DESC:The term “Solifenacin” as used herein includes the pharmaceutically acceptable salts, polymorphs, stereoisomers and mixtures thereof, the term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.

The term, "pharmaceutically acceptable excipients" as used herein refers to diluents, disintegrants, binders, lubricants, glidants, polymers, coating agents, solvents, co-solvents, preservatives, wetting agents, thickening agents, antifoaming agents, sweetening agents, flavoring agents, antioxidants, colorants, solubilizers, plasticizer or dispersing agents and the like. The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients.

The term "diluent" employed in a composition of the present invention is capable for providing bulkiness to obtain a desired pharmaceutical composition. The diluents of instant invention include, but are not limited to inorganic phosphates such as dibasic calcium phosphate, calcium sulphate or dicalcium phosphate dihydrate; sugars such as lactose, lactose hydrate, lactose monohydrate, lactose anhydrate, sucrose, dextrose, erythritol, lactilol, xylitol, sorbitol, mannitol or malitol; cellulose or cellulose derivatives such as microcrystalline cellulose.

The term "fillers" employed in a composition of the present invention is capable for providing bulkiness to obtain a desired pharmaceutical composition. The fillers of instant invention includes, but are not limited to inorganic phosphates such as dibasic calcium phosphate, calcium sulphate or dicalcium phosphate dihydrate; sugars such as lactose, lactose hydrate, lactose monohydrate, lactose anhydrate, sucrose, dextrose, erythritol, lactilol, xylitol, sorbitol, mannitol or malitol; cellulose or cellulose derivatives such as microcrystalline cellulose; Avicel, Avicel PH 101, Avicel PH 102 or Avicel PH 103, maize starch, Starcap-1500, Starlac and galenIQ-721.

The term "binder" employed in a composition of the present invention is capable for holding the ingredients together and forming the granules with required mechanical strength. The binders of instant invention include, but are not limited to, but are not limited to, polyvinylpyrrolidone (povidone), polyethlylene glycol (PEG), saccharides, gelatins, pregelatinized starches, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (HPMC) and cellulose ethers.

The term "lubricant" employed in a composition of the present invention is capable of preventing the ingredients from clumping together and from sticking to the apparatus on which it is formed, for example, preventing adherence to the face of the upper punch (picking) or lower punch (sticking) of a compression machine. Preferred lubricants of instant invention includes, but are not limited to fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmitostearate, talc, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, aluminum stearate, stearic acid or hydrogenated vegetable oil; polyalkylene glycols such as polyethylene glycol (PEG) or sodium benzoate and the like.

The term "composition" or "pharmaceutical composition" or “dosage form” as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.

The term "excipient" means a pharmacologically inactive component such as diluent, disintegrant, carrier, filler, lubricant, binder, and solvent, coating agent or the like. These are generally safe, nontoxic. Reference to an excipient includes both one and more than one such excipient.

The term "stable" as used herein refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.

The term "about" as used herein refers to a defined range of the value by + 10 %. For example, about 2 % means 1.8 % to 2.2 %, about 5 % means 4.5 % to 5.5 %, about 10 % means 9 % to 11 % and about 40 % means 36 % to 44 %.

The term "oral dosage forms" includes all conventional oral solid dosage forms like Tablet, Capsule, Syrups, Suspension, Granules, Pill, Caplet, Pellets, Powder, Sachet, or any other orally ingestible dosage form comprising Solifenacin and its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

The terms “prevent” and “preventing” as used herein refers the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.

The terms “treat” and “treating” as used herein refers are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.

The term "oral dosage forms" includes all conventional oral solid dosage forms like a Tablet, capsule, Syrups, Suspension, granules, a pill, a tablet, a caplet, pellets, a powder or a sachet, or any other orally ingestible dosage form comprising Solifenacin or its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

The term "Parenteral dosage forms” includes all conventional oral solid dosage forms like a
Intramuscular injection, Intravenous injection, subcutaneous injection any other Parenteral dosage forms comprising Solifenacin its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a diluent" means one diluent or more than one diluent.

Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", "having", "containing" "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

The present invention relates to process for preparation of Solifenacin or its pharmaceutically acceptable salt thereof and one or more pharmaceutical acceptable excipients.

In certain exemplary embodiments, the pharmaceutical composition comprises, or is in the form of a pharmaceutically acceptable salt, as generally described below. Some preferred, but non-limiting examples of suitable pharmaceutically acceptable organic and/or inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the references referred to below).

In certain exemplary embodiments, the exemplary compound (Solifenacin) contain an acidic group as well as a basic group, the compound can form internal salts, which can also be used in the compositions and methods described herein. When an exemplary compound contains a hydrogen-donating heteroatom (e.g., NH), salts are contemplated to cover isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule. Pharmaceutically acceptable salts of the exemplary compounds include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases can also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth, incorporated herein by reference. Physiologically acceptable salts of the exemplary compounds are those that are formed internally in a subject administered compound for the treatment or prevention of disease. Suitable salts include those of lithium, sodium, potassium, magnesium, calcium, manganese, bile salts.

In certain embodiment the present invention relates to a process for preparation comprising a pharmaceutically acceptable excipient and a compound disclosed herein, pharmaceutical composition is in the form of solid dosage form, semi-solid dosage form and liquid dosage form.

In certain embodiments compounds described herein can be formulated in a variety of ways. Formulations containing one or more compounds can be prepared in various pharmaceutical forms, such as granules, tablets, capsules, suppositories, powders, controlled release formulations, suspensions, emulsions, creams, gels, ointments, salves, or lotions and the like. In certain embodiments, the formulations are employed in solid dosage forms suitable for simple, and preferably oral, administration of precise dosages. Solid dosage forms for oral administration include, but are not limited to, tablets, soft or hard gelatin or non-gelatin capsules, and caplets. However, liquid dosage forms, such as solutions, syrups, suspension etc. can also be utilized. In another embodiment, the formulation is administered topically. Suitable topical formulations include, but are not limited to lotions, ointments, creams, and gels.

In an embodiment of the present invention relates to a process for preparation of Solifenacin or its pharmaceutically acceptable salts, lactose monohydrate, maize starch/ corn starch, hypromellose, magnesium stearate and one or more pharmaceutically acceptable excipients.

In yet another embodiment of the pharmaceutical composition of the present invention can be formulated as dosage forms which include, but are not limited to, powders, granules, pills, tablets, coated tablets, capsules, pellets, patches, implants, films, liquids, semi-solids, gels, aerosols, emulsions, elixirs and the like.

In further embodiments of the present invention relates to the pharmaceutical compositions is prepared by known technological procedures, e.g. direct compression, dry granulation or wet aqueous granulation, using well known and readily available excipients. In the preparation of the compositions of Solifenacin the active ingredient will usually be mixed with an excipient or mixture of excipients, or diluted by an excipient or mixture of excipients, or enclosed within an excipient or mixture of excipients which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle or medium for Solifenacin or pharmaceutically acceptable salts or derivatives thereof.

In an another embodiment of the present invention relates to a process for the preparation of Solifenacin composition, where in the said composition comprising of Solifenacin or pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipient, the present invention further relates to methods of preparing and administering such pharmaceutical compositions.

In an another embodiment of the present invention relates to a process for preparation of Solifenacin composition, where in the process involves the dispersion of Solifenacin in the binder solution, the said composition comprising of Solifenacin or pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipient, the present invention further relates to composition and administering such pharmaceutical preparation which is suitable in the treatment or prevention of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.

In an another embodiment of the present invention relates to a pharmaceutical composition of Solifenacin, where in the said composition comprising of Solifenacin or pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipient, the present invention further relates to composition and administering such pharmaceutical preparation which is suitable in the treatment or prevention of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.

In an another embodiment of the present invention relates to a formulation process for preparation of Solifenacin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipient, where in the formulation process involves the preparation of binder solution with Solifenacin and one or more pharmaceutically acceptable excipients using wet granulation method.

In an another embodiment of the present invention relates to a formulation process for preparation of Solifenacin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipient, where in the formulation process involves the addition of Solifenacin in to composition involving dispersion of drug in the binder solution using wet granulation method.

In an another embodiment of the present invention relates to a process for preparation of Solifenacin wherein said composition comprises:
(a) Solifenacin or its pharmaceutical salt thereof,
(b) One or more diluents;
(d) One or more binder;
(e) One or more filler;
(e) One or more lubricant; and
(f) Optionally one or more pharmaceutical acceptable excipients.

In an another embodiment of the present invention relates to a process for preparation of Solifenacin wherein said composition comprises:
(a) from about 5% to about 25% of Solifenacin or its pharmaceutical salt thereof,
(b) from about 50 % to about 80 % of one or more diluents;
(d) from about 0.10 % to about 10 % binder;
(e) from about 0.5 % to about 5 % lubricant;
(f) from about 10% to about 30 % Filler; and
(f) optionally one or more pharmaceutical acceptable excipients.

In an another embodiment of the present invention relates to a formulation process for preparation of Solifenacin or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient where in Solifenacin is used in the percentage from 20-90%, preferably 20-70% and more preferably 05-20% from total weight of the concentration.

In an another embodiment of the present invention relates to a formulation process for preparation of Solifenacin or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, where in the tablet for oral administration comprises 05 mg of Solifenacin.

In an another embodiment of the present invention relates to a formulation process for preparation of Solifenacin or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, where in the tablet for oral administration comprises 10 mg of Solifenacin.

In an another embodiment of the present invention relates to a formulation process for preparation of Solifenacin or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, where in drug coating layer consisting 04-20% from the total weight of the composition.

In an another embodiment of the present invention relates to a formulation process for preparation of Solifenacin or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, where in the composition is an immediate release or delayed release or extended release tablet dosage form.

In an another embodiment of the present invention to provide a particle size distribution of the Solifenacin or its salts thereof, may have particle size (D90) is less than 200 µm, preferably less than 100 µm, and more preferably less than 10 µm are combination thereof.

In an another embodiment of the present invention relates to a formulation process for preparation of Solifenacin composition by sifting the intragranular excipients, preparation of binding solution by dissolving binder in a suitable solvent and dispersing solifinacin in the above binder solution. The intragranular mixture is granulated using the drug dispersed binding solution to obtained suitable size granules. The extra granular excipients are added to the above said granules and lubricated with suitable lubricant. The lubricated granules are punched in tablets.

Examples:
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example-1:
Manufacturing Formula:
S.No. Ingredients Qty per Unit (mg)
5 mg 10 mg % w/w
Intra granular
1 Lactose Monohydrate
(Pharmatose 200M) 56.35 112.70 75.13
2 Maize Starch/ Corn Starch 12.70 25.40 16.93
Binder Solution
3 Solifenacin Succinate 5.00 10.00 6.67
4 Hypromellose (E3) 0.20 0.40 0.27
5 Purified Water4 qs qs --
Extra granular
6 Magnesium Stearate
(Ligamed MF-2-V) 0.75 1.50 1.00
75.00 150.00 100.00
Film Coating3 (3.0 % w/w weight build up, 12 % w/w solid content)
7 Opadry Yellow
(02B220012) 2.25 -- 3.00
8 Opadry Pink
(03F540440) -- 4.50 3.00
9 Purified Water4 qs qs --
77.25 154.50 --
Brief Manufacturing Procedure:
Sifting
i. Co-sift Lactose Monohydrate and Maize starch through sieve #40 ASTM (425 µm) and collect in doubled lined polybag.
ii. Resift the step no-i of sifted material through sieve #40 ASTM (425 µm).
iii. Sift magnesium stearate through sieve #60 ASTM (250 µm) and collect in doubled lined polybag.
Dry Mixing
iv. Load the sifted material of step-ii into the Rapid Mixer Granulator and mix for 5 minutes at fast impeller speed (150 RPM) and slow Chopper speed (1500 RPM).
Binder Solution
v. Dispense required quantity of Purified water in SS container.
vi. Disperse the Hypromellose (E3) in step- v under stirring and stir for clear solution obtained.
vii. Disperse the Solifenacin Succinate in step – vi under stirring and stirring was continuous for clear solution obtained
Granulation
viii. Granulate step-iv dry mix by using step-vii binder solution with the following granulation parameters.
Step Specification Impeller Speed Chopper Speed
Dry mixing 5 minutes 150 RPM 1500 RPM
Binder addition 2 - 6 minutes 150 RPM 1500 RPM
Extra water (for raising) 60 seconds 150 RPM 1500 RPM
Kneading 1 - 6 minutes 150 RPM 1500 RPM
Total granulation time 1 min – 6 min
Total % fluid uptake
(excluding extra water) 8 - 12 % w/w
ix. Unload the wet mass through co-mill fitted with 6.0 mm screen at slow speed.
Drying
x. Dry the granules of step-ix, until the % LOD of the granules reaches 1.00 - 2.00 % w/w at 105°C.
Sifting and Milling:
xi. Sift the dried granules of step-x through sieve #30 ASTM (600 µm).
xii. Mill the retentions of step-xi by using co-mill fitted with 2.0 mm screen at slow speed and sift through sieve #30 ASTM (600 µm).
xiii. Mill the retentions of step-xii by using co-mill fitted with 1.0 mm screen at slow speed and sift through sieve #30 ASTM (600 µm). Continue this to mill the granules with 1.0 mm screen until all the material passes through sieve #30 ASTM (600 µm).
Sifting of extra-granular materials
xiv. Sift Magnesium stearate through sieve #60 ASTM (250 µm) and collect in doubled lined polybag.
Blending and Lubrication
xv. Load the milled granules of step-xiii in octagonal blender and mix for 10 minutes at 16 rpm.
xvi. Add sifted magnesium stearate of step-xiv to step-xv and mix for 5 minutes at 16 rpm
Compression
xvii. Compress the above blend with suitable tooling.
Film Coating
xviii. Coat the tablets of step 10 with film coating material.
,CLAIMS:1) A process for preparing a solid oral pharmaceutical composition of Solifenacin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, wherein the process comprises following steps:
a) Sifting the intragranular excipients, preparation of binding solution by dissolving binder in a suitable solvent,
b) dispersing Solifenacin in the above binder solution,
c) the intragranular mixture is granulated using the drug dispersed binding solution to obtained suitable size granules,
d) the extra granular excipients are added to the above said granules and lubricated with suitable lubricant, and
e) The lubricated granules are punched in tablets.

2) The process for preparing a solid oral pharmaceutical composition as claimed in claim 1, where in the composition comprises:
(a) from about 5% to about 25% of Solifenacin or its pharmaceutical salt thereof,
(b) from about 50 % to about 80 % of one or more diluents;
(c) from about 0.10 % to about 10 % binder;
(d) from about 0.5 % to about 5 % lubricant;
(e) from about 10% to about 30 % Filler; and
(f) optionally one or more pharmaceutical acceptable excipients.

3) The process for preparing a solid oral pharmaceutical composition as claimed in claim 1, where in the drug coating layer consisting 4-25% from the total weight of the composition.

4) The process for preparing a solid oral pharmaceutical composition as claimed in claim 1, where in the composition is an immediate release or delayed release or extended release tablet dosage form.

5) The process for preparing a solid oral pharmaceutical composition as claimed in claim 1, where in the particle size distribution of the Solifenacin (D90) is less than 200 µm, preferably less than 100 µm, and more preferably less than 50 µm are combination thereof.

6) The process for preparing a solid oral pharmaceutical composition as claimed in claim 1, where in the pharmaceutical excipients are lactose monohydrate, maize Starch, hypromellose, magnesium stearate.

7) The process for preparing a solid oral pharmaceutical composition as claimed in claim 1, where in the composition is used for the treatment or prevention of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.