TECHNICAL FIELD

The present invention relates to the process of preparing a stable pharmaceutical composition of the Solifenacinand/or its pharmaceutical salts thereof. In particular, the present invention is directed to the process for thepreparation of oral compositionsofSolifenacin succinate.

BACKGROUND TO THE INVENTION

Solifenacin is an excellent muscarnic M3 receptor antagonists, which is chemically
known as(1S,3'R)-quinuclidin-3',-yl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate and is represented by the following chemical structure Solifenacin Succinate is a urinary antispasmodic, acting as a selective antagonist to the M(3)-receptor. It is used for the treatment of symptoms of overactive bladder, such as urinary urgency and increased frequency, as may occur in patients with overactive bladder syndrome

Solifenacin Succinate 5mg and 10mg tablets (i.e. Vesicare, Flomin and Uriclin), which are approved to AstellasPharma are currently marketed across US, Canada, Europe and Asia. It is manufactured by Ranbaxy (Soliten) and Dr.Reddv's Laboratories (Bispec) in India for the treatment of Over-active bladder. Solifenacin succinate is .reported to be under clinical trials in order to use as a therapeutic agent for pollakiuria and incontinence of urine due to hyperactive bladder.

Additionally, there are reports about its efficacy on, for example intestinal cystitis, irritable bowel syndrome, tension relaxation of ciliary muscle as well as respiratory diseases such as chronic occlusive lung diseases, chronic bronchitis, asthma and rhinitis, which are disclosed in WO 2003/6019, JP-A-2002-104968 and Current Opinion in Central & Peripheral Nervous System Investigational Drugs, 2000, Vol. 2, No. 3, pg. 321-325.

Solifenacin was first reported in EP 0 801' 067 B1, which discloses a series of quinuclidine derivatives including Solifenacin and its salts thereof. This patent also discloses the process for the preparation of preparing Solifenacin and also the composition comprising Solifenacin.

EP 1 728 791 discloses compositions of solifenacin or a salt thereof for the use in solid formulation and the manufacture process of the formulation by adding suitable excipient which may or may not contain the solvent. It suggests to keep the ratio of amorphous solifenacin to crystalline solifenacin at a given value or lower, by addition of appropriate inhibitors preventing amorphization.

EP 1 832 288 discloses a stable granular pharmaceutical composition which contains solifenacin or a salt thereof and a binding agent which is sprayed onto the nuclei to have a stabilizing action on the solifenacin or salt thereof. As per examples disclosed, Per 10 part of solifenacin succinate, 3.4 parts of binder is used.

2782/KOLNP/2006 discloses an oral solid pharmaceutical formulation of crystal solifenacin or a salt thereof, wherein the amorphous content is within a range showing no influence on product stability and its manufacturing process which follows a granulation method comprising the steps of blending solifenacin or a saltthereof with an excipient with or without using any solvent.

WO 2008/013851 discloses the process of preparing the polymorphs (Crystalline and Amorphous forms) of Solifenacin Succinate by employing varioussolvents.

According to the literature, the main cause of the degradation of the active pharmaceutical ingredient over time was presumably amorphous Solifenacin succinate generated in the manufacturing process of the formulation.

The present invention addresses the need in the art for stable solid oral dosage forms of Solifenacin or its pharmaceutically acceptable salts thereof by employing novel use of solvents or mixture of solvents and/or antisolvents.

The current process for the preparation of the Solifenacin compositions shows improved stability and the lesser amounts of impurities and the degradation products, which are industrially advantageous.

OBJECT OF THE INVENTION

The main object of the present invention is to provide a process for preparing tablets or granuleswith improved stability comprising Solifenacin or its pharmaceutically acceptable salts thereof by employing various solvents and/or antisolvents or combinations thereof.

SUMMARY OF THE INVENTION

The main aspect of the present invention is to provide a wet granulation method for preparing the granules comprising Solifenacin or its pharmaceutically acceptable salts thereof, comprising the following steps: a) dispersing the Solifenacin or its pharmaceutically acceptable salts thereof in a solvent or a mixture of solvents b) preparing a dry blend by mixing pharmaceutically acceptable excipients; c) adding the binder solution to the dry blend to obtain granules d) drying the granules obtained;e) optionally compressing the granules into tablets.

The other aspect of the present invention is to provide film coated tablets of Solifenacinby using a wet granulation method comprising the following steps:

a) preparing the binder solution by dissolving the Solifenacin in solvent or mixture of solvents and antisolvents;

b) preparing a dry blend by mixing hydroxyl propyl methyl cellulose (HPMC), lactose and other pharmaceutically acceptable excipients;

c) adding the binder solution to the dry blend to obtain granules

d) drying the granules obtained;

e) compressing the granules into tablets; f) and coating the tablets with film coating agents.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 illustrates a PXRD pattern of CrystallineSolifenacin Succinate Form I API.

Figure 2 illustrates a PXRD pattern of Solifenacin Succinate Tablet 10mg.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a wet granulation method for preparing the granules comprising Solifenacin or its pharmaceutically acceptable salts thereof, which can be used in making any solid oral dosage forms comprising the following steps:

a) preparing the binder solution by dissolving the Solifenacin in solvent or mixture of solvents and/or antisolvents;

b) preparing a dry blend by mixing pharmaceutically acceptable excipients;

c) adding the binder solution to the dry blend to obtain granules

d) drying the granules obtained;

e) optionally compressing the granules into tablets.

The first embodiment of the present invention is the solvent.selected from the group comprising of C3-C5carbonate, acetonitrile, methanol, dimethylsulfoxide, dichloromethane, dimethoxypropane, C6-C9 aromatic hydrocarbon, diethyl ether, diisopropyl ether, C5-C9 ester, C1-C4alcohol, C3-C9ketone,cyclohexane, heptane and mixtures thereof.

Preferably the solvent is selected from the group consisting of Acetonit'rile, methanol, ethanol, propanol, Acetone, methyl ethyl ketone, dimethylsulfoxide and dichloromethane.

Preferably the antisolvent is selected from the group of Acetone, Diethyl ether, methyl t-butyl ether, methyl acetate, Isobutyl acetate, 2-Butyl alcohol, methylethyl ketone, Isopropyl ether, Carbon tetrachloride, toluene, ethyl acetate and hexane.

More preferably the solvent or antisolvent is selected from the group consisting of ethyl acetate, acetonitrile.diethyl ether, a mixture of acetonitrile and diethyl ether are used.

These solvents help to maintain the drug in the crystalline state, which may enhance the stability of the dosage form prepared.

The second embodiment of the present invention is the other pharmaceutical acceptable excipients used include diluents, lubricants, glidants, bindersanddisintegrants known to the person skilled in the art.

The "pharmaceutically acceptable salt of solifenacin" for use in accordance with the invention includes acid addition salts of solifenacin with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid, and quaternary ammonium salts thereof. Specifically, Solifenacin succinate is preferable in providing a pharmaceutical product and also achieves the stabilization effect greatly in accordance with the invention.

According to one of the embodiment of the present invention the Solifenacin granules can be compressed to tablets or the granules can be filled into the capsules.

According to further embodiment of the present invention the Solifenacin granules can be compressed to tablets and coated with a film forming agents known to the person skilled in the art, preferably Opadry.

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.

EXAMPLES

Example 1: Preparation of 10 Mg Solifenacin Succinate film coated tablet

Tablet Preparation procedure:

1. Weighed quantities of Lactose monohydrate. Corn starch were sifted using #40 mesh. .

2. Transferred the sifted materials to Rapid Mixer Granulaor and the main impeller was set to a speed of 100 rpm and mixed for 5 minutes.

3. Granulation fluidwas prepared by dispersing Solifenacin Succinate into acetonitrile and Diethyl ether (1:1)

4. The main impeller was set to a speed 100 rpm and the granulation fluidwas added slowly for about 2-3 minutes into the dry mix blend in the Rapid Mixer Granulator.

5. After completion of the granulation, the wet mass was sieved using 12# mesh and dried at 45 ± 5.0°C for 30 minutes.

6. Dried granules were compressed by using 6.5 mm round shaped concave punch set.

Tablet Coating

Opadrywhitewas mixed with Dichloromethane and Isopropyl alcoholand transferred into the centre of the propeller and stirredto form a vortex without drawing air into the liquid and prepared dispersion was coated with using Auto coater.

Stability Data:

Example 2: Preparation of 5 Mg Solifenacin Succinate film coated tablet

The procedure for preparing 5mg tablets of Solifenacin Succinate is similar to the process used in Example 1.

Stability Data:
Example 3: Preparation of 10 Mg Solifenacin Succinate film coated tablet

Tablet preparation procedure:

1. Weighed quantities of Lactose monohydrate, Corn starch and Hypromelose were sifted using #40 mesh.

2. Transferred the sifted materials to Rapid Mixer Granulator and the main impeller was set to a speed of 100 rpm and mixed for 5 minutes.

3. Granulation fluidwas prepared by dispersing Solifenacin Succinate intoethyl
acetate.

4. The main impeller was set to a speed 100 rpm and the granulation fluid was added slowly for about 2-3 minutes into the dry mix blend in the Rapid Mixer Granulator.

5. After completion of the granulation, the wet mass was sieved using 12# mesh and dried at 45 ± 5.0°C for 30 minutes.

6. Dried granules were compressed by using 6.5 mm round shaped concave punch
set.

Tablet Coating

Opadrywhitewas mixed with Dichloromethane and isopropyl alcoholand transferred into the centre of the propeller and stirredto form a vortex without drawing air into the liquid and prepared dispersion was coated with using Auto coater.

Stability Data:

Example 4: Preparation of 5 Mg Solifenacin Succinate film coated tablet

The procedure for preparing 5mg tablets of Solifenacin Succinate is similar to the process used in Example 3.

Stability Data:

CLAIMS

1. A process for the preparation of Solifenacin composition comprising the steps of: a) dispersing the Solifenacin or its pharmaceutically acceptable salts thereof into the solvent; b) preparing a dry blend by mixing pharmaceutically acceptable excipients; c) adding the granulating fluid to the dry blend to obtain granules; d) drying the granules obtained; e) optionally compressing the granules into tablets.

2. A process for the preparation of Solifenacin composition comprising the steps of: a) dispersing the Solifenacin or its pharmaceutically acceptable salts thereof into a mixture containing a solvent and an antisolvent; b) preparing a dry blend by mixing pharmaceutically acceptable excipients; c) adding the granulating fluid to the dry blend to obtain granules; d) drying the granules obtained; e) optionally compressing the granules into tablets.

3. The pharmaceutical composition according to claims 1 and 2, the solvent is selected from the group comprising of acetonitrile, methanol, dimethylsulfoxide, dichloromethane, acetone, propanol, methylethyl ketone and ethanol, preferably acetonitrile, methanol, dimethylsulfoxide and dichloromethane.

4. The pharmaceutical composition according to claims2 and 3, the antisolvent is selected from the group comprising of acetone, diethyl ether, methyl t-butyl ether, methyl acetate, isobutyl acetate, 2-butyl alcohol, methylethyl ketone, isopropyl ether, carbon tetra chloride, toluene, ethyl acetate and hexane, preferably diethyl ether and ethyl acetate.

5. According to claims 1 and 2, the pharmaceutically acceptable excipients are selected from the group of binders, surfactants, glidants, lubricants, fillers, disintegrants, diluents, solutions.

6. The pharmaceutical composition of Solifenacin according to claims 1 and 2, wherein the related dosage form is selected from the group of tablets, mups, capsules, sachets.