US009248195B2

(12) United States Patent (10) Patent No.: US 9.248,195 B2

Rariyet al. (45) Date of Patent: *Feb. 2, 2016
(54) ABUSE-DETERRENT PHARMACEUTICAL (52) U.S. Cl.
COMPOSITIONS OF OPODS AND OTHER CPC ............... A61K 47/46 (2013.01); A61 K9/1617
DRUGS (2013.01); A61 K9/5026 (2013.01); A61 K
31/485 (2013.01); A61K 45/06 (2013.01);
(71) Applicant: COLLEGIUM PHARMACEUTICAL, A61K47/12 (2013.01)
INC., Canton, MA (US) (58) Field of Classification Search
(72) Inventors: Roman V. Rariy, Allston, MA (US); CPC ......... A61K 9/141; A61 K9/148: A61 K9/20:
Alison B. Fleming, North Attleboro, MA A61 K9/48: A61 K9/145; A61 K9/16: A61 K
(US); Jane Hirsh, Wellesley, MA (US); 9/1617; A61 K9/50: A61 K9/2013: A61 K
Alexander M. Klibanov, Boston, MA 9/2077; A61K31/135; A61K31/485
(US) See application file for complete search history.
(73) Assignee: Collegium Pharmaceutical, Inc., (56) References Cited
Canton, MA (US)
U.S. PATENT DOCUMENTS
(*) Notice: Subject to any disclaimer, the term of this
patent is extended or adjusted under 35 2,404,319 A 7, 1946 Shelton
U.S.C. 154(b) by 114 days. 3,015,128 A 1/1962 Somerville, Jr.
3,336,200 A 8, 1967 Krause et al.
This patent is Subject to a terminal dis 3,773.955 A 11/1973 Pachter et al.
claimer. 3,966,940 A 6, 1976 Pachter et al.
3,980,766 A 9, 1976 Shaw et al.
4,070,494 A 1/1978 Hoffmeister et al.
(21) Appl. No.: 14/054,513
(Continued)
(22) Filed: Oct. 15, 2013
FOREIGN PATENT DOCUMENTS
(65) Prior Publication Data
EP O253104 A1 1, 1988
US 2014/O 105987 A1 Apr. 17, 2014 EP O375,063 A1 6, 1990
(Continued)
Related U.S. Application Data OTHER PUBLICATIONS
(60) Division of application No. 12/473,073, filed on May “Castor oil, hydrogenated.” European Pharmacopoeia V.5, p. 1197.-
27, 2009, now Pat. No. 8,557,291, which is a 1198 (2005).
continuation-in-part of application No. 1 1/149,867,
filed on Jun. 10, 2005, now Pat. No. 7,771,707, said (Continued)
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. Primary Examiner — Lakshmi Channavaljala
10/614.866, filed on Jul. 7, 2003, now Pat. No. (74) Attorney, Agent, or Firm — Cooley LLP
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, which is a continuation-in-part (57) ABSTRACT
of application No. 10/614,866. An abuse-deterrent pharmaceutical composition has been
(60) Provisional application No. 60/579,191, filed on Jun. developed to reduce the likelihood of improper administra
12, 2004, provisional application No. 60/463,518, tion of drugs, especially drugs such as opioids. In a preferred
filed on Apr. 15, 2003, provisional application No. embodiment, a drug is modified to increase its lipophilicity. In
60/463,514, filed on Apr. 15, 2003, provisional Some embodiments the modified drug is homogeneously dis
application No. 60/443,226, filed on Jan. 28, 2003, persed within spherical microparticles composed of a mate
provisional application No. 60/436,523, filed on Dec. rial that is either slowly soluble or not soluble in water. In
23, 2002, provisional application No. 60/393,876, Some embodiments the drug containing microparticles or
filed on Jul. 5, 2002. drug particles are coated with one or more coating layers,
where at least one coating is water insoluble and/or organic
(51) Int. Cl. solvent insoluble. The abuse-deterrent composition retards
A6 IK 9/14 (2006.01) the release of drug, even if the physical integrity of the for
A6 IK9/20 (2006.01) mulation is compromised (for example, by chopping with a
A6 IK9/48 (2006.01) blade or crushing) and the resulting material is placed in
A6 IK 47/46 (2006.01) water, snorted, or Swallowed. However, when administered as
A6 IK 9/16 (2006.01) directed, the drug is slowly released from the composition as
A 6LX 9/50 (2006.01) the composition is passes through the GI tract.
A6 IK3I/485 (2006.01)
A6 IK 45/06 (2006.01)
A6 IK 47/12 (2006.01) 22 Claims, No Drawings
 US 9.248,195 B2
Page 2

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 US 9.248,195 B2
1. 2
ABUSE-DETERRENT PHARMACEUTICAL “high”. Since relatively simple methods (crushing, grinding,
COMPOSITIONS OF OPODS AND OTHER chewing and/or dissolution in water) can be used to transform
DRUGS such formulations into an abusable form, they provide virtu
ally no deterrent to a potential abuser.
CROSS REFERENCE TO RELATED For example, the FDA recently strengthened the warnings
APPLICATIONS and precautions sections in the labeling of OxyContin R (oxy
codone HC1 controlled release) tablets, a narcotic drug
This application is a divisional of U.S. Ser. No. 12/473,073, approved for the treatment of moderate to severe pain,
now U.S. Pat. No. 8,557.291 filed May 27, 2009, which is a because of continuing reports of abuse and diversion. Oxy
continuation-in-part of U.S. Ser. No. 12/112,993, filed Apr. 10 ContinR contains oxycodone HCl (available in 10, 20, 40 and
30, 2008, which is a divisional of U.S. Ser. No. 10/614,866, 80 mg strengths), an opioid agonist with an addiction poten
now U.S. Pat. No. 7,399,488, filed Jul. 7, 2003, which claims tial similar to that of morphine. Opioid agonists are Sub
priority to U.S. Ser. No. 60/393,876 filed Jul. 5, 2002 entitled stances that act by attaching to specific proteins called opioid
“Abuse-Resistant Formulations of Oxycontin and Other receptors, which are found in the brain, spinal cord, and
Drugs” by Alexander M. Klibanov, Stephen L. Buchwald, 15 gastrointestinal tract. When these drugs attach to certain
Timothy M. Swager, and Whe-Yong Lo: U.S. Ser. No. opioid receptors in the brain and spinal cord they can effec
60/436,523 filed Dec. 23, 2002 by Alison B. Fleming, Roman tively block the transmission of pain messages to the brain.
V. Rariy, Alexander M. Klibanov, Whe-Yong Lo, and Jane OxyContin R is supplied in a controlled-release dosage
Hirsh; U.S. Ser. No. 60/443,226 filed Jan. 28, 2003 by Jane form and is intended to provide up to 12 hours of relief from
Hirsh, Alison B. Fleming, Alexander M. Klibanov, and Whe moderate to severe pain. The warning specifically states that
Yong Lo: U.S. Ser. No. 60/463,514 filed Apr. 15, 2003 by Jane the tablet must be taken whole and only by mouth. When the
C. Hirsh, Alison B. Fleming, Roman V. Rariy, Stephen L. tablet is chewed or crushed and its contents are swallowed,
Buchwald, and Timothy M. Swager; and U.S. Ser. No. Snorted into the nostrils or dissolved and Subsequently
60/463,518 filed Apr. 15, 2003 by Jane C. Hirsh, Alison B. injected intravenously, the controlled release mechanism is
Fleming and Roman V. Rariy. 25 destroyed and a potentially lethal dose of oxycodone
U.S. Ser. No. 12/473,073 also is a continuation-in-part of becomes bioavailable.
Ser. No. 12/112.937, filed Apr. 30, 2008, which is a continu In recent years, there have been numerous reports of Oxy
ation-in-part of U.S. Ser. No. 10/614.866, now U.S. Pat. No. codone diversion and abuse in several states. For example, the
7,399,488, filed Jul. 7, 2003, which claims priority to U.S. DEA's Office of Diversion Control reported 700 OxyCon
Ser. No. 60/393,876 filed Jul. 5, 2002; U.S. Ser. No. 60/436, 30 tin R thefts in the United States between January 2000 and
523 filed Dec. 23, 2002; U.S. Ser. No. 60/443,226 filed Jan. June 2001. Some of these reported cases have been associated
28, 2003: U.S. Ser. No. 60/463,514 filed Apr. 15, 2003; and with serious consequences including death. According to a
U.S. Ser. No. 60/463,518 filed Apr. 15, 2003. report from the Abuse and Mental Health Services Adminis
U.S. Ser. No. 12/473,073 is also a continuation-in-part of tration, Results from the 2004 National Survey on Drug Use
U.S. Ser. No. 1 1/149,867, now U.S. Pat. No. 7,771,707, filed 35 and Health: National Findings (Rockville, Md.: US Dept. of
Jun. 10, 2005, which claims priority to U.S. Ser. No. 60/579, Health and Human Services, Office of Applied Studies, 2005,
191, filed Jun. 12, 2004. 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
FIELD OF THE INVENTION 24.5 years. Comparable data on past year Oxycontin R initia
40 tion are not available for prior years, but calendar year esti
The present invention is generally in the field of pharma mates of Oxycontin R initiation show a steady increase in the
ceutical compositions, and specifically compositions that are number of initiates from 1995, the year this product was first
designed to reduce the potential for improper administration available, through 2003
of drugs, such as those subject to abuse. Oxycodone is a controlled substance in Schedule II of the
45 Controlled Substances Act (CSA), which is administered by
BACKGROUND OF THE INVENTION the Drug Enforcement Administration (DEA). Despite the
fact that Schedule II provides the maximum amount of con
Oxycodone, morphine, and other opioid analgesics are trol possible under the CSA for approved drug products, in
Successful and therapeutically useful medications, e.g., as practice it is difficult for law enforcement agencies to control
pain killers, when administered orally. Unfortunately, they 50 the diversion or misuse of legitimate prescriptions. Although
also pose a severe threat for willful abuse due to their ability abuse, misuse, and diversion are potential problems for all
to alter mood and/or cause a sense of euphoria. Currently opioids; including Oxycodone, opioids are a very important
available Sustained release formulations of such drugs, which part of the medical armamentarium for the management of
contain a relatively large amount of drug meant to be released pain when used appropriately under the careful Supervision of
from the formulation over an extended time period, are par 55 a physician.
ticularly attractive to abusers since the Sustained release Currently available formulations for such drugs are
action can be destroyed by crushing or grinding the formula designed for oral administration but are vulnerable to alter
tion. The resulting material (i.e., the crushed formulation) can ations in their dissolution characteristics by physical manipu
no longer control the release of drug. Depending on the drug, lation of the formulation as discussed above. Such formula
abusers can then (1) Snort the material. (2) Swallow the mate 60 tions are also vulnerable due to the inherently high water
rial or (3) dissolve the material in water and subsequently solubility of the API contained therein. Because of their
inject it intravenously. The dose of drug contained in the nature, these formulations do not prevent or deter improper
formulation is absorbed immediately through the nasal or GI methods of administration Such as chewing, injection and
mucosa (for Snorting or Swallowing, respectively) or is Snorting. This represents a serious problem given the large
administered in a bolus to the systemic circulation (for IV 65 number of legitimate prescriptions written in the US; for
injection). These abuse methods result in the rapid bioavail example, the medical use of opioids within the US increased
ability of relatively high doses of drug, giving the abuser a 400% from 1996 to 2000. The problems with abuse are sig
 US 9.248,195 B2
3 4
nificant and longstanding, and efforts to design new abuse made using a process which increases the lipophilicity and/or
resistant or abuse-deterrent formulations have been largely water-insolubility of the composition. In some embodiments,
unsuccessful. the composition additionally contains one or more antioxi
U.S. Pat. No. 3,980,766 to Shaw et al. (“Shaw'), U.S. Pat. dants.
No. 4,070,494 to Hoffmeisteret al. (“Hoffmeister), and U.S. The abuse-deterrent composition retards the release of
Pat. No. 6,309,668 to Bastinet al. (“Bastin') describe formu drug, even if the physical integrity of the dosage form is
lations designed to prevent the injection of compositions compromised (for example, by chopping with a blade or
meant for oral administration. crushing) and the resulting material is placed in water,
Shaw describes the incorporation of an ingestible solid snorted, or swallowed. However, when administered as
which causes a rapid increase in viscosity upon concentration 10 directed, the drug is released slowly (typically over a period
of an aqueous solution thereof. of 4-18 hours) from the composition by diffusion as the
Hoffmeister describes the incorporation of a non-toxic, composition is broken down or dissolved gradually within the
water getable material in an amount Sufficient to render the GI tract by a combination of surfactant action of bile acids,
drug resistant to aqueous extraction. mechanical erosion and/or enzymatic degradation.
Bastin describes a tablet for oral administration containing 15 In some embodiments, the individual drug-containing
two or more layers containing one or more drugs and one or microparticles or drug particles are coated with one or more
more gelling agents within separate layers of the tablet. The independent coating layers. At least one of the coating mate
resulting tablet forms a gel when combined with the volume rials is water-insoluble and/or organic solvent-insoluble, so
of water necessary to dissolve the drug allegedly reducing the that in vitro degradation of the formulation will require more
extractability of the drug from the tablet. than one step. Thus, the drug is not easily extractable from the
It should be noted that although these compositions alleg formulations by conventional chemical means. In contrast,
edly preclude abuse by injection, this approach fails to pro when administered to the gastrointestinal tract via Swallow
hibit rapid dissolution of the drug once the dosage form is ing, the drug will gradually be released from the coated
crushed into Smaller particles or pieces. Thus, these formula microparticles as a consequence of diffusion, the gradual
tions are Vulnerable to abuse by crushing and Swallowing or 25 break down of the formulation via surfactant action of bile
Snorting the formulation, which are commonly reported acids, mechanical erosion and/or enzymatic degradation.
methods of abuse associated with OxyContinR). The pharmaceutical composition, when administered
U.S. Pat. Nos. 3,773,955 and 3,966,940 to Pachter et al. orally, results in a desired drug release profile. The release
describe formulations containing a combination of opioid profile provides a therapeutic effect for an extended period of
agonists and antagonists, in which the antagonist does not 30 time, typically from 6 to 24 hours, preferably from 12 to 24
block the therapeutic effect when the admixture is adminis hours. Additional compositions are provided which achieve a
tered orally, but which does not produce analgesia, euphoria Small immediate release dose that precedes the sustained
orphysical dependence when administered parenterally by an release of drug. The compositions disclosed herein may
abuser. optionally contain a drug having no appreciable abuse poten
U.S. Pat. No. 4,457,933 to Gordonetal, describes a method 35 tial.
for decreasing both the oral and parenteral abuse potential of
strong analgetic agents by combining an analgesic dose of the DETAILED DESCRIPTION OF THE INVENTION
analgetic agent with an antagonist in specific, relatively nar
row ratios. Disclosed herein are an abuse-deterrent pharmaceutical
U.S. Pat. Nos. 6,277,384, 6,375,957 and 6,475,494 to 40 compositions and the method of making and using the com
Kaiko et al. describe oral dosage forms including a combina positions.
tion of an orally active opioid agonist and an orally active I. Compositions
opioid antagonist in a ratio that, when delivered orally, is As used herein, "composition” refers to the drug dosage
analgesically effective but that is aversive in a physically unit for administration to a patient. "Composition' may also
dependent subject. While such a formulation may be success 45 be used in reference solely to the active ingredient, or to a
ful in deterring abuse, it also has the potential to produce formulation containing the active ingredient.
adverse effects in legitimate patients. The currently available Sustained release dosage forms
It is therefore an object of the present invention to provide containing narcotic analgesics and other drugs are subject to
a pharmaceutical composition that significantly reduces the misuse, in part, because mechanical destruction of the dosage
potential for improper administration or use of drugs but 50 form exposes the encapsulated drug and allows for immediate
which, when administered as directed, is capable of deliver dissolution of the drug into aqueous media. Three properties
ing a therapeutically effective dose. of the dosage form that contribute to this outcome are, (1) the
high water solubility of the drug salt form; (2) the lack of
SUMMARY OF THE INVENTION protection offered by the hydrophilic and/or water soluble
55 excipients in the formulation; and (3) the ease with which the
An abuse-deterrent pharmaceutical composition and meth Surface area of the formulation is increased by simple chew
ods of making and using thereof have been developed. The ing or crushing. Susceptibility to simple methods such as
compositions can be used to reduce the likelihood of chewing or crushing is particularly problematic for mono
improper administration of drugs, especially drugs prone to lithic controlled-release dosage forms. For monolithic dosage
abuse Such as oxycodone. The technology is useful for a 60 forms, such as tablets, even splitting the unit into a few pieces
number of other drugs where sustained release oral delivery is (without completely crushing it) can result in a dramatic
desired, and there is potential for abuse if the drug dose is increase in the dissolution rate.
made immediately available for nasal, intravenous (IV) or In the compositions disclosed herein, one or more of these
oral administration. In a preferred embodiment, the drug is properties are altered in order to achieve an abuse-deterrent
chemically modified to increase its lipophilicity and is for 65 composition. Specifically, in the one embodiment, the drug is
mulated as microparticles. In other embodiments, the formu modified to increase its lipophilicity which reduces its water
lation contains lipophilic or water-insoluble materials or is solubility. The modified drug is then homogeneously dis
 US 9.248,195 B2
5 6
persed within one or more carrier materials that are either Solvates, hydrates, complexes with one or more molecules,
slowly soluble or not soluble in water. Dispersion within prodrugs, active metabolites, analogs, and the like. When the
these materials further reduces the accessibility of the drug terms 'active agent”, “pharmacologically active agent” and
when crushed and exposed to an aqueous media. In some 'drug are used, or when a particular drug, Such as oxyc
embodiments, the drug may be partially or fully dispersed in 5 odone, is identified, it is to be understood as including the
the carrier materials on a molecular level. The intimate mix active agent per se as well as pharmaceutically acceptable
ture of modified drug and carrier materials is Subsequently salts, Solvates, hydrates, complexes with one or more mol
formulated into microparticles, producing a formulation ecules, prodrugs, active metabolites, and analogs.
whose Surface area is minimally influenced by chewing or Examples of preferred drugs include, 1-phenylcyclohexy
crushing. 10 lamine, 1-piperidinocyclohexanecarbonitrile, alfentanil,
The terms “abuse-deterrent composition” or “abuse-deter alphacetylmethadol, alphaprodine, alprazolam, amobarbital,
rent formulation' are used interchangeably herein to refer to amphetamine, anilleridine, apomorphine, aprobarbital, bar
compositions that reduce the potential for improper adminis bital, barbituric acid derivative, bemidone, benzoylecgonine,
tration of drugs but that deliver a therapeutically effective benzphetamine, betacetylmethadol, betaprodine, bezitra
dose when administered as directed. Improper administration 15 mide, bromazepam, buprenorphine, butabarbital, butalbital,
includes tampering with the dosage form and/or administer butorphanol, camazepam, cathine, chloral, chlordiazepoxide,
ing the drug by any route other than instructed. For example, clobazam, clonazepam, cloraZepate, clotiazepam, clox
for a tablet or capsule, methods of tampering with the dosage aZolam, cocaine, codeine, chlorphentermine, delorazepam,
form may include, but are not limited to, breaking, crushing, dexfenfluramine, dextromoramide, dextropropoxyphen,
grinding, chewing and/or dissolving the tablet or the contents dezocine, diazepam, diethylpropion, difenoxin, dihydroco
of the capsule. For oral administration, improper administra deine, dihydromorphine, dioxaphenty1 butyrate, dipanone,
tion includes administering the drug by any route other than diphenoxylate, diprenorphine, ecgonine, enadoline, eptaZo
via Swallowing. cine, estaZolam, ethoheptazine, ethyl loflazepate, ethylmor
The abuse deterrent compositions preferably contain a phine, etorphine, femproponex, fencamfamin, fenfluramine,
drug modified to increase its lipophilicity. In some embodi 25 fentanyl, fludiazepam, flunitrazepam, flurazepam, glutethim
ments, the drug is homogenously dispersed within micropar ide, halazepam, haloxazolam, hexalgon, hydrocodone,
ticles composed of a material that is either slowly soluble in hydromorphone, isomethadone, hydrocodone, ketamine,
water or water insoluble. The compositions maintain the slow ketazolam, ketobemidone, levanone, levoalphacetylmeth
the release of drug if the dosage form is chopped or crushed adol, levomethadone, levomethadyl acetate, levomethor
and the resulting material is placed in water, Snorted, or Swal 30 phan, levorphanol, lofentanil, loperamide, loprazolam,
lowed since most of the drug will remain associated with or lorazepam, lormetazepam, lysergic acid, lysergic acid amide,
entrapped within portions of the core material of the micro mazindol, medazepam, mefenorex, meperidine, meptazinol,
particles. In other embodiments, the drug containing micro metazocine, methadone, methamphetamine, methohexital,
particles or individual drug particles are coated with one or methotrimeprazine, methyldihydromorphinone, meth
more coating layers, where at least one coating is water 35 ylphenidate, methylphenobarbital, metopon, morphine,
insoluble and/or organic solvent insoluble. The components nabilone, nalbuphine, nalbupine, nalorphine, narceline, nefo
of the resulting coated microparticles are not mutually pam, nicomorphine, nimetazepam, nitrazepam, nordiaz
soluble in water or organic solvents, such that no one solvent epam, normethadone, normorphine, oxazepam, oxazolam,
orenzyme solution is capable of dissolving the formulation in oxycodone, oxymorphone, pentazocine, pentobarbital, phen
its entirety in vitro. Therefore, extraction of the drug from the 40 adoxone, phenazocinc, phencyclidine, phendimetrazine,
formulation cannot be carried out in one step. However, when phenmetrazine, pheneridine, piminodine, prodilidine, prope
administered as directed, the drug is slowly released from the ridine, propoxyphene, racemethorphan, racemorphan,
formulation via diffusion and erosion within the environment racemoramide, remifentanil, secobarbital, Sufentanil, talb
of the gastrointestinal tract. utal, thebaine, thiamylal, thiopental, tramadol, trimeperidine,
A. Drugs to be Formulated 45 and vinbarbital.
There are many drugs which can be delivered using the In addition to the compounds above, the following sched
compositions described herein. The Controlled Substances uled drugs may be incorporated into the composition: allo
Act (CSA), Title II of the Comprehensive Drug Abuse Pre barbitone, alprazolam, amylobarbitone, aprobarbital, bar
vention and Control Act of 1970, places all substances that are bital, barbitone, benzphetamine, brallobarbital,
regulated under existing federal law into one offive schedules 50 bromazepam, brotizolam, buspirone, butalbital, butobarbi
based upon the Substance's medicinal value, harmfulness, tone, butorphanol, camazepam, captodiame, carbromal,
and potential for abuse or addiction. Drugs that are preferred carfentanil, carpipramine, cathine, chloral, chloral betaine,
include those classified as Schedule II, III, IV and V drugs. chloral hydrate, chloralose, chlordiazepoxide, chlorhexadol,
Drugs that are most preferable include those, like oxycodone, chlormethiazole edisylate, chlormeZanone, cinolazepam,
that are currently formulated as sustained or controlled 55 clobazam, potassium cloraZepate, clotiazepam, cloxazolam,
release compositions, where drug release is intended to occur cyclobarbitone, delorazepam, dexfenfluramine, diazepam,
over a prolonged period of time through the gastrointestinal diethylpropion, difebarbamate, difenoxin, enciprazine, esta
tract, and immediate or burst release, for example, by inhala Zolam, ethyl loflazepate, etizolam, febarbamate, fencam
tion or injection, is undesirable. As used herein, drugs prone famin, fenfluramine, fenproporex, fluianisone, fludiazepam,
to abuse refer to controlled substance specified as schedule II, 60 flunitraam, flunitrazepam, flurazepam, flutoprazepam,
III, IV and V drugs. gepirone, glutethimide, halazepam, haloxazolam, hexobarbi
The terms “drug”, “active agent, and “pharmacologically tone, ibomal, ipsapirone, ketazolam, loprazolam mesylate,
active agent” are used interchangeably herein to refer to a lorazepam, lormetazepam, mazindol, mebutamate,
chemical compound that induces a desired pharmacological, medazepam, inefenorex, mephobarbital, meprobamate,
physiological effect. The terms also encompass pharmaceu 65 metaclazepam, methaqualone, methohexital, methylpen
tically acceptable derivatives of those active agents specifi tynol, methylphenobarbital, midazolam, milaZolam, mor
cally mentioned herein, including, but not limited to, salts, phine, nimetazepam, nitrazepam, nordiazepam, oxazepam,
 US 9.248,195 B2
7 8
oxazolam, paraldehyde, pemoline, pentabarbitone, pentazo tampering by mechanisms that are intended to increase the
cine, pentobarbital, phencyclidine, phenobarbital, phendime Surface area and, consequently, the release rate of drug (Such
trazine, phenmetrazine, phenprobamate, phentermine, phen as chewing or crushing).
yacetone, pinazepam, pipradol, prazepam, proxibarbal, The terms "lipophilic derivative' and “lipophililic drug
quazepam, quinalbaritone, secobarbital, secbutobarbitone, derivative', as used herein, refer to derivatives of the drug that
Sibutramine, temazepam, tetrazepam, triazolam, triclofos, are less soluble or dissolve less rapidly in water than the most
Zalepan, Zaleplon, Zolazepam, Zolpidem, and Zopiclone. Cer soluble salt of the drug; the most soluble salt being selected
tain compounds described herein may exist in particular geo from either base addition salts (for acidic drugs) or acid
metric or stereoisomeric forms. The composition disclosed 10
addition salts (for basic drugs), such as by the addition of
herein contemplates all such compounds, including cis- and inorganic acids. The examples of the latter include but are not
trans-isomers, R- and S-enantiomers, diastereomers, (D)-iso limited to hydrohalates, sulfates, and nitrates. Some of the
mers, (L)-isomers, the racemic mixtures thereof, compounds methods that can be used to alter the drug's lipophilicity are
of different spacial conformations, and other mixtures outlined below. It is understood that two or more approaches
thereof, as falling within the scope of the invention. Addi 15 can be combined to achieve a desired solubility profile.
tional asymmetric carbon atoms may be present in a Substitu Methods for Increasing Lipophilicity
ent such as an alkyl group. All Such isomers, as well as In one embodiment, the drug is made more lipophilic by
mixtures thereof, are intended to be included in this invention. eliminating or reducing the overall charge of the drug mol
As used herein, “pharmaceutically acceptable salts' refer ecule. For example, for a basic drug, a water Soluble salt (Such
to derivatives of the disclosed compounds wherein the parent as hydrochloride, Sulfate, or maleate) can be converted to a
compound is modified by making acid or base salts thereof. free base using techniques known in the art. In the case of an
Examples of pharmaceutically acceptable salts include, but acidic drug, a water Soluble salt (Such as Sodium, potassium,
are not limited to, mineral or organic acid salts of basic or the like) can be converted to a free acid.
residues such as amines; alkali or organic salts of acidic In another embodiment, the drug's lipophilicity is
residues such as carboxylic acids; and the like. The pharma 25 increased by forming a salt between a drug molecule and a
ceutically acceptable salts include the conventional non-toxic charged lipophilic compound. In this case the lipophilicity of
salts or the quaternary ammonium salts of the parent com the resulting salt can be manipulated by varying the lipophi
pound formed, for example, from non-toxic inorganic or licity of the counter-ion. In general, lipophilic acids oramines
organic acids. For example. Such conventional non-toxic salts 30
with chain lengths between Cs-Co are lipophilic counter-ion
include those derived from inorganic acids such as hydro candidates. Some specific examples include, but are not lim
chloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric ited to, linoleic acid, octanoic acid, lauric acid, Stearic acid,
and the like; and the salts prepared from organic acids such as palmitic acid, myristic acid, oleic acid, octyl amine, lauryl
acetic, propionic, Succinic, glycolic, Stearic, myristic, palm amine, Stearyl amine, palmityl amine, linoleyl amine, and
itic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, 35 oleylamine. Other salts which may increase lipophilicity and,
hydroxymaleic, phenylacetic, glutamic, benzoic, Salicylic, hence, lipid solubility relative to the parent drug compound
Sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulfonic, meth include, but are not limited to, pectinate, tannate, phytate,
anesulfonic, ethane disulfonic, oxalic, and isethionic. salicylate, Saccharinate, acesulfamate, gallate, and terephtha
The pharmaceutically acceptable salts of the compounds late salts.
can be synthesized from the parent compound, which con 40 In still a further embodiment, drug lipophilicity is
tains a basic oracidic moiety, by conventional chemical meth increased via complexation with poorly water-soluble cyclo
ods. Generally, such salts can be prepared by reacting the free dextrin. For example, ethylated beta-cyclodextrin has been
acid or base forms of these compounds with a stoichiometric shown to decrease aqueous solubility of complexed drug
amount of the appropriate base or acid in water or in an molecules.
organic solvent, or in a mixture of the two: generally, non 45 In another embodiment, a drug is covalently modified to
aqueous media like ether, ethyl acetate, ethanol, isopropanol, increase its lipophilicity. For example, a lipophilic compound
oracetonitrile are preferred. Lists of suitable salts are found in can be covalently attached to a drug molecule via an ester or
Remington’s Pharmaceutical Sciences, 20th ed., Lippincott amide linkage. Such drug derivatives are cleaved in Vivo, thus
Williams & Wilkins, Baltimore, Md., 2000, p. 704, the dis releasing the parent compound.
closure of which is hereby incorporated by reference. 50 C. Drug Containing Microparticles
Optionally, the composition described herein can further In Some embodiments, the drug is formulated with a carrier
include a drug having no appreciable abuse potential. material to form microparticles. As used herein, the term
B. Drug Solubility Modification “microparticle' refers to a composition containing a drug
In some embodiments, the solubility characteristics of a dispersed within a carrier material and “coated microparticle'
drug are altered. Modification of the drug to produce a more 55 refers to a composition containing a drug containing micro
lipophilic derivative serves to reduce the water solubility of particle or a drug particle coated with one or more coating
the drug and thus reduce the aqueous extractability of the layers of material. Microparticles and coated microparticles
drug. Furthermore, if the drug is made more lipophilic, it can have a size range of 10 to 3000 microns in diameter, more
be solubilized in a molten fatty substance or wax like mixture, preferably from 10 to 1000 microns.
rather than physically dispersed in a particulate form. Solu 60 Within microparticles, the drug is preferably homoge
bilization of the drug enhances the abuse-deterrent properties neously dispersed in the form of fine particles within the
of microparticles formulated from the mixture as it is difficult carrier material. More preferably, the drug is partially solu
to extract drug from an intimately dispersed composition. bilized in a molten carrier material or partially dissolved with
Furthermore, Such a composition is capable of controlling the the carrier material in a mutual solvent during the formulation
release of drug, even when formulated into relatively small 65 of the microparticles. Most preferably, the drug is completely
microparticles. Microparticulate compositions, in contrast to solubilized in the molten carrier material or completely dis
monolithic compositions, are inherently less Susceptible to solved with the carrier material in a co-solvent during the
 US 9.248,195 B2
10
formulation of the microparticles. This is accomplished dissolved in the carrier material, or a mixture thereof. Micro
through the selection of materials and the manner in which particles can be subsequently formulated through several
they are processed. methods including, but not limited to, congealing, extrusion,
Carrier materials appropriate for the fabrication of drug spray chilling or aqueous dispersion. In a preferred process,
containing microparticles either dissolve slowly in water or 5 one or more carrier materials are heated above its melting
are insoluble in water. As used herein, the term “dissolves temperature, the drug is added, and the molten carrier mate
slowly in water refers to materials that are not completely rial-drug mixture is congealed to form Solid, spherical par
dissolved in water within a period of 30 minutes. Suitable ticles via a spraying or spinning cylinder or disk processes.
materials include fats, fatty Substances, waxes, wax-like Sub Alternatively, the molten carrier material-drug mixture can be
stances and mixtures thereof. Suitable fats and fatty sub 10 extruded and pelletized to form pellets or beads. Detailed
stances include fatty alcohols (such as lauryl, myristyl descriptions of these processes can be found in "Reming
Stearyl, cetyl or cetostearyl alcohol), fatty acids and deriva ton The science and practice of pharmacy”, 20" Edition,
tives, including but not limited, to fatty acid esters, fatty acid Jennaro et. Al. (Phila, Lippencott, Williams, and Wilkens,
glycerides (mono-, di- and tri-glycerides), and hydrogenated 2000. Spinning disk processes are described in U.S. Pat. Nos.
fats. Specific examples include, but are not limited to hydro 15 3,015,128 and 7,261,529.
genated vegetable oil, hydrogenated cottonseed oil, hydroge In a preferred process, spherical particles are produced.
nated castor oil, hydrogenated oils available under the trade Spherical particles may introduce an additional barrier to
name SteroteX(R), Stearic acid, cocoa butter, glyceryl behenate deter tampering with the composition. Smaller, round par
(available under the trade name COMPRITOL 888(R), glyc ticles act as “ball bearings” that are more difficult to crush or
eryl dipalmitostearate (available under the trade name PRE grind, and if crushed, do not allow for significant decrease in
CIROL(R), and stearyl alcohol. Mixtures of mono-, di- and particle size or surface areas of the particles in order to effect
tri-glycerides and mono- and di-fatty acid esters of polyeth an increase in release rate.
ylene glycol, available under the trade name GELUCIRER) For compositions containing salts composed of a pharma
are also suitable fatty materials. Suitable waxes and wax-like ceutically active agent and one or more fatty acids or amines,
materials include natural or synthetic waxes, hydrocarbons, 25 the salt may be formed during the formulation process itself.
and normal waxes. Specific examples of waxes include bees To accomplish this, the one or more fatty acids or amines are
wax, glycowax, castor wax, carnauba wax, paraffins and can melted and mixed with the free base oracid form of the active
delilla wax. As used herein, a wax-like material is defined as agent at a temperature above the melting point(s) of the fatty
any material which is normally solid at room temperature and acid(s) or amine(s). Once a homogeneous mixture is formed,
has a melting point of from about 30 to 300° C. 30 one or more additional carrier materials, such as fat, fatty
In some cases, it may be desirable to alter the rate of water Substance(s), wax or wax-like Substance(s) can be added to
penetration into the hydrophobic drug containing micropar the molten mixture to yield a single phase composition. The
ticles. To this end, rate-controlling (wicking) agents may be molten solution is then solidified into microparticles using
formulated along with the fats or waxes listed above. one of the techniques described above.
Examples of rate-controlling materials include certain starch 35 The molar concentration offatty acid oramine may need to
derivatives (e.g., waxy maltodextrin and drum dried corn be higher than that of the drug in order to achieve a homoge
starch), cellulose derivatives (e.g., hydroxypropylmethylcel neous single phase. For example, it has been found that, for
lulose, hydroxypropylcellulose, methylcellulose, and car oxycodone, a molar ratio in excess of about 7:1 (fatty acid to
boxymethylcellulose), alginic acid, lactose and talc. Addi drug) results in a homogeneous melt using this technique. The
tionally, a pharmaceutically acceptable Surfactant (for 40 molar ratio needed to obtain a homogeneous melt may
example, lecithin) may be added to facilitate the degradation depend on the type and quantity of additional carrier materi
and/or dissolution of the microparticles. als added. In one embodiment, the molar ratio offatty acid or
Proteins which are water insoluble, such as Zein, are suit fatty amine is from about 1:1 to about 15:1, preferably from
able carrier materials for the formation of drug containing about 6:1 to about 15:1. However, molar ratios greater than
microparticles. Additionally, proteins, polysaccharides and 45 15:1, for example 15:1 to 25:1, preferably 15:1-20:1, may be
combinations thereof which are water soluble can be formu required depending on the fatty acid or fatty amine, the drug
lated with drug into microparticles and Subsequently cross to be formulated, and/or the carrier material(s).
linked to form an insoluble network. For example, cyclodex For some carrier materials it may be desirable to use a
trins can be complexed with individual drug molecules and Solvent evaporation technique to produce drug containing
Subsequently cross-linked. 50 microparticles. In this case drug and carrier material are co
Certain polymers may also be used as carrier materials in dissolved in a mutual solvent and microparticles can Subse
the formulation of drug containing microparticles. Suitable quently be produced by several techniques including, but not
polymers include ethylcellulose and other natural or synthetic limited to, forming an emulsion in water or other appropriate
cellulose derivatives. Polymers which are slowly soluble and media, spray drying or by evaporating off the solvent from the
form a gel in an aqueous environment, such as hydroxypropyl 55 bulk solution and milling the resulting material.
methylcellulose or polyethylene oxide may also be suitable as In addition to modification of the drug itself, processing
carrier materials for drug containing microparticles. conditions can be used to influence the dispersion of the drug
Encapsulation or incorporation of drug into carrier mate within water-insoluble or slowly water soluble materials. For
rials to produce drug containing microparticles can be example, in the case where the water in-soluble or slowly
achieved through known pharmaceutical formulation tech 60 soluble material is melted and the drug is fully or partially
niques. To create a composition that protects drug from expo dissolved under Stirring conditions, the temperature, agitation
Sure upon mechanical disruption (eg, grinding, chewing, or rate and time of processing will influence the degree of dis
chopping), the drug is intimately dispersed within the carrier Solution achieved. More specifically, a more homogenous
material. In the case of formulation in fats, waxes or wax-like dispersion may be achieved with a higher temperature, faster
materials, the carrier material is heated above its melting 65 stirring rate and/or longer processing time. Ultrasound can
temperature and the drug is added to form a mixture contain also be applied to the molten mixture to increase the degree of
ing drug particles Suspended in the carrier material, drug dispersion and/or the rate of dissolution of the drug.
 US 9.248,195 B2
11 12
In some embodiments, the drug in a particulate form is matic means; for example, transglutaminase has been
homogeneously dispersed in a water-insoluble or slowly approved as a GRAS Substance for cross-linking seafood
water soluble material. To minimize the size of the drug products. Finally, cross-linking can be initiated by physical
particles within the composition, the drug powder itself may means such as thermal treatment, UV irradiation and gamma
be milled to generate fine particles prior to formulation. The irradiation.
process ofjet milling, known in the pharmaceutical art, can be To produce a coating layer of cross-linked protein Sur
used for this purpose. In some embodiments drug in a par rounding drug containing microparticles or drug particles, a
ticulate form is homogeneously dispersed in a wax or wax water soluble protein can be spray coated onto the micropar
like Substance by heating the wax or wax like Substance above ticles and Subsequently cross-linked by one of the methods
its melting point and adding the drug particles while stirring 10 described above. Alternatively, drug containing micropar
the mixture. In this case a pharmaceutically acceptable Sur ticles can be microencapsulated within protein by coacerva
factant may be added to the mixture to facilitate the dispersion tion-phase separation (for example, by the addition of salts)
of the drug particles. and Subsequently cross-linked. Some Suitable proteins for
D. Coated Drug Containing Microparticles this purpose include gelatin, albumin, casein, and gluten.
In some embodiments, drug containing microparticles or 15 Polysaccharides can also be cross-linked to form a water
drug particles are encapsulated. Drug containing micropar insoluble network. For many polysaccharides, this can be
ticles can be encapsulated in water insoluble materials, accomplished by reaction with calcium salts or multivalent
slowly water soluble materials, organic insoluble materials cations which cross-link the main polymer chains. Pectin,
and/or materials with pH dependent solubilities. alginate, dextran, amylose and guar gum are Subject to cross
In general, any coating procedure which provides a con linking in the presence of multivalent cations. Complexes
tiguous coating on each microparticle can be used. Coating between oppositely charged polysaccharides can also be
procedures known in the pharmaceutical arts include, but are formed; pectin and chitosan, for example, can be complexed
not limited to, fluid bed coating processes and microencap via electrostatic interactions. Insoluble coatings can be
Sulation may be used to obtain appropriate coatings. Detailed formed on particles in this fashion. It should be noted that in
descriptions of these processes can be found in "Reming 25 many cases polysaccharides are broken down specifically by
ton The science and practice of pharmacy”, 20" Edition, enzymes produced by bacteria within the colon.
Jennaro et. Al. (Phila, Lippencott, Williams, and Wilkens, In some cases a water-insoluble but enzymatically degrad
2OOO. able coating including both a protein and a polysaccharide
The water-insoluble coating materials may be selected can be produced if the components are oppositely charged
from natural or synthetic film-formers used singly, in admix 30 polyelectrolytes. Under the proper temperature, pH, and con
ture with each other, and in admixture with plasticizers, pig centrations, the two polymers can interact through their oppo
ments and other substances to alter the characteristics of the site electrical charges and form a water-insoluble complex. If
coating. A water-insoluble but water-permeable diffusion a core particle is present at the time the complex phase sepa
barrier may contain ethyl cellulose, methyl cellulose and rates, it will be coated. For example, gelatin and gum arabic
mixtures thereof. The water-permeable diffusion barrier may 35 can be coated onto a core particle utilizing this process.
also include ammonia methacrylate copolymers sold under Optionally, the complex can be made irreversibly insoluble
the trade name EUDRAGITR (Rohm Pharma), such as by Subsequent cross-linking induced by chemical or physical
EUDRAGITRS, EUDRAGITRL, EUDRAGITNE and mix CaS.
tures thereof. Other synthetic polymers, for example, polyvi Coating materials may also include a pH sensitive polymer
nyl acetate (available under the trade name KOLLICOATR), 40 which is insoluble in the acid environment of the stomach,
can also be used to form water-insoluble but permeable coat and soluble in the more basic environment of the GI tract.
1ngS. These coatings, referred to as enteric coatings, create a dosage
The coating may also include a water-insoluble but enzy form designed to prevent drug release in the stomach. Pre
matically degradable material. In some instances the Sub venting drug release in the stomach has the advantage of
strates of digestive enzymes are naturally water-insoluble and 45 reducing side effects associated with irritation of the gastric
can be utilized in the formulation without further processing. mucosa and/or of minimizing exposure of drug to very low
Solid esters of fatty acids, which are hydrolyzed by lipases, pH. Avoiding release within the stomach can be achieved
can be spray coated onto microparticles or drug particles. using enteric coatings known in the art. The enteric coated
Mixtures of waxes (beeswax, carnauba wax, etc.) with glyc formulation remains intact or Substantially intact in the stom
eryl monostearate, Stearic acid, palmitic acid, glyceryl mono 50 ach, however, once the formulation reaches the Small intes
palmitate and cetyl alcohol will also form films that are dis tines, the enteric coating dissolves and exposes either drug
solved slowly or broken down in the GI tract. Zein is an containing carrier particles or drug-containing carrier
example of a naturally water-insoluble protein. It can be particles coated with extended release coating.
coated onto drug containing microparticles or drug particles Enteric coated particles can be prepared as described in
by spray coating or by wet granulation techniques. In addition 55 "Pharmaceutical dosage form tablets’, eds. Liberman et. al.
to naturally water-insoluble materials, some Substrates of (New York, Marcel Dekker, Inc., 1989), “Remington The
digestive enzymes can be treated with cross-linking proce science and practice of pharmacy”. 20th ed., Lippincott Wil
dures, resulting in the formation of non-soluble networks. liams & Wilkins, Baltimore, Md., 2000, and "Pharmaceutical
Many methods of cross-linking proteins, initiated by both dosage forms and drug delivery systems’, 6th Edition, Ansel
chemical and physical means, have been reported. In some 60 et. al., (Media, Pa.; Williams and Wilkins, 1995). Examples of
embodiments, chemical cross-linking agents are used. Suitable coating materials include, but are not limited to,
Examples of chemical cross-linking agents include aldehydes cellulose polymers, such as cellulose acetate phthalate,
(gluteraldehyde and formaldehyde), epoxy compounds, car hydroxypropyl cellulose, hydroxypropyl methylcellulose
bodiimides, and genipin. In addition to these cross-linking phthalate and hydroxypropyl methylcellulose acetate Succi
agents, oxidized and native Sugars have been used to cross 65 nate; polyvinyl acetate phthalate, acrylic acid polymers and
link gelatin (Cortesi, R., et al., Biomaterials 19 (1998) 1641 copolymers, and certain methacrylic resins that are commer
1649). Cross-linking can also be accomplished using enzy cially available under the trade name EUDRAGIT (Rohm
 US 9.248,195 B2
13 14
Pharma). Additionally the coating material may contain con or fully dissolved within the carrier material during the manu
ventional carriers such as plasticizers, pigments, colorants, facturing process, are coated with one or more coatings to
glidants, stabilization agents, and Surfactants. form coated microparticles. In a further embodiment, drug
In some cases it may be desirable to coat the particles with particles are coated directly with one or more coatings to form
a coating which is soluble in aqueous solutions but insoluble coated microparticles.
in hydroalcoholic Solutions. In this case the coating material The microparticles, coated microparticles, or a mixture
may or may not have pH sensitive solubility in aqueous solu thereof are formed into a solid dosage form suitable for oral
tions. administration. For example, microparticles or coated micro
In other cases it may be desirable to combine coating particles can be incorporated into hard shell capsules, dis
materials to produce a tailored release of drug. For example, 10 persed within a softgelatin capsule, or combined with appro
combinations of insoluble polymers and pH dependent poly priate excipients such as magnesium Stearate as lubricant,
mers can produce a pH dependent Sustained release profile. colloidal silicon dioxide as glidant, sodium starch glycolide,
Combinations of insoluble polymers (eg, ethylcellulose), Sodium croScarmellose or crospovidone as disintegrant,
water-soluble polymers (eg. HPMC or PEG) and pH depen sodium dodecyl sulfate or Polyoxyethylene (20) sorbitan
dent Swellable polymers (eg. carboxyvinylpolymer) have 15 monooleate, polyvinyl pyrrolidone or hydroxypropylmethyl
also been reported to produce pH dependent Sustained release cellulose as crystallization inhibitor, and lactose and micro
profiles (See, for example, Journal of Controlled Release, crystalline cellulose as fillers, and tableted by compression.
2006, 111:309-315). In Some embodiments, the compositions are coated with an
In one embodiment, the particles are coated with cellulose enteric coating. Enteric coatings known in the art are applied
acetate phthalate. Cellulose acetate phthalate is typically used directly to the abuse-deterrent microparticle or coated micro
as an enteric coating. particle compositions or are applied to the Surface of a capsule
E. Antioxidants or tablet containing the abuse deterrent microparticle and/or
In some embodiments, the composition includes one or coated microparticle compositions. Enteric coatings known
more antioxidants. Suitable antioxidants include, but are not in the art include, for example, acrylic polymers that are
limited to, butylated hydroxytoluene (BHT); ascorbic acid, 25 commercially available under the trade name EUDRAGITR),
its salts and esters; Vitamin E, tocopherol and its salts; sulfites cellulose acetate phthalate, hydroxypropylmethylcellulose
Such as sodium metabisulphite; cysteine and its derivatives; phthalate, polyvinylacetate phthalate, shellac, hydroxypro
citric acid; propyl gallate, and butylated hydroxyanisole pylmethylcellulose Succinate, cellulose acetate trimelliate or
(BHA). mixtures thereof. In one embodiment, the particles are coated
Antioxidants may be necessary to prevent oxidative deg 30 with cellulose acetate phthalate.
radation of the active pharmaceutical ingredient and/or the Dosage forms can include one or more drugs. When the
one or more inactive carrier materials in the composition. dosage form includes two or more drugs they can be Sched
Oxidation of one or more components may occur during the uled drugs or can be a combination of Scheduled and non
formulation process itself or during the shelf-life of the com Scheduled drugs. The drugs can be incorporated into separate
position. Oxidation may result from exposure to the oxygen 35 microparticle compositions where the Scheduled drugs are
content of air or, alternatively, may be related to impurities in incorporated into abuse deterrent microparticle compositions
the carrier materials. For example, highly reactive species and the non-Scheduled drugs are incorporated into abuse
Such as peroxides, Superoxides, hypochlorites and formic deterrent microparticle compositions, Sustained release com
acid may be present in carrier materials as manufacturing positions known in the art or immediate release compositions
related impurities. Also, trace metal impurities in carrier 40 known in the art. The compositions containing the different
materials, such as iron and copper, can catalyze oxidation drugs are formulated into a single solid dosage form Suitable
reactions. An antioxidant may be included in the composition for oral administration, for example, they can be incorporated
to mitigate the degradation of the drug in Such cases. If the into a gelatin capsule, or combined with appropriate excipi
Source of oxidation is a reactive manufacturing-related impu ents and compressed into a tablet form. Examples of non
rity in one or more of the carrier materials, the anti-oxidant 45 scheduled drugs that may be included in dosage forms
can be co-melted with the carrier materials prior to the intro described herein include, but are not limited to, aspirin,
duction of the drug into the formulation in order to protect the acetaminophen, non-steroidal anti-inflammatory drugs,
drug from these reactive species. cyclooxygenase II inhibitors, N-methyl-D-aspartate receptor
The concentration of the antioxidant is generally from antagonists, glycine receptor antagonists, triptans, dex
about 0.001% to about 1% w/w, preferably from about 0.01% 50 tromethorphan, promethazine, fiorinal, guaifenesin, butalbi
to about 0.5% w/w. However, concentrations of less than tal, and caffeine.
0.001% or greater than 0.5% may be used, provided the An immediate release dose can be incorporated into the
concentration is sufficient to stabilize the formulation and is formulation in several ways. Immediate release micropar
non-toxic. ticles can be made utilizing standard methodologies and for
F. Dosage Forms 55 mulated along with abuse-deterrent microparticle and/or
In one embodiment a drug is partially dissolved within a coated microparticle compositions in a Suitable oral dosage
water-insoluble or slowly water soluble material during the form. Alternatively, a coating containing drug which is avail
manufacturing process, for example, by mixing at a tempera able for immediate release can be placed on a tablet contain
ture above the melting point of the carrier material, and the ing abuse-deterrent microparticle and/or coated microparticle
mixture is formulated into microparticles. In another embodi 60 compositions plus appropriate excipients. Additionally, an
ment a drug is fully dissolved within a water-insoluble or immediate dose of drug can be granulated or blended with
slowly water Soluble material during the manufacturing pro rapidly dissolving excipients and Subsequently compressed
cess, for example, by mixing at a temperature above the (1) as one layer of bi-layer tablets in which the abuse-deter
melting point of the carrier material, and the mixture is for rent microparticle and/or coated microparticle compositions
mulated into microparticles. In still a further embodiment, the 65 are compressed as the other layer, or (2) as the outer layer of
drug containing microparticles, where the drug is homoge compression-coated tablets in which the abuse-deterrent
neously dispersed in a particulate form, or has been partially microparticle and/or coated microparticle compositions are
 US 9.248,195 B2
15 16
compressed as the inner core, or (3) into tablets in which release of drug over an extended time period. This is a natural
abuse-deterrent microparticle and/or coated microparticle consequence of the fact that, in the present formulation, drug
compositions are embedded. is slowly released from a predominantly water-insoluble,
In some embodiments, the immediate release portion of the hydrophobic matrix as it passes through the GI tract. The
dosage form contains a lipophilic drug derivative. For barrier components may be degraded as the matrix passes
example, salt derivatives or complexes that are insoluble at a through the GI tract, for example, by enzymes, the Surfactant
neutral pH but dissociate, thereby releasing the parent com action of bile acids and mechanical erosion.
pound, at an acidic pH are ideal for immediate release within In some embodiments, an immediate release of drug is
the stomach. In the case of oxycodone some salts that may achieved within the stomach in order to provide rapid thera
exhibit this property include, but are not limited to, the tan 10 peutic onset.
nate, phthalate, salicylate, gallate, pectinate, phytate, saccha The pharmaceutical drug composition is administered
rinate, aseSulfamate and terephthalate salts. Complexes of orally. The appropriate dosage formulations can be obtained
drug with one or more metalions and, optionally, one or more by calculation of the pharmacokinetics of the formulation,
lipophilic counter-ions may also be used for immediate drug then adjusting using routine techniques to yield the appropri
release. Use of salts or complexes in the immediate release 15 ate drug levels based on the approved dosage forms. Any
portion of the dosage form reduces the abuse potential of the Suitable amount of drug containing microparticles or coated
immediate release dose if the formulation is crushed and (1) microparticles can be included in the final formulation. The
snorted or (2) dissolved in water since these salts will be selection of a suitable amount of drug containing micropar
poorly soluble under these conditions. It is understood by the ticles depends on the dosage desired and is readily deter
one of ordinary skill in the art that Such salts or complexes mined by those skilled in the art.
may also be used to formulate an immediate release dosage In addition to oral administration, some embodiments may
form without a Sustained release portion. also be administered by other routes, including; but not lim
Additional mechanisms to reduce the potential for abuse ited to, rectal and nasal administration. Some embodiments
can also be incorporated during the process of formulating may also be suitable for formulation as oral liquids.
tablets. For example, ingredients can be added to deter chew 25 The present composition and method of making and using
ing or Snorting of the final formulation. For example, an the composition will be further understood by reference to the
intensely bitter Substance may deter chewing, while an following non-limiting examples.
intensely spicy ingredient, such as capsaicin, may deter Snort EXAMPLES
ing. The addition of a colored dye, which would stain the skin
and mucosal Surface of the nose following Snorting may also 30
Example 1
serve to reduce this practice.
Optional excipients present in the oral dosage form con Preparation of Drug Containing Microparticles
taining abuse deterrent microparticles or coated micropar
ticles include, but are not limited to diluents, binders, lubri
cants, disintigrants, colorants, plasticizers and the like. 35
TABLE 1
Diluents, also termed “fillers.” are typically necessary to
increase the bulk of a Solid dosage form so that a practical size Compositions
is provided for compression of tablets. Examples of diluents
include cellulose, dry starch, microcrystalline cellulose, Composition Composition Composition Composition
of of of of
dicalcium phosphate, calcium Sulfate, sodium chloride con 40
Formulation Formulation Formulation Formulation
fectioner's Sugar, compressible Sugar, dextrates, dextrin, dex Ingredient A. B C D
trose, Sucrose, mannitol, powdered cellulose, Sorbitol, and
lactose. Binders are used to impart cohesive qualities pow Oxycodone 5g 5g 10 g 5g
Base
dered materials and can include materials such as starch, Myristic Acid 50 g 30 g
gelatin, Sugars, natural and synthetic gums, polyethylene gly 45 Stearic Acid 34g 34g
col, ethylcellulose, methylcellulose, hydroxypropylmethyl Yellow 10 g 10 g 10 g
cellulose, carboxymethylcellulose, waxes and polyvinyl pyr Beeswax
Carnauba wax 5g 10g 20 g 10 g
rolidone. Lubricants are used to facilitate tablet manufacture;
examples of lubricants include talc, magnesium Stearate, cal
cium Stearate, hydrogenated vegetable oils Stearic acid, 50 Procedure:
Sodium Stearyl fumarate, sodium benzoate, sodium acetate, 1. Fatty acid (myristic or Stearic acid) was melted in an erlen
leucine, Sodium oleate, sodium lauryl Sulfate, magnesium meyer flask in a silicone oil bath at 100° C. The mixture
lauryl Sulfate and polyethylene glycol. Disintegrants can be was stirred and kept under an argonblanket for this and all
added to pharmaceutical formulations in order to facilitate Subsequent steps.
“breakup” or disintegration after administration. Materials 55 2. Oxycodone base was introduced into the molten fatty acid
used for this purpose include starches, clays, celluloses, and the melt was stirred until the oxycodone base was
aligns, gums, and cross-linked polymers. A plasticizer may be completely dissolved and a clear liquid was formed.
included in coating materials to alter their mechanical prop 3. Yellow beeswax was added and dissolved under constant
erties. Examples of plasticizers include benzyl benzoate, stirring.
chlorobutanol, dibutyl sebacate, diethyl phthalate, glycerin, 60 4. Carnauba wax was added and dissolved under constant
mineral oil, polyethylene glycol, Sorbitol, triacetin, triethyl stirring.
citrate, glycerol, etc. In addition to the additives above, col 5. The resulting homogeneous molten solution was poured
oring and flavoring agents may also be incorporated into the onto aluminum foil and allowed to solidify at room tem
composition. perature.
II. Methods of Administration 65 6. The bulk material obtained was combined with small quan
In addition to providing a deterrent to common methods of tities of dry ice and Subjected to size reduction in a mortar
abuse/diversion, the formulation can provide a Sustained and pestle.
 US 9.248,195 B2
17 18
7. The dry ice was allowed to dissipate and the particles were Procedure:
sieved to obtain various size ranges. Particles 20-40 mesh 1. Myristic acid was melted at 85°C. in a silicone oil bath
in size (400-841 micron) were subjected to testing. while constantly flowing argon above the Surface of the
Solution.
Example 2 5
2. Beeswax was added to the molten fatty acid and mixed until
a clear, homogeneous solution was obtained.
Release of Drug from Crushed Microparticles 3. Carnauba wax was added to the molten solution and mixed
until a clear, homogeneous solution was obtained.
In vitro testing was conducted in order to assess the influ 10
4. Oxycodone base was added to the molten solution and
ence of crushing of the microparticles produced in Example 1 mixed until a clear, homogeneous Solution was obtained.
on the release in simulated stomach conditions. A currently 5. The resulting molten solution was transferred to a feed
marketed Sustained release formulation of oxycodone, Oxy kettle and continuously metered onto a spinning disk atom
Contin R, was also Subjected to crushing and dissolution for izer in order to form solid, spherical microparticles.
comparison purposes. 15
Microparticles (Formulations A, B, C or D, all 20-40 mesh Example 4
in starting particle size) or tablets were crushed using a glass
mortar & pestle. The resulting crushed material was placed in Preparation of Coated Drug Containing
a dissolution vessel equipped with paddles (USP Apparatus Microparticles
II).900 mL of 0.1N HC1 pre-warmed to 37° C. was added to
the vessels and stirred for 15 minutes. After 15 minutes the The drug-containing particles from Example 3 can be
amount of oxycodone released was determined. The results spray coated with cellulose acetate phthalate
are shown in Table 2.
Example 5
TABLE 2 25
Preparation of Oxymorphone Containing
Drug Release from Crushed Compositions Microparticles
% Released in
15 minutes in Batch Size: 630.6 g.
O.1NHCI 30
Sample (n = 3)
Component Quantity(g), Batch
Oxycontin (R) (40 mg Tablet) 95.6+f- 2.7
Formulation A 31.6 +/- 2.6 Oxymorphone base 60
(microparticles containing 40 mg Stearic Acid 420
oxycodone HCl equivalent) Beeswax 30
Formulation B 19.7+f- 1.4 35 Carnauba Wax NF 120
(microparticles containing 40 mg Butylated Hydroxyanisole O.6
oxycodone HCl equivalent)
Formulation C 14.8 +/- 1.1 Total 630.6
(microparticles containing 20 mg
oxycodone HCl equivalent)
Formulation D 18.2 +/- 1.6 40 Procedure:
(microparticles containing 20 mg 1. Stearic acid was melted in an erlenmeyer flaskin a silicone
oxycodone HCl equivalent)
oil bath at 100° C. Note the composition was subjected to
stirring and was kept under an argonblanket for this and all
As illustrated in the table above, the microparticle compo Subsequent steps.
sitions of Example 1 release only a fraction of the total drug 45 2. Butylated hydroxyanisole was added to the molten stearic
load in simulated Stomach conditions when crushed. In con acid while mixing.
trast, a currently marketed Sustained release composition, 3. Oxymorphone base was introduced into the molten fatty
OxyContin R, releases approximately 96% of the drug load acid and the melt was stirred until all oxymorphone base
when crushed and exposed to identical conditions. dissolved and a clear liquid was formed.
50 4. Beeswax was added and dissolved under constant stirring.
Example 3 5 . Carnauba wax was added and dissolved under constant
stirring.
Preparation of Oxycodone Containing Microparticles 6. The resulting homogeneous molten solution was poured
Using a Spinning Disk Atomization Process onto aluminum foil and allowed to solidify at room tem
55 perature.
7. The bulk wax obtained was combined with dry ice and
Batch Size: 1000 g Subjected to size reduction in a mortar and pestle.
8. The dry ice was allowed to dissipate and the particles were
Component Quantity(g), Batch
sieved to obtain particles in the 40-80 mesh size range.
60
Oxycodone base 91 Example 6
Myristic acid 545
Beeswax
Carnauba Wax
182
182
Preparation of Capsules for Oral Administration
Total 1OOO.O 65 The drug containing microparticles from Examples 1, 3, 4,
or 5 can be blended with a lubricant and incorporated into
standard hard gelatin capsules
 US 9,248,195 B2
19 20
We claim: 11. The method of claim 10, wherein the antioxidant com
1. A method of administering an abuse-deterrent pharma prises butylated hydroxytoluene (BHT); ascorbic acid, its
ceutical composition comprising orally administering to a salts and esters: Vitamin E, tocopherol and its salts; sodium
patient in need thereof an abuse-deterrent oral dosage form metabisulphite; cysteine; citric acid; propyl gallate; butylated
comprising a plurality of microparticles, where each micro- 5 hydroxyanisole (BHA); or combinations thereof.
particle comprises: 12. The method of claim 1 or 2, wherein each microparticle
a fatty acid salt of one or more drugs prone to abuse; and further comprises an enteric coat.
one or more carrier material(s) comprising fats, fatty sub 13. The method of claim 1 or 2, wherein the oral dosage
stances, Waxes, wax-like Substances or mixtures thereof form is a controlled-release oral dosage form.
wherein the oral dosage form retards the release of the one or 10 14. The method of claim 1 or 2, wherein each microparticle
more drugs prone to abuse, even if the physical integrity of the further comprises a pharmaceutically acceptable surfactant.
dosage form is compromised and the compromised dosage 15. The method of claim 1 or 2, wherein the microparticles
form is placed in water. are spherical.
2. A method of administering an abuse-deterrent pharma 16. The method of claim 1 or 2, wherein the one or more
ceutical composition comprising orally administering to a 15 drugs prone to abuse is a stimulant.
patient in need thereof an abuse-deterrent oral dosage form 17. The method of claim 16, wherein the stimulant is
comprising a plurality of microparticles, where each micro amphetamine, methamphetamine or methylphenidate.
particle comprises:
a solidified solution of a fatty acid salt of one or more drugs 18. The method of claim 2, wherein the one or more drugs
prone to abuse; and 2O prone to abuse is uniformly dispersed in the carrier material of
one or more carrier material(s) comprising fats, fatty sub each microparticle.
stances, waxes, wax-like Substances or mixtures thereof. 19. The method of claim 2, wherein each microparticle
3. The method of claim 2, wherein the oral dosage form comprises one or more fatty acids as carrier materials in an
retards the release of the one or more drugs prone to abuse, amount sufficient to solubilize the one or more drugs prone to
even if the physical integrity of the dosage form is compro- 25 abuse in the carrier material(s).
mised and the compromised dosage form is placed in water. 20. A method for the management of pain comprising
4. The method of claim 1 or 2, wherein the one or more administering to a patient in need thereof an abuse-deterrent
drugs prone to abuse is an opioid. oral dosage form comprising a plurality of microparticles,
5. The method of claim 4, wherein the opioid is an opioid where each microparticle comprises:
agonist. 30 a fatty acid salt of one or more drugs prone to abuse; and
6. The method of claim 5, wherein the opioid agonist is one or more carrier material(s) comprising fats, fatty sub
hydrocodone, hydromorphone, morphine, oxycodone, oxy stances, waxes, wax-like Substances or mixtures thereof
morphone or tramadol. wherein the oral dosage form retards the release of the one or
7. The method of claim 1 or 2, wherein the fatty acid salt is more drugs prone to abuse, even if the physical integrity of the
the stearate, palmitate or the myristate fatty acid salt. 35 dosage form is compromised and the compromised dosage
8. The method of claim 1 or 2, wherein the one or more form is placed in water; and
carrier materials comprise myristic acid, stearic acid, palmitic wherein the one or more drugs prone to abuse is an opioid.
acid, beeswax, carnauba wax, hydrogenated oil or mixtures 21. The method of claim 20, wherein the opioid is an opioid
thereof. agonist.
9. The method of claim 1 or 2, wherein the oral dosage form 40 22. The method of claim 21, wherein the opioid agonist is
is a capsule or a tablet. hydrocodone, hydromorphone, morphine, oxycodone, oxy
10. The method of claim 1 or 2, wherein the oral dosage morphone or tramadol.
form further comprises an antioxidant. ck k k k k