PUBLICATION NUMBER: WO/2009/021127

International Application No.: PCT/US2008/072500
Publication Date: 12.02.2009
International Filing Date: 07.08.2008

IPC: A61K 9/22 (2006.01), A61K 9/50 (2006.01)
A61K 9/22 (2006.01), A61K 9/50 (2006.01)(en) -->
A HUMAN NECESSITIES
61 MEDICAL OR VETERINARY SCIENCE; HYGIENE
K PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
9 Medicinal preparations characterised by special physical form
20 Pills, lozenges or tablets
22 Sustained or differential release type
A HUMAN NECESSITIES
61 MEDICAL OR VETERINARY SCIENCE; HYGIENE
K PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
9 Medicinal preparations characterised by special physical form
48 Preparations in capsules, e.g. of gelatin, of chocolate
50 Microcapsules

Applicants:
NEUROGEN CORPORATION [US/US]; 35 NE Industrial Rd., Branford, Connecticut 06405 (US) (For All Designated States Except US).CHU, Jennifer, Hsing-Chung [US/US]; (US) (For US Only).SHOCKEY, Joshua, R. [US/US]; (US) (For US Only)

Inventors:
CHU, Jennifer, Hsing-Chung; (US).SHOCKEY, Joshua, R.; (US)

Agent:
FIDEL, Seth, A.; Cantor Colburn LLP, 20 Church Street, 22nd Flr., Hartford, Connecticut 06103 (US)

Priority Data:
60/954,561 07.08.2007 US

TITLE & ABSTRACT:
(EN) CONTROLLED RELEASED COMPOSITIONS
(FR) COMPOSITIONS Ë LIBÉRATION LENTE

Abstract:
(EN)Provided are controlled-release compositions that include a therapeutically effective amount of adipiplon and a pharmaceutically acceptable carrier. The controlled-release compositions can be a formulation with multiple components, e.g., layers or particles which release adipiplon at different rates. Also provided are methods for inducing sleep and for treating CNS disorders, which methods include administering an effective amount of a controlled-release adipiplon composition to a patient.
(FR)Cette invention concerne des compositions ˆ libŽration lente comprenant une quantitŽ efficace du point de vue thŽrapeutique d'adipiplon et un excipient acceptable du point de vue pharmaceutique. Ces compositions ˆ libŽration lente peuvent consister en une formulation de plusieurs composants, par exemple, des couches ou des particules permettant la libŽration d'adipiplon ˆ des vitesses diffŽrentes. Cette invention concerne Žgalement des mŽthodes permettant d'induire le sommeil et permettant de traiter des troubles du systme nerveux central. Ces mŽthodes consistent ˆ administrer une quantitŽ efficace d'une composition d'adipiplon ˆ libŽration lente ˆ un patient.

Designated States:
AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.African Regional Intellectual Property Org. (ARIPO) (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW)Eurasian Patent Organization (EAPO) (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM)European Patent Office (EPO) (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR)African Intellectual Property Organization (OAPI) (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).

Publication Language:
English (EN)
Filing Language:
English
(EN)

DETAILED DESCRIPTION:





CONTROLLED RELEASE COMPOSITIONS

This application claims priority from US provisional application Serial No. 60/954,561 filed August 7, 2007, and from US provisional application Serial No. 61/085,048, filed July 31, 2008. BACKGROUND Adipiplon is the non-proprietary name for 7-[[2-(3-fluoro-2-pyridinyl)-lH-imidazol-1 -yl]methyl]-2-methyl-8-propyl-[l ,2,4]triazolo[l ,5-c]pyrimidine,

a GABAA receptor partial agonist that is useful in the treatment of sleep disorders as well as in the treatment of other CNS disorders, such as anxiety disorders and cognitive deficits associated with schizophrenia. This compound, along with methods of preparing it and pharmaceutical compositions containing it, is described in US Patent No. 7,271,170. Already tested in clinical trials as a sedative-hypnotic, adipiplon may provide advantages (e.g., faster onset, more refreshing sleep) over currently marketed drugs for the treatment of sleep disorders.

It remains a challenge to develop new formulations for the controlled delivery of adipiplon exhibiting improved pharmacokinetic profiles or other advantages. The present disclosure provides such formulations, and therapeutic methods of using such formulations. SUMMARY OF THE DISCLOSURE Provided herein are novel formulations of adipiplon. As used hereinafter, "adipiplon" includes the free base and any of its pharmaceutically acceptable salts, cocrystalline forms and polymorphs, as well as any hydrates or pharmaceutically acceptable solvates of the foregoing forms of 7-[[2-(3-fluoro-2-pyridinyl)-lH-imidazol-l-yl]methyl]-2-methyl-8-propyl-[l,2,4]triazolo[l,5-c]pyrimidine.

Controlled-release (CR) compositions are provided, preferably as dosage forms that include a therapeutically effective amount of adipiplon together with a pharmaceutically acceptable carrier. Such CR compositions preferably include at least one carrier that comprises at least one release-controlling excipient, which excipient modulates the rate of release of adipiplon from the composition when contacted with an aqueous medium (e.g., a body fluid in the mouth, stomach, small intestine, large intestine, etc.). Representative polymeric release-controlling excipients include KOLLIDON SR, ethylcellulose, and hydroxypropylmethyl cellulose (HPMC - hypromellose). The composition may further include one or more additional excipients, such as diluent(s)/tableting aid(s)/filler(s) (e.g., bulking material(s) that help form the tablet), binder(s) (e.g., material(s) that hold the tableting excipients together to form a tablet), disintegrant(s) (e.g., materials that aid in the wetting and disintegration of a tablet when contacted with an aqueous medium and aids in the dissolution of the active ingredient) and/or lubricant(s) that reduce friction between the tableting excipients/active ingredient and the tableting equipment.

The composition may also be formulated as a multi-component formulation, e.g., comprising two or more components that release adipiplon at different rates or times. For instance, the composition may include at least one immediate-release (IR) component and at least one modified-release (MR) component. The IR and MR components may be combined in any suitable manner e.g., as multiple particles or layers, into unit dosage forms, e.g., a capsule, tablet, pill, troche, pastille or lozenge, or the like. Alternately, they may be administered as a plurality of MR and IR dosage forms administered concurrently or sequentially. The IR component provides rapid onset and the MR component provides delayed onset or sustainment of drug levels.

In certain embodiments, CR compositions provided herein comprise one or more multi-component particles. The multi-component particle may be formulated, e.g., in a multi-layered form, which includes an inert core and one or more surrounding layers. In such an IR multi-component particle, the inert core is surrounded by a layer that comprises the adipiplon. In such an MR multi-component particle, the inert core is typically surrounded by a first layer comprising adipiplon and a sweller material; and a second layer surrounding the first layer, wherein the second layer comprises at least one release-controlling excipient that regulates the diffusion of liquid into the particle. The first layer may comprise the adipiplon admixed with sweller material, or may comprise adipiplon and sweller material in separate sub-strata (i.e., a drug layer and a sweller layer) in either order.

In manufacturing layered multi-component particles it is often desirable to place inert layers between functional layers for purposes such as improved chemical or physical compatibility. Such layers are generally made of water soluble polymers such as HPMC or hydroxypropyl cellulose (HPC), but may be water insoluble (e.g., ethylcellulose) if they are directly on the inert core. These types of barrier layers are well known. They may be placed between any two consecutive components or layers (e.g., API-containing layers) in IR and MR multi-component particles as described herein. Representative multi-component particles are illustrated in Figures 1-4. Compositions provided herein may comprise MR multi-component particles, and may (but need not) further comprise IR multi-component particles.

Also provided are methods for treating CNS disorders, which methods include administering to a patient in need thereof a therapeutically effective amount of a CR composition provided herein. Representative CNS disorders include, e.g., anxiety, cognitive deficits associated with schizophrenia, epilepsy and other convulsive disorders, and sleep disorders, such as, insomnia, primary insomnia, circadian rhythm sleep disorder, dyssomnia NOS, parasomnias including nightmare disorder, sleep terror disorder, sleepwalking, sleep disorders secondary to depression, anxiety and/or other mental disorders and substance-induced sleep disorder. In certain embodiments, the CR compositions provided herein are used to induce and/or maintain sleep in a patient.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the structures of representative IR and MR multi-component spray layered particles, which may be prepared in accordance with, e.g., Examples 7, 12, 13, 14, 15, and/or 16. 1 - Drug layer, 2 - Inert core, 3 - sweller layer, 4 - MR layer.

Figure 2 illustrates the structures of representative IR and MR multi-component melt spray congeal particles, which may be prepared in accordance with, e.g., Example

18. 5 - MR matrix, 6 - Drug, 7 - IR matrix. Figure 3 illustrates the structures of representative multi-component spray-layered melt spray congeal particles. 8 - Drug layer, 9 - Matrix, 10 - MR layer, 11 - Matrix + disintegrant. In the exemplified MR particle, drug layer 8 is situated between outer layer 10 and core 11.

Figure 4 illustrates the structure of a representative multi-component tablet with IR and MR layers, which may be prepared in accordance with, e.g., Examples 4, 5, 6, 8, 9, 10, and/or 11. 12 - IR layer, 13 - MR layer.

Figure 5 depicts pharmacokinetic data associated with representative compositions provided herein (see Example 3). The figure shows mean adipiplon plasma concentration versus time profiles in insomnia patients following oral administration of 1 mg IR+ 2 mg MR or 2 mg IR + 5 mg MR adipiplon tablet formulations (Data source: Study NG2-73-202). X axis - Time (h), Y axis - Cone. (ng/niL). Upper curve (% ) 2mg IR + 5mg MR. Lower curve ( &f ) lmg IR + 2mg MR.

DETAILED DESCRIPTION Provided herein are CR compositions that include a therapeutically effective amount of adipiplon, and a pharmaceutically acceptable carrier. Adipiplon is free base is preferred. Polymorphic forms of adipiplon include Form I and Form II, as described in priority application 61/085,048, filed July 31, 2008, having properties as set forth in the table below. Form II is preferred.

Representative Physical/Chemical Properties of adipiplon Form I and Form II

In one aspect, a CR composition is provided that includes a therapeutically effective amount of adipiplon, which is formulated in accordance with U.S. Patent No. 6,309,668, 4,963,365, 4,865,849, 5,425,950, 5,387,421, 5,976,571, 6,485,746,

4,576,604, 5,840,329, 5,672,360, 5,750,143, 6,500,454, 6,605,300, 6,632451, 6,663,888, 4,994,273, 5,609,590, 5,698,220, 4,871,549, 5,260,069, 6,627,223,

7,048,945, 5,229,134, 5,482,718, 5,540,945, 5,654,009, 5,788,987, 5,891,474, 6,039,975, 6,190,692, 6,764,697, 6,972,132, RE039239, 4,186,184, 4,200,098,

4,285,987 4,298,003, 4,320,759, 4,327,725, 4,361,546, 4,522,625, 4,539,198, 4,576,604 4,608,048, 4,612,008, 4,643,731, 4,681,583, 4,716,041, 4,773,907,

4,777,049, 4,783,337, 4,986,987, 5,141,752, 5,156,850, 6,638,535, 5,068,112, 5,395,628, 5,328,697, 5,516,531, 5,516,531, 5,626,876, 5,711,967, 5,840,329, 5,855,914, 5,958,459, 6,103,261, 4,844,9009, 4,990,341, 5,478,577, 5,891,471, 6,399,096, 6,099,862, 6,284,275, 6,485,746, 6,495,162, 6,514,531, 6,899,896, 6,913,768, 5,972,938, 4,626,538, 5,213,800, 6,07,2086, 6,200,602 or 6,319,683, or in accordance with U.S. Patent Application Pub. No. 2006/0159744, 2006/0189633, 2004/0258750 or 2003/0091632, or in accordance with EP 100583, WO 96/41617, EP 0908177, WO 01/00181 or WO 98/13029.

The composition preferably includes a carrier that contains excipients, such as those found in the Handbook of Pharmaceutical Excipients (ISBN 0853696187), which provides additional suitable examples of lubricants, binders, disintegrants, diluents, and the other types of excipients disclosed herein. Certain preferred compositions include at least one release-controlling excipient, which controls the rate of release of adipiplon from the composition upon administration to a patient. Such release may occur, for example, upon contact with an aqueous medium (e.g., in the mouth, stomach, small intestine, large intestine, etc.). The release-controlling excipient preferably includes a polymer, such as a vinyl polymer, e.g., polyvinyl acetate, polyvinylpyrrolidone (PVP, povidone) or a mixture thereof. A representative mixture that can be used as a release controlling excipient, is marketed by BASF under the trademark KOLLIDON SR, which is supplied as a physical mixture of polyvinyl acetate (80 wt%) and PVP (19 wt%), and also includes sodium lauryl sulfate (0.8%) and silica (0.2%), which act as stabilizers. Suitable release-controlling polymers also may include one or more cellulose derivatives, e.g., one or more alkyl celluloses, e.g., HPMC or ethylcellulose, e.g., Dow ETHOCEL. Other matrix polymers such as polyethylene oxide (PEO) may also be used.

The composition may further include a diluent, filler and/or tableting aid. Suitable diluents, fillers and/or tableting aids may include, for example, one or more saccharides, polysaccharides or a mixture thereof. Representative diluents include sucrose, lactose, mannitol, and microcrystalline cellulose. Lactose is among the preferred diluents for use in the compositions provided herein.

The composition may comprise a binder. Representative binders may include, e.g., one or more of HPC, PVP, HPMC, PEO, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, methyl cellulose, polydextrose, guar gum, dextrose, dextrin, alginic acid or mixtures thereof.

Alternatively, or in addition, the composition may include a lubricant. Suitable lubricants include, for example, fatty acids (e.g., stearic acid) and salts thereof (e.g., magnesium stearate).

The composition may be formulated to include two or more components that release the adipiplon at different rates. In one embodiment, the composition includes at least one immediate-release (IR) component and at least one MR component, wherein the IR and MR components release at least a portion of the adipiplon at different rates. The IR component is formulated to dissolve rapidly with the aim of providing rapid onset of therapeutic activity associated with the adipiplon following administration of the composition to a patient in need thereof (e.g., inducing sleep onset in a mammal such as, e.g., a human, within about 60 minutes, 45 minutes or preferably 30 minutes or more preferably 15 minutes following oral administration). The MR component is formulated to sustain, delay and/or prolong the dissolution of the adipiplon therein so as to sustain, delay and/or prolong its therapeutic activity (e.g., by delaying or slowing dissolution and absorption of the adipiplon in the gastrointestinal tract, such that it is released at a rate that provides blood (e.g., plasma) concentrations within the therapeutic range over a period of time that is at least 2-4 hours, preferably at least 5 hours, and more preferably at least 6 hours). Representative formulations comprising IR and MR components are described in U.S. Pat. Nos. 6,309,668, 4,963,365, 4,865,849, 5,425,950, 5,387,421, 5,976,571, 6,485,746, 4,576,604, 5,840,329, 5,672,360, 5,750,143, 6,500,454, 6,605,300, 6,632,451, and 6,663,888.

IR and MR components may be formulated in any suitable manner, e.g., multiple layers or granules in a unit dosage form. For instance, the composition may be formulated as dosage forms that include a first layer and a second layer (first and second here do not indicate order of assembly or operation), wherein the first layer includes an IR component and the second layer includes an MR component. Such layers may be arranged in any suitable configuration, e.g., wherein first and second layers described herein are fused together side by side in the form of a bilayer tablet, for example, as shown in Figure 4. In other embodiments, the MR and IR components may be formulated as separate compositions (e.g., tablets or particles such as multi-component particles) that are administered together (e.g., simultaneously or sequentially in either order). Representative IR tablets may be formulated, for example, in accordance with any of U.S. Patent Nos. 5,082,669, 5,211,957, or 6,531,152, or WO 99/09958.

The MR component preferably includes at least one release-controlling excipient, e.g., as described herein. For instance, the MR component may include one or more release-controlling polymers such as, e.g., one or more vinyl polymers, e.g., polyvinyl acetate, PVP or a mixture thereof (such as, e.g., KOLLIDON SR), one or more cellulose derivatives, e.g., one or more alkyl celluloses (such as, e.g.,

ETHOCEL ethylcellulose polymers), one or more grades of HPMC (such as, e.g. METHOCEL),and PEO and the like, and combinations thereof.

In certain embodiments, the IR component comprises a disintegrant. Suitable disintegrants may include, for example, one or more carboxyalkylcellulose derivatives such as, e.g., cross-linked carboxyalkylcellulose derivatives (e.g., croscarmellose sodium, which is an internally cross-linked form of carboxymethylcellulose sodium).

Compositions provided herein also may comprise one or more diluents, e.g., one or more saccharides, polysaccharides or a mixture thereof as described herein, e.g., lactose, mannitol, cellulose (e.g., microcrystalline cellulose), and the like, and mixtures thereof. Alternatively, or in addition, the composition may comprise one or more lubricants, e.g., one or more fatty acids and salts thereof (e.g., stearic acid, magnesium stearate, and the like, and mixtures thereof). Alternatively, or in addition, the composition may comprise one or more binders, e.g., one or more of HPC, PVP, HPMC, PEO, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, methyl cellulose, polydextrose, guar gum, dextrose, dextrin, alginic acid, or the like.

In a bilayer tablet embodiment, a tablet is provided having first and second layers, wherein the first layer contains an IR formulation and the second layer includes an MR component. The first layer of the bilayer tablet includes at least a portion of the adipiplon and, in certain embodiments, at least one diluent, at least one disintegrant and optionally, at least one lubricant. The adipiplon is preferably present in the first layer in an amount ranging from about 0.1 wt% to about 5 wt%, from about 0.1 wt% to about 3 wt%, from about 0.1 wt% to about 2 wt%, from about 0.5 wt% to about 2 wt%, or preferably from about 0.5 wt% to about 1 wt%, based on the weight of the first layer (uncoated). The diluent, which includes, for example, lactose, microcrystalline cellulose or a combination thereof, is preferably present in the first layer in an amount ranging from about 60 wt% to about 97 wt%, from about 75 wt% to about 97 wt%, from about 80 wt% to about 97 wt%, from about 90 wt% to about 97 wt%, or from about 90 wt% to about 96 wt%, based on the weight of the first layer (uncoated). In certain embodiments, the diluent in the first layer is a combination of lactose and microcrystalline cellulose, wherein the lactose is present in an amount ranging from about 30 wt% to about 70 wt%, from about 40 wt% to about 70 wt%, or from about 40 wt% to about 50 wt% (e.g., about 50 wt%), and the microcrystalline cellulose is present in an amount ranging from about 30 wt% to about 70 wt%, from about 30 wt% to about 60 wt%, based from about 30 wt% to about 50 wt%, or from about 40 wt% to about 50 wt% (e.g., about 45 wt%), based on the weight of the first layer (uncoated). The disintegrant, which includes, for example, croscarmellose sodium, is preferably present in the first layer in an amount ranging from about 0.5 wt% to about 10 wt%, from about 1 wt% to about 5 wt%, from about 2 wt% to about 5 wt%, or from about 2 wt% to about 4 wt% (e.g., about 3 wt%), based on the weight of the first layer (uncoated). The lubricant, which includes, for example, stearic acid, is preferably present in the first layer in an amount ranging from about 0.1 wt% to about 5 wt%, from about 0.1 wt% to about 2 wt%, or from about 0.5 wt% to about 2 wt% (e.g., about 1 wt%), based on the weight of the first layer (uncoated). The second layer of the bilayer tablet includes at least a portion of the adipiplon and, in certain embodiments, a release-controlling polymer such as KOLLIDON SR, optionally at least one diluent and optionally at least one lubricant. The adipiplon is preferably present in the second layer in an amount ranging from about 0.1 wt% to about 10 wt%, from about 1 wt% to about 5 wt%, from about 1 wt% to about 2 wt%, from about 2 wt% to about 8 wt%, or from about 5 wt% to about 8 wt%, based on the weight of the second layer (uncoated). The release-controlling polymer (e.g., KOLLIDON SR) is preferably present in the second layer in an amount ranging from about 30 wt% to about 70 wt%, from about 30 wt% to about 60 wt%, from about 40 wt% to about 60 wt%, from about 40 wt% to about 55 wt%, or from about 45 wt% to about 55 wt%, based on the weight of the second layer (uncoated). The diluent, which includes, for example, lactose, is preferably present in the second layer in an amount ranging from about 30 wt% to about 70 wt%, from about 40 wt% to about 70 wt%, from about 40 wt% to about 60 wt%, from about 40 wt% to about 50 wt% based on the weight of the second layer (uncoated). The lubricant (e.g., stearic acid) is preferably present in the second layer in an amount ranging from about 0.1 wt% to about 5 wt%, from about 0.1 wt% to about 2 wt%, or from about 0.5 wt% to about 2 wt% (e.g., about 1 wt%), based on the weight of the second layer (uncoated).

The bilayer tablet comprising the first and second layers is, in certain embodiments, coated with a film coating that includes a suitable film-forming polymer (e.g., OPADRY 85F). The film coating preferably constitutes from about 1 wt% to about 10 wt%, from about 1 wt% to about 8 wt%, from about 1 wt% to about 6 wt%, from about 2 wt% to about 6 wt%, from about 3 wt% to about 5 wt% (e.g., about 4 wt%), based on the total weight of the tablet (uncoated).

In one embodiment, the bilayer tablet consists essentially of about 100 mg of a first layer (uncoated weight), which consists essentially of from about 0.1 wt% to about 5 wt% adipiplon, from about 60 wt% to about 97 wt% of a diluent, which is a combination of lactose and microcrystalline cellulose, wherein the lactose and microcrystalline cellulose are each present in an amount ranging from about 30 wt% to about 70 wt%, individually, from about 0.5 wt% to about 10 wt% croscarmellose sodium, and from about 0.1 wt% to about 5 wt% stearic acid, based on the weight of the first layer (uncoated), and about 100 mg of a second layer (uncoated weight), which consists essentially of from about 0.1 wt% to about 10 wt% adipiplon, from about 30 wt% to about 70 wt% KOLLIDON SR, from about 30 wt% to about 70 wt% lactose, and from about 0.1 wt% to about 5 wt% stearic acid, based on the weight of the second layer (uncoated), and the tablet is coated with from about 1 wt% to about 10 wt%, preferably 3 wt% to 5 wt%, e.g., about 4 wt%, of a film coating. The components of the bilayer tablet also may be present in any suitable combination of any of the other ranges described herein.

The composition also may be formulated as a multi-component particle comprising adipiplon. As used herein, a "multi-component particle" is a solid material such as a bead, pellet, microsphere or granulate that comprises multiple internal components, at least one of which comprises adipiplon. In one embodiment, the multi-component particle is a multi-layered particle, which comprises an inert core layer (e.g., a microcrystalline cellulose core) and one or more surrounding layers. In an IR multi-layer particle, the inert core is typically surrounded by an adipiplon-containing layer. In an MR multi-component particle, the inert core is typically surrounded by a first layer comprising adipiplon and a sweller material; and a second layer surrounding the first layer, wherein the second layer comprises at least one release-controlling excipient that regulates the diffusion of liquid into the particle. The first layer may comprise the adipiplon admixed with sweller material, or may comprise adipiplon and sweller material in separate sub-strata (i.e., a drug layer and a sweller layer) in either order.

Representative multi-component particles are described in U.S. Pat. Nos. 4,994,273, 5,609,590, 5,698,220, 4,871,549, 5,260,069, 6,627,223, and 7,048,945.

In another embodiment, the MR composition releases up to about 60% of the adipiplon within about one hour, up to about 80% of the adipiplon within about 2 hours, and at least about 95% of the adipiplon within about 6 hours, in 0.1 N HCl.

In another embodiment, the CR composition releases up to about 60% of the adipiplon within about 30 minutes, up to about 75% of the adipiplon within about 1 hour, and at least about 85% of the adipiplon within about 4 hours, in 0.1 N HCl.

In another embodiment, the MR composition releases up to about 10% of the adipiplon within about 30 minutes, up to about 75% of the adipiplon within about 2 hours, and at least about 90% of the adipiplon within about 3 hours, in pH 6.8 Phosphate buffer.

In another embodiment, the MR composition releases up to about 10% of the adipiplon within about 1 hour, up to about 75% of the adipiplon within about 3 hours, and at least about 90% of the adipiplon within about 4 hours, in pH 6.8 Phosphate buffer.

Preferably, the composition releases the adipiplon at a rate such that the Tmax (time at which maximum blood levels are achieved in vivo) is from about 0.5 h to about 5 h when administered orally to a human, hi one embodiment the plasma concentrations of adipiplon provided are > 2ng/mL at 40 minutes, > 2 ng/mL from 4-6 hours, and < 2ng/mL at 8 hours.

If desired, the adipiplon may exist as a mixture in combination with one or more additional excipients, e.g., one or more cellulose derivatives such as HPMC, e.g., METHOCEL E5).

Any suitable inert core may be used in the multi-component particle. Suitable inert core materials may include, e.g., one or more sugars (e.g., sucrose) or microcrystalline cellulose. A representative inert core includes sucrose spheres sold under the trademark NUPAREILS or microcrystalline cellulose cores sold under the name of CELPHERE.

Any optional inert layer such as seal coat (i.e., a coating that may protect the core from attrition during processing) or overcoat layers (i.e., coatings that may protect the particle from attrition prior to administration) layers may contain any suitable material(s) known in the art including, for example, cellulose derivatives (e.g., an alkyl cellulose as described herein, e.g., ethylcellulose). The seal coat may further include one or more additional ingredients (e.g. plasticizers) such as, e.g., dibutyl sebacate (DBS). In one embodiment, the multi-component particle includes an overcoat layer that contains a hydroxyalkylcellulose, such as HPMC, e.g., hypromellose E5.

As noted above, the sweller material may be admixed with adipiplon, or may be present in a separate sweller layer. As used herein, a "sweller material" is a material that increases in volume (i.e., swells) after exposure to water. In certain embodiments, the sweller layer comprises a disintegrant, e.g., carboxymethylcellulose (e.g., AC-DI-SOL) or sodium starch glycolate (e.g., EXPLOTAB). In addition, the sweller layer may further comprise a binder, e.g., hydroxypropylcellulose (KLUCEL) or hypromellose.

Also contemplated is the formulation of adipiplon in multi-component particle in accordance with U.S. Patent No. 5,609,590.

The multi-component particle may exist in a multi-layered configuration as described herein. Representative multi-layered configurations are illustrated in Figures 1, 3, and 4.

The composition provided herein may be in any suitable form for oral administration. Such forms may include, for example, tablets, troches, lozenges, or hard or soft capsules.

Compositions may further include one or more components such as sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide appealing and palatable preparations. Tablets may contain other physiologically acceptable excipients that are suitable for their manufacture such as, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic acid), binding agents (e.g., starch, gelatin or acacia) and lubricating agents (e.g., magnesium stearate, stearic acid or talc). Compositions for oral administration also may be presented as hard gelatin capsules or as soft gelatin capsules, troches, lozenges, or the like.

As used herein, a "therapeutically effective amount" is an amount that, upon administration to a patient, results in a discernible patient benefit (e.g., diminution of one or more symptoms of a CNS disorder or a desired effect on sleep). Such an amount or dose generally results in a concentration of compound in cerebrospinal fluid that is sufficient to inhibit the binding of GABAA receptor ligand to GABAA receptor in vitro, as determined using the assay described in Example 6 of US Patent No. 7,271,170. It will be apparent that the therapeutically effective amount will depend upon the indication it is administered, as well as any co-administration of other CNS agent(s). The discernible patient benefit may be apparent after administration of a single dose, or may become apparent following repeated administration of the therapeutically effective dose according to a predetermined regimen, depending upon the indication for which the compound is administered.

In certain embodiments, compositions providing dosage levels ranging from about 0.1 mg to about 2 mg per kilogram of body weight per day are preferred (about 0.5 mg to about 0.1 g per human patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 120 mg of an active ingredient. It will be understood, however, that the optimal dose for any particular patient will depend upon a variety of factors, including the nature of the specific formulation employed; the age, body weight, general health, sex and diet of the patient; the time and route of administration; the rate of excretion; any simultaneous treatment, such as a drug combination; and the type and severity of the particular disease undergoing treatment. Optimal dosages may be established using routine testing and procedures that are well known in the art.

The composition provided herein may be packaged for treating a CNS disorder such as anxiety, depression, a sleep disorder, attention deficit disorder or a cognitive disorder such as short-term memory loss or Alzheimer's dementia. Packaged pharmaceutical preparations may include a container holding a therapeutically effective amount of adipiplon and instructions (e.g., labeling) indicating that the contained composition is to be used for treating the CNS disorder.

Also provided are methods for treating a CNS disorder, e.g., as described in US 2005/0038043, which methods include administering to a patient in need thereof a CNS disorder-inhibiting effective amount of the controlled-release composition as provided herein. CNS disorders that may be treated as described herein include, for example, anxiety and sleep disorders. In one embodiment, the method includes treating a sleep disorder, e.g., by administering the composition provided herein in an amount effective to alleviate one or more symptoms associated with a sleep disorder.

The following examples are by way of non-limiting illustration.


EXAMPLES
EXAMPLE 1 This example demonstrates the manufacture and release testing of a modified-release tablet as provided herein.

Modified-release tablets having 2.0 mg or 5.0 of adipiplon free base are manufactured in a batch from the components provided in Table IA.

Table IA

All components are passed through a 30 mesh screen before dispensing.

To prepare the 1 mg tablets, the following procedures are followed. For preparing the 5 mg tablets, these procedures are followed with appropriate modifications, e.g., as to amounts of excipients added in each step.

Item 1, the adipiplon and KOLLIDON SR (Item 2A) is charged into a 2 qt. V-blender and mixed for approximately 5 minutes at 25 rpm +/- 1 rpm.

The blend is discharged into a labeled container lined with double polyethylene bags. The resulting product and KOLLIDON SR (Item 2B) are charged into a 4 qt. V-blender and blended for approximately 5 minutes at 25 rpm +/- 1 rpm.

Lactose FAST FLO (Item 3A) is added to the 4 qt V blender containing the blend, and blended for approximately 5 minutes at 25 rpm +/- 1 rpm. The resulting product is passed through a 30 mesh screen and the blend is collected into a labeled container lined with double polyethylene bags.

Lactose FAST FLO (Item 3B), the bagged blend from the preceding step, stearic acid (Item 5), KOLLIDON SR (Item 2C), and ETHOCEL (Item 4) are charged into a 16 qt blender in the listed order. The components are blended for 7 minutes at 25 rpm +/- 1 rpm.

The remaining blend is discharged into a tared container and sealed.

The blend lot is then compressed using a rotary tablet press and tablet deduster with 6 mm standard concave plain upper and lower punches. The tablets are collected in a tared container and sealed.

Tablets manufactured according to this method may be administered alone, or in combination with other formulations of adipiplon provided herein, and have the formula provided at Table IB.

Table IB

Table 2 provides a 1 mg IR tablet formulation that may be manufactured using typical blending and compression procedures. Table 2

EXAMPLE 2 This example describes a method for determination of dissolution release of controlled-release tablets as provided herein.

Dissolution testing is performed on 2 mg controlled-release tablets, prepared as in Example 1, above.

USP Dissolution Apparatus II (Paddle Method) is used at 50 RPM. The tablet is dissolved in 900 mL of 0.1N HCl at 37.0 0C +/- 0.5 0C. Dissolution is sampled (10 mL, with dissolution medium replacement) at 0.5, 1, 2, 4, 6, and 8 hours, and at infinity (30 minutes at 250 RPM). A 45 1/4m nylon Acrodisc syringe filter is used.

HPLC analysis is performed on each dissolution sample in an Inertsil ODS-3, 5 1/4m, 150 mm x 4.6 mm or equivalent column, at ambient temperature, for UV detection at 250 nm. The mobile phase is 50% Phosphate buffer (pH 3.5, 50 mM sodium phosphate in DI water, adjusted with phosphoric acid) and 50% methanol. The injection volume is 100 1/4L, and the flow rate is 1.2 mL/min. The approximate run time is 10 minutes, with an approximate retention time of the active agent of 6.2 minutes.

Peak area responses are quantified as shown in Table 3.

Table 3

Based on these results, a dissolution profile for a controlled-release composition provided herein can be understood. EXAMPLE 3 This example demonstrates the pharmacokinetic data of controlled-release compositions comprising adipiplon.

Two dosage regimens are provided to different groups of patients. A first group of patients receives 1 mg of adipiplon free base in an IR tablet formulation, plus 2 mg of MR adipiplon free base in an MR tablet formulation, each as described above in Example 1.

A second group of patients receives 2 of the 1 mg IR tablets, and concurrently receives 5 mg of adipiplon free base in a separate MR tablet formulation as per Example 1.

Pharmacokinetic data for the first dosage regimen is presented in Table 4.

Table 4

Pharmacokinetic data for the second dosage regimen is provided in Table 5

Table 5

The dosage regimen having 2 mg IR and 5 mg MR have a higher peak serum concentration (Cmax) as well as a higher concentration at all timepoints up to 12 hours (Figure 5). Peak serum levels (Tmax) occurr later for this formulation as well, at 2.07 h as opposed to 1.63 h.

EXAMPLE 4 This example demonstrates the preparation of bilayer tablets having an immediate-release layer and a modified-release layer.

Representative bilayer tablets, which can be prepared according to this example, are shown in Table 6a.

Table 6a

Notes: a) Assumes 100% potency of adipiplon b) For IR layer, adjust microcrystalline cellulose amount for potency if necessary c) For MR layer, adjust lactose amount for potency if necessary d) Water is volatile component used for film coating suspension solvent e) 1.5 = 1 + 0.5 mg/tablet, 3.0 = 1.0 + 2.0 mg/tablet, 6.0 = 1.0 + 5.0 mg/tablet, 9.0 = 1.0 + 8.0 mg/tablet. Bilayer tablets can be prepared as follows.

Preparation of the MR layer Step 1. To prepare the MR portion of the bilayer tablet, place 86.2 g FAST FLO Lactose in a 2 qt. V-blender, followed by 75.0 g adipiplon free base and then 86.3 g FAST FLO Lactose, then blend for 2 minutes. Add 172.5 g FAST FLO Lactose and the mix for another 2 minutes. Pass the mixture through a #40 mesh screen.

Step 2. Add 532.5 g KOLLIDON SR to the 2 qt. V-blender, mix for 2 minutes, and then pass through a #40 mesh screen. Pass an additional 532.5 g KOLLIDON¨ SR through a #40 mesh screen without blending.

Step 3. Pass 15.O g of stearic acid through a #40 mesh screen.

Step 4. Add the products from steps 1-3 to a 4-quart V-blender, blend for 6 minutes, pass through a #40 mesh screen and blend for an additional 6 minutes.

Preparation of the IR layer

Step 1. Place 375.2 g FAST FLO Lactose in a 2 qt. V-blender, followed by 7.7 g adipiplon free base and blend the mixture for 1 minute. Add 375.2 g of FAST FLO Lactose and blend for another 1 minute. Add 45.1 g of croscarmellose sodium and blend the mixture for 1 minute. Pass the contents of the blender through a #30 mesh screen.

Step 2. Pass 15.1 g of stearic acid through a #30 mesh screen.

Step 3. Add the products from steps 1 and 2, along with 682.7 g AVICEL PH 102, to the V-blender and blend for 6 minutes.

Tabletting

Compress the blends into tablets as outlined below:

Tooling: 9/32" round standard concave

MR layer target weight = 100.0 mg

IR layer target weight = 100.0 mg Additional bilayer tablet formulations can be prepared by adapting these methods to the first layer formulations set forth below in Table 6b combined with a second layer selected from that of Table 6c, 6d or 6e. In each table, a first preferred concentration range (First Range) is specified for each ingredient, along with a more preferred concentration range for that ingredient (Preferred Range). In each range, each wt% value should be read as about that wt%. Preferred types and proportions (to each other) of lactose and microcrystalline cellulose are those set forth for the IR layer in Table 6a. Preferred proportions of METHOCEL E4M to METHOCEL E5 are about 4 to 3. Of course, total concentrations for all components in each layer will add up to 100 wt%.





EXAMPLE 5 This example demonstrates formulations for modified-release and immediate release layers in representative bilayer tablets. MR layers containing 1 mg and 5 mg of adipiplon are described in Table 7.

Table 7

IR layers containing 0.5 mg, 1 mg and 2 mg of adipiplon are described in Table 8. Table 8

The MR and IR layers described in this example can be combined to form representative bilayer tablets. EXAMPLE 6 This example demonstrates additional representative formulations for modifed- release components of bilayer tablets.

Table 9

Table 10 - Additional modified-release formulations

EXAMPLE 7 This example describes a representative controlled-release composition that contains multi-layer particles.

Table 11

EXAMPLE 8 This example demonstrates the preparation of preferred bilayer tablets having an IR layer and an MR layer. Representative bilayer tablets, which can be prepared according to this Example, are shown in Table 12.

Table 12

1.5 = 1 + 0.5 mg/tablet, 3.0 = 1.0 + 2.0 mg/tablet, 6.0 = 1.0 + 5.0 mg/tablet, 9.0 = 1.0 + 8.0 mg/tablet. Bilayer tablets are prepared as follows: A. Preparation of the IR layer Step 1. The adipiplon is micronized and passed through a 16 mesh screen before weighing. All raw materials are then weighed as indicated in Table 12.

Step 2. The AVICEL PH 102 is placed in a VG-25 granulator. The stearic acid is passed through a 40 mesh screen into the VG-25 granulator and mixed for 1 min (impeller speed = 180 rpm; chopper speed = 1400 rpm).

Step 3. The micronized drug, together with PHARMATOSE DCLI l and Croscarmellose sodium are placed in the VG-25 granulator in the order listed, and mixed for 5 min (impeller speed = 180 rpm; chopper speed = 1400 rpm).

Step 4. The filter bag is shaken and the lid and walls of the granulator scraped. The mixture is then mixed for 5 min (impeller speed = 180 rpm; chopper speed = 1400 rpm).

B. Preparation of the MR layer

Step 1. The adipiplon is micronized and passed through a 16 mesh screen before weighing. AU raw materials are then weighed as indicated in Table 12.

Step 2. The KOLLIDON SR is placed in a VG-25 granulator. The stearic acid is passed through a 40 mesh screen into the VG-25 granulator and mixed for 1 min (impeller speed = 180 rpm; chopper speed = 1400 rpm).

Step 3. The micronized drug and PHARMATOSE DCLl 1 are placed in the VG-25 granulator in the order listed, and mixed for 5 min (impeller speed = 180 rpm; chopper speed = 1400 rpm).

Step 4. The filter bag is shaken and the lid and walls of the granulator scraped. The mixture is then mixed for 5 min (impeller speed = 180 rpm; chopper speed = 1400 rpm).

Step 5. The filter bag is shaken and the lid and walls of the granulator scraped. The mixture is then mixed for 5 min (impeller speed = 180 rpm; chopper speed = 1400 rpm).

C. Tableting

The blends are compressed into tablets as outlined below:

Tooling: 9/32" round standard concave

MR layer target weight = 100.0 mg

IR layer target weight = 100.0 mg

D. Coating

Step 1. The tables are added to the coating pan.

Step 2. The coating material is weighed in an amount sufficient to achieve a 4 % coating weight gain on the tablet, plus about 50% extra for wastage.

Step 3. The coating material is dispersed with the aid of a mixer in a sufficient amount of water to result in 20% solids concentration.

Step 4. The coating pan and tablets are warmed.

Step 5. The tablets are coated with the coating material until a weight gain of 4 % is achieved.

Step 6. The tablets are dried and allowed to cool.

Step 7. The tablets are discharged into tared, labeled polybags.

EXAMPLE 9 This example describes a method for determination of dissolution release of controlled-release tablets as provided herein.

Dissolution testing is performed on controlled-release tablets, such as those prepared in Example 8, above.

USP Dissolution Apparatus II (Paddle Method) is used at 50 RPM. The tablet is dissolved in 900 mL of 0.1N HCl at 37.0 0C +/- 0.5 ĄC. Dissolution is sampled (10 mL, with dissolution medium replacement) at 5, 10, 20, and 30 min,and 1, 2, 4, 6, and 8 hours, and at infinity (30 minutes at 250 RPM). A 45 1/4m nylon Acrodisc syringe filter is used.

HPLC analysis is performed on each dissolution sample in an Inertsil ODS-3, 5 1/4m, 150 mm x 4.6 mm or equivalent column, at ambient temperature, for UV detection at 250 nm. The mobile phase is 50% Phosphate buffer (pH 3.5, 50 niM sodium phosphate in DI water, adjusted with phosphoric acid) and 50% methanol. The injection volume is 100 1/4L, and the flow rate is 1.2 mL/min. The approximate run time is 10 minutes, with an approximate retention time of the active agent of 6.2 minutes.

Peak area responses are quantified as shown in Table 13, below.

Table 13

Based on these results, a dissolution profile for a controlled-release composition provided herein can be understood.

EXAMPLE 10 This example demonstrates an additional representative formulation and manufacturing process for the modified-release component of a bilayer tablet provided herein.

Table 14

Step 1. Separated adipiplon free based into two equal portions.

Step 2. Layered one portion of the adipiplon between layers of METHOCEL E4M in a V-shell blender and blended for 7 minutes. Discharged into a poly-bag.

Step 3. Added half of the mannitol to the V-shell blender and blended for 3 minutes. Discharged into the poly-bag.

Step 4. Layered second portion of the adipiplon between layers of METHOCEL E5 in a V-shell blender and blended for 7 minutes. Discharged into a poly-bag.

Step 5. Added remaining half of the mannitol to the V-shell blender and blended for 3 minutes. Discharged into the poly-bag.

Step 6. Added the citric acid to 267 g of water and stirred using overhead mixer until totally dissolved.

Step 7. Weighed lOOg of water into separate container.

Step 8. Transferred the contents of the poly-bags into a high shear granulator bowl.

Step 9. Mixed in the high shear granulator bowl for 3 minutes using 200 rpm impeller speed.

Step 10. Granulated with citric acid solution addition of approximately 82 g/min, 300 rpm impeller speed, and 1500 rpm chopper speed for 3-4 minutes.

Step 11. Mixed for additional 1-2 minutes using 300 rpm impeller speed and 1500 rpm chopper speed.

Step 12. Granulated with additional lOOg of water using same parameters as previously.

Step 13. Mixed for additional 3 minutes using 300 rpm impeller speed and 1500 rpm chopper speed.

Step 14. Dried using a fluid bed dryer with inlet temperature of approximately 65 0C until loss on drying is at or below 1.5%.

Milled granulation using a Fitz mill with a size 0033 round hole screen.

EXAMPLE I l This example describes a method for determination of dissolution release of controlled-release tablets as provided herein.

Dissolution testing is performed on 5 mg controlled-release tablets, such as those prepared in Example 10, above.

USP Dissolution Apparatus II (Paddle Method) is used at 50 RPM. The tablet is dissolved in 900 mL of 0.1N HCl at 37.0 ĄC +/- 0.5 ĄC. Dissolution is sampled (10 mL, with dissolution medium replacement) at 5, 10, 20, and 30 min,and 1, 2, 4, 6, and 8 hours, and at infinity (30 minutes at 250 RPM). A 45 1/4m nylon Acrodisc syringe filter is used.

HPLC analysis is performed on each dissolution sample in an Inertsil ODS-3, 5 1/4m, 150 mm x 4.6 mm or equivalent column, at ambient temperature, for UV detection at 250 nm. The mobile phase is 50% Phosphate buffer (pH 3.5, 50 mM sodium phosphate in DI water, adjusted with phosphoric acid) and 50% methanol. The injection volume is 100 1/4L, and the flow rate is 1.2 mL/min. The approximate run time is 10 minutes, with an approximate retention time of the active agent of 6.2 minutes.

Peak area responses are quantified as shown in Table 15.

Table 15

Based on these results, a dissolution profile for a controlled-release composition provided herein can be understood.

EXAMPLE 12 This example demonstrates formulations for modified-release and immediate release components in representative multi-component particles.

A representative IR component is described in Table 16. Representative MR components are described in Tables 17-19.

Table 16



Table 17

Table 18

Table 19

EXAMPLE 13 This example demonstrates the manufacture of IR multi-component particles as provided herein.

IR multi-component particles having 97.5 mg adipiplon free base/g particle are manufactured in a batch from the components provided in Table 20.

Table 20

Item 4 is sieved and material retained between 20 and 25 mesh. The retained material is charged into a Fluid air Model 002 with Wurster column with 2L bowl size fluid bed coater with 1.2mm spray nozzle.

The drug layer coating suspension is prepared by charging items 1 and 3 into a blender and mixing for 2 minutes on low setting.

Item 2 is added to the blender and mixed for 12 minutes on high liquefy setting.

The drug layer coating suspension is stirred on a stir plate at low-medium setting during application to the seed cores. Drug layer coating suspension is applied to a coating weight of 10% w/w coating solids to total final particle weight. Coating suspension tubing size is 3.2mm ID, and spray rate is 4g/min. Inlet temperature is set to 65ĄC, inlet air is 13 SCFM, Atomization air is 25 psi and outlet temperature is 38ĄC.

Drug layer coated particles are discharged from the fluid bed coater and sieved through a size 14 mesh screen to remove agglomerates.

Multi-component particles manufactured according to this method have the formula provided at Table 21, below.

Table 21

Dissolution of the particles is tested using USP Dissolution Apparatus I (Basket Method) at 100 RPM. A unit dose of the particles is tested in 900 niL of pH 6.8 5OmM phosphate buffer at 37.0 ĄC +/- 0.5 0C. Dissolution is sampled (5 niL, with dissolution medium replacement) at 10, 20, 30, 45 and 60 minutes. A 45 1/4m nylon syringe filter is used.

HPLC analysis is performed on each dissolution sample in an Inertsil ODS-3, 5 1/4m, 150 mm x 4.6 mm or equivalent column, at ambient temperature, for UV detection at 250 run. The mobile phase is 50% Phosphate buffer (pH 3.5, 50 mM sodium phosphate in DI water, adjusted with phosphoric acid) and 50% methanol. The injection volume is 100 1/4L, and the flow rate is 1.2 mL/min. The approximate run time is 10 minutes, with an approximate retention time of the active agent of 6.2 minutes.

Peak area responses are quantified as shown in Table 22, below.

Table 22

Based on these results, a dissolution profile for an immediate-release multi-component particle composition provided herein can be understood.

EXAMPLE 14 This example demonstrates the manufacture of MR multi-component particles as provided herein.

MR particles having 43.9, 41.4 and 39.0 mg adipiplon free base/g particle respectively are manufactured in a batch from the components provided in Table 23.

Table 23



Item 4 is sieved and material retained between 20 and 25 mesh. The retained material is charged into a Fluid air Model 002 with Wurster with 2L howl size fluid bed coater with 1.2mm spray nozzle.

The drug layer coating suspension is prepared by charging items 1 and 3 into a blender and mixing for 2 minutes on low setting.

Item 2 is added to the blender and mixed for 12 minutes on high liquefy setting.

The drug layer coating suspension is stirred on a stir plate at low-medium setting during application to the seed cores. Drug layer coating suspension is applied to a coating weight of 13% w/w coating solids to total final drug layer coated particle weight. Coating suspension tubing size is 3.2mm ID, and spray rate is 4g/min. Inlet temperature is set to 65ĄC, inlet air is 13 SCFM, Atomization air is 25 psi and outlet temperature is 38ĄC.

Drug layer coated particles are discharged from the fluid bed coater and sieved through a size 14 mesh screen to remove agglomerates.

Item 6 is milled to a particle size OfDs0= 51/4m and Dp0 = 121/4m.

The sweller layer coating suspension is prepared by charging itemĚ and half item 7 into a blender and mixing for 15 minutes on high liquefy setting.

Item 5 and the remaining item 7 are added to a separate container for the blender and mixed for 15 minutes on high liquefy setting.

Solutions/suspensions from the two steps above are combined and mixed on a stir plate for 90 minutes.

325mg of drug layer coated particles are charged into the fluid bed coater.

The sweller layer coating suspension is stirred on a stir plate at low-medium setting during application to the sweller layer coated particles. Sweller layer coating suspension is applied to a coating weight of 50% w/w coating solids to total final sweller layer coated particle weight. Coating suspension tubing size is 3.2mm ID, and spray rate is 7g/min. Inlet temperature is set to 40ĄC, inlet air is 13 SCFM, Atomization air is 25 psi and outlet temperature is 30ĄC.

Sweller layer coated particles are discharged from the fluid bed coater and sieved through a size 8 mesh screen to remove agglomerates.

The release controlling layer coating suspension is prepared by charging items 8 and 10 into a blender and mixing for 10 minutes on high liquefy setting.

Item 9 is added to the blender and mixed for 15 minutes on high liquefy setting.

350mg of the sweller layer coated particles are charged into the fluid bed coater.

The release controlling layer coating suspension is stirred on a stir plate at low-medium setting during application to the release controlling layer coated particle. Release controlling layer coating suspension is applied to a coating weight of 10, 15 or 20% w/w coating solids to total final release controlling layer coated particle weight. Coating suspension tubing size is 1.6mm ID, and spray rate is 5g/min. Inlet temperature is set to 450C, inlet air is 15 SCFM, Atomization air is 25 psi and outlet temperature is 33ĄC.

Release controlling layer coated particles are discharged from the fluid bed coater and sieved through a size 8 mesh screen to remove agglomerates.

Multi-component particles manufactured according to this method have the formula provided at Table 24, below.

Table 24

EXAMPLE 15 MR particles having 33.8, 31.9, and 29.4 mg adipiplon free base/g particle were manufactured in a batch from the components provided in Table 25.

Table 25

Item 3 is sieved and material retained between 20 and 25 mesh. The retained material is charged into a Fluid air Model 002 with Wurster with 2L bowl size fluid bed coater with 1.2mm spray nozzle.

The seal coat solution is prepared by charging items 1 and 2 into a blender and mixing for 3 minutes on high liquefy setting.

Seal coat coating solution is applied to a coating weight of 2% w/w coating solids to total final seal coated particle weight. Coating solution spray rate is 2 g/min. Inlet temperature is set to 68 0C, inlet air is 10 SCFM, Atomization air is 25 psi and outlet temperature is 40 0C.

Seal coated particles are discharged from the fluid bed coater and sieved through a size 14 mesh screen to remove agglomerates.

The drug layer coating suspension is prepared by charging items 4 and 6 into a blender and mixing for 2 minutes on low setting.

Item 5 is added to the blender and mixed for 12 minutes on high liquefy setting.

51Og of the seal coated particles are charged into the fluid bed coater.

The drug layer coating suspension is stirred on a stir plate at low-medium setting during application to the seed cores. Drug layer coating suspension is applied to a coating weight of 10% w/w coating solids to total final drug layer coated particle weight. Coating suspension tubing size is 3.2mm ID, and spray rate is 4g/min. Inlet temperature is set to 65ĄC, inlet air is 13 SCFM, Atomization air is 25 psi and outlet temperature is 38ĄC.

Drug layer coated particles are discharged from the fluid bed coater and sieved through a size 14 mesh screen to remove agglomerates.

Item 8 is milled to a particle size of D50 = 51/4m and D90 = 121/4m.

The sweller layer coating suspension is prepared by charging item 8 and half item 9 into a blender and mixing for 15 minutes on high liquefy setting.

Item 7 and the remaining item 9 are added to a separate container for the blender and mixed for 15 minutes on high liquefy setting.

Solutions/suspensions from the two steps above are combined and mixed on a stir plate for 90 minutes.

300mg of drug layer coated particles are charged into the fluid bed coater.

The sweller layer coating suspension is stirred on a stir plate at low-medium setting during application to the sweller layer coated particles. Sweller layer coating suspension is applied to a coating weight of 50% w/w coating solids to total final sweller layer coated particle weight. Coating suspension tubing size is 3.2mm ID, and spray rate is 7g/min. Inlet temperature is set to 40ĄC, inlet air is 13 SCFM, Atomization air is 25 psi and outlet temperature is 30ĄC.

Sweller layer coated particles are discharged from the fluid bed coater and sieved through a size 8 mesh screen to remove agglomerates.

The release controlling layer coating suspension is prepared by charging items 10 and 12 into a blender and mixing for 10 minutes on high liquefy setting.

Item 11 is added to the blender and mixed for 15 minutes on high liquefy setting.

300mg of the sweller layer coated particles are charged into the fluid bed coater.

The release controlling layer coating suspension is stirred on a stir plate at low-medium setting during application to the DR layer coated particles. Release controlling layer coating suspension is applied to a coating weight of 10, 15 or 20% w/w coating solids to total final DR layer coated particle weight. Coating suspension tubing size is 1.6mm ID, and spray rate is 5g/min. Inlet temperature is set to 45ĄC, inlet air is 15 SCFM, Atomization air is 25 psi and outlet temperature is 33ĄC.

Release controlling layer coated particles are discharged from the fluid bed coater and sieved through a size 8 mesh screen to remove agglomerates.

The overcoat solution is prepared by charging items 13 and 14 into a blender and mixing for 10 minutes on high liquefy setting.

352g of release controlling layer coated particles are charged into the fluid bed coater.

Overcoat coating solution is applied to a coating weight of 2% w/w coating solids to total final overcoated particle weight. Coating spray rate is 3 g/min. Inlet temperature is set to 62 0C, inlet air is 15 SCFM, Atomization air is 25 psi and outlet temperature is 40 0C.

Overcoated particles are discharged from the fluid bed coater and sieved through a size 8 mesh screen to remove agglomerates.

Multi-component particles manufactured according to this method have the formula provided at Table 26, below.

Table 26

EXAMPLE 16 Dissolution of the MR multi-component particles is tested using USP Dissolution Apparatus I (Basket Method) at 100 RPM. A unit dose of the particles is tested in 900 mL of pH 6.8 5OmM phosphate buffer at 37.0 0C +/- 0.5 ĄC. Dissolution is sampled (5 mL, with dissolution medium replacement) at 0.5, 1, 2, 3, 4, 5, 6 hours. A 45 1/4m nylon syringe filter is used.

HPLC analysis is performed on each dissolution sample in an Inertsil ODS-3, 5 1/4m, 150 mm x 4.6 mm or equivalent column, at ambient temperature, for UV detection at 250 nm. The mobile phase is 50% Phosphate buffer (pH 3.5, 50 mM sodium phosphate in DI water, adjusted with phosphoric acid) and 50% methanol. The injection volume is 100 1/4L, and the flow rate is 1.2 mL/min. The approximate run time is 10 minutes, with an approximate retention time of the active agent of 6.2 minutes.

Peak area responses are quantified as shown in Table 27, below.

Table 27

20% Coating Time Min Max Mean (%) RSD r/o (min) 0.5 1.4 3.0 2.1 0.8 1 2.2 3.8 2.8 0.9 2 3.4 6.4 4.6 1.6 3 8.7 10.6 9.4 1.0 4 20.2 20.7 20.8 0.6 5 55.5 64.4 60.6 4.6 6 85.3 92.3 89.2 3.6

Based on these results, a dissolution profile for modifled-release compositions provided herein can be understood.

EXAMPLE 17 This example demonstrates the preparation of a multiparticulate dosage form having both an IR component and a continuous MR component. The IR component is prepared as described in Example 12. The MR component is prepared by coating an aliquot of the IR component with a sustained release coating of ethyl cellulose. The IR and MR components are then combined into a single dosage form.

EXAMPLE 18

This example demonstrates the preparation of a multiparticulate dosage form having both an IR component and a delayed release MR component. The IR component is prepared by forming a multiparticulate by spray-congealing a mixture of glyceryl behenate (COMPRITOL), PLURONIC F- 127 and adipiplon to produce small (< 500 1/4m) particles that have an immediate release dissolution profile. The second type of multiparticulate, the delayed release modified release component is prepared by forming a multiparticulate by spray-congealing a mixture of glyceryl behenate (COMPRITOL), PLURONIC F-127 and adipiplon to produce small (< 500 1/4m) particles that have a modified release dissolution profile with continuous release for approximately 2 hours. The IR and MR components are then combined into a single dosage form, preferably in a capsule.

EXAMPLE 19 This example demonstrates the preparation of a tablet dosage form having both an IR component and a delayed release modified release component. The dosage form is made by compressing microcrystalline cellulose into tablets using standard tabletting equipment. The tablets are then coated in a pan coater with a mixture of HPMC E5 premium and adipiplon API (25:75) in water such that the resultant tablets have a potency in the range of 0.5 mg to 10 mg. Next the tablets are coated in a pan coater with a sweller layer consisting of KLUCEL EF and milled AC-DI-SOL (28.6/71.4) in ethanol. Next the tablets are coated with a release controlling layer that is a mixture of talc and ethylcellulose (50/50) in ethanol. Finally the tablets are coated with the same mixture of HPMC E5 and adipiplon to create an IR layer. This tablet is then coated with a standard over coat if desired.

Each and every domestic (US), foreign, or international application and patent referred to hereinabove, including each US priority provisional application, is incorporated herein by reference to the same extent as if each were individually and specifically indicated to be incorporated by reference and to the same extent as if each were set forth in its entirety herein.

The use of the terms "a" and "an" and "the" and similar referents in the context of this disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.

Preferred embodiments are described herein, including the best mode known to the inventors for carrying out their invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for their invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
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