U.S. patent application number 12/383906 was filed with the patent office on 2010-08-26 for method and compositions for deterring abuse of opioid containing dosage forms.
This patent application is currently assigned to Acura Pharmaceuticals, Inc.. Invention is credited to David DIXON, Vijai KUMAR, Divya TEWARI, Dilip WADGAONKAR.
Application Number | 20100216829 12/383906 |
Document ID | / |
Family ID | 34592331 |
Filed Date | 2010-08-26 |
United States Patent
Application |
20100216829 |
Kind Code |
A2 |
KUMAR; Vijai ; et
al. |
August 26, 2010 |
METHOD AND COMPOSITIONS FOR DETERRING ABUSE OF OPIOID CONTAINING
DOSAGE FORMS
Abstract
This invention relates to an abuse deterrent dosage form of
opioid analgesics, wherein an analgesically effective amount of
opioid analgesic is combined with a polymer to form a matrix.
Inventors: |
KUMAR; Vijai; (Morris
Plains, NJ) ; DIXON; David; (Woodside, NY) ;
TEWARI; Divya; (Suffern, NY) ; WADGAONKAR; Dilip;
(Suffern, NY) |
Correspondence
Address: |
MORGAN, LEWIS & BOCKIUS LLP
1701 MARKET STREET
PHILADELPHIA
PA
19103-2921
UNITED STATES
215-963-5000
215-963-5001
jtroilo@morganlewis.com
|
Assignee: |
Acura Pharmaceuticals, Inc.
616 N. Court
Palatine
IL
60067
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20090253730 A1 |
October 8, 2009 |
|
|
Family ID: |
34592331 |
Appl. No.: |
12/383906 |
Filed: |
March 30, 2009 |
Current U.S.
Class: |
514/282 |
Current CPC
Class: |
A61K 47/32 20130101;
A61K 9/2059 20130101; A61K 9/2853 20130101; A61K 9/2031 20130101;
A61K 9/2013 20130101; A61K 9/2095 20130101; A61P 25/04 20180101;
A61K 47/34 20130101; A61K 31/485 20130101; A61K 47/38 20130101;
A61P 25/36 20180101; A61K 9/2866 20130101; A61K 9/2027 20130101;
A61K 9/2009 20130101; A61K 9/2893 20130101 |
Class at
Publication: |
514/282 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61P 25/36 20060101 A61P025/36 |
Claims
1-21. (canceled)
22. A therapeutic pharmaceutical composition comprising: a mixture
including (a) a drug susceptible to abuse; (b) sodium starch
glycolate and croscarmellose sodium; (c) carboxymethylcellulose at
3 to 40% by weight; (d) a lipid at 0.01 to 20% by weight; and (e) a
sorbitan ester surfactant.
23. The therapeutic composition of claim 22, wherein the lipid
comprises carrot oil.
24. The therapeutic composition of claim 22, wherein the drug
comprises a drug selected from the group consisting of (a)
alfentanil, buprenorphine, butorphanol, carfentanil, codeine,
dezocine, diacetylmorphine, dihydrocodeine, dihydromorphine,
diprenorphine, etorphine, fentanyl, hydrocodone, hydromorphone,
-hydroxy-3-methylfentanyl, levo-.alpha.-acetylmethadol,
levorphanol, lofentanil, meperidine, methadone, morphine,
nalbuphine, oxycodone, oxymorphone, pentazocine, pethidine,
propoxyphene, remifentanil, sufentanil, tilidine, tramadol and a
pharmaceutically acceptable salt thereof.
25. A therapeutic pharmaceutical composition comprising: a mixture
including (a) a drug susceptible to abuse; (b) sodium starch
glycolate and croscarmellose sodium at 2 to about 25% by weight;
(c) carboxymethylcellulose at 3 to about 40% by weight; (d) a lipid
a 0.01 to 20% by weight; and (e) a sorbitan ester surfactant.
26. The therapeutic composition of claim 25, wherein the drug
comprises a drug selected from the group consisting of (a)
alfentanil, buprenorphine, butorphanol, carfentanil, codeine,
dezocine, diacetylmorphine, dihydrocodeine, dihydromorphine,
diprenorphine, etorphine, fentanyl, hydrocodone, hydromorphone,
beta.-hydroxy-3-methylfentanyl, levo-.alpha.-acetylmethadol,
levorphanol, lofentanil, meperidine, methadone, morphine,
nalbuphine, oxycodone, oxymorphone, pentazocine, pethidine,
propoxyphene, remifentanil, sufentanil, tilidine, tramadol and a
pharmaceutically acceptable salt thereof.
27. A method of making an extended release abuse deterrent dosage
form comprising: a. mixing: (a) PEO having a molecular weight of
from about 300,000 to about 5,000,000; (b) magnesium stearate; and
(c) a drug susceptible to abuse selected from the group consisting
of codeine, hydrocodone, hydromorphone, meperidine, methadone,
morphine, oxycodone, oxymorphone, pentazocine, tramadol and a
pharmaceutically acceptable salt thereof; b. forming a matrix from
the mixture of PEO, magnesium stearate and drug; c. heating the
matrix to melt at least a portion of the PEO in the matrix; d.
layering HPMC and PEG, either separately or in a mixture, onto the
matrix that was heated to form a dosage form; wherein the dosage
form provides extended release of the drug.
28. An extended release abuse deterrent dosage form comprising: a.
a core matrix comprising a blended mixture of: (a) PEO having a
molecular weight of from about 300,000 to about 5,000,000; (b)
magnesium stearate; and (c) a drug susceptible to abuse selected
from the group consisting of codeine, hydrocodone, hydromorphone,
meperidine, methadone, morphine, oxycodone, oxymorphone,
pentazocine, tramadol and a pharmaceutically acceptable salt
thereof; and wherein the matrix is heated to melt at least a
portion of the PEO included in the matrix; and b. HPMC and PEG
layered, either separately or as a mixture, onto the core matrix;
and, wherein the dosage form provides extended release of the
drug.
29. An extended release abuse deterrent dosage form comprising: a.
a core matrix comprising a blended mixture of: (a) PEO having a
molecular weight of from about 300,000 to about 5,000,000; (b)
magnesium stearate; and (c) oxycodone or a pharmaceutically
acceptable salt thereof; wherein the matrix is heated to melt at
least a portion of the PEO included in the matrix; and b. HPMC and
PEG layered, either separately or as a mixture, onto the core
matrix; wherein the dosage form provides extended release of the
drug.
Description
STATEMENT OF RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. Nos. 10/723,654, filed on Nov. 26, 2003; and
11/716,122, filed on Mar. 9, 2007, the entire contents of which are
hereby incorporated by reference.
FIELD OF INVENTION
[0002] This invention pertains to abuse deterrent compositions
containing a drug (e.g., an analgesic opioid). Additionally, the
invention relates to a method of administering a dose of an
analgesic from a dosage form, which is abuse deterrent.
BACKGROUND OF THE INVENTION
[0003] The class of drugs exhibiting opium or morphine-like
properties are referred to as opioids, or opioid agonists. Certain
opioids act as agonists, interacting with stereo specific and
saturable binding sites in the brain and other tissues. Endogenous
opioid-like peptides are present in areas of the central nervous
system that are presumed to be related to the perception of pain;
to movement, mood and behavior, and to the regulation of
neuroendocrinological functions. Three classical opioid receptor
types, mu (.mu.), delta (.delta.), and kappa (.kappa.), have been
studied extensively. Each of these receptors has a unique
anatomical distribution in the brain, spinal cord, and the
periphery. Most of the clinically used opioids are relatively
selective for .mu. receptors, reflecting their similarity to
morphine. However, it is important to note that opioid containing
drugs that are relatively selective at standard doses will often
interact with additional receptor subtypes when given at
sufficiently high doses, leading to possible changes in their
pharmacological effect. This is especially true as opioid doses are
escalated to overcome tolerance.
[0004] The potential for the development of tolerance, physical
and/or psychological, dependence (i.e., addiction) with repeated
opioid use is a characteristic feature of most opioid containing
drugs. The possibility of developing addiction is one of the major
concerns in the use of opioids for the management of pain. Another
major concern associated with the use of opioids is the diversion
of these drugs from a patient in legitimate pain to other
individuals (non-patients) for recreational purposes.
[0005] Drug abusers and/or addicts typically may take a dosage form
containing one or more opioid analgesics and crush, shear, grind,
chew, dissolve and/or heat, extract or otherwise damage the product
so that a significant amount or even an entire amount of the drug
becomes available for immediate absorption by 1) injection, 2)
inhalation, and/or 3) oral consumption.
[0006] There are three basic patterns of behavior leading to opioid
abuse. The first involves individuals whose opioid drug use begins
in the context of medical treatment and who obtain their initial
drug supplies through prescriptions from physicians. The second
begins with experimental or "recreational" drug use and progresses
to more intensive use. A third pattern of abuse involves users who
begin in one or another of the preceding ways but later switch to
oral opioids such as methadone, obtained from organized addiction
treatment programs.
[0007] There are various routes of administration an abuser may
commonly attempt to abuse an opioid containing drug formulation.
The most common methods include 1) parenteral (e.g. intravenous
injection), 2) intranasal (e.g., snorting), and 3) repeated oral
ingestion of excessive quantities of orally administered tablets or
capsules. One mode of abuse of oral solid drugs involves the
extraction of the opioid component from the dosage form by first
mixing the dosage form with a suitable solvent (e.g., water), and
then subsequently extracting the opioid component from the mixture
for use in a solution suitable for intravenous injection of the
opioid to achieve a "high."
[0008] Attempts have been made to diminish abuse of orally
administered opioid drugs. These attempts generally centered on the
inclusion in the oral dosage form of an opioid antagonist which is
not orally active but which will substantially block the analgesic
effects of the opioid if one attempts to dissolve the opioid and
administer it parenterally.
[0009] For example, commercially available Talwin.RTM.Nx tablets
from Sanofi-Winthrop contain a combination of pentazocine and
naloxone. Pentazocine is a partial agonist of .mu. receptors and
also has affinity for .kappa. receptors, whereas, naloxone is an
antagonist of .mu. receptors. Talwin.RTM.Nx contains pentazocine
hydrochloride equivalent to 50 mg base and naloxone hydrochloride
equivalent to 0.5 mg base. Talwin.RTM.Nx is indicated for the
relief of moderate to severe pain. The amount of naloxone present
in this combination has no action when taken orally, and will not
interfere with the pharmacologic action of pentazocine. However,
this amount of naloxone given by injection has profound
antagonistic action to opioid analgesics. Thus, the inclusion of
naloxone is intended to curb a form of misuse of oral pentazocine,
which occurs when the dosage form is solubilized and injected.
Therefore, this dosage has lower potential for parenteral misuse
than previous oral pentazocine formulations.
[0010] U.S. Pat. No. 6,559,159 (Carroll et al.) describes the use
of kappa receptors antagonist for the treatment of opioid related
addictions. One such compound is naltrexone, which is commercially
available in the tablet form Revia.RTM. for the treatment of
alcohol dependence and for the blockade of exogenously administered
opioids. (Physicians Desk Reference 57.sup.th ed., Montvale,
N.J.)
[0011] U.S. Pat. No. 6,375,957 (Kaiko et al.) describes in detail
the combination of opioid agonist, NSAID, and an orally active
opioid antagonist. The purpose of adding the opioid antagonist is
the same as discussed above.
[0012] U.S. Pat. No. 4,457,933 (Gordon et al.) describes in detail
a method for decreasing both the oral and parenteral abuse
potential of analgesic agents such as oxycodone, propoxyphene and
pentazocine by combining an analgesic dose of the analgesic agents
with naloxone in specific, relatively narrow ranges.
[0013] U.S. Pat. No. 6,228,863 B1 (Palermo et al.) describes a
method for reducing the abuse potential of an oral dosage form of
an opioid analgesic, whereby an orally active opioid agonist is
combined with an opioid antagonist into an oral dosage form
requiring at least a two-step extraction process to be separated
from the opioid agonist, the amount of opioid antagonist included
being sufficient to counteract opioid effects if extracted together
with the opioid agonist and administered parenterally.
[0014] The prior art describes several other methods and
compositions to minimize the abuse of an opioid containing drug.
One such method is discussed in U.S. Pat. No. 6,593,367 (Dewey et
al.), describing a method whereby the addiction-related behavior of
a mammal suffering from addiction could be changed by a combination
of drugs. The method includes administering to the mammal an
effective amount of gamma vinyl GABA (GVG) or a pharmaceutically
acceptable salt, or an enantiomer or a racemic mixture, where the
effective amount is sufficient to diminish, inhibit or eliminate
behavior associated with craving or use of the combination of
abused drugs.
[0015] U.S. Pat. Nos. 4,175,119 and 4,459,278 (Porter et al.)
describe compositions and methods useful for the prevention of
accidental and/or intentional oral overdoses of a drug.
[0016] In summary, various attempts have been made and are
described in prior art to develop abuse-deterrent dosage forms.
Clearly there is a need for a delivery system for commonly used
oral dosage formulations (e.g., immediate release, sustained or
extended release and delayed release) of drugs, and in particular
analgesics such as opioid analgesics, for patients seeking drug
therapy and which deters abuse and minimizes or reduces the
potential for physical or psychological dependency.
SUMMARY OF THE INVENTION
[0017] The present invention includes a therapeutic pharmaceutical
composition including an analgesic, a gel forming polymer, a
surfactant, and one or more other excipients.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] The present invention will be better understood by examining
the following figures which illustrate certain properties of the
present invention wherein:
[0019] FIG. 1 shows a percentage amount of certain opioid drugs
available in solution for injection after standard dosage forms are
crushed and exposed to a solvent;
[0020] FIG. 2 shows a percentage amount of certain opioid drugs
available in solution for injection after dosage forms of the
present invention are crushed and exposed to a solvent;
[0021] FIG. 3 shows an amount of drug recoverable from a solvent
contacted with five embodiments of the present invention compared
to a standard formulation;
[0022] FIG. 4 shows a dissolution profile of six embodiments of the
present invention;
[0023] FIG. 5a shows various methods used to formulate the dosage
forms having one or more abuse deterrent properties of the present
invention;
[0024] FIG. 5b shows a particular dosage form having one or more
abuse deterrent properties of the present invention;
[0025] FIG. 5c shows a particular dosage form having one or more
abuse deterrent properties of the present invention and a
disintegrant;
[0026] FIG. 6 shows a process flow chart for the manufacture of a
dosage form of the present invention; and
[0027] FIG. 7 shows a dissolution profile of three extended release
formulations of the present invention.
[0028] With reference to the Figures, features that are the same
across the Figures are denoted with the same reference numbers.
DETAILED DESCRIPTION OF THE INVENTION
[0029] The present invention includes an abuse deterrent
formulation for reducing the potential for one or more of a)
parenteral abuse, b) inhalation (e.g., intranasal abuse), and/or c)
oral abuse of a drug, typically an opioid analgesic type drug, for
satisfaction of a physical or psychological dependence. In one
embodiment, the present invention deters parenteral abuse by
providing a pharmaceutical composition which includes an analgesic
with one or more gel forming agents such that upon contact with a
solvent (e.g., water), the agents swell by absorbing the solvent
thereby 1) entrapping the drug in a gel matrix and/or 2) reducing
or preventing a significant amount of the opioid analgesic from
being drawn into a syringe. In one embodiment, the present
invention deters inhalation abuse by providing a pharmaceutical
composition which includes a therapeutically active pharmaceutical
(e.g., an analgesic), with one or more mucous membrane, mucosa or
mucosal tissue irritants (collectively referred to as mucous
membrane irritants). In one embodiment, the mucosal tissue is nasal
passageway tissue.
[0030] Upon contact with a mucous membrane, the irritants induce
temporary pain and/or irritation of the membranes and/or tissues to
thereby deter abuse. For example, if inhaled by snorting, the
mucous membrane in the nasal passageway will be irritated and
result in pain to the individual. In one embodiment, the present
invention provides a pharmaceutical composition which includes an
analgesic with one or more emetics, such that after oral
consumption of more than a typically prescribed amount of the
dosage form, emesis is induced.
[0031] In one embodiment, two or more of the abuse deterrents can
be combined into one composition according to the present
invention.
[0032] The present invention describes formulations which have
abuse deterrent properties as described herein. Examples of
specific oral solid dosage forms containing morphine, hydrocodone
and oxycodone were evaluated using suitable analytical test
methods, such as UV/VIS spectrophotometry. In the evaluation,
dosage forms were crushed and contacted with a small amount of
water (about a teaspoon or tablespoon). After attempting to
dissolve the dosage form, the resultant material was drawn into a
syringe, volume was measured and opioid content was quantitated. As
shown in FIG. 1, almost 100% of the opioid can be extracted from
standard formulations. Comparatively, as shown in FIG. 2, an abuse
deterrent formulation of the present invention for the same
opioids, provides a significantly lower percentage of extractable
opioid. As shown in FIG. 1, approximately 93%, 103% and 99% of the
opioid analgesic drugs contained in a dosage form were recoverable
using the above described techniques. Comparatively, as shown in
FIG. 2, using an abuse deterrent polymer of the present invention,
only 9%, 5%, and 6% of the opioid analgesic drugs were
recoverable.
[0033] In another embodiment, the present invention is a
pharmaceutical composition that includes an opioid analgesic, one
or more gel forming agents, and one or more mucous membrane
irritants or nasal passageway tissue irritants. In another
embodiment, the present invention includes a pharmaceutical
composition, which includes an analgesic, one or more gel forming
agents and one or more emetics as described herein. In another
embodiment, the present invention includes a pharmaceutical
composition, which includes an opioid analgesic, one or more mucous
membrane irritants or nasal passageway tissue irritants and one or
more emetics as described herein. In one particular embodiment, the
present invention includes a pharmaceutical composition which
includes an analgesic, one or more gel forming agents, one or more
mucous membrane irritants and/or nasal passageway tissue irritants,
and one or more emetics.
[0034] Each of the components of the pharmaceutical composition of
the present invention are described in more detail below.
A. Drugs Suitable for Use with the Present Invention
[0035] Any drug, therapeutically acceptable drug salt, drug
derivative, drug analog, drug homologue, or polymorph can be used
in the present invention. In one embodiment, the drug can be orally
administered. In certain embodiments, drugs susceptible to abuse
are used. Drugs commonly susceptible to abuse include psychoactive
drugs and analgesics, including but not limited to opioids and
drugs that can cause psychological and/or physical dependence on
the drug.
[0036] A drug for use in the present invention can be one or more
of the following: alfentanil, amphetamines, buprenorphine,
butorphanol, carfentanil, codeine, dezocine, diacetylmorphine,
dihydrocodeine, dihydromorphine, diphenoxylate, diprenorphine,
etorphine, fentanyl, hydrocodone, hydromorphone,
.beta.-hydroxy-3-methylfentanyl, levo-.alpha.-acetylmethadol,
levorphanol, lofentanil, meperidine, methadone, methylphenidate,
morphine, nalbuphine, nalmefene, o-methylnaltrexone, naloxone,
naltrexone, oxycodone, oxymorphone, pentazocine, pethidine,
propoxyphene, remifentanil, sufentanil, tilidine and tramodol,
salts, derivatives, analogs, homologues, polymorphs thereof, and
mixtures of any of the foregoing.
[0037] In one embodiment, a pharmaceutical composition of the
present invention includes one or more opioids such as hydrocodone,
morphine and oxycodone and/or salts thereof, as the therapeutically
active ingredient. Typically when processed into a suitable dosage
form, as described in more detail below, the drug can be present in
such dosage forms in an amount normally prescribed, typically about
0.5 to about 25 percent on a dry weight basis, based on the total
weight of the formulation.
[0038] With respect to analgesics in unit dose form, such an amount
can be typically from about 5, 25, 50, 75, 100, 125, 150, 175 or
200 mg. More typically, the drug can be present in an amount from 5
to 500 mg or even 5 to 200 mg. In other embodiments, a dosage form
contains an appropriate amount of drug to provide a therapeutic
effect.
B. Gel Forming Agents
[0039] As described above, the present invention can include one or
more gel forming agents. The total amount of gel forming agent is
typically about 3 to about 40 percent on a dry weight basis of the
composition.
[0040] Suitable gel forming agents include compounds that, upon
contact with a solvent (e.g., water), absorb the solvent and swell,
thereby forming a viscous or semi-viscous substance that
significantly reduces and/or minimizes the amount of free solvent
which can contain an amount of solubilized drug, and which can be
drawn into a syringe. The gel can also reduce the overall amount of
drug extractable with the solvent by entrapping the drug in a gel
matrix. In one embodiment, typical gel forming agents include
pharmaceutically acceptable polymers, typically hydrophilic
polymers, such as hydrogels.
[0041] In some embodiments, the polymers exhibit a high degree of
viscosity upon contact with a suitable solvent. The high viscosity
can enhance the formation of highly viscous gels when attempts are
made by an abuser to crush and dissolve the contents of a dosage
form in an aqueous vehicle and inject it intravenously.
[0042] More specifically, in certain embodiments the polymeric
material in the present invention provides viscosity to the dosage
form when it is tampered. In such embodiments, when an abuser
crushes and dissolves the dosage form in a solvent (e.g., water or
saline), a viscous or semi-viscous gel is formed. The increase in
the viscosity of the solution discourages the abuser from injecting
the gel intravenously or intramuscularly by preventing the abuser
from transferring sufficient amounts of the solution to a syringe
to cause a desired "high" once injected.
[0043] Suitable polymers include one or more pharmaceutically
acceptable polymers selected from any pharmaceutical polymer that
will undergo an increase in viscosity upon contact with a solvent.
Preferred polymers include polyethylene oxide, polyvinyl alcohol,
hydroxypropyl methyl cellulose and carbomers. In preferred
embodiments, the polymers include:
[0044] a) Polyethylene Oxide [0045] In some embodiments, the
polymer includes polyethylene oxide. The polyethylene oxide can
have an average molecular weight ranging from about 300,000 to
about 5,000,000, more preferably from about 600,000 to about
5,000,000, and most preferably at least about 5,000,000. In one
embodiment, the polyethylene oxide includes a high molecular weight
polyethylene oxide. [0046] In one embodiment, the average particle
size of the polyethylene oxide ranges from about 840 to about 2,000
microns. In another embodiment, the density of the polyethylene
oxide can range from about 1.15 to about 1.26 g/ml. In another
embodiment, the viscosity can range from about 8,800 to about
17,600 cps. [0047] The polyethylene oxide used in a directly
compressible formulation of the present invention is preferably a
homopolymer having repeating oxyethylene groups, i.e.,
--(--O--CH.sub.2--CH.sub.2--).sub.n--, where n can range from about
2,000 to about 180,000. Preferably, the polyethylene oxide is a
commercially available and pharmaceutically acceptable homopolymer
having moisture content of no greater than about 1% by weight.
Examples of suitable, commercially available polyethylene oxide
polymers include Polyox.RTM., WSRN-1105 and/or WSR-coagulant,
available from Dow chemicals. [0048] In some embodiments, the
polyethylene oxide powdered polymers can contribute to a consistent
particle size in a directly compressible formulation and eliminate
the problems of lack of content uniformity and possible
segregation.
[0049] b) Polyvinyl Alcohol [0050] In one embodiment, the gel
forming agent includes polyvinyl alcohol. The polyvinyl alcohol can
have a molecular weight ranging from about 20,000 to about 200,000.
The specific gravity of the polyvinyl alcohol can range from about
1.19 to about 1.31 and the viscosity from about 4 to about 65 cps.
The polyvinyl alcohol used in the formulation is preferably a
water-soluble synthetic polymer represented by
--(--C.sub.2H.sub.4O--).sub.n--, where n can range from about 500
to about 5,000. Examples of suitable, commercially available
polyvinyl alcohol polymers include PVA, USP, available from
Spectrum Chemical Manufacturing Corporation, New Brunswick, N.J.
08901.
[0051] c) Hydroxypropyl Methyl Cellulose [0052] In one embodiment,
the gel forming agent includes hydroxypropyl methyl cellulose
(Hypromellose). The hydroxypropyl methyl cellulose can have a
molecular weight ranging from about 10,000 to about 1,500,000, and
typically from about 5000 to about 10,000, i.e., a low molecular
weight hydroxypropyl methyl cellulose polymer. The specific gravity
of the hydroxypropyl methyl cellulose can range from about 1.19 to
about 1.31, with an average specific gravity of about 1.26 and a
viscosity of about 3600 to 5600. The hydroxypropyl methyl cellulose
used in the formulation can be a water-soluble synthetic polymer.
Examples of suitable, commercially available hydroxypropyl
methylcellulose polymers include Methocel K100 LV and Methocel K4M,
available from Dow chemicals.
[0053] d) Carbomers [0054] In one embodiment, the present invention
includes carbomers. The carbomers can have a molecular weight
ranging from 700,000 to about 4,000,000,000. The viscosity of the
polymer can range from about 4000 to about 39,400 cps. Examples of
suitable, commercially available carbomers include carbopol 934P
NF, carbopol 974P NF and carbopol 971P NF, available from Noveon
Pharmaceuticals.
[0055] Following the teachings set forth herein, other suitable gel
forming agents can include one or more of the following polymers:
ethyl cellulose, cellulose acetate, cellulose acetate propionate,
cellulose acetate butyrate, cellulose acetate phthalate and
cellulose triacetate, cellulose ether, cellulose ester, cellulose
ester ether, and cellulose, acrylic resins comprising copolymers
synthesized from acrylic and methacrylic acid esters, the acrylic
polymer may be selected from the group consisting of acrylic acid
and methacrylic acid copolymers, methyl methacrylate copolymers,
ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic
acid), poly(methacrylic acid), methacrylic acid alkylamide
copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl
methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate
copolymer, poly(methacrylic acid anhydride), and glycidyl
methacrylate copolymers.
[0056] Any of the above described polymers can be combined together
or combined with other suitable polymers, and such combinations are
within the scope of the present invention.
[0057] In one embodiment, the abuse deterrent, gel forming agent
can prevent less than or equal to about 95%, 94%, 70%, 60%, 54%,
50%, 45%, 40%, 36%, 32%, 30%, 27%, 20%, 10%, 9%, 6%, 5% or 2% of
the total amount of drug in a dosage form from being recovered from
a solvent in contact with a dosage form of the present invention.
As shown in FIG. 3, formulations A3, B3, C3, D3 and E3 reduce the
amount of drug extractable or recoverable from a dosage for of the
present invention. Specifically, formulation A3 provides for
recovery of 26.77% of the total amount of drug in the dosage form,
formulation B3 provides for recovery of 31.8% of the total amount
of drug in the dosage form, formulation C3 provides for recovery of
35.75% of the total amount of drug in the dosage form, formulation
D3 provides for recovery of 35.8% of the total amount of drug in
the dosage form, and formulation E3 provides for recovery of 42.5%
of the total amount of drug in the dosage form. In FIG. 3, all five
formulations A3 through E3 are compared with a standard dosage form
of oxycontin, which provided for recovery of 98.6% of the total
amount of drug in the dosage form.
[0058] The five formulations A3 through E3 are set forth in
Examples 14 through 18, respectively.
[0059] It should be noted that the above described formulations
also have dissolution profiles as determined by the USP 2-paddle
method, as shown in FIG. 4. In particular, for formulations A3
through E3, about 50% to about 82% of each formulation dissolves
after about 15 minutes and about 80% to about 95% dissolves after
90 minutes. FIG. 4 further includes the dissolution profile of
Formulation F3. With respect to FIG. 4, the composition of
formulation F3 is set forth in Example 19.
[0060] The above described gel forming agents can be further
optimized as necessary or desired in terms of viscosity, molecular
weight, etc.
C. Mucous Membrane Irritants and/or Nasal Passageway Tissue
Irritants
[0061] As described above, the present invention can include one or
more mucous membrane irritants and/or nasal passageway tissue
irritants. In one embodiment, suitable mucous membrane irritants
and/or nasal passageway tissue irritants include compounds that are
generally considered pharmaceutically inert, yet can induce
irritation. Such compounds include, but are not limited to
surfactants. In one embodiment, suitable surfactants include sodium
lauryl sulfate, poloxamer, sorbitan monoesters and glyceryl
monooleates. Other suitable compounds are believed to be within the
knowledge of a practitioner skilled in the relevant art, and can be
found in the Handbook of Pharmaceutical Excipients, 4th Ed. (2003),
the entire content of which is hereby incorporated by
reference.
[0062] In one embodiment of the present invention, the irritant can
be present in amount of from 1 to 20 percent by weight on a solid
basis, preferably 1 to 10 percent by weight on a solid basis. In
another embodiment, the amount of irritant can be present in an
amount of 5 to 15 percent by weight. In another embodiment, the
irritant can be present in an amount of at least 5 percent by
weight. In yet another embodiment, the irritant can be present in
an amount from 1 to 5 percent by weight. In another embodiment, the
amount of irritant can be present in an amount from 1 to 3 percent
by weight.
[0063] In certain embodiments, the irritant can deter abuse of a
dosage form when a potential abuser tampers with a dosage form of
the present invention. Specifically, in such embodiments, when an
abuser crushes the dosage form, the irritant is exposed. The
irritant discourages inhalation of the crushed dosage form by
inducing pain and/or irritation of the abuser's mucous membrane
and/or nasal passageway tissue. In one embodiment, the irritant
discourages inhalation (e.g., via snorting through the nose) by
inducing pain and/or irritation of the abuser's nasal passageway
tissue.
[0064] In one embodiment, the present invention includes one or
more mucous membrane irritants to cause irritation of mucous
membranes located anywhere on or in the body, including membranes
of the mouth, eyes and intestinal tract. Such compositions can
deter abuse via oral, intra-ocular or rectal or vaginal routes.
[0065] The above-described irritants can be further optimized as
necessary or desired in terms of concentration, irritation
severity, etc.
D. Emetics
[0066] As described above, the present invention can include one or
more emetics or emesis inducing agents. Preferably, the emetic is a
pharmaceutically acceptable inert excipient that only induces
emesis after a certain threshold amount is ingested. In another
embodiment, the emetic can be a pharmaceutically active emetic.
[0067] In one embodiment, the amount of emetic present in a
pharmaceutical composition of the present invention can be tied
directly to the amount of drug in the pharmaceutical composition.
Thus, by controlling the quantity of the emetic compound in the
pharmaceutical composition, emesis can be avoided if normal
prescription directions are followed. However, if an overdosage
occurs by ingesting more than a prescribed quantity of a drug in a
pharmaceutical composition of the present invention, the amount of
ingested emetic can exceed the threshold amount necessary to induce
emesis.
[0068] In some embodiments, the threshold amount of emetic for
inducing emesis can be reached when the normal prescription
directions are inappropriately increased by factors of 2, 3, 4, 5,
6, 7, or 8 times, or more. Thus, in some embodiments, the amount of
emetic present in a pharmaceutical composition of the present
invention is an amount such that the amount of emetic ingested does
not exceed the threshold amount necessary for inducing emesis until
a subject ingests 2, 3, 4, 5, 6, 7, or 8 or more times the amount
of drug normally prescribed. In some embodiments, emesis can
preclude death or serious illness in the subject.
[0069] In one embodiment, the emetic includes zinc sulfate. Zinc
sulfate is an excipient, which can induce emesis when more than
about 0.6 to 2.0 gm is ingested, typically more than about 0.6 gm.
In one embodiment, a pharmaceutically acceptable inert excipient
which can induce emesis (e.g., zinc sulfate) can be present at
about 5 to 60 percent by weight on a solid basis, or about 5 to 40
percent by weight on a solid basis or about 5 to 25 percent by
weight on a solid basis more typically about 5 to 10 percent by
weight on a solid basis.
[0070] Accordingly, pharmaceutical compositions of the present
invention can be easily designed to induce emesis if a prescribed
dosage is exceeded and/or if prescription directions are not
followed for dosage forms containing a composition of the present
invention. In some embodiments of the present invention, a dosage
form can include about 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35,
0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.90, 0.95,
1.0 grams of a pharmaceutically acceptable inert excipient which
can induce emesis (e.g., zinc sulfate) or pharmaceutically active
emetic. In another embodiment, the present invention includes an
inert excipient which can induce emesis (e.g., zinc sulfate) or
pharmaceutically active emetic in an amount that is a summation of
two or more of the above described amounts.
[0071] In another embodiment, the present invention can include 1,
2, 3, 4, or 5 times, or more, of the above described amounts of
pharmaceutically acceptable inert excipient which can induce emesis
(e.g., zinc sulfate) or a pharmaceutically active emetic.
Typically, suitable embodiments of the present invention include
from about 0.1 gm to about 2.0 gm of zinc sulfate. In other
embodiments the present invention can include about 0.6 to less
than about 2.0 gm of zinc sulfate.
[0072] For example, in one embodiment, if a practitioner desires to
create a dosage form that will induce emesis only after four or
more dosage forms are ingested, the amount of zinc sulfate in each
dosage form should not exceed about 0.19 gm. Thus, if three dosage
forms are ingested, the amount of emetic is 0.57 gm, which is less
than a typical threshold amount of the particular emetic. However,
if a fourth dosage form having 0.19 gm. of zinc sulfate is
ingested, the amount of emetic exceeds the threshold amount, and
emesis is induced.
[0073] The above-described emetics can be further optimized as
necessary or desired in terms of concentration in the
pharmaceutical composition, etc.
[0074] Other suitable emetics can include one or more of
cephaeline, methyl cephaeline, psychotrine, O-methylpsychotrine,
ammonium chloride, potassium chloride, magnesium sulfate, ferrous
gluconate, ferrous sulfate, aloin, and emetine.
E. Other Ingredients
[0075] The present invention can also optionally include other
ingredients to enhance dosage form manufacture from a
pharmaceutical composition of the present invention and/or alter
the release profile of a dosage forming including a pharmaceutical
composition of the present invention.
[0076] Some embodiments of the present invention include one or
more pharmaceutically acceptable fillers/diluents. In one
embodiment, Avicel PH (Microcrystalline cellulose) is a filler used
in the formulation. The Avicel PH can have an average particle size
ranging from 20 to about 200 .mu.m, preferably about 100 .mu.m. The
density ranges from 1.512-1.668 g/cm.sup.3. The Avicel PH should
have molecular weight of about 36,000. Avicel PH effectiveness is
optimal when it is present in an amount of from about 10 to 65
percent, by weight on a solid basis, of the formulation. Typical
fillers can be present in amounts from 10 to 65 percent by weight
on a dry weight basis. Other ingredients can include sugars and/or
polyols.
[0077] Other ingredients can also include dibasic calcium phosphate
having a particle size of about 75 to about 425 microns and a
density of about 0.5 to about 1.5 g/ml, as well as calcium sulfate
having a particle size of about 1 to about 200 microns and a
density of about 0.6 to about 1.3 g/ml and mixtures thereof.
Further, lactose having a particle size of about 20 to about 400
microns and a density of about 0.3 to about 0.9 g/ml can also be
included.
[0078] In some embodiments of the invention, the fillers which can
be present at about 10 to 65 percent by weight on a dry weight
basis, also function as binders in that they not only impart
cohesive properties to the material within the formulation, but can
also increase the bulk weight of a directly compressible
formulation (as described below) to achieve an acceptable
formulation weight for direct compression. In some embodiments,
additional fillers need not provide the same level of cohesive
properties as the binders selected, but can be capable of
contributing to formulation homogeneity and resist segregation from
the formulation once blended. Further, preferred fillers do not
have a detrimental effect on the flowability of the composition or
dissolution profile of the formed tablets.
[0079] In one embodiment, the present invention can include one or
more pharmaceutically acceptable disintegrants. Such disintegrants
are known to a skilled artisan. In the present invention,
disintegrants can include, but are not limited to, sodium starch
glycolate (Explotab.RTM.) having a particle size of about 104
microns and a density of about 0.756 g/ml, starch (e.g., Starch 21)
having a particle size of about 2 to about 32 microns and a density
of about 0.462 g/ml, Crospovidone.RTM. having a particle size of
about 400 microns and a density of about 1.22 g/ml, and
croscarmellose sodium (Ac-Di-Sol) having a particle size of about
37 to about 73.7 microns and a density of about 0.529 g/ml. The
disintegrant selected should contribute to the compressibility,
flowability and homogeneity of the formulation. Further the
disintegrant can minimize segregation and provide an immediate
release profile to the formulation. In some embodiments, the
disintegrant (s) are present in an amount from about 2 to about 25
percent by weight on a solid basis of the directly compressible
formulation.
[0080] In one embodiment, the present invention can include one or
more pharmaceutically acceptable glidants, including but not
limited to colloidal silicon dioxide. In one embodiment, colloidal
silicon dioxide (Cab-O-Sil.RTM.) having a density of about 0.029 to
about 0.040 g/ml can be used to improve the flow characteristics of
the formulation. Such glidants can be provided in an amount of from
about 0.1 to about 1 percent by weight of the formulation on a
solid basis. It will be understood, based on this invention,
however, that while colloidal silicon dioxide is one particular
glidant, other glidants having similar properties which are known
or to be developed could be used provided they are compatible with
other excipients and the active ingredient in the formulation and
which do not significantly affect the flowability, homogeneity and
compressibility of the formulation.
[0081] In one embodiment, the present invention can include one or
more pharmaceutically acceptable lubricants, including but not
limited to magnesium stearate. In one embodiment, the magnesium
stearate has a particle size of about 450 to about 550 microns and
a density of about 1.00 to about 1.80 g/ml. In one embodiment,
magnesium stearate can contribute to reducing friction between a
die wall and a pharmaceutical composition of the present invention
during compression and can ease the ejection of the tablets,
thereby facilitating processing. In some embodiments, the lubricant
resists adhesion to punches and dies and/or aid in the flow of the
powder in a hopper and/or into a die. In an embodiment of the
present invention, magnesium stearate having a particle size of
from about 5 to about 50 microns and a density of from about 0.1 to
about 1.1 g/ml is used in a pharmaceutical composition. In certain
embodiments, a lubricant should make up from about 0.1 to about 2
percent by weight of the formulation on a solids basis. Suitable
lubricants are stable and do not polymerize within the formulation
once combined. Other lubricants known in the art or to be developed
which exhibit acceptable or comparable properties include stearic
acid, hydrogenated oils, sodium stearyl fumarate, polyethylene
glycols, and Lubritab.RTM..
[0082] In certain embodiments, the most important criteria for
selection of the excipients are that the excipients should achieve
good content uniformity and release the active ingredient as
desired. The excipients, by having excellent binding properties,
and homogeneity, as well as good compressibility, cohesiveness and
flowability in blended form, minimize segregation of powders in the
hopper during direct compression.
[0083] In another embodiment, the present invention can include an
opioid antagonist in addition to the other ingredients, or as a
substitute for one of the other abuse deterrent ingredients of a
formulation of the present invention. Suitable antagonists are
described above. One particular antagonist includes naloxone. As
described above, typically naloxone has no action when taken
orally, and will not interfere with the pharmacologic action of an
opioid agonist. However, when given by injection naloxone can have
profound antagonistic action to opioid agonists. An appropriate
antagonist can be used in combination with one or more of gel
forming agents, mucous membrane irritants and/or nasal passageway
tissue irritants, or emetics in the present invention. An
appropriate antagonist can also be used as a substitute for one or
more of gel forming agents, mucous membrane irritants and/or nasal
passageway tissue irritants, or emetics in the present invention.
Suitable opioid receptor antagonists can include but are not
limited to the antagonists described in U.S. Pat. Nos. 6,559,159
and 6,375,957, the entire content of which are hereby incorporated
by reference.
F. Dosage Forms of the Present Invention
[0084] A pharmaceutical composition of the present invention
including one or more drug components, one or more of gel forming
agents, mucous membrane irritants and/or nasal passageway tissue
irritants, and emetics, and optionally other ingredients, can be
suitably modified and processed to form a dosage form of the
present invention. As referred to herein and in FIGS. 5a, 5b, 5c
and 6, an "abuse deterrent composition" or "ADC" (labeled "40" in
these Figures) includes a composition having one or more gel
forming agents and/or mucous membrane irritants and/or nasal
passageway tissue irritants, and/or emetics according to the
teachings set forth herein. In this manner, an abuse deterrent
composition can be layered onto, coated onto, applied to, admixed
with, formed into a matrix with, and/or blended with a drug and
optionally other ingredients, thereby providing a therapeutic
composition of the present invention.
[0085] As shown in FIG. 5a, an abuse deterrent composition can be
combined with a drug and/or opioid analgesic (e.g., hydrocodone) in
one or more layered dosage forms.
[0086] According to the present invention, drug 50 can be a layer
on or near the surface (I) of ADC 40 of the present invention, or
sandwiched between two or more distinct layers (II and III) of ADC
40 of the present invention. In other embodiments, drug 50 can be a
coating (IV) on ADC 40. Drug 50 can be any of the pharmaceutically
active ingredients (e.g., opioids) described herein and can be
combined with other excipients, e.g. disintegrants including but
not limited to sodium starch glycolate or Explotab.RTM..
[0087] As shown in FIG. 5b an abuse deterrent composition 40 of the
present invention can be combined with drug 50, e.g., hydrocodone,
in a blended mixture. In such embodiments, drug 50 and ADC 40 can
be evenly mixed.
[0088] As shown in FIG. 5c abuse deterrent composition 40 of the
present invention can be combined with drug 50, e.g., hydrocodone,
in a blended mixture with other ingredients 60, e.g., a
disintegrant.
[0089] FIG. 6 shows one embodiment of the present invention for
making a dosage form of the present invention. Specifically, a
first step (step 1) of FIG. 4 shows drug 50 combined with abuse
deterrent composition 40 of the present invention. ADC 40 can
contain one or more gel forming agents and/or mucous membrane
irritants and/or nasal passageway tissue irritants, and/or emetics
according to the teachings set forth herein. In a second step (step
2), the combination of drug 50 and ADC 40 can then be blended with
other ingredients 60, e.g. disintegrants and lubricants, to form a
mix 100. Lastly, in a third step (step 3) combination 100 can then
be processed using conventional practices 110, e.g., compression,
into a suitable unit dosage form 120, e.g. tablets.
[0090] Suitable formulations and dosage forms of the present
invention include but are not limited to powders, caplets, pills,
suppositories, gels, soft gelatin capsules, capsules and compressed
tablets manufactured from a pharmaceutical composition of the
present invention. The dosage forms can be any shape, including
regular or irregular shape depending upon the needs of the
artisan.
[0091] Compressed tablets including the pharmaceutical compositions
of the present invention can be direct compression tablets or
non-direct compression tablets. In one embodiment, a dosage form of
the present invention can be made by wet granulation, and dry
granulation (e.g., slugging or roller compaction). The method of
preparation and type of excipients are selected to give the tablet
formulation desired physical characteristics that allow for the
rapid compression of the tablets. After compression, the tablets
must have a number of additional attributes such as appearance,
hardness, disintegrating ability, and an acceptable dissolution
profile.
[0092] Choice of fillers and other excipients typically depend on
the chemical and physical properties of the drug, behavior of the
mixture during processing, and the properties of the final tablets.
Adjustment of such parameters is understood to be within the
general understanding of one skilled in the relevant art. Suitable
fillers and excipients are described in more detail above.
[0093] The manufacture of a dosage form of the present invention
can involve direct compression and wet and dry granulation methods,
including slugging and roller compaction. However, in the present
invention, it is preferred to use direct compression techniques
because of the lower processing time and cost advantages.
[0094] Accordingly, and as described further below, a directly
compressible pharmaceutical composition of the present invention
can be designed following the teachings set forth herein that can
deter one or more of a) parenteral abuse of a drug, b) inhalation
abuse of a drug, and c) oral abuse of a drug.
[0095] Such compositions and dosage forms are formed according to
the present invention are described. Steps for making the
compositions or dosage forms include the step of providing one or
more drugs and/or analgesics described above and an amount of a gel
forming polymer having a desired molecular weight or viscosity as
described above, and/or providing a nasal tissue irritant, and/or
providing an emetic in the amounts as described above.
[0096] By controlling the molecular weight and/or viscosity of the
gel forming polymer, and/or by controlling the amount of mucous
membrane irritant and/or nasal tissue irritant such that nasal
tissue irritation occurs if the composition is inhaled (e.g.
snorting), and/or by controlling the amount of emetic such that
emesis ensues if more than a prescribed amount of the analgesic is
consumed, a therapeutic composition suitable for use to deter drug
abuse can be formed. The compositions according to the present
invention can deter abuse of the analgesic by (1) forming a viscous
substance upon contact with a solvent such that the substance and
analgesic cannot be easily drawn into a syringe and/or (2) by
inducing mucous membrane irritation and/or nasal tissue irritation
if the composition is inhaled, and/or (3) by inducing emesis if
more than a prescribed amount of the analgesic is consumed.
[0097] The present invention can be used to manufacture immediate
release, and controlled drug release formulations. Controlled
release formulations can include delayed release and extended
release oral solid dosage preparations. Examples 25 (formulation A7
of FIG. 7), 26 (formulation B7 of FIG. 7) and 27 (formulation C7 of
FIG. 7) provide embodiments of the invention that can provide
controlled release of a drug. The release profiles of the
controlled release dosage forms of the present invention are shown
in FIG. 7. The dosage forms in FIG. 7 include hydrocodone
bitartrate (HCBT) as an active. As shown in FIG. 7, about 80 to 95%
of the drug in a controlled release dosage form of the present
invention is released after about 10 hours, as compared to an
immediate release dosage form (a conventional dosage form) which is
at least 75% dissolved after about 45 minutes. Other opioid
formulations having an extended effect, which can be modified to
further include one or more of the abuse deterrent compositions of
the present invention, are described in U.S. Pat. No. 6,572,885,
the entire content of which is hereby incorporated by
reference.
[0098] For example, embodiments of the present invention may be
prepared via melt techniques. In certain embodiments the opioid may
be combined with one or more polymers of the present invention and
optionally other ingredients to form a homogenous mixture and then
the mixture can be subjected to a temperature for a duration
sufficient to melt at least a portion of the polymer.
[0099] Certain aspects of the present invention may be better
understood as illustrated by the following examples, which are
meant by way of illustration and not limitation.
Example 1
[0100] A direct compression formulation, as shown in Table 1, for
an immediate release opioid analgesic, e.g. hydrocodone bitartrate,
tablet having 5 mg of hydrocodone bitartrate was formed by weighing
each component separately and mixing the hydrocodone bitartrate and
the polymer in a V-blender for about 5 to 10 minutes at low shear
conditions or in a high shear blender by mixing 2 to 5 minutes. The
other formulation excipients were added to the above blend
excepting the lubricant and mixed at the same rate for additional 5
to about 10 minutes. Finally, the lubricant, magnesium stearate was
added to the formulation and blended at the same rate for an
additional 3 to 5 minutes. This polymeric matrix containing the
drug and other excipients was further compressed on a rotary tablet
press to form pharmaceutically acceptable tablets.
[0101] The tablets were monitored for weight, hardness, thickness
and friability. The tablets were tested for assay, release
characteristics (in-vitro dissolution method) and abuse deterrent
properties.
[0102] Samples of the tablets were subjected to dissolution testing
using USP Apparatus 2 (U.S. Pharmacopoeia, XXVI, 2003), speed 50
rpm at 37.degree. C., in purified water as dissolution medium for a
period of 90 minutes. The acceptable dissolution criterion is not
less than 75 percent of the drug dissolved in 45 minutes.
[0103] To evaluate abuse deterrent properties of the formulation a
method has been developed that mimics the street abuser's method
for abuse. [0104] (i) The tablets are crushed and the resulting
powder is placed into table/teaspoon. [0105] (ii) Measured amount
of water is added to the spoon. Contents of the spoon are heated
for about 1 to 2 minutes. [0106] (iii) Contents of the spoon are
withdrawn using a syringe equipped with a needle.
[0107] (iv) The volume of the sample removed from the spoon is
measured and the contents of the syringe are tested for the active,
using a suitable analytical test method such as UV/VIS
spectrophotometry. TABLE-US-00001 TABLE 1 Component Weight
(mg)/tablet Hydrocodone bitartrate 5 Polyvinyl alcohol 160 Avicel
PH 102 333 Starch 21 54 Zinc sulfate 30 Explotab 15 Cab-O-Sil 1.5
Magnesium stearate 1.5 Total 600
[0108] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0109] The drug extracted by the abuse-test method detailed above
was about 34 percent.
Example 2
[0110] TABLE-US-00002 TABLE 2 Component Weight (mg)/tablet
Hydrocodone bitartrate 5 Polyvinyl alcohol 160 Crospovidone 90
Avicel PH 102 120 Starch 21 43 Zinc sulfate 30 Cab-O-Sil 1
Magnesium stearate 1 Total 450
[0111] As shown by Table 2, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0112] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0113] The drug extracted by the abuse-test method was about 31
percent.
Example 3
[0114] TABLE-US-00003 TABLE 3 Component Weight (mg)/tablet
Hydrocodone bitartrate 5 Polyox 70 Crospovidone 152 Avicel PH 102
304 Zinc sulfate 150 Sodium lauryl sulfate 1 Cab-O-Sil 14 Magnesium
stearate 4 Total 700
[0115] As shown by Table 3, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0116] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0117] The drug extracted by the abuse-test method was about 11
percent.
Example 4
[0118] TABLE-US-00004 TABLE 4 Component Weight (mg)/tablet
Hydrocodone bitartrate 5 Polyvinyl alcohol 80 Polyox 15 Avicel PH
102 300 Zinc sulfate 50 Sodium lauryl sulfate 7 Crospovidone 100
Cab-O-Sil 2 Magnesium stearate 1 Total 560
[0119] As shown by Table 4, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0120] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0121] The drug extracted by the abuse-test method was about 6.5
percent.
Example 5
[0122] TABLE-US-00005 TABLE 5 Component Weight (mg)/tablet
Hydrocodone bitartrate 5 Methocel K100 LV 25 Avicel PH 102 300 Zinc
sulfate 50 Sodium lauryl sulfate 7 Crospovidone 100 Cab-O-Sil 2
Magnesium stearate 1 Total 490
[0123] As shown by Table 5, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0124] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0125] The drug extracted by the abuse-test method was about 17
percent.
Example 6
[0126] TABLE-US-00006 TABLE 6 Component Weight (mg)/tablet
Oxycodone hydrochloride 5 Polyox 25 Avicel PH 102 300 Zinc sulfate
50 Sodium lauryl sulfate 7 Crospovidone 100 Cab-O-Sil 2 Magnesium
stearate 1 Total 490
[0127] As shown by Table 6, a direct compression formulation of
oxycodone hydrochloride immediate release formulation including a
dosage of 5 mg of oxycodone hydrochloride was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0128] An in-vitro dissolution criterion of NLT 70% of the drug
dissolved in 45 minutes was met.
[0129] The drug extracted by the abuse-test method was about 9
percent.
Example 7
[0130] TABLE-US-00007 TABLE 7 Component Weight (mg)/tablet Morphine
sulfate 20 Polyox 20 Avicel PH 102 300 Zinc sulfate 50 Sodium
lauryl sulfate 7 Crospovidone 100 Cab-O-Sil 2 Magnesium stearate 1
Total 500
[0131] As shown by Table 7, a direct compression formulation of
morphine sulfate immediate release formulation including a dosage
of 20 mg of morphine sulfate was prepared and tested using the
blending conditions and procedure as stated in Example 1.
[0132] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0133] The drug extracted by the abuse-test method was about 16
percent.
Example 8
[0134] TABLE-US-00008 TABLE 8 Component Weight (mg)/tablet Morphine
sulfate 20 Polyvinyl alcohol 160 Avicel PH 102 318 Zinc sulfate 30
Explotab 30 Starch 21 54 Cab-O-Sil 1.5 Magnesium stearate 1.5 Total
615
[0135] As shown by Table 8, a direct compression formulation of
morphine sulfate immediate release formulation including a dosage
of 20 mg of morphine sulfate was prepared and tested using the
blending conditions and procedure as stated in Example 1.
[0136] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0137] The drug extracted by the abuse-test method was about 12
percent.
Example 9
[0138] TABLE-US-00009 TABLE 9 Component Weight (mg)/tablet Morphine
sulfate 40 Polyox 15 Avicel PH 102 300 Zinc sulfate 50 Sodium
lauryl sulfate 7 Crospovidone 100 Cab-O-Sil 2 Magnesium stearate 1
Total 515
[0139] As shown by Table 9, a direct compression formulation of
morphine sulfate immediate release formulation including a dosage
of 40 mg of morphine sulfate was prepared and tested using the
blending conditions and procedure as stated in Example 1.
[0140] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0141] The drug extracted by the abuse-test method was about 15
percent.
Example 10
[0142] TABLE-US-00010 TABLE 10 Component Weight (mg)/tablet
Morphine sulfate 40 Polyvinyl alcohol 200 Avicel PH 102 278 Zinc
sulfate 30 Explotab 30 Starch 21 54 Cab-O-Sil 1.5 Magnesium
stearate 1.5 Total 635
[0143] As shown by Table 10, a direct compression formulation of
morphine sulfate immediate release formulation including a dosage
of 40 mg of morphine sulfate was prepared and tested using the
blending conditions and procedure as stated in Example 1.
[0144] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0145] The drug extracted by the abuse-test method was about 6
percent.
Example 11
[0146] TABLE-US-00011 TABLE 11 Component Weight (mg)/tablet
Hydrocodone bitartrate 7.5 Polyox 25 Avicel PH 102 297.5
Crospovidone 100 Zinc sulfate 50 Sodium lauryl salfate 7 Cab-O-Sil
2 Magnesium stearate 1 Total 490
[0147] As shown by Table 11, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 7.5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0148] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0149] The drug extracted by the abuse-test method was about 5
percent.
Example 12
[0150] TABLE-US-00012 TABLE 12 Component Weight (mg)/tablet
Hydrocodone bitartrate 10 Polyvinyl alcohol 80 Polyox 15 Avicel PH
102 295 Crospovidone 100 Zinc sulfate 50 Sodium lauryl sulfate 7
Cab-O-Sil 2 Magnesium stearate 1 Total 560
[0151] As shown by Table 12, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 10 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0152] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0153] The drug extracted by the abuse-test method was about 9.5
percent.
Example 13
[0154] TABLE-US-00013 TABLE 13 Component Weight (mg)/tablet
Hydrocodone bitartrate 5 Carbopol 971P 10 Avicel PH 102 300
Crospovidone 100 Zinc sulfate 50 Sodium lauryl sulfate 7 Cab-O-Sil
2 Magnesium stearate 1 Total 490
[0155] As shown by Table 13, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0156] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0157] The drug extracted by the abuse-test method was about 27
percent.
Example 14
[0158] TABLE-US-00014 TABLE 14 Formulation A3 Component Weight
(mg/tablet) Hydrocodone Bitartrate 5 Polyvinyl Alcohol 160 Avicel
PH 102 318 Zinc Sulfate 30 Starch 21 54 Explotab 30 Cab-O-Sil 1.5
Magnesium Stearate 1.5 Total 600
[0159] As shown by Table 14, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0160] An in-vitro dissolution showed about 62% of the drug
dissolved in 45 minutes.
[0161] The drug extracted by the abuse-test method was about 26.77
percent.
Example 15
[0162] TABLE-US-00015 TABLE 15 Formulation B3 Component Weight
(mg/tablet) Hydrocodone Bitartrate 5 Polyvinyl Alcohol 160 Avicel
PH 102 333 Zinc Sulfate 30 Explotab 15 Starch 21 54 Cab-O-Sil 1.5
Magnesium Stearate 1.5 Total 600
[0163] As shown by Table 15, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0164] An in-vitro dissolution showed about 72% of the drug
dissolved in 45 minutes.
[0165] The drug extracted by the abuse-test method was about 31.8
percent.
Example 16
[0166] TABLE-US-00016 TABLE 16 Formulation C3 Component Weight
(mg/tablet) Hydrocodone Bitartrate 5 Polyvinyl Alcohol 160 Avicel
PH 102 120 Zinc Sulfate 30 Crospovidone (PVP XL) 40 Starch 21 43
Cab-O-Sil 1 Magnesium Stearate 1 Total 400
[0167] As shown by Table 16, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0168] An in-vitro dissolution showed about 75% of the drug
dissolved in 45 minutes.
[0169] The drug extracted by the abuse-test method was about 35.75
percent.
Example 17
[0170] TABLE-US-00017 TABLE 17 Formulation D3 Component Weight
(mg/tablet) Hydrocodone Bitartrate 5 Polyvinyl Alcohol 160 Avicel
PH 102 120 Zinc Sulfate 30 Crospovidone (PVP XL) 100 Starch 21 33
Cab-O-Sil 1 Magnesium Stearate 1 Total 450
[0171] As shown by Table 17, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0172] An in-vitro dissolution showed about 82% of the drug
dissolved in 45 minutes.
[0173] The drug extracted by the abuse-test method was about 35.8
percent.
Example 18
[0174] TABLE-US-00018 TABLE 18 Formulation E3 Component Weight
(mg/tablet) Hydrocodone Bitartrate 5 Polyvinyl Alcohol 160 Avicel
PH 102 333 Zinc Sulfate 30 Starch 21 54 Crospovidone (PVP XL) 15
Cab-O-Sil 1.5 Magnesium Stearate 1.5 Total 600
[0175] As shown by Table 18, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0176] An in-vitro dissolution showed about 79% of the drug
dissolved in 45 minutes.
[0177] The drug extracted by the abuse-test method was about 42.5
percent.
Example 19
[0178] TABLE-US-00019 TABLE 19 Formulation F3 Component Weight
(mg/tablet) Hydrocodone Bitartrate 5 Polyvinyl Alcohol 160 Avicel
PH 102 119 Zinc Sulfate 30 Crospovidone (PVP XL) 100 Starch 21 33
Cab-O-Sil 1 Magnesium Stearate 2 Total 450
[0179] As shown by Table 19, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0180] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0181] The drug extracted by the abuse-test method was about 54
percent.
Example 20
[0182] TABLE-US-00020 TABLE 20 Component Weight (mg/tablet)
Hydrocodone Bitartrate 5 Polyvinyl Alcohol 95 Avicel PH 102 192
Zinc Sulfate 30 Starch 21 140 Ac-Di-Sol 35 Cab-O-Sil 1 Magnesium
Stearate 2 Total 500
[0183] As shown in Table 20, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0184] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0185] The drug extracted by the abuse-test method was about 60
percent.
Example 21
[0186] TABLE-US-00021 TABLE 21 Component Weight (mg/tablet)
Oxycodone Hydrochloride 5 Avicel PH 102 119 Zinc Sulfate 30
Crospovidone (PVP XL) 100 Starch 21 33 Cab-O-Sil 1 Magnesium
Stearate 2 Total 290
[0187] As shown by Table 21, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0188] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0189] The drug extracted by the abuse-test method was about 94
percent.
Example 22
[0190] TABLE-US-00022 TABLE 22 Component Weight (mg/tablet)
Hydrocodone Bitartrate 5 Polyvinyl Alcohol 50 Avicel PH 102 192
Zinc Sulfate 30 Starch 21 140 Ac-Di-Sol 35 Cab-O-Sil 1 Magnesium
Stearate 2 Total 455
[0191] As shown in Table 22, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0192] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0193] The drug extracted by the abuse-test method was about 70
percent.
Example 23
[0194] TABLE-US-00023 TABLE 23 Component Weight (mg/tablet)
Hydrocodone Bitartrate 5 Polyvinyl Alcohol 160 Avicel PH 102 318
Zinc Sulfate 30 Explotab 30 Cab-O-Sil 1.5 Magnesium Stearate 1.5
Total 600
[0195] As shown in Table 23, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0196] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0197] The drug extracted by the abuse-test method was about 33
percent.
Example 24
[0198] TABLE-US-00024 TABLE 24 Component Weight (mg/tablet)
Hydrocodone Bitartrate 10 Avicel PH 102 318 Zinc Sulfate 50
Crospovidone (PVP XL) 100 Sodium Lauryl Sulfate 7 Cab-O-Sil 1.5
Magnesium Stearate 1.5 Total 488
[0199] As shown in Table 24, a direct compression formulation of
hydrocodone bitartrate immediate release formulation including a
dosage of 5 mg of hydrocodone bitartrate was prepared and tested
using the blending conditions and procedure as stated in Example
1.
[0200] An in-vitro dissolution criterion of NLT 75% of the drug
dissolved in 45 minutes was met.
[0201] The drug extracted by the abuse-test method was about 85
percent.
Example 25
[0202] TABLE-US-00025 TABLE 25 Formulation A7 Component Weight
(mg/tablet) Hydrocodone Bitartrate 22 Polyvinyl Alcohol 250
Cab-O-Sil 1.38 Magnesium Stearate 2.76 Total 276.14
[0203] An in-vitro dissolution showed about 98% dissolution after
10 hours.
Example 26
[0204] TABLE-US-00026 TABLE 26 Formulation B7 Component Weight
(mg/tablet) Hydrocodone Bitartrate 44 Polyvinyl Alcohol 450
Cab-O-Sil 1.5 Magnesium Stearate 2.0 Total 497.5
[0205] An in-vitro dissolution showed about 82% dissolution after
10 hours.
Example 27
[0206] TABLE-US-00027 TABLE 27 Formulation C7 Component Weight
(mg/tablet) Hydrocodone Bitartrate 88 Polyvinyl Alcohol 600
Cab-O-Sil 1.5 Magnesium Stearate 2.0 Total 691.5
[0207] An in-vitro dissolution showed about 80% dissolution after
10 hours.
Example 28
[0208] TABLE-US-00028 TABLE 28 Component Weight (mg)/tablet
Oxycodone hydrochloride 5 Polyox 25 Avicel PH 102 250 Zinc sulfate
100 Sodium lauryl sulfate 7 Crospovidone 100 Cab-O-Sil 2 Magnesium
Stearate 1 Total 490
[0209] As shown by Table 28, a direct compression formulation of
oxycodone hydrochloride immediate release formulation including a
dosage of 5 mg of oxycodone hydrochloride was prepared using the
blending conditions and procedure as stated in Example 1.
Example 29
[0210] TABLE-US-00029 TABLE 29 Component Weight (mg)/tablet
Oxycodone hydrochloride 5 Polyox 25 Avicel PH 102 200 Zinc sulfate
150 Sodium lauryl sulfate 7 Crospovidone 100 Cab-O-Sil 2 Magnesium
stearate 1 Total 490
[0211] As shown by Table 29, a direct compression formulation of
oxycodone hydrochloride immediate release formulation including a
dosage of 5 mg of oxycodone hydrochloride was prepared using the
blending conditions and procedure as stated in Example 1.
[0212] It will be appreciated by persons skilled in the art that
numerous variations and/or modifications may be made to the
invention shown in the specific embodiments without departing form
the spirit and scope of the invention as broadly described.
Further, each and every reference cited above is hereby
incorporated by reference as if fully set forth herein.
* * * * *