(12) United States Patent
`Rariy et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,592,200 B2
`*Mar. 14, 2017
`
`USO09592200B2
`
`(54)
`
`(71)
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`(72)
`
`(73)
`
`(*)
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`(21)
`(22)
`(65)
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`(60)
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`(51)
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`ABUSE-DETERRENT PHARMACEUTICAL
`COMPOSITIONS OF OPODS AND OTHER
`DRUGS
`
`Inventors:
`
`Applicant: COLLEGIUM
`PHARMACEUTICAL, INC., Canton,
`MA (US)
`Roman V. Rariy, Allston, MA (US);
`Alison B. Fleming, North Attleboro,
`MA (US); Jane Hirsh, Wellesley, MA
`(US); Alexander M. Klibanov, Boston,
`MA (US)
`Assignee: COLLEGIUM
`PHARMACEUTICAL, INC., Canton,
`MA (US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`This patent is Subject to a terminal dis
`claimer.
`
`Notice:
`
`Appl. No.: 14/946,275
`
`Filed:
`
`Nov. 19, 2015
`
`Prior Publication Data
`US 2016/OO7432.6 A1
`Mar. 17, 2016
`
`Related U.S. Application Data
`Continuation of application No. 14/054.513, filed on
`Oct. 15, 2013, which is a division of application No.
`12/473,073, filed on May 27, 2009, now Pat. No.
`8,557.291, which is a continuation-in-part of
`application No. 11/149,867, filed on Jun. 10, 2005,
`now Pat. No. 7,771,707, said application No.
`12/473,073 is a continuation-in-part of application
`No. 12/112,993, filed on Apr. 30, 2008, now
`abandoned, which is a division of application No.
`10/614.866, filed on Jul. 7, 2003, now Pat. No.
`7,399,488, said application No. 12/473,073 is a
`continuation-in-part of application No. 12/112.937,
`filed on Apr. 30, 2008.
`Provisional application No. 60/579,191, filed on Jun.
`12, 2004, provisional application No. 60/463,518,
`filed on Apr. 15, 2003, provisional application No.
`60/463,514, filed on Apr. 15, 2003, provisional
`application No. 60/443,226, filed on Jan. 28, 2003,
`provisional application No. 60/436.523, filed on Dec.
`(Continued)
`
`Int. C.
`A6 IK 9/14
`A6 IK 3/485
`A6 IK 9/16
`A6 IK 9/20
`A6 IK 9/48
`A 6LX 9/50
`A6 IK3I/3
`A6 IK 3L/20
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(2006.01)
`(2006.01)
`
`A6II 45/06
`A6II 47/12
`(52) U.S. Cl.
`CPC ............ A61K 9/1617 (2013.01); A61K 9/145
`(2013.01); A61K 9/1664 (2013.01); A61 K
`9/2013 (2013.01); A61K 9/4858 (2013.01);
`A61K 9/5015 (2013.01); A61K 31/13
`(2013.01); A61K 31/20 (2013.01); A61 K
`31/485 (2013.01); A61K 45/06 (2013.01);
`A61K 47/12 (2013.01)
`Field of Classification Search
`CPC ... A61 K9/1617; A61 K 9/1664: A61K 31/485;
`A61K 47/12: A61 K 9/14
`See application file for complete search history.
`
`(58)
`
`(56)
`
`References Cited
`
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`(Continued)
`Primary Examiner — Lakshmi Channavaljala
`(74) Attorney, Agent, or Firm — Cooley LLP
`
`ABSTRACT
`(57)
`An abuse-deterrent pharmaceutical composition has been
`developed to reduce the likelihood of improper administra
`tion of drugs, especially drugs such as opioids. In a preferred
`embodiment, a drug is modified to increase its lipophilicity.
`In some embodiments the modified drug is homogeneously
`dispersed within spherical microparticles composed of a
`material that is either slowly soluble or not soluble in water.
`In some embodiments the drug containing microparticles or
`drug particles are coated with one or more coating layers,
`where at least one coating is water insoluble and/or organic
`solvent insoluble. The abuse-deterrent composition retards
`the release of drug, even if the physical integrity of the
`formulation is compromised (for example, by chopping with
`a blade or crushing) and the resulting material is placed in
`water, snorted, or Swallowed. However, when administered
`as directed, the drug is slowly released from the composition
`as the composition is passes through the GI tract.
`
`22 Claims, No Drawings
`
`Purdue 2019
`Collegium v. Purdue, PGR2018-00048
`
`

`

`US 9,592,200 B2
`Page 2
`
`Related U.S. Application Data
`23, 2002, provisional application No. 60/393,876,
`filed on Jul. 5, 2002.
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`Purdue 2019
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`
`

`

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`Purdue 2019
`Collegium v. Purdue, PGR2018-00048
`
`

`

`US 9,592,200 B2
`
`1.
`ABUSE-DETERRENT PHARMACEUTICAL
`COMPOSITIONS OF OPODS AND OTHER
`DRUGS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`2
`the rapid bioavailability of relatively high doses of drug,
`giving the abuser a “high”. Since relatively simple methods
`(crushing, grinding, chewing and/or dissolution in water)
`can be used to transform Such formulations into an abusable
`form, they provide virtually no deterrent to a potential
`abuser.
`For example, the FDA recently strengthened the warnings
`and precautions sections in the labeling of OxyContinR)
`(oxycodone HC1 controlled-release) tablets, a narcotic drug
`approved for the treatment of moderate to severe pain,
`because of continuing reports of abuse and diversion. Oxy
`ContinR contains oxycodone HCl (available in 10, 20, 40
`and 80 mg strengths), an opioid agonist with an addiction
`potential similar to that of morphine. Opioid agonists are
`Substances that act by attaching to specific proteins called
`opioid receptors, which are found in the brain, spinal cord,
`and gastrointestinal tract. When these drugs attach to certain
`opioid receptors in the brain and spinal cord they can
`effectively block the transmission of pain messages to the
`brain.
`OxyContin R is supplied in a controlled-release dosage
`form and is intended to provide up to 12 hours of relief from
`moderate to severe pain. The warning specifically states that
`the tablet must be taken whole and only by mouth. When the
`tablet is chewed or crushed and its contents are Swallowed,
`Snorted into the nostrils or dissolved and Subsequently
`injected intravenously, the controlled release mechanism is
`destroyed and a potentially lethal dose of oxycodone
`becomes bioavailable.
`In recent years, there have been numerous reports of
`Oxycodone diversion and abuse in several states. For
`example, the DEA's Office of Diversion Control reported
`700 OxyContin(R) thefts in the United States between Jan.
`2000 and Jun. 2001. Some of these reported cases have been
`associated with serious consequences including death.
`According to a report from the Abuse and Mental Health
`Services Administration, Results from the 2004 National
`Survey on Drug Use and Health: National Findings (Rock
`ville, Md.: US Dept. of Health and Human Services, Office
`of Applied Studies, 2005, p. 50), in 2004, the number of new
`non-medical users of OxyContin R) was 615,000, with an
`average age at first use of 24.5 years. Comparable data on
`past year Oxycontin R initiation are not available for prior
`years, but calendar year estimates of Oxycontin R initiation
`show a steady increase in the number of initiates from 1995,
`the year this product was first available, through 2003
`Oxycodone is a controlled substance in Schedule II of the
`Controlled Substances Act (CSA), which is administered by
`the Drug Enforcement Administration (DEA). Despite the
`fact that Schedule II provides the maximum amount of
`control possible under the CSA for approved drug products,
`in practice it is difficult for law enforcement agencies to
`control the diversion or misuse of legitimate prescriptions.
`Although abuse, misuse, and diversion are potential prob
`lems for all opioids, including Oxycodone, opioids are a
`very important part of the medical armamentarium for the
`management of pain when used appropriately under the
`careful Supervision of a physician.
`Currently available formulations for such drugs are
`designed for oral administration but are vulnerable to altera
`tions in their dissolution characteristics by physical manipu
`lation of the formulation as discussed above. Such formu
`lations are also vulnerable due to the inherently high water
`solubility of the API contained therein. Because of their
`nature, these formulations do not prevent or deter improper
`methods of administration Such as chewing, injection and
`Snorting. This represents a serious problem given the large
`
`10
`
`15
`
`This application is a continuation of U.S. Ser. No. 14/054,
`513, filed Oct. 15, 2013 which is a divisional of U.S. Ser. No.
`12/473,073, now U.S. Pat. No. 8,557,291 filed May 27,
`2009, which is a continuation-in-part of U.S. Ser. No.
`12/112,993, filed Apr. 30, 2008, which is a divisional of U.S.
`Ser. No. 10/614,866, now U.S. Pat. No. 7,399,488, filed Jul.
`7, 2003, which claims priority to U.S. Ser. No. 60/393,876
`filed Jul. 5, 2002 entitled “Abuse-Resistant Formulations of
`Oxycontin and Other Drugs” by Alexander M. Klibanov,
`Stephen L. Buchwald, Timothy M. Swager, and Whe-Yong
`Lo: U.S. Ser. No. 60/436,523 filed Dec. 23, 2002 by Alison
`B. Fleming, Roman V. Rariy, Alexander M. Klibanov, Whe
`Yong Lo, and Jane Hirsh; U.S. Ser. No. 60/443.226 filed Jan.
`28, 2003 by Jane Hirsh, Alison B. Fleming, Alexander M.
`Klibanov, and Whe-Yong Lo: U.S. Ser. No. 60/463,514 filed
`Apr. 15, 2003 by Jane C. Hirsh, Alison B. Fleming, Roman
`V. Rariy, Stephen L. Buchwald, and Timothy M. Swager;
`and U.S. Ser. No. 60/463,518 filed Apr. 15, 2003 by Jane C.
`Hirsh, Alison B. Fleming and Roman V. Rariy.
`U.S. Ser. No. 12/473,073 is also a continuation-in-part of
`U.S. Ser. No. 12/112.937, filed Apr. 30, 2008, which is a
`continuation-in-part of U.S. Ser. No. 10/614.866, now U.S.
`Pat. No. 7,399,488, filed Jul. 7, 2003, which claims priority
`to U.S. Ser. No. 60/393,876 filed Jul. 5, 2002; U.S. Ser. No.
`60/436,523 filed Dec. 23, 2002; U.S. Ser. No. 60/443,226
`filed Jan. 28, 2003: U.S. Ser. No. 60/463,514 filed Apr. 15,
`2003; and U.S. Ser. No. 60/463,518 filed Apr. 15, 2003,
`U.S. Ser. No. 12/473,073 is also a continuation-in-part of
`35
`U.S. Ser. No. 1 1/149,867, now U.S. Pat. No. 7,771,707, filed
`Jun. 10, 2005, which claims priority to U.S. Ser. No.
`60/579,191, filed Jun. 12, 2004.
`
`25
`
`30
`
`FIELD OF THE INVENTION
`
`40
`
`The present invention is generally in the field of pharma
`ceutical compositions, and specifically compositions that are
`designed to reduce the potential for improper administration
`of drugs, such as those Subject to abuse.
`
`45
`
`BACKGROUND OF THE INVENTION
`
`Oxycodone, morphine, and other opioid analgesics are
`Successful and therapeutically useful medications, e.g., as
`pain killers, when administered orally. Unfortunately, they
`also pose a severe threat for willful abuse due to their ability
`to alter mood and/or cause a sense of euphoria. Currently
`available Sustained release formulations of Such drugs,
`which contain a relatively large amount of drug meant to be
`released from the formulation over an extended time period,
`are particularly attractive to abusers since the Sustained
`release action can be destroyed by crushing or grinding the
`formulation. The resulting material (i.e., the crushed formu
`lation) can no longer control the release of drug. Depending
`on the drug, abusers can then (1) Snort the material. (2)
`swallow the material or (3) dissolve the material in water
`and Subsequently inject it intravenously. The dose of drug
`contained in the formulation is absorbed immediately
`through the nasal or GI mucosa (for Snorting or Swallowing,
`respectively) or is administered in a bolus to the systemic
`circulation (for IV injection). These abuse methods result in
`
`50
`
`55
`
`60
`
`65
`
`Purdue 2019
`Collegium v. Purdue, PGR2018-00048
`
`

`

`3
`number of legitimate prescriptions written in the US; for
`example, the medical use of opioids within the US increased
`400% from 1996 to 2000. The problems with abuse are
`significant and longstanding, and efforts to design new
`abuse-resistant or abuse-deterrent formulations have been
`largely unsuccessful.
`U.S. Pat. No. 3,980,766 to Shaw et al. (“Shaw'), U.S. Pat.
`No. 4,070,494 to Hoffmeister et al. (“Hoffmeister”), and
`U.S. Pat. No. 6,309,668 to Bastin et al. (“Bastin') describe
`formulations designed to prevent the injection of composi
`tions meant for oral administration.
`Shaw describes the incorporation of an ingestible solid
`which causes a rapid increase in Viscosity upon concentra
`tion of an aqueous solution thereof.
`Hoffmeister describes the incorporation of a non-toxic,
`water gelable material in an amount Sufficient to render the
`drug resistant to aqueous extraction.
`Bastin describes a tablet for oral administration contain
`ing two or more layers containing one or more drugs and one
`or more gelling agents within separate layers of the tablet.
`The resulting tablet forms a gel when combined with the
`Volume of water necessary to dissolve the drug allegedly
`reducing the extractability of the drug from the tablet.
`It should be noted that although these compositions
`allegedly preclude abuse by injection, this approach fails to
`prohibit rapid dissolution of the drug once the dosage form
`is crushed into Smaller particles or pieces. Thus, these
`formulations are Vulnerable to abuse by crushing and Swal
`lowing or Snorting the formulation, which are commonly
`reported methods of abuse associated with OxyContin R.
`U.S. Pat. Nos. 3,773,955 and 3,966,940 to Pachter et al.
`describe formulations containing a combination of opioid
`agonists and antagonists, in which the antagonist does not
`block the therapeutic effect when the admixture is admin
`istered orally, but which does not produce analgesia, eupho
`ria or physical dependence when administered parenterally
`by an abuser.
`U.S. Pat. No. 4,457,933 to Gordon et al. describes a
`method for decreasing both the oral and parenteral abuse
`potential of strong analgetic agents by combining an anal
`gesic dose of the analgetic agent with an antagonist in
`specific, relatively narrow ratios.
`U.S. Pat. Nos. 6,277,384, 6,375,957 and 6,475,494 to
`Kaiko et al. describe oral dosage forms including a combi
`nation of an orally active opioid agonist and an orally active
`opioid antagonist in a ratio that, when delivered orally, is
`analgesically effective but that is aversive in a physically
`dependent subject. While such a formulation may be suc
`cessful in deterring abuse, it also has the potential to produce
`adverse effects in legitimate patients.
`It is therefore an object of the present invention to provide
`a pharmaceutical composition that significantly reduces the
`potential for improper administration or use of drugs but
`which, when administered as directed, is capable of deliv
`ering a therapeutically effective dose.
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`SUMMARY OF THE INVENTION
`
`An abuse-deterrent pharmaceutical composition and
`methods of making and using thereof have been developed.
`The compositions can be used to reduce the likelihood of
`improper administration of drugs, especially drugs prone to
`abuse Such as oxycodone. The technology is useful for a
`number of other drugs where sustained release oral delivery
`is desired, and there is potential for abuse if the drug dose
`is made immediately available for nasal, intravenous (IV) or
`oral administration. In a preferred embodiment, the drug is
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`US 9,592,200 B2
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`4
`chemically modified to increase its lipophilicity and is
`formulated as microparticles. In other embodiments, the
`formulation contains lipophilic or water-insoluble materials
`or is made using a process which increases the lipophilicity
`and/or water-insolubility of the composition. In some
`embodiments, the composition additionally contains one or
`more antioxidants.
`The abuse-deterrent composition retards the release of
`drug, even if the physical integrity of the dosage form is
`compromised (for example, by chopping with a blade or
`crushing) and the resulting material is placed in water,
`snorted, or swallowed. However, when administered as
`directed, the drug is released slowly (typically over a period
`of 4-18 hours) from the composition by diffusion as the
`composition is broken down or dissolved gradually within
`the GI tract by a combination of surfactant action of bile
`acids, mechanical erosion and/or enzymatic degradation.
`In some embodiments, the individual drug-containing
`microparticles or drug particles are coated with one or more
`independent coating layers. At least one of the coating
`materials is water-insoluble and/or organic solvent-in
`soluble, so that in vitro degradation of the formulation will
`require more than one step. Thus, the drug is not easily
`extractable from the formulations by conventional chemical
`means. In contrast, when administered to the gastrointestinal
`tract via Swallowing, the drug will gradually be released
`from the coated microparticles as a consequence of diffu
`Sion, the gradual break down of the formulation via Surfac
`tant action of bile acids, mechanical erosion and/or enzy
`matic degradation.
`The pharmaceutical composition, when administered
`orally, results in a desired drug release profile. The release
`profile provides a therapeutic effect for an extended period
`of time, typically from 6 to 24 hours, preferably from 12 to
`24 hours. Additional compositions are provided which
`achieve a small immediate release dose that precedes the
`Sustained release of drug. The compositions disclosed herein
`may optionally contain a drug having no appreciable abuse
`potential.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Disclosed herein are an abuse-deterrent pharmaceutical
`compositions and the method of making and using the
`compositions.
`I. Compositions
`As used herein, "composition” refers to the drug dosage
`unit for administration to a patient. "Composition' may also
`be used in reference solely to the active ingredient, or to a
`formulation containing the active ingredient.
`The currently available Sustained release dosage forms
`containing narcotic analgesics and other drugs are subject to
`misuse, in part, because mechanical destruction of the
`dosage form exposes the encapsulated drug and allows for
`immediate dissolution of the drug into aqueous media. Three
`properties of the dosage form that contribute to this outcome
`are, (1) the high water solubility of the drug salt form; (2) the
`lack of protection offered by the hydrophilic and/or water
`soluble excipients in the formulation; and (3) the ease with
`which the surface area of the formulation is increased by
`simple chewing or crushing. Susceptibility to simple meth
`ods such as chewing or crushing is particularly problematic
`for monolithic controlled-release dosage forms. For mono
`lithic dosage forms, such as tablets, even splitting the unit
`into a few pieces (without completely crushing it) can result
`in a dramatic increase in the dissolution rate.
`
`Purdue 2019
`Collegium v. Purdue, PGR2018-00048
`
`

`

`US 9,592,200 B2
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`In the compositions disclosed herein, one or more of these
`properties are altered in order to achieve an abuse-deterrent
`composition. Specifically, in the one embodiment, the drug
`is modified to increase its lipophilicity which reduces its
`water solubility. The modified drug is then homogeneously
`dispersed within one or more carrier materials that arc either
`slowly soluble or not soluble in water. Dispersion within
`these materials further reduces the accessibility of the drug
`when crushed and exposed to an aqueous media. In some
`embodiments, the drug may be partially or fully dispersed in
`the carrier materials on a molecular level. The intimate
`mixture of modified drug and carrier materials is Subse
`quently formulated into microparticles, producing a formu
`lation whose Surface area is minimally influenced by chew
`ing or crushing.
`The terms “abuse-deterrent composition' or “abuse-de
`terrent formulation' are used interchangeably herein to refer
`to compositions that reduce the potential for improper
`administration of drugs but that deliver a therapeutically
`effective dose when administered as directed. Improper
`administration includes tampering with the dosage form
`and/or administering the drug by any route other than
`instructed. For example, for a tablet or capsule, methods of
`tampering with the dosage form may include, but are not
`limited to, breaking, crushing, grinding, chewing and/or
`dissolving the tablet or the contents of the capsule. For oral
`administration, improper administration includes adminis
`tering the drug by any route other than via Swallowing.
`The abuse deterrent compositions preferably contain a
`drug modified to increase its lipophilicity. In some embodi
`ments, the drug is homogenously dispersed within micropar
`ticles composed of a material that is either slowly soluble in
`water or water insoluble. The compositions maintain the
`slow the release of drug if the dosage form is chopped or
`crushed and the resulting material is placed in water,
`Snorted, or Swallowed since most of the drug will remain
`associated with or entrapped within portions of the core
`material of the microparticles. In other embodiments, the
`drug containing microparticles or individual drug particles
`are coated with one or more coating layers, where at least
`one coating is water insoluble and/or organic solvent
`insoluble. The components of the resulting coated micropar
`ticles are not mutually soluble in water or organic solvents,
`Such that no one solvent or enzyme solution is capable of
`dissolving the formulation in its entirety in vitro. Therefore,
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`extraction of the drug from the formulation cannot be carried
`out in one step. However, when administered as directed, the
`drug is slowly released from the formulation via diffusion
`and erosion within the environment of the gastrointestinal
`tract.
`A. Drugs to be Formulated
`There are many drugs which can be delivered using the
`compositions described herein. The Controlled Substances
`Act (CSA), Title II of the Comprehensive Drug Abuse
`Prevention and Control Act of 1970, places all substances
`that are regulated under existing federal law into one of five
`schedules based upon the Substance's medicinal value,
`harmfulness, and potential for abuse or addiction. Drugs that
`are preferred include those classified as Schedule II, III, IV
`and V drugs. Drugs that are most preferable include those,
`like oxycodone, that are currently formulated as Sustained or
`controlled release compositions, where drug release is
`intended to occur over a prolonged period of time through
`the gastrointestinal tract, and immediate or burst release, for
`example, by inhalation or injection, is undesirable. As used
`herein, drugs prone to abuse refer to controlled Substance
`specified as schedule II, III, IV and V drugs.
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`The terms “drug”, “active agent, and “pharmacologically
`active agent” are used interchangeably herein to refer to a
`chemical compound that induces a desired pharmacological,
`physiological effect. The terms also encompass pharmaceu
`tically acceptable derivatives of those active agents specifi
`cally mentioned herein, including, but not limited to, salts,
`Solvates, hydrates, complexes with one or more molecules,
`prodrugs, active metabolites, analogs, and the like. When the
`terms 'active agent”, “pharmacologically active agent' and
`'drug are used, or when a particular drug, Such as oxyco
`done, is identified, it is to be understood as including the
`active agent per se as well as pharmaceutically acceptable
`salts, Solvates, hydrates, complexes with one or more mol
`ecules, prodrugs, active metabolites, and analogs.
`Examples of preferred drugs include, 1-phenylcyclohex
`ylamine, 1-piperidinocyclohexanecarbonitrile, alfentanil,
`alphacetylmethadol, alphaprodine, alprazolam, amobarbital,
`amphetamine, anilleridine, apomorphine, aprobarbital, bar
`bital, barbituric acid derivative, bemidone, benzoylecgo
`nine, benZphetamine, betacetylmethadol, betaprodine, beZ
`itramide, bromazepam, buprenorphine, butabarbital,
`butalbital, butorphanol, camazepam, cathine, chloral,
`chlordiazepoxide, clobazam, clonazepam, cloraZepate, clo
`tiazepam, cloxazolam, cocaine, codeine, chlorphentermine,
`delorazepam, dexfenfluramine, dextromoramide, dextro
`propoxyphen,
`dezocine,
`diazepam,
`diethylpropion,
`difenoxin, dihydrocodeine, dihydromorphine, dioxaphentyl
`butyrate, dipanone, diphenoxylate, diprenorphine, ecgonine,
`enadoline, eptazocine, estazolam, ethoheptazine, ethyl
`loflazepate, ethylmorphine, etorphine, femproponex, fen
`camfamin, fenfluramine, fentanyl, fludiazepam, flunitraze
`pam, flurazepam, glutethimide, halazepam, haloxazolam,
`hexalgon, hydrocodone, hydromorphone, isomethadone,
`hydrocodone, ketamine, ketazolam, ketobemidone, leva
`none, levoalphacetylmethadol, levomethadone, levometh
`adyl acetate, levomethorphan, levorphanol, lofentanil, lop
`eramide, loprazolam, lorazepam, lormetazepam, lysergic
`acid, lysergic acid amide, mazindol, medazepam,
`mefenorex, meperidine, meptazinol, metazocine, metha
`done, methamphetamine, methohexital, methotrimeprazine,
`methyldihydromorphinone, methylphenidate, methylpheno
`barbital, metopon, morphine, nabilone, nalbuphine, nal
`bupine, nalorphine, narceline, nefopam, nicomorphine, nim
`etazepam,
`nitrazepam,
`nordiazepam,
`normethadone,
`normorphine, oxazepam, oxazolam, oxycodone, oxymor
`phone, pentazocine, pentobarbital, phenadoxone, phenaZo
`cine, phencyclidine, phendimetrazine, phenmetrazine, phen
`eridine,
`piminodine,
`prodilidine,
`properidine,
`propoxyphene, racemethorphan, racemorphan, racemor
`amide, remifentanil, secobarbital, Sufentanil, talbutal, the
`baine, thiamylal, thiopental, tramadol, trimeperidine, and
`Vinbarbital.
`In addition to the compounds above, the following sched
`uled drugs may be incorporated into the composition; allo
`barbitone, alprazolam, amylobarbitone, aprobarbital, barbi
`tal, barbitone, benzphetamine, brallobarbital, bromazepam,