WO2002102385A1

WO2002102385A1 - Compositions comprising cgmppde5 inhibitor for transdermal delivery to the erectile tissue of the penis

Info

Publication number: WO2002102385A1
Application number: PCT/IN2001/000210
Authority: WO
Inventors: Sampad Bhattacharya; Kiran Kumar Tumbalam
Original assignee: Sampad Bhattacharya; Kiran Kumar Tumbalam
Priority date: 2001-06-14
Filing date: 2001-11-27
Publication date: 2002-12-27
Also published as: EP1404336A1

Abstract

The invention relates to a pharmaceutical composition comprising cyclic guanosine monophosphate phosphodiesterase type 5 (cGMP PDE5) inhibitor, sildenafil citrate, pharmaceutically acceptable solubilisers and penetration enhancers, along with thickening agents, buffers, emulsifiers and pharmaceutically acceptable surfactants and preservatives, for transdermal delivery to the erectile tissue of the penis, a process of preparing the said composition and method for treatment of erectile dysfunction / vasculogenic impotence by direct/topical application of the transdermal composition to the tissues covering the corpus cavernosum and to the glans penis. The transdermal delivery vehicle for topical application of the composition according to this invention may be in various forms such as gels, ointments, creams, lotions, emulsions and sprays.

Description

COMPOSITIONS COMPRISING cGMPPDE5 INHIBITOR FOR TRANSDERMAL DELIVERY TO THE ERECTILE TISSUE OF THE PENIS

FIELD OF THE INVENTION

The invention relates to a pharmaceutical composition comprising cyclic guanosine monophosphate phosphodiesterase type 5 (cGMP PDE5) inhibitor, sildenafil citrate, pharmaceutically acceptable solubilisers and penetration enhancers, along with thickening agents, buffers, emulsifiers and / surfactants and preservatives, for transdermal delivery to the erectile tissue of the penis, a process of preparing the said composition and method for treatment of erectile dysfunction / vasculogenic impotence by direct/topical application of the transdermal composition to the tissues covering the corpus cavernosum and to the glans penis. The transdermal delivery vehicle for topical application of the composition according to this invention may be in various forms such as gels, ointments, creams, lotions, emulsions and sprays.

BACKGROUND ART:

In erectile dysfunction there is a consistent inability to achieve or sustain an erection of sufficient rigidity for sexual intercourse, which may be manifested in many ways, and the causes can be vasculogenic, neurogenic, endocrinoiogic and psychogenic.

Vasculogenic impotence is thought to be the frequent cause of impotence. In vascular insufficiency, blood flow in the vasculature of the penis is insufficient to obtain and / or maintain an erect state.

The use of l-[[3-(6,7-dihydro-l-methyl-7-oxo-3-propyl-lH-pyrazolo [4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate as a potent and selective inhibitor of cyclic guanosine monophosphate phosphodiesterase type 5 (cGMP PDE5) is well known.

Administration of cGMP PDE5 inhibitors block the action of endogenous cGMP PDE5 which causes increased levels of cGMP in the corpus cavernosum tissue of penis resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum and subsequent erection.

In the prior art compositions comprising sildenafil citrate are known wherein the dosage forms used for administration of active ingredients in patients are tablets for oral administration, nasal spray, buccal delivery, and rectal delivery.

The side effects associated with oral administration in the form of tablets is well known and documented, which are Headache, Colour vision, Priapism or painful erections which last for longer periods than required and also pose enormous risks in patients with cardiac disease and stroke.

In case of Nasal administration, the very route of administration limits the amount of the active ingredient, which can be made available to render any pharmacological effect. The anatomy of the nose does not permit for administration of compositions upwards of 150 microlitres. Moreover the intended effect is achieved by the drug entering the systemic circulation at a site which is far form the site of action, which necessitates increasing amounts of drug to be administered which is likely to cause the same side effects associated with oral drug therapy as only very potent drugs are normally effectively administered via the Nasal route for any systemic effect.

In case of Buccal and Rectal administration the amount of active ingredient that can be made available is not limited as in case of Nasal spray, but since therapeutic levels of drug in the blood achieve the intended effect, the associated side effects will manifest in a similar fashion as in case of Oral therapy.

Thus the administration of all the prior Art compositions comprising cGMP PDE5 inhibitors sildenafil citrate by oral, buccal, sublingual or nasal methods have different drawbacks.

OBJECT OF THE INVENTION:

The main object of this invention is to provide a new different method and pharmaceutical composition comprising cGMP PDE5 inhibitor in combination with transdermal delivery vehicles for treating erectile dysfunction in patients by topical application directly to the tissues covering the corpus cavernosum and to the glans penis so that even a small amount of active ingredient that penetrates through the tissue layers covering the corpus cavernosum is enough to elicit the required pharmacological response and there is a scope for almost nil or very negligible amounts of the active ingredient to reach the systemic circulation, thus avoiding all ^" possible side effects.

Another object of this invention is to provide a new and different method and composition for treating of erectile dysfunction, which addresses the need of different patients more particularly in patients with cardiac, and stroke risks.

Further object of this invention is to provide a new and different method and composition for treatment of erectile dysfunction which improves the quality of life in patients who might suffer from side effects like colour vision or headache.

Further object of this invention is to provide a new and different method and composition for treatment of erectile dysfunction, which permits rapid response and eliminates the waiting period i.e. is associated with oral and any other therapy know in the prior art.

SUMMARY OF THE INVENTION:

The present invention relates to pharmaceutical compositions which include a therapeutically effective amount of sildenafil citrate solubilised or dispersed in pharmaceutically acceptable solubilisers and penetration enhancers, along with the thickening agents, buffers, emulsifiers and pharmaceutically acceptable surfactants and preservatives as will be appreciated by those skilled in the art of drug formulation, preparation and delivery, to provide a method for safely and conveniently administering cGMP PDE5 inhibitor sildenafil citrate in patients for treatment of erectile dysfunction.

The method comprises direct administration of an effective amount of sildenafil citrate to the penis to produce an erection sufficient to permit intercourse.

The invention provides a method of treating erectile dysfunction. This method includes administering to the tissues covering the corpus cavernosum and to the glans penis a therapeutically effective dosage of cGMP PDE5 inhibitor sildenafil citrate in combination with a transdermal delivery vehicle that includes solubilisers, penetration enhancers, thickening agents, surfactants and preservatives.

Preferred formulations for transdermal use herein are gels, ointments, creams, lotions, emulsions and sprays. All these preparations contain solubilisers by which cGMP PDE5 inhibitor sildenafil citrate is in a solubilised or dispersed form and penetration enhancers, which will facilitate therapeutic drug concentrations at the site of action, the corpus cavernosum tissue of the penis.

A topical application dosage unit for transdermal delivery is provided for treating erectile dysfunction in patients. This dosage unit includes an effective amount of a cyclic guanosine monophosphate phosphodiesterase inhibitor in combination with a topical application formulation for transdermal delivery. These formulations contain pharmaceutically acceptable solubilisers, penetration enhancers, thickening agents, buffers, emulsifiers, surfactants and preservatives.

The solubilisers, penetration enhancers and surfactants are selected to facilitate effective concentration of sildenafil citrate at the site of action, the corpus cavernosum tissue of penis. DETAILED DESCRIPTION OF THE INVENTION:

The present invention is directed to pharmaceutical compositions and methods for treating erectile dysfunction in patients. The compositions include a cyclic guanosine monophosphate phosphodiesterase type 5 inhibitor in combination with a transdermal delivery vehicle.

The term "erectile dysfunction" is indicated to involve medically related symptoms resulting in the inability of a male to perform sexually including impotence. The term "impotence" is used to indicate an inability to achieve or sustain an erection of sufficient rigidity for vaginal penetration and sexual intercourse.

The term "phosphodiesterase inhibitor" as used herein is intended to mean an agent that is capable of inhibiting or selectively reducing the activity of any one or more phosphodiesterases. Desirably the phosphodiesterase inhibitor is sildenafil citrate also known as l-[[3-(6,7-dihydro-l-methyl-7-oxo-3-propyl-lH-pyrazolo [4,3-d] pyrimidin- 5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate. The term "transdermal" delivery includes both transdermal (percutaneous) and transmucosal administration i.e. delivery of a drug by passage through the skin or mucosal tissue, and is also intended to include delivery of a drug by passage across scrotal tissue, wherein the transdermal delivery is achieved by topical application of the pharmaceutical compositions in a sufficient quantity to the skin of the penis and by application to the tissues covering the corpus cavernosum and to the glans penis which are exposed when the foreskin of the penis is retracted and folded back.

The term "penetration enhancers" used herein relates to an increase in the permeability of the skin of the penis and the tissues covering the corpus cavernosum and the glans penis to the cGMP PDE5 inhibitor.

The term "effective" amount used herein is intended to mean a sufficient amount of the cGMP PDE5 inhibitor to provide the desired effect i.e. treatment of erectile dysfunction.

The term "delivery vehicle" used herein refers to carrier materials suitable for topical application for transdermal delivery. Carriers or vehicles used herein include any such material known in the art which are nontoxic and do not interact with other components of the composition in a deleterious manner.

The term "topical application" is used to mean external application to the skin or mucosa of the composition to ultimately deliver transdermally cGMP PDE5 inhibitor to the site of action, the corpus cavernosum tissue of the penis.

The transdermal delivery vehicles for topical application can take various forms including for example, gels, ointments, creams, lotions and sprays.

The various forms of the delivery vehicle are made by solubilising or dispersing Sildenafil Citrate in pharmaceutically acceptable solubilisers and can include pharmaceutically acceptable penetration enhancers, thickening agents, emulsifiers, surfactants and preservatives.

The solubilisers in the delivery vehicle of the present invention that can be used include for example diethyleneglycol monoethyl ether, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, dimethyl isosorbide, 2-pyrrolidone, N-methyI-2- pyrrolidone, propylene glycol, glycerin, and mixtures thereof. The concentration of the solutions will depend upon the type of delivery vehicle selected. Such agents will also be used as penetration enhancers in the delivery vehicle of the present invention.

The viscosity of the delivery vehicles of the present invention can be maintained at a desired level using pharmaceutically acceptable thickening agents. Thickening agents that can be used in accordance with the present invention include carbomer, cetostearyl alcohol, stearic acid, polyethylene glycols, poloxamers, paraffins, stearyl alcohols, polyvinyl alcohol, polycarbophils, methyl hydroxy ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, microcrystalline wax, and mixtures thereof. The concentration of the thickening agent will depend upon the type of delivery vehicle selected and the viscosity desired. The emulsifiers, in the delivery vehicles of the present invention that can be used include polyoxyl-35 castor oil, cetomacrogol 1000, glyceryl stearate and polyethylene glycol 75 stearate, polyoxyl 40- hydrogenated castor oil, polyethylene glycol-6-32 stearate and glycol stearate, polysorbate 80 and mixtures thereof. The concentration of the emulsifiers will depend upon the type of delivery vehicle selected. Such agents can also be used as surfactants and may be present in a concentration ranging from about 0.001 to 30% by weight.

In the present invention, other optional ingredients may also be included into the transdermal delivery vehicle provided they do not interfere with the action or decrease the penetration of the inhibitor. Such pharmaceutically acceptable excipients may be preservatives.

Preservatives that can be used with the present delivery vehicles include methyl paraben, propyl paraben, ethyl paraben, butyl paraben, sodium benzoate and combinations thereof. The preservatives will be present in the present delivery vehicles in a concentration of upto about 0.6% by weight.

In another embodiment of the present invention, the composition, as described above are applied topically to the skin of the penis and to the tissues covering the corpus cavernosum and glans penis when the foreskin is retracted and folded, to treat erectile impotence. For purpose of the present invention, "applied topically" or "topical application" is intended to mean that the cGMP PDE5 inhibitor is combined with a suitable delivery vehicle for transdermal delivery or absorption to the corpus cavernosum tissue of the penis.

Another embodiment of the present invention is topically applied composition for transdermal delivery which may include a therapeutically, effective amount of cGMP PDE5 inhibitor solubilised or dispersed in a pharmaceutically acceptable solubilisers, thickening agents and pharmaceutically acceptable emulsifiers and surfactants. "Therapeutically significant" amount as used herein means a unit dosage of the present vehicle to be applied to the skin of the penis and the tissues covering the corpus cavernosum of the penis in patients to render the intended physiological effect i.e. to allow an erection in impotent patients.

The cGMP PDE5 inhibitor is desirably l-[[3-(6,7-dihydro-l-methyl-7-oxo-3-propyl- lH-pyrazolo [4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate. In a further embodiment of the present invention a method for treating impotence includes topical application to the penis for transdermal delivery through the tissues covering the corpus cavernosum and glans penis a therapeutically effective dosage of cGMP PDE5 inhibitor in combination with a transdermal delivery vehicle. The inhibitor used herein is sildenafil citrate.

A further embodiment of the present invention, include a transdermal delivery dosage unit by topical application for treating impotency in patients. This transdermal delivery dosage unit includes an effective amount of cGMP PDE5 inhibitor, sildenafil citrate in combination with pharmaceutically acceptable delivery vehicle. This delivery vehicle includes solubilisers, penetration enhancers, thickening agents and pharmaceutically acceptable surfactants and preservatives. The pH of the delivery vehicle is selected so as to facilitate cGMP PDE5 inhibitor permeation through the tissue covering the corpus cavernosum and the glans penis, and is adjusted between 4 to 8 by selecting the concentration of the buffers and mixtures thereof. Buffers that may be suitable for use in the present invention include for example phosphate, acetate, citrate, citrophosphate and tris buffers.

Depending upon the exact nature of the dosage form required the pharmaceutically acceptable carrier would be different. Suitable dosage forms developed with the present cGMP PDE5 inhibitor, sildenafil citrate are found in Remingtons pharmaceutical sciences 19^th edition, which is incorporated by reference, and include gels, ointments, creams, lotions and sprays.

Range of Excipients

Process of preparing the composition according to this invention comprises the following steps: i. Sildenafil Citrate is solubilised or dispersed in a mixture of solvents, co- solvents and/or penetration enhancers as herein described, the preservatives as herein described are further dissolved in the same; ii. The thickening agent as herein described are melted by heating or dispersed in Purified Water as the case may be; iii. The solution of step 1 is mixed with the thickening agent as herein described properly to obtain a homogenous mixture; iv. Adequate buffering agents and/or pH adjusting agent as herein described are added slowly to the above and mixed properly; v. Where necessary the congealed mass of Ointment or Cream may be homogenised or passed through a Colloidal mill and again mixed properly; vi. The finished product is then filled in different dosage units.

Examples: Example: 1

A preferred embodiment was prepared by solubilising the cGMP PDE5 inhibitor, Sildenafil Citrate 2.8 g in a mixture of 2-pyrrolidone 30 g, N-methyl 2-pyrrolidone 5 g, Polyoxyl 40 Hydrogenated Castor Oil 2g. Added Methyl Paraben 0.1 g, Propyl Paraben 0.01 g to the above mixture and stirred to dissolve. Added Poloxamer to Purified Water and stirred to dissolve and mixed the above solution under stirring to form a Gel. The gel was filled in tubes and jars.

Example: 2

In a preferred embodiment solubilised the cGMP PDE5 inhibitor, Sildenafil Citrate 2.8 g in a mixture of 2-pyrrolidone 25 g, N-methyl 2-pyrrolidone 10 g, Polyoxyl 40 Hydrogenated Castor Oil 2 g, Added Methyl Paraben 0.1 g, Propyl Paraben 0.01 g to the above mixture and stirred to dissolve. Dispersed Carbomer 934 P 0.4 g in Purified Water and to it, added the above solution and stirred. Heating Cetostearyl Alcohol 4 g and Stearic Acid 1 g to 70 degree Centigrade. Mixed the mixture of Carbomer - Sildenafil Citrate with the mixture of Cetostearyl Alcohol and Stearic Acid and stirred rapidly. Adding Triethanolamine 0.2 g drop by drop and continued stirring. Homogenised the mixture for a few minutes and stirred till the soft mass attained ambient temperature to congeal into a Creamy Gel.

Example: 3

Solubilised cGMP PDE5 inhibitor, Sildenafil Citrate 2.8 g in a mixture of N-methyl 2- pyrrolidone 25 g, Propylene Glycol 3 g, Added Methyl Paraben 0.1 g, Propyl Paraben 0.01 g to the above and stirred to dissolve, Added Purified Water to the above and heated to 60 degree centigrade, Heated a mixture of Cetostearyl Alcohol 5.6 g, Cetomacrogol-1000, 1.5 g, White Soft Paraffin 5 g and Liquid Paraffin 5 g to 65 degree centigrade, Mixed both the aqueous and oily phases and stirred continuously till the mixture cooled and formed the Cream.

Example: 4

In another preferred embodiment solubilised the cGMP PDE5 inhibitor, Sildenafil Citrate 2.8 g in 2-pyrrolidone 25 g, Heated Polyethylene Glycol 4000, 23 g and Polyethylene Glycol 400, 49.09 g to 70 degree centigrade, Added methyl Paraben 0.1 g and Propyl Paraben 0.01 g and the solution of sildenafil Citrate and stirred continuously till the mixture congealed. Passed the entire mass through a Colloidal mill and mixed homogenously. The Ointment thus obtained was filled in tubes and jars.

Example: 5

Solubilised Sildenafil Citrate 2.8 g in a mixture of 2-pyrrolidone 30 g, Diethylene Glycol Monoethyl Ether 10 g, Glycerin lOg and added Methyl Paraben 0.1 g and Propyl Paraben 0.01 g and stirred to dissolve, Dispersed Carbomer 980 0.4 g, in Purified Water and to it added the above solution and stirred well, Added Triethanolamine 0.2 g drop by drop under continuous stirring and mixed properly. The Lotion was filled in containers.

Example : 6 A preferred embodiment was prepared by solubilising the cGMP PDE5 inhibitor, Sildenafil Citrate 2.8 g in a mixture of 2-pyrrolidone 30 g, N-methyl 2-pyrrolidone 5 g, Polyoxyl 40 Hydrogenated Castor Oil 2 g. Added Methyl Paraben 0.1 g, Propyl Paraben 0.01 g to the above mixture and stirred to dissolve. Added Poloxamer to Purified Water and stirred to dissolve. Added 20 ml of Acetate Buffer pH 4 to the drug solution and mixed. Mixed the drug solution containing buffer with dispersion of Poloxamer under stirring to form a Gel. The gel was filled in tubes and jars.

Example: 7 Solubilised cGMP PDE5 inhibitor, Sildenafil Citrate 2.8 g in a mixture of N-methyl 2- pyrrolidone 25 g, Propylene Glycol 3 g. Added Methyl Paraben 0.1 g, Propyl Paraben 0.01 g and 15 ml of Citro-phosphate buffer pH 5 to the above and stir. Added Purified Water to the above and heated to 60 degrees centigrade. Heated a mixture of Cetostearyl Alcohol 5.6. g, Cetomacrogol-1000, 1.5 g, White Soft Paraffin 5 g and Liquid Paraffin 5 g to 65 degree Centigrade. Mixed both the aqueous and oily phases and stirred continuously till the mixture cooled and formed the Cream.

Test reports

+ - Not Good

++ - Satisfactory +++ - Good ++++ - Very Good Justifications of the invention (Topically applied delivery vehicles comprising sildenafil citrate for transdermal delivery to the erectile tissue of the penis) are given below.

The invention relates to a new and different method and compositions for treatment of erectile dysfunction which addresses the needs of different patients more particularly in patients with cardiac, and stroke risks where oral or other types of administration pose enormous risk and also helps improve the quality of life in patients who might suffer from side effects like Colour vision or Headache.

2. The invention allows direct application of the transdermal preparation to the tissues covering the corpus cavernosum and to the glans penis.

The preparation contains penetration enhancers, which will facilitate effective concentrations of Sildenafil Citrate at the site of action i.e. the corpus cavernosum.

The site of action of sildenafil Citrate for erectile dysfunction is the corpus cavernosum in the penis.

In case of topically applied preparations for transdermal delivery, the amount of active ingredient that normally permeates across the dermal and subdermal tissues is one-tenth to two tenths of the amount applied. In the proposed invention as the composition is applied directly to the intended site of action, even a small amount of active ingredient that permeates through the tissue layers that cover the corpus cavernosum, is enough to elicit the required pharmacological response. Also there is scope for almost nil or very negligible amounts of the active ingredient to reach the systemic circulation, thus avoiding all possible side effects

6. As Sildenafil Citrate has been classified broadly as a drug that has changed the life style of various patients, suffering from vassculogenic impotence the method of administration permits rapid response and eliminates the waiting period that is associated with oral and any other therapy.

7. It has been found that the cGMP PDE5 inhibitor in a transdermal delivery vehicle which when applied topically to the penis, the desired effect is achieved within 30 minutes or less as compared to 1 hour or longer for other routes. The present invention described in conjunction with the preferred embodiments, and also the examples are intended to illustrate rather than to limit the scope of the invention. The invention may be varied in many ways and all such modifications are intended to be included within the scope of the following claims.

Claims

CLAIMS: L A pharmaceutical composition for transdermal delivery to the erectile tissue of the penis for treatment of erectile dysfunction comprising cyclic guanosine monophosphate phosphodiesterase type 5 (cGMP PDE5) inhibitor in combination with pharmaceutically acceptable transdermal delivery for topical application to the skin of the penis and the tissue covering corpus cavernosum and glans penis.

2. The pharmaceutical composition as claimed in claim 1, wherein the said cGMP PDE5 inhibitor is selected from the group consisting of sildenafil citrate.

3. The pharmaceutical composition as claimed in claim 1, wherein the said cGMP PDE5 inhibitor is l-[[3-(6,7-dihydro-l-methyl-7-oxo-3-proρyl-lH- pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfony]-4-methylpiperazine citrate.

4. The pharmaceutical composition as claimed in claim 1, wherein the said transdermal delivery vehicle for topical application comprises pharmaceutically acceptable solubiliser(s) and/or penetration enhancer(s), thickening agent(s) and surfactant(s)/emulsifier(s).

5. The pharmaceutical composition as claimed in claim 4 further comprising one or more pharmaceutical excipients.

6. The pharmaceutical composition as claimed in claim 5 further comprising a buffer to maintain the pH.

7. The pharmaceutical composition as claimed in 5 further comprising a pharmaceutically acceptable preservative.

8. The pharmaceutical composition as claimed in claim 4 wherein the said solubiliser(s) and/or penetration enhancer(s) are selected from the group consisting of diethyleneglycol monoethyl ether, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, dimethyl isosorbide, 2-pyrrolidone, N- methyl-2-pyrrolidone, propylene glycol, glycerin and mixtures thereof.

9. The pharmaceutical composition as claimed in claim 4, wherein the said thickening agent(s) is selected from the group consisting of carbomer, stearic acid, cetostearyl alcohol, polyethylene glycols, poloxamers, paraffins, stearyl alcohols, polyvinyl alcohol, polycarbophils, methyl hydroxy ethyl cellulose, hydroxypropyl methyl cellulose, carbomethyl cellulose sodium, hydroxypropyl cellulose microcrystalline wax and mixtures thereof.

10. The pharmaceutical composition as claimed 4, wherein the said surfactant(s)/emulsifiers is selected from the group consisting of cetomacrogol 1000, glyceryl stearate and polyethylene glycol 75 stearate, polyethylene glycol-6-32 stearate and glycol stearate, polysorbate-80, polyoxyl-35 castor oil, polyoxyl-40-hydrogenated castor oil and mixtures thereof.

11. A pharmaceutical composition as claimed in claim 6 wherein the pH of the composition is from about 4 to 8.

12. The pharmaceutical composition as claimed in claim 6 wherein the said buffer for adjusting and maintaining the pH are selected from phosphate, acetate, citrophosphate, citrate and tris and mixtures thereof.

13. A process of preparing the pharmaceutical composition as claimed in claim 1 comprising the following steps: i. Sildenafil Citrate is solubilised or dispersed in a mixture of solvents, co-solvents and/or penetration enhancers as herein described, the preservatives as herein described are further dissolved in the same; ii. The thickening agent as herein described are melted by heating or dispersed in Purified Water as the case may be; iii. The solution of step 1 is mixed with the thickening agent as herein described properly to obtain a homogenous mixture; iv. Adequate buffering agents and/or pH adjusting agent as herein described are added slowly to the above and mixed properly; v. Where necessary the congealed mass of Ointment or Cream may be homogenised or passed through a Colloidal mill and again mixed properly; vi. The finished product is then filled in different dosage units.

14. The process as claimed in claim 13 wherein the said solvents and/or penetration enhancers are from 0.2 to 35%, the said thickening agents are from 0.2 to 60% and the said preservatives are from 0.001 to 0.6%.

15. A method of treatment of erectile dysfunction/impotence in male patients comprising transdermally administering the pharmaceutical composition of claim 1 by topical application to the skin of the penis and the tissues covering the corpus cavernosum and glans penis which is exposed when the foreskin of the penis is retracted and folded back.

16. A topically applied pharmaceutical composition for transdermal delivery comprising a therapeutically effective amount of a cyclic guanosine monophosphate phosphodiesterase type 5 inhibitor solubilised or dispersed in pharmaceutically acceptable solubilisers and penetration enhancers, pharmaceutically acceptable thickening agents, emulsifiers and surfactants.

17. A topically applied pharmaceutical composition for transdermal delivery of claim 2, wherein the said cGMP PDE5 inhibitor is l-[[3-6,7-dihydro-l- methyl-7-oxo-3-propyl-lH-pyrazolo [4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfony]-4-methylpiperazine citrate.

18. A method of treating impotence in patients in need of such treatment comprising administering to the skin of the penis and the tissues covering the corpus cavernosum and to the glans penis for transdermal delivery to the corpus cavernosum tissue of the penis, a therapeutically effective dosage of cGMP PDE5 inhibitor in combination with a transdermal delivery vehicle comprising pharmaceutically acceptable solubilisers and penetration enhancers; thickening agents, buffers, emulsifiers surfactants and preservatives.

19. A method of administering a therapeutically effective amount of a cGMP PDE5 inhibitor to patients by topical application of a transdermal delivery vehicle comprising pharmaceutically acceptable solubilisers, penetration enhancers, thickening agents, buffers, emulsifiers, surfactants and preservatives.

20. The method of claim 19, wherein the said inhibitor is effective for the treatment of erectile dysfunction in patients.

21. A topical application dosage unit for transdermal delivery for treating impotence in patients comprising an effective amount of cGMP PDE5 inhibitor sildenafil citrate in combination with a transdermal delivery vehicle for topical application comprising pharmaceutically acceptable solubilisers, penetration enhancers, whose concentration is selected to enhance penetration of the said inhibitor and to produce an erection sufficient to permit intercourse within 30 minutes of applying the said dosage unit to the skin of the patient's penis and to the tissues covering corpus cavernosum and to the glans penis when the foreskin of the patient's penis is retracted and folded back.

22. The topical application dosage unit for transdermal delivery as claimed in claim 21, wherein the transdermal delivery vehicle is selected from a group consisting of gels, ointments, creams, lotions and sprays.

23. The topical application dosage units for transdermal delivery as claimed in claim 22, further comprising pharmaceutically acceptable preservatives.

24. The topical application dosage unit for transdermal delivery of claim 22, further comprising pharmaceutically acceptable thickening agents.

25. The topical application dosage unit of claim 22 for transdermal delivery wherein the pH of the delivery vehicle is selected so as to facilitate penetration of the said inhibitor and is adjusted by selected the concentration of the buffers and mixtures thereof, to produce an erection of the penis within 30 minutes of applying the said dosage unit to the skin of the patients penis, and to the tissues covering the corpus cavernosum and to the glans penis which are exposed when the foreskin of the patient's penis is retracted and folded back.