I 1111111111111111 11111 111111111111111 IIIII IIIII 1111111111 111111111111111111
`US007919499B2
`
`c12) United States Patent
`Ehrich
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 7,919,499 B2
`Apr. 5, 2011
`
`(54) NALTREXONE LONG ACTING
`FORMULATIONS AND METHODS OF USE
`
`(75)
`
`Inventor: Elliot Ehrich, Lincoln, MA (US)
`
`(73) Assignee: Alkermes, Inc., Waltham, MA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1673 days.
`
`(21) Appl. No.: 11/083,167
`
`(22) Filed:
`
`Mar. 17, 2005
`
`(65)
`
`Prior Publication Data
`
`US 2005/0245558 Al
`
`Nov. 3, 2005
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/564,542, filed on Apr.
`22, 2004.
`
`(51)
`
`Int. Cl.
`A61K 31144
`(2006.01)
`A61K 31156
`(2006.01)
`A0lN 43142
`(2006.01)
`A0lN 45100
`(2006.01)
`A61F 13/00
`(2006.01)
`(52) U.S. Cl. ......................... 514/282; 514/171; 424/422
`( 58) Field of Classification Search . ... ... ... ... .. ... 514/282,
`514/171; 424/422
`See application file for complete search history.
`
`(56)
`
`References Cited
`
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`4/ 1996 Dante
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`8/ 1997 Herbert et al.
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`8/ 1998 Rickey et al.
`6,143,314 A *
`11/2000 Chandrashekar et al.
`6,264,987 Bl
`7/2001 Wright et al.
`10/2001 Ticeetal.
`6,306,425 Bl
`6,358,443 Bl
`3/2002 Herbert et al.
`6,495,155 Bl
`12/2002 Tice et al.
`2004/0151774 Al
`8/2004 Pauletti et al.
`
`FOREIGN PATENT DOCUMENTS
`3/2001
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`01/43726 A
`8/2004
`WO 2004/064752 A2
`12/2004
`WO 2004/108084 A2
`
`WO
`WO
`WO
`WO
`
`.... 424/426
`
`OTHER PUBLICATIONS
`O'Malley, Stephanie S. et al., "Initial and Maintenance Naltrexone
`Treatment for Alcohol Dependence Using Primary Care vs Specialty
`Care. A Nested Sequence of3 Randomized Trials," Arch Intern Med.,
`163: 1695-1704 (2003).
`Latt, Noeline C. et al., "Naltrexone in alcohol dependence: a
`randomised controlled trial of effectiveness in a standard clinical
`setting," MJA, 176: 530-534 (2002).
`Heinala, Pekka et al., "Targeted Use of Naltrexone Without Prior
`Detoxification in the Treatment of Alcohol Dependence: A Factorial
`
`J
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`Clinical
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`Trial,"
`Placebo-Controlled
`Double-Blind,
`Psychopharmacology, 21(3):287-292 (2001).
`"Evidence for the Efficacy ofNaltrexone in the Treatment of Alcohol
`Dependence (Alcoholism)," Addiction Treatment Forum, Ed.,
`Leavitt, Stewart, pp. 1-8 (2002).
`Renning, R.H., et al., "Pharmacokinetic quantitation of naltrexone
`release from several sustained-released delivery," NIDA, Research
`Monograph, Institute on Drug Abuse, 28: 172-184, (1981).
`Yolles, S., et al., "Long acting delivery for narcotic antagonists II:
`release reates of naltrexone from Poly(lactic acid) composites," PDA
`J. of Pharm. Sci and Tech., 64(2):348-349, (1995).
`Bartus, et al., Vivitrex®, an Injectable, Extended-Release Formula(cid:173)
`of Naltrexone,
`Provides
`Pharmacokinetic
`and
`tion
`Pharmacodynamic Evidence of Efficacy for 1 Month in Rats,
`Neuropsychopharmacology, 28:1973-1982 (Aug. 2003).
`Comer, Sandra D. et al., "Depot Naltrexone: Long-lasting Antago(cid:173)
`nism of the Effects of Heroin in Humans," Psychopharmacology,
`159:351-360 (2002).
`Chiang, C.N. et al., "Kinetics of a Naltrexone Sustained-release
`Preparation," Clinical Pharmacology and Therapeutics, 36(5): 704-
`708.
`U.S. Appl. No. 60/554,658, filed Mar. 19, 2004, Elliott Ehrich, et al.
`U.S. Appl. No. 60/554,785, filed Mar. 19, 2004, Elliott Ehrich, et al.
`U.S. Appl. No. 11/082,420, filed Mar. 17, 2005, Elliott Ehrich, et al.
`U.S.Appl. No.11/082,534, filedMar.17, 2005, Elliott Ehrich, etal.
`Swift, Robert M., "Drug Therapy for Alcohol Dependence," New
`England J of Med., 340(19): 1482-1490 (1999).
`Karam-Hage, Maher and Brower, Kirk J., "Gabapentin Treatment for
`Insonmia Associated With Alcohol Dependence," Am. J Psychiatry,
`157(1): 151-153 (2000).
`Myrick, M.D., Hugh, et al., "Gabapentin Treatment of Alcohol With(cid:173)
`drawal," Am. J of Psychiatry, 155(11): 1626-1627, (1998).
`Malcolm, M.D., Robert, et al., "Update on Anticonvulsants for the
`Treatment of Alcohol Withdrawal," Am. J on Addictions, 10(1):
`16-23, Abstract Only, (2001).
`Swift, R., et al., "Naltrexone Effects on Diazepam Intoxication and
`Pharmacokinetics in Humans," Psychopharmacology, 135(3): 256-
`262 (1998), Abstract Only.
`Chaves, M.L., et al., "Diazepam Inhibits Retroactive Interference of
`Memory in Humans: Pretreatment with Naltrexone Does Not Alter
`This Effect," Braz. J Med. Biol. Res., 23(5): 417-421 (1990),
`Abstract Only.
`Fidecka, S. and Langwinski, R., "Effects of Opioid Antagonists on
`Anticonvulsant and Hypnotic Activity of Benzodiazepines," Pol. J
`Pharmacol., 48(4): 409-414 (1996), Abstract Only.
`Longo, L.P., et al., "Divalproex Sodium (Depakote) for Alcohol
`Withdrawal and Relapse Prevention," J Addict Dis., 21(2): 55-64
`(2002), Abstract Only.
`Minuk, G.Y., et al., "The Use of Sodium Valproate in the Treatment
`of Alcoholism," J Addict Dis., 14(2): 67-74 (1995), Abstract Only.
`Reoux, J.P., et al., "Divalproex Sodium in Alcohol Withdrawal: A
`Randomized Double Blind Placebo-Controlled Clinical Trial," Alco(cid:173)
`hol Clin. Exp. Res., 25(9): 1324-1329 (2001), Abstract Only.
`
`* cited by examiner
`
`Primary Examiner - Sreeni Padmanabhan
`Assistant Examiner - Kendra D Carter
`(74) Attorney, Agent, or Firm - Elmore Patent Law Group,
`P.C.; Carolyn S. Elmore; Darlene A. Vanstone
`
`(57)
`
`ABSTRACT
`The inventions described herein arose from unexpected dis(cid:173)
`coveries made during clinical trials with a long acting formu(cid:173)
`lation of naltrexone. As such, the invention includes a method
`for treating an individual in need of naltrexone comprising the
`step of parenterally administering a long acting formulation
`comprising naltrexone and to the use of naltrexone in the
`manufacture of medicaments for use in such methods.
`
`15 Claims, 4 Drawing Sheets
`
`Merk Sharp & Dohme Corp. Exhibit 2012
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 1
`
`

`

`U.S. Patent
`
`Apr. 5, 2011
`
`Sheet 1 of 4
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`Merk Sharp & Dohme Corp. Exhibit 2012
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 2
`
`

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`U.S. Patent
`
`Apr. 5, 2011
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`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 3
`
`

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`U.S. Patent
`
`Apr. 5, 2011
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`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 4
`
`

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`U.S. Patent
`
`Apr. 5, 2011
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`Merk Sharp & Dohme Corp. Exhibit 2012
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 5
`
`

`

`US 7,919,499 B2
`
`1
`NALTREXONE LONG ACTING
`FORMULATIONS AND METHODS OF USE
`
`2
`has not used oral naltrexone within five days, such as within
`ten days, before said administration.
`
`RELATED APPLICATION
`
`BRIEF SUMMARY OF THE DRAWINGS
`
`FIGS. lA-lC shows the cumulative mean event rate of
`heavy drinking during the study by treatment group and gen(cid:173)
`der. As an example, at day 100, the mean number of cumula(cid:173)
`tive heavy drinking days for the overall study population was
`22.3 for the long-acting naltrexone 380 mg patients, 27 .3 for
`long-acting naltrexone 190 mg patients, and 30.0 for placebo
`patients.
`FIG. 2 shows median heavy drinking days per month for
`each treatment group, overall and by gender. Asterisks repre(cid:173)
`sent interquartile range (25%, 75%).
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`This application claims the benefit of U.S. Provisional
`Application No. 60/564,542, filed on Apr. 22, 2004. The
`entire teachings of the above application are incorporated
`herein by reference.
`
`10
`
`BACKGROUND OF THE INVENTION
`
`Alcohol dependence is a chronic disorder that results from
`a variety of genetic, psychological and environmental factors.
`Traditional treatment has consisted of two phases: detoxifi- 15
`cation and rehabilitation. Detoxification ameliorates the
`symptoms and signs of withdrawal; rehabilitation helps the
`patient avoid future problems with alcohol. In the past, most
`rehabilitative treatments have been psychosocial. With
`advances in neurobiology, there is increasing interest in drug 20
`therapy for alcohol dependence. For a discussion of the devel(cid:173)
`opment of this field, see Swift, R., Drug Therapy for Alcohol
`Dependence, NEJM, May 13, 1999, 1482-1490. Yet, the suc(cid:173)
`cessful treatment of alcoholism has many serious challenges
`and complications. Patient compliance is a serious problem. 25
`Accordingly, there is a need for improving naltrexone
`therapies.
`
`The inventions relate to the administration of a naltrexone
`containing formulation, preferably a long acting naltrexone
`formulation, to patients in need thereof and to the use of
`naltrexone in the manufacture of medicaments for use in such
`methods.
`In one embodiment, the invention includes a method for
`treating an individual in need of naltrexone comprising the
`step of parenterally administering a long acting formulation
`comprising naltrexone to the individual wherein the serum
`AUC of naltrexone is at least about two times, preferably at
`least about three times, more preferably about 3.3 times
`greater than that achieved by 50 mg/day oral administration.
`This invention arose from the unexpected discovery that sub-
`30 stantially improved serum levels of naltrexone can be
`achieved by administering long acting formulations of naltr(cid:173)
`exone, such as the Alkermes, Inc. formulation, Vivitrex®
`injectable suspension, made employing its Medisorb® deliv(cid:173)
`ery system. Indeed, it was not expected that serum levels of
`35 about 3.3 times that achieved by a 50 mg/day oral dose could
`be achieved by a single IM administration ofVivitrex®.
`The inventions also include a method of treating an indi(cid:173)
`vidual in need of naltrexone comprising administering naltr(cid:173)
`exone, such as in a long acting formulation, in the absence of
`40 co-administering alcohol, to an individual who has not
`abstained from alcohol within three days, such as five days,
`prior to the naltrexone administration. In this embodiment, it
`was unexpectedly discovered that good to excellent results
`could be achieved without either requiring alcohol abstinence
`or requiring alcohol consumption during therapy, as taught by
`45 Sinclair, U.S. Pat. No. 4,882,335. Further, good to excellent
`results were achieved in patients that did not receive oral
`naltrexone in advance of the long acting formulation admin(cid:173)
`istration, contrary to the clinical protocols as taught by Drug
`Abuse Sciences. Thus, the inventions also include adminis-
`50 tering a long acting formulation to individuals who did not
`receive a prior oral dose of naltrexone, for example, within 3,
`such as within about 5 days or about 10 days of commencing
`therapy.
`As such, the inventions also include a method of treating an
`55 individual in need of naltrexone comprising administering a
`long acting formulation in a dose comprising between about
`160 mg and 240 mg of naltrexone or about 310 mg to about
`480 mg of naltrexone and formulations for use in the methods
`described herein. Preferred formulations are administered in
`a dose comprising about 190 mg or about 380 mg naltrexone.
`The naltrexone can be in any form, including anhydrous,
`hydrate, solvate or salt forms or combinations thereof. It can
`be crystalline or non-crystalline or combinations thereof. A
`preferred naltrexone form comprises a naltrexone ethanolate,
`such as that described in U.S. Patent Application No. 60/475,
`65 863, filed on Jun. 4, 2003, which is incorporated herein by
`reference and/or anhydrous naltrexone. A particularly pre(cid:173)
`ferred naltrexone form is that produced by the encapsulation
`
`60
`
`SUMMARY OF THE INVENTION
`
`The inventions described herein arose from unexpected
`discoveries made during clinical trials with a long acting
`formulation of naltrexone. As such, the invention includes a
`method for treating an individual in need of naltrexone com(cid:173)
`prising the step of parenterally administering a long acting
`formulation comprising naltrexone to the individual wherein
`the serum AUC of naltrexone is at least about two times,
`preferably at least about three times, more preferably about
`3.3 times greater over the course of the month than that
`achieved by 50 mg/day oral administration.
`The inventions also include a method of treating an indi(cid:173)
`vidual in need of naltrexone comprising administering a long
`acting formulation in a dose comprising at least about 160 mg
`of naltrexone, preferably between about 160 mg and about
`480 mg naltrexone, more preferably between about 160 and
`240 mg of naltrexone or about 310 to about 480 mg of naltr(cid:173)
`exone.
`The inventions also include a method of treating an indi(cid:173)
`vidual in need of naltrexone comprising administering naltr(cid:173)
`exone, such as in a long acting formulation, in the absence of
`co-administering alcohol, to an individual who has not
`abstained from alcohol within three days, such as five days,
`prior to the naltrexone administration.
`The invention also includes a method of treating an indi(cid:173)
`vidual in need of naltrexone comprising administering naltr(cid:173)
`exone as a long acting formulation in the absence of concomi(cid:173)
`tant psychosocial treatment/intervention.
`The inventions include a method of increasing the days
`prior to occurrence of alcohol consumption in an individual in
`need of naltrexone comprising administering a long acting
`formulation comprising naltrexone, in the absence of co(cid:173)
`administering alcohol, to an individual who has not abstained
`from alcohol within three days, such as five days, prior to the
`naltrexone administration.
`The inventions include a method of treating an individual
`in need of naltrexone comprising administering a long acting
`formulation comprising naltrexone in a dosage between
`about 160 mg to about 480 mg naltrexone every four weeks
`for a period of about 24 weeks or more wherein the individual
`
`Merk Sharp & Dohme Corp. Exhibit 2012
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 6
`
`

`

`US 7,919,499 B2
`
`3
`process described in U.S. Pat. No. 6,264,987, by Wright et al.,
`which is incorporated herein by reference.
`The naltrexone can be combined with any of the well(cid:173)
`known biodegradable and bioerodible carriers, such as poly(cid:173)
`lactides, poly(lactic acids) and poly-lactide-co-glycolides
`and collagen formulations. A particularly preferred polymer
`is a polylactide-co-glycolide polymer which possesses a
`molecular weight of at least 100,000 daltons, such as those
`described below in the exemplification. Such materials may
`be in the form of solid implants, sponges, and the like.
`As stated above, the naltrexone is preferably in a long
`acting formulation. Long acting ( also referred to as extended,
`sustained, or controlled release) preparations may be
`achieved through the use of polymers (preferably poly-lactide
`or poly-lactide-co-glycolide polymers) to entrap or encapsu(cid:173)
`late the naltrexone described herein. Extended release formu(cid:173)
`lations can be made by spray drying polymer-drug mixtures,
`emulsion-based technologies, coacervation based technolo(cid:173)
`gies, film casting, extrusion based technologies and other
`processes to manufacture polymer-drug microparticles pos(cid:173)
`sessing an extended release profile. Examples of suitable
`extended release technologies that can be used to incorporate
`the novel naltrexone forms described herein include, without
`limitation, the MEDISORB® technology, as described in, for
`example, U.S. Pat. No. 6,264,987 to Wright, U.S. Pat. Nos.
`5,654,008 and/or 5,792,477, for example; the PROLEASE®
`technology, as described, for example in U.S. Pat. No. 6,358,
`443 to Herbert; the technologies described by Southern
`Research Institute, as described for example in U.S. Pat. Nos.
`6,306,425 and 5,407,609; and "Method of Preparing Sus(cid:173)
`tained Release Microparticles," U.S. Application No. 60/441,
`946, filed Jan. 23, 2003, and the technologies described by
`Alza Corp., including theALZAMER® Depot injection tech(cid:173)
`nology. The contents of these patents are incorporated herein
`by reference in their entirety.
`In another embodiment, the novel naltrexone forms
`described herein may be used in combination with other
`treatments including but not limited to psychotherapy and/or
`other medications. Other medications that may be combined
`with the long acting naltrexone of the invention include but
`are not limited to anticonvulsants (see U.S. Patent Applica(cid:173)
`tion No. 60/554,658 filed on Mar. 17, 2005, incorporated
`herein by reference), dopamine D2 partial agonists (see U.S.
`Patent Application No. 60/554,785 filed on Mar. 17, 2005,
`incorporated herein by reference) and cannabinoid receptor
`antagonist. Examples of anticonvulsants useful in conjunc(cid:173)
`tion with the present invention include but are not limited to
`carbamezepine, valproic acid, lamotrigine, gabapentin, topi(cid:173)
`ramate, phenobarbital, diphenylhydantoin, phenytoin,
`mephenytoin, ethotoin, mephobarbital, primidone, ethosux(cid:173)
`imide, methsuximinde, phensuximide, trimethadione, phena(cid:173)
`cemide, acetazolamide, progabide, clonazepam, divalproex
`sodium, magnesium
`sulfate
`injection, metharbital,
`paramethadione, phenytoin sodium, clobazam, sulthiame,
`dilantin, zolpidem tartrate, zaleplon, indiplon, and zopiclone.
`Examples of dopamine D2 partial agonists useful in the
`present invention include but are not limited to Aripiprazole,
`7-{ 4-[ 4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy }-3-,4-
`dihydro carbostyril or 7-{ 4-[ 4-(2,3-dichlorophenyl)-1-piper(cid:173)
`azinyl]-butoxy }-3,4-dihydro-2(1H)-quinolinone, and
`the
`partial dopamine agonist (-)3-(3-hydroxyphenyl)-N-n-pro(cid:173)
`pylpiperidine [(-)-3PPP, see U.S. Pat. No. 4,719,219].
`In a preferred embodiment, the long acting formulation
`delivers therapeutically beneficial amounts of naltrexone to
`the patient for a period of at least one week, preferably at least
`about two weeks, more preferably at least about 3 or about 4
`or more weeks. A four week delivery is often referred to as a
`monthly delivery.
`In one preferred embodiment, the naltrexone is present in 65
`the extended release device or formulation in an amount of at
`least about 5% by weight, preferably at least about 10% by
`
`4
`weight, more preferably at least about 30% by weight, such as
`about 35% by weight naltrexone of the total weight of the
`device, or formulation.
`Alternatively, instead of incorporating naltrexone into
`5 polymeric particles, it is possible to entrap these materials in
`microparticles prepared, for example, by coacervation tech(cid:173)
`niques or by interfacial polymerization (for example,
`hydroxymethylcellulose or gelatine-microcapsules and poly(cid:173)
`(methylmethacrylate) microcapsules, respectively), in colloi-
`10 dal drug delivery systems (for example, liposomes, albumin,
`microparticles, microemulsions, nanoparticles, andnanocap(cid:173)
`sules ), or in macroemulsions.
`When the composition is to be used as an injectable mate(cid:173)
`rial, including but not limited to needle-less injection, it can
`be formulated into a conventional injectable carrier. Suitable
`15 carriers include biocompatible and pharmaceutically accept(cid:173)
`able solutions. The injection can be intramuscular or subcu(cid:173)
`taneous.
`While the formulation may contain additional excipients,
`as is well known in the art, the present invention can achieve
`20 an excellent release profile with the simple formulation
`described herein. Such additional excipients can increase or
`decrease the rate of release of the agent. Ingredients which
`can substantially increase the rate of release include pore
`forming agents and excipients which facilitate polymer deg-
`25 radation. For example, the rate of polymer hydrolysis is
`increased in non-neutral pH. Therefore, an acidic or a basic
`excipient such as an inorganic acid or inorganic base can be
`added to the polymer solution, used to form the micropar(cid:173)
`ticles, to alter the polymer erosion rate.
`A preferred embodiment of the described sustained release
`30 formulations consists essentially of the biocompatible poly(cid:173)
`mer and naltrexone. By "consists essentially of' is meant the
`absence ofingredients which substantially increase the rate of
`release of the active agent from the formulation. Examples of
`additional excipients which would not be expected to sub-
`35 stantially increase or decrease the rate of release of the agent
`include additional active agents and inert ingredients.
`In yet another embodiment, the formulation consists of the
`biocompatible polymer and naltrexone. By "consists of' is
`meant the absence of components or ingredients other than
`40 those listed and residual levels of starting materials, solvents,
`etc. from the process.
`As stated above, the formulation preferably releases naltr(cid:173)
`exone over a period of at least about one, two, three or four
`weeks. As such, the formulation can be administered using a
`dosing schedule which achieves the desired therapeutic levels
`45 for the desired period of time. For example, the formulation
`can be administered and, optionally, the patient monitored
`until levels of the drug being delivered return to baseline.
`Following an actual or projected return to baseline, the for(cid:173)
`mulation can be administered again. Alternatively, the subse-
`50 quent administration of the formulation can occur prior to
`achieving baseline levels in the patient. As such, the formu(cid:173)
`lation can be advantageously administered weekly, with a one
`week release formulation, biweekly with a two week release
`formulation, or monthly with a four week release formula-
`55 tion. Vivitrex is a four week release formulation with a
`monthly (e.g., every four weeks) administration. The therapy
`can end after a single dose or can be maintained for longer
`periods of time. In one embodiment, the therapy can main(cid:173)
`tained for at least about 4, 8, 12, 16, 20 and 24 weeks or more.
`Where more than one administration is given, the second
`60 administration can be given at least about 7 days, preferably
`at least about 14 days, more preferably at least about 21 days,
`such as about 28 days, after the first administration and com(cid:173)
`binations thereof. In this context "about" preferably means
`within three days of the targeted date.
`Particularly good results were achieved upon administer(cid:173)
`ing the same formulation and same dose with each adminis(cid:173)
`tration. Thus, where a 380 mg dose was given in the first
`
`Merk Sharp & Dohme Corp. Exhibit 2012
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 7
`
`

`

`US 7,919,499 B2
`
`5
`administration, good to excellent results were achieved when
`the second and subsequent doses were about 380 mg. Sur(cid:173)
`prisingly, good to excellent results were also obtained when
`each dose administered contained 190 mg naltrexone, par(cid:173)
`ticularly in men and women who were abstinent from alcohol 5
`in the three or five days prior to commencing treatment. As
`such, in one embodiment of the invention, the doses and/or
`formulations administered in each subsequent administration
`were similar or the same. As stated above, the formulation is
`preferably a micro sphere formulation and is administered by
`IM injection. Administration to the buttock in a volume ofup 10
`to about 4 mL in an injectable diluent was performed in the
`trials leading up to these inventions.
`The methods of the inventions achieved good to excellent
`results in women and, in particular, men. Good to excellent
`results were achieved in young individuals (defined as less 15
`than 50 years of age), particularly men. Individuals afflicted
`by alcohol dependency, such as a heavy drinker achieved
`good to excellent results. A heavy drinker is understood in the
`art to include women who consume four or more alcoholic
`beverages in a day and men who consume five or more alco- 20
`holic beverages in a day.
`In yet another embodiment, the inventions include a
`method of increasing the days prior to occurrence of alcohol
`consumption in an individual in need of naltrexone compris(cid:173)
`ing administering a long acting formulation comprising nal-
`trexone in accordance with the protocols and/or dosing regi(cid:173)
`mens described herein. In one embodiment, the increase in
`days prior to occurrence of alcohol consumption can include
`the consumption of a single alcoholic beverage or it can
`include consumption of four or five alcoholic beverages, such
`as the number of drinks characterizing an episode of "heavy 30
`drinking," above. In general, the greater the number of days
`that transpire prior to alcohol consumption indicates a more
`successful therapy.
`
`25
`
`6
`The outflow of the first or second static mixer can flow into
`an extraction vessel containing primary extraction solution.
`The solvents (BA and EtAc) are substantially extracted from
`the organic phase of the emulsion in this primary solvent
`extraction step, resulting in nascent microparticles comprised
`mainly of polymer and drug. The primary solvent extraction
`step lasts for approximately six hours.
`The microparticles can be collected, and vacuum dried,
`optionally with a nitrogen bleed using a customized vibratory
`sieve. After collection and prior to drying, the microparticles
`are rinsed with a 25% ethanol solution that removes the
`emulsifying agent (PVA), and enhances yield by aiding in the
`transfer of the microparticles to the cold dryer. This step is
`conducted, preferably at cold temperatures, until the desired
`level of dryness is achieved. As can be seen in the examples
`below, the degree of dryness ( as measured, for example, by a
`humidity probe), impacts upon the degree of crystallinity
`achieved in the final product. For example, it can be advan(cid:173)
`tageous to select a drying time of at least about 8, 16, 24 or 40
`hours of drying. For example, it can be advantageous to select
`a drying time of at least about 8, 16, 24 or 40 hours where
`drying is 40%, 70%, 95% or 100% complete respectively.
`Drying is considered complete when the absolute humidity of
`the effluent gas reaches approximately O g/m3
`•
`The microparticles can then be resuspended in a second
`extraction solution. The second solution can contain the sol(cid:173)
`vent desired to form the polymorphic form, such as ethanol.
`For example, a solution comprising at least about 10% by
`volume, preferably at least about 20% ethanol, can be used.
`This can be conveniently called the reslurry and secondary
`solvent extraction steps. The solvent, such as ethanol, can
`facilitate further extraction of BA and EtAc. Further, the
`crystallinity of the drug increases during the step. The sec-
`ondary solvent extraction step is carried out in an extraction
`vessel for approximately two, three, four or more hours. This
`step can be conveniently completed at room temperature.
`35 However, other temperatures can be selected as well. In the
`collection/final dry step, the microparticles are collected, and
`vacuum dried with a nitrogen bleed using a customized vibra(cid:173)
`tory sieve.
`In the final harvest step, the microparticles can be trans-
`40 ferred into a sterile container and stored, for example, in a
`freezer at -20° C., until filling into vials. Preferably, the
`stored microparticles are sieved through a 150 micron screen
`to remove any oversized material prior to filling into vials.
`Preparation ofNaltrexone Base Microparticles.
`The naltrexone base microparticles were produced using a
`45 co-solvent extraction process. The theoretical batch size was
`15 to 20 grams. The polymer (MEDISORB® 7525 DL poly(cid:173)
`mer, MEDISORB® 8515 DL polymer and MEDISORB®
`6536 DL polymer, all available from Alkermes, Inc., Blue
`Ash, Ohio) was dissolved in ethyl acetate to produce a 16.7%
`50 w/w polymer solution. The naltrexone base anhydrous was
`dissolved in benzyl alcohol to produce a 30.0% w/w solution.
`In various batches, the amount of drug and polymer used was
`varied to produce microparticles with different theoretical
`drug loading ranging from 30%-75%. The ambient polymer
`55 and drug solutions were mixed together until a single homo(cid:173)
`geneous solution ( organic phase) was produced. The aqueous
`phase was at ambient conditions and contained 1 % w/w poly(cid:173)
`vinyl alcohol and a saturating amount of ethyl acetate. These
`two solutions were pumped via positive displacement pumps
`at a ratio of 3: 1 (aqueous:organic) through a¼' in-line mixer
`60 to form an emulsion. The emulsion was transferred to a stir(cid:173)
`ring solvent extraction solution consisting of 2.5% w/w of
`ethyl acetate dissolved in distilled water at 5-10° C., at a
`volume of0.5 L of extraction solution per-theoretical gram of
`microparticles. Both the polymer and drug solvents were
`65 extracted into the extraction solution from the emulsion drop(cid:173)
`lets to produce microparticles. The initial extraction process
`ranged from two to four hours. The microparticles were col-
`
`EXEMPLIFICATION
`
`Example 1
`
`Method for Manufacturing Vivitrex® Long Acting Formula(cid:173)
`tions
`The invention includes a preferred method for manufactur(cid:173)
`ing extended release devices, wherein the resulting device
`contains a mixture of the described polymorphic forms.
`Polymer solution can be formed by dissolving a poly(lac(cid:173)
`tide )-co-glycolide polymer, such as a 75:25 DL PLGA (poly
`(lactide)-co-glycolide) in a polymer solvent, such as ethyl
`acetate (EtAc ), to form a solution. Preferred PLGA polymers
`are high molecular weight polymers, such as polymers pos(cid:173)
`sessing a molecular weight of at least about 100,000 daltons.
`A naltrexone solution can be formed by dissolving naltrexone
`base in a suitable solvent, such as benzyl alcohol (BA), to
`form a solution. The polymer solution and the naltrexone
`solution are preferably mixed together to form a drug/poly(cid:173)
`mer solution that will be the "organic" or "oil" phase of the
`emulsion.
`The "aqueous" or "continuous" phase of the emulsion
`(emulsifying solution) is prepared. The aqueous phase pref(cid:173)
`erably contains poly(vinyl alcohol) (PVA) and polymer sol(cid:173)
`vent, such as EtAc. The organic phase and the aqueous phase
`can be conveniently combined in a first static mixer to form an
`oil-in-water emulsion.
`In an optional partial extraction step, the emulsion flows
`out of the first static mixer and into a second static mixer
`where the emulsion can be combined with a primary extrac(cid:173)
`tion solution which enters the second static mixer. The pri(cid:173)
`mary extraction solution (such as can be for