WO2011107922A2

WO2011107922A2 - Extended release composition of milnacipran

Info

Publication number: WO2011107922A2
Application number: PCT/IB2011/050830
Authority: WO
Inventors: Sumit Madan; Vinod Kumar Arora
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2010-03-04
Filing date: 2011-02-25
Publication date: 2011-09-09
Also published as: WO2011107922A3

Abstract

The present invention relates to an extended release composition comprising milnacipran or its pharmaceutically acceptable salts for oral administration, and process for their preparation.

Description

EXTENDED-RELEASE COMPOSITION OF MILNACIPRAN

Field of the Invention

The present invention relates to an extended release composition that includes milnacipran or its pharmaceutically acceptable salts for oral administration, and processes for their preparation.

Background of the Invention

Milnacipran is chemically known as (+)-c/s-2-amino methyl-N,N-diethyl-l -phenyl cyclopropane carboxamide.

Milnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI) with negligible effects on any presynaptic or postsynaptic receptors. Milnacipran has unique pharmacokinetic and pharmacodynamic characteristics that distinguish it from the other marketed serotonin and norepinephrine reuptake inhibitors, (i.e., venlafaxine,

desvenlafaxine, and duloxetine) such as equipotent serotonin and norepinephrine reuptake inhibition and a linear dose-concentration trend at therapeutic doses. In addition, milnacipran does not inhibit the cytochrome P 450 system, indicating minimal propensity for drug-drug interactions. The antidepressant efficacy of milnacipran has been clearly established in a number of randomized, double-blind, placebo-controlled clinical trials, and it has been widely used for treating major depressive disorder. Moreover, evidence suggests that milnacipran is effective and tolerable in the treatment of fibromyalgia and may have usefulness for fatigue and anxiety symptoms.

Milnacipran is commercially available as an immediate-release formulation in the form of tablets and capsules. The half-life of milnacipran is short, approximately 8 hours. This results in milnacipran being administered twice daily, and because of the adverse effects associated with milnacipran, the dosage needs to be titrated slowly in order to get to the therapeutic dose levels required for the treatment. A lack of patient compliance in keeping to this daily dosing schedule is liable to produce discontinuation problems.

Sudden discontinuation of milnacipran can result in withdrawal symptoms, which can include dysphoric mood, irritability, agitation, dizziness, sensory disturbances, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus and seizures. Accordingly, milnacipran is an excellent candidate for an extended release oral formulation meant for once a day administration; thus improving the patient compliance.

Further, milnacipran is associated with a number of side effects. Milnacipran has demonstrated numerous adverse reactions in human clinical trials with tolerability decreasing with increasing dose. In the placebo controlled trials in patients with fibromyalgia, the most frequent spontaneously reported adverse events for 100 mg/day & 200 mg/day milnacipran were as follows: nausea (6%), palpitations (3%), headache (2%), constipation (1%), heart rate increased (1%) and hyperhidrosis (1%), vomiting (1%), and dizziness (1% ). Discontinuation due to adverse reactions was generally more common among patients treated with 200 mg/day compared to 100 mg/day. The adverse effects can originate from the fluctuation in the plasma drug concentrations of an active substance following administration and subsequent metabolism and/or elimination from the body. These effects are sometimes referred to as peaks and troughs. Such fluctuations can be overcome by administration of the active substance in a controlled-release or extended- release composition. In this manner, the active substance is more slowly administered to the body over a much longer period of time. In some instances, the amount of active substance in a controlled-release composition can be less than that required in an immediate-release composition and still achieve a comparable therapeutic effect.

It is therefore an object of the present invention to provide a milnacipran extended- release composition which will lower the incidence and intensity of side effects, especially for higher dosages, and lower or reduce the frequency of dosing and the need to slowly titrate the drug in order to get to the therapeutic dose levels required for treatment of these disorders, avoiding discontinuation problems.

WO 98/08495 discloses prolonged-release formulation of milnacipran, having a multiparticulate form containing a plurality of microgranules being coated with a film of water-insoluble polymer.

WO 2004/037190 discloses a modified-release composition of milnacipran providing delayed-release of active ingredient followed by extended-release in the intestine. These compositions start releasing the drug after a lag time followed by sustained-release in intestine. These compositions would lead to a delay in the response to drug due to initial delay in the release of the active ingredient. WO 2004/067039 discloses a multiparticulate milnacipran composition made by complexing milnacipran with an ion exchange resin in the form of small particles which are coated to give different release profiles. The formulation includes enteric coated particles, extended-release particles, enteric coated extended-release particles or delayed- release particles.

WO 2004/039361 discloses a once a day oral milnacipran pulsatile-release composition. The compositions have two or three dosage units, having a different drug release profile.

The formulations described in prior art involve complex manufacturing steps leading to increased cost and time expenditure. There is a need in the art to develop drug formulations which provide a therapeutically effective blood concentration level of milnacipran for an extended period that involve simple methods of production.

Summary of the Invention

In one general aspect, the present invention provides for an extended-release composition, which includes:

(a) milnacipran or a pharmaceutically acceptable salt thereof, in a concentration from about 2% to about 40% by weight of the composition;

(b) one or more extended-release materials, in a concentration from about 2% to about 95% by weight of the composition; and

(c) one or more pharmaceutically acceptable excipients.

Embodiments of this aspect may include one or more of the following features. For example, the composition may include from about 5 mg to about 500 mg of milnacipran. The composition may be a matrix type composition or a reservoir type composition; or combinations thereof.

The extended-release material includes hydrophilic polymers, hydrophobic polymers, water- swellable polymers, hydrophobic material, or mixtures thereof.

The hydrophilic polymers include cellulose derivatives, alginates, polyvinyl alcohol, povidone, carbomer, xanthan gum, guar gum, locust bean gum, potassium pectate, potassium pectinate, polyvinylpyrrolidone, polysaccharide, polyalkylene oxides, polyalkyleneglycol, starch and derivatives, and mixtures thereof.

The hydrophobic polymers include ethyl cellulose, hydroxyethylcellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic acid esters, polyvinyl acetate, and mixtures thereof.

The water-swellable polymer includes polyethylene oxide, poly(hydroxy alkyl methacrylate), poly( vinyl) alcohol, a mixture of methyl cellulose, cross-linked agar and carboxymethyl cellulose; Carbopol® carbomer, Cyanamer® polyacrylamides; cross- linked water-swellable indene-maleic anhydride polymers; Goodrich® polyacrylic acid, starch graft copolymers; Aqua-Keeps® acrylate polymer polysaccharides, Amberlite® ion exchange resins; Explotab® sodium starch glycolate; and Ac-Di-Sol® croscarmellose sodium.

The hydrophobic materials include waxes, fatty acids, fatty alcohols, fatty acid esters, vegetable oil and mineral oil.

The composition may also include one or more pharmaceutically acceptable excipients selected from one or more of binders, fillers, anti-adherents, lubricants, glidants, coloring agents and flavoring agents.

In another general aspect, the present invention provides for a process for the preparation of an extended-release composition. The process includes the steps of:

(a) blending/mixing milnacipran and one or more extended-release materials with one or more pharmaceutically acceptable excipients; and

(b) compressing the blend of step (a) into tablets.

In yet another general aspect, the present invention provides for a process for the preparation of an extended-release composition. The process includes the steps of:

(a) blending/mixing milnacipran and one or more extended-release materials with one or more pharmaceutically acceptable excipients;

(b) granulating the mixture of step (a); and

(c) compressing the granules of step (b) into tablets or filling into capsules. Embodiments of this aspect may include one or more of the following features. For example, the granulation may be carried out by wet granulating milnacipran and the pharmaceutically acceptable excipients with a solution or dispersion of an extended- release material. The granulation may also be carried out by wet granulating the extended- release material and the pharmaceutically acceptable excipients with a solution or dispersion of milnacipran. The granulation may also be carried out by wet granulating milnacipran, extended-release material and the pharmaceutically acceptable excipients with a solvent. Finally, the granulation may also be carried out by dry blending

milnacipran, the pharmaceutically acceptable excipients and the extended-release materials and compacting to form granules.

(a) granulating milnacipran and one or more pharmaceutically acceptable

excipients;

(b) blending/mixing the mixture of step (a) with at least one extended-release material and one or more pharmaceutically acceptable excipients; and

(c) compressing the blend of step (b) into tablets.

In yet another general aspect, the present invention provides for a process for the preparation of the extended-release composition. The process includes the steps of:

(a) preparing a core, which includes milnacipran, optionally one or more

extended-release materials and one or more pharmaceutically acceptable excipients; and

(b) coating the core with the extended-release materials.

In another general aspect, the present invention provides for a method of treatment of depression, fibromyalgia syndrome, chronic fatigue syndrome, pain, attention deficit/hyperactivity disorder, and visceral pain syndromes (VPS), noncardiac chest pain (NCCP), functional dyspepsia, interstitial cystitis, essential vulvodynia, urethral syndrome, orchialgia, and affective disorders, including depressive disorders and anxiety disorders, premenstrual dysphoric disorder, temperomandibular disorder, atypical face pain, migraine headache, and tension headache, which includes administering an extended release composition that includes milnacipran or a pharmaceutically acceptable salt thereof.

The extended-release compositions may also be administered in combination with other therapeutic agents.

Detailed Description of the Invention

The present invention relates to an extended-release composition that includes milnacipran prepared by applying simple and conventional formulation technology.

The extended-release composition of the present invention includes:

(i) milnacipran or a pharmaceutically acceptable salt thereof, in a concentration from about 2% to about 40% by weight of the composition;

(ii) one or more extended-release materials, in a concentration from about 2% to about 95% by weight of the composition; and

(iii) one or more pharmaceutically acceptable excipients.

The composition of the present invention may be a matrix type composition, a reservoir type composition or combinations of both. Matrix type compositions are those in which the drug is distributed uniformly in the one or more extended-release materials and reservoir type compositions utilize extended-release coating over the core of the milnacipran. A combination of the reservoir and matrix type includes extended or sustained-release coatings on extended-release matrices.

The term "extended release", as used herein, refers to a release which is not an immediate-release. Further, the term "extended-release", as used herein, refers to the release of an active ingredient from a pharmaceutical composition or composition, in which the active ingredient is released over an extended period of time and/or at a particular location and is taken to encompass sustained-release, controlled-release, modified-release, prolonged-release, delayed-release, and the like.

The term "composition" or "formulation" as used in this specification, refers to physically discrete units, wherein each unit contains a predetermined quantity of active ingredient in association with the required pharmaceutically acceptable excipients. The composition of the invention may be in the form of tablets, capsules, sachets, pellets, beads, granules, multiparticulates or powder.

"Milnacipran" as used herein, also encompasses pharmaceutically acceptable, pharmacologically active derivatives of milnacipran including both individual enantiomers of milnacipran (dextrogyral and levrogyral enantiomers) and their pharmaceutically acceptable salts, mixtures of milnacipran enantiomers and their pharmaceutically acceptable salts, and active metabolites of milnacipran and their pharmaceutically acceptable salts, unless otherwise noted.

The term "pharmaceutically acceptable salt" of milnacipran refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Suitable non-toxic acids include inorganic acids, such as, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.

Particularly suitable is hydrochloric acid.

The extended-release compositions of the present invention contain from about 5 mg to about 500 mg of milnacipran. Preferably, the compositions contain about 5 mg to about 200 mg of milnacipran. More preferably, the compositions contain about 10 mg to 140 mg of milnacipran.

The extended-release materials used in the composition include hydrophilic polymers, hydrophobic polymers, water- swellable polymers, other hydrophobic materials and mixtures thereof. The extended-release material may be present from about 2% to about 95% by weight of the composition.

Examples of hydrophilic polymers include one or more of cellulose derivatives, such as, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose, carboxymethylcellulose, sodium

carboxymethylcellulose, carboxymethylcellulose calcium or combinations thereof;

ammonium alginate, sodium alginate, potassium alginate, calcium alginate, propylene glycol alginate, alginic acid, polyvinyl alcohol, povidone, carbomer, xanthan gum, guar gum, locust bean gum, potassium pectate, potassium pectinate, polyvinylpyrrolidone, polysaccharide, polyalkylene oxides , polyalkyleneglycol, starch and derivatives; and mixtures thereof.

Examples of hydrophobic polymers include ethyl cellulose, hydroxyethylcellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic acid esters, ammonio methyacrylate copolymer (Eudragit® RL or Eudragit® RS), methyacrylic acid copolymers (Eudragit® L or

Eudragit® S), methacrylic acid-acrylic acid ethyl ester copolymer (Eudragit® L 100-5), methacrylic acid esters neutral copolymer (Eudragit® NE 30D),

dimethylaminoethylmethacrylate-methacrylic acid esters copolymer (Eudragit® E 100), vinyl methyl ether/maleic anhydride copolymers, their salts and esters (GANTREZ^®), polyvinyl acetate, and mixtures thereof.

Examples of water-swellable polymers include polyethylene oxide having a molecular weight of 100,000 to 8,000,000; poly(hydroxy alkyl methacrylate) having a molecular weight of from 30,000 to 5,000,000; poly( vinyl) alcohol, having a low acetal residue, which is cross-linked with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization of from 200 to 30,000; a mixture of methyl cellulose, cross- linked agar and carboxymethyl cellulose; a water-insoluble, water-swellable copolymer produced by forming a dispersion of a finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, butylene or isobutylene cross-linked with from 0.001 to 0.5 moles of saturated cross-linking agent per mole of maleic anhydride in the copolymer; Carbopol® carbomer which is as acidic carboxy polymer having a molecular weight of 450,000 to 4,000,000; Cyanamer® polyacrylamides; cross-linked water swellable indene- maleic anhydride polymers; Goodrich® polyacrylic acid having a molecular weight of 80,000 to 200,000; starch graft copolymers; Aqua Keeps® acrylate polymer

polysaccharides composed of condensed glucose units such as diester cross-linked polyglucan, and the like; Amberlite® ion exchange resins; Explotab® sodium starch glycolate; Ac-Di-Sol® croscarmellose sodium; and combinations that include one or more of the foregoing materials. Examples of other hydrophobic materials include waxes, such as, beeswax, carnauba wax, microcrystalline wax, candelilla wax, spermaceti, montan wax,

hydrogenated vegetable oil, lecithin, hydrogenated cottonseed oil, hydrogenated tallow, paraffin wax, shellac wax, petrolatum, ozokerite, and the like, as well as, synthetic waxes, e. g., polyethylene, and the like; fatty acids such as, stearic acid, palmitic acid, lauric acid, eleostearic acids, and the like; fatty alcohols, such as, lauryl alcohol, cetostearyl alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol; fatty acid esters, such as, glyceryl monostearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate and glyceryl behenate; vegetable oil, such as, hydrogenated castor oil; mineral oil; and combinations that include one or more of the foregoing materials.

The extended-release composition of the present invention including one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients are those known to those skilled in the art and may be one or more of binders, fillers, anti- adherents, lubricants, glidants, coloring agents and flavoring agents.

Examples of binders include povidones, starches, corn starch, pregelatinized starch, microcrystalline celluloses (MCC), silicified MCC (e.g., Prosolv® HD 90), microfine celluloses, lactose, calcium carbonate, calcium sulfate, sugar, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, stearic acid, gums, hydroxypropyl methylcelluloses or hypromelloses (e.g., Klucel®EF, Methocel® E5 premium), and mixtures thereof.

Examples of fillers or diluents include corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium dihydrogen phosphate dihydrates, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch and starch pregelatinized. Particularly, the fillers comprise lactose, microcrystalline cellulose, calcium hydrogen phosphate dehydrate, or mixtures thereof. Examples of anti-adherents include magnesium stearate, talc, calcium stearate, glyceryl behenate, polyethylene glycols, hydrogenated vegetable oil, mineral oil, stearic acid, and combinations thereof.

Examples of lubricants and glidants include colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax, and combinations thereof.

The coloring agents and flavoring agents of the present invention may be selected from any FDA approved colors and flavors for oral use.

The extended-release compositions of the present invention optionally have one or more coatings, which are functional or non-functional. Functional coatings include modified-release coatings and non-functional coatings include seal coatings and elegant coatings. Additional excipients such as film forming polymers, solvents, plasticizers, antiadherents, opacifiers and optionally colorants, pigments, antifoam agents, and polishing agents can be used in coatings.

Examples of film- forming agents include cellulose derivatives, such as, soluble alkyl- or hydroalkyl-cellulose derivatives, such as, methylcelluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethylethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, etc., insoluble cellulose derivatives such as ethylcelluloses and the like, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acids, polyvinyl alcohols, polyvinyl acetates, polyvinylpyrrolidones, polymethacrylates and derivatives thereof (Eudragit® products), chitosan and derivatives thereof, shellac and derivatives thereof, waxes and fat substances.

Useful enteric coating materials include materials, such as, cellulosic polymers like cellulose acetate phthalates, cellulose acetate trimellitates, hydroxypropyl methylcellulose phthalates, polyvinyl acetate phthalates, etc., methacrylic acid polymers and copolymers (Eudragit®), and mixtures thereof.

The coating can also be performed using any commercially available ready to coat preparations such as Opadry® AMB, Opadry® White, Opadry® Clear, etc. Opadry® formulations generally include polymer, plasticizer and, if desired, pigment in a dry concentrate. Opadry® products produce attractive, elegant coatings on a variety of tablet cores and can be used in both aqueous and organic coating procedures.

Some of the excipients are used as adjuvants to the coating process, including excipients such as plasticizers, opacifiers, antiadhesives, polishing agents, and the like.

Examples of plasticizers include castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycols, triacetin, triethyl citrate, and mixtures thereof. An opacifier like titanium dioxide may also be present in an amount ranging from about 10% (w/w) to about 20% (w/w) based on the total weight of the coating.

Anti-adhesives are frequently used in the film-coating process to avoid sticking effects during film formation and drying. An example of an anti-adhesive for this purpose is talc.

Examples of polishing agents include polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants (e.g., glycerol monostearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (e.g., carnauba wax, candelilla wax and white wax).

Suitable solvents used in the processes of preparing pharmaceutical composition of the present invention include water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, N,N-dimethylformamide, tetrahydrofuran, and mixtures thereof.

The composition may be prepared by conventional techniques, for example, either by direct compression, or first compacting some of the ingredients, milling the compacts, blending with the remaining ingredients and then compressing as appropriate.

The composition may also be prepared using wet granulation techniques. The process may include granulation of milnacipran and the extended-release material with a solvent or granulation of milnacipran and pharmaceutically acceptable excipients with a solvent or granulation of milnacipran and pharmaceutically acceptable excipients with a solution or dispersion of the extended-release material or granulation of extended-release material and pharmaceutically acceptable excipients with a solution or dispersion of milnacipran. The process may further include drying the granules prior to compressing into tablets.

The reservoir type composition of milnacipran may be prepared by coating the core which includes milnacipran, optionally, one or more extended-release materials and one or more pharmaceutically acceptable excipients, with the extended-release coating layer.

The composition of the invention may be made into a dosage form, such as a granule, bead, pellet, particulate, tablet, minitablet, or agglomerate.

The extended-release composition of milnacipran may be used for the treatment of depression, fibromyalgia syndrome, chronic fatigue syndrome, pain, attention

deficit/hyperactivity disorder, and visceral pain syndromes (VPS), such as, irritable bowel syndrome (IBS), noncardiac chest pain (NCCP), functional dyspepsia, interstitial cystitis, essential vulvodynia, urethral syndrome, orchialgia, and affective disorders, including depressive disorders (major depressive disorder, dysthymia, atypical depression) and anxiety disorders (generalized anxiety disorder, phobias, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder), premenstrual dysphoric disorder, temperomandibular disorder, atypical face pain, migraine headache, and tension headache.

The extended-release composition of milnacipran may be administered in combination with other therapeutic agents such as analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchodilators, anti asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro- intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics and anti-narcoleptics.

The present invention is illustrated below by reference to the following example. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention. EXAMPLES

Examples 1, 2 & 3: Extended Release Matrix Tablets of Milnacipran Hydrochloride

Procedure:

1. Milnacipran hydrochloride, lactose anhydrous, colloidal anhydrous silica, polyvinyl pyrrolidone, talc and magnesium stearate were mixed well, compacted and milled to get granules.

2. The granules of step (1) were mixed with lactose anhydrous, polyvinylpyrrolidone, colloidal anhydrous silica, and hydroxypropylcellulose, hydroxypropylmethylcellulose, talc and magnesium stearate.

3. The blend of step (2) was compressed to give a matrix tablet.

Example 4: Extended-Release Matrix Tablets of Milnacipran Hydrochloride

Procedure:

1. Milnacipran hydrochloride, microcrystalline cellulose and sodium carboxymethyl cellulose were mixed well and granulated with purified water.

2. The granules of step (1) were dried and mixed with hydroxypropylmethylcellulose and magnesium stearate.

3. The blend of step (2) was compressed to give a matrix tablet.

Examples 5 & 6: Extended Release Matrix Tablets of Milnacipran Hydrochloride

Procedure:

1. Milnacipran hydrochloride, calcium hydrogen phosphate,

hydroxypropylmethylcellulose, silicon dioxide and magnesium stearate were mixed well and compressed to give a matrix tablet. 2. Tablets were coated with dispersion of Opadry® in purified water.

Examples 7 & 8: Extended- Release Matrix Tablets of Milnacipran Hydrochloride

Procedure:

1. Polyethylene oxide and polyethylene glycol were mixed well and granulated with the dispersion of milnacipran in ethanol.

2. The granules of step (1) were dried and mixed with colloidal anhydrous silica and magnesium stearate.

3. The blend of step (2) was compressed to give a matrix tablet.

4. Tablets were coated with dispersion of Opadry® in isopropyl alcohol and methylene chloride.

Examples 9 - 12: Extended Release Reservoir Tablets of Milnacipran Hydrochloride

Procedure:

1. Milnacipran and microcrystalline cellulose were mixed well and granulated with the solution of polyvinyl pyrrolidone in water.

2. The granules of step (1) were dried and mixed with microcrystalline cellulose,

magnesium stearate and talc.

3. The blend of step (2) was compressed to give a tablet.

4. Hydroxypropylmethylcellulose solution was prepared and added to dispersion of ethyl cellulose, dibutyl sebacate and triethyl citrate.

5. Tablets were coated with the dispersion of step (4) to the desired weight build up. Examples 13-15: Extended- Release Capsules of Milnacipran Hydrochloride

Procedure:

1. Milnacipran, water and microcrystalline cellulose were mixed in a rapid granulator mixer, dried and sifted.

2. Magnesium stearate was mixed with the mixture of step (1) and granulated with

methacrylic acid-ethyl acrylate copolymer (1:1) dispersion by extrusion and spheronization.

3. The beads of step (2) were dried and coated with the dispersion of Methacrylic acid- ethyl acrylate copolymer (1:1) in purified water.

4. Coated beads were dried, lubricated and filled in the capsule shells.

While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention.

Claims

We claim:

1. An extended-release composition comprising:

(b) one or more extended-release material, in a concentration from about 2% to about 95% by weight of the composition; and

(c) one or more pharmaceutically acceptable excipients.

2. The extended-release composition of claim 1, wherein the composition comprises from about 5 mg to about 500 mg of milnacipran.

3. The extended-release composition of claim 1, wherein the composition is matrix type composition or reservoir type composition or combinations thereof.

4. The extended-release composition of claim 1, wherein the extended-release material comprises hydrophilic polymers, hydrophobic polymers, water- swellable polymers, hydrophobic material, or mixtures thereof.

5. The extended-release composition of claim 4, wherein the hydrophilic polymer comprises cellulose derivatives, alginates, polyvinyl alcohol, povidone, carbomer, xanthan gum, guar gum, locust bean gum, potassium pectate, potassium pectinate, polyvinylpyrrolidone, polysaccharide, polyalkylene oxides, polyalkyleneglycol, starch and derivatives, and mixtures thereof.

6. The extended-release composition of claim 4, wherein the hydrophobic polymer comprises ethyl cellulose, hydroxyethylcellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic acid esters, polyvinyl acetate, and mixtures thereof.

7. The extended-release composition of claim 4, wherein the water-swellable polymer comprises polyethylene oxide, poly(hydroxy alkyl methacrylate), poly( vinyl) alcohol, a mixture of methyl cellulose, cross-linked agar and carboxymethyl cellulose; Carbopol® carbomer, Cyanamer® polyacrylamides; cross-linked water-swellable indene- maleic anhydride polymers; Goodrich® polyacrylic acid, starch graft copolymers; Aqua- Keeps® acrylate polymer polysaccharides, Amberlite® ion exchange resins; Explotab® sodium starch glycolate; and Ac-Di-Sol® croscarmellose sodium.

8. The extended-release composition of claim 4, wherein the hydrophobic materials comprise waxes, fatty acids, fatty alcohols, fatty acid esters, vegetable oil and mineral oil.

9. The extended-release composition of claim 1, wherein the composition comprises one or more pharmaceutically acceptable excipients selected from one or more of binders, fillers, anti- adherents, lubricants, glidants, coloring agents and flavoring agents.

10. A process for the preparation of an extended-release composition, wherein the process comprises the steps of:

(b) compressing the blend of step (a) into tablets.

11. A process for the preparation of the extended-release composition, wherein the process comprises the steps of:

(b) granulating the mixture of step (a); and

(c) compressing the granules of step (b) into tablets or filling into capsules.

12. The process according to claim 11, wherein the granulation is carried out by wet granulating milnacipran and the pharmaceutically acceptable excipients with a solution or dispersion of an extended-release material.

13. The process according to claim 11, wherein the granulation is carried out by wet granulating the extended-release material and the pharmaceutically acceptable excipients with a solution or dispersion of milnacipran.

14. The process according to claim 11, wherein the granulation is carried out by wet granulating milnacipran, extended-release material and the pharmaceutically acceptable excipients with a solvent.

15. The process according to claim 11, wherein the granulation is carried out by dry blending milnacipran, the pharmaceutically acceptable excipients and the extended- release materials and compacting to form granules.

16. A process for the preparation of the extended-release composition, wherein the process comprises the steps of:

(a) granulating milnacipran and one or more pharmaceutically acceptable

excipients;

(b) blending/mixing the mixture of step (a) with at least one extended-release material and one or more pharmaceutically acceptable excipients; and (c) compressing the blend of step (b) into tablets.

17. A process for the preparation of the extended-release composition, wherein the process comprises the steps of:

(a) preparing a core comprising milnacipran, optionally one or more extended- release materials and one or more pharmaceutically acceptable excipients; and (b) coating the core with the extended-release materials.

18. A method of treatment of depression, fibromyalgia syndrome, chronic fatigue syndrome, pain, attention deficit/hyperactivity disorder, and visceral pain syndromes (VPS), noncardiac chest pain (NCCP), functional dyspepsia, interstitial cystitis, essential vulvodynia, urethral syndrome, orchialgia, and affective disorders, including depressive disorders and anxiety disorders, premenstrual dysphoric disorder, temperomandibular disorder, atypical face pain, migraine headache, and tension headache comprising administering an extended release composition comprising milnacipran or a

pharmaceutically acceptable salt thereof.

19. The extended-release composition of claim 1, wherein the composition is administered in combination with other therapeutic agents.