WO2011107921A2

WO2011107921A2 - Modified release composition of milnacipran

Info

Publication number: WO2011107921A2
Application number: PCT/IB2011/050825
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: WO2011107921A3

Abstract

The present invention relates to a modified release composition comprising milnacipran or its pharmaceutically acceptable salts, and process for their preparation.

Description

MODIFIED RELEASE COMPOSITION OF MILNACIPRAN

Field of the Invention

The present invention relates to a modified release composition, which includes milnacipran or its pharmaceutically acceptable salts, and process for their preparation.

Background of the Invention

Milnacipran is chemically known as (+)-c/s-2-amino methyl-N, N-diethyl-1- 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, (z.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 a 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 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 a modified release oral formulation that can be dosed once a day, thus improving 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 an 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 dosage form. 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 dosage form can be less than that required in an immediate release dosage form and still achieve a comparable therapeutic effect.

It is therefore an object of the present invention to provide milnacipran modified release dosage forms 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.

Sustained release formulations known in the art include specially coated pellets, coated tablets and capsules, and ion exchange resins, wherein the slow release of the active medicament is brought about through selective breakdown of the coating of the preparation or through formulating with a polymeric matrix to affect the release of a drug. Some sustained release formulations provide for pulsatile/sequential release of a single dose of an active compound at predetermined periods after administration. WO 98/08495 discloses a prolonged release formulation of milnacipran, having a multiparticulate form containing plurality of microgranules being coated with a film of water insoluble polymer.

WO 2004/037190 discloses a modified release composition of milnacipran providing a delayed release of the 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.

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.

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

When a modified release dosage form is administered, many physiological factors influence both the gastric transit time and release of the drug from a modified release dosage form and thus uptake of drug into the systemic circulation.

This has led to a shift in modified release technology from the use of monolithic systems to multiple unit systems, as these dosage forms exhibit a reproducible gastrointestinal transit time; thus avoiding intra-and inter-individual variations. A multiple unit type formulation is a formulation having two or more units which are co- present in a single formulation and differ from each other in the drug release rates, as opposed to a single unit type formulation having a single unit.

Multiple unit dosage forms possess a large surface area, which advantageously promotes complete and uniform absorption, minimizes peak plasma fluctuations and thus reduces the potential for systemic side effects. A further advantage of these dosage forms is that high local concentrations of the active substance in the system is avoided as a consequence of the units being distributed freely throughout the tract. Summary of the Invention

In one general aspect, the present invention provides for a modified release composition, which includes:

(i) an immediate release unit that includes milnacipran or salts of milnacipran; and

(ii) one or more of modified release units that includes milnacipran or salts of milnacipran.

Embodiments of this aspect may include one or more of the following features. For example, the ratio of immediate release unit to the modified release unit(s) ranges from about 5:95 to about 95:5 by weight. The modified release unit may be a controlled release unit, enteric release unit or enteric coated controlled release unit. The composition may also be a two unit system that includes an immediate release unit and one modified release unit. The composition may also be a multiple unit system that includes an immediate release unit and two or more modified release units.

In another general aspect, the present invention provides for a modified release composition, which includes:

(i) a controlled release unit that includes milnacipran or salts of milnacipran; and

(ii) one or more of enteric release units that include milnacipran or salts of milnacipran.

Embodiments of this aspect may include one or more of the following features. For example, the ratio of controlled release unit to the enteric release unit(s) may range from about 5:95 to about 95:5 by weight. The enteric release unit may be an enteric coated immediate release unit or an enteric coated controlled release unit. The composition may be a two unit system that includes a controlled release unit and an enteric release unit or an enteric coated controlled release unit. The composition may also be a multiple unit system that includes a controlled release unit, an enteric release unit and an enteric coated controlled release unit. The immediate release unit of the composition may further include one or more pharmaceutically acceptable excipients. The modified release unit of the composition may further include one or more pharmaceutically acceptable excipients and one or more rate-controlling and/or enteric agents.

The pharmaceutically acceptable excipients may be one or more of diluents, binders, disintegrants, lubricants, glidants, surfactants, buffers, wetting agents, coloring agents, flavoring agents and combinations thereof.

The modified release compositions may be in the form of discrete or aggregated particles, pellets, beads or granules.

The modified release compositions may be used in the 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 by administering to a person in need thereof.

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

Detailed Description of the Invention

The present invention relates to a modified release composition for the oral administration of milnacipran, which includes:

(i) an immediate release unit, which includes milnacipran or salts of

milnacipran, and

(ii) one or more of modified release unit(s), which include milnacipran or salts of milnacipran.

The ratio of the immediate release unit to the modified release units may range from about 5:95 to about 95:5 by weight.

The term "modified release", as used herein, includes any type of modified release such as prolonged release, sustained release, controlled release, extended release, delayed release and enteric release. The term "modified release agents", as used herein, includes the agents that provide/facilitate modified release such as prolonged release, sustained release, controlled release, extended release, delayed release and enteric release.

The term "unit", as used herein, includes spheroids, beads, microspheres, seeds, granules, pellets, mini tablets, ion-exchange resin beads and other multi-particulate systems. The "unit" may also include a mixture of different types of units mentioned here.

"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 solid state form of the milnacipran used in the composition of the present invention is not critical. For example, milnacipran can be amorphous or crystalline.

The salts of milnacipran used in the composition include 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, methane sulfonic, ethane disulfonic, oxalic, and isethionic. Particularly suitable is hydrochloric acid.

The composition of the present invention may be a two unit system, which includes an immediate release unit and a modified release unit or may be a multiple unit system, which includes an immediate release unit and two or more of modified release units.

The immediate release units, which include milnacipran or salt of milnacipran, can be formulated as a plurality of discrete or aggregated particles, pellets, beads, granules or mini tablets. The process for preparing the units can be accomplished by blending milnacipran or salt of milnacipran with one or more pharmaceutically acceptable excipients using any processes known in the art, such as, simple granulation followed by sieving; extrusion and marumerization or spheronization; rotogranulation; pelletization; micropelletization, etc. Alternatively, the immediate release units are formulated by layering milnacipran or salt of milnacipran with one or more

pharmaceutically acceptable excipients over inert cores. The active ingredient is layered over the inert cores as powder; or as suspension or solution in a suitable solvent. The immediate release unit may also be present as powder.

The inert core may be hydrosoluble or hydroinsoluble. Examples of inert cores include sucrose, lactose, maltodextrin, microcrystalline cellulose, pregelatinized starch, dicalcium phosphate, celphere and non-pareils. The cores may be of any geometric shape, though spheres are particularly used for the case of uniform coating.

The modified release unit, which includes milnacipran or salt of milnacipran, can be formulated by blending milnacipran or salt of milnacipran with one or more rate-modifying agents (rate-controlling/enteric agents) and other pharmaceutically acceptable excipients, by the processes known in the art, such as, simple granulation followed by sieving; extrusion and marumerization or spheronization; rotogranulation; pelletization; micropelletization, etc. Alternatively, the blend which includes milnacipran or salt of milnacipran and one or more rate-modifying agents (rate- controlling/enteric agents) may be layered onto inert cores as powder or as suspension or solution in a suitable solvent.

The modified release unit can also be prepared by providing a coating of rate- modifying agents (rate-controlling/enteric agents) over the immediate release units that include milnacipran or salt of milnacipran. Alternatively the modified release unit can contain the combination of both rate-controlling and enteric agents.

The controlled release unit that includes milnacipran or salt of milnacipran can be formulated by blending milnacipran or salt of milnacipran with one or more rate- controlling agents and other pharmaceutically acceptable excipients, by the processes known in the art, such as, simple granulation followed by sieving; extrusion and marumerization or spheronization; rotogranulation; pelletization; micropelletization, etc. Alternatively, the blend that includes milnacipran or salt of milnacipran and one or more rate-controlling agents may be layered onto inert cores as powder or as suspension or solution in a suitable solvent.

The controlled release unit can also be prepared by providing a coating of rate- controlling agents over the immediate release units comprising milnacipran or salt of milnacipran. Alternatively the controlled release unit can contain the combination of both rate-controlling and rate-modifying agents.

The enteric release unit that includes milnacipran or salt of milnacipran can be formulated by blending milnacipran or salt of milnacipran with one or more enteric agents and other pharmaceutically acceptable excipients, by the processes known in the art, such as, simple granulation followed by sieving; extrusion and marumerization or spheronization; rotogranulation; pelletization; micropelletization, etc. Alternatively, the blend that includes milnacipran or salt of milnacipran and one or more enteric agents may be layered onto inert cores as powder or as suspension or solution in a suitable solvent.

The enteric release unit can also be prepared by providing a coating of enteric agents over the immediate release units that include milnacipran or salt of milnacipran. Alternatively, the enteric release unit can contain the combination of both rate- controlling and rate-modifying agents.

The enteric coated controlled release unit can be prepared by providing a coating of enteric agents over the controlled release units.

The rate-controlling agents can be hydrophilic or hydrophobic or combinations of both.

Suitable examples of hydrophilic rate-controlling agents include cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose,

methylcellulose, sodium carboxy methylcellulose or combinations thereof;

polyvinylpyrrolidone, polyvinyl acetate, copolymer of vinylpyrrolidone and vinyl acetate, polysaccharides, polyalkylene glycols, starch, gums and derivatives; and combinations comprising one or more of the foregoing materials. Suitable examples of hydrophobic rate-controlling agents include ethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic acid esters, waxes, shellac, zein, castor oil, hydrogenated vegetable oils and combinations comprising one or more of the foregoing materials.

The enteric agents/enteric polymers would facilitate erosion and breakdown of the composition in the pH of the lower GI tract. The enteric polymer should be nontoxic and is predominantly soluble in the intestinal fluid, but substantially insoluble in the gastric juices.

Suitable examples of enteric polymers include polyvinyl acetate phthalate

(PVAP), hydroxypropylmethyl-cellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), methacrylic acid copolymer, hydroxy propyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, hydroxypropyl methylcellulose hexahydrophthalate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate trimellitate, cellulose acetate butyrate, cellulose acetate propionate, methacrylic acid/methacrylate polymer (acid number 300 to 330 and also known as Eudragit® L or Eudragit® S, which are anionic copolymers based on methacrylate and available as a powder) also known as methacrylic acid copolymer, type A NF, methacrylic acid- methyl methacrylate copolymer, ethyl methacrylate-methylmethacrylate- chlorotrimethylammonium ethyl methacrylate copolymer, and the like, and

combinations comprising one or more of the foregoing enteric polymers. Other examples include natural resins, such as shellac, Sandarac®, copal collophorium, and combinations comprising one or more of the foregoing polymers. Additional examples of enteric polymers include synthetic resins bearing carboxyl groups. The methacrylic acid:acrylic acid ethyl ester 1:1 copolymer solid substance of the acrylic dispersion sold under the trade designation Eudragit® L- 100-55 may be suitable.

The rate-controlling layers and enteric coating layers may contain one or more pharmaceutically acceptable plasticizers in order to obtain desirable mechanical properties, improve flexibility and strength of the coating. Example of plasticizers include triacetin, citric acid esters, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, phthalic acid esters, diethyl phthalate, dibutyl sebacate, cetyl alcohol, polyethylene glycols, propylene glycol, triethylene glycol, polysorbates, oleic acid, ethyleneglycol monoleate, glyceryl monostearate, castor oil and mixtures thereof.

Along with the rate-modifying agents, the modified release unit may also include one or more pore-formers. The pore-formers can be organic or inorganic, and include one or more hydrophilic polymers, such as starch, gums, alginates,

polysaccharides, polyvinylprrolidone, polyethylene glycol, acrylic acid derivatives, and cellulose derivatives like hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose,

methylcellulose, sodium carboxy methylcellulose and mixtures thereof; polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain. Alternatively, suitable pore formers include small molecules such as lactose or metal stearates, and combinations that include one or more of the foregoing materials.

The coating layers over the composition may be applied as solution/dispersion of coating ingredients using any conventional technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor or dip coating.

Example of solvents used for preparing a solution/dispersion of the coating ingredients 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, Ν,Ν-dimethylformamide, tetrahydrofuran, and mixtures thereof.

The composition of the invention may contain suitable amounts of

pharmaceutically acceptable excipients that would be necessary for preparing appropriate dosage forms. Examples of pharmaceutically acceptable excipients that can be used in the composition of the present invention include one or more diluents, binders, disintegrants, lubricants/glidants, surfactants, buffers, wetting agents, coloring agents, flavoring agents, and combinations 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 a mixture thereof.

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 other pharmaceutically acceptable substances with cohesive properties.

Examples of disintegrants include cross-linked polyvinyl pyrrolidone, corn starch, potato starch, maize starch and modified starches, agar-agar, calcium carbonate, sodium carbonate, alginic acids, cross- carmellose sodium, sodium starch glycolate, microcrystalline cellulose, and mixtures thereof.

Examples of lubricants and glidants that can be used in the present invention include colloidal silicon dioxide, such as Aerosil® 200, talc, stearic acid, magnesium stearate, calcium stearate, solid polyethylene glycols, sodium stearyl fumarate, silica gel and mixtures thereof and other substances with lubricating or gliding properties.

The term "surfactant" is used in its conventional sense in the present invention. Any surfactant is suitable, whether it is amphoteric, non-ionic, cationic or anionic.

Examples of suitable surfactants include sodium lauryl sulfate, polysorbates such as polyoxyethylene sorbitan monooleate, monolaurate, monopalmitate, monstearate or another ester of polyoxyethylene sorbitan (e.g., the commercially available Tweens), sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamers (e.g., Pluronics F68® and Fl 08®, which are block copolymers of ethylene oxide and propylene oxide); polyoxyethylene castor oil derivatives, or mixtures thereof. Examples of buffers that can be used in the present invention include phosphate, acetate, citrate, succinate and histidine buffers. Examples of wetting agents that can be used in the present invention include ammonium lauryl sulfate and sodium lauryl sulfate.

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

The modified release composition of the present invention having multiple-units that include immediate release units of milnacipran or salts of milnacipran and modified release units of milnacipran or salts of milnacipran are filled into capsules or sachets or compressed into tablets. The ratio of immediate release unit to the modified release unit(s) may range from about 5:95 to about 95:5 by weight.

The modified release composition of the present invention having multiple-units that include controlled release units of milnacipran or salts of milnacipran and enteric release units of milnacipran or salts of milnacipran are filled into capsules or sachets or compressed into tablets. The ratio of controlled release unit to the enteric release unit(s) may range from about 5:95 to about 95:5 by weight.

The composition of the invention may be used in treating conditions such as 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 modified release composition of milnacipran may be administered in combination with other therapeutic agents such 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

Example 1 : Modified Release Tablets of Milnacipran Hydrochloride

Procedure: Preparation of Immediate Release Granules

1. Milnacipran hydrochloride, microcrystalline cellulose and crosspovidone were mixed well and granulated with solution of

hydroxypropylmethylcellulose in purified water.

2. The granules of step (1) were dried and sized.

Preparation of Enteric Coated Pellets

1. Milnacipran hydrochloride and microcrystalline cellulose were mixed well and blended with solution of hydroxypropylmethylcellulose in purified water.

2. The blend of step (1) was extruded, spheronized and dried.

3. Coating solution was prepared by dispersing hydroxypropylmethylcellulose acetate succinate in the solution of triethyl citrate and sodium lauryl sulphate in purified water.

4. The pH of the dispersion of step (3) was maintained at 5.6 to 5.9 and talc was added.

5. The spheres of step (2) were coated with the coating preparation of step (4). Preparation of Sustained Release Pellets

2. The blend of step (1) was extruded, spheronized and dried.

3. Coating solution was prepared by dispersing Eudragit® in purified water and adding ammonia solution.

4. Talc and triethyl citrate were added to the dispersion of step (3).

5. The spheres of step (2) were coated with the coating preparation of step (4). Tablet compression

1. Immediate release granules, enteric coated pellets and sustained release pellets were blended with microcrystalline cellulose and crosspovidone.

2. The blend of step (1) was lubricated with aerosol and magnesium stearate. 3. The lubricated blend of step (2) was compressed into a tablet.

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

1. A modified release composition comprising:

(i) an immediate release unit comprising milnacipran or salts of milnacipran; and

(ii) one or more of modified release units comprising milnacipran or salts of milnacipran.

2. The modified release composition of claim 1, wherein the ratio of immediate release unit to the modified release unit(s) ranges from about 5:95 to about 95:5 by weight.

3. The modified release composition of claim 1, wherein the modified release unit is a controlled release unit, enteric release unit or enteric coated controlled release unit.

4. The modified release composition of claim 1, wherein the composition is a two unit system comprising an immediate release unit and one modified release unit.

5. The modified release composition of claim 1, wherein the composition is a multiple unit system comprising an immediate release unit and two or more modified release units.

6. A modified release composition comprising:

(i) a controlled release unit comprising milnacipran or salts of milnacipran; and (ii) one or more of enteric release units comprising milnacipran or salts of

milnacipran.

7. The modified release composition of claim 6, wherein the ratio of controlled release unit to the enteric release unit(s) ranges from about 5:95 to about 95:5 by weight.

8. The modified release composition of claim 6, wherein the enteric release unit comprises an enteric coated immediate release unit and an enteric coated controlled release unit.

9. The modified release composition of claim 6, wherein the composition is a two unit system comprising a controlled release unit and an enteric release unit or an enteric coated controlled release unit.

10. The modified release composition of claim 6, wherein the composition is a multiple unit system comprising a controlled release unit, an enteric release unit and an enteric coated controlled release unit.

11. The modified release composition of claim 1 , wherein the immediate release unit of the composition further comprises one or more pharmaceutically acceptable excipients.

12. The modified release composition of claim 1, wherein the modified release unit of the composition further comprises one or more pharmaceutically acceptable excipients and one or more rate-controlling and/or enteric agents.

13. The modified release compositions of claim 11 & 12, wherein the

pharmaceutically acceptable excipients comprise one or more of diluents, binders, disintegrants, lubricants, glidants, surfactants, buffers, wetting agents, coloring agents, flavoring agents and combinations thereof.

14. The modified release compositions of claim 1 and claim 6, in the form of discrete or aggregated particles, pellets, beads or granules.

15. The modified release compositions of claim 1 and claim 6, wherein

compositions are used for treating 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 by administering to a person in need thereof.

16. The modified release compositions of claim 1 and claim 6, wherein the compositions are administered in combination with other therapeutic agents.