickness of the
composition.
[0042] The barrier layer serves a number of functions. For example,
the barrier layer acts as barrier between the diffusion layer and
the expansion layer, decreasing the amount of liquid that can enter
into the expansion layer when the dosage form is in an intact form.
Further, the barrier layer acts to improve the mechanical strength
of the composition.
[0043] The barrier layer comprises a polymer. Typical barrier layer
polymers include, but are not limited to, polyacrylates and the
copolymers thereof (such as those marked under the tradename
EUDRAGIT.RTM. NE 30 D), EUDRAGIT.RTM. FS 30 D, EUDRAGIT.RTM. RS 30
D, SURELEASE.RTM. from COLORCON.RTM., AQUACOAT.RTM. from FMC.RTM.,
and mixtures of EUDRAGIT.RTM. NE 30 D and AQUACOAT.RTM.,
polyethylene glycol, polyethylene oxides, polyethylenes,
polypropylenes, polyvinyl chlorides, polycarbonates, polystyrenes,
and the like. The preferred polymers of the barrier layer are
polyacrylate and polyethylene glycol and in particular, a
polyacrylate dispersion. In embodiments wherein the pharmaceutical
composition comprises an expansion layer, the barrier layer may
also contain an adhesion agent to help it adhere to the expansion
layer. The use of polymers resistant to biodegradation, adhesion
agents or combinations thereof is generally known in the
pharmaceutical arts, and as would be understood to one skilled in
the art, any suitable bioresistant polymer or adhesion enhancing
agent may be used in conjunction with the present invention and
embodiments thereof.
[0044] Preferably, when a dosage form containing the abuse
deterrent pharmaceutical composition of the present invention is
administered to a subject in the intact form, the barrier layer
polymer does not substantially dissolve in the GI tract, mucous
membranes, blood vessels or lungs. Rather, the barrier layer
polymer passes through the body in a substantially undissolved
form. "Substantially undissolved" means that less than 30%, more
preferably less than 20% and most preferably less than 10% of the
polymer is dissolved.
[0045] The diffusion layer substantially covers the barrier layer.
Substantial covering of the barrier layer means that more that 80%,
more preferably more than 90%, and most preferably more than 95% of
the expansion layer is covered by the barrier layer. 100% coverage
is most suitable.
[0046] The diffusion layer comprises a polymer and a drug,
preferably a drug which is substantially homogeneously distributed
in the polymer. "Substantially homogeneously distributed" means
that more that 80%, more preferably more than 90%, and most
preferably more than 95% of the drug is homogeneously distributed.
The polymer and drug dispersion of the diffusion layer is applied
and bonded to the barrier layer.
[0047] The diffusion layer preferably is a thin layer with a large
surface area relative to the thickness of the layer. The diffusion
layer preferably has a thickness of about 0.1 to 1.0 mm, more
preferably about 0.15 to 0.7 mm, and most preferably about 0.2 to
0.4 mm. The thickness of the diffusion layer is preferably about 1
to 30%, more preferably about 2 to 20%, and most preferably about 3
to 10% of the thickness of the tablet. In the preferred embodiments
of this invention, the diffusion layer is relatively thin as
compared to the surface area of the diffusion layer.
[0048] In some preferred embodiments, one or more of the layers can
contain dye which, when in contact with liquid or mouth saliva,
will produce a stain or color. This could aid in abuse resistant
characteristics of the tablets of the present invention. Examples
of dyes include, but are not limited to, FD&C Red #3, FD&C
Red #28 and FD&C Blue #1.
[0049] The drug incorporated in the pharmaceutical compositions of
the invention can be any drug, or any combinations of two or more
drugs. However, typically, the drug or drugs will be one that is
often abused, such as central nervous system stimulants and
depressants. Examples of central nervous system stimulants include,
but are not limited amphetamines and agents such as cocaine.
Examples of central nervous depressants include, but are not
limited to opioids, barbiturates, benzodiazepines, and other
anxiety and sleep medications. Examples of combinations of two
drugs include oxycodone and morphine.
[0050] Examples of opioids include, but are not limited to the
following: alfentanil, allylprodine, alphaprodine, anileridine,
benzylmorphine, bezitramide, buprenorphine, butorphanol,
clonitazene, codeine, desomorphine, dextromoramide, dezocine,
diampromide, diamorphone, dihydrocodeine, dihydromorphine,
dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl
butyrate, dipipanone, eptazocine, ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene, hydrocodone,
hydromorphone, hydroxypethidine, isomethadone, ketobemidone,
levorphanol, levophenacylmorphan, lofentanil, meperidine,
meptazinol, metazocine, methadone, metopon, morphine, myrophine,
narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,
nalbuphene, normorphine, norpipanone, opium, oxycodone,
oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,
phenazocine, phenoperidine, piminodine, piritramide, propheptazine,
promedol, properidine, propoxyphene, sufentanil, tilidine, and
tramadol. Any opioid or pharmaceutically acceptable salt or ester
thereof may be used in the abuse deterrent composition. Preferred
opioids include fentanyl, sufentanil, carfentanil, lofentanil,
alfentanil, hydromorphone, oxycodone, morphine, hydroxycodone,
propoxyphene, pentazocine, methadone, tilidine, butorphanol,
buprenorphine, levorphanol, codeine, oxymorphone, meperidine, and
dihydrocodeinone. More preferred opioids include oxycodone,
hydrocodone, codeine, morphine, oxymorphone and hydromorphone, and
pharmaceutically acceptable salts and esters thereof. The most
particularly preferred opioids are oxycodone and morphine and
pharmaceutically acceptable salts thereof.
[0051] Examples of barbiturates include, but are not limited to
mephobarbital (which is sometimes marketed under the tradename
MEBARAL.RTM.) and pentobarbital sodium (which is sometimes marketed
under the tradename NEMBUTAL.RTM.). Barbiturates are often
prescribed to treat anxiety, tension, and sleep disorders.
[0052] Examples of benzodiazepines and benzodiazepine derivatives
include, but are not limited to diazepam (sometimes marketed under
the tradename VALIUM.RTM.), alprazolam (sometimes marketed under
the tradename XANAX.RTM.), triazolam (HALCION.RTM.), and estazolam
(PROSOM.RTM.). Benzodiazepines are often prescribed to treat
anxiety, acute stress reactions, and panic attacks.
[0053] An example of another CNS depressant is zaleplon, which is
sometimes marked under the tradename SONATA.RTM..
[0054] Although the various classes of CNS depressants work
differently, they all can produce a beneficial drowsy or calming
effect in individuals suffering from such conditions as sleep
disorders and anxiety. However, if one uses these drugs over a long
period of time, the body can develop tolerance, and larger doses
may be needed to achieve the initial effects. In addition,
continued use can lead to physical dependence and, when use is
reduced or stopped, withdrawal symptoms. Both barbiturates and
benzodiazepines have the potential for abuse and should be used
only as prescribed. As with opioids, an overdose of these drugs can
be fatal.
[0055] Stimulants increase heart rate, blood pressure and
metabolism, sometimes providing feelings of exhilaration and energy
and increased mental alertness. Amphetamines such as
methylphenidate (sometimes marketed under the tradename
RITALIN.RTM.) and dextroamphetamine (sometimes marketed under the
tradenames ADDERALL.RTM. and DEXEDRINE.RTM.) are often prescribed
for the treatment of narcolepsy, attention-deficit/hyperactivity
disorder, and depression that has not responded to other
treatments. They also may be used for short-term treatment of
obesity. Individuals may become addicted to the sense of well-being
and enhanced energy that stimulants can generate. Taking high doses
of stimulants repeatedly over a short time, however, can lead to
feelings of hostility or paranoia. Additionally, taking high doses
of stimulants may result in dangerously high body temperatures and
an irregular heartbeat.
[0056] Preferred embodiments of the invention include a drug and
amounts as follows: oxycodone or a pharmaceutically acceptable salt
thereof, which is present in an amount of about 5 mg to about 400
mg; morphine or a pharmaceutically acceptable salt thereof, which
is present in an amount of about 15 mg to about 800 mg;
hydromorphone or a pharmaceutically acceptable salt thereof, which
is present in an amount of about 1 mg to about 64 mg; hydrocodone
or a pharmaceutically acceptable salt thereof, which is present in
an amount of about 5 mg to about 400 mg; and oxymorphone or a
pharmaceutically acceptable salt thereof, which is present in an
amount of about 4 mg to about 80 mg.
[0057] In addition to one or more drugs, the diffusion layer
contains one or more polymers. Examples of polymers which can be
used in the diffusion layer include, but are not limited to, ethyl
cellulose, a quaternary ammonium acrylic or methacrylic polymers,
an acrylic or a methacrylic ester copolymers or a mixture thereof,
which can also be used as sustained release agents. Common
tradenames include various grades of EUDRAGIT.RTM.s (all from
Rohm), and SURELEASE.RTM. (from COLORCON.RTM.). The preferred
polymers of the diffusion layer are acrylic or methacrylic polymers
and particularly ethyl acrylate or methyl methylacrylate
dispersions. The use of diffusion polymers, preferably gradually
abrading polymers, is generally known in the pharmaceutical arts,
and as would be understood to one skilled in the art, any suitable
gradually abrading polymers or agent may be used in conjunction
with the present invention and embodiments thereof.
[0058] Suitable waxes may replace a portion or all of the polymer
in the diffusion layer. Suitable waxes include both synthetic and
natural waxes, as well as wax-like substances, fats and fatty
substances, hydrocarbons like paraffin, beeswax, carnauba wax, and
the like, including combinations of these substances. These
substances dissolve very slowly or not at all in the GI tract. The
use of wax-like substances is generally known in the pharmaceutical
arts, and as would be understood to one skilled in the art, any
suitable wax-like substances may be used in conjunction with the
present invention and embodiments thereof.
[0059] The diffusion layer may optionally also contain sustained or
extended release and/or enteric coating. Examples of such materials
are cellulose acetate phthalate, hydroxypropyl methylcellulose
phthalate, polyvinyl acetate phthalate, methacrylic acid:acrylic
ester copolymer, hydroxypropyl methylcellulose acetate succinate,
shellac, cellulose acetate trimellitate, and mixtures thereof. The
diffusion layer may also contain water-soluble polymers such as
polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, polyethylene glycol having a molecular weight of
from 1,700 to 20,000 and polyvinyl alcohol and monomers therefor
and mixtures thereof. The use of sustained, extended and enteric
coating materials is generally known in the pharmaceutical arts,
and as would be understood to one skilled in the art, any suitable
sustained, extended and enteric coating materials or similar agents
may be used in conjunction with the present invention and
embodiments thereof.
[0060] In the preferred embodiments, for the barrier as well as the
diffusion layer, the acrylic coating is an acrylic lacquer used in
the form of an aqueous dispersion that is commercially available
from Rohm Pharma under the tradename EUDRAGIT.RTM..
[0061] The substantially homogeneous distribution of drug within
the polymer of the diffusion layer allows for the release of drug
at a defined desired rate within the GI tract, for example, such
that it slowly releases the drug. The diffusion layer may be an
immediate release layer or an extended release layer. The diffusion
layer preferably maintains the same release profile, preferably up
to 24 hours, as conventional intact formulations, even when the
layer is broken up into smaller pieces. The presence of the drug in
the diffusion layer is thought to contribute to the formation of
pores in the polymers of the diffusion layer. The presence of pores
allows for the gradual erosion of the diffusion layer and release
of the drug. The release rate of drug can be adjusted by changing
the polymer pore size. For example, reduction in polymer pore size
can reduce the release rate of the drug. Stretching or exposing the
diffusion layer to solvents will also reduce polymer pore size and
reduce the release rate of the drug.
[0062] The diffusion and barrier layers are bonded to each other.
The layers may be bonded by any method known in the art. In some
embodiments, the layers are chemically bonded, or preferably, they
are physically bonded. In preferred embodiments, a physical bond is
formed between layers by heat curing. In another preferred
embodiment, the layers are in powder form and are physically bonded
by using a tablet press. In some embodiments, the expansion and
barrier layers may be manufactured as bulk tablets and stored for a
period of time, preferably up to seven days, as long as the barrier
layer is not cured.
[0063] Preferably, the composition is configured such that when the
pharmaceutical composition is physically compromised and particles
of the pharmaceutical composition containing the diffusion layer
and the barrier layer are formed, the bond between the diffusion
layer and barrier layer within the particles is substantially
preserved. In the preferred embodiments of this invention,
compromising the drug product in this manner will result in pieces
of the diffusion layer and pieces of the barrier layer tightly
bonded together within the particles resulting from the
compromising activity. Thus, in the preferred embodiments of this
invention, the relative surface area of the diffusion layer will
increase only marginally (e.g., no more than 50%, preferably no
more than 25%, most preferably no more than 10%), when particles
are produced in a range of 500 mesh to 8 mesh. The control of drug
diffusion surface area in the preferred embodiments of this
invention prevents a rapid release of the drug product from the
drug product components, even if compromised.
[0064] The formation of a bond between the diffusion layer and the
barrier layer is important in achieving abuse resistance because
when the dosage forms of the invention are physically compromised,
the barrier layer protects the inner side of the diffusion layer,
preventing significant increase in drug release. Therefore, the
drug substance maintains release gradually at substantially its
designed rate from the outer side of the diffusion layer.
[0065] The layer bonding design feature may be optimized by
applying the diffusion layer immediately after the barrier layer is
applied and then curing them together.
[0066] The diffusion layer polymer is able to hold the drug within
and thus prevent the dumping of drug substance after alteration of
the dosage form. The barrier layer and optional expansion layer
enhance the abuse resistant feature of the pharmaceutical
composition.
[0067] Other components may be added to any or all of the various
layers provided that they do not interfere with the drug and
provide a desired benefit to the pharmaceutical. Exemplary of such
other components are: plasticizers, anti-adhesive, inert fillers,
lipophilic agents and pigments used in a known manner. Tackiness of
the water-dispersible film forming substance may be overcome by
simply incorporating an anti-adhesive in the coating. Examples of
anti-adhesive are metallic stearates, microcrystalline cellulose,
calcium phosphate, AEROSIL.RTM. 200, and talc. Those of ordinary
skill in the art would understand the need for and applicability of
such other components to overcome manufacturing, shelf-life or
release profile issues.
[0068] Examples of plasticizers for use in accordance with the
present invention include triacetin, acetylated monoglyceride,
olive oil, acetyl tributyl citrate, acetyl triethyl citrate,
glycerin, sorbitol, polyethylene glycol, and
polypropyleneglycol.
[0069] Fillers/diluents/binders may be incorporated such as
sucrose, sorbitol, mannitol, various grades of lactose, various
grades of microcrystalline cellulose, dextrins, maltodextrins,
starches or modified starches, sodium phosphate, calcium phosphate,
calcium carbonate, gelatin, polyvinylpyrrolidone, and sodium
carboxymethylcellulose.
[0070] Disintegrants may be used such as cellulose derivatives,
including microcrystalline cellulose, low-substituted hydroxypropyl
cellulose, croscarmellose sodium, alginic acid, insoluble
polyvinlypyrrolidone, and sodium carboxymethyl starch.
[0071] Glidants and lubricants may be incorporated such as stearic
acid, metallic stearates, talc, waxes, and glycerides with high
melting temperatures, colloidal silica, sodium stearyl fumarate,
polyethyleneglycols, and alkyl sulphates.
[0072] Surfactants may be employed such as non-ionic (various
grades of polysorbate); anionic such as docusate sodium and sodium
lauryl sulfate, and cationic such as benzalkonium chloride. An
example of an amphoteric surfactant is
1,2-diacyl-L-phosphatidylcholine. The preferred surfactants are
TWEEN.RTM. 80, BRIJO, and Nanoxyl-100.
[0073] Other appropriate pharmaceutically acceptable excipients may
include colorants, flavoring agents, pH adjusting agents,
solubilizing agents, wetting agents, solvent resistant agents and
buffering agents.
[0074] One or more other layers may be disposed under the expansion
layer, or between the expansion layer and the barrier layer or
above or on top of the diffusion layer. For example, in some
embodiments, the expansion layer is not in direct contact with the
barrier layer, as one or more layers may be disposed between the
expansion layer and the barrier layer. In other embodiments, the
expansion layer can cover another layer that is disposed under the
expansion layer. In some embodiments, one or more additional
release layers comprising one or more additional drugs can be on
top of the diffusion layer. In some embodiments, the additional
release layer can be an extended release layer or an immediate
release layer. In some embodiments, both an extended release layer
and an immediate release layer can be on top of the diffusion
layer. The one or more additional drugs can be any drug, including
drugs that may be part of the diffusion layer of the composition,
such as central nervous system stimulants and depressants such as
opioids, barbiturates, benzodiazepines, and amphetamines.
Preferably, the layer on top of the diffusion layer is an immediate
release layer, and drugs in the immediate release layer include,
but are not limited to acetaminophen and nonsteroidal
anti-inflammatory drugs.
[0075] Because of the described features above, the abuse potential
of the pharmaceutical composition of the present invention is
decreased. Further, the features can in some embodiments deter a
patient from cutting a dosage form into smaller pieces containing a
fraction of the dosage of the intact tablet. For example, a patient
seeking to cut an 80 mg tablet into four 20 mg tablet pieces would
be unable to achieve the necessary therapeutic effect with the cut
20 mg tablet pieces, in comparison to uncompromised 20 mg tablets.
This is the case, because in this embodiment of the invention, the
cut 20 mg tablet pieces would not release the full 20 mg amount of
drug in the tablet piece.
[0076] Preferably, when administered properly in an intact form,
the drug is released at a desired release rate from the diffusion
layer, and the remainder of the pharmaceutical composition passes
through the patient's body in an inert manner, because the barrier
layer prevents the remainder of the composition from being broken
down in the GI tract. The desired release rate may be the release
rate typically obtained from the intended use, such as described in
the prescribing information associated with a commercial drug
product.
[0077] In a preferred embodiment of the invention wherein the
composition comprises an expansion layer, physically compromising
the drug product results in the expansion layer being dispersed
between particles containing diffusion layer and barrier layer
components, as a component of the particles containing diffusion
layer and barrier layer components, or both. Thus, in preferred
embodiments of the invention, once exposed to bodily fluids or
other liquids, the particles containing the diffusion layer and
barrier layer components become embedded in the swelled expansion
layer, such that the net diffusion of the drug substance into such
bodily fluids or other liquids occurs at substantially lower rates
than those observed from the diffusion out of the uncompromised
drug product.
[0078] In preferred embodiments of the invention, the resulting
pharmaceutical composition will have both a mechanism to control
and largely maintain the rate of diffusion of the drug substance
from the drug substance containing compartments of the composition,
as well as a mechanism to retard diffusion of the drug substance
from the drug-substance containing compartments of the composition
and to retain a substantial proportion of the drug substance once
the composition is compromised and exposed, in whole or in part, to
a liquid. A benefit of the invention is that it will be difficult
for any person intending to abuse the drug substance by rapidly
extracting the drug substance from the drug product through some
kind of compromising activity and snorting, swallowing or
injecting. As a result, improper administration of the present
invention, compared to conventional formulations, results in a
decreased intensity and quality of euphoria, as well as a decrease
in the rate at which the euphoria occurs. Therefore, abusers hoping
to attain a "high" or experience euphoria by improperly using the
present composition may be unable to achieve the desired "high" or
euphoria. Rather, a less intense effect, if any, is achieved at a
much slower rate. Unless sophisticated and time-consuming
extraction methods are employed, by applying the invention, a
substantial share of the drug substance will become trapped in and
not be separable from the resulting compromised drug product, thus
reducing the overall bioavailability upon snorting, swallowing or
injecting.
[0079] In preferred embodiments, the present composition, when
compromised, releases substantially the same or a lower percentage
of drug compared to an intact, uncompromised composition. In
preferred embodiments, within a time period selected from the group
consisting of 2 hours, 4 hours, 8 hours and 16 hours, a compromised
composition release no more than 90%, more preferably no more than
75%, and more preferably no more than 60% of the drug compared to
intact, uncompromised tablets over the same amount of time.
[0080] The mechanisms and benefits described above are measurable
by conventional pharmaceutical in vivo and in vitro analytical
techniques, such as in vivo plasma measurements or in vitro drug
dissolution. With these techniques, the release of drug substance
present in the pharmaceutical composition over time can be
monitored and expressed as a released percentage of the drug
substance originally present such composition. In preferred
embodiments of the invention, the percentage of the drug substance
released will be substantially lower when a pharmaceutical
composition employing the invention is physically compromised and
then tested in an in vitro dissolution test.
[0081] In discussing release characteristics of products of the
invention, the dosage form comprising an effective amount of a drug
has a dissolution rate in vitro that is measured by the USP Paddle
Method of U.S. Pharmacopoeia, with USP Apparatus I, at 100 rpm
(basket) at 900 mL aqueous buffer at pH 1.6 and 7.2 and at
37.degree. C.
[0082] Preferably, the in vitro release is about 5% to about 50%
(by wt.) drug substance released after 1 hour, from about 20% to
about 65% (by wt.) drug substance released after 4 hours, from
about 35% to about 85% (by wt.) drug substance released after 8
hours and greater than 60% (by wt.) drug substance released after
16 hours; more preferably about 5% to about 40% after 1 hour, about
15% to about 60% after 4 hours; about 40% to about 80% after 8
hours; and about 50% to about 90% after 16 hours; more preferably
about 10% to about 35% after 1 hour, about 15% to about 55% after 4
hours; about 35% to about 75% after 8 hours; and about 50% to about
80% after 16 hours; most preferably about 10% to about 30% after 1
hour, about 25% to about 60% after 4 hours; about 40% to about 80%
after 8 hours; and about 55% to about 75% after 16 hours. The
mechanisms and benefits described above are also measurable by
conventional pharmacokinetic research techniques typically employed
in the characterization of drug kinetics in human patients or other
mammals.
[0083] The most relevant pharmacokinetic parameters for
understanding the features and benefits of the invention are Cmax
(maximum blood serum concentration of the drug substance and/or
active metabolites) and AUC (area under the serum concentration
curve: the integral of the blood serum concentration of the drug
substance and/or active metabolites over time). In preferred
embodiments of the invention, when the pharmaceutical composition
is administered in physically compromised form to a subject, the
Cmax and/or AUC achieved after a time period selected from the
group consisting of 2 hours, 4, hours, 8 hours, 12 hours, 24 hours,
and 48 hours after administration is substantially the same or
lower, preferably about 20-75% lower, than the Cmax and/or AUC
achieved when the pharmaceutical composition is administered in an
intact form.
[0084] One embodiment of the invention relates to a pharmaceutical
composition configured such that when the pharmaceutical
composition is administered in physically compromised form to a
subject, the Cmax and/or AUC resulting from the compromised drug
product achieved after a time period selected from the group
consisting of 2 hours, 4, hours, 8 hours, 12 hours, 24 hours, and
48 hours after administration, will be lower, preferably about
20-75% lower, than the Cmax and/or AUC resulting from an equal
amount of a physically compromised bioequivalent composition that
does not employ means for deterring abuse. A "bioequivalent" drug
composition refers to an intact composition which contains the same
drug and has an AUC and Cmax within the range of 80 to 125% of the
AUC and Cmax of the reference drug composition.
[0085] Another embodiment of the invention relates to a
pharmaceutical composition configured such that when the
pharmaceutical composition is administered in physically
compromised form to a subject, the Cmax/AUC ratio resulting from
the compromised drug product achieved after a time period selected
from the group consisting of 2 hours, 4, hours, 8 hours, 12 hours,
24 hours, and 48 hours after administration, will be or lower,
preferably 20-75% lower, than the Cmax/AUC ratio resulting from a
physically compromised bioequivalent drug product that does not
comprise means for deterring abuse.
[0086] Another preferred embodiment of the invention is an oral
pharmaceutical composition, comprising a drug in a pharmaceutically
effective amount, wherein the pharmaceutical composition is
configured such that when the pharmaceutical composition is
administered in an intact form at least 50%, preferably at least
60%, of the amount of drug is released after 8 hours and when the
pharmaceutical composition is administered in physically
compromised form no more than 40%, preferably no more than 35%,
more preferably no more than 30%, and most preferably no more than
25%, of the amount of drug is released after 1 hour. Preferably,
when the pharmaceutical composition is administered in physically
compromised form no more than 35%, more preferably no more than
30%, and most preferably no more than 25%, of the amount of drug is
released in 15 minutes.
[0087] Another preferred embodiment of the invention is an oral
pharmaceutical composition, comprising a drug in a pharmaceutically
effective amount, wherein the pharmaceutical composition is
configured such that when the pharmaceutical composition is
administered in an intact form at least 90% of the amount of drug
is released after 1 hour and when the pharmaceutical composition is
administered in physically compromised form no more than 75%,
preferably no more than 60%, of the amount of drug is released
after 1 hour.
[0088] The present invention also relates to an oral pharmaceutical
composition, comprising a drug in a pharmaceutically effective
amount, wherein the pharmaceutical composition is configured such
that when the pharmaceutical composition is administered in
physically compromised form to a subject, the intensity of the
euphoria is substantially the same or lower than the intensity of
the euphoria achieved after administration of a physically
compromised bioequivalent composition not comprising means for
deterring abuse. Euphoria is a high or feeling of extreme elation,
which is often experienced after an abuser is administered a
pharmaceutical composition containing a central nervous system
drug. The amount or intensity of euphoria can be measured in a
number of different ways. Methods or techniques of measuring
euphoria are sometimes similar to methods or techniques of
measuring other conditions, such as pain. For example, the amount
or intensity of euphoria can be measured in a numerical or linear
scale, and the person experiencing the euphoria can quantify or
rate the amount or intensity of the euphoria. For example, in some
embodiments, the amount or intensity of euphoria can be measured on
a scale from 0 to 10, wherein a high amount of euphoria is
designated by the number 10, and no euphoria is designated by the
number 0. Similarly, in some embodiments, the amount or intensity
of euphoria can be measured on a linear scale, wherein one end of
the line represents no euphoria, and the opposite end of the line
represents a high amount of euphoria. In some embodiments, the
pharmaceutical composition is configured such that when the
pharmaceutical composition is administered in physically
compromised form to a subject, the intensity of the euphoria is
substantially the same or preferably less than 10%, more preferably
less then 30%, and more preferably less than 50% than the intensity
of the euphoria achieved after administration of a physically
compromised bioequivalent composition not comprising means for
deterring abuse.
[0089] The drug composition of the present invention is preferably
independent of pH in its release profile. Further, there is
preferably no significant change (preferably, less than 10% change)
in the release rate of the formulation after 3 months of storage at
40.degree. C. at 75% relative humidity, when measured by the USP
basket method of U.S. Pharmacopoeia, with USP Apparatus I, at 100
rpm (basket) at 900 mL aqueous buffer at pH 1.6 and 7.2 and at
37.degree. C.
[0090] All references cited herein are hereby incorporated by
reference in their entirety.
[0091] The following examples are employed to demonstrate and
illustrate the present invention.
Example 1
TABLE-US-00001 [0092] Mannitol 90 mg Microcrystalline Cellulose 50
mg CARBOPOL .RTM. 71G 128 mg Hydroxypropyl Methylcellulose, type
2910 128 mg (METHOCEL .TM. K4M CR) Magnesium Stearate 4 mg
[0093] Procedure: Mannitol, Microcrystalline Cellulose,
CARBOPOL.RTM. 71 G, and METHOCEL.TM. K4M CR were sifted through #20
mesh and blended in a blender for 10 minutes. Magnesium Stearate
was sifted through #40 mesh and added in to the blender and mixed
for 5 minutes to lubricate the blend. The final blend was
compressed at 400-mg tablet weight and hardness between 8-15
kp.
Example 2
TABLE-US-00002 [0094] Mannitol 22.5 mg Microcrystalline Cellulose
12.5 mg CARBOPOL .RTM. 71G 32 mg Hydroxypropyl Methylcellulose,
type 2910 32 mg (METHOCEL .TM. K4M CR) Magnesium Stearate 1 mg
[0095] Procedure: Mannitol, Microcrystalline Cellulose,
CARBOPOL.RTM. 71 G, and METHOCEL.TM. K4M CR were sifted through #20
mesh and blended in a blender for 10 minutes. Magnesium Stearate
was sifted through #40 mesh and added in to the blender and mixed
for 5 minutes to lubricate the blend. The final blend was
compressed at 100-mg tablet weight and hardness between 4-9 kp.
Example 3
TABLE-US-00003 [0096] Mannitol 135 mg Microcrystalline Cellulose 75
mg CARBOPOL .RTM. 71G 192 mg Hydroxypropyl Methylcellulose, 192 mg
type 2910 (METHOCEL .TM. K4M CR) Magnesium Stearate 6 mg
[0097] Procedure: Mannitol, Microcrystalline Cellulose,
CARBOPOL.RTM. 71 G, and METHOCEL.TM. K4M CR were sifted through #20
mesh and blended in a blender for 10 minutes. Magnesium Stearate
was sifted through #40 mesh and added in to the blender and mixed
for 5 minutes to lubricate the blend. The final blend was
compressed at 600-mg tablet weight and hardness between 8-15
kp.
Example 4
TABLE-US-00004 [0098] Mannitol 70 mg Microcrystalline Cellulose 50
mg CARBOPOL .TM. 71G 128 mg Hydroxypropyl Methylcellulose, 128 mg
type 2910 (METHOCEL .TM. K4M CR) Croscarmellose sodium 20 mg
(AC-DI-SOL .RTM.) Magnesium Stearate 4 mg
[0099] Procedure: Mannitol, CARBOPOL.RTM. 71 G, Microcrystalline
Cellulose, METHOCEL.TM. K4CR, and AC-DI-SOL.RTM. were sifted
through #20 mesh and blended in a blender for 10 minutes. Magnesium
Stearate was sifted through #40 mesh and added in to the blender
and mixed for 5 minutes to lubricate the blend. The final blend was
compressed at 400-mg tablet weight and hardness between 8-15
kp.
[0100] The combination of CARBOPOL.RTM. and METHOCEL.TM. (Example
4) is a preferred formulation as it provided relatively rapid
expansion capability. The addition of super disintegrant like
AC-DI-SOL.RTM. aids in expanding capability. Also different
expansion layer tablet weight as shown in example 1 through 3
produced the same desired characteristics of the expansion
layer.
Example 5
TABLE-US-00005 [0101] Mannitol 45 mg Microcrystalline Cellulose 25
mg CARBOPOL .TM. 71G 64 mg Hydroxypropyl Methylcellulose, 64 mg
type 2910 (METHOCEL .TM. K4M CR) Magnesium Stearate 2 mg
[0102] Procedure: Mannitol, CARBOPOL.RTM. 71 G, Microcrystalline
Cellulose, and METHOCEL.TM. K4CR were sifted through #20 mesh and
blended in a blender for 10 minutes. Magnesium Stearate was sifted
through #40 mesh and added in to the blender and mixed for 5
minutes to lubricate the blend. The final blend was compressed at
400-mg tablet weight and hardness between 8-15 kp.
Example 6
TABLE-US-00006 [0103] Expansion layer tablet (example 4) 370 g
EUDRAGIT .RTM.NE 30D Dispersion 300 g Calcium Stearate powder 15 g
Simethicone solids 0.15 g Purified water 85 g
[0104] Procedure: Expansion layer tablet having 400 mg unit weight
were loaded in to a conventional coating pan and EUDRAGIT.RTM.
NE30D, Simethicone Emulsion 30%, Calcium Stearate & Purified
Water suspension was sprayed on to the expansion layer tablet using
conventional coating techniques creating the barrier layer. The
suspension was prepared by first adding Simethicone Emulsion into
the Purified Water while mixing. After about 10 minutes of mixing,
Calcium Stearate powder was added while mixing. After about 15
minutes of mixing, the Calcium Stearate suspension was homogenized
for 10 minutes at a medium speed using a suitable homogenizer. In a
separate container, required amount of Eudragit.RTM. NE 30 D was
added and while mixing, Calcium Stearate suspension was added. The
final coating suspension was mixed for about 20 minutes before
spraying onto the tablets. The coated barrier layer tablets were
then cured at 60.degree. C. for 1-3 hours to stabilize the film.
The cured tablets were then used for the diffusion layer.
Throughout the coating process, product temperature of
30-35.degree. C. was maintained. The spray rate range was between
2-10 g/min.
Example 7
TABLE-US-00007 [0105] Expansion layer tablet (example 4) 370 g
EUDRAGIT .RTM. NE 30D Dispersion 300 g Calcium Stearate 15 g
Simethicone Emulsion solids 0.15 g Purified water 85 g
[0106] Procedure: The preparation of the coating suspension and the
coating process of the barrier layer were same as the previous
example. In this example the diffusion layer coat was immediately
applied after barrier layer coat was over and then the tablets were
cured at 60.degree. C. for 1-3 hours. Throughout the coating
process, product temperature of 30-35.degree. C. was maintained.
The spray rate range was between 2-10 g/min.
Example 8
TABLE-US-00008 [0107] Expansion layer tablet (example 5) 400 g
EUDRAGIT .RTM. NE 30D Dispersion 150 g Calcium Stearate 5 g
Simethicone Emulsion solids 0.05 g Purified water 28 g
[0108] Procedure: Expansion layer tablet having 200 mg unit weight
were loaded in to a conventional coating pan. The coating
suspension containing EUDRAGIT.RTM. NE30D, Calcium Stearate,
Simethicone Emulsion 30% suspension and Purified Water was prepared
similar to the example 6 and was sprayed on to the expansion layer
tablet using conventional coating techniques, creating the barrier
layer. The application of the barrier layer, diffusion layer and
curing process was similar to Example 7. Throughout the coating
process, product temperature of 30-35.degree. C. was maintained.
The spray rate range was between 2-10 g/min.
Example 9
TABLE-US-00009 [0109] Expansion layer tablet (example 3) 600 g
EUDRAGIT .RTM. NE 30D Dispersion 150 g Aerosil 200 5 g
[0110] Procedure: Expansion layer tablet having 600 mg unit weight
were loaded in to a conventional coating pan and EUDRAGIT.RTM.
NE30D, Aerosil 200 & Purified Water suspension was sprayed on
to the expansion layer tablet using conventional coating
techniques, creating the barrier layer. The coating suspension was
prepared by adding Aerosil 200 into the required quantity of
Eudragit.RTM. NE30D while mixing. The final coating suspension was
mixed for about 20 minutes before spraying onto the tablets. The
application of the barrier layer, diffusion layer and curing
process was similar to Example 7 & 8. Throughout the coating
process, product temperature of 30-35.degree. C. was maintained.
The spray rate range was between 2-10 g/min.
Example 10
TABLE-US-00010 [0111] Expansion layer tablet (example 2) 400 g
EUDRAGIT .RTM. NE 30D Dispersion 150 g Talc 15 g Purified water 50
g
[0112] Procedure: Expansion layer tablet having 100 mg unit weight
were loaded in to a conventional coating pan and EUDRAGIT.RTM.
NE30D, Talc & Purified Water dispersion was sprayed on to the
expansion layer tablet using conventional coating techniques,
creating the barrier layer. The Barrier layer coating suspension
was prepared by mixing Talc with the required amount of the
purified water while mixing. After about 15 minutes of mixing, the
suspension was homogenized for 10 minutes at a medium speed. In a
separate container, Eudragit NE30D was added. While mixing, Talc
suspension was added and the resulting coating suspension was mixed
for about 20 minutes for spraying onto the tablets. The application
of the barrier layer, diffusion layer and curing process was
similar to Example 7, 8, and 9. The barrier layer separates the
diffusion layer and expansion layer and also makes the tablet
resistant to crushing, smashing and other physical means of
applying pressure.
Example 11
TABLE-US-00011 [0113] Expansion layer tablet (example 4) 370 g
EUDRAGIT .RTM. NE 30D Dispersion 200 g EUDRAGIT .RTM. RS 30D
Dispersion 100 g Talc 25 g Purified water 142 g
[0114] Procedure: Expansion layer tablet having 400 mg unit weight
were loaded in to a conventional coating pan and EUDRAGIT.RTM.
NE30D, EUDRAGIT.RTM. RS30D, Talc & Purified Water suspension
was sprayed on to the expansion layer tablet using conventional
coating techniques, creating the barrier layer. The coating
suspension preparation was very similar to the previous example. It
is possible to enhance the water impermeable characteristic of
EUDRAGIT.RTM. NE30D polymer by incorporating EUDRAGIT.RTM. RS30D
polymer in the barrier layer coating.
[0115] The barrier coated tablet strength and water impermeability
characteristic was independent of anti-tacking agent such as Talc,
Aerosil 200, Calcium Stearate, Magnesium Stearate and Glyceryl
Monostearate. The barrier coat of 5-95 weight % of dry matter
calculated based on the starting weight of the expansion layer
tablet provided relatively crush resistant and water impermeable
tablet. The preferred range for the barrier coat was between 10-60
weight %. The barrier coat and subsequent diffusion polymer coat
were inseparable upon smashing, grinding or crushing if diffusion
layer was applied immediately after the barrier coat and then cured
together.
Example 12
TABLE-US-00012 [0116] Barrier coated tablets (example 7) 475 g
Oxycodone Hydrochloride 37 g EUDRAGIT .RTM.NE 30D dispersion 175 g
Tween .RTM. 80 1.5 g Aerosil .RTM. 200 2.0 g Purified Water 100
g
[0117] Procedure: After completion of the barrier coating, the
diffusion layer was immediately applied in a conventional coating
pan. The drug-polymer coat consisting of Oxycodone Hydrochloride,
Tween.RTM. 80, Aerosil.RTM. 200 and EUDRAGIT.RTM. NE30D suspension
was sprayed on to the barrier coated tablet. The suspension was
prepared by first adding Tween.RTM. 80 in the required amount of
the Purified Water while mixing. The mixing was continued for about
10 more minutes. While mixing, Aerosil.RTM. 200 powder was added
into the previous step suspension and mixed for about 10 minutes.
In a separate container, required amount of Eudragit NE30D was
added and while mixing, Oxycodone hydrochloride powder was added
and mixing was continued for about 15 more minutes to achieve the
homogenous suspension. While mixing, suspension-containing
Tween-Aerosil was added and the final suspension was mixed for
about 20 minutes before spraying onto the tablets. The diffusion
layer coated tablets were then cured at 60.degree. C. for 1-3 hours
to stabilize the film. Throughout the coating process, product
temperature of 30-35.degree. C. was maintained. The spray rate
range was between 5-15 g/min.
Example 13
TABLE-US-00013 [0118] Barrier coated tablets (example 7) 475 g
Oxycodone Hydrochloride 37 g EUDRAGIT .RTM. NE 30D dispersion 275 g
Calcium Stearate 6 g Simethicone Emulsion solids 0.06 g Purified
water 34.4 g
[0119] Procedure: After completion of the barrier coating, the
diffusion layer coat was immediately applied in a conventional
coating pan. The suspension was prepared by first adding
Simethicone Emulsion into the Purified Water while mixing. After
about 10 minutes of mixing, Calcium Stearate powder was added while
mixing. After about 15 minutes of mixing, the Calcium Stearate
suspension was homogenized for 10 minutes at a medium speed using a
suitable homogenizer. In a separate container, required amount of
Eudragit NE30D was added and while mixing, Oxycodone hydrochloride
powder was added and continued mixing for about 15 minutes to
achieve the homogenous suspension. In this homogenous suspension,
Calcium Stearate suspension was added. The final coating suspension
was mixed for about 20 minutes before spraying onto the tablets.
The diffusion-layered tablets were then cured at 60.degree. C. for
1-3 hours to stabilize the film. Throughout the coating process,
product temperature of 30-35.degree. C. was maintained. The spray
rate range was between 5-15 g/min.
Example 14
TABLE-US-00014 [0120] Barrier coated tablets (example 11) 485 g
Oxycodone Hydrochloride 74 g EUDRAGIT .RTM. NE 30D dispersion 350 g
Tween 80 2 g Calcium Stearate 11 g Simethicone Emulsion solids 0.11
g Purified water 60 g
[0121] Procedure: After completion of the barrier coating, the
diffusion layer was immediately applied in a conventional coating
pan. The diffusion layer consisting of Oxycodone hydrochloride,
EUDRAGIT.RTM. NE30D, Calcium Stearate, Simethicone Emulsion
dispersion 30% and Purified Water suspension was sprayed on to the
barrier coated tablet. The suspension was prepared by first adding
Simethicone Emulsion into the Purified Water while mixing. After
about 10 minutes of mixing, Calcium Stearate powder was added while
mixing. After about 15 minutes of mixing, the Calcium Stearate
suspension was homogenized for 10 minutes at a medium speed using a
suitable homogenizer. In a separate container, required amount of
Eudragit NE30D was added and while mixing, Tween.RTM. 80 was added
and mixing was continued for about 10 minutes. After that,
Oxycodone hydrochloride powder was added and while mixing. After
about 15 minutes of mixing Calcium Stearate suspension was added.
The final coating suspension was mixed for about 20 minutes before
spraying onto the tablets. The diffusion-layered tablets were then
cured at 60.degree. C. for 1-3 hours to stabilize the film.
Throughout the coating process, product temperature of
30-35.degree. C. was maintained. The spray rate range was between
5-15 g/min.
Example 15
TABLE-US-00015 [0122] Barrier coated tablets (example 8) 450 g
Oxycodone Hydrochloride 10 g EUDRAGIT .RTM. NE 30D dispersion 100 g
Aerosil 200 2 g Purified water 100 g
[0123] Procedure: After completion of the barrier coating, the
diffusion layer was immediately applied in a conventional coating
pan. The diffusion layer consisting of Oxycodone hydrochloride,
EUDRAGIT.RTM. NE30D, Aerosil.RTM. 200 & Purified Water
dispersion was sprayed on to the barrier coated tablet and then the
diffusion layer coated tablets were then cured at 60.degree. C. for
1-3 hours to stabilize the film. Refer to example 12 for the
coating suspension preparation.
Example 16
TABLE-US-00016 [0124] Barrier coated tablets (example 7) 475 g
Hydrocodone Bitartrate 9.25 g EUDRAGIT .RTM. NE 30D dispersion 155
g AEROSIL .RTM. 200 powder 5 g TWEEN 80 .RTM. 1.5 g Purified water
185 g
[0125] Procedure: After completion of the barrier coating, the
diffusion layer was immediately applied in a conventional coating
pan. The diffusion layer dispersion was prepared by first adding
TWEEN.RTM. 80 and AEROSIL.RTM. 200 powder into Purified water and
mixing the suspension for about 10 minutes. Then Hydrocodone
Bitartrate powder was added into the suspension. The suspension was
mixed for about 15 minutes to achieve the uniform distribution of
the drug. In a separate container add the required amount of
Eudragit NE30D. While mixing, add the active-Tween-Aerosil
suspension in the Eudragit NE30D dispersion and mix for not less
than 20 minutes before spraying on to the barrier coated tablet.
The diffusion layer coated tablets were then cured at 60.degree. C.
for 1-3 hours to stabilize the film. Throughout the coating
process, product temperature of 30-35.degree. C. was maintained.
The spray rate range was between 5-15 g/min.
Example 17
TABLE-US-00017 [0126] Barrier coated tablets (example 7) 475 g
Morphine Sulfate 55.6 g EUDRAGIT .RTM. NE 30D dispersion 275 g
Aerosil 200 5.0 g Purified water 150 g
[0127] Procedure: After completion of the barrier coating, the
diffusion layer was immediately applied in a conventional coating
pan. The diffusion layer consisting of Morphine Sulfate,
EUDRAGIT.RTM. NE30D, Aerosil.RTM. 200 & Purified Water
dispersion was sprayed on to the barrier coated tablet and then the
diffusion layer coated tablets were then cured at 60.degree. C. for
1-3 hours to stabilize the film. The diffusion layer dispersion was
prepared by first adding AEROSIL.RTM. 200 powder into Purified
water and mixing the suspension for about 10 minutes. Then add the
Morphine sulfate powder into the suspension. Mix until uniform
suspension is achieved. The suspension was homogenized for about 10
minutes at a medium speed. In a separate container add the required
amount of Eudragit NE30D. While mixing, add the drug-Aerosil
suspension in the Eudragit NE30D dispersion and mix for not less
than 20 minutes before spraying on to the barrier coated
tablet.
Example 18
TABLE-US-00018 [0128] Barrier coated tablets (example 7) 475 g
Hydromorphone Hydrochloride 14.8 g EUDRAGIT .RTM. NE 30D dispersion
250 g Aerosil .RTM. 200 5.0 g Purified water 100 g
[0129] Procedure: After completion of the barrier coating, the
diffusion layer was immediately applied in a conventional coating
pan. The diffusion layer consisting of Hydromorphone Hydrochloride,
EUDRAGIT.RTM. NE30D, Aerosil.RTM. 200 & Purified Water
dispersion was sprayed on to the barrier coated tablet and then the
diffusion layer coated tablets were then cured at 60.degree. C. for
1-3 hours to stabilize the film. Throughout the coating process,
product temperature of 30-35.degree. C. was maintained. The spray
rate range was between 5-15 g/min. Refer to the previous example
for the preparation of the suspension.
Example 19
TABLE-US-00019 [0130] Barrier coated tablets (example 7) 475 g
Oxymorphone Hydrochloride 37 g EUDRAGIT .RTM. NE 30D dispersion 220
g Tween .RTM. 80 2.5 g Aerosil .RTM. 200 5.0 g Purified water 100
g
[0131] Procedure: After completion of the barrier coating, the
diffusion layer was immediately applied in a conventional coating
pan. The diffusion layer consisting of Oxymorphone Hydrochloride,
EUDRAGIT.RTM. NE30D, Tween.RTM. 80, Aerosil.RTM. & Purified
Water dispersion was sprayed on to the barrier coated tablet. The
diffusion layer dispersion was prepared by first adding TWEEN.RTM.
80 and AEROSIL.RTM. 200 powder into Purified water and mixing the
suspension for about 10 minutes. Then Oxymorphone hydrochloride
powder was added into the suspension. The suspension was mixed for
about 15 minutes to achieve the uniform distribution of the drug.
In a separate container add the required amount of Eudragit NE30D.
While mixing, add the active-Tween-Aerosil suspension in the
Eudragit NE30D dispersion and mix for not less than 20 minutes
before spraying on to the barrier coated tablet. The diffusion
layer coated tablets were then cured at 60.degree. C. for 1-3 hours
to stabilize the film. Throughout the coating process, product
temperature of 30-35.degree. C. was maintained. The spray rate
range was between 5-15 g/min.
Example 20
TABLE-US-00020 [0132] Barrier coated tablets (example 8) 475 g
Dexmethylphenidate Hydrochloride 10 g EUDRAGIT .RTM. NE 30D
dispersion 100 g Aerosil 200 1 g Purified water 100 g
[0133] Procedure: After completion of the barrier coating, the
diffusion layer was immediately applied in a conventional coating
pan. The diffusion layer consisting of Dexmethylphenidate
Hydrochloride, EUDRAGIT.RTM. NE30D, Aerosil.RTM. 200 & Purified
Water dispersion was sprayed on to the barrier coated tablet and
then the diffusion layer coated tablets were then cured at
60.degree. C. for 1-3 hours to stabilize the film. Throughout the
coating process, product temperature of 30-35.degree. C. was
maintained. The spray rate range was between 5-15 g/min.
Example 21
TABLE-US-00021 [0134] Barrier coated tablets (example 10) 450 g
Zaleplon 20 g EUDRAGIT .RTM. NE 30D dispersion 100 g Aerosil .RTM.
200 1 g Tween .RTM. 80 5 g Purified water 100 g
[0135] Procedure: After completion of the barrier coating, the
diffusion layer was immediately applied in a conventional coating
pan. The diffusion layer consisting of Zaleplon, EUDRAGIT.RTM.
NE30D, Aerosil.RTM. 200, Tween.RTM. 80, & Purified Water
dispersion was sprayed on to the barrier coated tablet. The
diffusion layer dispersion was prepared by first adding TWEEN.RTM.
80 and AEROSIL.RTM. 200 powder into Purified water and mixing the
suspension for about 10 minutes. Then Zaleplon powder was added
into the suspension. The suspension was mixed for about 15 minutes
and homogenized for 10 minutes to achieve the uniform distribution
of the drug. In a separate container add the required amount of
Eudragit NE30D. While mixing, add the active-Tween-Aerosil
suspension in the Eudragit NE30D dispersion and mix for not less
than 20 minutes before spraying on to the barrier coated tablet.
The diffusion layer coated tablets were then cured at 60.degree. C.
for 1-3 hours to stabilize the film. Throughout the coating
process, product temperature of 30-35.degree. C. was maintained.
The spray rate range was between 5-15 g/min.
Example 22
TABLE-US-00022 [0136] Barrier coated tablets (example 9) 695 g
Propranolol Hydrochloride 80 g EUDRAGIT .RTM. NE 30D dispersion 150
g Aerosil .RTM. 200 5 g TWEEN .RTM. Solution 1 g Purified water 100
g
[0137] Procedure: After completion of the barrier coating, the
diffusion layer was immediately applied in a conventional coating
pan. The diffusion layer consisting of Propranolol hydrochloride,
Aerosil.RTM. 200, TWEEN.RTM. 80, EUDRAGIT.RTM. NE30D, and Purified
Water dispersion was sprayed on to the barrier coated tablet and
then the diffusion layer coated tablets were then cured at
60.degree. C. for 1-3 hours to stabilize the film. Throughout the
coating process, product temperature of 30-35.degree. C. was
maintained. The spray rate range was between 5-15 g/min.
Example 23
TABLE-US-00023 [0138] Barrier coated tablets (example 6) 475 g
Tramadol Hydrochloride 92.6 g EUDRAGIT .RTM. NE 30D dispersion 290
g Tween .RTM. 80 0.5 g AEROSIL .RTM. 200 5 g Purified water 250
g
[0139] Procedure: After completion of the barrier coating, the
diffusion layer was immediately applied in a conventional coating
pan. The diffusion layer consisting of Tramadol hydrochloride,
EUDRAGIT.RTM. NE30D, Tween.RTM. 80, AEROSIL.RTM. 200 and Purified
Water dispersion was sprayed on to the barrier coated tablet and
then the diffusion layer coated tablets were then cured at
60.degree. C. for 1-3 hours to stabilize the film. Throughout the
coating process, product temperature of 30-35.degree. C. was
maintained. The spray rate range was between 5-15 g/min.
Example 24
Multi-Drug Product, Conventional Immediate-Release
TABLE-US-00024 [0140] Barrier coated tablets (example 8) 450 g
Oxycodone Diffusion Coat: Oxycodone Hydrochloride 10 g EUDRAGIT
.RTM. NE 30D dispersion 100 g Aerosil .RTM. 200 1 g Purified water
100 g Sub Coat, Acetaminophenone Coat and Seal Coat: 5% HPMC
solution Sub-coat 100 g Acetaminophenone Powder 2000 g 10% HPMC
solution 1000 g Purified Water 1000 g 5% HPMC Seal coat 100 g
[0141] Procedure: After completion of the barrier coating, the
Oxycodone hydrochloride diffusion layer was immediately applied in
a conventional coating pan. The diffusion layer consisting of
Oxycodone hydrochloride, EUDRAGIT.RTM. NE30D, Aerosil.RTM. 200
& Purified Water suspension was sprayed on to the barrier
coated tablet. The diffusion layer coated tablets were then cured
at 60.degree. C. for 1-3 hours to stabilize the film. Once the
curing process was completed, 5% HPMC sub-coat was applied followed
by Acetaminophenone coat. The Acetaminophenone HPMC-suspension was
sprayed on to the tablets at 5-25 g/min. The Acetaminophenone
suspension was prepared by first mixing 10% Methocel solution with
the required quantity of the purified water and then suspending the
active drug while mixing. The suspension was mixed for about 15
minutes and then homogenized for 10 minutes before spraying on to
the tablets. Alternatively, the active drug powder can be dusted
into the coating pan suing a powder feeder and 10% HPMC solution
can be sprayed using a spray nozzle. The product temperature was
kept around 30-35.degree. C. Once all of the suspension was
applied, HPMC seal coat was applied. The tablets were dried for 5
minutes at product temperature between 38-40.degree. C. before
discharging from the coating pan.
Example 25
TABLE-US-00025 [0142] Barrier coated tablets 475 g Diffusion layer
coating: Oxycodone Hydrochloride 37 g EUDRAGIT .RTM. NE 30D
dispersion 275 g Tween .RTM. 80 2.5 g Calcium Stearate 6 g
Simethicone solids 0.06 g Purified Water 34.4 g Sustained-Release
layer coating: EUDRAGIT .RTM. NE 30D dispersion 30 g HPMC 10%
Solution 30 g Aerosil .RTM. 200 2.5 g Purified Water 66 g
[0143] After completion of the barrier coating, the diffusion layer
was immediately applied in a conventional coating pan. The
diffusion layer consisting of Oxycodone hydrochloride,
EUDRAGIT.RTM. NE30D, Tween.RTM. 80, Calcium Stearate, Simethicone
Emulsion 30% dispersion and Purified Water suspension was sprayed
on to the barrier coated tablet followed by the sustained-release
coating suspension. The sustained-release coating suspension was
prepared by mixing (about 15 minutes) Eudragit.RTM. NE 30D, 10%
HPMC solution, Aerosil.RTM.200 and Purified Water. After the
completion of the coating, the coated tablets were then cured at
60.degree. C. for 1-3 hours to stabilize the film. Throughout the
coating process, product temperature of 30-35.degree. C. was
maintained. The spray rate range was between 5-15 g/min.
Example 26
TABLE-US-00026 [0144] Diffusion Layer tablets (example 13) 600 g
Opadry 85F18422 White Powder 50 g Purified Water 250 g
[0145] After completion of Diffusion coat, the color coat is
immediately applied in a conventional coating pan. The Color
coating suspension is prepared by suspending Opadry powder in
Purified water. About 300 g of Color Suspension is sprayed onto the
diffusion layer coated tablets at a spray rate of 5-15 g/min. The
product temperature of 36-38.degree. C. is maintained throughout
the process.
Example 27
TABLE-US-00027 [0146] Barrier coated tablets (example 8) 450 g
Oxycodone Hydrochloride 10 g Morphine Sulfate 20 g EUDRAGIT .RTM.NE
30D dispersion 125 g Tween .RTM. 80 1.0 g Aerosil .RTM. 200 2.0 g
Purified Water 100 g
[0147] Procedure: After completion of the barrier coating, the
diffusion layer was immediately applied in a conventional coating
pan. The drug-polymer coat consisting of Oxycodone Hydrochloride,
Morphine Sulfate, Tween.RTM. 80, Aerosil.RTM. 200 and EUDRAGIT.RTM.
NE30D suspension was sprayed on to the barrier coated tablet.
Throughout the coating process, product temperature of
30-35.degree. C. was maintained. The spray rate range was between
5-15 g/min.
Example 28
TABLE-US-00028 [0148] Barrier coated tablets (example 7) 475 g
Oxycodone Hydrochloride 9.3 g Morphine Sulfate 18.5 g EUDRAGIT
.RTM.NE 30D dispersion 275 g Tween .RTM. 80 2.0 g Aerosil .RTM. 200
2.5 g Purified Water 100 g
[0149] Procedure: After completion of the barrier coating, the
diffusion layer was immediately applied in a conventional coating
pan. The drug-polymer coat consisting of Oxycodone Hydrochloride,
Morphine Sulfate, Tween.RTM. 80, Aerosil.RTM. 200 and EUDRAGIT.RTM.
NE30D suspension was sprayed on to the barrier coated tablet.
Throughout the coating process, product temperature of
30-35.degree. C. was maintained. The spray rate range was between
5-15 g/min.
Example 29
Abuse-Resistant Capsule Formulation
TABLE-US-00029 [0150] Expansion layer Mannitol 52.5 mg
Microcrystalline Cellulose 37.5 mg Carbopol 71G 96 mg Hydroxypropyl
Methylcellulose, type 2910 96 mg (METHOCEL .TM. K4M CR)
Croscarmellose sodium 15 mg (AC-DI-SOL .RTM.) Magnesium Stearate 3
mg HPMC Size # 2 Capsules 60 mg Barrier layer EUDRAGIT .RTM. NE 30D
solids 97.3 mg Calcium Stearate 16.2 mg Simethicone Emulsion 0.2 mg
Purified water -- Diffusion layer Oxycodone Hydrochloride 40 mg
EUDRAGIT .RTM. NE 30D solids 63.5 mg Aerosil .RTM. 200 2.5 mg Tween
80 .RTM. 80 1.5 mg Purified water -- Sustained-Release coat
EUDRAGIT .RTM. NE 30D solids 15 mg Aerosil .RTM. 200 2.5 mg HPMC E6
solids 5 mg Purified water -- Color coat Opadry 85F18422 Powder 30
mg Purified Water --
[0151] Procedure: Mannitol, Microcrystalline Cellulose,
CARBOPOL.RTM. 71 G, and METHOCEL.TM. K4M CR were sifted through #20
mesh and blended in a blender for 10 minutes. Magnesium Stearate
was sifted through #40 mesh and added in to the blender and mixed
for 5 minutes to lubricate the blend. The final blend was
encapsulated into HPMC Size #2 Capsules at 300-mg weight. The
Expansion layer Capsules were loaded in to a conventional coating
pan and EUDRAGIT.RTM. NE30D, Calcium Stearate, Simethicone Emulsion
& Purified Water suspension was sprayed on to the capsules
creating the barrier layer. After completion of the barrier
coating, the diffusion layer followed by the sustained-release
coating was immediately applied in a conventional coating pan. The
Sustained-release coated capsules were then cured at 60.degree. C.
for 1-3 hours to stabilize the film. After the curing process,
color coat was applied. Throughout the coating process, product
temperature of 30-35.degree. C. was maintained. The spray rate
range was between 5-15 g/min.
Example 30
Abuse-Resistant Pellet Formulation
TABLE-US-00030 [0152] Expansion layer Mannitol 35 mg
Microcrystalline Cellulose 25 mg Carbopol 71G 64 mg Hydroxypropyl
Methylcellulose, type 2910 64 mg (METHOCEL .TM. K4M CR)
Croscarmellose sodium 10 mg (AC-DI-SOL .RTM.) Methocel E6 solids 20
mg Purified Water -- Barrier layer EUDRAGIT .RTM. NE 30D solids 97
mg EUDRAGIT .RTM. RS 30D solids 32 mg Talc Powder 50 mg Purified
water -- Diffusion layer Oxycodone Hydrochloride 40 mg EUDRAGIT
.RTM. NE 30D solids 89 mg Aerosil .RTM. 200 2 mg Purified water --
Tablet Formula Avicel PH 102 100 mg Avicel PH 200 100 mg Magnesium
Stearate 8 mg Color coat Opadry 85F18422 Powder 30 mg Purified
Water --
[0153] One or more active ingredients may be placed into one or
more individual pellet. In some embodiments, two or more different
types of pellets may be used together, wherein each type of pellet
contains a different active ingredient.
[0154] Procedure: Mannitol, Microcrystalline Cellulose,
CARBOPOL.RTM. 71 G, and METHOCEL.TM. K4M CR were sifted through #20
mesh and loaded in a Fluid Bed Dryer/Coater fitted with a Top-Spray
coating nozzle. A 10% Methocel solution was sprayed as a binder
solution to granulate the powder. After desired granulation was
achieved, the granules are dried to moisture level of about 2%. The
Dried granules are discharged from the Fluid Bed machine and sized
using suitable milling machine such as Stokes Oscillating
granulator. The dry-sized granules were then loaded into the same
Fluid bed dryer/coater and EUDRAGIT.RTM. NE30D, Eudragit.RTM. RS
30D, Talc & Purified Water dispersion was sprayed on to the
pellets/granules creating the barrier layer. After completion of
the barrier coating, the diffusion layer was immediately applied.
The diffusion layer consisting of Oxycodone hydrochloride,
EUDRAGIT.RTM. NE30D, Aerosil.RTM. 200 and Purified Water suspension
was sprayed on to the barrier coated capsules and then the
diffusion layer coated pellets were cured at 60.degree. C. for 1-3
hours to stabilize the film. Throughout the coating process,
product temperature of 30-35.degree. C. was maintained. The spray
rate range was between 5-15 g/min. The Cured pellets were then
blended with Avicel PH 102 and Avicel PH 200 for about 10 minutes
using a suitable blender. The Magnesium stearate was added to the
blender and blended for 5 minutes. The final blend was compress at
766 mg tablet weight and hardness of 8-16 kp. The Compressed
tablets were then loaded into the conventional coating pan for
color coating.
Example 31
TABLE-US-00031 [0155] Expansion layer Mannitol 70 mg
Microcrystalline Cellulose 50 mg Carbopol 71G 128 mg Hydroxypropyl
Methylcellulose, type 2910 128 mg (METHOCEL .TM. K4M CR)
Croscarmellose sodium 20 mg (AC-DI-SOL .RTM.) Magnesium Stearate 4
mg Barrier layer EUDRAGIT .RTM. NE 30D solids 97.3 mg Calcium
Stearate 16.2 mg Simethicone Emulsion 0.2 mg Purified water --
Diffusion layer Oxycodone Hydrochloride 40 mg EUDRAGIT .RTM. NE 30D
solids 89.2 mg Aerosil .RTM. 200 2 mg Tween .RTM. 80 2 mg Purified
water -- Color coat Opadry 85F18422 Powder 30 mg Purified Water
--
[0156] This formulation with respect to oxycodone was tested by
comparing the release rate of a tablet made according to Example 31
when taken properly (intact) as compared to a ground form of the
same tablet formulation. The results are reported in FIG. 1 and
show that most of the medication is released to the patient when
the tablet is properly taken.
[0157] Tablets comprising the pharmaceutical composition of Example
31 were cut into 2 and 8 pieces using a sharp device such as a
knife and scissors. The expansion layer powder was completely
removed. FIG. 4 shows the comparison of such rate. This
demonstrates that when the tablets of the current invention are
physically compromised, the physical bond between the diffusion
layer and the barrier layer is substantially preserved. The
relative surface area of the diffusion layer increases only
marginally, preventing a significant increase in the drug release.
Therefore, in some embodiments, even when the dosage form
containing the pharmaceutical composition of the invention is
physically compromised, the drug substance maintains essentially
the same release profile, as compared to an intact dosage form.
* * * * *