FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
PHARMACEUTICAL COMPOSITION OF
SILDENAFIL


Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near
Dinesh Hall, Ahmedabad 380 009, Gujarat,
India

The following specification describes the invention


PHARMACEUTICAL COMPOSITION OF SILDENAFIL
FIELD OF THE INVENTION
The present invention relates to a stable, solid oral pharmaceutical composition of sildenafil manufactured by nonaqueous granulation. It also relates to the process involved therein.
BACKGROUND OF THE INVENTION
Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5) and acts on the nitric oxide (NO)/ cyclic guanosine monophosphate (cGMP) pathway. It is approved and marketed as sildenafil citrate for the treatment of erectile dysfunction and pulmonary arterial hypertension. It is commercially available in the brand name of Viagra® and Revatio®. Viagra® is available in 25, 50 and 100 mg tablet dosage form for the treatment of erectile dysfunction, whereas Revatio® is available in 20 mg tablet dosage form for the treatment of pulmonary arterial hypertension. Sildenafil is disclosed in EP 0463756 as potent and selective inhibitors of cyclic guanosine 3', 5'-monophosphate phosphodiesterase (cGMP PDE). It also discloses that it can be used for the treatment of various cardio vascular disorders including angina, hypertension, heart failure and atherosclerosis.
Sildenafil citrate is a white to off-white crystalline powder having solubility of 3.5mg/ml in water and a molecular weight of 666.7. Absolute bioavailability of sildenafil is 40% first pass metabolism is particularly responsible for the reduction of its bioavailability. Maximal plasma concentration is reached after about 1 hour of oral administration.

The commercially available dosage forms are prepared by compaction process. The inactive ingredients present in the dosage forms are microcrystalline cellulose, anhydrous calcium hydrogen phosphate, croscarmellose sodium and magnesium stearate. Compaction / dry granulation process results in dusting of drug in the manufacturing area. This will expose the manufacturing personnel to drugs like sildenafil and cause health hazards.
EP 0941075 Bl discloses rapidly releasing and taste-masking pharmaceutical dosage form comprising a core containing a sildenafil citrate, low-substituted hydroxy propyl cellulose containing not less than 5.0% and not more than 16.0% hydroxypropoxy groups on a dried bass, and microcrystalline cellulose. The patent discloses aqueous wet granulation of sildenafil citrate with diluent and binder. Aqueous granulation method may lead to hydrolytic degradation of the drug. The manufacturing process involved is also a lengthy one.
EP 1120120 discloses intra oral quickly disintegrating tablet comprising sildenafil, a saccharide selected from the group consisting of mannitol, xylitol, and erythritol, and further comprising at least one selected from surfactant and a water-soluble polymer. The manufacturing process include granulation by mixing them, adding an organic solvent, water or an aqueous organic solvent thereto, followed by kneading, and subjecting it to a compression-molding. The compression molding process is tedious process and not suitable for commercial purpose.
US 6469012 claims the use of pyrazolopyrimidinones compounds for the treatment or prophylaxis of erectile dysfunction in male mammals. It also discloses that the compound of the present invention can be administered to the patient orally.
WO2005115345 discloses a solid pharmaceutical composition of a therapeutic compound which is a base or salt of the base, an amphoteric compound or salt of the
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amphoteric base. It particularly relates to a swallow formulation of the active substance. It uses at least a pH modulating compound preferably a carbonate compound.
WO 2007113856 A2 discloses directly compressible composite for an orally disintegrating tablet comprising at least one water-soluble excipient and calcium silicate prepared by co-processing. Direct compression process is the simplest and economical method for the preparation of solid dosage form. But not all active agents possess required characteristics to let them for direct compression. The selection of compatible excipients for direct compression also needs careful selection as large variation in densities between the active and excipients will lead to demixing of the final powders resulting in poor content uniformity of the product. Direct compression method can not be applied for non-potent actives as this may lead to increase in the size of final dosage form.
Inventors of the present invention have surprisingly developed stable, solid oral pharmaceutical composition of sildenafil manufactured by nonaqueous granulation. The present inventors have overcome the different problems associated with direct compression and aqueous wet granulation method by devising a non-aqueous granulation process for the preparation of pharmaceutical composition of sildenafil. Non aqueous granulation also provides added advantage of fast processing of different steps involved in the development of dosage form. This method saves considerable amount of time and cost associated with aqueous wet granulation process. It also reduces dusting associated with powder drugs. So it also reduces the amount of exposure of medicament that an operator will generally encounter in other process. Hydrolytic decomposition of the drug is completely eliminated.
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SUMMARY OF THE INVENTION
The present invention relates to a stable, solid oral pharmaceutical composition of sildenafil.
One embodiment of the present invention is to provide a stable, solid oral pharmaceutical composition of sildenafil comprising sildenafil citrate and at least one pharmaceutically acceptable excipient wherein the pharmaceutical composition is manufactured by nonaqueous wet granulation.
Another embodiment of the present invention is to provide a stable, solid oral pharmaceutical composition comprising sildenafil citrate, which is manufactured by nonaqueous wet granulation, wherein nonaqueous solvents are methanol and methylene chloride
Another embodiment of the present invention is to provide a stable, solid oral pharmaceutical composition comprising sildenafil citrate, which is manufactured by nonaqueous wet granulation, wherein solid oral pharmaceutical composition has in vitro dissolution profile of at least 70% release of sildenafil in 30 minutes.
Another embodiment of the present invention is to provide a method of preparing a stable, solid oral pharmaceutical composition of sildenafil comprising the following steps of:
a) Mixing Sildenafil with atleast one pharmaceutically acceptable excipient,
b) Preparing granulating solution using atleast one nonaqueous solvent to form a granulating solution, which can optionally contain one or more excipients such as a binder;
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c) Granulating the drug blend by using the granulating solution and forming a wet
granulate, drying the wet granules, more preferably performed in a fluidized bed
drier;
d) Mixing the dried granules with one or more pharmaceutically acceptable excipients and forming a final blend.
e) Compressing the final blend into tablets.
DETAILED DESCRIPTION OF THE INVENTION
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
The term "dosage form" or "composition" or "formulation" or "pharmaceutical composition" as used herein refers to any suitable physical form of the drug containing fixed dose of the active ingredient alone or in combination with other active ingredients. Composition of the present invention includes without limitation a wider variety of dosage form like e.g. tablets, capsules, sachets, powders.
The term "stable" as used herein refers to dosage form which is physically, chemically or polymorphically stable. The dosage form according to present invention may remain physically stable, that is there are no substantial changes with respect to physical attributes like colour etc. The dosage form according to present invention may remain polymorphically stable that is the polymorph (crystalline or amorphous) in the dosage form does not rearranges into another form upon storage. It is known that different polymorphic forms of the same compound may have completely different physico-chemical properties. In such a case it is very important that the dosage form should retain the same polymorphic form in formulation
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throughout the shelf life in order to ensure the same therapeutical activity of the drug on the patients.
The term "sildenafil" or "active agent" or "drug" or "active ingredient' is to be understood to encompass all non-toxic salts, solvates, any amorphous form or crystalline form of the drug. The textbook "Analytical Profiles of Drug Substances and Excipients", volume: 27; discloses that Sildenafil Citrate exhibits polymorphism. According to this book, Sildenafil Citrate exists as Form I, II and III.
The dosage form of the present invention comprises the sildenafil in a range of about 1 mg to about 300 mg. Preferably dosage form may contain 10 mg to about 100 mg.
The term "hydrolytic degradation" as used herein is related to any significant change in chemical or physical nature of the drug in presence of water.
The term "non-aqueous granulation" or "non-aqueous wet granulation" as used herein is wet granulation process in which solvent essentially consists of non toxic solvents other than water. The solvent may belong to the group of organic compounds like alcohols, ketones and other acceptable solvents or their mixture. It is preferably Methanol or Methylene chloride or mixtures thereof.
The term "pharmaceutically acceptable excipient" comprises of excipients that are commonly used in the preparation of pharmaceutical dosage form. It may include binders, disintegrant, diluent, lubricating agent, flavouring agent, sweetening agent, glidant, coating agent, colorants, opacifying agents etc.
The diluents that can be used in the present invention can be exemplified by one or more of calcium carbonate, calcium phosphate, dibasic calcium phosphate (preferably anhydrous), tribasic calcium sulphate, powdered cellulose, silicified microcrystalline
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cellulose, compressible sugar, dextranes, dextrin dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, microcrystalline cellulose, polydextrose, sorbitol, starch, pregelatinized starch, sucrose, trehalose, xylitol or mixtures thereof. These examples are for illustrative purpose only. It should not be considered as limiting in nature. The preferred diluent in the present invention is cellulose derivatives most preferably it is microcrystalline cellulose and di calcium phosphate or mixtures thereof. The diluent in the invention is present in an amount preferably in the range of 5% to about 90 % w/w with respect to total weight of dosage form.
Disintegrants that can be used in the present invention may be, for instance one or more of following: alginic acid, carboxymethylcellulose, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, starch or pre-gelatinized starch or mixtures thereof. The preferable disintegrant in the present invention is croscarmellose sodium. The disintegrant is present in the instant invention in amount 0% to 10% w/w with respect to total weight of dosage form.
Glidants that can be used in the present invention can be one or more of the following: calcium silicate, powdered cellulose, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, starch and talc. The preferable glidant is silicone dioxide or talc.
The lubricant may be for instance one or more of following: calcium stearate, glycerin monostearate, sodium stearyl fumarate, glyceryl behenate, hydrogenated castor oil, hydrogenated vegetable oil, magnesium lauryl sulphate, magnesium stearate, medium-chain triglycerides, poloxamer, polyethylene glycol, stearic acid, talc, sucrose stearate and zinc stearate. The preferable lubricant in the present
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invention is sodium stearyl fumarate. The description above should not be considered as limiting in nature.
Binders can be added to the present dosage form to enhance compaction property of granules prepared. They help in increasing the cohesiveness of the powders or granules involved in the preparation of tablets or capsules. The binders that can be used in the present invention can be exemplified by any one or combination of following: acacia, alginic acid, carbomer, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hypromellose, methylcellulose, microcrystalline cellulose, polydextrose, polyethylene oxide, polymethacrylates, povidone, sodium alginate, starch, pregelatined starch, sucrose and zein. The preferable binder that can be used in the present invention is hydroxyl propyl methyl cellulose. The binder is present in the instant invention in amount 0% to 10% w/w with respect to total weight of dosage form.
The dosage form of the present invention is optionally coated by a coating solution. The coating solution of the present invention contains opacifying agent, coloring agent, solvent, plasticizers, binding agent and other pharmaceutically acceptable excipients. The coating solution used in the present invention comprises of conventional excipients like hydroxy propyl methyl cellulose (hypromellose), ethyl cellulose, methyl cellulose etc; the opacifying agents that can be used in the present invention are most commonly used opacifying agents like metallic oxide e.g. titanium oxide, zinc oxide, magnesium oxide etc; the colouring agents that can be used in the present invention are officially approved FD & C colour; the plasticizer that can be used in the present invention are propylene glycol, polyethylene glycol, triethyl citrate, triacetin, dibutyl phthalate and the like.
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The pharmaceutical composition of the present invention may be prepared in any dosage form such as a compressed granulates in the form of a tablet for example. Also, uncompressed granulates and powder mixes that are obtained by the method of the present invention in the pre-compression steps can be simply provided in dosage form of a capsule or sachet. Therefore, dosage forms of pharmaceutical composition of the present invention include solid dosage forms like tablets, powders, capsules, sachets, troches and lozenges.
The general method of manufacturing stable, solid oral pharmaceutical composition of sildenafil is described as under:
a) Mixing Sildenafil with atleast one pharmaceutically acceptable excipient,
b) Preparing granulating solution using atleast one nonaqueous solvent to form a granulating solution, which can optionally contain one or more excipients such as a binder;
c) Granulating the drug blend by using the granulating solution of step b) and forming a wet granulate, drying the wet granules, more preferably performed in a fluidized bed drier;

d) Mixing the dried granules with one or more pharmaceutically acceptable excipients and forming a final blend.
e) Compressing the final blend into tablets or filled into capsules or sachets.
The present invention can be explained by following examples. These examples are for the illustration of the invention only. It should not be considered as limiting in nature. In all the subsequent examples, the dissolution of the prepared tablets was determined in a basket apparatus. The rotation speed was set at 100 revolutions per minute, the dissolution medium of 0.01 N HCl maintained at a fixed temperature of 37°C ± 0.5°C. The total Volume of the dissolution fluid was 900 ml.
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Examples Example-1
Table 1

Ingredients Mg / Tablet
Step I: Dry mixing
Sildenafil Citrate equivalent to Sildenafil 100 mg 140.483
Microcrystalline Cellulose 247.017
Qicalcium Phosphate, Anhydrous 105.400
Croscarmellose Sodium 31.000
Step 2: Binder solution
Hypromellose 15.500
Methanol q.s
Methylene Chloride q.s
Step 3: Lubrication
Microcrystalline Cellulose 58.900
Sodium Stearyl Fumarate 9.300
Core Tablet Weight 607.600
Step 4 : Coating
Hypromellose 8.600
Titanium Dioxide 1.800
Triacetin 1.400
FD&C blue no 2 Lake 0.600
Methanol q.s
Methylene chloride q.s
Coated Tablet Weight 620.000
% Dissolution at 30 minutes 95.4%
Manufacturing process:
1. All the ingredients of Step-1 were sifted through sieves of appropriate mesh size.
2. Ingredients of Step-1 were mixed thoroughly in a RMG.
3. Binder solution was prepared with the ingredients of step-2.
4. Ingredients of step no.l were granulated by using binder solution of Step-2.
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5. The granulated mass was dried and sized through granulator with appropriate sieves.
6. The sized granules were blended and lubricated with the ingredients of Step-3V.
7. The lubricated blend was compressed with suitable punches.
8. The coating solution was prepared with the ingredients of Step-4.
9. Compressed tablets were than coated with the coating solution.
Dated this 24th day of June, 2008
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For Torrent Pharmaceuticals Ltd, Praveen Chand Gandhi
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