• I
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`CSE
`04/22/04
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`4000.3010 us
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`- 1 -
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`Express Mail Label No.
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`EV 373377224 US
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`Inventor:
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`Attorney's Docket No.:
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`Elliot Ehrich
`4000.3010 us
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`NAL TREXONE LONG ACTING FORMULATIONS AND METHODS OF USE
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`BACKGROUND OF THE INVENTION
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`Alcohol dependence is a chronic disorder that results from a variety of genetic,
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`psychological and environmental factors. Traditional treatment has consisted of two
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`phases: detoxification and rehabilitation. Detoxification ameliorates the symptoms and
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`signs of withdrawal; rehabilitation helps the patient avoid future problems with alcohol.
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`In the past, most rehabilitative treatments have been psychosocial. With advances in
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`neurobiology, there is increasing interest in drug therapy for alcohol dependence. For a
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`discussion of the development of this field, see Swift, R., Drug Therapy for Alcohol
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`Dependence, NEJM, May 13, 1999, 1482-1490. Yet, the successful treatment of
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`alcoholism has many serious challenges and complications. Patient compliance is a
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`serious problem.
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`Accordingly, there is a need for improving naltrexone therapies.
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`SUMMARY OF THE INVENTION
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`The inventions described herein arose from unexpected discoveries made during
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`clinical trials with a long acting formulation of naltrexone. As such, the invention
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`includes a method for treating an individual in need of naltrexone comprising the step of
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`parenterally administering a long acting formulation comprising naltrexone to the
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`individual wherein the serum AUC of naltrexone is at least about two times, preferably
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`at least about three times, more preferably about 3.3 times greater than that achieved by
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`50 mg/day oral administration.
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`APOTEX EXHIBIT 1003
`Apotex v. Alkermes
`IPR2025-00514
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`The inventions also include a method of treating an individual in need of
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`naltrexone comprising administering a long acting formulation in a dose comprising at
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`least about 160 mg of naltrexone, preferably between about 160 mg and about 480 mg
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`naltrexone, more preferably between about 160 and 240 mg of naltrexone or about 310
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`to about 480 mg of naltrexone.
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`The inventions also include a method of treating an individual in need of
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`naltrexone comprising administering naltrexone, such as in a long acting formulation, in
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`the absence of co-administering alcohol, to an individual who has not abstained from
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`alcohol within three days, such as five days, prior to the naltrexone administration.
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`The inventions include a method of increasing the days prior to occurrence of
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`alcohol consumption in an individual in need of naltrexone comprising administering a
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`long acting formulation comprising naltrexone, in the absence of co-administering
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`alcohol, to an individual who has not abstained from alcohol within three days, such as
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`five days, prior to the naltrexone administration.
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`The inventions include a method of treating an individual in need of naltrexone
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`comprising administering a long acting formulation comprising naltrexone in a dosage
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`between about 160 mg to about 480 mg naltrexone every four weeks for a period of
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`about 24 weeks or more wherein the individual has not used oral naltrexone within five
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`days, such as within ten days, before said administration.
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`BRIEF SUMMARY OF THE ORA WINGS
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`Figure lA-lC shows the cumulative mean event rate of heavy drinking during
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`the study by treatment group and gender. As an example, at day 100, the mean number
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`of cumulative heavy drinking days for the overall .study population was 22.3 for the
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`long-acting naltrexone 380 mg patients, 27.3 for long-acting naltrexone 190 mg
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`patients, and 30.0 for placebo patients.
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`Figure 2 shows median heavy drinking days per month for each treatment group,
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`overall and by gender.
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`DETAILED DESCRIPTION OF THE INVENTION
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`The inventions relate to the administration of a naltrexone containing
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`formulation, preferably a long acting naltrexone formulation, to patients in need thereof
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`and to the use of naltrexone in the manufacture of medicaments for use in such
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`5 methods.
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`In one embodiment, the invention includes a method for treating an individual in
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`need of naltrexone comprising the step of parenterally administering a long acting
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`formulation comprising naltrexone to the individual wherein the serum AUC of
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`naltrexone is at least about two times, preferably at least about three times, more
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`preferably about 3.3 times greater than that achieved by 50 mg/day oral administration.
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`This invention arose from the unexpected discovery that substantially improved serum
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`levels of naltrexone can be achieved by administering long acting formulations of
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`naltrexone, such as the Alkermes, Inc. formulation, Vivitrex® injectable suspension,
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`made employing its Medisorb® delivery system. Indeed, it was not expected that serum
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`levels of about 3.3 times that achieved by a 50 mg/day oral dose could be achieved by a
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`single IM administration of Vivitrex®.
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`The inventions also include a method of treating an individual in need of
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`naltrexone comprising administering naltrexone, such as in a long acting formulation, in
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`the absence of co-administering alcohol, to an individual who has not abstained from
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`alcohol within three days, such as five days, prior to the naltrexone administration. In
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`this embodiment, it was unexpectedly discovered that good to excellent results could be
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`achieved without either requiring alcohol abstinence or requiring alcohol consumption
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`during therapy, as taught by Sinclair, United States Patent No. 4,882,335. Further, good
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`to excellent results were achieved in patients that did not receive oral. naltrexone in
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`advance of the long acting formulation administration, contrary to the clinical protocols
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`as taught by Drug Abuse Sciences. Thus, the inventions also include administering a
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`long acting formulation to individuals who did not receive a prior oral dose of
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`naltrexone, for example, within 3, such as within about 5 days or about 10 days of
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`commencing therapy.
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`As such, the inventions also include a method of treating an individual in need
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`of naltrexone comprising administering a long acting formulation in a dose comprising
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`between about 160 mg and 240 mg of naltrexone or about 310 mg to about 480 mg of
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`naltrexone and formulations for use in the methods described herein .. Preferred
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`formulations are administered in a dose comprising about 190 mg or about 380 mg
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`naltrexone.
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`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
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`thereof. A preferred naltrexone form comprises a naltrexone ethanolate, such as that
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`described in United States Patent Application No. 60/475,863, filed on June 4, 2003,
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`which is incorporated herein by reference and/or anhydrous naltrexone. A particularly
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`preferred naltrexone form is that produced by the encapsulation process described in
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`United States Patent No. 6,264,987, by Wright et al., which is incorporated herein by
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`reference.
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`The naltrexone can be combined with any of the well-known biodegradable and
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`bioerodible carriers, such as polylactides, poly(lactic acids) and poly-lactide-co(cid:173)
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`glycolides and collagen formulations. A particularly preferred polymer is a polylactide(cid:173)
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`co-glycolide polymer which possesses a molecular weight of at least 100,000 daltons,
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`such as those described below in the exemplification. Such materials may be in the
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`form of solid implants, sponges, and the like.
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`As stated above, the naltrexone is preferably in a long acting formulation. Long
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`acting (also referred to as extended, sustained, or controlled release) preparations may
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`be achieved through the use of polymers (preferably poly-lactide or poly-lactide-co(cid:173)
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`glycolide polymers) to entrap or encapsulate the naltrexone described herein. Extended
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`release formulations can be made by spray drying polymer-drug mixtures, emulsion(cid:173)
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`based technologies, coacervation based technologies, film casting, extrusion based
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`technologies and other processes to manufacture polymer-drug microparticles
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`possessing an extended release profile. Examples of suitable extended release
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`technologies that can be used to incorporate the novel naltrexone forms described herein
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`include, without limitation, the MEDISORB® technology, as described in, for example,
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`US Patent Nos. 6,264,987 to Wright, 5,654,008 and/or 5,792,477, for example; the
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`PROLEASE® technology, as described, for example in US Patent 6,358,443 to Herbert;
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`the technologies described by Southern Research Institute, as described for example in
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`US Patents 6,306,425 and 5,407,609; and "Method of Preparing Sustained Release
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`5 Microparticles," U.S. Application No. 60/441,946, filed January 23, 2003, and the
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`technologies described by Alza Corp., including the ALZAMER® Depot injection
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`technology. The contents of these patents are incorporated herein by reference in their
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`entirety.
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`In a preferred embodiment, the long acting formulation delivers therapeutically
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`beneficial amounts of naltrexone to the patient for a period of at least one week,
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`preferably at least about two weeks, more preferably at least about 3 or about 4 or more
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`weeks. A four week delivery is often referred to as a monthly delivery.
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`In one preferred embodiment, the naltrexone is present in the extended release
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`device or formulation in an amount of at least about 5% by weight, preferably at least
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`about I 0% by weight, more preferably at least about 30% by weight, such as about 35%
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`by weight naltrexone of the total weight of the device, or formulation.
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`Alternatively, instead of incorporating naltrexone into polymeric particles, it is
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`possible to entrap these materials in microparticles prepared, for example, by
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`coacervation techniques or by interfacial polymerization (for ex~mple,
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`hydroxymethylcellulose or gelatine-microcapsules and poly-(methylmethacrylate)
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`microcapsules, respectively), in colloidal drug delivery systems (for example,
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`liposomes, albumin, microparticles, microemulsions, nanoparticles, and nanocapsules),
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`or in macroemulsions.
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`When the composition is to be used as an injectable material, including but not
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`limited to needle-less injection, it can be formulated into a conventional injectable
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`carrier. Suitable carriers include biocompatible and pharmaceutically_ acceptable
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`solutions. The injection can be intramuscular or subcutaneous.
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`While the formulation may contain additional excipients, as is well known in the
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`art, the present invention can achieve an excellen~ release profile with the simple
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`formulation described herein. Such additional excipients can increase or decrease the
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`rate of release of the agent. Ingredients which can substantially increase the rate of
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`release include pore forming agents and excipients which facilitate polymer
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`degradation. For example, the rate of polymer hydrolysis is increased in non-neutral pH.
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`Therefore, an acidic or a basic excipient such as an inorganic acid or inorganic base can
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`be added to the polymer solution, used to form the microparticles, to alter the polymer
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`erosion rate.
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`A preferred embodiment of the described sustained release formulations consists
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`essentially of the biocompatible polymer and naltrexone. By "consists essentially of' is
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`meant the absence of ingredients which substantially increase the rate of release of the
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`active agent from the formulation. Examples of additional excipients which would not
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`be expected to substantially increase or decrease the rate of release of the agent include
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`additional active agents and inert ingredients.
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`In yet another embodiment, the formulation consists of the biocompatible
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`polymer and naltrexone. By "consists of' is meant the absence of components or
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`ingredients other than those listed and residual levels of starting materials, solvents, etc.
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`from the process.
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`As stated above, the formulation preferably releases naltrexone over a period of
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`at least about one, two, three or four weeks. As such, the formulation can be
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`administered using a dosing schedule which achieves the desired therapeutic levels for
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`the desired period oftime. For example, the formulation can be administered and,
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`optionally, the patient monitored until levels of the drug being delivered return to
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`baseline. Following an actual or projected return to baseline, the formulation can be
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`administered again. Alternatively, the subsequent administration of the formulation can
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`occur prior to achieving baseline levels in the patient. As such, the formulation can be
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`advantageously administered weekly, with a one week release formulation, biweekly.
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`with a two week release formulation, or monthly with a four week release formulation.
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`Vivitrex is a four week release formulation with a monthly (e.g., every four weeks)
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`administration. The therapy can end after a single dose or can be maintained for longer
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`periods oftime. In one embodiment, the therapy can maintained for at least about 4, 8,
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`12, 16, 20 and 24 weeks or more. Where more than one administration is given, the
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`second administration can be given at least about 7 days, preferably at least about 14
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`days, more preferably at least about 21 days, such as about 28 days, after the first
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`administration and combinations thereof. In this context "about" preferably means
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`within three days of the targeted date.
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`Particularly good results were achieved upon administering the same
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`formulation and same dose with each administration. Thus, where a 380 mg dose was
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`given in the first administration, good to excellent results were achieved when the
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`second and subsequent doses were about 380 mg. Surprisingly, good to excellent
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`results were also obtained when each dose administered contained 190 mg naltrexone,
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`particularly in men and women who were abstinent from alcohol in the three or five
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`days prior to commencing treatment. As such, in one embodiment of the invention, the
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`doses and/or formulations administered in each subsequent administration were similar
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`or the same. As stated above, the formulation is preferably a microsphere formulation
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`and is administered by IM injection. Administration to the buttock in a volume ofup to
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`about 4 mL in an injectable diluent was performed in the trials leading up to these
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`inventions.
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`The methods of the inventions achieved good to excellent results in women and,
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`in particular, men. Good to excellent results were achieved in young individuals
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`( defined as less than 50 years of age), particularly men. Individuals afflicted by alcohol
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`dependency, such as a heavy drinker achieved good to excellent results. A heavy
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`drinker is understood in the art to include women who consume four or more alcoholic
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`beverages in a day and men who consume five or more alcoholic beverages in a day.
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`In yet another embodiment, the inventions include a method of increasing the
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`days prior to occurrence of alcohol consumption in an individual in need of naltrexone
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`25
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`comprising administering a long acting formulation comprising naltrexone in
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`accordance with the protocols and/or dosing regimens described herein. In one
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`embodiment, the increase in days prior to occurrence of alcohol consumption can
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`include the consumption of a single alcoholic beverage or it can include consumption of
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`four or five alcoholic beverages, such as the number of drinks characterizing an episode
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`of "heavy drinking," above. In general, the greater the number of days that transpire
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`prior to alcohol consumption indicates a more successful therapy.
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`EXEMPLIFICATION
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`5 Method for Manufacturing Vivitrex® Long Acting Formulations
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`The invention includes a preferred method for manufacturing ·extended release
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`devices, wherein the resulting device contains a mixture of the described polymorphic
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`forms.
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`Polymer solution can be formed by dissolving a poly(lactide )-co-glycolide
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`polymer, such as a 75:25 DL PLGA (poly(lactide)-co-glycolide) in a polymer solvent,
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`such as ethyl acetate (EtAc), to form a solution. Preferred PLGA polymers are high
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`molecular weight polymers, such as polymers possessing a molecular weight of at least
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`about 100,000 daltons. A naltrexone solution can be formed by dissolving naltrexone
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`base in a suitable solvent, such as benzyl alcohol (BA), to form a solution. The polymer
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`solution and the naltrexone solution are preferably mixed together to form a
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`drug/polymer solution that will be the "organic" or "oil" phase of the. emulsion.
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`The "aqueous" or "continuous" phase of the emulsion (emulsifying solution) is
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`prepared. The aqueous phase preferably contains poly(vinyl alcohol) (PVA) and
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`polymer solvent, such _as EtAc. The organic phase and the aqueous phase can be
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`conveniently combined in a first static mixer to form an oil-in-water emulsion.
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`In an optional partial extraction step, the emulsion flows out of the first static
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`mixer and into a second static mixer where the emulsion can be combined with a
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`primary extraction solution which enters the second static mixer. The primary
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`extraction solution (such as can be formed by an EtAc aqueous solution) can initiate
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`solvent extraction from the microdroplets of the emulsion during the partial primary
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`extraction step in the second static mixer.
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`The outflow of the first or second static mixer can flow into ah extraction vessel
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`containing primary extraction solution. The solvents (BA and EtAc) are substantially
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`extracted from the organic phase of the emulsion in this primary solvent extraction step,
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`resulting in nascent microparticles comprised mainly of polymer and drug. The primary
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`solvent extraction step lasts for approximately six hours.
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`The microparticles can be collected, and vacuum dried, optionally with a
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`nitrogen bleed using a customized vibratory sieve. After collection and prior to drying,
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`the microparticles are rinsed with a 25% ethanol solution that removes the emulsifying
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`agent (PVA), and enhances yield by aiding in the transfer of the microparticles to the
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`cold dryer. This step is conducted, preferably at cold temperatures, until the desired
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`level of dryness is achieved. As can be seen in the examples below, the degree of
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`dryness (as measured, for example, by a humidity probe), impacts upon the degree of
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`crystallinity achieved in the final product. For example, it can be advantageous to select
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`a drying time of at least about 8, 16, 24 or 40 hours of drying. For example, it can be
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`advantageous to select a drying time of at least about 8, 16, 24 or 40 hours where drying
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`is 40%, 70%, 95% or 100% complete respectively. Drying is considered complete when
`the absolute humidity of the effluent gas reaches approximately 0 g/m3
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`•
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`15
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`The microparticles can then be resuspended in a second extraction solution. The
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`second solution can contain the solvent desired to form the polymorphic form, such as
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`ethanol. For example, a solution comprising at least about 10% by volume, preferably
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`at least about 20% ethanol, can be used. This can be conveniently called the reslurry
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`and secondary solvent extraction steps. The solvent, such as ethanol, can facilitate
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`further extraction of BA and EtAc. Further, the crystallinity of the drug increases
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`during the step. The secondary solvent extraction step is carried out in an extraction
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`vessel for approximately two, three, four or more hours. This step can be conveniently
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`completed at room temperature. However, other temperatures can be selected as well.
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`In the collection/final dry step, the microparticles are collected, and vacuum dried with
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`· 25
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`a nitrogen bleed using a customized vibratory sieve.
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`In the final harvest step, the microparticles can be transferred into a sterile
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`container and stored, for example, in a freezer at -20°C, until filling into vials.
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`Preferably, the stored microparticles are sieved through a 150 micro_n screen to remove
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`any oversized material prior to filling into vials.
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`4000.3010 us
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`Example 1
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`- 10 -
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`The naltrexone base microparticles were produced using a co~solvent extraction
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`process. The theoretical batch size was 15 to 20 grams. The polymer (MEDISORB®
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`7525 DL polymer, MEDISORB® 8515 DL polymer and MEDISORB® 6536 DL
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`5
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`polymer, all available from Alkermes, Inc., Blue Ash, Ohio.) was dissolved in ethyl
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`acetate to produce a 16. 7% w/w polymer solution. The naltrexone base anhydrous was
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`dissolved in benzyl alcohol to produce a 30.0% w/w solution. In various batches, the
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`amount of drug and polymer used was varied to produce microparticles with different
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`theoretical drug loading ranging from 30%-75%. The ambient polymer and drug
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`solutions were mixed together until a single homogeneous solution (organic phase) was
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`produced. The aqueous phase was at ambient conditions and contained I% w/w
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`polyvinyl alcohol and a saturating amount of ethyl acetate. These two solutions were
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`pumped via positive displacement pumps at a ratio of 3: 1 (aqueous: organic) through a
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`1/4" in-line mixer to form an emulsion. The emulsion was transferred to a stirring
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`15
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`solvent extraction solution consisting of 2.5% w/w of ethyl acetate dissolved in distilled
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`water at 5-10° C, at a volume of 0.5L of extraction solution per theoretical gram of
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`microparticles. Both the polymer and drug solvents were extracted into the extraction
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`solution from the emulsion droplets to produce microparticles. The initial extraction
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`process ranged from two to four hours. The microparticles were collected on a 25 µm
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`20
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`sieve and rinsed with a cold ( <5°C) 25% w/w ethanol solution. The microparticles were
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`dried cold overnight (approximately 17 hours) using nitrogen. The microparticles were
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`then transferred to the reslurry solution, which consisted of a vigorously stirring 25%
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`w/w ethanol solution at 5-10°C After a short mixing time (five to fifteen minutes), the
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`reslurry solution and the microparticles were transferred to a stirring 25% w/w ethanol
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`25
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`~econdary extraction solution (approximately 25°C at a volume of0.2 L of secondary
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`extraction solution per theoretical gram of microparticles ). The microparticles stirred
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`for six hours enabling additional solvent removal from the microparticles to take place.
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`The microparticles were then collected on a 25 µm sieve and rinsed 'Yith a 25% w/w
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`ethanol solution at ambient temperature. These microparticles dried in a hood under
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`ambient conditions overnight (approximately 17 hours), were sieved to remove
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`agglomerated microparticles and then placed into a freezer for storage.
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`Example 2
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`A 1 kg batch of naltrexone microspheres was prepared as follows. Polymer
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`5
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`solution was formed by dissolving 75:25 DL PLGA (poly(lactide)-co-glycolide) in ethyl
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`acetate (EtAc) to form a solution of 16.7% polymer and 83.3% EtAc. A naltrexone
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`solution was formed by dissolving naltrexone base in benzyl alcohol (BA) to form a
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`solution of 30% naltrexone base anhydrous and 70% BA. The polymer solution and the
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`naltrexone solution were mixed together to form a drug/polymer solution that was the
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`"organic" or "oil" phase of the emulsion.
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`The "aqueous" or "continuous" phase of the emulsion (emulsifying solution)
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`was prepared by dissolving poly(vinyl alcohol) (PV A) and EtAc in water-for-injection
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`(WFI). The organic phase and the aqueous phase were combined in a first static mixer
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`to form an oil-in-water emulsion. The droplet size of the emulsion was determined by
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`15
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`controlling the flow rates of the two phases through the first static mixer.
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`In a partial primary extraction step, the emulsion flowed out of the first static
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`mixer and into a second static mixer where the emulsion was combined with a Primary
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`extraction solution which enters the second static mixer. The primary extraction
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`solution (2.5% EtAc and 97 .5% WFI at approximately 6°C) initiated solvent extraction
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`20
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`from the microdroplets of the emulsion during the partial primary extraction step in the
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`second static mixer.
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`The outflow of the second static mixer (combined flow stream of the emulsion
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`and the primary extraction solution) flowed into an extraction vessel containing primary
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`extraction solution. The solvents (BA and EtAc) were further extracted from the
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`organic phase of the emulsion in this primary solvent extraction step, resulting in
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`nascent microparticles comprised mainly of polymer and drug. The primary solvent
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`extraction step lasted for approximately six hours.
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`The microparticles were collected, and vacuum dried with a nitrogen bleed using
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`a customized vibratory sieve. After collection and prior to drying, the microparticles
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`were rinsed with a 25% ethanol solution that removes the emulsifying agent (PV A), and
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`enhances yield by aiding in the transfer of the microparticles to the dryer.
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`To further reduce the solvent levels the microparticles were resuspended in a
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`second extraction solution of 25% ethanol and 75% WFI in the reslurry and secondary
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`5
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`solvent extraction steps. The ethanol facilitated further extraction of BA and EtAc. The
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`secondary solvent extraction step was carried out in an extraction vessel for
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`approximately four hours. In the collection/final dry step, the microparticles were
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`collected, and vacuum dried with a nitrogen bleed using a second customized vibratory
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`sieve.
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`10
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`In the final harvest step, the microparticles were transferred into a sterile
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`container and stored in a freezer at -20°C until filling into vials. Preferably, the stored
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`microparticles were sieved through a 150 micron screen to remove any oversized
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`material prior to filling into vials.
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`Example 3
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`Screening and Eligibility Criteria
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`Participants were male or nonpregnant, nonlactating female outpatients ~ 18
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`years old with a current diagnosis of alcohol dependence. Patients had a minimum of
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`two episodes of heavy drinking (~5 alcoholic drinks/day for men and.~4 drinks/day for
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`women) per week during the 30 days prior to screening.
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`Exclusion criteria included evidence of liver failure; alanine aminotransferase
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`(ALT) or aspartate aminotransferase (AST) levels greater than three times the upper
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`limit of normal; history of pancreatitis; major depression with suicidal ideation,
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`psychosis, or bipolar disorder (patients with treated depression and stable
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`pharmacotherapy for at least 8 weeks were not excluded); dependence within the past
`
`25
`
`year on benzodiazepines, opiates, or cocaine; more than 7 days of inpatient treatment
`
`for substance abuse during the month prior to screening; or use of opiates, oral
`
`naltrexone, or disulfiram during the two weeks prior to screening.
`
`Detoxification prior to randomization was performed only if indicated by
`
`investigator judgment and had to be completed seven days before initiation of study
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`

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`4000.3010 us
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`- 13 -
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`therapy. Use of benzodiazepines was prohibited during the week prior to the first dose
`
`of study medication.
`
`Randomization procedures
`
`Patients were randomized to one of three treatment groups: long-acting
`
`5
`
`injectable naltrexone 380 mg, long-acting injectable naltrexone 190 mg, or matching
`
`volumes of placebo ( one-half of the placebo patients received an injection volume
`
`corresponding to 380 mg and the other halfreceived an injection volume
`
`corresponding to 190 mg). The study used a dynamic randomization procedure to
`
`balance allocation on gender, patient-specified goal of total abstinence, self-reported
`
`10
`
`abstinence for the 7-day period prior to first injection, and study site.
`
`Study Procedures and Outcome Definitions
`
`Patients received an injection of study medication at 4-week intervals over 24
`
`weeks, alternating between the left and right gluteus maximus. Injections were
`
`15
`
`prepared and administered by individuals who were not involved in any of the safety
`
`or efficacy assessments, and treatment assignment was blinded to all study personnel.
`
`All patients received standardized supportive therapy (12 sessions) using the
`
`BRENDA model (Volpicelli JR, Pettinati HM, McLellan AT, O'Brien CP. Combining
`
`medication and psychosocial. treatments for addictions: the BRENDA approach. New
`
`20 York: The Guilford Press; 2001), a six-stage low-intensity intervention designed to
`
`facilitate direct feedback with respect to addiction-related consequences. During this
`
`trial, BRENDA sessions were administered by study site personnel including
`
`psychologists, nurses, therapists, counselors, and physicians.
`
`The number of standard drinks consumed per day was recorded using the
`
`25
`
`Timeline Follow Back (TLFB) method (Sobell LC, Sobell MB. Timeline Followback:
`
`a technique for assessing self-reported ethanol consumption. In: Allen J, Litten RZ,
`
`eds. Measuring alcohol consumption: psychosocial and biological methods. Totowa,
`
`NJ: Humana Press, 1992:41-72). Breath alcohol levels of :'.::0.02 gm/dL were required
`
`before self-report data were collected. Patients who discontinued study drug treatment
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`

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`4000.3010 us
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`- 14 -
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`prematurely were allowed to remain in the study, continue to follow the established
`
`visit and procedure schedule, and receive BRENDA treatment.
`
`Study Formulation: Naltrexone long-acting injection (Vivitrex®) consists of
`
`5 microspheres (approximately 100 µM) composed of naltrexone and polylactide-co(cid:173)
`
`glycolide polymeric matrix (Medisorb®), a common biodegradable medical polymer
`
`with an extensive history of human use in absorbable sutures and extended-release
`
`pharmaceuticals. Following injection, naltrexone on the surface of the microspheres is
`
`released, yielding peak concentrations within three days. Thereafter, by a combination
`
`10
`
`of diffusion and erosion, naltrexone is further released for greater than 30 days.
`
`Definition of Outcomes. The primary efficacy endpoint was the event rate of
`
`heavy drinking over the 24 weeks of treatment. The definition of heavy drinking (~5
`
`drinks per day for men and ~4 drinks per day for women) is consistent with that used
`
`15
`
`in previous trials of oral naltrexone. Secondary endpoints included the event rate of
`
`"risky" drinking (>2 drinks per day for men and> 1 drink per day for women)
`
`specified by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) (U.S.
`
`Department of Agriculture/U.S. Department of Health and Human Services. Home
`
`and Garden Bulletin no. 232. Nutrition and yo_ur health: dietary guidelines for
`
`20 Americans. 3rd ed. Washington, DC: Supt. of Docs., U.S. Government. Printing
`
`Office, 1990) and the event rate of any drinking days. Exploratory endpoints included
`
`serum gamma-glutamyl transferase (GGT) changes over time, and time to patient
`
`discontinuation. Adverse events were coded using the MedDRA dictionary of
`
`preferred terms.
`
`25
`
`Statistical Methods
`
`The primary analysis for the primary and secondary endpoints was performed
`
`on an intention-to-treat population (i.e., all randomized patients who received at least
`
`one dose of study medication). The primary objective was to determine whether
`
`30
`
`treatment with long-acting naltrexone (at either 190 mg or 380 mg) decreased the
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`

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`4000.3010 us
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`event rate of heavy drinking relative to treatment with placebo injection. Statistical
`
`methods to analyze multiple drinking episodes in alcoholism treatment clinical trials
`
`have been described by Wang et al., Short of complete abstinence: an analysis
`
`exploration of multiple drinking episodes in alcoholism treatment trials. Alcohol Clin
`
`5
`
`Exp Res. 2002;26: 1803-9. The primary analysis for the primary endp.oint was
`
`performed using a stratified recurrent event Andersen-Gill like model with robust
`
`variance estimation (Lin DY, Wei LJ, Yang I, and Ying Z. Semiparametric regression
`
`for the mean and rate functions of recurrent events. J Royal Stat Soc (B) 2000;62:
`
`711-30; SAS/STAT user's guide. Version 8. Cary, NC: SAS Institute, 1999:2596).
`
`10
`
`The parameters estimated in the model were those representing the treatment effect of
`
`190