. .. CRUSH-RESISTANT SOLID ORAL DOSAGE FORM
Field of the Invention
The present invention relates .to a method of imparting crush-resistance to an oral solid dosage
form comprising a drug prone to abuse, so as to prev.ent the unintended and illicit use of the dosage
form.
Background of the Invention
Abuse potential refers to the use of a drug in non-medical situations, repeatedly or even
sporadically, for its positive psychoactive effects. These drugs are characterized by their central
nervous system (CNS) activity. Hence, the most common drugs prone to abuse include opioid
analgesics, CNS stimulants, and CNS depressants. These drugs may produce psychic or physical
dependence and may lead to addiction, which promotes drug-seeking behavior. Drug abusers and/or
addicts typically may use any of the means (e.g., crush, shear, grind, chew, dissolve, heat, extract,
andlor otherwise damage the product) to obtain a significant amount or even the entire amount of the
drug available by 1) injection, 2) inhalation, and/or 3) oral consumption for immediate absorption.
Several attempts have been made to diminish abuse of orally administered drugs.
U.S. Patent No. 4,070,494 discloses adding a swellable agent to the dosage form in order to
prevent abuse. When water is added to extract the drug, this agent swells and ensures that the filtrate
separated from the gel contains only a small quantity of drug.
PCT Publication No. WO 19951020947 discloses a multilayer tablet based on a similar
approach of preventing parenteral abuse, said tablet containing the drug prone to abuse and at least
one gel-former, each in different layers.
Another known strategy for abuse deterrent formulations involves adding an antagonist to the
drug in the dosage form, e.g., antagonists such as naloxone or naltrexone are added in the case of
opioids.
U.S. Patent No. 7,201,920 discloses compositions comprising an opioid analgesic, a gelforming
polymer, a nasal tissue irritant, and an emetic for deterring abuse of the drug. It uses aversive
substances which are otherwise inert, but produce an unacceptable reaction and irritation when
tampered with and administered by the unintended route. Specifically disclosed aversive substances
are sodium lauryl sulfate used as a nasal tissue irritant and zinc sulfate used as an emetic.
U.S. Publication No. 201010249045 discloses a dosage form for oral administration, the.
dosage form cqmprising: a) a drug combined with, b) at least two abuse-deterring ingredients
selected from the group consisting of: (i) hydrogenated vegetable oils; (ii) polyoxyethylene stearates;
(iii) glycerol monostearate; and (iv) poorly water soluble waxes having'a melting point in the range
from 45°C to 100°C.
U.S. Paten't No. 8,114,383 discloses an abuse-proof, thermoformed dosage form containing
one or more. drugs prone to abuse together with physiologically acceptable auxiliary substances, and
at' least one synthetic or natural polymer with a breaking strength of at least 500 N.
. Nonetheless, there is a continuing need for an alternative delivery system which deters abuse
and minimizes or reduces the potential for physical or psychological dependence, through all possible
routes such as oral, parenteral, and nasal.
Summary of the Invention
The present invention relates to a method of imparting crush-resistance to an oral solid
dosage form comprising a drug prone to abuse, so as to prevent the unintended and illicit use of the
dosage form.
Detailed Descri~tiono f the Invention
A first aspect of the present invention provides a crush-resistant oral solid dosage form,
comprising:
a) a therapeutically effective amount of a drug prone to abuse; and
b) a chewing gum base comprising a chewable plastic polymer;
wherein the amount of said gum base is such that it causes the dosage form to deform plastically
without breaking into a powder when said dosage form is tampered for abuse.
According to one embodiment of this aspect, the chewable plastic is selected from the group
comprising polyisobutylene, butadiene styrene, polyvinyl acetate, terpene resins, ester gums;
ethylene vinyl acetate, and mixtures thereof.
According to one embodiment of this aspect, the chewing gum base is present in an amount
from about 20% wlw to about 85% wlw of the composition.
According to one more embodiment of this aspect, the solid dosage form further comprises a
release-controlling polymer.
According to another embodiment of this aspect, the release-controlling polymer is selected
from the group comprising hydroxypropylmethyl cellulose, hydroxyethyl cellulose, polyethylene
glycol, polyethylene oxide, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose ethers,
cellulose esters, polymethacrylic acid esters copolymers, aminoalkyl methacrylate copolymers,
copolymers of polyvinyl acetate and polyvinyl pyrrolidone, polyvinyl alcohol, glyceryl behenate,
carnauba wax, xanthan gum, starch, sodium alginate, tragacanth, poloxamers, carbomers, and
mixtures thereof.
According to another embodiment of this aspect, the chewing gum base is present .in an
amount from about 20% wlw to about 85% wlw, and the release-co'ntrolling polymer is present in an
amount from about 10% wlw to about 7'5% wlw.
.. . , . . According to another.embodiment-of this aspect, the chewing gum. base is present in an
% ' amount from about 50%'w/w to about 85%. wlw, and the release-controlling polymer is present in an
. . amount from about 10% wlw to about 50% w1.w.
According to another embodiment of this aspect, the release-controlling polymer is
polyethylene dxide.
According to another embodiment of this aspect, the chewing gum base and polyethylene
oxide are present in a ratio of about 7: 1 to about 1 : 1 ..
According to another embodiment of this aspect, the chewing gum base and polyethylene
oxide are present in a ratio of about 5: 1.
I According to another embodiment of this aspect, the solid dosage form further comprises one
or more aversive agents.
According to another embodiment of this aspect, the solid dosage may be in the form of
caplets, pills, mini-tablets, tablets, or capsules; optionally caplets, pills, mini-tablets, or tablets can
be filled into capsules.
According to another aspect, the present invention is a crush-resistant oral solid dosage form
that consists essentially of:
a) a therapeutically effective amount of a drug prone to abuse; and
i
1 b) a chewing gum base comprising a chewable plastic polymer;
!
I wherein the amount of said gum base is such that it causes the dosage form to deform plastically
!
! without breaking into powder when said dosage form is tampered for abuse.
According to another aspect, the present invention is a crush-resistant oral solid dosage form
that consists essentially of:
a) a therapeutically effective amount of a drug prone to abuse;
b) a chewing gum base comprising a chewable plastic polymer; and
c) one or more aversive agents,
wherein the .amount of said gum base is such that it causes the dosage form to deform plastically
withoutbreaking into powder when said dosage form is tampered for abuse.
A'second aspect of the present invention provides a process for the preparation of a crushresistant
oral solid dosage form, the process comprising:
1) blending a drug prone to abuse, a chewing gum base, and optionally, one or more
pharmaceutically acceptable excipients;
2) compressing the blend of step 1) to obtain caplets, pills, mini-tablets, or tablets;
3) optionally, filling the compressed blend of step 2) into capsules.
According to one embodiment of this aspect, the process further involves heating the
+P c m ~ ~blee&ait ~ W p p a H gafho pt 5Q'Q to' about 8n°C fnr ahorlt 5 minutes to about 75
4
I / . ,
A third aspect of the present- invention provides a process for the preparation of a crush-
I, resistant oral solid dosage form, the process comprising:
I 1) . blending a drug prone to abuse, a chewing gum base, a release-controlling polymer; and
optionally one or more pharmaceutically acceptable excipients;
2) compressing the blend'of step 1) to obtain caplets, pills, mini-tablets, or tablets;
3) heating the compressed. blend of step 2) in a coating pan at a temperature of about
5 0 0t~o about 80°C for about 5 minutes to about 75 minutes;
4) optionally, filling the heated compressed blend of step 3) into capsules.
According to one embodiment of this aspect, the process involves heating the compressed
blend at a temperature of about 80°C for about 10 minutes.
The terms "crush-resistant" or "crush-resistance," as used herein, refer to the property of the
I dosage form that makes it less prone to being powdered or extracted to minimize the likelihood of
I
I abuse by snorting or extraction in a solvent for injection. The crush-resistant dosage form of the
I
I invention will deform plastically upon application of breaking force rather than disintegrating into
I powder form. It should be understand that in crushing the dosage form of the invention, there may
be a small amount of powder formed, e.g., 'kom the coating or other excipients present in the
formulation, but at least a majority of the crushed dosage form will not be disintegrated into a
powder form.
Crush-resistance in the dosage forms of the invention has been achieved by the use of chewing
gum bases. The chewing gum bases comprise chewable plastic polymers to impart gummy and
stretching properties to the dosage form. The commercially available chewing gum bases comprise
plastic polymer (gum), sugar, anti-tackifiers, and plasticizers. In particular, the commercially
available chewing gum bases containing chewable plastic polymers used in the present invention
include PG Nutra PEPP 2T by Gum Base Co. and Health in Gum@ PWD-03 by Cafosa.
The stretchable plastically deformed dosage form is unsuitable for snorting or inhalation.
- Further, the gummy.plastic does not allow easy extraction of the drug in a solvent in sufficient
quantity to be injected. Therefore, the potential for drug abuse is minimized through inhalation and
injection route.
Release-controlling polymer(s) could be added to further improve the abuse-deterrent
properties and to achieve the desired release profile.
The abuse-deterrent properties of the dosage form may be tested by the following
techniques:
Crushing Test
,.... .In the crushing test, the dosage form issubjected to crushing using a hammer, pestle-mortar,
or :an apparatus designed to measure the hardness of an oral dosage form. If the dosage form
I disintegrates into particles, then it may be possible to dissolve or suspend these particles or use the
powder for snorting or sniffing and use them'for abuse purposes. However, if it is not possible to I
crush the dosage form in this test, then there will be no particles to use for such abuse purposes. . .
Melting Test
In the melting test, the dosage form is subjected to heating, e.g., on a spoon or by exposure to
microwave induced heating. If the dosage form melts to form a plastic or rubbery mass, the dosage
form is not suitable for abuse purposes. However; if the dosage form liquefies so that it is possible
.to inject it without being too hot, then the dosage form may be prone to abuse.
Extraction Test
In the extraction test, the dosage form is subjected to extraction in various solvents that are
commonly available, e.g., water, ethanol, and those which have potentially relevant solvent
characteristics (pH,.polarity vs. aprotic, e.g., HC1). In the evaluation, the dosage form is crushed and
contacted with a small amount of a solvent. After attempting to dissolve the dosage form, the volume
is measured and the amount of the drug extracted is analysed and quantified. If a significant amount
of drug is extracted such that it -could then be injected by intravenous or subcutaneous routes to
produce euphoric effects, then the dosage form may be prone to abuse.
Further, certain aversive agents may be added to the dosage form to cause disliking or
aversion for subsequent use, if the dosage form is chewed to extract the drug for oral abuse. Usually,
their amount ranges from about 0.1% wlw to about 1 .O% wlw, in particular from about 0.2% wlw to
about 0.5% w/w.
Unpalatable substances may include bittering agents or hot and pungent additives. Bittering
agents may be selected from the group comprising quinine, sucrose octaacetate, quassin, brucine,
quercetin, denatonium, and mixtures thereof. Pungent additives may be selected from capsaicinoids,
e.g., capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, and homodihydrocapsaicin,
to hrther deter oral drug abuse.
Irritants may be of natural or synthetic origin and include mustard and its derivatives, e.g.,
ally1 isothiocyanate and p-hydroxybenzyl isothiocyanate; emetics, e.g., ipecac and chemotherapeutic
agents; laxatives, e.g., aloe Vera, bisacodyl, casanthranol, cascara sagrada, castor oil, dehydrocholic
acid, phenolphthalein, senna, and sennosides.
Propylene glycol may be added additionally to the crush-resistant dosage form to provide a
further abuse-deterrent effect. It has been found that when used via the injection route, propylene
I- a g b ~ ~ p ~ c & c e s ~ $- r n qpas~em ~n;d&rit~ip&n ;a lso causes irritation of the respiratory system if
6
. . .. . inhaled,-and leads to 'gastrointestinal distress'upon accidental ingestion in large quantities.. Hence,
this may provide a further aversive effect in case the dosage form is successfully tampered with and
the drug is extracted for injection. The amount of propylene glycol added may be from about 5%
WIW to about 15% wlw, in particular about 10% wlw.
The dosage forms of the present invention include but are not limited to caplets, pills,
capsules, mini-tablets, or tablets. Alternatively, the drug and excipients may be compressed to form
mini-tablets or pills, which may then be filled into capsules. The dosage form of the present invention
in the form of tablets can be made by wet granulation, dry granulation (e.g., slugging or roller
compaction), direct compression, melt granulation, or hot-melt extrusion. The method of preparation
and type of excipients may be selected based on the desired physical characteristics of the tablet
formulation. Wet granulation may be carried out in the presence of aqueous or non-aqueous solvents.
Non-aqueous solvents may be selected from ethanol, isopropyl alcohol, or suitable mixtures of
ethano1:water and isopropyl alcoho1:water.
Drugs prone to abuse or their pharmaceutically acceptable salts, derivatives, analogs or
polymorphs may include psychoactive drugs and analgesics, including but not limited to opioids and ,
drugs that can cause psychological andlor physical dependence on the drug. A drug for use in the
. present invention may be selected from alfentanil, amphetamines, bupropion, buprenorphine,
butorphanol, carfentanyl, codeine, dezocine, diacetylmorphine, dihydrocodeine, dihydromorphine,
diphenoxylate, diprenorphine, etorphine, fentanyl, hydrocodone, hydromorphone, levorphanol,
lofentanil, meperidine, methadone, gabapentin, methylphenidate, morphine, oxycodone,
oxymorphone, pentazocine, pethidine, propoxyphene, remifentanil, sufentanil, tilidine, tramadol, and
salts, derivatives, analogs, homologues, and polymorphs thereof, or mixtures of any of the foregoing.
The dosage form of the present invention may in particular include one or more opioids, e.g.,
hydrocodone, morphine, oxymorphone, and oxycodone and/or salts thereof, as the therapeutically
effective drug. Particularly, when processed into a suitable dosage form, the drug can be present in
an amount ranging from about 0.5% wlw to about 30% wlw.
In addition, the dosage form may contain other pharmaceutically acceptable 'excipients to
facilitate the manufacturing process. The other pharmaceutically acceptable excipients are selected
from diluents, binders, lubricants, and mixtures thereof, and other excipients known to the person
skilled in the art. Some of these excipients may result in a powder when the dosage form is crushed
but the drug and chewing gum base generally cannot be crushed into a powder.
Binders may be selected from the group comprising microcrystalline cellulose, polyvinyl ,
pyrrolidone, starch, maltrin, methyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl
cellulose, sucrose sol,ution, dextrose solution, acacia, tragacanth, locust bean gum, pre-gelatinized
-I-P Q ~~rg$~ggvid!n-gs,@ &c, %t),g@atin&@ly~e@acrylat~s, synthetic resins, and mixtures themof. .
7
Binders may be present in an amount from about 2% wlw to about 20% wlw.
Diluents may be selected from the group comprising lactose, microcrystalline .cellulose,
calcium hydrogen phosphate (dihydrate), calcium hydrogen phosphate (anhydrous), tribasic calcium.
phosphate, calcium carbonate, kaolin, magnesium carbonate, magnesium oxide, and mixtures
thereof. Diluents may be present in amounts from about 5% wlw to about 40% wlw.
Lubricants may be selected from the 'group comprising stearic acid, polyethylene glycol,
magnesium stearate, calcium stearate; zinc stearate, talc, sodium -stearyl fumarate, and mixtures
thereof. Lubricants may be present in an amount fiom about 0.1% wlw to about 2%.w/w.
The dosage form of the invention may optionally be provided with a coating layer. The
coating may be done with coating polymers, e.g., ~ u d r a g i te~th,y l cellulose, or HPMC. Organic or
aqueous solvents may be used during the coating process. Solvents may be selected from the group
comprising water, acetone, isopropyl alcohol, ethanol, methylene chloride, and mixtures thereof.
Plasticizers used during coating may be selected from the group comprising polyethylene
glycols, dibityl phthalate, diethyl phthalate, triethyl citrate, tributyl citrate, tributyrin, butyl phthalyl
butyl glycolate, triacetin, castor oil, citric acid esters, and mixtures thereof. The.se plasticizers.are
present in an amount to facilitate the coating process and to obtain an even coating of film with
enhanced physical stability. Generally, the coating material comprises from about 0.5% wlw to about
50% wlw of a plasticizer, particularly from about 10% wlw to about 20% wlw of t.he enteric polymer.
Commerc'ially available coatings may be employed, e.g., OpadryB. The tablet coating is about 2%
WIW to about 5% wlw of the core tablet weight. In particular, about 3% wlw of the core tablet. weight
may be used for coating.
In addition, the coating material may also comprise inert solid particulates. In particular, talc
and titanium dioxide are used as opacifiers. Lakes and dyes are also used to impart color to the
coating. These include iron oxide (red or yellow), aluminum lakes, and natural colouring materials,
e.g., anthocyanins, carotenoids.
The invention may be illustrated by the following non-limiting examples;
During the development stage, lactose monohydrate was used in the dosage forms (Example
1 to Example 1 1) in place of the drug prone to abuse, to evaluate the crush-resistance potential of the
dosage form.
Amount Per Tablet (% wlw)
Ingredients
1 2 3 4 5 6
Lactose 10.00 10.00 10.00 10.00 10.00 10.00
Chewing gum base
20.00 44.00 - 69.00 69.00 44.00
(PG Nutra PEPP 2T)
Chewing gum base - - 44.00 - - -
(Health in Gum@ PWD 0 1)
Polyethylene oxide
69.00 45.00 45.00 20.00 - (~olyox@W SR-N80) -
Hydroxypropylmethyl
cellulose - - - - 20.00 -
( ~ e t h o c eKl1~5 MCR)
Hydroxypropylmethyl
cellulose - - - - - 45.00
(~ethoceI@E 1 0 MCR)
Carbopolm 97 1 P - - - - - -
Magnesium stearate 1 .OO 1.00 1.00 1.00 1 .OO 1 .OO
Isopropyl alcohol:water - - - - - -
Total (Core Tablet) 100.00 100.00 100.00 100.00 100.00 100.00
* OpadryBfilm coating was applied (3.00 % wlw of the total weight of the core
tablet) to all dosage forms of Examples 1-6
Examples 7- 1 1
Manufacturing Process (ExampIes 1-91
1) Lactose (substitute for drug prone to abuse) was mixed with chewing gum base (PG Nutra
xpi3 csELEx c7%%($.-& - &- -g -3 lg 2 7 ii&
9
Ingredients
Lactose
Chewing gum base
(PG Nutra PEPP@ 2T)
Chewing gum base
(Health in ~ u mP@W D 0 1)
Polyethylene oxide
(PolyoxB W SR-N80)
Hydroxypropylmethyl cellvlose
(MethocelQ K 1 5 MCR)
Hydroxypropylmethyl cellulose
(MethocelB E 10 MCR)
~arbopol@97 1P
Magnesium stearate
Isopropyl alcoho1:water
Total Core Tablet
* OpadryBFi1m coating was applied (3.00 % w/w of the total weight of the core
tablet) to all dosage forms of Examples 7-11
Amount Per Tablet (% w/w)
7
10.00
-
44.00
-
-
45.00
-
1 .OO
-
100.00
8
10.00
-
20.00
-
-
69.00
-
1.00
-
100.00
10
10.00
20.00
-
-
-
-
69.00
1 .OO
q.s.
100.00
9 -
10.00
69.00
-
-
-
-
20.00
1.00
-
100.00
11
10.00
-
44.00
-
-
-
45.00
1 .OO
q.s.
100.00
PEPP 2T/ Health in ~ u mP@W D 01) and release-controlling polymer ( ~ o l ~ o Wx @SR -
~80/~ethoceKl@ 15 M ~ ~ / ~ e t h o cEe 1l0@ ~ C ~ I C a r b o ~9o7 l1P@ ).
6'
2) The blend of step 1) was lubricated using magnesium stearate and compressed using a
suitable tablet press and tooling.
3) The compressed tablets of step 2) were film coated using an aqueous OpadryB coating
dispersion in a tablet coating pan apparatus.
Manufacturing Process (Examples 10 and' 11)
1) Lactose was mixed with chewing gum base and CarbopolB 971P.
2) The blend of step 1) was granulated with a mixture of isopropyl alcoho1:water in a rapid
mixer granulator.
3) The wet granules of step 2) were dried in a fluidized bed drier and milled to a suitable size.
4) The granules of step 3) were lubricated using magnesium stearate.
5) The lubricated blend of step 4) was compressed using a suitable tablet press and tooling.
6) The compressed tablets of step 5) were film coated using an aqueous OpadryB coating
dispersion in a tablet coating pan apparatus.
Examples 1 - 1 1 were subjected to crushing test using a pestle-mortar in order to determine
their ability to resist crushing upon tampering and misuse. The observations of the crushing test are
provided in Table 1. These compositions may be extended to drugs prone to abuse by replacing
lactose with the drug.
Table 1: Observations of Crushing Test for Examples 1 to 11
, .
c Chewing Gu'm . ' . . Ex.. ; Polymer Used
. Base used . . .
1 PGNutraPEPP
2T . . .
2 PG Nutra PEPP ..
,
' 2T
3 Health in Gum@ ' ~ o l ~ e t h ~ loexnidee
PWD-01 '
4 PG Nutra PEPP
2T
5 PG Nutra PEPP Hydroxypropylmethyl
2T cellulose
(MethocelB K15 MCR)
6 PG Nutra PEPP Hydroxypropylmethyl
2T cellulose
7 Health in Gum@ (MethocelB El 0 MCR)
PWD-0 1
8 Health in ~ u m @ Hydroxypropylmethyl
PWD-02 cellulose
(MethocelB E I0 MCR)
9 PG Nutra PEPP
2T
10 PG Nutra PEPP
CarbopolB
2T
11 Health in ~ u m @ '
PWD-03
Observation Upon
Crushing Test
Hard mass which
cannot be broken
into a fine
powder
Hard mass which
cannot be broken
into a fine
powder
Gritty particles
obtained
Hard mass which
cannot be broken
into a fine
powder
Gritty particles
obtained
Hard mass which
cannot be broken
into a fine
powder
% Composition
. Chewing
Gum
Base
20%
44%
.
44%
69%
69%
44%
44%
20%
69%
20%
44%
Polymer
69%
45%
45%
20%
20%
45%
45%
69%
20%
69%
45%
Examples 12-1 5
Manufacturing Process (Examples 12-14)
J
1) All the ingredients were accurately weighed.
2) Bupropion HCl, MethocelB Kl00 or ~ o l ~ o3x0@3, a nd Health in ~ u mP@W D-0 1 were
Amount Per Tablet (% wlw)
Ingredients Example
mixed in a suitable mixer and sifted through a sieve.
3) The material of step 2) was mixed in a blender for 5 minutes.
12 13 14
Bupropion HCI 12.50 12.50 12.50
Lactose anhydrous - - - .
AvicelB PH- 102 - - -
(Hydroxypropylmethyl cellulose) 25.00
~ethocel@K 1 0 0M
- -
Polyethylene oxide - 25.00 14.62
( ~ o l ~ oWx @SR -303)
Chewing gum base 61.00 61.00 71.38
(Health in Gum@ PWD-0 1)
Colloidal Silicon dioxide
(AerosilB 200)
0.50 0.50 0.50
Magnesium stearate 1 .OO 1 .OO 1 .OO
Total Core Tablet 100.00 100.00 100.00
4) AerosilD 200 and magnesium stearate were passed through a sieve.
15
12.50
30.00
31.00
25.00
-
-
0.50
1 .OO
100.00
5 ) The materials of step 3) and step 4) were mixed in a blender for 5 minutes.
6) The blend of step 5) was compressed into tablets.
7) The tablets of step 6) were heated at about 80°C in a coating pan for 10 minutes to obtain . '
pre-heated tablets.
*Opadry@Film coating (3.00 O/O wlw of the total weight of the core tablet) to be
applied to all dosage forms of Examples 12-14
8) The tablets of step 7) were film coated using an aqueous OpadryB coating dispersion in a
tablet-coating pan apparatus.
Manufacturing Process (Example 15)
1) All the ingredients were accurately weighed.
2) Bupropion HCl, lactose anhydrous, MethocelmK 1 OOM, and ~vicel@PH - 102 were mixed in
a suitable mixer and the blend was sifted through a sieve.
3) The material of step 2) was mixed in a blender for 5 minutes.
4) ~erosil@20 0 and magnesium stearate were passed through a sieve.
5) The materials of step 3) and step 4) were mixed in a blender for 5 minutes.
6) The blend of step 5) was compressed into tablets.
zPx3 EzkGE 9, - [-?J ig - 2 Q, m'& - g, 1 7 ":3 8.
12
7) The tablets of step 6) were.film coated using aqueous opadryB coating dispersion in a
tablet-coating pan apparatus.
Dissolution Study
The tablets of Examples 12- 15 were subjected to dissolution. The amount of bupropion
dissolved at time points 0.5, l,2, 3,4, 6, and 8 hours is tabulated in Table 2.
Table 2: Dissolution Study data indicating % drug release at various time points
Extraction Study
! Time
(Hours)
0.5
1
2
3
4
6
8
The tablets of Examples 12 and 1'5 were extracted in various solvents. The tablets were
crushed with a mortar and pestle. The mass so ,obtained was then mixed with 30 mL of a solvent
(water or ethanol). The contents were mixed for 30 minutes. The percentage amount of bupropion
extracted at 15 minutes is tabulated in Table 3.
Table 3: Extraction Study data indicating the percentage of drug extracted
Example 12
3 5
47
64
7 7
8 7
10 1
-
The tablets of Example 14 were extracted in water and ethanol according to the extraction
Example 13
45
64
8 8
93
99
-
-
Solvent
Water
Ethanol
method given above. The percentage amount of bupropion extracted at 15 minutes is tabulated in
Table 4.
Table 4: Extraction Study data indicating the percentage of drug extracted
Example 14
36
46
6 5
76
83
9 1
96
Example No.
Example 12
Example 15
Example 12
Example 15
Example 15
(Control)
33
42
59
71 . -
8 3
95
100
% Drug Extracted
10.1
36.9
45.44
83.22
Based on the above experimental data, it was observed that the dosage form of the present
Solvent
Water
Ethanol
invention comprising a chewing gum base possessed-crush-resistance and were less prone to abuse.
" a:E-&>&-.Zg O:g.@,-G ,-2 .03.,2g J F :* &',&.
13
Example No.
Example 14
Example 14
% Drug Extracted
1.3
6.1

WE CLAIM:
1. A crush-resistant oral solid dosage form, comprising:
a) a therapeutically effective amount of a drug prone to abuse; and
b) ,a chewing gum base comprising a chewable pl.astic polymer,
wherein the amount of said gum base is such that it causes the dosage form to deform
plastically without breaking into powder when said dosage form is tampered with for abuse.
2. The solid dosage form according to claim 1, wherein the chewable plastic polymer present
is selected from the group comprising polyisobutylene, butadiene styrene, polyvinyl acetate,
terpene resins, ester gums, ethylene vinyl acetate, and mixtures thereof.
3. The solid dosage form according to. claim 1, wherein the chewing gum base is present in an
amount from about 20% wlw to about 85% wlw.
I 4. The solid dosage form according to claim 1, further comprising a release-controlling polymer.
5. The solid dosage form according to claim 4, wherein the release-controlling polymer is
selected from the group comprising hydroxypropylmethyl cellulose, hydroxyethyl cellulose,
polyethylene glycol, polyethylene oxide, hydroxypropyl cellulose, carboxymethyl cellulose,
cellulose ethers, cellulose esters, polymethacrylic acid esters copolymers, aminoalkyl
methacrylate copolymers, copolymers of polyvinyl acetate and polyvinyl pyrrolidone,
I polyvinyl alcohol, glyceryl behenate, carnauba wax, xanthan gum, starch, sodium alginate,
tragacanth, poloxamers, carbomers, and mixtures thereof.
6. The solid dosage form according to claim 4, wherein the chewing gum base is present in an
amount from about 20% wlw to about 85% wlw, and the release-controlling polymer is
present in an amount from about 10% wlw to about 75% wlw.
7. The solid dosage form according to claim 6, wherein the chewing gum base is present in an
amount from about 50% wlw to about 85% wlw, and the release-controlling polymer is
present in an amount from about 10% wlw to about 50% wlw.
8. The solid dosage form according to claim 5, wherein the release-controlling polymer is
- polyethylene oxide. EPQ i39- 8 g - ?,- al6 I 8 b.
14
9. The solid dosage form according to claim 8, wherein the chewing gum base and
polyethylene oxide are present in a ratio of about 7: 1 to about 1 : 1.
10. The solid dosage form according to claim 9, wherein the. chewing gum base and
polyethylene oxide are present in a ratio of about '5: 1.
1 1. The solid dosage form according to claim 1, further comprising one or more aversive
agents.
12. The solid dosage form according to claim 1, in the form of caplets, pills, mini-tablets,
tablets, or capsules; optionally, caplets, pills, mini-tablets, or tablets can be filled into
capsules.
13. The crush-resistant oral solid dosage form.according to claim 1, wherein the dosage form
consists essentially of (a) a therapeutically effective amount of a drug prone to abuse; and
(b) a chewing gum base comprising a chewable plastic polymer in an amount such that it
causes the dosage form to deform plastically without breaking into powder when said
dosage form is tampered with.
14. A process for the preparation of a crush-resistant oral solid dosage form, the process
comprising:
1) blending a drug prone to abuse, a chewing gum base, and optionally one or more
pharmaceutically acceptable excipients;
2) compressing the blend of step 1) to obtain caplets, pills, mini-tablets, or tablets; .
3) optionally, filling the compressed blend of step 2) into capsules.
15. The process according to claim 14, wherein the compressed blend is heated at a temperature
of about 50°C to about 80°C for about 5 minutes to about 75 minutes.
. 16. . A process for the.preparation of a crush-resistant oral solid dosage form, the process
comprising:
1) blending a drug prone to abuse, a chewing gum base, a release-controlling polymer,
and optionally one or more pharmaceutically acceptable excipients;
2) compressing the blend of step 1) to obtain caplets, pills, mini-tablets, or tablets;
3) heating the compressed blend of step 2) in a coating pan at a temperature of about
50°C to about 80°C for about 5 minutes to about 75 minutes;
4) optional1y;filling the heated compressed blend of step 3) into capsules.
17. The process according to claim 16, wherein the compressed blend is heated.at a temperature
of about 80°C for about 10 minutes.