FIELD OF THE INVENTION;

The present invention relates to a pharmaceutical composition comprising Milnacipran and its pharmaceutically acceptable salts thereof. The present invention specifically relates to stable composition comprising Milnacipran and its pharmaceutically acceptable salts and crospovidone.

BACKGROUND OF THE INVENTION:

(1R, 2S)-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropanecarboxamide hydrochloride is commonly known as Milnacipran hydrochloride of structural formula I

Formula -1

Milnacipran hydrochloride is a selective norepinephrine and serotonin reuptake inhibitor (NSRI) and is useful in the treatment of depression and chronic pain conditions like fibromyalgia and lupus.

Milnacipran is first disclosed in U.S. patent no. 4,478,836 provides a process for the preparation of Milnacipran hydrochloride by salifying Milnacipran base with hydrochloric acid. In this method Milnacipran hydrochloride is obtained as white crystals with melting point of 180°C.

Milnacipran hydrochloride is marketed in the United States under the brand name Savella® in the form of 12.5, 25, 50 and 100 mg tablets. In Europe, it is available under the brand name of Ixel® in the form of 25, 50 and 100 mg capsules for depression. Ixel® typically uses dibasic calcium phosphate, carboxymethylcellulose calcium, povidone, colloidal silicone dioxide, magnesium stearate and talc as inactive ingredients.

European patent application number EP 1 894 565 Al relates to a stabilized formulation of Milnacipran wherein Milnacipran is adsorbed on the porous carrier containing anhydrous calcium hydrogen phosphate. It also highlights the problems related to Milnacipran formulations such as drop in the dissolution, discoloration of the formulation during handling and adhesion of individual dosage forms during storage.

A research article by Carolina Lupi Dias et al, (Dissolution technologies, August 2011, pp 47-53) deliberates changes in dissolution rate and a slower dissolution profile of Milnacipran. The observed changes in dissolution profile were pronounced which may affect in vivo performance especially with capsules approaching the expiry date. Therefore there is need of a composition of Milnacipran having stable and constant dissolution characteristics.

The present inventors have found that the stable composition of Milnacipran can be prepared using crospovidone and pharmaceutically acceptable excipients without any drop in dissolution profile even during stability period.

OBJECTIVE OF THE INVENTION:

The main object of the present invention is to provide a pharmaceutical composition comprising Milnacipran and its pharmaceutically acceptable salts.

Another object of the present invention is to provide a stable pharmaceutical composition comprising Milnacipran and its pharmaceutically acceptable salts with a superdisintegrant.

SUMMARY OF THE INVENTION:

The first aspect of the present invention is to provide a pharmaceutical composition comprising Milnacipran or its pharmaceutically acceptable salts.

Second aspect of the present invention is to provide a stable pharmaceutical composition comprising Milnacipran and its pharmaceutically acceptable salts and a superdisintegrant.

Third aspect of the present invention is to provide a stable composition comprising Milnacipran and its pharmaceutically acceptable salts, crospovidone and other pharmaceutically acceptable excipients.

Fourth aspect of the present invention is to provide a process for the preparation of a stable pharmaceutical composition comprising Milnacipran.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides a pharmaceutical composition comprising Milnacipran and its pharmaceutically acceptable salts, a superdisintegrant and other pharmaceutically acceptable excipients.

The first embodiment of the present invention provides a pharmaceutical composition of Milnacipran comprising a superdisintegrant. Superdisintegrants are in a concentration from 0.1 to 50% by weight based on the weight of the pharmaceutical preparation. Superdisinegrant which is essential for achieving the object of the present invention is known to the person skilled in the art, includes but not limited to cross linked alginic acid, croscarmellose sodium, crospovidone, pregelatinized starch, sodium starch glycolate, ion exchange resins. The concentration of superdisintegrant ranges from 25 to 45%, preferably from 5 to 25% and more preferably from 3 to 10%.

The main advantage of the present invention emphasizes the usage of superdisintegrant, which will improve the solubility of the preparation and also enhances the stability of the preparation.

A preferred embodiment of the present invention is to provide a stable pharmaceutical composition comprising Milnacipran and its pharmaceutically acceptable salts, crospovidone and other pharmaceutically acceptable excipients.

According to another embodiment, the pharmaceutical composition of Milnacipran include binders, diluents, lubricants, glidants, surfactants, film coating agents and coloring agents. As understood by a person skilled in the art, these excipients are conventional excipients which are well known in the pharmaceutical art.

According to one embodiment of the present invention binders include, but are not limited to, acacia, alginic acid, carbomers, carboxymethyl cellulose sodium, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, confectioners sugar, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glucose, glyceryl behenate, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxy ethyl methyl cellulose, hydroxyl propyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, poloxamer, polydextrose, polyethylene oxide, polymethyl acrylates, povidone, sodium alginate, starch, pregelantized starch, stearic acid, sucrose, sunflower oil, zein and mixtures thereof. According to the invention, the binder preferably used is polyvinyl pyrrolidone. This is commercially available, for example under the name povidone. The pharmaceutical composition advantageously utilizes from 0.1 to 15%, preferably from 0.5 to 8%, more preferably from 2 to 4% of povidone.

According to another embodiment of the present invention diluents that includes diluents known to the person skilled in the art except anhydrous calcium hydrogen phosphate, but are not limited to dibasic calcium phosphate dihydrate, kaolin, hydrous silicone dioxide, calcium silicate, magnesium silicate, light anhydrous silicate, magnesium metasilicate aluminate, calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, ethyl cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, microcrystalline cellulose, polymethylacrylates, potassium chloride, powdered cellulose, sodium alginate, sodium chloride, sorbitol, starch, pregelantized starch, sterilizable maize, sucrose, sugar spheres, talc, tragacanth, tribasic calcium phosphate, xylitol and mixtures thereof. The pharmaceutical composition advantageously utilizes from 1 to 90%, preferably from 30 to 80%, more preferably from 25 to 65% of the diluent.

In another embodiment of the present invention lubricants include, but are not limited to, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, light mineral oil, magnesium lauryl sulfate, magnesium stearate, medium chain triglycerides, mineral oil, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and mixtures thereof.

According to one more embodiment of the present invention surfactants comprises non-ionic surfactants like alkyl poly(ethylene oxide),a poly(ethyleneoxide), Copolymers of poly(ethylene oxide) and poly(propylene oxide) (commercially called Poloxamers or Poloxamines), alkyl polyglucosides like octly glucoside, decyl maltoside, fatty alcohols like Cetyl alcohol, oleyl alcohol, Cocamide MEA, Cocamide DEA, Polysorbates like Tween 20, Tween 80; anionic surfactants such as Perfluorooctanoate, perfluorooctanesulfonate, sodium dodecyl sulfate, ammonium lauryl sulfate, sodium lauryl sulfate, alkyl benzene sulfonate, soaps or fatty acid salts and cationic surfactants such as Cetyl trimethylammonium bromide, cetylpyridinium chloride, polyethoxylated tallow amine, benzalkonium chloride, benzethonium chloride, and cetrimide (alkyltrimethylammonium bromide, predominantly C14 alkyl).

According to further embodiment of the present invention solvent comprises; Isopropyl alcohol, ethanol, n-butanol, acetone, purified water or combination thereof.

Milnacipran present in the composition is in the form of racemic mixtures. As used herein "Milnacipran" also includes pharmaceutically acceptable, pharmacologically active derivatives of Milnacipran including both individual enantiomers of milacipran and their pharmaceutically acceptable salts, mixtures of Milnacipran enantiomers and their pharmaceutically acceptable salts, and active metabolites of Milnacipran and their pharmaceutically acceptable salts.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the salts prepared from 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 isothionic.

The pharmaceutical composition of this invention may be present in several oral dosage forms, but not limited to tablets, capsules or granules, sachets, powders, MUPS, preferably tablets or capsules.

The tablet dosage form may optionally be coated. Film coat concentration can be varied up to about 10% to complement the drug amount, and preferably from about 2.0% to about 3.5%.

Film coating suspensions include combinations of one, two or three of the following components: carboxymethylcellulose sodium, camauba wax, cellulose acetate phthalate, cetyl alcohol, confectioner's sugar, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, maltodextrin, methyl cellulose, microcrystalline wax, Opadry and Opadry II, polymethacrylates, polyvinyl alcohol, shellac, sucrose, talc, titanium dioxide, and zein.

The pharmaceutical composition according to the invention is preferably used for the treatment depression and chronic pain conditions like fibromyalgia and lupus.

Further embodiment of the present invention provides a process for manufacturing the pharmaceutical composition of Milnacipran comprises the following steps:

(1) screening Milnacipran and pharmaceutically acceptable excipients;

(2) dry mixing the content of step (1);

(3) preparing a binder solution;

(4) adding the binder solution of step (3) to the dry blend of step (2);

(5) granulating the content of step (2) using binder solution;

(6) drying the granules obtained from step (5);

(7) screening the dried granules obtained from step (6);

(8) pre-lubricating the screened granules obtained from step (7)

(9) screening the lubricant and adding and mixing lubricant with the pre-lubricated screened granules obtained from step (8);

(10) filling the obtained granules from step (9) in capsules shells;

(11) optionally, compressing the content of step (9) to tablets;

(12) optionally, film coating of the tablets obtained from step (11).

In one embodiment, the dry mixing can be carried out using high shear mixer, rapid mixer granulator and planetary mixers preferably using rapid mixer granulator. The granules can be prepared using high shear mixer, rapid mixer granulator, fluid bed granulator or extrusion-spheronization, preferably by rapid mixer granulator.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The present invention can be illustrated in one of its embodiment by the following non-limiting examples.

Example 1: Preparation of 25 mg tablets of Milnacipran hydrochloride:
Manufacturing Procedure:

(1) Milnacipran and pharmaceutically acceptable excipients were screened;

(2) the content of step (1) was dry mixed;

(3) binder solution was prepared;

(4) the binder solution of step (3) was added to the dry blend of step (2);

(5) granulated the content of step (2) using binder solution;

(6) the granules obtained from step (5) was dried;

(7) the dried granules obtained from step (6) were screened;

(8) the screened granules obtained from step (7) were pre-lubricated;

(9) the lubricant was screened and mixed with the pre-lubricated screened granules obtained from step (8);

(10) the content of step (9) were Compressed to tablets;

(11) the tablets obtained from step (10) were film coated.

Example 2: Preparation of 25 mg capsules of Milnacipran hydrochloride:
Manufacturing Procedure:

(1) Milnacipran and pharmaceutically acceptable excipients were screened;

(2) the content of step (1) were dry mixed;

(3) binder solution was prepared;

(4) the binder solution of step (3) was added to the dry blend of step (2);

(5) the content of step (2) were granulated using binder solution;

(6) the granules obtained from step (5) were dried;

(7) the dried granules obtained from step (6) were screened;

(8) pre-lubricated the screened granules obtained from step (7);

(9) the lubricant was screened and mixed lubricant with the pre-lubricated screened granules obtained from step (8);

(10) the obtained granules from step (9) were filed in hard gelatin capsule shells.

Example 3: Preparation of 25 mg capsules of Milnacipran hydrochloride:

The process for the preparation of example 3 is as follows:

(1) Milnacipran hydrochloride, calcium hydrogen phosphate dihydrate, crospovidone were screened through a 30 mesh screen;

(2) the content of step (1) was mixed in a rapid mixer granulator with an impeller speed set at 100 rpm for 5 minutes;

(3) the binder solution was prepared by dissolving povidone in purified water;

(4) the binder solution of step (3)was slowly added to the dry blend of step (2) for approximately 1-2 minutes;

(5) granulation was performed in rapid mixer granulator with an impeller speed set at 100 rpm;

(6) the wet mass obtained was dried in tray dryer by maintaining the product temperature 50° C till the loss on drying of the granules was between 3.0- 5.0%;

(7) dried granules were sifted through 24# mesh;

(8) dried granules were pre-lubricated using crospovidone;

(9) pre-lubricated granules were lubricated using magnesium stearate, talc and aerosol;

(10) the lubricated granules were filled in capsule using capsule filling machine (size 3 for 50 mg and size 4 for 25 mg).

The capsules obtained from Example 3 were subsequently tested for in vitro dissolution rate, measured by Apparatus II (USP Paddle Method), using the following parameters:

o Speed: 75 rpm

o Dissolution Media: 0.1 N Hydrochloric acid

o Volume: 900 ml

o Temperature: 37 °C ± 0.5 °C

Dissolution Rate of Milnacipran hydrochloride capsules of Example 3:

Milnacipran hydrochloride capsules of above mentioned example 1, are packed in PVC/ALU blisters, stored at 40°C ± 2°C /75% RH ± 5% RH for stability studies up to six months. The dissolution rate of Milnacipran hydrochloride capsules are shown in below table.

Dissolution Rate of Milnacipran hydrochloride capsules (25 mg) of Example 3 during six months of stability testing:

Dissolution Rate of Milnacipran hydrochloride capsules (50 mg) of Example 3 during six months of stability testing:

We Claim;

1) A pharmaceutical composition comprising Milnacipran or its pharmaceutically acceptable salts and a superdisintegrant in amount of 0.1% to 50%, preferably 2% to 20% by weight of the composition.

2) A pharmaceutical composition comprising Milnacipran or its pharmaceutically acceptable salts thereof, crospovidone and other pharmaceutically acceptable excipients.

3) A pharmaceutical composition according to claim 1, comprises 0.1 to 50%, preferably 2% to 20% of crospovidone.

4) The pharmaceutical composition according to claim 1, further comprises pharmaceutically acceptable excipients, selected from the group of glidants, lubricants, fillers, binders, disintegrants, diluents, surfactants, and solutions.

5) The pharmaceutical composition according to claim 1, wherein the related dosage forms are selected from the group of capsules, tablets, powder, mups and sachets.

6) The pharmaceutical composition according to claim 1, is used in the treatment of depression and chronic pain conditions like fibromyalgia and lupus.