Title of Invention	SILDENAFIL CITRATE MOUTH DISPERSIBLE TABLETS
Abstract	A composition for use in the treatment of erectile dysfunction, said composition being in the form of a taste masked, rapid release tablet comprising a phospho-diesterase inhibitor drug, resin and optionally one or more additives wherein said resin and said phospho-diesterase inhibitor drug is present in the ratio of 1:1 to 2:1.

Full Text

FORM 2 THE PATENTS ACT, 1970 COMPLETE SPECIFICATION (Section 10) TITLE OF THE INVENTION "Composition for use in the treatment of erectile dysfunction and method of preparation thereof?' Cadila Healthcare Limited, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad, Gujarat, India. The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed: cSWr7fc Field of invention The present invention relates to a taste masked, rapid releasing tablet form of a phospho diesterase inhibitor drug such as Sildenafil, tadalafil or vardenafil for the treatment of erectile dysfunction. Background of the invention "Impotence can be defined literally as a lack of power, in the male, to copulate and may involve an inability to achieve penile erection or ejaculation, or both. More specifically, erectile impotence or dysfunction may be defined as an inability to obtain or sustain an erection adequate for intercourse." Generally, in man, oral administration of the phospho diesterase inhibitors is the preferred route, being the most convenient and avoiding the disadvantages associated with intra cutaneous administration. Phospho diesterase inhibitors include drugs such as Vardenafil, Tadalafil & Sildenafil Citrate and they are available in the market in form of a film-coated tablet, wherein, film-coating has to dissolve and tablet has to disintegrate into granules and further the drug has. to release for dissolution in acidic media of stomach. Normal mouth dispersible tablets release the drug for absorption in oral cavity but if it happens in case of Sildenafil Citrate, it can lower blood pressure like nitrates. Further Sildenafil is very bitter to taste & other PDE inhibitors such as Vardenafil or Tadalafil are also not very pleasant to taste; hence formulation development is very critical. Effectiveness of any phospho diesterase inhibitor formulation will depend upon initial complexation to the extent necessary to by pass taste buds without detection with the ability to subsequently release the drug from the complex after pH adjustment in digestive tract. Dispersible tablets are the formulations that elude the process of disintegration that occurs with conventional formulation, dispersible tablets are formulated to make the drug product bio-available at a faster rate for immediate action. It is in view of the above scenario, that a rapid release, taste masked formulation of phospho diesterase inhibitor drug is disclosed. 2 PRIOR ART: The original reference for a rapid release dosage form of Sildenafil Citrate comes from a Pfizer Patent application, WO-9830209. It discloses a rapidly- releasing, taste masked formulation of Sildenafil Citrate comprising a core containing the drug, low substituted hydroxy propyl cellulose 8s microcrystalline cellulose 8s an inner core layer formed on the above-described core & containing a water soluble polymer & an outer coating layer formed on this inner layer. Thus in essence, it is a multi layered drug 8s though successful at taste masking, it may not give a rapid release of the drug. US Patent Application No. 2003/195220 arising from Japanese App. 2000-270061 too discloses phospho diesterase inhibitor formulations containing fumaric acid 8& calcium carbonate. US Patent No. 6,200,591 discloses an oral administration route for administering Sildenafil Citrate. WO 00/20033 discloses a phospho diesterase inhibitor formulation with a binder 8s a saccharide wherein this mixture is kneaded into a dough 8B finally compression molded. Objects of the invention It is an object of the present invention is to provide a rapid releasing mouth dispersible tablet dosage form for phospho diesterase inhibitor drugs. Another object of the present invention is to provide for a taste masked tablet of phospho diesterase inhibitors, ensuring better patient compliance/ acceptability. Further object of the invention is to present a readily acceptable tablet form of phospho diesterase inhibitors. Summary of the invention The above and other objects of the present invention are achieved by the composition of the present invention which is provided in the form of taste masked, rapid release tablet comprising essentially of a phospho¬diesterase inhibitor drug, resin and additives. 3 In a preferred embodiment, the phosphodiesterase drug is selected from a group consisting of sildenafil citrate, tadalafil or vardenafil or their pharmaceutically acceptable salts, thereof. In another embodiment, the resin is present in a proportion of 1 to 2 times of the drug, more preferably, in a proportion of 1.5 times of the drug. In another embodiment, the additives are selected from the group consisting of binders, sweeteners, lubricants, disintegrating agents, super disintegrating agents, colouring agents, flavouring agents, diluents, bulking agents, solvents. The present invention also relates to a process for the preparation of a composition in the form of a taste masked, rapid release tablet wherein: a) a phopho-diesterase inhibitor drug is mixed with a taste masking agent, binder(s) and/or additives and wetted with pharmaceutically acceptable solvent(s); b) the mixture is granulated, dried and graded; c) the dried granules are optionally mixed with one or more additives, bulking agent(s), diluents, super disintegrating agent(s), disintegrating agent(s), lubricant(s), sweetener(s) and colouring agent(s) and compressed to form tablets. As will be apparent from the description contained hereinafter, the composition of the present invention is a synergistic composition having improved and unexpected properties. Detailed Description A significant part of the adult male population suffers from male erectile dysfunction. MED becomes more prevalent in older men. In some males MED takes the form of a total inability to achieve an erection. In others the erection may be incomplete or last insufficiently long to achieve any or satisfactory sexual intercourse. In others the penis may stay erect for a long time or permanently (priapism). It is probable that there are a number of different causes of MED. The present invention provides a novel pharmaceutically acceptable rapidly dissolving tablet form of phospho diesterase inhibitor drugs such as sildenafil citrate, tadalafil or vardenafil. Employing the present invention, 4 the drug may be introduced into the patient's bloodstream almost as fast as through injection and much faster than using conventional oral route administration. Thus, the present invention provides a method of manufacture and composition for accomplishing noninvasive administration of drug to a patient in order to rapidly induce a desired systemic effect. It is to be noted that there are two conjoint objectives for this formulation. One is rapid release rate, the second is the taste masking of such a rapid release formulation. Initially taste-masking trials were conducted using Eudragit E 100 but bitterness as well as handling / hardness problems were encountered 85 focus was then shifted to other taste masking agents. Sildenafil citrate is taste masked with help a resin. Polacrillin Potassium (trade name: Amberlite) is a complexing agent which makes complex with API, it is cationic resin which replace the cation of Sildenafil Citrate i.e. citrate + - na is prepared. Sildenafil Citrate + Amberlite IRP 88 u Sildenafil Amberlite Complex u Complex breaks in Acidic media Dissolves in Acidic media An initial trial at the ratio of 1:2 sildenafil and Polacrillin Potassium was conducted and complete taste masking as achieved. Further trials revealed that for optimisation of Polacrillin potassium which exhibited that 1:1.5 ratio is optimum to mask the bitter taste of sildenafil and thereafter other diluents were selected. Perlitol SD 200 (granular Mannitol) was selected as sweetening as well as bulking agent and also to provide the good hardness, better mouth feel to the tablet &s alleviate the softness and friablility in the tablets. Following ingredients were selected. - Graded Povidone as a binder -Aspartame as a sweetener 5 -Colloidal Silicon dioxide, Magnesium Stearate as lubricants -Cross Carmellose sodium as Super disintegrant -Added coloring agent, flavouring agent -Microcrystalline cellulose as a diluent as well as a bulking agent. The above constituents are non limiting in character 8s those skilled in the art can effectively substitute other similar constituents instead of the above named. To derive a rapid disintegration tablet, a Super Disintegrant 8s disintegrant is used. Rapid disintegration tablet can be derived with the use of Avicel 102 and cross carmellose sodium as disintegrant, wherein Avicel 102 is used as super-disintegrant. Tablets containing disintegrant picks up the water on the tongue within the tablet causing break-down of the tablet into small particles. Due to high swelling capacity of cross carmellose and Avicel, the volume of tablet increases leading to break up of tablet into small particles. Wicking (i.e. uptake of water) and dissociation processes promote rapid tablet disintegration of the tablet. Tablets were manufactured by compressing taste-masked granules of phospho-diesterase drugs such as Tadalafil or Sildenafil citrate or Vardenafil. [1] Task masking of the drug. Taste masking is done using Ion exchange resin (Polacrillin Potassium). The drug and Polacrillin K are mixed together and wetted with water solution. The completely wetted granules are mixed with granular mannitol 8B kneaded with povidone solution. This is further graded, dried completely. Dried granules are graded and used for lubrication. For compression - LOD Not More Than 3%. Temperature 8s Humidity should not be more than 25C 8s 30% respectively. [2] Dry mixing 8s Lubrication: Dried granules are collected 8s mixed with micro-crystalline cellulose 8s lubricated with magnesium stearate, Aspartame, colouring agents such as iron oxide, flavour(s), Aerosil, 8s cross carmellose sodium. 6 Compression of granules: Lubricated granules are compressed at the weight shown below. [3] COMPOSITION: For the final formulations, following three trials were conducted. It is to be noted that since tadalfil 8s vardenafil are less bitter drugs as compared to Sildenafil Citrate 8s hence the quantity of aspartame has been reduced. Such reduction in sweetener amount will NOT have any detrimental effect as concerns the taste masking. The ready granules from above procedure were compressed using a load of NMT 3% 8s humidity NMT 30% is maintained. 7 8 We. Claim: 1. A composition for use in the treatment of erectile dysfunction, said composition being in the form of a taste masked, rapid release tablet comprising a phospho-diesterase inhibitor drug, resin and optionally one or more additives wherein said resin and said phospho-diesterase inhibitor drug is present in the ratio of 1:1 to 2:1. 2. A composition as claimed in claim 1 wherein the phospho-diesterase drug is selected from the group consisting of sildenafil citrate, tadalafil or vardenafil or their pharmaceutically acceptable salts thereof. 3. A composition as claimed claims 1 to 2 wherein said resin is present in a proportion 1.5 times of said phospho-diesterase inhibitor drug. 4. A composition as claimed in any one of claims 1 to 3 wherein the additives are selected from a group consisting of binders, sweeteners, lubricants, disintegrating agents, super disintegrating agents, colouring agents flavouring agents, diluents, bulking agents, solvents. 5. A process for the preparation of a composition for use in the treatment of erectile dysfunction, said composition being in the form of a taste masked, rapid release tablet, said process comprising: (a) mixing a phospho-diesterase inhibitor drug with a taste masking agent, binder(s) and optionally with one or more additives and wetting with pharmaceutically acceptable solvent(s); (b) subjecting said mixture to granulation, and grading said mixture; (c) and optionally, mixing said dried granules with one or more additives, bulking agent(s), diluents, super disintegrating agent(s), disintegrating agent(s), lubricant(s), sweetener(s), colouring agent(s) and compressing the granules to form tablets. 9 10 6. A composition for use in the treatment of erectile dysfunction substantially as herein described with reference to the foregoing examples. 7. A process for the preparation of a composition for use in the treatment of erectile dysfunction substantially as herein described with reference to the foregoing examples.

Documents:

1055-mum-2002-cancelled pages(3-4-2008).pdf

1055-mum-2002-claim(granted)-(3-4-2008).doc

1055-mum-2002-claims(granted)-(3-4-2008).pdf

1055-mum-2002-claims-complete.doc

1055-mum-2002-claims-complete.pdf

1055-mum-2002-correspondence(24-3-2008).pdf

1055-MUM-2002-CORRESPONDENCE(8-2-2013).pdf

1055-mum-2002-correspondence(ipo)-(30-5-2008).pdf

1055-mum-2002-correspondence-received-150103.pdf

1055-mum-2002-correspondence-received-180204.pdf

1055-mum-2002-correspondence-received-201102.pdf

1055-mum-2002-correspondence-received-311202.pdf

1055-mum-2002-correspondence-received.pdf

1055-mum-2002-descripiton (complete).pdf

1055-mum-2002-descripiton (provisional).pdf

1055-mum-2002-form 1(28-11-2002).pdf

1055-mum-2002-form 1(31-12-2002).pdf

1055-mum-2002-form 18(8-9-2006).pdf

1055-mum-2002-form 2(granted)-(3-4-2008).doc

1055-mum-2002-form 2(granted)-(3-4-2008).pdf

1055-mum-2002-form 3(28-11-2002).pdf

1055-mum-2002-form 4(20-2-2004).pdf

1055-mum-2002-form 5(20-2-2004).pdf

1055-mum-2002-form-1.pdf

1055-mum-2002-form-18.pdf

1055-mum-2002-form-2-complete.doc

1055-mum-2002-form-2-complete.pdf

1055-mum-2002-form-2-provisional.doc

1055-mum-2002-form-2-provisional.pdf

1055-mum-2002-form-26.pdf

1055-mum-2002-form-3.pdf

1055-mum-2002-form-4.pdf

1055-mum-2002-form-5.pdf

1055-mum-2002-power of authority(1-10-2002).pdf