Title of Invention	A NOVEL NASAL ADMINISTRATION CONTAINING SILDENAFIL SALT FOR TREATING MALE ERECTILE DYSFUNCTION
Abstract	The invention disclosed in this application relates to a novel pharmaceutical composition containing sildenafil useful for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes. The composition is also effective in patients with erectile dysfunction due to spinal cord injury. The pharmaceutical composition of the present invention is in the form of a solution or a colloidal dispersion in a pharmaceutical vehicle filled into specially designed dosing device for nasal administration.The invention disclosed in this application also provides a method for preparing the pharmaceutical composition containing sildenafil for nasal application for the treatment of male erectile dysfunction.

Title of Invention

A NOVEL NASAL ADMINISTRATION CONTAINING SILDENAFIL SALT FOR TREATING MALE ERECTILE DYSFUNCTION

Abstract

The invention disclosed in this application relates to a novel pharmaceutical composition containing sildenafil useful for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes. The composition is also effective in patients with erectile dysfunction due to spinal cord injury. The pharmaceutical composition of the present invention is in the form of a solution or a colloidal dispersion in a pharmaceutical vehicle filled into specially designed dosing device for nasal administration.The invention disclosed in this application also provides a method for preparing the pharmaceutical composition containing sildenafil for nasal application for the treatment of male erectile dysfunction.

Full Text	The present invention relates to a novel pharmaceutical composition containing sildenafil useful for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes. The composition is also particularly effective in patients with erectile dysfunction due to spinal cord injury. The pharmaceutical composition of the present invention may be in the form of a solution or a colloidal dispersion in a pharmaceutical vehicle. The composition can be filled into specially designed dosing device for nasal administration. Sildenafil has the chemical formula C22H30N6O4S Sildenafil is potent and selective inhibitor of type V cyclic guanosine mono phosphodiestrase (cGMP) with utility for the treatment of male erectile dysfunction. Recently, it has been hypothesized that penile erections are dependent on nitric oxide (NO) and its second messenger CGMP. Sildenafil amplifies the neuronal nitric oxide (NO) / cGMP pathway implicated in the relaxation of the corpus cavernosum. The drug is well tolerated orally with headache, dyspepsia, facial flushing and muscular ache are the most common adverse events reported [Steers, W. D. et al. 2nd Meet Eur. Soc. Impotence Res. (Oct 1-4, Madrid)i997, Abst 80]. It is administered orally at a dose of 25mg to 100mg. sildenafil treated patients have a significant improvement in sex life satisfaction rating compared with the placebo groups [Terret et al. Bio Org. Med.Chem. Lett., 6(15), 1819-1824(1996); Boolell. et al. Br.J.Urol. 78(2),257-261(1996)]. The pharmaceutical composition available in markets for oral administration contains sildenafil citrate (Manufactured by M/s Pfizer Inc.). Sildenafil citrate is soluble in dimethylformamide, sparingly soluble in acetic acid, slightly soluble in alcohol. About 3.5 mg is soluble in water. In JP 10298062 a pharmaceutical composition in the form of tablets that rapidly soluble in the oral cavity and manufacturing procedure has been disclosed. In WO 9830209 a rapidly releasing and taste masking pharmaceutical composition comprising a core containing sildenafil, an inner coating layer formed of a water soluble polymer and an outer coating layer formed on inner coating containing saliva insoluble polymer and a process for preparing such oral dosage form has been disclosed. In US patent, US 5,874,437 nitrosated and nitrosylated phosphodiestrase inhibitors having the formula NOn , where n = 1 or 2 and compositions comprising such compound in pharmaceutically acceptable carrier and a method for treating male impotence in humans by administering the compounds and compositions thereof has been disclosed. With the development of various devices for application of drugs in the nasal cavity and the specialized anatomy and physiology of nasal cavity and its ready accessibility made the nasal cavity a particularly attractive delivery site for the systemic administration of drugs, since no injection is required, and first pass metabolism is circumvented. Although the permeability of nasal epithelium to drug molecules varies greatly depending on the chemical and physical properties of the drug, a number of strategies have been explored to increase the nasal membrane permeability. These include 1) increasing the residence time of the drug in the nasal mucosa. 2) increasing the blood flow to the nasal mucosa. 3) modifying drug-membrane characteristic with surface active agents. No pharmaceutical composition containing sildenafil for nasal administration has been reported till date. The main objective of present invention is to provide a pharmaceutical composition containing sildenafil, for application in the nasal cavity which can elicit rapid onset of action at a reduced dose when compared to the oral dosage form available for treatment of male erectile dysfunction. Another objective of the invention is to provide a method for preparing the pharmaceutical composition containing sildenafil for nasal application. The new pharmaceutical composition of the present invention is in the form of a solution or colloidal dispersion in a suitable pharmaceutical vehicle, comprising of a solvent, co-solvent and / or solubilizing agent, penetration enhancer, stabilising agent and buffering agent; optionally contain an anti¬microbial preservatives and / or viscosity modifying agents. The composition can be filled into a suitable container fitted with nasal applicator. The active substance is present in the form of base or its salt with organic or inorganic acids. The preferred dosage form is "Monospray", which is a unidose device supplied by M/s Valois, filled with single dose of medicament. The active substance in the pharmaceutical composition sildenafil may be present as a base or its salt form with organic acids such as citric acid, lactic acid, acetic acid and the like or inorganic acids such as sulphuric acid, hydrochloric acid, nitric acid, orthophosphoric acid etc. The amount of sildenafil or its salt present in the pharmaceutical composition may range from 2.5 to 25.0 percent, preferably 5.0 to 20.0 percent more preferably 7.5 to 15.0 percent. The pharmaceutical composition of the present invention contains sildenafil or its salt in the form of a liquid solution or colloidal dispersion in a suitable inert pharmaceutical vehicle. The pharmaceutical vehicle comprises of a solvent in which sildenafil is dissolved or dispersed, a co-solvent and / or solubilising agent which aids in dissolving sildenafil, a penetration enhancer for improving the penetration of sildenafil through the barriers in nasal mucosa, a stabilizing agent to prevent degradation of sildenafil and a buffering agent to adjust pH of the pharmaceutical composition. The poor solubility of sildenafil in water alone necessitates the use of other solvents, co-solvents and / or solubilising agets to dissolve it in the pharmaceutical composition. The solvents used in the pharmaceutical composition may be selected from a group of "Protogenic" solvents, which act as proton donors, such as liquid hydrochloric acid, sulphuric acid, lactic acid, solutions of ascorbic acid, citric acid. The volume of such solvents and co-solvents present in the pharmaceutical composition may range from 10.0 to 80.0 percent, preferably 20.0 to 60.0 percent. The co-solvents used in the pharmaceutical composition may be selected from a group of "Amphiprotic" solvents, which act as both proton acceptors and proton donors, such as the alcohols ethyl alcohol, propylene glycol, glycerol and polyethylene glycols having a nominal molecular weight of 200 - 600 or N-methyl-2-pyrrolidone, which enhances the solubility of sildenafil or its salts byformation of complex. The volume of such co-solvents and co-solvents present in the pharmaceutical composition may range from 4.0 to 40.0 percent, preferably 15.0 to 30.0 percent. The solubilising agent used in the pharmaceutical composition may be selected from surface-active agents such as polysorbate 80, polymers which can form molecular adducts and have anti-nucleating properties such as poloxamers, polyvinylpyrrolidone. The amount of such solubilising agent present in the pharmaceutical composition may range from 1.0 to 30.0 percent, preferably 5.0 to 15.0 percent. The buffering agent used in the pharmaceutical composition may be selected from hydrochloric acid, sodium acetate, glacial acetic acid, orthophosphoric acid, potassium dihydrogen orthophosphate, sodium hydroxide and the like. The penetration enhancers for intranasal application known in the art are ethyl alcohol, propylene glycol, N-methyl-2-pyrrolidone, bile salts, cyclodextrins etc. The penetration enhancers used in the pharmaceutical composition of the present invention is selected from among these and the amount present in each ml of the composition may range from 10.0 to 30.0 percent, preferably 15.0 to 25.0 percent. The pharmaceutical substances used as stabilizing agents, known in the art are disodium ethylene diamine tetra acetic acid, ascorbic acid etc. The stabilizing agent used in the pharmaceutical composition for stabilisation of sildenafil may be selected from among these substances. The amount of such stabilizing agents present in the composition may range from 0.01 to 0.1 percent. The pharmaceutical composition may optionally contain anti-microbial preservative. The anti-microbial agent may be selected from benzalkonium chloride, phenyl mercuric acetate, phenylethyl alcohol and the like. The amount of such anti-microbial preservative may range from 0.02 to 0.5 percent. The pharmaceutical composition may optionally contain a viscosity building agent to increase the viscosity of the composition, thereby prolongs the contact time of the composition with the nasal mucosa, preventing its rapid drain to the larynx region of throat. The viscosity building agent may be selected from hydrocollids such as hydroxypropyl methylcellulose, poly acrylic acid and the like or water soluble polymers such as carbopol, sodium carboxy methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose etc. The amount of such viscosity building agent used in the pharmaceutical composition may range from 1.0 to 5.0 percent. The pharmaceutical composition is prepared by dissolving or dispersing sildenafil or its salt in the pharmaceutical vehicle comprising of solvent, co-solvent and / or solubilising agent, penetration enhancer along with other optional ingredients. The pH of the pharmaceutical composition is adjusted using a buffering agent. The pharmaceutical composition is then filled in either a multiple dose container fitted with a mechanical pump and a nasal applicator with an over cap or a "Monospray"(supplied by M/s Valois) nasal liquid unidose device. The preferred device is "Monospray". The "Monospray" is a nasal liquid unidose device useful in administrating high potency molecules enabling less frequent administration and treatment of crisis conditions. The device comprises an actuator with over cap, spring, piston, dosage chamber and a ball for closing the dosage chamber rear end after filling with medicine. A "Monospray" with a nominal volume of the dosage chamber in between 50.0 to 150.0 microlitres is selected to deliver 2.5 to 37.5mg, preferably 5.0 to 25.0mg, more preferably 7.5 to 15.0 mg of sildenafil. Advantages: Advantages of the invention are 1) Rapid onset of action when compared to conventional oral formulation of sildenafil. 2) Reduction in the total amount of drug required to elicit desire therapeutic response there by reducing the side effects. 3) Improved patient compliance The present invention relates to an improved pharmaceutical composition containing sildenafil intended for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes. The composition is also particularly effective in patients with erectile dysfunction due to spinal cord injury. The pharmaceutical composition of the present invention may be in the form of a solution or a colloidal dispersion in a pharmaceutical vehicle. The composition can be filled into specially designed dosing device for nasal administration. Sildenafil has the chemical formula C22H30N6O4S Sildenafil is potent and selective inhibitor of type V cyclic guanosine mono phosphodiestrase (cGMP) with utility for the treatment of male erectile dysfunction. Recently, it has been hypothesized that penile erections are dependent on nitric oxide (NO) and its second messenger cGMP. Sildenafil amplifies the neuronal nitric oxide (NO) / cGMP pathway implicated in the relaxation of the corpus cavernosum. The drug is well tolerated orally. Headache, dyspepsia, facial flushing and muscular ache are the common adverse events reported [Steers, W. D. et al. 2nd Meet Eur. Soc. Impotence Res. (Oct 1-4, Madrid) 1997, Abst 80]. It is administered orally at a dose of 25mg to lOOmg. Sildenafil treated patients have a significant improvement in sex life satisfaction rating compared with the placebo groups [Terret et al. Bio Org. Med.Chem. Lett., 6(15),1819-1824(1996); Boolell. et al. Br.J.Urol. 78(2),257-261(1996)]. The pharmaceutical compositions available in the markets for oral administration contains sildenafil citrate (M/s Pfizer Inc.). Sildenafil citrate is soluble in dimethylformamide, sparingly soluble in acetic acid, slightly soluble in alcohol. About 3.5 mg is soluble in water. In JP 10298062 a pharmaceutical composition in the form of tablets that rapidly soluble in the oral cavity and manufacturing procedure has been disclosed. In WO 9830209 a rapidly releasing and taste masking pharmaceutical composition comprising a core containing Sildenafil, an inner coating layer formed of a water soluble polymer and an outer coating layer formed on inner coating containing saliva insoluble polymer and a process for preparing such oral dosage form has been disclosed. According to the above patents sildenafil is administered orally about one hour before intercourse. This is a major disadvantage of the oral formulations, creating in convenience to the partners. Rapid onset of action is highly desirable in such therapeutic indication for patients. Considering the above parameters an attempt has been made to develop an intranasal formulation containing sildenafil citrate or base in a solution form which possesses rapid onset of action at a reduced dose when compare to the oral dosage form available for the treatment of male erectile dysfunction. With the development of various devices for application of drugs in the nasal cavity and the specialized anatomy and physiology of nasal cavity and its ready accessibility made the nasal cavity a particularly attractive delivery site for the systemic administration of drugs, since no injection is required, and first pass metabolism is circumvented. Although the permeability of nasal epithelium to drug molecules varies greatly depending on the physicochemical properties of the drug, a number of strategies have been explored to increase the nasal membrane permeability. These include 1) increasing the residence time of the drug in the nasal mucosa. 2) increasing the blood flow to the nasal mucosa. 3) modifying drug-membrane characteristic with surface-active agents. In US patent, US 5,874,437 nitrosated and nitrosylated phosphodiestrase inhibitors having the formula NOn , where n = 1 or 2 and compositions comprising such compound in pharmaceutically acceptable carrier and a method for treating male impotence in humans by administering the compounds and compositions thereof has been disclosed. In WO 00/00199 an intranasal dosage unit of cyclic guanosine monophosphate specific phosphodiesterase inhibitors are described which are combined with suitable intranasal carriers having a buffer, surfactant and absorption enhancers, in order to achieve a peak plasma concentration of the inhibitor in less than 1 hour, and desirably with in 30 minutes of administration in mammals. In this active ingredient is dispersed in a buffer followed by thickening agent, humectant and surfactant are added. However the disadvantage associated with this type of suspension formulations is that the dispersed drug particles in the viscous medium may have to over come the resistance caused by the medium to reach onto the surface of the mucous membrane for its dissolution and penetration through the membrane. Further the drug is in solid state with less fluid volume and surface area made available for dissolution and penetration that reduces the absorption of drug compared to solution. The dispersion system may delay onset of action initially, though it prolongs the duration of action due to slow penetration. The delay in the onset of action may cause patient incompliance. Further, the limited solubility of the sildenafil citrate may leads to improper dosing of the formulation. In EP 0967214 intranasal formulations of Sildenafil mesylate together with a pharmaceutically acceptable diluent or carrier for the treatment of male erectile dysfunction or female sexual disorders are described. In this, sildenafil free base is added to an aqueous solution of methane sulfonic acid and solubility enhancer (Caffeine) and a buffer are added. Similarly compositions are prepared using nicotinamide, vanillin or benzyl alcohol instead of caffeine as penetration enhancers. However, the above process in making the solution involves the conversion of sildenafil into mesylate followed by solubilising the mesylate salt. This process involves conversion of sildenafil to mesylate salt, which is tedious and time consuming. The above patent also claimed an intranasal powder formulation by using sildenafil mesylate and lactose. The composition was milled to an average particles of 20 microns size and filled into a gelatin capsule for use with a commercial nasal device. Inhalation of this powder may cause irritation to the mucous membrane, and absorption of the active ingredient is slow compared to the solution form as described above. In WO 9966933 a method for rapidly and reliably delivering sildenafil to the systemic circulation of a patient intranasally in a pharmaceutical composition contained sildenafil or a pharmaceutically acceptable salts and carrier was disclosed. According to this method sildenafil citrate was dissolved with the help of mesylic acid and the pH adjusted to 2.8 to 3.0 with sodium hydroxide. It has also disclosed a "sildenafil nasal spray solution" containing sildenafil hydrochloride dissolved in phosphate buffer and isotonicity adjusted with sodium chloride. It also discloses an "aqueous nasal gel" which contains sildenafil hydrochloride, methocel and an acetate buffer. It has also disclosed a composite nasal spray solution containing sildenafil hydrochloride, and apomorphine hydrochloride. Considering the importance attached to removal of the drawbacks/disadvantages of the presently available composition containing sildenafil we undertook research work towards developing an improved composition which can be administered through nasal route wherein the active drug gets rapidly absorbed. The main objective of the present invention is to provide an improved pharmaceutical composition intended for nasal administration for the treatment of male erectile dysfunction due to organic, pyschogenic and mixed causes containing sildenafil for nasal application. Yet another objective of the present invention is to provide an improved pharmaceutical composition in the form of a solution or colloidal dispersion intended for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes containing sildenafil for nasal application in a suitable pharmaceutical vehicle, comprising of a solvent, co-solvent and / or solubilizing agent, penetration enhancer, stabilising agent, buffering agent, and a tonicity agent; optionally contain an anti-microbial agent and / or viscosity modifying agents. Still another objective of the invention is to provide a method for preparing the improved pharmaceutical composition containing sildenafil in the form of a solution or colloidal dispersion intended for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes. The present invention is based on our finding that the poorly water soluble sildenafil or its salt, dissolves completely in mild acids such as lactic acid, hydrochloric acid, ascorbic acid, citric acid, succinic acid, maleic acid, orthophosphoric acid or methyl sulfonic acid and the resulting solution when mixed with solubilisers and penetration enhancers such as polyethyleneglycol, propylene glycol, glycerol, ethyl alcohol, purified diethylene glycol monoethyl ether, propyleneglycol monolaurate and the pH is adjusted 3.0 to 8.0 with citrate, acetate or phosphate buffer and tonicity is adjusted with sodium chloride or dextrose or mannitol, the resulting composition acquires unique property of promoting rapid absorption of sildenafil resulting in rapid onset of action when administered through the nasal route due to synergistic activities of the above said components. It was noticed that the free base of sildenafil is preferably more soluble in ascorbic acid and diethylene glycol monoethyl ether. We have further noted that lactic acid, is more preferable as it is highly biocompatible and is present in organs such as lever, kidney, thymus gland, stratum coraeum, human amniotic fluid and other organs and body fluids. The above said pharmaceutical composition has rapid onset of action upon administration through nasal route with out any adverse effects due to the synergistic effect of the ingredients employed in the composition which results in keeping the active ingredient namely sildenafil or its salt in solution or dispersion form and absorption is further promoted by penetration enhancers making it absorb readily when the composition is administered through the nasal route for eliciting the desired therapeutic response. The above said composition can be filled into a suitable container fitted with nasal applicator. The composition can be filled either in multiple dose container fitted with an applicator or "Monospray" (supplied by M/s Valois India Pvt, Ltd., 407, Madhava,Bandra-kurla Complex, Bondra(E), Mumbai- 400 051), filled with single dose of medicament. Accordingly, the present invention provides an improved pharmaceutical composition intended for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes in the form of solution or colloidal dispersion, which comprises solution or colloidal dispersion of Sildenafil or its salt in a "Protogenic" solvent containing solubilisers and penetration enhancers, stabilizing agent, buffering agents and an isotonicity agent, the solution or the dispersion having a pH in the range of 3.0 to 8.0. The solution or the dispersion is stable at room temperature and sub ambient temperatures as well without any precipitation and/or re-crystallisation. The composition is not a mere admixture of the ingredients employed resulting in a composition having the aggregate properties of the said ingredients. The composition in solution form is preferred to the dispersion form as the former has more rapid absorption and onset of action than that of a dispersion form. The pharmaceutical composition so formed is then filled in either a multiple dose containers fitted with a mechanical pump and a nasal applicator with an over cap or a "Monospray" (supplied by M/s Valois India Pvt., Ltd., 407, Madhava, Bandra-kurla Complex, Bondra(E), Mumbai- 400 051), nasal liquid unidose device. The preferred device is "Monospray". Sildenafil employed in the pharmaceutical composition may be the base or its salt form with organic acids such as citric acid, lactic acid, acetic acid, succinic acid, maleic acid and the like or inorganic acids such as sulphuric acid, hydrochloric acid, orthophosphoric acid etc. The amount of sildenafil or its salt employed in the pharmaceutical composition may range from 2.5 to 25.0% w/v, preferably 5.0 to 20.0% w/v more preferably 7.5 to 15.0% w/v. The pH of the pharmaceutical composition may preferably be in the range of 3.5 to 5.0. The "Protogenic" solvents, which act as proton donors, used in the pharmaceutical composition may be selected from a group of mild acids such as hydrochloric acid, sulphuric acid, lactic acid, solutions of ascorbic acid, citric acid and amphiprotic solvents such as water or their mixtures. The volume of such solvents present in the pharmaceutical composition may range from 10.0 to 80.0%v/v, preferably 20.0 to 60.0% v/v. The co-solvents when used in the pharmaceutical composition may be selected from a group of "Amphiprotic" solvents, which act as both proton acceptors and proton donors such as the alcohols e.g. ethyl alcohol, propylene glycol, glycerol and polyethylene glycols having a nominal molecular weight of 200 - 600 or N-methyl-2-pyrrolidone, which enhances the solubility of sildenafil or its salts by formation of complex. The volume of such co-solvents present in the pharmaceutical composition may range from 1.0 to 50.0% v/v preferably 15.0 to 30.0% v/v. The solubilising agents used in the pharmaceutical composition may be selected from purified diethylene glycol monoethyl ether, cyclodextrins, glycerol monostearate, lecithin, poloxomer, polyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, stearic acid, citric acid, and ascorbic acid and the like; surface active agents such as polysorbates, sorbiton esters, polyvinyl alcohol, benzal konium chloride, benzithonium chloride, cetrimide, docusate sodium, sodium lauryl sulphate, octoxynol and the like or a combination of these. The amount of such solubilising agent present in the pharmaceutical composition may range from 0.01 to 30.0% w/v, preferably 5.0 to 15.0%w/v. The solubility enhancers used in the composition may be selected from DL-methionine, caffeine, nicotinamide, vanillin,,, benzyl alcohol known in art as solubility enhancers when added to the solutions of other substances. The buffering agent used in the pharmaceutical composition may be selected from hydrochloric acid, sodium acetate, glacial acetic acid, orthophosphoric acid, potassium dihydrogen orthophosphate and the like. The penetration enhancers used in the pharmaceutical composition of the present invention are selected from ethyl alcohol, propylene glycol, N-methyl-2-pyrrolidone, bile salts, cyclodextrins, propyleneglycol monolaurate in combination with purified diethylene glycol monoethyl ether and the like known in the art for intranasal application. The amount of such penetration enhancer present in each ml of the composition may range from 0.1 to 30.0%v/v or w/v, preferably 5.0 to 25.0%v/v or w/v. The stabilizing agent used in the pharmaceutical composition maybe selected from among those substances known in the art such as sodium metabisulphite, 9 sodium bisulphite, disodium EDTA, ascorbic acid etc. The amount of such stabilizing agents present in the composition may range from 0.01 to 0.5% w/v. The pharmaceutical composition may optionally contain anti-microbial agent. The anti-microbial agent may be selected from benzyl alcohol, benzalkonium chloride, phenyl mercuric acetate, phenylethyl alcohol and the like. The amount of such anti-microbial agent may range from 0.001 to 2.0% w/v preferably 0.02 to 0.5%w/v The pharmaceutical composition may also optionally contain a viscosity building agent to increase the viscosity of the composition, there by prolongs the contact time of the composition with the nasal mucosa, preventing its rapid drain to the larynx region of throat. The viscosity building agent may be selected from hydrocolloids such as hydroxypropyl methylcellulose, poly acrylic acid and the like or water soluble polymers such as carbopol, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and various grades of polyvinylpyrrolidone i.e. K-15, K-30, K-60 and K-90 etc. The amount of such viscosity building agent used in the pharmaceutical composition may range from 0.1 to 5.0%w/v. The "Monospray" is a nasal liquid unidose device useful in administrating high potency molecules enabling less frequent administration and treatment of crisis conditions. The device comprises an actuator with over cap, spring, piston, dosage chamber and a ball for closing the dosage chamber from rear end after filling with medicine. A "Monospray" with a nominal volume of the dosage chamber in between 50.0 to 150.0 microliters is selected to deliver 2.5 to 37.5mg, preferably 5.0 to 25.0mg, more preferably 7.5 to 15.0 mg of active substance. When a multiple dose container is used the percentage of the drug dissolved may range from 2.5 to 25.0%w/v preferably from 5.0 to 15.0%w/v more preferably from 7.5 to 15.0% w/v. The dose required may constitute one or more number of actuations depending on the dosing device used and the concentration of drug present in the formulation. The invention is described in detail 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 Each ml contains Sildenafil citrate 7.500 % w/v Lactic acid 10.000 % v/v Sodium acetate 0.041% w/v Glacial acetic acid 0.057 % v/v Phenylethyl alcohol 0.500 % v/v Pyrogen free water to make up to 1.0 ml Sildenafil citrate is dissolved in lactic acid and pyrogen free water. Phenylethyl alcohol is added as preservative. Sodium acetate and Glacial acetic acid are added to adjust the pH 3.0. Final volume adjusted to 1.0ml with pyrogen free water. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "Monospray". EXAMPLE -2 Each ml contains Sildenafil citrate 7.500 % w/v N-methyl-2-pyrrolidone 10.000 % v/v Potassium dihydrogen Orthophosphate 1.360 % w/v Orthophospharic acid 0.080 % v/v Benzalkonium chloride 0.020 % v/v Pyrogen free water to make up to 1.0 ml Sildenafil citrate is dissolved in mixture of N-methyl-2-pyrrolidone, and pyrogen fee water Benzalkonium chloride solution is added, pH is adjusted to 3.5 with Potassium dihydrogen orthophosphate and Phosphoric acid. Final volume is adjusted to 1.0ml with Pyrogen free water. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "MonosDrav". EXAMPLE-3 Each ml contains Sildenafil citrate 10.000 % w/v Polyethylene glycol - 300 30.000 % v/v Ethyl alcohol 20.000 % v/v Hydrochloric acid 10.000 % v/v Pyrogen free water to make up to 1.0 ml Sildenafil citrate is dissolved in a mixture of polyethylene glycol, ethyl alcohol and hydrochloric acid. pH is adjusted to 3.0 with sodium hydroxide. Pyrogen free water is added to make up to one ml. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "Monospray". EXAMPLE - 4 Each ml contains Sildenafil citrate 7.500 % w/v Propylene glycol 20.000 % v/v Ethyl alcohol 20.000 % v/v Hydrochloric acid 10.000 % v/v Pyrogen free water to make up to 1.0ml Sildenafil citrate is dissolved in a mixture of propylene glycol, ethyl alcohol and hydrochloric acid. pH is adjusted 3.0 with sodium hydroxide. Pyrogen free water is added to make up the volume to one ml. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "Monospray". EXAMPLE - 5 Each ml contains Sildenafil citrate 10.000 % w/v Polyethylene glycol - 300 30.000 % v/v Glycerol 20.000 % v/v Hydrochloric acid 10.000 % v/v Pyrogen free water to make up to 1.0ml Sildenafil citrate is dissolved in a mixture of polyethylene glycol, glycerol, hydrochloric acid. pH is adjusted to 3.2 with sodium hydroxide. Pyrogen free water is added to make up to one ml. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "Monospray". EXAMPLE - 6 Each ml contains Sildenafil citrate 10.000 %w/v Purified diethylene glycol monoethyl ether 2.000 % w/v Octoxynol 0.007 % w/v Sodium ascorbate 5.000 % w/v Disodium EDTA 0.020% w/v Polyvinylpyrrolidone (K-30) 1.000% w/v Phenyl ethyl alcohol 0.500 % v/v Pyrogen free water to make up to 1.0ml Sildenafil citrate is dissolved in a mixture of pyrogen free water, purified diethylene glycol monoethyl ether and octoxynol. Disodium EDTA, polyvinylpyrrolidone K-30, Sodium ascorbate and phenyl ethyl alcohol are added to the above solution. pH is adjusted to 4.0 with sodium acetate and glacial acetic acid. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "Monospray". EXAMPLE - 7 Each ml contains Sildenafil free base 7.500 % w/v Ascorbic acid 5.000 % w/v Disodium EDTA 0.020% w/v Polyvinylpyrrolidone (K-l 5) 2.000% w/v Purified diethylene glycol monoethyl ether 1.000 % w/v Benzyl alcohol 0.200 % v/v Pyrogen free water to make up to 1.0ml Sildenafil is dissolved in a mixture of pyrogen free water, purified diethylene glycol monoethyl ether. Ascorbic acid, disodium EDTA, Polyvinylpyrrolidone, benzyl alcohol are added under continuous mixing. pH is adjusted to 4.0 with sodium acetate and glacial acetic acid. Final volume adjusted to one ml with pyrogen free water. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "Monospray". EXAMPLE - 8 Each ml contains Sildenafil citrate 10.000 % w/v Hydrochloric acid 10.000% w/v Sodium acetate 0.180% w/v Glacial acetic acid 3.100% w/v Disodium EDTA 0.020% w/v Purified diethylene glycol monoethyl ether 0.500 % w/v Polyvinylpyrrolidone (K-15) 2.000% w/v Propylene glycol 2.000% w/v Phenyl ethyl alcohol 0.500% w/v Pyrogen free water to make up to 1.0ml Sildenafil citrate is dissolved in a mixture of pyrogen free water and hydrochloric acid. Purified diethylene glycol monoethyle ether, disodium EDTA, polyvinylpyrrolidone (K-15), propylene glycol and phenyl ethyl alcohol is added under continuous mixing. pH is adjusted to 4.0 with sodium acetate and glacial acetic acid. Final volume is adjusted to one ml with pyrogen free water. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "Monospray". Advantages: Advantages of the invention are 1) Rapid onset of action when compared to conventional oral formulation of sildenafil. 2) Reduction in the total amount of drug required to elicit desire therapeutic response there by reducing the side effects. 3) Improved patient compliance 4) Accurate dosing compared to other extravascular routes. We Claim: 1) An improved pharmaceutical composition, intended for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes in the form of solution or colloidal dispersion, which comprises a synergistic solution or colloidal dispersion of sildenafil or its salt in the range of 2.5 to 25.0% w/v in a "protogenic" solvent such as water, diluted hydrochloric acid, ascorbic acid in the range of 10 to 80.0% v/v containing co-solvents in the range of 1.0 to 50.0% w/v, solubilizing agents in the range of 1.0 to 30.0% w/v, Solubility enhancer in the range of 1.0 to 20%, buffering agent in the range of 1.0 to 10.0% w/v, penetration enhancers in the range of 0.1 to 25.0% v/v or w/v, stabilizing agents in the range of 0.01 to 0.5% w/v, antimicrobial preservatives in the range of 0.001 to 2.0% w/v, viscosity building agent in the range of 0.1 to 5.0% w/v, and the dispersion having a pH in the range of 3.0 to 8.0, and the composition filled into containers fitted with a spraying device for nasal application. 2) An improved pharmaceutical composition as claimed in claim 1 where in the salt form of sildenafil employed is selected from the salt formed by reacting sildenafil with ascorbic acid, citric acid, lactic acid, acetic acid, methyl sulphonic acid, succinic acid, maleic acid, sulfuric acid, hydrochloric acid, nitric acid, orthophosphoric acid, preferably ascorbic acid, methyl sulphonic acid and hydrochloric acid. 3) An improved pharmaceutical composition as claimed in claim 1 and 2 where in the amount of Sildenafil or its salt employed in the solution or dispersion ranges from 2.5 to 25.0% w/v, preferably form 5.0 to 20.0% w/v more preferably from 7.5 to 15.0% w/v. 4) An improved pharmaceutical composition as claimed in claim 1 and 3, where in the solvent used is selected from water, diluted hydrochloric acid, dilutted sulphuric acid, lactic acid and the like are employed in the nasal solution. 05)An improved pharmaceutical composition as claimed in claims 1 to 4, where in the amount of solvent ranges from 10.0 to 80.0% v/v, preferably 20.0 to 60.0% v/v. 06) An improved pharmaceutical composition as claimed in claims 1 to 5, where in the co-solvent(s) such as ethyl alcohol, propylene glycol polyethylene glycols having a nominal molecular weight of 200 to 600, N-methyl-2-pyrolidone, glycerol or a mixture thereof are employed. 07)An improved pharmaceutical composition as claimed in claims 1 to 6, where in the amount of co-solvent(s) ranges from 1.0 to 50.0% v/v, preferably from 15.0 to 30.0% v/v. 08)An improved pharmaceutical composition as claimed in claims 1 to 7 where in the solubilizing agents such as purified diethylene glycol monoethyl ether, cyclodextrins, glycerol monostearate, lecithin, poloxomer, polyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, stearic acid, citric acid, and ascorbic acid and the like; surface active agents such as polysorbates, sorbiton esters, polyvinyl olcohol, benzal konium chloride, benzithonium chloride, cetrimide docsate sodium, sodium lauryl syulphate, octoxynol and the like or a combination of these are employed. 09)An improved pharmaceutical composition as claimed in claims 1 to 8 where in the amount of solubilizing agents employed ranges from 1.0 to 30.0% w/v, preferably 5.0 to 15.0% w/v. 10) An improved pharmaceutical composition as claimed in claims 1 to 9 where in the solubility enhancers are selected from benzyl alcohol, DL-Methionine, nicotinamide, vanilin, caffine are employed. 11) An improved pharmaceutical composition as claimed in claims 1 to 10 where in the amount of solubility enhancers employed ranges from 1.0 to 20% w/v preferably 5.0 to 15.0% w/v. 12) An improved pharmaceutical composition as claimed in claims 1 to 11 where in the buffering agents such as diluted hydrochloric acid, sodium acetate, sodium acetate, glacial acetic acid, disodium hydrogen orthophosphate, potassium dihydrogen orthophosphate, orthophosporic acid and the like are employed. 13) An improved pharmaceutical composition as claimed in claims 1 to 12 where in the penetration enhancer such as ethyl alcohol, propylene glycol, N- methyl-2-pyrrolidone, bile salts, cyclodextrins, and a mixture of propylene glycol monolaurate and purified diethylene glycol monoethyl ether and the like is used. 14) An improved pharmaceutical composition as claimed in claims 1 to 13 where in the amount of penetration enhancers ranges from 0.1 to 25.0% v/v or w/v, preferably 5.0 to 13% v/v or w/v. 15) An improved pharmaceutical composition as claimed in claims 1 to 14 where in the stabilizing agent such as sodium metabisulphite, sodium bisulphite, disodium ethylene diamine terra acetic acid, ascorbic acid and the like is employed. 16)An improved pharmaceutical composition as claimed in claims 1 to 15 where in the amount of stabilizing agent ranges from 0. 01 to 0.5% w/v. 17) An improved pharmaceutical composition as claimed in claims 1 to 16, where in the antimicrobial preservatives such as benzyl alcohol, benzalkonium chloride, phenyl mercuric acetate, phenylethyl alcohol and the like are employed. 18) An improved pharmaceutical composition as claimed in claim 17 where in the amount of antimicrobial preservative employed ranges from 0.001 to 2.0% w/v. 19) An improved pharmaceutical composition as claimed in claims 1 to 18, where in the viscosity building agent such as hydrocollids such as hydroxypropyl methyl cellulose, poly acrylic acid and the like or water soluble polymers such as carbopol, sodium carboxy methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, various grades of polyvinylpyrrolidone i.e. K-15, K-30, K-60 and K-90 are employed. 20) An improved pharmaceutical composition as claimed in claims 19 where in the amount of viscosity building agent ranges from 0.1 to 5.0% w/v preferably 0.3 to 3.0% w/v. 21) A process for the preparation of improved pharmaceutical composition, intended for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes in the form of solution or colloidal dispersion, which comprises a synergistic solution or colloidal dispersion of sildenafil or its salt in the range of 2.5 to 25.0% w/v in a "protogenic" solvent such as water, diluted hydrochloric acid, ascorbic acid in the range of 10 to 80.0% v/v containing co-solvents in the range of 1.0 to 50.0% w/v, solubilizing agents in the range of 1.0 to 30.0% w/v, Solubility enhancer in the range of 1.0 to 20%, buffering agent in the range of 1.0 to 10.0% w/v, penetration enhancers in the range of 0.1 to 25.0% v/v or w/v, stabilizing agents in the range of 0.01 to 0.5% w/v, antimicrobial preservatives in the range of 0.001 to 2.0% w/v, viscosity building agent in the range of 0.1 to 5.0% w/v, and the dispersion having a pH in the range of 3.0 to 8.0 and the composition filled into containers fitted with a sparying device for nasal application. 22) A process where in the salt form of sildenafil employed is selected from the salt formed by reacting with ascorbic acid, citric acid, lactic acid, acetic acid, methyl sulphonic acid, succinic acid, maleic acid, sulfuric acid, hydrochloric acid, nitric acid, orthophosphoric acid, preferably ascorbic acid, methyl sulphonic acid and hydrochloric acid. 23) A process as claimed in claims 21 and 22 where in the amount of Sildenafil or its salt employed in the solution or dispersion ranges from 2.5 to 25.0% w/v, preferably form 5.0 to 20.0% w/v more preferably from 7.5 to 15.0% w/v. 24)A process as claimed in claim 21 and 23 where in the solvent such as water, diluted hydrochloric acid, diluted sulphuric acid, lactic acid and the like is employed. 25)A process as claimed in claim 21 and 24 where in the amount of solvent ranges from 10.0 to 80.0% v/v, preferably 20.0 to 60.0% v/v. 26)A process as claimed in claim 21 and 25 where in the co-solvent(s) such as ethyl alcohol, propylene glycol polyethylene glycols having a nominal molecular weight of 200 to 600, N-methyl-2-pyrolidone, glycerol or a mixture thereof are employed. 27)A process as claimed in claim 21 and 26 where in the amount of co-solvent(s) employed ranges from 1.0 to 50.0% v/v, preferably from 15.0 to 30.0% v/v. 28)A process as claimed in claim 21 and 27 where in the solubilizing agents such as purified diethylene glycol monoethyl ether, cyclodextrins, glycerol monostearate, lecithin, poloxomer, polyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, stearic acid, citric acid, and ascorbic acid and the like; surface active agents such as polysorbates, sorbiton esters, polyvinyl alcohol, benzalkonium chloride, benzithonium chloride, cetrimide docusate sodium, sodium lauryl syulphate, octoxynol and the like or a combination of these are employed. 29)A process as claimed in claim 21 and 28 where in the amount of solubilizing agents employed ranges from 1.0 to 30.0% w/v, preferably 5.0 to 15.0% w/v. 30)A process as claimed in claim 21 and 29 where in the solubility enhancers such as benzyl alcohol, DL-Methionine, nicotinamide, vanilin, caffine and the like is employed. 31)A process as claimed in claim 21 and 30 where in the amount of solubility enhancers employed ranges from 1.0 to 20% w/v preferably 5.0 to 15.0% w/v. 32)A process as claimed in claim 21 and 31 where in the buffering agents such as diluted hydrochloric acid, sodium hydroxide, sodium acetate, glacial acetic acid, disodium hydrogen orthophosphate, potassium dihydrogen orthophosphate, orthophosporic acid and the like are employed. 33)A process as claimed in claim 21 and 32 where in the penetration enhancer such as ethyl alcohol, propylene glycol, N-methyl-2-pyrrolidone, bile salts, cyclodextrins, propylene glycol monolaurate in combination with purified diethylene glycol monoethyl ether and the like is employed. 34) A process as claimed in claim 21 and 33 where in the amount of penetration enhancers ranges from 0.1 to 25.0% v/v or w/v, preferably 5.0 to 13.0 % v/v or w/v. 35)A process as claimed in claim 21 and 34 where in the stabilizing agent such as sodium metabisulphite, sodium bisulphite, disodium ethylene diamine tetra acetic acid, ascorbic acid and the like is employed. 36)A process as claimed in claim 21 and 35 where in the amount of stabilizing agent employed ranges from 0. 01 to 0.5% w/v. 37)A process as claimed in claim 21 and 36 where in the antimicrobial preservatives such as benzyl alcohol, benzalkonium chloride, phenyl mercuric acetate, phenylethyl alcohol and the like are employed. 38)A process as claimed in claim 37 where in the amount of antimicrobial preservative ranges from 0.001 to 2.0% w/v. 39) A process as claimed in claim 21 and 38 where in the viscosity building agent such as hydrocollids such as hydroxypropyl methyl cellulose, poly acrylic acid and the like or water soluble polymers such as carbopol, sodium carboxy methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose various grades of polyvinylpyrrolidone i.e. K-15, K-30, K-60 and K-90. 40) A process as claimed in claim 39 where in the amount of viscosity building agent ranges from 0.1 to 5.0% w/v preferably 0.3 to 3.0% w/v. 41)The pharmaceutical composition as claimed in claims 1 to 40 where in the the composition is filled in the nasal delivery spraying device. 42) An improved pharmaceutical composition intended for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic, and mixed causes in the form of solution or colloidal dispersion substantially as herein described with reference to the examples 1 to 8. 13)A process for the preparation of an improved pharmaceutical composition intended for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes in the form of solution in colloidal dispersion substantially as herein described with reference to the examples 1 to 8.

Full Text

The present invention relates to a novel pharmaceutical composition containing sildenafil useful for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes. The composition is also particularly effective in patients with erectile dysfunction due to spinal cord injury. The pharmaceutical composition of the present invention may be in the form of a solution or a colloidal dispersion in a pharmaceutical vehicle. The composition can be filled into specially designed dosing device for nasal administration.
Sildenafil has the chemical formula C22H30N6O4S
Sildenafil is potent and selective inhibitor of type V cyclic guanosine mono phosphodiestrase (cGMP) with utility for the treatment of male erectile dysfunction. Recently, it has been hypothesized that penile erections are dependent on nitric oxide (NO) and its second messenger CGMP. Sildenafil amplifies the neuronal nitric oxide (NO) / cGMP pathway implicated in the relaxation of the corpus cavernosum. The drug is well tolerated orally with headache, dyspepsia, facial flushing and muscular ache are the most common
adverse events reported [Steers, W. D. et al. 2nd Meet Eur. Soc. Impotence Res. (Oct 1-4,
Madrid)i997, Abst 80]. It is administered orally at a dose of 25mg to 100mg. sildenafil treated patients have a significant improvement in sex life satisfaction rating compared with the placebo groups [Terret et al. Bio Org.
Med.Chem. Lett., 6(15), 1819-1824(1996); Boolell. et al. Br.J.Urol. 78(2),257-261(1996)].
The pharmaceutical composition available in markets for oral administration contains sildenafil citrate (Manufactured by M/s Pfizer Inc.). Sildenafil citrate is soluble in dimethylformamide, sparingly soluble in acetic acid, slightly soluble in alcohol. About 3.5 mg is soluble in water.

In JP 10298062 a pharmaceutical composition in the form of tablets that rapidly soluble in the oral cavity and manufacturing procedure has been disclosed.
In WO 9830209 a rapidly releasing and taste masking pharmaceutical composition comprising a core containing sildenafil, an inner coating layer formed of a water soluble polymer and an outer coating layer formed on inner coating containing saliva insoluble polymer and a process for preparing such oral dosage form has been disclosed.
In US patent, US 5,874,437 nitrosated and nitrosylated phosphodiestrase inhibitors having the formula NOn , where n = 1 or 2 and compositions comprising such compound in pharmaceutically acceptable carrier and a method for treating male impotence in humans by administering the compounds and compositions thereof has been disclosed.
With the development of various devices for application of drugs in the nasal cavity and the specialized anatomy and physiology of nasal cavity and its ready accessibility made the nasal cavity a particularly attractive delivery site for the systemic administration of drugs, since no injection is required, and first pass metabolism is circumvented.
Although the permeability of nasal epithelium to drug molecules varies greatly depending on the chemical and physical properties of the drug, a number of strategies have been explored to increase the nasal membrane permeability. These include
1) increasing the residence time of the drug in the nasal mucosa.
2) increasing the blood flow to the nasal mucosa.

3) modifying drug-membrane characteristic with surface active agents.
No pharmaceutical composition containing sildenafil for nasal administration has been reported till date.
The main objective of present invention is to provide a pharmaceutical composition containing sildenafil, for application in the nasal cavity which can elicit rapid onset of action at a reduced dose when compared to the oral dosage form available for treatment of male erectile dysfunction.
Another objective of the invention is to provide a method for preparing the pharmaceutical composition containing sildenafil for nasal application.
The new pharmaceutical composition of the present invention is in the form of a solution or colloidal dispersion in a suitable pharmaceutical vehicle, comprising of a solvent, co-solvent and / or solubilizing agent, penetration enhancer, stabilising agent and buffering agent; optionally contain an anti¬microbial preservatives and / or viscosity modifying agents.
The composition can be filled into a suitable container fitted with nasal applicator. The active substance is present in the form of base or its salt with organic or inorganic acids. The preferred dosage form is "Monospray", which is a unidose device supplied by M/s Valois, filled with single dose of medicament.
The active substance in the pharmaceutical composition sildenafil may be present as a base or its salt form with organic acids such as citric acid, lactic

acid, acetic acid and the like or inorganic acids such as sulphuric acid, hydrochloric acid, nitric acid, orthophosphoric acid etc.
The amount of sildenafil or its salt present in the pharmaceutical composition may range from 2.5 to 25.0 percent, preferably 5.0 to 20.0 percent more preferably 7.5 to 15.0 percent. The pharmaceutical composition of the present invention contains sildenafil or its salt in the form of a liquid solution or colloidal dispersion in a suitable inert pharmaceutical vehicle.
The pharmaceutical vehicle comprises of a solvent in which sildenafil is dissolved or dispersed, a co-solvent and / or solubilising agent which aids in dissolving sildenafil, a penetration enhancer for improving the penetration of sildenafil through the barriers in nasal mucosa, a stabilizing agent to prevent degradation of sildenafil and a buffering agent to adjust pH of the pharmaceutical composition.
The poor solubility of sildenafil in water alone necessitates the use of other solvents, co-solvents and / or solubilising agets to dissolve it in the pharmaceutical composition.
The solvents used in the pharmaceutical composition may be selected from a group of "Protogenic" solvents, which act as proton donors, such as liquid hydrochloric acid, sulphuric acid, lactic acid, solutions of ascorbic acid, citric acid. The volume of such solvents and co-solvents present in the pharmaceutical composition may range from 10.0 to 80.0 percent, preferably 20.0 to 60.0 percent.

The co-solvents used in the pharmaceutical composition may be selected from a group of "Amphiprotic" solvents, which act as both proton acceptors and proton donors, such as the alcohols ethyl alcohol, propylene glycol, glycerol and polyethylene glycols having a nominal molecular weight of 200 - 600 or N-methyl-2-pyrrolidone, which enhances the solubility of sildenafil or its salts byformation of complex. The volume of such co-solvents and co-solvents present in the pharmaceutical composition may range from 4.0 to 40.0 percent, preferably 15.0 to 30.0 percent.
The solubilising agent used in the pharmaceutical composition may be selected from surface-active agents such as polysorbate 80, polymers which can form molecular adducts and have anti-nucleating properties such as poloxamers, polyvinylpyrrolidone. The amount of such solubilising agent present in the pharmaceutical composition may range from 1.0 to 30.0 percent, preferably 5.0 to 15.0 percent.
The buffering agent used in the pharmaceutical composition may be selected from hydrochloric acid, sodium acetate, glacial acetic acid, orthophosphoric acid, potassium dihydrogen orthophosphate, sodium hydroxide and the like.
The penetration enhancers for intranasal application known in the art are ethyl alcohol, propylene glycol, N-methyl-2-pyrrolidone, bile salts, cyclodextrins etc. The penetration enhancers used in the pharmaceutical composition of the present invention is selected from among these and the amount present in each ml of the composition may range from 10.0 to 30.0 percent, preferably 15.0 to 25.0 percent.

The pharmaceutical substances used as stabilizing agents, known in the art are disodium ethylene diamine tetra acetic acid, ascorbic acid etc. The stabilizing agent used in the pharmaceutical composition for stabilisation of sildenafil may be selected from among these substances. The amount of such stabilizing agents present in the composition may range from 0.01 to 0.1 percent.
The pharmaceutical composition may optionally contain anti-microbial preservative. The anti-microbial agent may be selected from benzalkonium chloride, phenyl mercuric acetate, phenylethyl alcohol and the like. The amount of such anti-microbial preservative may range from 0.02 to 0.5 percent.
The pharmaceutical composition may optionally contain a viscosity building agent to increase the viscosity of the composition, thereby prolongs the contact time of the composition with the nasal mucosa, preventing its rapid drain to the larynx region of throat. The viscosity building agent may be selected from hydrocollids such as hydroxypropyl methylcellulose, poly acrylic acid and the like or water soluble polymers such as carbopol, sodium carboxy methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose etc. The amount of such viscosity building agent used in the pharmaceutical composition may range from 1.0 to 5.0 percent.
The pharmaceutical composition is prepared by dissolving or dispersing sildenafil or its salt in the pharmaceutical vehicle comprising of solvent, co-solvent and / or solubilising agent, penetration enhancer along with other optional ingredients. The pH of the pharmaceutical composition is adjusted using a buffering agent. The pharmaceutical composition is then filled in either a multiple dose container fitted with a mechanical pump and a nasal

applicator with an over cap or a "Monospray"(supplied by M/s Valois) nasal liquid unidose device. The preferred device is "Monospray".
The "Monospray" is a nasal liquid unidose device useful in administrating high potency molecules enabling less frequent administration and treatment of crisis conditions. The device comprises an actuator with over cap, spring, piston, dosage chamber and a ball for closing the dosage chamber rear end after filling with medicine. A "Monospray" with a nominal volume of the dosage chamber in between 50.0 to 150.0 microlitres is selected to deliver 2.5 to 37.5mg, preferably 5.0 to 25.0mg, more preferably 7.5 to 15.0 mg of sildenafil.
Advantages:
Advantages of the invention are
1) Rapid onset of action when compared to conventional oral formulation of
sildenafil.
2) Reduction in the total amount of drug required to elicit desire therapeutic
response there by reducing the side effects.
3) Improved patient compliance

The present invention relates to an improved pharmaceutical composition containing sildenafil intended for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes. The composition is also particularly effective in patients with erectile dysfunction due to spinal cord injury. The pharmaceutical composition of the present invention may be in the form of a solution or a colloidal dispersion in a pharmaceutical vehicle. The composition can be filled into specially designed dosing device for nasal administration.
Sildenafil has the chemical formula C22H30N6O4S
Sildenafil is potent and selective inhibitor of type V cyclic guanosine mono phosphodiestrase (cGMP) with utility for the treatment of male erectile dysfunction. Recently, it has been hypothesized that penile erections are dependent on nitric oxide (NO) and its second messenger cGMP. Sildenafil amplifies the neuronal nitric oxide (NO) / cGMP pathway implicated in the relaxation of the corpus cavernosum. The drug is well tolerated orally. Headache, dyspepsia, facial flushing and muscular ache are the common adverse events reported [Steers, W. D. et al. 2nd Meet Eur. Soc. Impotence Res. (Oct 1-4, Madrid) 1997, Abst 80]. It is administered orally at a dose of 25mg to lOOmg. Sildenafil treated patients have a significant improvement in sex life satisfaction rating compared with the placebo groups [Terret et al. Bio Org. Med.Chem. Lett., 6(15),1819-1824(1996); Boolell. et al. Br.J.Urol. 78(2),257-261(1996)].
The pharmaceutical compositions available in the markets for oral administration contains sildenafil citrate (M/s Pfizer Inc.). Sildenafil citrate is soluble in dimethylformamide, sparingly soluble in acetic acid, slightly soluble in alcohol. About 3.5 mg is soluble in water.
In JP 10298062 a pharmaceutical composition in the form of tablets that rapidly soluble in the oral cavity and manufacturing procedure has been disclosed.
In WO 9830209 a rapidly releasing and taste masking pharmaceutical composition comprising a core containing Sildenafil, an inner coating layer formed of a water soluble polymer and an outer coating layer formed on inner coating containing saliva insoluble polymer and a process for preparing such oral dosage form has been disclosed.
According to the above patents sildenafil is administered orally about one hour before intercourse. This is a major disadvantage of the oral formulations, creating in convenience to the partners. Rapid onset of action is highly desirable in such therapeutic indication for patients. Considering the above parameters an

attempt has been made to develop an intranasal formulation containing sildenafil citrate or base in a solution form which possesses rapid onset of action at a reduced dose when compare to the oral dosage form available for the treatment of male erectile dysfunction.
With the development of various devices for application of drugs in the nasal cavity and the specialized anatomy and physiology of nasal cavity and its ready accessibility made the nasal cavity a particularly attractive delivery site for the systemic administration of drugs, since no injection is required, and first pass metabolism is circumvented.
Although the permeability of nasal epithelium to drug molecules varies greatly depending on the physicochemical properties of the drug, a number of strategies have been explored to increase the nasal membrane permeability. These include
1) increasing the residence time of the drug in the nasal mucosa.
2) increasing the blood flow to the nasal mucosa.
3) modifying drug-membrane characteristic with surface-active agents.
In US patent, US 5,874,437 nitrosated and nitrosylated phosphodiestrase inhibitors having the formula NOn , where n = 1 or 2 and compositions comprising such compound in pharmaceutically acceptable carrier and a method for treating male impotence in humans by administering the compounds and compositions thereof has been disclosed.
In WO 00/00199 an intranasal dosage unit of cyclic guanosine monophosphate specific phosphodiesterase inhibitors are described which are combined with suitable intranasal carriers having a buffer, surfactant and absorption enhancers, in order to achieve a peak plasma concentration of the inhibitor in less than 1 hour, and desirably with in 30 minutes of administration in mammals. In this active ingredient is dispersed in a buffer followed by thickening agent, humectant and surfactant are added.
However the disadvantage associated with this type of suspension formulations is that the dispersed drug particles in the viscous medium may have to over come the resistance caused by the medium to reach onto the surface of the mucous membrane for its dissolution and penetration through the membrane. Further the drug is in solid state with less fluid volume and surface area made available for dissolution and penetration that reduces the absorption of drug compared to solution. The dispersion system may delay onset of action initially, though it prolongs the duration of action due to slow penetration. The delay in the onset of action may cause patient incompliance. Further, the limited

solubility of the sildenafil citrate may leads to improper dosing of the formulation.
In EP 0967214 intranasal formulations of Sildenafil mesylate together with a pharmaceutically acceptable diluent or carrier for the treatment of male erectile dysfunction or female sexual disorders are described. In this, sildenafil free base is added to an aqueous solution of methane sulfonic acid and solubility enhancer (Caffeine) and a buffer are added. Similarly compositions are prepared using nicotinamide, vanillin or benzyl alcohol instead of caffeine as penetration enhancers.
However, the above process in making the solution involves the conversion of sildenafil into mesylate followed by solubilising the mesylate salt. This process involves conversion of sildenafil to mesylate salt, which is tedious and time consuming.
The above patent also claimed an intranasal powder formulation by using sildenafil mesylate and lactose. The composition was milled to an average particles of 20 microns size and filled into a gelatin capsule for use with a commercial nasal device. Inhalation of this powder may cause irritation to the mucous membrane, and absorption of the active ingredient is slow compared to the solution form as described above.
In WO 9966933 a method for rapidly and reliably delivering sildenafil to the systemic circulation of a patient intranasally in a pharmaceutical composition contained sildenafil or a pharmaceutically acceptable salts and carrier was disclosed. According to this method sildenafil citrate was dissolved with the help of mesylic acid and the pH adjusted to 2.8 to 3.0 with sodium hydroxide. It has also disclosed a "sildenafil nasal spray solution" containing sildenafil hydrochloride dissolved in phosphate buffer and isotonicity adjusted with sodium chloride.
It also discloses an "aqueous nasal gel" which contains sildenafil hydrochloride, methocel and an acetate buffer. It has also disclosed a composite nasal spray solution containing sildenafil hydrochloride, and apomorphine hydrochloride.
Considering the importance attached to removal of the drawbacks/disadvantages of the presently available composition containing sildenafil we undertook research work towards developing an improved composition which can be administered through nasal route wherein the active drug gets rapidly absorbed.
The main objective of the present invention is to provide an improved pharmaceutical composition intended for nasal administration for the treatment

of male erectile dysfunction due to organic, pyschogenic and mixed causes containing sildenafil for nasal application.
Yet another objective of the present invention is to provide an improved pharmaceutical composition in the form of a solution or colloidal dispersion intended for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes containing sildenafil for nasal application in a suitable pharmaceutical vehicle, comprising of a solvent, co-solvent and / or solubilizing agent, penetration enhancer, stabilising agent, buffering agent, and a tonicity agent; optionally contain an anti-microbial agent and / or viscosity modifying agents.
Still another objective of the invention is to provide a method for preparing the improved pharmaceutical composition containing sildenafil in the form of a solution or colloidal dispersion intended for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes.
The present invention is based on our finding that the poorly water soluble sildenafil or its salt, dissolves completely in mild acids such as lactic acid, hydrochloric acid, ascorbic acid, citric acid, succinic acid, maleic acid, orthophosphoric acid or methyl sulfonic acid and the resulting solution when mixed with solubilisers and penetration enhancers such as polyethyleneglycol, propylene glycol, glycerol, ethyl alcohol, purified diethylene glycol monoethyl ether, propyleneglycol monolaurate and the pH is adjusted 3.0 to 8.0 with citrate, acetate or phosphate buffer and tonicity is adjusted with sodium chloride or dextrose or mannitol, the resulting composition acquires unique property of promoting rapid absorption of sildenafil resulting in rapid onset of action when administered through the nasal route due to synergistic activities of the above said components. It was noticed that the free base of sildenafil is preferably more soluble in ascorbic acid and diethylene glycol monoethyl ether.
We have further noted that lactic acid, is more preferable as it is highly biocompatible and is present in organs such as lever, kidney, thymus gland, stratum coraeum, human amniotic fluid and other organs and body fluids.
The above said pharmaceutical composition has rapid onset of action upon administration through nasal route with out any adverse effects due to the synergistic effect of the ingredients employed in the composition which results in keeping the active ingredient namely sildenafil or its salt in solution or dispersion form and absorption is further promoted by penetration enhancers making it absorb readily when the composition is administered through the nasal route for eliciting the desired therapeutic response.

The above said composition can be filled into a suitable container fitted with nasal applicator. The composition can be filled either in multiple dose container fitted with an applicator or "Monospray" (supplied by M/s Valois India Pvt, Ltd., 407, Madhava,Bandra-kurla Complex, Bondra(E), Mumbai- 400 051), filled with single dose of medicament.
Accordingly, the present invention provides an improved pharmaceutical composition intended for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes in the form of solution or colloidal dispersion, which comprises solution or colloidal dispersion of Sildenafil or its salt in a "Protogenic" solvent containing solubilisers and penetration enhancers, stabilizing agent, buffering agents and an isotonicity agent, the solution or the dispersion having a pH in the range of 3.0 to 8.0.
The solution or the dispersion is stable at room temperature and sub ambient temperatures as well without any precipitation and/or re-crystallisation. The composition is not a mere admixture of the ingredients employed resulting in a composition having the aggregate properties of the said ingredients. The composition in solution form is preferred to the dispersion form as the former has more rapid absorption and onset of action than that of a dispersion form.
The pharmaceutical composition so formed is then filled in either a multiple dose containers fitted with a mechanical pump and a nasal applicator with an over cap or a "Monospray" (supplied by M/s Valois India Pvt., Ltd., 407, Madhava, Bandra-kurla Complex, Bondra(E), Mumbai- 400 051), nasal liquid unidose device. The preferred device is "Monospray".
Sildenafil employed in the pharmaceutical composition may be the base or its salt form with organic acids such as citric acid, lactic acid, acetic acid, succinic acid, maleic acid and the like or inorganic acids such as sulphuric acid, hydrochloric acid, orthophosphoric acid etc.
The amount of sildenafil or its salt employed in the pharmaceutical composition may range from 2.5 to 25.0% w/v, preferably 5.0 to 20.0% w/v more preferably 7.5 to 15.0% w/v.
The pH of the pharmaceutical composition may preferably be in the range of 3.5 to 5.0.
The "Protogenic" solvents, which act as proton donors, used in the pharmaceutical composition may be selected from a group of mild acids such as hydrochloric acid, sulphuric acid, lactic acid, solutions of ascorbic acid, citric acid and amphiprotic solvents such as water or their mixtures. The volume of

such solvents present in the pharmaceutical composition may range from 10.0 to 80.0%v/v, preferably 20.0 to 60.0% v/v.
The co-solvents when used in the pharmaceutical composition may be selected from a group of "Amphiprotic" solvents, which act as both proton acceptors and proton donors such as the alcohols e.g. ethyl alcohol, propylene glycol, glycerol and polyethylene glycols having a nominal molecular weight of 200 - 600 or N-methyl-2-pyrrolidone, which enhances the solubility of sildenafil or its salts by formation of complex. The volume of such co-solvents present in the pharmaceutical composition may range from 1.0 to 50.0% v/v preferably 15.0 to 30.0% v/v.
The solubilising agents used in the pharmaceutical composition may be selected from purified diethylene glycol monoethyl ether, cyclodextrins, glycerol monostearate, lecithin, poloxomer, polyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, stearic acid, citric acid, and ascorbic acid and the like; surface active agents such as polysorbates, sorbiton esters, polyvinyl alcohol, benzal konium chloride, benzithonium chloride, cetrimide, docusate sodium, sodium lauryl sulphate, octoxynol and the like or a combination of these. The amount of such solubilising agent present in the pharmaceutical composition may range from 0.01 to 30.0% w/v, preferably 5.0 to 15.0%w/v.
The solubility enhancers used in the composition may be selected from DL-methionine, caffeine, nicotinamide, vanillin,,, benzyl alcohol known in art as solubility enhancers when added to the solutions of other substances.
The buffering agent used in the pharmaceutical composition may be selected from hydrochloric acid, sodium acetate, glacial acetic acid, orthophosphoric acid, potassium dihydrogen orthophosphate and the like.
The penetration enhancers used in the pharmaceutical composition of the present invention are selected from ethyl alcohol, propylene glycol, N-methyl-2-pyrrolidone, bile salts, cyclodextrins, propyleneglycol monolaurate in combination with purified diethylene glycol monoethyl ether and the like known in the art for intranasal application. The amount of such penetration enhancer present in each ml of the composition may range from 0.1 to 30.0%v/v or w/v, preferably 5.0 to 25.0%v/v or w/v.
The stabilizing agent used in the pharmaceutical composition maybe selected from among those substances known in the art such as sodium metabisulphite,

9
sodium bisulphite, disodium EDTA, ascorbic acid etc. The amount of such stabilizing agents present in the composition may range from 0.01 to 0.5% w/v.
The pharmaceutical composition may optionally contain anti-microbial agent. The anti-microbial agent may be selected from benzyl alcohol, benzalkonium chloride, phenyl mercuric acetate, phenylethyl alcohol and the like. The amount of such anti-microbial agent may range from 0.001 to 2.0% w/v preferably 0.02 to 0.5%w/v
The pharmaceutical composition may also optionally contain a viscosity building agent to increase the viscosity of the composition, there by prolongs the contact time of the composition with the nasal mucosa, preventing its rapid drain to the larynx region of throat. The viscosity building agent may be selected from hydrocolloids such as hydroxypropyl methylcellulose, poly acrylic acid and the like or water soluble polymers such as carbopol, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and various grades of polyvinylpyrrolidone i.e. K-15, K-30, K-60 and K-90 etc. The amount of such viscosity building agent used in the pharmaceutical composition may range from 0.1 to 5.0%w/v.
The "Monospray" is a nasal liquid unidose device useful in administrating high potency molecules enabling less frequent administration and treatment of crisis conditions. The device comprises an actuator with over cap, spring, piston, dosage chamber and a ball for closing the dosage chamber from rear end after filling with medicine. A "Monospray" with a nominal volume of the dosage chamber in between 50.0 to 150.0 microliters is selected to deliver 2.5 to 37.5mg, preferably 5.0 to 25.0mg, more preferably 7.5 to 15.0 mg of active substance.
When a multiple dose container is used the percentage of the drug dissolved may range from 2.5 to 25.0%w/v preferably from 5.0 to 15.0%w/v more preferably from 7.5 to 15.0% w/v. The dose required may constitute one or more number of actuations depending on the dosing device used and the concentration of drug present in the formulation.

The invention is described in detail 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
Each ml contains
Sildenafil citrate 7.500 % w/v
Lactic acid 10.000 % v/v
Sodium acetate 0.041% w/v
Glacial acetic acid 0.057 % v/v
Phenylethyl alcohol 0.500 % v/v
Pyrogen free water to make up to 1.0 ml
Sildenafil citrate is dissolved in lactic acid and pyrogen free water. Phenylethyl alcohol is added as preservative. Sodium acetate and Glacial acetic acid are added to adjust the pH 3.0. Final volume adjusted to 1.0ml with pyrogen free water. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "Monospray".

EXAMPLE -2
Each ml contains
Sildenafil citrate 7.500 % w/v
N-methyl-2-pyrrolidone 10.000 % v/v
Potassium dihydrogen
Orthophosphate 1.360 % w/v
Orthophospharic acid 0.080 % v/v
Benzalkonium chloride 0.020 % v/v
Pyrogen free water to make up to 1.0 ml
Sildenafil citrate is dissolved in mixture of N-methyl-2-pyrrolidone, and pyrogen fee water Benzalkonium chloride solution is added, pH is adjusted to 3.5 with Potassium dihydrogen orthophosphate and Phosphoric acid. Final volume is adjusted to 1.0ml with Pyrogen free water. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "MonosDrav".

EXAMPLE-3
Each ml contains
Sildenafil citrate 10.000 % w/v
Polyethylene glycol - 300 30.000 % v/v
Ethyl alcohol 20.000 % v/v
Hydrochloric acid 10.000 % v/v
Pyrogen free water to make up to 1.0 ml
Sildenafil citrate is dissolved in a mixture of polyethylene glycol, ethyl alcohol and hydrochloric acid. pH is adjusted to 3.0 with sodium hydroxide. Pyrogen free water is added to make up to one ml. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "Monospray".

EXAMPLE - 4
Each ml contains
Sildenafil citrate 7.500 % w/v
Propylene glycol 20.000 % v/v
Ethyl alcohol 20.000 % v/v
Hydrochloric acid 10.000 % v/v
Pyrogen free water to make up to 1.0ml
Sildenafil citrate is dissolved in a mixture of propylene glycol, ethyl alcohol and hydrochloric acid. pH is adjusted 3.0 with sodium hydroxide. Pyrogen free water is added to make up the volume to one ml. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "Monospray".

EXAMPLE - 5
Each ml contains
Sildenafil citrate 10.000 % w/v
Polyethylene glycol - 300 30.000 % v/v
Glycerol 20.000 % v/v
Hydrochloric acid 10.000 % v/v
Pyrogen free water to make up to 1.0ml
Sildenafil citrate is dissolved in a mixture of polyethylene glycol, glycerol, hydrochloric acid. pH is adjusted to 3.2 with sodium hydroxide. Pyrogen free water is added to make up to one ml. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "Monospray".

EXAMPLE - 6
Each ml contains
Sildenafil citrate 10.000 %w/v
Purified diethylene glycol
monoethyl ether 2.000 % w/v
Octoxynol 0.007 % w/v
Sodium ascorbate 5.000 % w/v
Disodium EDTA 0.020% w/v
Polyvinylpyrrolidone (K-30) 1.000% w/v
Phenyl ethyl alcohol 0.500 % v/v
Pyrogen free water to make up to 1.0ml
Sildenafil citrate is dissolved in a mixture of pyrogen free water, purified diethylene glycol monoethyl ether and octoxynol. Disodium EDTA, polyvinylpyrrolidone K-30, Sodium ascorbate and phenyl ethyl alcohol are added to the above solution. pH is adjusted to 4.0 with sodium acetate and glacial acetic acid. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "Monospray".

EXAMPLE - 7
Each ml contains
Sildenafil free base 7.500 % w/v
Ascorbic acid 5.000 % w/v
Disodium EDTA 0.020% w/v
Polyvinylpyrrolidone (K-l 5) 2.000% w/v
Purified diethylene glycol
monoethyl ether 1.000 % w/v
Benzyl alcohol 0.200 % v/v
Pyrogen free water to make up to 1.0ml
Sildenafil is dissolved in a mixture of pyrogen free water, purified diethylene glycol monoethyl ether. Ascorbic acid, disodium EDTA, Polyvinylpyrrolidone, benzyl alcohol are added under continuous mixing. pH is adjusted to 4.0 with sodium acetate and glacial acetic acid. Final volume adjusted to one ml with pyrogen free water. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "Monospray".

EXAMPLE - 8
Each ml contains
Sildenafil citrate 10.000 % w/v
Hydrochloric acid 10.000% w/v
Sodium acetate 0.180% w/v
Glacial acetic acid 3.100% w/v
Disodium EDTA 0.020% w/v
Purified diethylene glycol
monoethyl ether 0.500 % w/v
Polyvinylpyrrolidone (K-15) 2.000% w/v
Propylene glycol 2.000% w/v
Phenyl ethyl alcohol 0.500% w/v
Pyrogen free water to make up to 1.0ml
Sildenafil citrate is dissolved in a mixture of pyrogen free water and hydrochloric acid. Purified diethylene glycol monoethyle ether, disodium EDTA, polyvinylpyrrolidone (K-15), propylene glycol and phenyl ethyl alcohol is added under continuous mixing. pH is adjusted to 4.0 with sodium acetate and glacial acetic acid. Final volume is adjusted to one ml with pyrogen free water. The resultant solution is filtered aseptically and filled into containers fitted with a spraying device for nasal application or into a "Monospray".

Advantages:
Advantages of the invention are
1) Rapid onset of action when compared to conventional oral formulation of sildenafil.
2) Reduction in the total amount of drug required to elicit desire therapeutic response there by reducing the side effects.
3) Improved patient compliance
4) Accurate dosing compared to other extravascular routes.

We Claim:
1) An improved pharmaceutical composition, intended for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes in the form of solution or colloidal dispersion, which comprises a synergistic solution or colloidal dispersion of sildenafil or its salt in the range of 2.5 to 25.0% w/v in a "protogenic" solvent such as water, diluted hydrochloric acid, ascorbic acid in the range of 10 to 80.0% v/v containing co-solvents in the range of 1.0 to 50.0% w/v, solubilizing agents in the range of 1.0 to 30.0% w/v, Solubility enhancer in the range of 1.0 to 20%, buffering agent in the range of 1.0 to 10.0% w/v, penetration enhancers in the range of 0.1 to 25.0% v/v or w/v, stabilizing agents in the range of 0.01 to 0.5% w/v, antimicrobial preservatives in the range of 0.001 to 2.0% w/v, viscosity building agent in the range of 0.1 to 5.0% w/v, and the dispersion having a pH in the range of 3.0 to 8.0, and the composition filled into containers fitted with a spraying device for nasal application.
2) An improved pharmaceutical composition as claimed in claim 1 where in the salt form of sildenafil employed is selected from the salt formed by reacting sildenafil with ascorbic acid, citric acid, lactic acid, acetic acid, methyl sulphonic acid, succinic acid, maleic acid, sulfuric acid, hydrochloric acid, nitric acid, orthophosphoric acid, preferably ascorbic acid, methyl sulphonic acid and hydrochloric acid.

3) An improved pharmaceutical composition as claimed in claim 1 and 2 where in the amount of Sildenafil or its salt employed in the solution or dispersion ranges from 2.5 to 25.0% w/v, preferably form 5.0 to 20.0% w/v more preferably from 7.5 to 15.0% w/v.
4) An improved pharmaceutical composition as claimed in claim 1 and 3, where in the solvent used is selected from water, diluted hydrochloric acid, dilutted sulphuric acid, lactic acid and the like are employed in the nasal solution.
05)An improved pharmaceutical composition as claimed in claims 1 to 4, where in the amount of solvent ranges from 10.0 to 80.0% v/v, preferably 20.0 to 60.0%
v/v.
06) An improved pharmaceutical composition as claimed in claims 1 to 5, where in the co-solvent(s) such as ethyl alcohol, propylene glycol polyethylene glycols having a nominal molecular weight of 200 to 600, N-methyl-2-pyrolidone, glycerol or a mixture thereof are employed.
07)An improved pharmaceutical composition as claimed in claims 1 to 6, where in the amount of co-solvent(s) ranges from 1.0 to 50.0% v/v, preferably from 15.0 to 30.0% v/v.

08)An improved pharmaceutical composition as claimed in claims 1 to 7 where in the solubilizing agents such as purified diethylene glycol monoethyl ether, cyclodextrins, glycerol monostearate, lecithin, poloxomer, polyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, stearic acid, citric acid, and ascorbic acid and the like; surface active agents such as polysorbates, sorbiton esters, polyvinyl olcohol, benzal konium chloride, benzithonium chloride, cetrimide docsate sodium, sodium lauryl syulphate, octoxynol and the like or a combination of these are employed.
09)An improved pharmaceutical composition as claimed in claims 1 to 8 where in the amount of solubilizing agents employed ranges from 1.0 to 30.0% w/v, preferably 5.0 to 15.0% w/v.
10) An improved pharmaceutical composition as claimed in claims 1 to 9 where in the solubility enhancers are selected from benzyl alcohol, DL-Methionine, nicotinamide, vanilin, caffine are employed.
11) An improved pharmaceutical composition as claimed in claims 1 to 10 where in the amount of solubility enhancers employed ranges from 1.0 to 20% w/v preferably 5.0 to 15.0% w/v.
12) An improved pharmaceutical composition as claimed in claims 1 to 11 where in the buffering agents such as diluted hydrochloric acid, sodium acetate, sodium acetate, glacial acetic acid, disodium hydrogen orthophosphate, potassium dihydrogen orthophosphate, orthophosporic acid and the like are employed.
13) An improved pharmaceutical composition as claimed in claims 1 to 12 where in the penetration enhancer such as ethyl alcohol, propylene glycol, N- methyl-2-pyrrolidone, bile salts, cyclodextrins, and a mixture of propylene glycol monolaurate and purified diethylene glycol monoethyl ether and the like is used.
14) An improved pharmaceutical composition as claimed in claims 1 to 13 where in the amount of penetration enhancers ranges from 0.1 to 25.0% v/v or w/v, preferably 5.0 to 13% v/v or w/v.
15) An improved pharmaceutical composition as claimed in claims 1 to 14 where in the stabilizing agent such as sodium metabisulphite, sodium bisulphite, disodium ethylene diamine terra acetic acid, ascorbic acid and the like is employed.
16)An improved pharmaceutical composition as claimed in claims 1 to 15 where in the amount of stabilizing agent ranges from 0. 01 to 0.5% w/v.

17) An improved pharmaceutical composition as claimed in claims 1 to 16, where in the antimicrobial preservatives such as benzyl alcohol, benzalkonium chloride, phenyl mercuric acetate, phenylethyl alcohol and the like are employed.
18) An improved pharmaceutical composition as claimed in claim 17 where in the amount of antimicrobial preservative employed ranges from 0.001 to 2.0% w/v.
19) An improved pharmaceutical composition as claimed in claims 1 to 18, where in the viscosity building agent such as hydrocollids such as hydroxypropyl methyl cellulose, poly acrylic acid and the like or water soluble polymers such as carbopol, sodium carboxy methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, various grades of polyvinylpyrrolidone i.e. K-15, K-30, K-60 and K-90 are employed.
20) An improved pharmaceutical composition as claimed in claims 19 where in the amount of viscosity building agent ranges from 0.1 to 5.0% w/v preferably 0.3 to 3.0% w/v.
21) A process for the preparation of improved pharmaceutical composition,
intended for nasal administration for the treatment of male erectile dysfunction
due to organic, psychogenic and mixed causes in the form of solution or
colloidal dispersion, which comprises a synergistic solution or colloidal
dispersion of sildenafil or its salt in the range of 2.5 to 25.0% w/v in a
"protogenic" solvent such as water, diluted hydrochloric acid, ascorbic acid in
the range of 10 to 80.0% v/v containing co-solvents in the range of 1.0 to 50.0%
w/v, solubilizing agents in the range of 1.0 to 30.0% w/v, Solubility enhancer in
the range of 1.0 to 20%, buffering agent in the range of 1.0 to 10.0% w/v,
penetration enhancers in the range of 0.1 to 25.0% v/v or w/v, stabilizing agents
in the range of 0.01 to 0.5% w/v, antimicrobial preservatives in the range of
0.001 to 2.0% w/v, viscosity building agent in the range of 0.1 to 5.0% w/v, and
the dispersion having a pH in the range of 3.0 to 8.0 and the composition filled
into containers fitted with a sparying device for nasal application.
22) A process where in the salt form of sildenafil employed is selected from the salt formed by reacting with ascorbic acid, citric acid, lactic acid, acetic acid, methyl sulphonic acid, succinic acid, maleic acid, sulfuric acid, hydrochloric acid, nitric acid, orthophosphoric acid, preferably ascorbic acid, methyl sulphonic acid and hydrochloric acid.
23) A process as claimed in claims 21 and 22 where in the amount of Sildenafil or its salt employed in the solution or dispersion ranges from 2.5 to 25.0% w/v, preferably form 5.0 to 20.0% w/v more preferably from 7.5 to 15.0% w/v.

24)A process as claimed in claim 21 and 23 where in the solvent such as water, diluted hydrochloric acid, diluted sulphuric acid, lactic acid and the like is employed.
25)A process as claimed in claim 21 and 24 where in the amount of solvent ranges from 10.0 to 80.0% v/v, preferably 20.0 to 60.0% v/v.
26)A process as claimed in claim 21 and 25 where in the co-solvent(s) such as ethyl alcohol, propylene glycol polyethylene glycols having a nominal molecular weight of 200 to 600, N-methyl-2-pyrolidone, glycerol or a mixture thereof are employed.
27)A process as claimed in claim 21 and 26 where in the amount of co-solvent(s) employed ranges from 1.0 to 50.0% v/v, preferably from 15.0 to 30.0% v/v.
28)A process as claimed in claim 21 and 27 where in the solubilizing agents such as purified diethylene glycol monoethyl ether, cyclodextrins, glycerol monostearate, lecithin, poloxomer, polyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, stearic acid, citric acid, and ascorbic acid and the like; surface active agents such as polysorbates, sorbiton esters, polyvinyl alcohol, benzalkonium chloride, benzithonium chloride, cetrimide docusate sodium, sodium lauryl syulphate, octoxynol and the like or a combination of these are employed.
29)A process as claimed in claim 21 and 28 where in the amount of solubilizing agents employed ranges from 1.0 to 30.0% w/v, preferably 5.0 to 15.0% w/v.
30)A process as claimed in claim 21 and 29 where in the solubility enhancers such as benzyl alcohol, DL-Methionine, nicotinamide, vanilin, caffine and the like is employed.
31)A process as claimed in claim 21 and 30 where in the amount of solubility enhancers employed ranges from 1.0 to 20% w/v preferably 5.0 to 15.0%
w/v.
32)A process as claimed in claim 21 and 31 where in the buffering agents such as diluted hydrochloric acid, sodium hydroxide, sodium acetate, glacial acetic acid, disodium hydrogen orthophosphate, potassium dihydrogen orthophosphate, orthophosporic acid and the like are employed.

33)A process as claimed in claim 21 and 32 where in the penetration enhancer such as ethyl alcohol, propylene glycol, N-methyl-2-pyrrolidone, bile salts, cyclodextrins, propylene glycol monolaurate in combination with purified diethylene glycol monoethyl ether and the like is employed.
34) A process as claimed in claim 21 and 33 where in the amount of penetration enhancers ranges from 0.1 to 25.0% v/v or w/v, preferably 5.0 to 13.0 % v/v or w/v.
35)A process as claimed in claim 21 and 34 where in the stabilizing agent such as sodium metabisulphite, sodium bisulphite, disodium ethylene diamine tetra acetic acid, ascorbic acid and the like is employed.
36)A process as claimed in claim 21 and 35 where in the amount of stabilizing agent employed ranges from 0. 01 to 0.5% w/v.
37)A process as claimed in claim 21 and 36 where in the antimicrobial preservatives such as benzyl alcohol, benzalkonium chloride, phenyl mercuric acetate, phenylethyl alcohol and the like are employed.
38)A process as claimed in claim 37 where in the amount of antimicrobial preservative ranges from 0.001 to 2.0% w/v.
39) A process as claimed in claim 21 and 38 where in the viscosity building agent such as hydrocollids such as hydroxypropyl methyl cellulose, poly acrylic acid and the like or water soluble polymers such as carbopol, sodium carboxy methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose various grades of polyvinylpyrrolidone i.e. K-15, K-30, K-60 and K-90.
40) A process as claimed in claim 39 where in the amount of viscosity building agent ranges from 0.1 to 5.0% w/v preferably 0.3 to 3.0% w/v.
41)The pharmaceutical composition as claimed in claims 1 to 40 where in the the composition is filled in the nasal delivery spraying device.
42) An improved pharmaceutical composition intended for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic, and mixed causes in the form of solution or colloidal dispersion substantially as herein described with reference to the examples 1 to 8.

13)A process for the preparation of an improved pharmaceutical composition intended for nasal administration for the treatment of male erectile dysfunction due to organic, psychogenic and mixed causes in the form of solution in colloidal dispersion substantially as herein described with reference to the examples 1 to 8.

Documents:

1128-mas-1999 abstract-duplicate.pdf

1128-mas-1999 abstract.pdf

1128-mas-1999 claims-duplicate.pdf

1128-mas-1999 claims.pdf

1128-mas-1999 correspondence-others.pdf

1128-mas-1999 correspondence-po.pdf

1128-mas-1999 description(complete)-duplicate.pdf

1128-mas-1999 description(provisional).pdf

1128-mas-1999 form-1.pdf

1128-mas-1999 form-11.pdf

1128-mas-1999 form-19.pdf

1128-mas-1999 form-3.pdf

1128-mas-1999 form-5.pdf

1128-mas-1999 pct search report.pdf

1128-mas-1999 pct.pdf

1128-mas-1999 petition.pdf

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Patent Number

218429

Indian Patent Application Number

1128/MAS/1999

PG Journal Number

21/2008

Publication Date

23-May-2008

Grant Date

01-Apr-2008

Date of Filing

18-Nov-1999

Name of Patentee

NATCO PHARMA LIMITED

Applicant Address

NATCO HOUSE, ROAD NO. 2 , BANJARA HILLS, HYDERABAD - 500 033,

Inventors:

#	Inventor's Name	Inventor's Address
1	RAMAKRISHNA RAO VALLABHANENI	NATCO PHARMA LIMITED, NATCO HOUSE, ROAD NO. 2, BANJARA HILLS, HYDERABAD - 500 033,

PCT International Classification Number

A61K 31/50

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA