U.S. patent application number 10/016336 was filed with the patent office on 2003-04-10 for dosage forms.
Invention is credited to Bellamy, Simon Andrew, Hughes, Lyn.
Application Number | 20030068276 10/016336 |
Document ID | / |
Family ID | 26688465 |
Filed Date | 2003-04-10 |
United States Patent
Application |
20030068276 |
Kind Code |
A1 |
Hughes, Lyn ; et
al. |
April 10, 2003 |
Dosage forms
Abstract
Solid oral dosage forms of controlled substances containing
aversive agents are useful in reducing abuse by chewing or
inhaling.
Inventors: |
Hughes, Lyn; (Harleysville,
PA) ; Bellamy, Simon Andrew; (Surrey, GB) |
Correspondence
Address: |
ROHM AND HAAS COMPANY
PATENT DEPARTMENT
100 INDEPENDENCE MALL WEST
PHILADELPHIA
PA
19106-2399
US
|
Family ID: |
26688465 |
Appl. No.: |
10/016336 |
Filed: |
November 2, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60322624 |
Sep 17, 2001 |
|
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|
Current U.S.
Class: |
424/10.4 ;
424/760 |
Current CPC
Class: |
A61K 31/485 20130101;
A61P 25/36 20180101; A61K 45/06 20130101; A61K 9/4858 20130101;
A61P 25/30 20180101; A61K 9/2027 20130101; A61K 9/5078 20130101;
A61K 9/2013 20130101 |
Class at
Publication: |
424/10.4 ;
424/760 |
International
Class: |
A61K 035/78 |
Claims
We claim:
1. An oral pharmaceutical dosage form not susceptible to abuse by
respiratory mucosal membrane administration comprising one or more
aversive agents.
2. An oral pharmaceutical dosage form not susceptible to abuse by
chewing comprising one or more aversive agents.
3. An oral pharmaceutical dosage form not susceptible to abuse by
respiratory mucosal membrane administration comprising one or more
aversive agents and a controlled substance.
4. An oral pharmaceutical dosage form not susceptible to abuse by
chewing comprising one or more aversive agents and a controlled
substance.
5. An oral pharmaceutical dosage form according to claim 3, wherein
said aversive agent is a respiratory irritant selected from the
group consisting of capsaicin, capsacutin dihydrocapsaicin,
nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin,
capsaicinoids, gingerol, piperine, isopiperine, zingerone, shogaol,
and vanyllylamide derivatives, and mixtures thereof.
6. An oral pharmaceutical dosage form according to claim 4, wherein
said aversive agent is a bitter substance selected from the group
consisting of denatonium benzoate, denatonium capsaicinate,
denatonium chloride, denatonium saccharide, limonin, linalool,
linalool acetate, naringin, quassin, quercitin, sucrose benzoate,
and sucrose octaacetate, and mixtures thereof.
7. An oral pharmaceutical dosage form according to claim 5, wherein
said controlled substance is selected from the group consisting of
Schedule II, III, IV, and V controlled substances.
8. An oral pharmaceutical dosage form according to claim 6, wherein
said controlled substance is selected from the group consisting of
Schedule II, III, IV, and V controlled substances.
9. An oral pharmaceutical dosage form according to claim 7, wherein
said controlled substance is a Schedule II controlled
substance.
10. An oral pharmaceutical dosage form according to claim 8,
wherein said controlled substance is a Schedule II controlled
substance.
Description
[0001] This application claims benefit to provisional application
No. 60/322,624 filed Sep. 17, 2001.
BACKGROUND
[0002] Abuse of controlled substances is a serious and growing
problem throughout the world. For example, the abuse of an extended
release form of oxycodone has been the recent subject of many
articles such as `Playing With Pain Killers` and `How One Town Got
Hooked`. See, Newsweek, Apr. 9, 2001, pages 45-51. Further, The New
York Times profiled the problem of oxycodone abuse by inhalation of
the crushed pill. See, The New York Times, Jul. 29, 2001. It is
estimated that in America four million people over the age of 12
used prescription painkillers and stimulants for non-medical
reasons in the space of just one month, approximately half of them
saying they'd done it for the first time. Emergency room visits
related to such abuse approximately doubled between 1992 and
1999.
[0003] There are three main routes that drug abusers use for
administering the drug substances: parenteral, oral, and
inhalation. The parenteral route is commonly called `mainlining`
and requires the drug substance to be in solution such that it can
be injected intravenously with a syringe. For solid dosage form
drugs this requires some type of extraction and concentration
procedure to render the drug substance suitable for injection.
Inhalation of a solid drug substance through the nose is commonly
called `snorting`. For solid dosage form drugs this requires only
that the dosage form be crushed into a powder, or emptied from a
capsule. Breathing in vapors is frequently known as `huffing`. Both
snorting and huffing result in the rapid absorption of the drug
substance through the mucosa of the respiratory system.
[0004] The potential for abuse is increased by the use of extended
release formulations because they typically contain more than the
immediate release single dose of active ingredient. Circumventing
the extended release mechanism delivers the full dose, which is
intended to be delivered over a longer time period, immediately.
For example, crushing an extended release oxycodone tablet
separates a gelling matrix from the oxycodone active ingredient,
such that when inhaled through the nose the gelling matrix cannot
exert the extended release effect. Similarly it is sometimes
possible to circumvent the extended release effect by chewing the
dosage form.
[0005] The use of coatings to extend the release of drug substances
is very well known in the art (Remington's Pharmaceutical Sciences,
16.sup.th Edition, Chapter 90). Such dosage forms are also subject
to said modes of abuse because the coating can be damaged by
crushing or chewing.
[0006] WO0108661 describes an extended release dosage form of
opioids that uses an ion exchange resin. This dosage form is also
subject to said modes of abuse because the ion exchange resin and
the active ingredient can be separated by crushing.
[0007] Various methods have been used to reduce the potential for
abuse of controlled substances. These methods have focussed on the
parenteral and oral routes of administration.
[0008] U.S. Pat. Nos. 3,773,955, 3,966,940, and 4,457,933 describe
oral dosage forms containing a combination of opioid agonists and
antagonists, in which the effect of the antagonist when
administered according to the correct procedure does not affect the
therapeutic pain management value of the agonist. However, when the
agonist and antagonist are extracted for parenteral administration
by an addict the effect of the agonist desired by the addict is
decreased. This approach was further adopted in WO9004965 where it
was incorporated into a transdermal delivery device, and in U.S.
Pat. No. 6,228,863 where it was developed into a dosage form from
which the agonist could not be separated from the antagonist except
by using a sophisticated multi-step procedure.
[0009] In U.S. Pat. No. 3,980,766 multiple methods for reducing
abuse potential are described. One method is to include a
thickening agent such that the concentrated extract containing the
drug can not be injected with a syringe. Another is the
incorporation of agents that cause the precipitation of the drug
during isolation, thus rendering it unsuitable for injection. The
addition of a thickener has also been used in U.S. Pat. No.
4,070,494, WO9107950, and WO9520947.
[0010] In WO0033835 additives are included in the dosage forms such
that when added to drinks create a visible change in the drink.
This invention reduces the potential for abuse by oral
administration of the substance by one person to another without
their knowledge.
[0011] The use of bitter and sour agents to minimize the risk of
ingestion of poisonous compounds is well known in the art. For
example, see U.S. Pat. No. 3,268,577, GB 2358585, JP 2000026260,
and Chemistry and Industry (London), volume 22, 721-723, 1998). In
all such cases the purpose of the bitter or sour agent is to
prevent ingestion.
[0012] However, none of the cited references solve the problem of
potential abuse of therapeutic compounds via inhalation or chewing.
Now, Applicants have surprisingly discovered a dosage form useful
in reducing the potential for drug abuse via inhalation or
chewing.
[0013] The term "high," as used herein means the non-therapeutic
effect desired by drug addicts and recreational drug users
[0014] The term "respiratory mucosal membrane" as used herein means
the mucous membrane lining the nasal and pharyngeal cavities, the
bronchial tubes, and the lungs. Typically, snorting into the nasal
cavity is the common, preferred route of abuse for a solid oral
dosage form which has been crushed by one intending to inhale said
crushed dosage form to obtain the high.
[0015] The term "respiratory irritant` as use herein means
substances that cause irritation when administered to the
respiratory mucosal membrane. Said irritation can include, but is
not limited to, coughing, dyspnea, rhinitis, nasal congestion, eye
irritation, lachrymation, and sneezing.
[0016] When describing dosage forms the term "immediate release" as
used herein means a dosage form from which the active ingredient is
dissolved as quickly as possible after administration. In the
pharmaceutical arts said immediate release dosage forms are
frequently referred to as "conventional" dosage forms.
[0017] When describing dosage forms the term "modified release" as
used herein means a dosage form whose drug-release characteristics
of time course and/or location are chosen to accomplish therapeutic
or convenience objectives not offered by conventional dosage forms.
Said modified release dosage forms include dosage forms commonly
known in the art as, delayed, sustained, extended, targeted,
prolonged, pulsatile, zero-order, constant rate, and
controlled.
[0018] The term "aversive response" as used herein means a response
in a person, resulting from administration of a dosage form
containing a controlled substance, via any of the known routes of
administration, sufficiently unpleasant that said person decides
not to administer said dosage form by the same route of
administration again
[0019] The term "aversive agent" as used herein means any substance
that is included in a dosage form that creates an aversive
response.
[0020] The term "nociceptive" as used herein means a response
characterized by pain. For example the term `nociceptive efficacy`
when applied to an irritant refers to the quantification of the
ability of said irritant to cause pain.
SUMMARY OF THE INVENTION
[0021] The present invention relates to an oral pharmaceutical
dosage form not susceptible to abuse by respiratory mucosal
membrane administration comprising one or more aversive agents.
[0022] The present invention further relates to an oral
pharmaceutical dosage form not susceptible to abuse by chewing
comprising one or more aversive agents.
DETAILED DESCRIPTION OF THE INVENTION
[0023] The present invention relates to an oral pharmaceutical
dosage form not susceptible to abuse by respiratory mucosal
membrane administration comprising one or more aversive agents.
[0024] The present invention further relates to an oral
pharmaceutical dosage form not susceptible to abuse by chewing
comprising one or more aversive agents.
[0025] In the practice of one embodiment of the invention, a
respiratory irritant such as powdered chili peppers, or
concentrated extracts of such products that contain capsaicin or
capsaicin-like components, is incorporated into the solid oral
dosage form of the controlled substance. When the oral dosage form
is used as prescribed, i.e. swallowed whole, said irritant causes
no aversive response. However, if the oral dosage form is rendered
into a powder and inhaled, said irritant creates intense discomfort
in the user, including coughing, dyspnea, rhinitis, nasal
congestion, eye irritation, lachrymation, and sneezing. This
intense discomfort has the effect of deterring people from using
said inhalation route as a means of administration, i.e. it elicits
an aversive response.
[0026] In the practice of another embodiment of the invention, a
bitter tasting agent such as denatonium benzoate (Bitr
[0027] ex.RTM.) or a sour tasting agent such as citric acid, is
incorporated into the solid oral dosage form of the controlled
substance. When the oral dosage form is used as prescribed, i.e.
swallowed whole, said bitter or sour substance causes no aversive
response. However, if the oral dosage form is chewed, said bitter
or sour substance creates an intensely unpleasant taste. This
unpleasant taste has the effect of deterring people from chewing
the dosage form, i.e. it elicits an aversive response.
[0028] The Controlled Substances Act of 1970 regulates the
manufacturing, distribution, and dispensing of drugs that have
abuse potential. The Drug Enforcement Agency (DEA) within the US
Department of Justice is the chief agency responsible for enforcing
said act. Drugs under the jurisdiction of said Act are divided into
five schedules (I thru V) based on their medical utility, potential
for abuse, and physical and psychological dependence. Schedule I
substances have high abuse potential and no accepted medical use.
Schedule II also have high abuse potential, but also have medical
utility. Schedules III, IV, and V have progressively lower abuse
potential.
[0029] Because the DEA rates abuse potential based on specific
dosage forms it is not uncommon for a drug to be rated in multiple
schedules. For example codeine appears as Schedule II, Schedule
III, and Schedule IV, depending on the specific dosage form and
dosage amount. To avoid duplication in the list of controlled
substance below, multiple occurrences have been removed and any
controlled substance that had multiple occurrences is placed in the
highest abuse potential category for which is has been scheduled.
For example, codeine has been included as Schedule II, but not
Schedule III or Schedule IV. This is not intended to limit the
scope of the invention. The utility of the Applicant's invention
lies in the fact that any controlled substance, regardless of what
schedule it appears on, is suitable for formulating into the
Applicant's dosage form.
[0030] Controlled substances useful in the practice of the
invention are those categorized by the DEA as Schedule II, III, IV,
and V controlled substances.
[0031] Schedule II substances include, but are not limited to,
1-1-Phenylcyclohexylamine, 1-Piperidinocyclohexanecarbonitrile,
Alfentanil, Alphaprodine, Amobarbital, Amphetamine, Anileridine,
Benzoylecgonine, Bezitramide, Carfentanil, Coca Leaves, Cocaine,
Codeine, Dextropropoxyphene, Dihydrocodeine, Diphenoxylate,
Diprenorphine, Ecgonine, Ethylmorphine, Etorphine HCl, Fentanyl,
Glutethimide, Hydrocodone, Hydromorphone, Isomethadone,
Levo-alphacetylmethadol, Levomethorphan, Levorphanol, Meperidine,
Meperidine intermediate-A, Meperidine intermediate-B, Meperidine
intermediate-C, Metazocine, Methadone, Methadone intermediate,
Methamphetamine, Methylphenidate, Metopon, Moramide-intermediate,
Morphine, Nabilone, Opium extracts, Opium fluid extract, Opium
poppy, Opium tincture, Opium, granulated, Opium, powdered, Opium,
raw, Oxycodone, Oxymorphone, Pentobarbital, Phenazocine,
Phencyclidine, Phenmetrazine, Phenylacetone, Piminodine, Poppy
Straw, Poppy Straw Concentrate, Racemethorphan, Racemorphan,
Remifentanil, Secobarbital, Sufentanil, Thebaine
[0032] Schedule III substances include, but are not limited to,
Amobarbital, Anabolic steroids, Aprobarbital, Barbituric acid
derivative, Benzphetamine, Boldenone, Butabarbital, Butalbital,
Chlorhexadol, Chlorotestosterone, Chlorphentermine, Clortermine,
Clostebol, Codeine, Dehydrochlormethyltestosterone, Dihydrocodeine,
Dihydrotestosterone, Dronabinol, Drostanolone, Ethylestrenol,
Ethylmorphine, Fluoxymesterone, Formebolone, Hydrocodone, Ketamine,
Lysergic acid, Lysergic acid amide, Mesterolone, Methandienone,
Methandranone, Methandriol, Methandrostenolone, Methenolone,
Methyltestosterone, Methyprylon, Mibolerone, Morphine, Nalorphine,
Nandrolone, Norethandrolone, Oxandrolone, Oxymesterone,
Oxymetholone, Pentobarbital, Phendimetrazine, Secobarbital,
Stanolone, Stanozolol, Sulfondiethylmethane, Sulfonethylmethane,
Sulfonmethane, Talbutal, Testolactone, Testosterone, Thiamylal,
Thiopental, Tiletamine, Trenbolone, Vinbarbital.
[0033] Schedule IV substances include, but are not limited to,
Alprazolam, Barbital, Bromazepam, Butorphanol, Camazepam, Cathine,
Chloral betaine, Chloral hydrate, Chlordiazepoxide, Clobazam,
Clonazepam, Clorazepate, Clotiazepam, Cloxazolam, Cocaine,
Delorazepam, Dexfenfluramine, Dextropropoxyphene, Diazepam,
Diethylpropion, Difenoxin, Estazolam, Ethchlorvynol, Ethinamate,
Ethyl loflazepate, Fencamfamin, Fenfluramine, Fenproporex,
Fludiazepam, Flunitrazepam, Flurazepam, Halazepam, Haloxazolam,
Ketazolam, Loprazolam, Lorazepam, Lormetazepam, Mazindol,
Mebutamate, Medazepam, Mefenorex, Meprobamate, Methohexital,
Methylphenobarbital, Midazolam, Modafinil, Nimetazepam, Nitrazepam,
Nordiazepam, Oxazepam, Oxazolam, Paraldehyde, Pemoline,
Pentazocine, Petrichloral, Phenobarbital, Phentermine, Pinazepam,
Pipradrol, Prazepam, Quazepam, Sibutramine, Temazepam, Tetrazepam,
Triazolam, Zaleplon, Zolpidem
[0034] Schedule V substances include, but are not limited to
Buprenorphine, Difenoxin, Dihydrocodeine, Diphenoxylate,
Pyrovalerone.
[0035] Preferred controlled substances useful in the practice of
the invention are those categorized by the DEA as Schedule II, III,
and IV controlled substances.
[0036] More preferred controlled substance useful in the practice
of the invention are those categorized by the DEA as Schedule II
and III controlled substances.
[0037] Most preferred controlled substance useful in the practice
of the invention are those categorized by the DEA as Schedule II
controlled substances. The most preferred Schedule II substance is
oxycodone.
[0038] Aversive agents useful in the practice of this invention
include, but are not limited to, respiratory irritants, bitter
substances, and sour substances.
[0039] Aversive agents useful in the practice of this invention are
solids. Said solid can be said agent in pure form or a solid
containing said agent.
[0040] Aversive agents useful in the practice of this invention are
of natural or synthetic origin.
[0041] An important aspect of this invention is the use of
capsaicinoids as an aversive agent which acts as a respiratory
irritant to create an aversive response. Capsaicinoids are alkaloid
substances which occur naturally in the fruit of various chile
pepper plants. The principal capsaicinoids found in most pepper
plants are capsaicin, dihydrocapsaicin, capsico, and capsacutin.
The principal capsaicinoid is capsaicin. There can be multiple
capsaicinoids in one pepper and different peppers have different
concentrations of capsaicinoids. The production of capsaicinoids is
a form of chemical defense against being eaten and thus acts
naturally as an animal repellant. See, Smith, R. L., Ecology and
Field Biology, p. 562 (3d Ed. 1980). Capsaicinoids are the
chemicals responsible for the "hot" sensation associated with
peppers. The hotness of the various capsicums is directly
attributable to their capsaicinoid content. Capsaicinoids generate
a spicy flavor in the mouth but are irritants when applied to
mucous membranes.
[0042] Capsicum is the formal term used to refer to the dried ripe
fruit of the various species of chili peppers.
[0043] Therapeutically, capsaicin is listed as a counterirritant
(Merck Index, 9th Ed., p. 224). Capsicum has Generally Regarded as
Safe (GRAS) status in the USA. Capsaicin, capsicum, and capsicum
oleoresin have monographs in the US Pharmacopeia 24.
[0044] Respiratory irritants useful in the practice of this
invention include, but are not limited to, pure compounds and
mixtures of capsaicin, capsico, capsacutin, dihydrocapsaicin,
nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin,
capsaicinoids, gingerol, chemical mace, piperine, isochavicine,
isopiperine, piperidine, chavicine, piperettine, zingerone,
shogaol, valleral, isovallerals, vanyllylamide, nonoyl vanyllamide,
vanyllylamide derivatives, synthetic derivatives of capsaicinoids,
and extracts, capsicums, and powders of, Capsicum frutescens
varieties, Capsicum anuum varieties, Capsicum chinense varieties,
Capsicum baccatum varieties, Capsicum pubescens varieties, Capsicum
species, Piper migrum varieties, Piper longum varieties, Piper
retrofractum varieties, Piper officinarum varieties, Piperaceae
species, Brassica juncea varieties, Brassica. nigra varieties,
Sinapis alba varieties, Sinapis arvensis varieties, Zingiber
officinale varieties, and Lactarius vellereus varieties and
mixtures thereof.
[0045] Preferred respiratory irritants useful in the practice of
the invention are pure compounds and mixtures of capsaicin,
capsico, capsacutin, dihydrocapsaicin, nordihydrocapsaicin,
homocapsaicin, homodihydrocapsaicin, capsaicinoids, gingerol,
chemical mace, piperine, isochavicine, isopiperine, piperidine,
chavicine, piperettine, zingerone, shogaol, valleral, isovallerals,
vanyllylamide, nonoyl vanyllamide, vanyllylamide derivatives,
synthetic derivatives of capsaicinoids, and extracts, capsicums,
and powders of, Capsicum frutescens varieties, Capsicum anuum
varieties, Capsicum chinense varieties, Piper migrum varieties,
Piper longum varieties, Piper retrofractum varieties, Piper
officinarum varieties, Brassica juncea varieties, Brassica. nigra
varieties, Sinapis alba varieties, Sinapis arvensis varieties, and
Zingiber officinale varieties and mixtures thereof.
[0046] More preferred respiratory irritants useful in the practice
of the invention are pure compounds and mixtures of capsaicin,
capsico, capsacutin dihydrocapsaicin, nordihydrocapsaicin,
homocapsaicin, homodihydrocapsaicin, capsaicinoids, gingerol,
piperine, isopiperine, piperidine, piperettine, zingerone, shogaol,
valleral, isovallerals, vanyllylamide, vanyllylamide derivatives,
and extracts, capsicums, and powders of, Capsicum frutescens
varieties, Capsicum anuum varieties, Capsicum chinense varieties,
Piper migrum varieties, Piper longum varieties, Piper retrofractum
varieties, Piper officinarum varieties, Brassica juncea varieties,
Brassica. nigra varieties, Sinapis alba varieties, Sinapis arvensis
varieties, and Zingiber officinale varieties and mixtures
thereof.
[0047] Most preferred respiratory irritants useful in the practice
of the invention are pure compounds and mixtures of capsaicin,
capsacutin dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin,
homodihydrocapsaicin, capsaicinoids, gingerol, piperine,
isopiperine, zingerone, shogaol, and vanyllylamide derivatives and
mixtures thereof.
[0048] The use of capsaicin with cocaine is contra-indicated.
[0049] The amount of respiratory irritant useful in the practice of
this invention is that which is sufficient to elicit an aversive
response in the user when said irritant is inhaled through the
respiratory mucosa but that which is not sufficient to elicit an
aversive response or an adverse medical response in the user when
said irritant is swallowed as a solid oral dosage form in the
manner prescribed.
[0050] The nociceptive efficacy of the respiratory irritants varies
greatly depending both on chemical structure of the active
ingredient of said irritant, and the amount of active ingredient in
said irritant. The following amounts of respiratory irritants are
provided as examples. Effective amounts of other respiratory
irritants can be determined using techniques well known to those
skilled in the art.
[0051] The preferred amount of the respiratory irritants capsaicin
and dihydrocapsaicin is a combined total of 0.002-100 mg per
dose.
[0052] The preferred amount of the respiratory irritant zingerone
is 0.04-200 mg per dose.
[0053] The preferred amount of the respiratory irritant shogaol is
0.04-200 mg per dose
[0054] The preferred amount of the respiratory irritant piperine is
0.04-200 mg per dose
[0055] The preferred amount of the respiratory irritants capsicums
of Capsicum annum, Capsicum frutescens, and Capsicum chinense is
0.1-450 mg per dose.
[0056] The more preferred amount of the respiratory irritants
capsaicin and dihydrocapsiacin is a combined total of 0.004-25 mg
per dose.
[0057] The more preferred amount of the respiratory irritant
zingerone 0.2-150 mg per dose.
[0058] The more preferred amount of the respiratory irritant
shogaol 0.2-150 mg per dose
[0059] The more preferred amount of the respiratory irritant
piperine is 0.2-150 mg per dose
[0060] The more preferred amount of the respiratory irritants
capsicums of Capsicum annum, Capsicum frutescens, and Capsicum
chinense is 0.4-350 mg per dose
[0061] The most preferred amount of the respiratory irritants
capsaicin and dihydrocapsiacin is a combined total of 0.02-15 mg
per dose.
[0062] The most preferred amount of the respiratory irritant
zingerone 0.2-100 mg per dose.
[0063] The most preferred amount of the respiratory irritant
shogaol 0.2-100 mg per dose
[0064] The most preferred amount of the respiratory irritant
piperine is 0.2-100 mg per dose
[0065] The most preferred amount of the respiratory irritants
capsicums of Capsicum annum, Capsicum frutescens, and Capsicum
chinense is 0.6-250 mg per dose
[0066] Bitter agents also create an aversive response. The use of
bitter agents is particularly useful in preventing abuse of
controlled substances by chewing the oral dosage form. Bitter
agents useful in the practice of this invention include, but are
not limited to, agaricic acid, benzyl acetate, brucine, brucine
sulfate, caffeine, capsaicin, catechin, dadzein, denatonium
benzoate (Bitrex.RTM.) and other denatonium salts, denatonium
capsaicinate, denatonium chloride, denatonium saccharide, diethyl
phthalate, epicatechin, genistein, gentian violet, gerianol,
hydroxytyrosol, kashin, limonin, linalool, linalool acetate, methyl
anthranilate, naringin, nobiletin, oleuropin, phenylethyl alcohol,
polyphenols, quassin, quebracho, quercitin, quinine, quinine
sulfate, quinine hydrochloride, sinensetin, sucrose benzoate,
sucrose octaacetate, and tangeretin and mixtures thereof.
[0067] Preferred bitter agents useful in the practice of this
invention are, denatonium benzoate (Bitrex.RTM.) and other
denatonium salts, denatonium capsaicinate, denatonium chloride,
denatonium saccharide, limonin, linalool, linalool acetate,
naringin, quassin, quercitin, sucrose benzoate, and sucrose
octaacetate and mixtures thereof.
[0068] Most preferred bitter agents useful in the practice of this
invention are denatonium benzoate (Bitrex.RTM.), denatonium
capsaicinate, denatonium saccharide, and sucrose octaacetate and
mixtures thereof.
[0069] Further, sour agents also create an aversive response. The
use of sour agents is particularly useful in preventing abuse of
controlled substances by chewing the oral dosage form. Sour agents
useful in the practice of this invention include, but are not
limited to, acidic organic compounds that contain one or more
acidic protons per molecule and mixtures thereof.
[0070] Preferred sour agent useful in the practice of the invention
are acidic organic compounds that contain two or more acidic
protons per molecule and mixtures thereof.
[0071] Most preferred sour agents useful in the practice of the
invention are citric acid and tartaric acid and mixtures
thereof.
[0072] The controlled substance and aversive agent are incorporated
into the dosage form using any of the methods known in the art for
preparation of solid oral dosage forms. See, Remington's
Pharmaceutical Sciences, 16.sup.th Edition.
[0073] Further, different combinations of aversive agents can be
combined in the same dosage form. For example, if it is desired to
reduce the potential for abuse via both inhalation and chewing, it
may be desirable to combine both a respiratory irritant and a
bitter agent in the same formulation. Further, combination of
avervise agents can sometime have a synergistic effect, such that
the combination has a greater effect than the sum of the
individuals taken separately. Still further, people have different
responses to taste, such that a mixture of bitter agents may be
needed to be effective in a larger fraction of the population.
[0074] In addition to the controlled substance and aversive agent,
excipients are used in the manufacture of the oral dosage forms of
the present invention. Excipients useful in the practice if this
invention include but are not limited to preservatives, viscosity
agents, fillers, lubricants, glidants, disintegrants, binders, and
encapsulants.
[0075] Preferred preservatives include, but are not limited to,
phenol, alkyl esters of parahydroxybenzoic acid, o-phenylphenol
benzoic acid and the salts thereof, boric acid and the salts
thereof, sorbic acid and the salts thereof, chlorobutanol, benzyl
alcohol, thimerosal, phenylmercuric acetate and nitrate,
nitromersol, benzalkonium chloride, cetylpyridinium chloride,
methyl paraben, and propyl paraben. Particularly preferred are the
salts of benzoic acid, cetylpyridinium chloride, methyl paraben and
propyl paraben. The compositions of the present invention generally
include from 0-2% preservatives.
[0076] Preferred viscosity agents include, but are not limited to,
methylcellulose, sodium carboxymethylcellulose,
hydroxypropyl-methylcellu- lose, hydroxypropylcellulose, sodium
alginate, carbomer, povidone, acacia, guar gum, xanthan gum and
tragacanth. Particularly preferred are methylcellulose, carbomer,
xanthan gum, guar gum, povidone, sodium carboxymethylcellulose, and
magnesium aluminum silicate. Compositions of the present invention
include 0-25% viscosity agents.
[0077] Preferred fillers include, but are not limited to, lactose,
mannitol, sorbitol, tribasic calcium phosphate, dibasic calcium
phosphate, compressible sugar, starch, calcium sulfate, dextro and
microcrystalline cellulose. The compositions of the present
invention contain from 0-75% fillers.
[0078] Preferred lubricants include, but are not limited to,
magnesium stearate, stearic acid, and talc. The pharmaceutical
compositions of the present invention include 0-2% lubricants.
[0079] Preferred glidants include, but are not limited to, talc and
colloidal silica. The compositions of the present invention include
from 0-5% glidants.
[0080] Preferred disintegrants include, but are not limited to,
starch, sodium starch glycolate, crospovidone, croscarmelose
sodium, polacrilin potassium, and microcrystalline cellulose. The
pharmaceutical compositions of the present invention include from
0-30% disintegrants.
[0081] Preferred binders include, but are not limited to, acacia,
tragacanth, hydroxypropylcellulose, pregelatinized starch, gelatin,
povidone, hydroxypropylcellulose, hydroxypropyl-methylcellulose,
methylcellulose, sugar solutions, such as sucrose and sorbitol, and
ethylcellulose. The compositions of the present invention include
0.1-10% binders.
[0082] Encapsulants useful in the practice of the present invention
include, but are not limited to permable coatings, impermeable
coatings, and matrices.
[0083] Permeable coatings useful in this invention are well know to
one skilled in the art and include Eudragit.RTM. RL, and
Eudragit.RTM. RS (Rohm-Pharma Darmstadt, Germany)
[0084] Non-permeable coatings useful in this invention are well
known to one skilled in the art and include Aquacoat CPD (FMC
Corporation, Philadelphia, Pa., USA), Eudragit.RTM. E100,
Eudragit.RTM. L100, Eudragit.RTM. S100 (Rohm-Pharma Darmstadt,
Germany), Kollicoat.RTM. MA 30 DP (BASF Aktiengesellschaft,
Ludwigshafen, Germany), Opadry light pink.
[0085] Plastizers for use with coatings useful in the practice of
the invention include but are not limited to, triethyl citrate,
1,2-propylene glycol, polyethylene glycols, and tracetin.
[0086] Matrices for encapsulation useful in the practice of the
invention include, but are not limited to, anion exchange resins,
cation exchange resins, polymeric adsorbents, carbonaceous
adsorbents, cellulosic polymers, and acrylic polymers.
[0087] Dosage forms of the present invention are immediate release
or modified release.
[0088] The following non limiting examples illustrate the present
invention:
EXAMPLE 1 30 MG EXTENDED RELEASE OXYCODONE TABLETS USING
CAPSAICIN
[0089]
1 Ingredient mg/tablet Oxycodone HCl 30 Lactose 200 Eudragit .RTM.
RS 45 PM Purified water as needed Stearyl alcohol 75 Talc 7.5
Magnesium 3.75 stearate Capsaicin 13.75
[0090] The required quantities of oxycodone hydrochloride, a
Schedule II controlled substance, spray-dried lactose, capsaicin,
and Eudragit.RTM. RS PM are placed into an appropriately-sized
mixer, and mixed for approximately 5 minutes. While the powders are
mixing, the mixture is granulated with enough water to produce a
moist granular mass. The granules are then dried in a fluid bed
dryer at 60.degree. C., and then passed through an 8-mesh screen.
Thereafter, the granules are redried and pushed through a 12-mesh
screen. The required quantity of stearyl alcohol is melted at
approximately 60-70.degree. C., and while the granules are mixing,
the melted stearyl alcohol is added. The warm granules are returned
to the mixer.
[0091] The coated granules are removed from the mixer and allowed
to cool. The granules are then passed through a 12-mesh screen. The
granulate is then lubricated by mixing the required quantity of
talc and magnesium stearate in a suitable blender. Tablets are
compressed to 375 mg in weight on a suitable tableting machine.
EXAMPLE 2 30 MG EXTENDED RELEASE MORPHINE SULFATE TABLETS USING
CAPSAICIN
[0092]
2 Ingredient mg/tablet Morphine 30 sulfate Lactose 79.5 Eudragit
.RTM. RL 12 Stearyl aclohol 24 Talc 3 Magnesium 1.5 stearate
Capsaicin 10
[0093] These tablets are prepared according to the following
method:
[0094] Morphine sulfate, a Schedule II controlled substance,
capsaicin, and lactose are intimately mixed in a suitable mixer. A
granulation is then prepared by incorporating the granulating fluid
into the mixing powders using Eudragit.RTM. RL. The granulate is
then dried and passed through a 12 mesh screen. The stearyl alcohol
is melted and incorporated into the warm granules using a suitable
mixer. After cooling, the granules are passed through a 12 mesh
screen. The granules are then lubricated by mixing in the talc and
stearyl alcohol. Tablets are then compressed on a suitable
tabletting machine using round biconvex tooling 10/32" in
diameter.
EXAMPLE 3 8 MG EXTENDED RELEASE HYDROMORPHONE CAPSULES USING
SHOGAOL
[0095]
3 Ingredient mg/capsule Loading Hydromorphone 8 HCl Opadry light 4
pink (Y-5-1442) Purified water as needed 18/20 mesh 148 sugar
spheres Overcoating Opadry light 8.4 pink (Y-5-1442) Purified water
as needed Retardant coating Eudragit .RTM. RS 7.6 30D Eudragit
.RTM. RL 0.8 30D Triethyl citrate 1.68 Talc 3.36 Purified water as
needed Second overcoat Opadry light 9.6 pink (Y-5-1442) Purified
water ass needed Encapsulatin Size #2 clear hard gelatin capsules
Shogaol 75
[0096] Hydromorphone beads are prepared by dissolving hydromorphone
HCl, a Schedule II controlled substance, in water, adding Opadry
Y-5-1442 and mixing for about 1 hour to obtain a 20% w/w
suspension. This suspension is then sprayed onto Nu-Pareil.RTM.
18/20 mesh beads using a Wurster insert.
[0097] First Overcoat
[0098] The loaded hydromorphone beads are then overcoated with a 5%
w/w gain of Opadry Light Pink using a Wurster insert. This overcoat
is applied as a protective coating.
[0099] Retardant Coat
[0100] After the first overcoat, the hydromorphone beads are then
coated with a 5% weight gain of a retardant coating mixture of
Eudragit.RTM. RS 30D and Eudragit.RTM. RL 30D at a ratio of 90:10,
RS to RL. The addition of Triethyl Citrate and Talc is also
included in the Eudragit suspension. The Wurster insert is used to
apply the coating suspension.
[0101] Second Overcoat
[0102] Once the retardant coating is complete, the hydromorphone
beads are given a final overcoat of Opadry Light Pink to a 5%
weight gain using a Wurster insert. This overcoat is also applied
as a protective coating.
[0103] Curing
[0104] After the completion of the final overcoat, the
hydromorphone beads are cured in a 45.degree. C. oven for 2
days.
[0105] Encapsulation
[0106] The beads are mixed with shogaol in a suitable mixer and the
mixture is then hand filled in size #2 clear gelatin capsules.
EXAMPLE 4 30 MG EXTENDED RELEASE OXYCODONE TABLETS USING
PIPERINE
[0107] Tablets are prepared as described in Example 1, except that
the respiratory irritiant used is piperine, and the quantities used
are as follows:
4 Ingredient mg/tablet Oxycodone HCl 30 Lactose 138.75 Eudragit
.RTM. RS 45 PM Purified water as needed Stearyl alcohol 75 Talc 7.5
Magnesium 3.75 stearate Piperine 75
EXAMPLE 5 30 MG EXTENDED RELEASE MORPHINE SULFATE TABLETS USING
DENATONIUM BENZOATE
[0108] These tablets are prepared as described in Example 2 except
that the capsaicin is replaced with 2 mg/tablet of denatonium
bezoate (available as Bitrex.RTM. from Macfarlan Smith, Edinburgh,
UK).
EXAMPLE 6
[0109] A Caucasian female, age 27, weighing 50 kg suffering from
back pain takes a 30 mg tablet of sustained release oxycodone from
Example 1 as prescribed, by swallowing said tablet whole. She
experiences 15 hours of pain relief without any aversive
response.
EXAMPLE 7
[0110] A Caucasian male recreational drug user, age 45, weighing 80
kg crushes a 30 mg tablet of sustained release oxycodone from
Example 1 to give a powder. He then inhales said powder through the
nose. He immediately experiences an aversive response, including an
intense burning sensation in the nasal passages, sneezing, watery
eyes and headache.
EXAMPLE 8
[0111] An African-American male, aged 18, weighing 66 kg, who has
never abused drugs crushes an extended release 30 mg morphine
tablet from Example 2 into a powder and then inhales said powder
through the nose. He immediately experiences an aversive response,
including an intense burning sensation in the nasal passages,
coughing, and watery eyes.
EXAMPLE 9
[0112] An Asian female, recreational drug user, aged 28, weighing
55 kg, breaks an 8 mg hydromorhone capsule from Example 3 and
empties out the contents from the capsule. She crushes the beads
into a fine powder and then inhales said powder through the nose.
She immediately experiences an aversive response, including an
intense burning sensation in the nasal passages and the throat,
coughing, and watery eyes.
EXAMPLE 10
[0113] At a party a Caucasian male recreational drug user, aged 17,
weighing 65 kg is offered a 30 mg morphine sulfate tablet, as
prepared in Example 5. He chews it and he immediately experiences
an aversive response causing him to spit out the chewed dosage
form.
* * * * *