Title of Invention	A NOVEL AND NON-INVASIVE PHARMACEUTICAL COMPOSITION USEFUL FOR THE TREATMENT IN SEXUAL IMPOTENCE, AND A PROCESS FOR PREPARING THE SAID COMPOSITION
Abstract	The invention disclosed in this application relates to a novel and non-invasive pharmaceutical composition in form of a soft gel capsule useful for the treatment of male erectile dysfunction which comprises of a gelatin capsule incorporating a composition comprising of a complex of Alprostadil and cyclodextrins mixed with Caprylocaproyl macrogol -8 glycerides or diethylene glycol mono ethyl ether or their mixtures dispersed in a suitable pharmaceutical vehicle and hydroxypropyl methylcellulose phthalate as a film forming material. This invention also discloses a process for the preparation of the above said composition.

Title of Invention

A NOVEL AND NON-INVASIVE PHARMACEUTICAL COMPOSITION USEFUL FOR THE TREATMENT IN SEXUAL IMPOTENCE, AND A PROCESS FOR PREPARING THE SAID COMPOSITION

Abstract

The invention disclosed in this application relates to a novel and non-invasive pharmaceutical composition in form of a soft gel capsule useful for the treatment of male erectile dysfunction which comprises of a gelatin capsule incorporating a composition comprising of a complex of Alprostadil and cyclodextrins mixed with Caprylocaproyl macrogol -8 glycerides or diethylene glycol mono ethyl ether or their mixtures dispersed in a suitable pharmaceutical vehicle and hydroxypropyl methylcellulose phthalate as a film forming material. This invention also discloses a process for the preparation of the above said composition.

Full Text	The present invention relates to a novel and Non-invasive Pharmaceutical composition useful for the treatment in male sexual impotence. The present invention particularly relates to a pharmaceutical composition containing the drug Alprostadil (otherwise IcnoAvn as prostaglandin Ei). The present invention also relates to a process for the preixn ation of the above said pharmaceutical composition Background of the invention: The term "impotence" has been used in this specification to signify the inability of the male to attain and maintain erection of the penis sufficient to permit satistactory sexual intercourse. The term "erectile dysfunction" has been suggested as a more precise term "to signify an inability of the male to achieve an erect penis as part of the overall muhifaceted process of male sexual function." Droller, MJ. et. al. Impotence. Consensus Development Conference Statement, National Institutes of Health (1993). Erectile dysfunction may result from psychological causes (psychogenic erectile dysfunction) or organic causes or a combination of both. Organic causes include physiological, nervous, vascular and hormonal pathologies or a combination thereof. The normal physiology of an erection involves nerve impulses, which signal certain muscles to relax. These muscles, when contracted, restrict blood flow through arteries in the penis. When relaxed, the muscles permit a significant increase in blood lltiw. The increased blood flow engorges three groups of erectile tissue within the penis with blood and the penis becomes less flaccid. The engorged erectile tissue and the muscle stiiicture of the penis depress adjacent veins, restricting the flow of blood out oi^ the i^enis. The restriction of blood flow out of the penis increases and sustains the erection Deficiencies of some hormones, such as testosterone, or elevation of otheis, such as prolactin, can cause erectile dysfunction. Many drugs, such as diuretics, anti hypertensives, anticonvulsants, narcotics, alcohol, and psychotropic drugs may cause erectile dystUnction as a side effect. Murray, F, T. et al. Amer. J. Medical Sci. 309: 99 - 109 (1995) Alprostadil (otherwise known as prostaglandin Ei) is a derivative of prostanoic acid, a 20-carbon atom lipid acid of the formula. q This drug is commercially available, e.g., from Chinoin Pharmaceutical and ( hemical Works Ltd. (Budapest, Hungary) under the designation 'Alprostadil IJSP\ from Pharmacia and Upjohn under the designation "Caverject" and from The Upjohn Company (Kalamazoo, Mich.) under the designation "Prostin VR". Damage to nerves and blood vessels may also provide an organic cause lor erectile dysfunction. Disease processes may involve several aspects. For example, diabetes, which causes damage to both nerves and blood vessels, can cause erectile dysllinction. A significant percent of all diabetic men will suffer from erectile dysfunction Methods proposed for the treatment of erectile dysfunction have included external devices, sex therapy, surgical implantation of internal prostheses, injection of drugs directly into the penis and topically applied medications. External devices include tourniquets (see U.S. Pat. No.2, 818,855) and externally applied vacuum erection aids. While some clinicians consider externally applied ereciion aids as a first option for treatment, some patients are unwilling to use such devices 0 Keefe, M., et al. Medical Clinics of North America 79: 415 - 434 (1995). External devices such as tourniquets and externally applied vacuum erection aids used for improving the erection have not been successflil due to the unwillingness ol' the patients to use such devices. Other devices such as surgically implanted mechanieai devices, such as hinged or solid rods and inflatable, spring driven or hydraulic prostheses used for similar purpose are not favored due to the penile pain and the localized damage to the penile tissue that may result with the application. A number of injectable products for the treatment of erectile dysfunction are available commercially for injecting into the penile tissue. For example US Pat. No 4J 27,1 18 to La Torre discloses an injectable vasodilator, Patent No. CA 2344435 describes an injectable mixture of the drugs Phentolamine mesylate. Papaverine hydrochloride and Alprosiadil in a suitable buffer and patent no. EP 0459377A2 refers to an injection of Alprostadil As per Martindale (The Extra Pharmacopoeia, 33^^ Edition) a major disadvantage of this method is the need for repeated self- injection of the penis and studies siiygesi that the long-term use may result in fibrosis and that priapism may also be a problem In one commercially available form (MUSE®, Vivus, Menlo Park Calit), /\l\|)iostadil is administered in a pellet deposited in the urethra using an applicator with a hollow stem 3.2 cm in length and 3.5mm in diameter. Martindale (The Extra Pharmacopoeia, 33"' lidition) reports that the common side effects include penile pain and urethral pain ov burning with this usage. Patent N0.US6, 323,241 Bl provides methods and compositions for the treatment of erectile dysfunction by the intranavicular application of pharmaceutical eonipositions to the mammalian penis. The composition comprises a vasodilator, preferably pii^siaglandin El, a penetration enhancer, a polysaccharide gum, a lipophilic compound, and an acidic buffer system. While the patent claims a number of advantages over plaeing such composition intranavicularly into the penis, the system may be expensive lo produce besides having problems of disposal due to the applicator used is non-biodegradable Working alone most drugs, prostaglandin formulations included, do not snniciently permeate the skin to provide drug concentration levels comparable to those obtained from other drug delivery routes. To overcome this problem, topical drugs formulations typically include skin permeability facilitators. Keeping in view of the limitations of the hitherto known methods and deviees we observed that if a simple and viable application which facilitates easy administration is ])rovided it can lead to increased tolerance and compliance by delivering the active medieament at an appropriate place with ease. Moreover such a process / device will also have a large-scale production capacity. It will have the tlexibility ot ease ot portability lead nig u) better compliance. The product if made extremely environmental friendly by making il totally biodegradable it will have additional advantages, which may not be the case with the earlier applications described in the literature. Comparatively the product / method may be less expensive than the present day used method / product. Till date, there is no such process / product which is commercially available in soft gelatin capsules. As a much simpler and more acceptable alternative, we have aimed to develop a soft gelatin capsule containing a pharmaceutically active topical composition oi" the drug prostaglandin El (more commonly known as Alprostadil) complexed with permeability facilitators in an emulsified and suitably buffered base with appropriate stabilizers and preservatives and which may contain optionally colouring agents and flavoring agents. Accordingly the main objective of the present invention is to provide a novel and Non¬invasive pharmaceutical composition in the form of a soft gelatin capsule containing prostaglandin El (Alprostadil) which is useful in the treatment oi male erectile dysfunction. Another objective of the present invention is to provide a novel and Non-invasive pharmaceutical composition in the form of soft gelatin capsules containing prostaglandin El (Alprostadil) which is useful in the treatment of male erectile dysfunction and which facilitates easy administration of the drug at an appropriate place with ease Still another objective of the present invention is to provide a novel and Non-invasive pharmaceutical composition in the form of a soft gelatin capsule containing prostaglandin El (Alprostadil) which is useful in the treatment of male erectile dysfunction, llexibility in ease of portability leading to better compliance. Yet another objective of the present invention is to provide a novel and NcM>invasive pharmaceutical composition containing a prostaglandin El (Alprosiadil) which is complexed with cyclodextrins such as a, P , y - cyclodextrins or derivatives there of which enhances the drug's solubility and hence improves the drug availability Still another objective of the present invention is to provide a novel and Non-invasive pharmaceutical composition in the form of a soft gelatin capsule containing prostaglandin El (Alprostadil) which is useful in the treatment of male erectile dysfunction and which is extremely environmental friendly and biodegradable. Still another objective of the present invention is to provide a novel and Non-nivasive pharmaceutical composition which is in the form of a soft gelatin capsule containing prostaglandin El (Alprostadil) and which contains hydroxy propyl methyl cellulose phthalate as a film forming material which provides adequate stiffness for the soCt gelatin capsule for easy entry into the urethra as well as prevents breakage of the capsule while being used. Still another objective of the present invention is to provide a novel and Non-invasive pharmaceutical composition containing prostaglandin El (Alprostadil) which also contains Caprylocaproyl macrogol - 8 glycerides (commercially available as labrosol) or diethylene glycol monoethyl ether (commercially known as Transcutol P) or their mixtui es to improve the permeation of the drug, prostaglandin El. By the term "Non-invasive" it meant to refer to administration of drug, without milicting damage to tissue, such as injection. Description of the invention: Accordingly the present invention provides a novel and Non-invasive phai'niaceutical composition in the form of soft gelatin capsules useful in the treatment of male erectile dysfunction which comprises a complex of Alprostadil and cyclodextrins mixed with Caprylocaproyl macrogol - 8 glycerides or diethylene glycol monoethyl ether or their mixtures dispersed in a suitable pharmaceutical vehicle such as a base, presei vatives, antioxidants, emulsifiers. Permeability facilitators, complexing agents, bulteis and hydroxypropyl methylcellulose phthalate as a film forming material encapsulated in a soft gelatin capsule. Optionally the complex of Alprostadil may also contain colouring agents and navouring agents. The soft gelatin capsule of the present invention is to be applied by the iiiuanavicular application to the penis. The capsule contains an elongate tip. The capsule is filled with the composition of the present invention . The application of the capsule is as tbllows : The Capsule containing the composition is squeezed out on the opening of the penis, i.e. in Fossa navicularis region. The composition from the capsule is squeezed out through the elongated tip of the capsule and the composition goes into the penis particiilail\' into the fossa navicular region. According to another embodiment of the invention there is also provided a piocess for the preparation of the novel and Non-invasive pharmaceutical composition in ihc ibrm of soft gelatin capsules useful in the treatment of male erectile dysfunction whicli comprises preparing gelatin soft gel composition by dissolving gelatin and hydroxy propyl methlcellulose phthalate in ammonia solution , adding to this resulting composition a solution containing plasticizers , opacifiers , preservaties with continuous stirring loading the resulting mass into a capsule forming hopper from which the desired uniform weight of the mass for the formulation of the shell and from the medicament hopper [\o\\\ which the desired uniform weight of the composition comprising of the inclusion of a com[)lex of Prostaglandin El (Alprostail) with Cyclodextrin admixed with other solid ingredients dispersed in oily materials, the inclusion having pH in the range of 3 0 to 7 4 being delivered to obtain a homogeneous soft gelatin capsule incorporating the active ingredient and if desired , trimming and poUshing the resulting soft gelatin capsule. The plasticiser such as sorbitol, glycerin my be used . The opacifier such as fitanium dioxide, and preservatives such as sodium methyl paraben, sodium propyl paral)en may be used . Optionally the capsule may contain colours such as Quinoline yellow / Brilliant Blue / Sunset yellow / Carmoisine / Ponceau 4 R) The soft gelatin or softgel capsule containing the active ingredient of the present invention has a tip that is soft to the fossa navicularis while applying the composition . The capsule is a single dose, single use device To ensure the tolerance of the capsule with the acidic pH within the space of fossa navicularis the composition is made of lowei pi 1 > 0 to 7.4 more preferably 3.0 to 6.5 which also provides for good solubility of prostaglandin II. The soft gelatin capsule has sufficient tensile strength so as to withstand the stress applied during its application as the ordinary soft gel capsule may have a chance to break during application leading to leakage of the medicament. Further the capsule which contains plasticisers like sorbitol and glycerin which not only soften the gelatin- hydroxy propyl methyl cellulose phthalate film network but also ease and ensure the diawiim of the medicament completely from the capsules. Each unit dose of the soft gelatin capsule of the present invention coniaiiis the active ingredient prostaglandin El (Alprostadil) in the range of 0.25mg to 2.5mg, more [iieferably in the range of 0.5 to 2.0 mg per capsule. The prostaglandin El is complexed with alpha, beta or gamma cyclo dextrin or their hydroxypropyl or other derivatives or a mixture thereof for facilitating its solubility and also for increasing its availability. The amount of the complexing agent used may range from 0.25mg to lOmg, preferably 1.0 mg to lO.Omg per capsule. The soft gelatin capsule shell may be made up of materials such as gelatin, hydroxypropyl methylcellulose phthalate, glycerin and sorbitol as plasticisers; titanium dioxide as opacifying agent; sodium methyl paraben, sodium propylparaben, sodium metabisulfite, sodium benzoate and the like., as preservatives; quinoline yellow, sunset yellow, carmoisine, ponceau 4R, brilliant blue, titanium dioxide as colouring agent eithei- singly or as mixtures of two or more. According to a feature of the invention the content of gelatin and hydroxypropyl methylcellulose phthalate may range from 50mg to 150mg and 5mg to 50mg pei capsule, more preferably 60mg to 140mg and lOmg to 40mg per capsule respectively The amount of glycerine and sorbitol may range from 5mg to 60 mg, more preferably lOmg to 50 mg per capsule. The amount of preservatives may range fiom O.Olmg to I.Omy pei capsule, more preferably 0.03mgto 0.75mg per capsule. The amount of colouring agent may range from 0.01 to l.Omg per capsule, more preferably 0.05 mg to 0.75 mg per capsule Other plasticisers that can be used are diethyl phthalate, dioctyl phthalate, tnethyi citrate, Triacetin, polyethylene glycol, propylene glycol and the like. The amount of oils used in the composition may range from 50 mg to 250 mg by weight, more preferably from 75 mg to 225 mg per capsule. The oils used in the vehicle are selected from vegetable origin for example, sesame oil, corn oil, maize oil, soyabean oil, sunflower oil, arachis oil, gingely oil and the like, either singly or as a mixtuie ot'two or more, the oils selected from animal origin may be fish oil, pig oil, beef oil and the like, either singly or as a mixture of two or more and also any mix of animal origin oils and vegetable origin oils or mineral oils such as light liquid paraffin. Esters ol" straight chain aliphatic oils such as sunsoft 700 p-2 (Taiho chemical company), panasete 810 (Nippon oils and fats); hydrogenated vegetable oils and the hydrophilic gels of polyaciylic acid derivatives can also be used. Materials like glyceryl monostearate, lecithin, polyoxyethylene castor oil derivatives such as cremophor RH 40, cremophor EL (BASF), polyoxyethylene sorbitan tatty acid esters, sodium lauryl sulfate, docussate sodium, and the like may be used as suspending / emulsifying agents, singly or in an appropriate combination and transcutol (Caprylocaproyl macrogol - 8 glycerides) and Labrosol (diethylene glycol monoethyl ethei) aie used as permeation facilitators. The amount of the solubilizer / emulsifying agent may range from 0.5 mg to 35.0 mg per capsule, preferably 1 mg to 30 mg per capsule The amount of permeation facilitators may range from 2 mg to 50 mg, preferably from 5mg to 30 mg per capsule. Buffering agents used may be selected from phthalates, phosphates or niixtiires thereof The phthalates can be selected from sodium phthalate, potassium biphthalate and phosphates are from sodium phosphate, dibasic sodium phosphate, potassium phosphate, dibasic potassium phosphate and mixtures thereof The amount of buffering agent may range from 0.25 mg to 5.0 mg, preferably 0.5 mg to 3.0 mg per capsule . Butylated Hydroxy Anisole, Butylated Hydroxy Toluene, sahs of p-hydroxy benzoic acid, benzoic acid and its salts and sodium metabisulfite can be used as antioxidants / preservatives for the vehicle in a concentration range from 0.005 to 0.5 mg per capsule, preferably 0.015 to 0.3 mg per capsule %. According to another feature of the invention Musk, Lavender oil and the like may be incorporated as flavours in a concentration in the range of 0.001% to 0.0 The details of the invention are given in the Examples provided below which are \|)rovided only to illustrate the invention and therefore they should not be construed to limit the scope of the present invention EXAMPLE -1 Each capsule contains mg/capsules Gelatin 120.00 Sorbitol 15.00 Glycerine 15.00 Hydroxypropyl Methylcellulose phthalate 20.00 Sodium methyl paraben 0.30 Sodium propyl paraben 0.03 Quinoline Yellow 0.10 Titanium dioxide 1.00 Alprostadi! 1.00 Purified water q.s Sunflower oil 220.00 Butylated Hydroxy anisole 0.20 Butylated Hydroxy Toluene 0.02 Lecithin 18.20 TranSCUtol (caprylocaproyl macrogol-8 glycerides) 3.00 Potassium bi phthalate 3.00 Sodium benzoate 3.00 Polysorbate 80 3.00 HP " p cycio dextrin 9.00 Lavender oil 0.01 The manufacturing process of soft gel capsules involves the following stages: 1. Preparation of gelatin - HPMCP mass. 2. Preparation of medicament composition 3. Encapsulation of medicament composition 4. Trimming and polishing Gelatin was dissolved in water and sorbitol , glycerine was added to the gelatin solution with continuous stirring. Sodium methyl paraben, sodium propyl paraben, quinoline yellow were dissolved in water and dispersed titanium dioxide and added to the gelaiiii solution with continuous stirring. Hydroxypropyl methycellulose phthalate was dissolved in ammonia solution \o which the gelatin solution was added with continuous stirring. The semi solid mass was loaded into capsules forming hopper from where uniform weight of mass was delivered to obtain homogeneous structural film. The inclusion complex of drug and HP-B cyclo dextrin was prepared by dissolving HP-6 cyclo dextrin in water first, adding Alprostadil under stirring and dissolvij)y sodium benzoate in the same solvent. The solution is vacuum dried at 50 ° C to get solid mass. The solid mass was pulverized to obtain fine particles of the complex. Lecithin was dissolved in Sunflower oil, transcutol and warmed upto 40 ° C and butylated hydroxy anisole and butylated hydroxy toluene were added to it. Potassium hi phthalate and polysorbate 80, flavoring agent lavender oil are mixed with the complex of Alprostadil and is added to the lecithin- sunflower oil solution with continuous stirring to form a suspension. The hopper of the capsule filling machine is loaded with the above medicament composition for delivering predetermined amount into the blister formed by semi solid containing film forming materials along with the additives. The filled geiaun capsules were trimmed and collected into a receptacle. EXAMPLE - 2 Each capsule contains mg/capsule Gelatin 120.00 Sorbitol 15.00 Glycerine 15.00 Hydroxypropyl Methylcellulose phthalate 20.00 Sodium methyl paraben 0.30 Sodium propyl paraben 0.03 Brilliant blue 0.05 Sunset yellow 0.10 Titanium dioxide 1.00 Alprostadil 1.00 Purified water q.s Soyabean oil 192.00 Butylated Hydroxy anisole 0.20 Butylated Hydroxy Toluene 0.02 Lecithin 19.00 Labrosol (diethylene glycol mono etliyl ether) 3.00 Potassium bi phthalate 3.00 Sodium benzoate 3.00 Polysorbate 80 9.00 HP - P cyclo dextrin 9.00 Lavender oil 0.01 The manufacturing process of soft gel capsules involves the following stages 1) Preparation of gelatin - HPMCP mass. 2) Preparation of medicament composition 3) Encapsulation of medicament composition 4) Trimming and polishing Gelatin was dissolved in water and sorbitol, glycerine was added to the gelatin solution with continuous stirring. Sodium methyl paraben, sodium propyl paraben. sunset yellow, brilliant blue were dissolved in water and dispersed titanium dioxide and added to the gelatin solution with continuous stirring. The hydroxypropyl methycellulose phthalate was dissolved in ammonia solution to which the gelatin solution was added with continuous stirring. The semi soHd mass was loaded into capsules forming hopper from where uniform weight of mass is deliveied lo obtain homogeneous structural film. The inclusion complex of drug and HP-B cyclo dextrin was prepared by dissolving tIP-B cyclo dextrin in water first, adding Alprostadil under stirring and dissolving sodium benzoate in the same solvent. The solution is vacuum dried at 50 ° C to get solid mass. The solid mass was pulverised to obtain fine particles of the complex. Lecitin is dissolved in Soyabean oil, lubrosol and warmed upto 40 ° C' and binylated hydroxy anisole and butylated hydroxy toluene were added to it. Potassium bi phthalate and polysorbate 80, flavouring agent Lavender oil are mixed with the complex of Alprostadil and is added to the lecithin- Soyabean oil solution with continuous stirring to form a suspension. The hopper of the capsule filling machine is loaded with the medicament composition for delivering predetermined amount into the blister formed by semi solid coi^iaining film forming materials along with the additives. The filled capsules are trimmed and collected into a receptacle. EXAMPLE - 3 Each capsule contains mg/capsule Gelatin 120.00 Sorbitol 15.00 Glycerine 15.00 Hydroxypropyl Methylcellulose phthalate 20.00 Sodium methyl paraben 0.30 Sodium propyl paraben 0.03 Quinoline Yellow 0.10 Titanium dioxide 1.00 Alprostadil 1.0 Purified water q.s Sunflower oil 220.00 TransCUtol (caprylocaproyl niacrogoI-8 glycerides) 18.20 Butylated Hydroxy anisole 0.25 Butylated Hydroxy Toluene 0.025 Potassium bi phthalate 3.0 Sodium benzoate 3.00 Polysorbate 80 3.00 HP - p cyclo dextrin 9.00 Musk 0.01 The manufacturing process of soft gel capsules involves the following stages; 1. Preparation of gelatin - HPMCP mass. 2. Preparation of medicament composition 3. Encapsulation of medicament composition 4. Trimming and polishing of soft gel Gelatin was dissolved in water and sorbitol , glycerine was added to the gelatiii solution with continuous stirring. Sodium methyl paraben, sodium propyl paraben, quinoline yellow were dissolved in water and dispersed titanium dioxide and added to the gelatin solution with continuous stirring. Hydroxypropyl methycellulose phthalate was dissolved in ammonia solution to which the gelatin solution was added with continuous stirring. The semi solid mass was loaded into capsules forming hopper from where uniform weight of mass is delivered to obtain homogeneous structural film. The inclusion complex of drug and HP-B cyclo dextrin was prepared by dissolving HP-6 cyclo dextrin in water first, adding Alprostadil under stirring and dissolving sodium benzoate in the same solvent. The solution is vacuum dried at 50 ° C to get solid mass. The solid mass was pulverised to obtain fine particles of the complex. Transctol is dissolved in Sunflower oil and warmed upto 40 * C and buiylaicd hydroxy anisole and butylated hydroxy toluene were added to it. Potassium bi phthalate and polysorbate 80, Flavouring agent Musk, are mixed with the complex of Alpiosiadil and is added to the Transcutol- sunflower oil solution with continuous stining lo form a suspension. The hopper of the capsule filling machine is loaded with the above medicament composition for delivering predetermined amount into the blister formed by semi solid containing film forming materials along with the additives. The filled capsules were trimmed and collected into a receptacle. EXAMPLE - 4 Each capsule contains mg/capsule Gelatin 120.00 Sorbitol 15.00 Glycerine 15.00 Hydroxypropyl Methylcellulose phthalate 20.00 Sodium methyl paraben 0.30 Sodium propyl paraben 0.03 Brilliant blue 0.05 Sunset yellow 0.10 Titanium dioxide 1.00 Alprostadil 1.00 Purified water q.s Soyabean oil 192.00 Butylated Hydroxy anisole 0.20 Butylated Hydroxy Toluene 0.02 Transcutol (caprylocaproyl macrogoI-8 glycerides) 19.00 Sodium phthalate 3.00 Sodium benzoate 3.00 Polysorbate 80 9.00 HP - P cyclo dextrin 9.00 Musk 0.01 The manufacturing process of soft gel capsules involves the following stages 1. Preparation of gelatin - HPMCP mass. 2. Preparation of medicament composition 3. Encapsulation of medicament composition 4. Trimming and poUshing of soft gel Gelatin was dissolved in water and sorbitol , glycerine was added to the gelatin solution with continuous stirring. Sodium methyl paraben, sodium propyl paraben, siinsei yellow, brilliant blue were dissolved in water and dispersed titanium dioxide and added to the gelatin solution with continuous stirring. The hydroxypropyl methycellulose phthalate was dissolved in ammonia solution to which the gelatin solution was added with continuous stirring. The semi solid mass was loaded into capsules forming hopper from where uniform weight of mass is delivered to obtain homogeneous structural film. The inclusion complex of drug and HP-B cyclo dextrin was prepared by dissolving HP-B cyclo dextrin in water first, adding Alprostadil under stirring and dissolving sodium benzoate in the same solvent. The solution is vacuum dried at 50 ° C to get solid niass. The solid mass was pulverised to obtain fine particles of the complex. Transcutol is dissolved in Soyabean oil and warmed upto 40 *^ C and buiylaied hydroxy anisole and butylated hydroxy toluene were added to it. Sodium phthalate and polysorbate 80, flavouring agent Musk are mixed with the complex of Alprostadil and is added to the Transcutol- Soyabean oil solution with continuous stirring to form a suspension The hopper of the capsule filling machine is loaded with the medicament composition for delivering predetermined amount into the blister formed by semi solid contaimng film forming materials along with the additives. The filled capsules are trimmed and collected into a receptacle. EXAMPLE - 5 Each capsule contains Gelatin Sorbitol Glycerine Hydroxypropyl Methylcellulose phthalate Sodium methyl paraben Sodium propyl paraben Quinoline Yellow Titanium dioxide Alprostadil Purified water Light liquid paraffin Labrosol (diethylene glycol mono ethyl ether) Butylated hydroxy toluene Butylated hydroxy anisole Sodium benzoate Disodium hydrogen phosphate HP p-cyclo dextrin Polysorbate 80 Lavendor oil mg/capsule 120.00 15.00 15,00 20.00 0.30 0.03 0.10 1.00 1.00 q.s 185.00 15.00 0.10 0.01 3.00 3.00 9.00 9.00 0.01 The manufacturing process of soft gel capsules involves the following stages 1) Preparation of gelatin - HPMCP mass. 2) Preparation of medicament composition 3) Encapsulation of medicament composition 4) Trimming and polishing Gelatin dissolved in water and sorbitol, glycerine was added to the gelatin sc^lution with continuous stirring. Sodium methyl paraben, sodium propyl paraben, quinohne yellow was dissolved in water and dispersed titanium dioxide and added to the gelatin soliiiion The hydroxypropyl methycellulose phthalate was dissolved in ammonia solution to which the gelatin solution was added with continuous stirring. The semi solid mass was loaded into capsules forming hopper from where uniform weight of mass is delivered to obtain homogeneous structural film. The inclusion complex of drug and HP-B cyclo dextrin was prepared by dissolving HP-B cyclo dextrin in water first, adding Alprostadil under stirring and dissolving sodium benzoate in the same solvent. The solution is vacuum dried at 50 ° C to get solid mass. The solid mass was pulverised to obtain fine particles of the complex. Labrosol is dissolved in light liquid paraffin and warmed upto 40 "" C and butylated hydroxy anisole and butylated hydroxy toluene were added to it. Disodiimi hydrogen phosphate, polysorbate 80, flavouring agent Lavendor oil are mixed with the eomplex of Alprostadil and is added to the Labrosol - Light Liquid Paraffin solution with continuous stirring to form a suspension. The hopper of the capsule filling machine is loaded with the medicament composition for delivering predetermined amount into the blister formed by semi solid containing film forming materials along with the additives. The filled capsules are trimmed and collected into a receptacle. EXAMPLE " 6 Each capsule contains mg / Capsule Gelatin 120.00 Sorbitol 15.00 Glycerine 15.00 Hydroxypropyl Methylcellulose phthalate 20.00 Sodium methyl paraben 0.30 Sodium propyl paraben 0.03 Quinoline Yellow 0.10 Titanium dioxide 1.00 Alprostadil 1.00 Purified water q.s Groundnut oil 186.00 Labrosol (diethylene glycol mono etliyl etlier) 18.00 Butylated hydroxy toluene 0.25 Butylated hydroxy anisole 0.025 Sodium benzoate 2.50 Disodium hydrogen phosphate 5.00 HP p-cyclo dextrin 9.00 Polysorbate 80 9.00 Musk 0.01 The manufacturing process of soft gel capsules involves the following stages 1) Preparation of gelatin - HPMCP mass. 2) Preparation of medicament composition 3) Encapsulation of medicament composition 4) Trimming and polishing Gelatin dissolved in water and sorbitol, glycerine was added to the gelatin sokiiion with continuous stirring. Sodium methyl paraben, sodium propyl paraben, quinoline yellow was dissolved in water and dispersed titanium dioxide and added to the gelatin sokiiion The hydroxypropyl methycellulose phthalate was dissolved in ammonia solmion lo which the gelatin solution was added with continuous stirring. The semi solid mass was loaded into capsules forming hopper from where uniform weight of mass is deliveied lo obtain homogeneous structural film. The inclusion complex of drug and HP-fi cyclo dextrin was prepared by dissolving liP-B cyclo dextrin in water first, adding Alprostadil under stirring and dissolving sodium benzoate in the same solvent. The solution is vacuum dried at 50 ° C to gel solid mass. The solid mass was pulverized to obtain fine particles of the complex. Labrosol is dissolved in Groundnut oil and warmed upto 40 ° C and buiylaied hydroxy anisole and butylated hydroxy toluene were added to it. Disodium hydrogen phosphate, polysorbate 80, Flavouring agent Musk, are mixed with the complex of Alpiosiadil and is added to the Labrosol - Groundnut oil solution with continuous stirring lo form a suspension. The hopper of the capsule filling machine is loaded with the medicament composition for delivering predetermined amount into the bUster formed by semi solid containing film forming materials along with the additives. The filled capsules are trimmed and collected into a receptacle. EXAMPLE " 7 Each capsule contains mg/capsule Gelatin 120.00 Sorbitol 15.00 Glycerine 15.00 Hydroxypropyl Methylcellulose phthalate 20.00 Sodium methyl paraben 0.30 Sodium propyl paraben 0.03 Quinoline Yellow 0.10 Titanium dioxide 1.00 Alprostadil 1.00 Purified water q.s Soyabean oil 175.00 Carbopol934 0.50 Labrosol (diethylene glycol mono ethyl etlier) 18.00 Butylated hydroxy toluene 0.015 Butylated hydroxy anisole 0.15 Sodium benzoate 2.50 Disodium hydrogen phosphate 5.00 HP p-cyclo dextrin 9.00 Polysorbate 80 9.00 Lavendor oil 0.01 The manufacturing process of soft gel capsules involves the following sta^^es 1) Preparation of gelatin - HPMCP mass. 2) Preparation of medicament composition 3) Encapsulation of medicament composition 4) Trimming and polishing Gelatin dissolved in water and sorbitol, glycerine was added to the gelatin solution with continuous stirring. Sodium methyl paraben, sodium propyl paraben, quinolinc yellow was dissolved in water and dispersed titanium dioxide and added to the gelatin solution. The hydroxypropyl methycellulose phthalate was dissolved in ammonia solution to which the gelatin solution was added with continuous stirring. The semi solid mass was loaded into capsules forming hopper from where uniform weight of mass is delivered to obtain homogeneous structural film. Carbopol gel was prepared by dispersing the carbopol in purified water, neutralizing with sodium hydroxide and allowed to swell for 24hours. This results in the foi niation of a transparent semi solid gel. The inclusion complex of drug and HP-B cyclo dextrin was prepared by dissolving HP-B cyclo dextrin in water first, adding Alprostadil under stirring and dissolving sodium benzoate in the same. The solution is vacuum dried at 50 ° C to get solid mass The solid mass was pulverised to obtain fine particles of the complex. Labrosol is dissolved in Soyabean oil and warmed upto 40 ° C and butylated hydroxy anisole and butylated hydroxy toluene were added to it. Disodium hydiogen phosphate, polysorbate 80, flavouring agent Lavendor oil, Carbopol 934 are mixed with the complex of Alprostadil and is added to the Labrosol -Soyabean oil solution with continuous stirring to form a suspension. The hopper of the capsule filling machine is loaded with the medicament composition for delivering predetermined amount into the blister formed by semi solid containing film forming materials along with the additives. The filled capsules are trimmed and collected into a receptacle. Advantages of the invention 1. The composition is completely biodegradable. 2. The administration of the composition in the fossa navicularis has high elficacy and low incidence of local side effects 3. The composition can be produced on a large scale without difficulty on coniinercially available equipments. 4. Due to the less number of steps involved in the process for the pieparation of the composition it is economical. 5. The patient can use the medicament discretely and easily . 6. The composition is easily portable . 7. The composition has the capability of large-scale acceptance by the users We claim: 1) A novel and non-invasive pharmaceutical composition in form of a sod gel capsule useful for the treatment of male erectile dysfunction which comprises of a gelatin capsule incorporating a composition comprising of a complex of Alpiostadil and cyclodextrins mixed with Caprylocaproyl macrogol - 8 glycerides or dieihylei)e glycol monoethyl ether or their mixtures dispersed in a suitable pharmaceuiical vehicle comprising of oils, preservatives, antioxidants, emulsifiers, Permeation facilitators, complexing agents, buffers and hydroxypropyl methylcellulose phihalaie as a film forming material. 2) A novel pharmaceutical composition as claimed in claim 1 wherein the amount of Alprostadil used in the composition ranges from 0.25 to 2.5mg, more pieferably 0.5 to 2.0mg per capsule. 3) A novel pharmaceutical composition as claimed in claims 1 and 2 wherein the soft gel shell is made up of materials such as film formers, plasticizeis, preservatives, opacifiers, colorants and optionally flavours. 4) A novel pharmaceutical composition as claimed in claims 1 to 3 wheiein the film formers are selected from gelatin, hydroxypropyl methylcellulose phthahite, cellulose acetate phthalate or mixture there of 5) A novel pharmaceutical composition as claimed in claims 1 to 4 wheiein the amount of film formers such as gelatin and phthalate derivatives ranges from 30 o to 150.0mg and 5.0 to SO.Omg per capsule, more preferably 60.0 to 120.0mg and 10 0 lo 40.0mg per capsule respectively. 6) A novel pharmaceutical composition as claimed in claim 1 to 5 wherein the Plasticizers such as glycerine, sorbitol.is used. 7) A novel pharmaceutical composition as claimed in claim 6 wherein the amount of plasticizers used ranges from 5.0 to 60.0mg, more preferably 10.0 to 50Omg per capsule. 8) A novel pharmaceutical composition as claimed in claim 1 to 7 wheiein the preservatives used are selected from paraben derivatives such as methyl paraben, sodium methyl paraben or mixture thereof 9) A novel pharmaceutical composition as claimed in claim 9 wherein the amount of preservatives used ranges from 0.005 to 2.0mg, more preferably 0.01 to I Oing per capsule. 10) A novel pharmaceutical composition as claimed in claim 1 to 9 wherein the colouring agents such as brilliant blue, sunset yellow, quinoline yellow, titanium dioxide or mixture thereof is used. 11) A novel pharmaceutical composition as claimed in claim 10 wherein the amount of colouring agents used ranges from 0.01 to l.Omg per capsule more prelerably 0.05 to 0.75mg per capsule. 12) A novel pharmaceutical composition as claimed in claims 1 to 11 wherein the oil used in the composition is selected from vegetable origin such as sesame oil, corn oil, maize oil, soybean oil, sunflower oil, arachis oil, gingly oil and the like; animal oi iyin such as fish oil, pig oil, beef oil and the like; esters of straight chain aliphatic oils such as SunSoft 700 P-2 (Taiho chemical company) Panasete 810 (Nippon oils and Fats); hydrogenated vegetable oils, the hydrophilic gels of poly acrylic acid derivatives such as carbopol 934, carbopol 940 or a mixture thereof 13) A novel pharmaceutical composition as claimed in claim 12 wherein the anuumt of oil used in the medicament composition ranges from 50.0 to 250.0 mg , more \|)ieferably from 75.0 to 225.Omg per capsule. 14) A novel pharmaceutical composition as claimed in claims 1 to 13 wherein materials such as glyceryl monostearate, lecithin, polyoxyethylene castor oil denvaiixe such as Cremophor RH 40, Cremophor EL (BASF) polyoxyethylene sorbitan tally acid esters, sodium lauryl sulphate, docusate sodium and the like is used as suspendiny agent / surface active agent. 15) A novel pharmaceutical composition as claimed in claim 14 wherein the amount of the surface-active agent and / or solublising agent used in the formulation ranges from 0.5 to 20.0mg, preferably 1.0 to 15.0mg per capsule. 16) A novel pharmaceutical composition as claimed in claims 1 to 15 wherein permeation facilitators are used 17) A novel pharmaceutical composition as claimed in claim 16 wherein the amount of permeation facilitators used ranges from 2.0 to 50.0mg, more preferably 5 () to 30.0mg per capsule. 18) A novel pharmaceutical composition as claimed in claims 1 to 17 wherein the buffering agents used are selected from phthalates, phosphates or mixtures thereof 19)A novel pharmaceutical composition as claimed in claim 18 wherein tlie phthalates used are selected from sodium phthalate; potassium phthalate and phosphates are selected from sodium phosphate, dibasic sodium phosphate, potassium \|:)hosphate, dibasic potassium phosphate and mixtures thereof 20) A novel pharmaceutical composition as claimed in claims 18 and 19 wherein the amount of the buffering agent ranges from 0.25 to lO.Omg, preferably 0 5 to 8 (img per capsule. 21) A novel pharmaceutical composition as claimed in claims 1 to 20 wherein the complexing agents used are selected from cyclodextrins such as a, P and y or derivative such as hydroxypropyl - p-cyclodextrine, hydroxymethyl - P-cyclodextrine or mixtures thereof 22) A novel pharmaceutical composition as claimed in claim 21 wherein the amount of the complexing agent used ranges from 1.0 to 20.0 mg, preferably 5.0 to IS.Omg per capsule. 23) A novel pharmaceutical composition as claimed in claims 1 to 22 wherein the antioxidants / preservatives used are selected from butylated hydroxy anisole, butylated hydroxy toluene, salts of p-hydroxy benzoic acid, benzoic acid and its salts and sodium metabisulfite or the mixtures thereof 24) A novel pharmaceutical composition as claimed in claim 23 wherein the amount of the antioxidants / preservatives used ranges from 0.0 Img to 0. 5mg per capsules preferably 0.015 to 0.2mg per capsule. 25) A novel pharmaceutical composition as claimed in claims 1 to 24 wherein flavouring agents are used which are selected from Musk, Lavender oil. 26) A novel pharmaceutical composition as claimed in claim 25 wherein the amount of the flavouring agent used ranges from O.OOlmg to 0. 05mg per capsule , preferably 0.005 mg to 0.02 mg per capsule. 27) A process for the preparation of the novel and Non-invasive pharmaceutical composition in the form of soft gelatin capsules useful in the treatment of male erectile dysfunction which comprises preparing gelatin soft gel composition by dissolving gelatin and hydroxy propyl methlcellulose phthalate in ammonia solution , adding to the resulting composition a solution containing plasticizers , opacifiers , preservaties with continuous stirring loading the resulting mass into a capsule forming hopper from which the desired uniform weight of the mass for the formulation of the shell and from the medicament hopper from which the desired uniform weight of the medicament mass comprisiong ofthe inclusion of a complex of Prostaglandin El (Alprostail) with Cyclodextrin admixed with other solid ingredients dispersed in oily materials, the inclusion having pH in the range of 3.0 to 7.4 being delivered to obtain a homogeneous soft gelatin capsule incorporating the active ingredient and if desired , trimming and polishing the resulting soft gelatin capsule. 28) A process as claimed in claim in claim 27 wherein the amount of Alprostadil in the composition ranges from 0.25 to 2.5mg, more preferably 0.5 to 2.0mg per capsule. 29) A process as claimed in claim 27 to 28 wherein the soft gel shell is made up of materials such as film formers, plasticizers, preservatives, opacifiers and optionally, colouring and flavouring agents . 30) A process as claimed in claim 29 wherein the film formers used are selected from gelatin, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate. 31) A process as claimed in claim 29 and 30 wherein the amount of film formers such as gelatin and phthalate derivatives used ranges from 50.0 to 150.0mg and 5.0 to 50.0mg per capsule, more preferably 60.0 to 120.0mg and 10.0 to 40.0mg per capsule respectively. 32) A process as claimed in claim 29 to 31 wherein Plasticizers such as glycerine and sorbitol or their mixtures are used. 33) A process as claimed in claim 32 wherein the amount of plasticizers used ranges fi'om 5.0 to 60.0mg, more preferably 10.0 to 50.0mg per capsule. 34) A process as claimed in claim31 to 33 wherein the preservatives used are selected from paraben derivatives such as methyl paraben, sodium methyl paraben or mixture thereof 35) A process as claimed in claim 34 wherein the amount of preservatives used ranges from 0.005 to 2.0mg , more preferably 0.01 tol.Omg per capsule . 36) A process as claimed in claim 27 to 35 wherein the colouring agents used are selected from brilliant blue, sunset yellow, quinoline yellow, titanium dioxide or mixtures thereof 37)37. A process as claimed in claim 27 to 36 wherein the amount of colouring agents used ranges from 0.01 to l.Omg per capsule more preferably 0.05 to 0.75mg per capsule. 38) A process as claimed in claims 27 to 37 wherein the oil in the composition used are selected from vegetable origin such as sesame oil, corn oil, maize oil, soybean oil, sunflower oil, arachis oil, gingly oil and the like; animal origin such as fish oil, pig oil, beef oil and the like; esters of straight chain aliphatic oils such as Sunsoft 700 P-2 (Taiho chemical company) Panasete 810 (Nippon oils and Fats); hydrogenated vegetable oils, the hydrophilic gels of poly acrylic acid derivatives such as carbopol 934, carbopol 940 or a mixture thereof 39) A process as claimed in claims 27 to 38 wherein the amount of oil used in the composition used ranges from 50.0 to 250.0 mg , more preferably from 75.0 to 225.Omg per capsule. 40) A process as claimed in claims 27 to 39 wherein materials such as glyceryl monostearate, lecithin, polyoxyethylene castor oil derivative such as Cremophor RH 40, Cremophor EL (BASF) polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulphate, docusate sodium and the like is used as suspending agent / surface active agent. 41) A Process as claimed in claim 40 wherein the amount of the surface-active agent and / or solublising agent used ranges from 0.5 to 20.Omg, preferably 1.0 to 15.Omg per capsule. 42) A process as claimed in claims 27 to 41 wherein the permeation facilitators used are selected from transcutol, lecithin or labrosol or the mixture thereof 43) A process as claimed in claim 42 wherein the amount of permeation facilitators may range from 2.0 to 50.0mg, more preferably 5.0 to 30.0mg per capsule. 44) A process as claimed in claims 27 to 43 wherein the buffering agents used are selected from phthalates, phosphates or mixtures thereof 45) A process as claimed in claim 44 wherein the amount of the buffering agent may ranges from 0.25 to lO.Omg, preferably 0.5 to S.Omg per capsule. 46) A process as claimed in claims 27 to 45 wherein the phthalates are selected from sodium phthalate; potassium phthalate and phosphates are selected from sodium phosphate, dibasic sodium phosphate, potassium phosphate, dibasic potassium phosphate and mixtures thereof 47) A process as claimed in claims 27 to 46 wherein the complexing agents used are selected from cyclodextrins such as a, P and y or derivative such as hydroxypropyl - p-cyclodextrine, hydroxymethyl - p-cyclodextrine or mixtures thereof. 48) A process as claimed in claim 47 wherein the amount of the complexing agent may ranges from 1.0 to 20.0 mg, preferably 5.0 to 15.0mg per capsule. 49) A Process as claimed in claims 27 to 48 wherein the antioxidants / preservatives used are selected from butylated hydroxy anisole, butylated hydroxy toluene, salts of p-hydroxy benzoic acid, benzoic acid and its salts and sodium metabisulfite or the mixtures thereof 50) A process as claimed in claim 49 wherein the amount of antioxidants / preservatives used ranges from 0.01 mg to 0.5mg per capsules preferably 0.015 to 0.2 mg per capsule. 51) A process as claimed in claims 27 to 50 wherein the flavouring agents used are selected from Musk, Lavender oil. 52) A process as claimed in claim 51 wherein the amount of the flavouring agent used ranges from 0.001 mg to 0. 05 mg per capsule preferably 0.005 mg to 0.02 mg. 53) A novel and non-invasive pharmaceutical composition in the form of a soft gel capsule useful for the treatment of substantially as herein described with reference to the Examples 1 to 5. 54) A process for the preparation of a novel and non-invasive pharmaceutical composition in the form of a soft gel capsule useful for the treatment of substantially as herein described with reference to the Examples 1 to 5.

Full Text

The present invention relates to a novel and Non-invasive Pharmaceutical composition useful for the treatment in male sexual impotence. The present invention particularly relates to a pharmaceutical composition containing the drug Alprostadil (otherwise IcnoAvn as prostaglandin Ei). The present invention also relates to a process for the preixn ation of the above said pharmaceutical composition
Background of the invention:
The term "impotence" has been used in this specification to signify the inability of the male to attain and maintain erection of the penis sufficient to permit satistactory sexual intercourse. The term "erectile dysfunction" has been suggested as a more precise term "to signify an inability of the male to achieve an erect penis as part of the overall muhifaceted process of male sexual function." Droller, MJ. et. al. Impotence. Consensus Development Conference Statement, National Institutes of Health (1993).
Erectile dysfunction may result from psychological causes (psychogenic erectile dysfunction) or organic causes or a combination of both. Organic causes include physiological, nervous, vascular and hormonal pathologies or a combination thereof.
The normal physiology of an erection involves nerve impulses, which signal certain muscles to relax. These muscles, when contracted, restrict blood flow through arteries in the penis. When relaxed, the muscles permit a significant increase in blood lltiw. The increased blood flow engorges three groups of erectile tissue within the penis with blood and the penis becomes less flaccid. The engorged erectile tissue and the muscle stiiicture of the penis depress adjacent veins, restricting the flow of blood out oi^ the i^enis. The restriction of blood flow out of the penis increases and sustains the erection
Deficiencies of some hormones, such as testosterone, or elevation of otheis, such as prolactin, can cause erectile dysfunction. Many drugs, such as diuretics, anti hypertensives, anticonvulsants, narcotics, alcohol, and psychotropic drugs may cause erectile dystUnction as a side effect. Murray, F, T. et al. Amer. J. Medical Sci. 309: 99 - 109 (1995)
Alprostadil (otherwise known as prostaglandin Ei) is a derivative of prostanoic acid, a 20-carbon atom lipid acid of the formula.

q
This drug is commercially available, e.g., from Chinoin Pharmaceutical and ( hemical Works Ltd. (Budapest, Hungary) under the designation 'Alprostadil IJSP\ from Pharmacia and Upjohn under the designation "Caverject" and from The Upjohn Company (Kalamazoo, Mich.) under the designation "Prostin VR".
Damage to nerves and blood vessels may also provide an organic cause lor erectile dysfunction. Disease processes may involve several aspects. For example, diabetes, which causes damage to both nerves and blood vessels, can cause erectile dysllinction. A significant percent of all diabetic men will suffer from erectile dysfunction
Methods proposed for the treatment of erectile dysfunction have included external devices, sex therapy, surgical implantation of internal prostheses, injection of drugs directly into the penis and topically applied medications.
External devices include tourniquets (see U.S. Pat. No.2, 818,855) and externally applied vacuum erection aids. While some clinicians consider externally applied ereciion aids as a first option for treatment, some patients are unwilling to use such devices 0 Keefe, M., et al. Medical Clinics of North America 79: 415 - 434 (1995).
External devices such as tourniquets and externally applied vacuum erection aids used for improving the erection have not been successflil due to the unwillingness ol' the patients to use such devices. Other devices such as surgically implanted mechanieai devices, such as hinged or solid rods and inflatable, spring driven or hydraulic prostheses used for similar purpose are not favored due to the penile pain and the localized damage to the penile tissue that may result with the application.

A number of injectable products for the treatment of erectile dysfunction are available commercially for injecting into the penile tissue. For example US Pat. No 4J 27,1 18 to La Torre discloses an injectable vasodilator, Patent No. CA 2344435 describes an injectable mixture of the drugs Phentolamine mesylate. Papaverine hydrochloride and Alprosiadil in a suitable buffer and patent no. EP 0459377A2 refers to an injection of Alprostadil
As per Martindale (The Extra Pharmacopoeia, 33*^^ Edition) a major disadvantage of this method is the need for repeated self- injection of the penis and studies siiygesi that the long-term use may result in fibrosis and that priapism may also be a problem
In one commercially available form (MUSE®, Vivus, Menlo Park Calit), /\l|)iostadil is administered in a pellet deposited in the urethra using an applicator with a hollow stem 3.2 cm in length and 3.5mm in diameter. Martindale (The Extra Pharmacopoeia, 33"' lidition) reports that the common side effects include penile pain and urethral pain ov burning with this usage.
Patent N0.US6, 323,241 Bl provides methods and compositions for the treatment of erectile dysfunction by the intranavicular application of pharmaceutical eonipositions to the mammalian penis. The composition comprises a vasodilator, preferably pii^siaglandin El, a penetration enhancer, a polysaccharide gum, a lipophilic compound, and an acidic buffer system. While the patent claims a number of advantages over plaeing such composition intranavicularly into the penis, the system may be expensive lo produce besides having problems of disposal due to the applicator used is non-biodegradable
Working alone most drugs, prostaglandin formulations included, do not snniciently permeate the skin to provide drug concentration levels comparable to those obtained from other drug delivery routes. To overcome this problem, topical drugs formulations typically include skin permeability facilitators.
Keeping in view of the limitations of the hitherto known methods and deviees we observed that if a simple and viable application which facilitates easy administration is ])rovided it can lead to increased tolerance and compliance by delivering the active medieament at an appropriate place with ease. Moreover such a process / device will also have a large-scale

production capacity. It will have the tlexibility ot ease ot portability lead nig u) better compliance. The product if made extremely environmental friendly by making il totally biodegradable it will have additional advantages, which may not be the case with the earlier applications described in the literature. Comparatively the product / method may be less expensive than the present day used method / product. Till date, there is no such process / product which is commercially available in soft gelatin capsules.
As a much simpler and more acceptable alternative, we have aimed to develop a soft gelatin capsule containing a pharmaceutically active topical composition oi" the drug prostaglandin El (more commonly known as Alprostadil) complexed with permeability facilitators in an emulsified and suitably buffered base with appropriate stabilizers and preservatives and which may contain optionally colouring agents and flavoring agents.
Accordingly the main objective of the present invention is to provide a novel and Non¬invasive pharmaceutical composition in the form of a soft gelatin capsule containing prostaglandin El (Alprostadil) which is useful in the treatment oi* male erectile dysfunction.
Another objective of the present invention is to provide a novel and Non-invasive pharmaceutical composition in the form of soft gelatin capsules containing prostaglandin El (Alprostadil) which is useful in the treatment of male erectile dysfunction and which facilitates easy administration of the drug at an appropriate place with ease
Still another objective of the present invention is to provide a novel and Non-invasive pharmaceutical composition in the form of a soft gelatin capsule containing prostaglandin El (Alprostadil) which is useful in the treatment of male erectile dysfunction, llexibility in ease of portability leading to better compliance.
Yet another objective of the present invention is to provide a novel and NcM>invasive pharmaceutical composition containing a prostaglandin El (Alprosiadil) which is complexed with cyclodextrins such as a, P , y - cyclodextrins or derivatives there of which enhances the drug's solubility and hence improves the drug availability

Still another objective of the present invention is to provide a novel and Non-invasive pharmaceutical composition in the form of a soft gelatin capsule containing prostaglandin El (Alprostadil) which is useful in the treatment of male erectile dysfunction and which is extremely environmental friendly and biodegradable.
Still another objective of the present invention is to provide a novel and Non-nivasive pharmaceutical composition which is in the form of a soft gelatin capsule containing prostaglandin El (Alprostadil) and which contains hydroxy propyl methyl cellulose phthalate as a film forming material which provides adequate stiffness for the soCt gelatin capsule for easy entry into the urethra as well as prevents breakage of the capsule while being used.
Still another objective of the present invention is to provide a novel and Non-invasive pharmaceutical composition containing prostaglandin El (Alprostadil) which also contains Caprylocaproyl macrogol - 8 glycerides (commercially available as labrosol) or diethylene glycol monoethyl ether (commercially known as Transcutol P) or their mixtui es to improve the permeation of the drug, prostaglandin El.
By the term "Non-invasive" it meant to refer to administration of drug, without milicting damage to tissue, such as injection.
Description of the invention:
Accordingly the present invention provides a novel and Non-invasive phai'niaceutical composition in the form of soft gelatin capsules useful in the treatment of male erectile dysfunction which comprises a complex of Alprostadil and cyclodextrins mixed with Caprylocaproyl macrogol - 8 glycerides or diethylene glycol monoethyl ether or their mixtures dispersed in a suitable pharmaceutical vehicle such as a base, presei vatives, antioxidants, emulsifiers. Permeability facilitators, complexing agents, bulteis and hydroxypropyl methylcellulose phthalate as a film forming material encapsulated in a soft gelatin capsule.
Optionally the complex of Alprostadil may also contain colouring agents and navouring agents.

The soft gelatin capsule of the present invention is to be applied by the iiiuanavicular application to the penis. The capsule contains an elongate tip. The capsule is filled with the composition of the present invention . The application of the capsule is as tbllows : The Capsule containing the composition is squeezed out on the opening of the penis, i.e. in Fossa navicularis region. The composition from the capsule is squeezed out through the elongated tip of the capsule and the composition goes into the penis particiilail\' into the fossa navicular region.
According to another embodiment of the invention there is also provided a piocess for the preparation of the novel and Non-invasive pharmaceutical composition in ihc ibrm of soft gelatin capsules useful in the treatment of male erectile dysfunction whicli comprises preparing gelatin soft gel composition by dissolving gelatin and hydroxy propyl methlcellulose phthalate in ammonia solution , adding to this resulting composition a solution containing plasticizers , opacifiers , preservaties with continuous stirring loading the resulting mass into a capsule forming hopper from which the desired uniform weight of the mass for the formulation of the shell and from the medicament hopper [\o\\\ which the desired uniform weight of the composition comprising of the inclusion of a com[)lex of Prostaglandin El (Alprostail) with Cyclodextrin admixed with other solid ingredients dispersed in oily materials, the inclusion having pH in the range of 3 0 to 7 4 being delivered to obtain a homogeneous soft gelatin capsule incorporating the active ingredient and if desired , trimming and poUshing the resulting soft gelatin capsule.
The plasticiser such as sorbitol, glycerin my be used . The opacifier such as fitanium dioxide, and preservatives such as sodium methyl paraben, sodium propyl paral)en may be used . Optionally the capsule may contain colours such as Quinoline yellow / Brilliant Blue / Sunset yellow / Carmoisine / Ponceau 4 R)
The soft gelatin or softgel capsule containing the active ingredient of the present invention has a tip that is soft to the fossa navicularis while applying the composition . The capsule is a single dose, single use device To ensure the tolerance of the capsule with the acidic pH within the space of fossa navicularis the composition is made of lowei pi 1 > 0 to 7.4 more preferably 3.0 to 6.5 which also provides for good solubility of prostaglandin II.

The soft gelatin capsule has sufficient tensile strength so as to withstand the stress applied during its application as the ordinary soft gel capsule may have a chance to break during application leading to leakage of the medicament. Further the capsule which contains plasticisers like sorbitol and glycerin which not only soften the gelatin- hydroxy propyl methyl cellulose phthalate film network but also ease and ensure the diawiim of the medicament completely from the capsules.
Each unit dose of the soft gelatin capsule of the present invention coniaiiis the active ingredient prostaglandin El (Alprostadil) in the range of 0.25mg to 2.5mg, more [iieferably in the range of 0.5 to 2.0 mg per capsule.
The prostaglandin El is complexed with alpha, beta or gamma cyclo dextrin or their hydroxypropyl or other derivatives or a mixture thereof for facilitating its solubility and also for increasing its availability. The amount of the complexing agent used may range from 0.25mg to lOmg, preferably 1.0 mg to lO.Omg per capsule.
The soft gelatin capsule shell may be made up of materials such as gelatin, hydroxypropyl methylcellulose phthalate, glycerin and sorbitol as plasticisers; titanium dioxide as opacifying agent; sodium methyl paraben, sodium propylparaben, sodium metabisulfite, sodium benzoate and the like., as preservatives; quinoline yellow, sunset yellow, carmoisine, ponceau 4R, brilliant blue, titanium dioxide as colouring agent eithei- singly or as mixtures of two or more.
According to a feature of the invention the content of gelatin and hydroxypropyl methylcellulose phthalate may range from 50mg to 150mg and 5mg to 50mg pei capsule, more preferably 60mg to 140mg and lOmg to 40mg per capsule respectively The amount of glycerine and sorbitol may range from 5mg to 60 mg, more preferably lOmg to 50 mg per capsule. The amount of preservatives may range fi*om O.Olmg to I.Omy pei capsule, more preferably 0.03mgto 0.75mg per capsule. The amount of colouring agent may range from 0.01 to l.Omg per capsule, more preferably 0.05 mg to 0.75 mg per capsule Other plasticisers that can be used are diethyl phthalate, dioctyl phthalate, tnethyi citrate, Triacetin, polyethylene glycol, propylene glycol and the like.

The amount of oils used in the composition may range from 50 mg to 250 mg by weight, more preferably from 75 mg to 225 mg per capsule. The oils used in the vehicle are selected from vegetable origin for example, sesame oil, corn oil, maize oil, soyabean oil, sunflower oil, arachis oil, gingely oil and the like, either singly or as a mixtuie ot'two or more, the oils selected from animal origin may be fish oil, pig oil, beef oil and the like, either singly or as a mixture of two or more and also any mix of animal origin oils and vegetable origin oils or mineral oils such as light liquid paraffin. Esters ol" straight chain aliphatic oils such as sunsoft 700 p-2 (Taiho chemical company), panasete 810 (Nippon oils and fats); hydrogenated vegetable oils and the hydrophilic gels of polyaciylic acid derivatives can also be used.
Materials like glyceryl monostearate, lecithin, polyoxyethylene castor oil derivatives such as cremophor RH 40, cremophor EL (BASF), polyoxyethylene sorbitan tatty acid esters, sodium lauryl sulfate, docussate sodium, and the like may be used as suspending / emulsifying agents, singly or in an appropriate combination and transcutol (Caprylocaproyl macrogol - 8 glycerides) and Labrosol (diethylene glycol monoethyl ethei) aie used as permeation facilitators. The amount of the solubilizer / emulsifying agent may range from 0.5 mg to 35.0 mg per capsule, preferably 1 mg to 30 mg per capsule The amount of permeation facilitators may range from 2 mg to 50 mg, preferably from 5mg to 30 mg per capsule.
Buffering agents used may be selected from phthalates, phosphates or niixtiires thereof The phthalates can be selected from sodium phthalate, potassium biphthalate and phosphates are from sodium phosphate, dibasic sodium phosphate, potassium phosphate, dibasic potassium phosphate and mixtures thereof The amount of buffering agent may range from 0.25 mg to 5.0 mg, preferably 0.5 mg to 3.0 mg per capsule .
Butylated Hydroxy Anisole, Butylated Hydroxy Toluene, sahs of p-hydroxy benzoic acid, benzoic acid and its salts and sodium metabisulfite can be used as antioxidants / preservatives for the vehicle in a concentration range from 0.005 to 0.5 mg per capsule, preferably 0.015 to 0.3 mg per capsule
%.
According to another feature of the invention Musk, Lavender oil and the like may be incorporated as flavours in a concentration in the range of 0.001% to 0.0

The details of the invention are given in the Examples provided below which are |)rovided only to illustrate the invention and therefore they should not be construed to limit the scope of the present invention
EXAMPLE -1
Each capsule contains
mg/capsules
Gelatin 120.00
Sorbitol 15.00
Glycerine 15.00
Hydroxypropyl Methylcellulose phthalate 20.00
Sodium methyl paraben 0.30
Sodium propyl paraben 0.03
Quinoline Yellow 0.10
Titanium dioxide 1.00
Alprostadi! 1.00
Purified water q.s
Sunflower oil 220.00
Butylated Hydroxy anisole 0.20
Butylated Hydroxy Toluene 0.02
Lecithin 18.20
TranSCUtol (caprylocaproyl macrogol-8 glycerides) 3.00
Potassium bi phthalate 3.00
Sodium benzoate 3.00
Polysorbate 80 3.00
HP " p cycio dextrin 9.00
Lavender oil 0.01

The manufacturing process of soft gel capsules involves the following stages:
1. Preparation of gelatin - HPMCP mass.
2. Preparation of medicament composition
3. Encapsulation of medicament composition
4. Trimming and polishing
Gelatin was dissolved in water and sorbitol , glycerine was added to the gelatin solution with continuous stirring. Sodium methyl paraben, sodium propyl paraben, quinoline yellow were dissolved in water and dispersed titanium dioxide and added to the gelaiiii solution with continuous stirring.
Hydroxypropyl methycellulose phthalate was dissolved in ammonia solution \o which the gelatin solution was added with continuous stirring. The semi solid mass was loaded into capsules forming hopper from where uniform weight of mass was delivered to obtain homogeneous structural film.
The inclusion complex of drug and HP-B cyclo dextrin was prepared by dissolving HP-6 cyclo dextrin in water first, adding Alprostadil under stirring and dissolvij)y sodium benzoate in the same solvent. The solution is vacuum dried at 50 ° C to get solid mass. The solid mass was pulverized to obtain fine particles of the complex.
Lecithin was dissolved in Sunflower oil, transcutol and warmed upto 40 ° C and butylated hydroxy anisole and butylated hydroxy toluene were added to it. Potassium hi phthalate and polysorbate 80, flavoring agent lavender oil are mixed with the complex of Alprostadil and is added to the lecithin- sunflower oil solution with continuous stirring to form a suspension.
The hopper of the capsule filling machine is loaded with the above medicament composition for delivering predetermined amount into the blister formed by semi solid containing film forming materials along with the additives. The filled geiaun capsules were trimmed and collected into a receptacle.

EXAMPLE - 2
Each capsule contains

mg/capsule
Gelatin 120.00
Sorbitol 15.00
Glycerine 15.00
Hydroxypropyl Methylcellulose phthalate 20.00
Sodium methyl paraben 0.30
Sodium propyl paraben 0.03
Brilliant blue 0.05
Sunset yellow 0.10
Titanium dioxide 1.00
Alprostadil 1.00
Purified water q.s
Soyabean oil 192.00
Butylated Hydroxy anisole 0.20
Butylated Hydroxy Toluene 0.02
Lecithin 19.00
Labrosol (diethylene glycol mono etliyl ether) 3.00
Potassium bi phthalate 3.00
Sodium benzoate 3.00
Polysorbate 80 9.00
HP - P cyclo dextrin 9.00
Lavender oil 0.01
The manufacturing process of soft gel capsules involves the following stages
1) Preparation of gelatin - HPMCP mass.
2) Preparation of medicament composition
3) Encapsulation of medicament composition
4) Trimming and polishing

Gelatin was dissolved in water and sorbitol, glycerine was added to the gelatin solution with continuous stirring. Sodium methyl paraben, sodium propyl paraben. sunset yellow, brilliant blue were dissolved in water and dispersed titanium dioxide and added to the gelatin solution with continuous stirring.
The hydroxypropyl methycellulose phthalate was dissolved in ammonia solution to which the gelatin solution was added with continuous stirring. The semi soHd mass was loaded into capsules forming hopper from where uniform weight of mass is deliveied lo obtain homogeneous structural film.
The inclusion complex of drug and HP-B cyclo dextrin was prepared by dissolving tIP-B cyclo dextrin in water first, adding Alprostadil under stirring and dissolving sodium benzoate in the same solvent. The solution is vacuum dried at 50 ° C to get solid mass. The solid mass was pulverised to obtain fine particles of the complex.
Lecitin is dissolved in Soyabean oil, lubrosol and warmed upto 40 ° C' and binylated hydroxy anisole and butylated hydroxy toluene were added to it. Potassium bi phthalate and polysorbate 80, flavouring agent Lavender oil are mixed with the complex of Alprostadil and is added to the lecithin- Soyabean oil solution with continuous stirring to form a suspension.
The hopper of the capsule filling machine is loaded with the medicament composition for delivering predetermined amount into the blister formed by semi solid coi^iaining film forming materials along with the additives. The filled capsules are trimmed and collected into a receptacle.
EXAMPLE - 3 Each capsule contains
mg/capsule
Gelatin 120.00
Sorbitol 15.00
Glycerine 15.00
Hydroxypropyl Methylcellulose phthalate 20.00
Sodium methyl paraben 0.30

Sodium propyl paraben 0.03
Quinoline Yellow 0.10
Titanium dioxide 1.00
Alprostadil 1.0
Purified water q.s
Sunflower oil 220.00
TransCUtol (caprylocaproyl niacrogoI-8 glycerides) 18.20
Butylated Hydroxy anisole 0.25
Butylated Hydroxy Toluene 0.025
Potassium bi phthalate 3.0
Sodium benzoate 3.00
Polysorbate 80 3.00
HP - p cyclo dextrin 9.00
Musk 0.01
The manufacturing process of soft gel capsules involves the following stages;
1. Preparation of gelatin - HPMCP mass.
2. Preparation of medicament composition
3. Encapsulation of medicament composition
4. Trimming and polishing of soft gel
Gelatin was dissolved in water and sorbitol , glycerine was added to the gelatiii solution with continuous stirring. Sodium methyl paraben, sodium propyl paraben, quinoline yellow were dissolved in water and dispersed titanium dioxide and added to the gelatin solution with continuous stirring.
Hydroxypropyl methycellulose phthalate was dissolved in ammonia solution to which the gelatin solution was added with continuous stirring. The semi solid mass was loaded into capsules forming hopper from where uniform weight of mass is delivered to obtain homogeneous structural film.

The inclusion complex of drug and HP-B cyclo dextrin was prepared by dissolving HP-6 cyclo dextrin in water first, adding Alprostadil under stirring and dissolving sodium benzoate in the same solvent. The solution is vacuum dried at 50 ° C to get solid mass. The solid mass was pulverised to obtain fine particles of the complex.
Transctol is dissolved in Sunflower oil and warmed upto 40 ** C and buiylaicd hydroxy anisole and butylated hydroxy toluene were added to it. Potassium bi phthalate and polysorbate 80, Flavouring agent Musk, are mixed with the complex of Alpiosiadil and is added to the Transcutol- sunflower oil solution with continuous stining lo form a suspension.
The hopper of the capsule filling machine is loaded with the above medicament composition for delivering predetermined amount into the blister formed by semi solid containing film forming materials along with the additives. The filled capsules were trimmed and collected into a receptacle.
EXAMPLE - 4
Each capsule contains
mg/capsule
Gelatin 120.00
Sorbitol 15.00
Glycerine 15.00
Hydroxypropyl Methylcellulose phthalate 20.00
Sodium methyl paraben 0.30
Sodium propyl paraben 0.03
Brilliant blue 0.05
Sunset yellow 0.10
Titanium dioxide 1.00
Alprostadil 1.00
Purified water q.s
Soyabean oil 192.00
Butylated Hydroxy anisole 0.20

Butylated Hydroxy Toluene 0.02
Transcutol (caprylocaproyl macrogoI-8 glycerides) 19.00
Sodium phthalate 3.00
Sodium benzoate 3.00
Polysorbate 80 9.00
HP - P cyclo dextrin 9.00
Musk 0.01
The manufacturing process of soft gel capsules involves the following stages
1. Preparation of gelatin - HPMCP mass.
2. Preparation of medicament composition
3. Encapsulation of medicament composition
4. Trimming and poUshing of soft gel
Gelatin was dissolved in water and sorbitol , glycerine was added to the gelatin solution with continuous stirring. Sodium methyl paraben, sodium propyl paraben, siinsei yellow, brilliant blue were dissolved in water and dispersed titanium dioxide and added to the gelatin solution with continuous stirring.
The hydroxypropyl methycellulose phthalate was dissolved in ammonia solution to which the gelatin solution was added with continuous stirring. The semi solid mass was loaded into capsules forming hopper from where uniform weight of mass is delivered to obtain homogeneous structural film.
The inclusion complex of drug and HP-B cyclo dextrin was prepared by dissolving HP-B cyclo dextrin in water first, adding Alprostadil under stirring and dissolving sodium benzoate in the same solvent. The solution is vacuum dried at 50 ° C to get solid niass. The solid mass was pulverised to obtain fine particles of the complex.
Transcutol is dissolved in Soyabean oil and warmed upto 40 *^ C and buiylaied hydroxy anisole and butylated hydroxy toluene were added to it. Sodium phthalate and polysorbate 80, flavouring agent Musk are mixed with the complex of Alprostadil and is added to the Transcutol- Soyabean oil solution with continuous stirring to form a suspension

The hopper of the capsule filling machine is loaded with the medicament composition for delivering predetermined amount into the blister formed by semi solid contaimng film forming materials along with the additives. The filled capsules are trimmed and collected into a receptacle.
EXAMPLE - 5

Each capsule contains
Gelatin
Sorbitol
Glycerine
Hydroxypropyl Methylcellulose phthalate
Sodium methyl paraben
Sodium propyl paraben
Quinoline Yellow
Titanium dioxide
Alprostadil
Purified water
Light liquid paraffin
Labrosol (diethylene glycol mono ethyl ether)
Butylated hydroxy toluene
Butylated hydroxy anisole
Sodium benzoate
Disodium hydrogen phosphate
HP p-cyclo dextrin Polysorbate 80 Lavendor oil

mg/capsule
120.00
15.00
15,00
20.00
0.30
0.03
0.10
1.00
1.00
q.s
185.00
15.00
0.10
0.01
3.00
3.00
9.00
9.00
0.01

The manufacturing process of soft gel capsules involves the following stages
1) Preparation of gelatin - HPMCP mass.
2) Preparation of medicament composition

3) Encapsulation of medicament composition
4) Trimming and polishing
Gelatin dissolved in water and sorbitol, glycerine was added to the gelatin sc^lution with continuous stirring. Sodium methyl paraben, sodium propyl paraben, quinohne yellow was dissolved in water and dispersed titanium dioxide and added to the gelatin soliiiion
The hydroxypropyl methycellulose phthalate was dissolved in ammonia solution to which the gelatin solution was added with continuous stirring. The semi solid mass was loaded into capsules forming hopper from where uniform weight of mass is delivered to obtain homogeneous structural film.
The inclusion complex of drug and HP-B cyclo dextrin was prepared by dissolving HP-B cyclo dextrin in water first, adding Alprostadil under stirring and dissolving sodium benzoate in the same solvent. The solution is vacuum dried at 50 ° C to get solid mass. The solid mass was pulverised to obtain fine particles of the complex.
Labrosol is dissolved in light liquid paraffin and warmed upto 40 "" C and butylated hydroxy anisole and butylated hydroxy toluene were added to it. Disodiimi hydrogen phosphate, polysorbate 80, flavouring agent Lavendor oil are mixed with the eomplex of Alprostadil and is added to the Labrosol - Light Liquid Paraffin solution with continuous stirring to form a suspension.
The hopper of the capsule filling machine is loaded with the medicament composition for delivering predetermined amount into the blister formed by semi solid containing film forming materials along with the additives. The filled capsules are trimmed and collected into a receptacle.
EXAMPLE " 6
Each capsule contains
mg / Capsule
Gelatin 120.00

Sorbitol 15.00
Glycerine 15.00
Hydroxypropyl Methylcellulose phthalate 20.00
Sodium methyl paraben 0.30
Sodium propyl paraben 0.03
Quinoline Yellow 0.10
Titanium dioxide 1.00
Alprostadil 1.00
Purified water q.s
Groundnut oil 186.00
Labrosol (diethylene glycol mono etliyl etlier) 18.00
Butylated hydroxy toluene 0.25
Butylated hydroxy anisole 0.025
Sodium benzoate 2.50
Disodium hydrogen phosphate 5.00
HP p-cyclo dextrin 9.00
Polysorbate 80 9.00
Musk 0.01
The manufacturing process of soft gel capsules involves the following stages
1) Preparation of gelatin - HPMCP mass.
2) Preparation of medicament composition
3) Encapsulation of medicament composition
4) Trimming and polishing
Gelatin dissolved in water and sorbitol, glycerine was added to the gelatin sokiiion with continuous stirring. Sodium methyl paraben, sodium propyl paraben, quinoline yellow was dissolved in water and dispersed titanium dioxide and added to the gelatin sokiiion
The hydroxypropyl methycellulose phthalate was dissolved in ammonia solmion lo which the gelatin solution was added with continuous stirring. The semi solid mass was loaded into capsules forming hopper from where uniform weight of mass is deliveied lo obtain homogeneous structural film.

The inclusion complex of drug and HP-fi cyclo dextrin was prepared by dissolving liP-B cyclo dextrin in water first, adding Alprostadil under stirring and dissolving sodium benzoate in the same solvent. The solution is vacuum dried at 50 ° C to gel solid mass. The solid mass was pulverized to obtain fine particles of the complex.
Labrosol is dissolved in Groundnut oil and warmed upto 40 ° C and buiylaied hydroxy anisole and butylated hydroxy toluene were added to it. Disodium hydrogen phosphate, polysorbate 80, Flavouring agent Musk, are mixed with the complex of Alpiosiadil and is added to the Labrosol - Groundnut oil solution with continuous stirring lo form a suspension.
The hopper of the capsule filling machine is loaded with the medicament composition for delivering predetermined amount into the bUster formed by semi solid containing film forming materials along with the additives. The filled capsules are trimmed and collected into a receptacle.
EXAMPLE " 7
Each capsule contains
mg/capsule
Gelatin 120.00
Sorbitol 15.00
Glycerine 15.00
Hydroxypropyl Methylcellulose phthalate 20.00
Sodium methyl paraben 0.30
Sodium propyl paraben 0.03
Quinoline Yellow 0.10
Titanium dioxide 1.00
Alprostadil 1.00
Purified water q.s
Soyabean oil 175.00
Carbopol934 0.50
Labrosol (diethylene glycol mono ethyl etlier) 18.00

Butylated hydroxy toluene 0.015
Butylated hydroxy anisole 0.15
Sodium benzoate 2.50
Disodium hydrogen phosphate 5.00
HP p-cyclo dextrin 9.00
Polysorbate 80 9.00
Lavendor oil 0.01
The manufacturing process of soft gel capsules involves the following sta^^es
1) Preparation of gelatin - HPMCP mass.
2) Preparation of medicament composition
3) Encapsulation of medicament composition
4) Trimming and polishing
Gelatin dissolved in water and sorbitol, glycerine was added to the gelatin solution with continuous stirring. Sodium methyl paraben, sodium propyl paraben, quinolinc yellow was dissolved in water and dispersed titanium dioxide and added to the gelatin solution.
The hydroxypropyl methycellulose phthalate was dissolved in ammonia solution to which the gelatin solution was added with continuous stirring. The semi solid mass was loaded into capsules forming hopper from where uniform weight of mass is delivered to obtain homogeneous structural film.
Carbopol gel was prepared by dispersing the carbopol in purified water, neutralizing with sodium hydroxide and allowed to swell for 24hours. This results in the foi niation of a transparent semi solid gel.
The inclusion complex of drug and HP-B cyclo dextrin was prepared by dissolving HP-B cyclo dextrin in water first, adding Alprostadil under stirring and dissolving sodium benzoate in the same. The solution is vacuum dried at 50 ° C to get solid mass The solid mass was pulverised to obtain fine particles of the complex.
Labrosol is dissolved in Soyabean oil and warmed upto 40 ° C and butylated hydroxy anisole and butylated hydroxy toluene were added to it. Disodium hydiogen phosphate,

polysorbate 80, flavouring agent Lavendor oil, Carbopol 934 are mixed with the complex of Alprostadil and is added to the Labrosol -Soyabean oil solution with continuous stirring to form a suspension.
The hopper of the capsule filling machine is loaded with the medicament composition for delivering predetermined amount into the blister formed by semi solid containing film forming materials along with the additives. The filled capsules are trimmed and collected into a receptacle.
Advantages of the invention
1. The composition is completely biodegradable.
2. The administration of the composition in the fossa navicularis has high elficacy and low incidence of local side effects
3. The composition can be produced on a large scale without difficulty on coniinercially available equipments.
4. Due to the less number of steps involved in the process for the pieparation of the composition it is economical.
5. The patient can use the medicament discretely and easily .
6. The composition is easily portable .
7. The composition has the capability of large-scale acceptance by the users

We claim:
1) A novel and non-invasive pharmaceutical composition in form of a sod gel capsule useful for the treatment of male erectile dysfunction which comprises of a gelatin capsule incorporating a composition comprising of a complex of Alpiostadil and cyclodextrins mixed with Caprylocaproyl macrogol - 8 glycerides or dieihylei)e glycol monoethyl ether or their mixtures dispersed in a suitable pharmaceuiical vehicle comprising of oils, preservatives, antioxidants, emulsifiers, Permeation facilitators, complexing agents, buffers and hydroxypropyl methylcellulose phihalaie as a film forming material.
2) A novel pharmaceutical composition as claimed in claim 1 wherein the amount of Alprostadil used in the composition ranges from 0.25 to 2.5mg, more pieferably 0.5 to 2.0mg per capsule.
3) A novel pharmaceutical composition as claimed in claims 1 and 2 wherein the soft gel shell is made up of materials such as film formers, plasticizeis, preservatives, opacifiers, colorants and optionally flavours.
4) A novel pharmaceutical composition as claimed in claims 1 to 3 wheiein the film formers are selected from gelatin, hydroxypropyl methylcellulose phthahite, cellulose acetate phthalate or mixture there of
5) A novel pharmaceutical composition as claimed in claims 1 to 4 wheiein the amount
of film formers such as gelatin and phthalate derivatives ranges from 30 o to 150.0mg
and 5.0 to SO.Omg per capsule, more preferably 60.0 to 120.0mg and 10 0 lo 40.0mg
per capsule respectively.
6) A novel pharmaceutical composition as claimed in claim 1 to 5 wherein the
Plasticizers such as glycerine, sorbitol.is used.

7) A novel pharmaceutical composition as claimed in claim 6 wherein the amount of plasticizers used ranges from 5.0 to 60.0mg, more preferably 10.0 to 50Omg per capsule.
8) A novel pharmaceutical composition as claimed in claim 1 to 7 wheiein the preservatives used are selected from paraben derivatives such as methyl paraben, sodium methyl paraben or mixture thereof
9) A novel pharmaceutical composition as claimed in claim 9 wherein the amount of preservatives used ranges from 0.005 to 2.0mg, more preferably 0.01 to I Oing per capsule.
10) A novel pharmaceutical composition as claimed in claim 1 to 9 wherein the colouring agents such as brilliant blue, sunset yellow, quinoline yellow, titanium dioxide or mixture thereof is used.
11) A novel pharmaceutical composition as claimed in claim 10 wherein the amount of colouring agents used ranges from 0.01 to l.Omg per capsule more prelerably 0.05 to 0.75mg per capsule.
12) A novel pharmaceutical composition as claimed in claims 1 to 11 wherein the oil used in the composition is selected from vegetable origin such as sesame oil, corn oil, maize oil, soybean oil, sunflower oil, arachis oil, gingly oil and the like; animal oi iyin such as fish oil, pig oil, beef oil and the like; esters of straight chain aliphatic oils such as SunSoft 700 P-2 (Taiho chemical company) Panasete 810 (Nippon oils and Fats); hydrogenated vegetable oils, the hydrophilic gels of poly acrylic acid derivatives such as carbopol 934, carbopol 940 or a mixture thereof
13) A novel pharmaceutical composition as claimed in claim 12 wherein the anuumt of oil used in the medicament composition ranges from 50.0 to 250.0 mg , more |)ieferably from 75.0 to 225.Omg per capsule.

14) A novel pharmaceutical composition as claimed in claims 1 to 13 wherein materials such as glyceryl monostearate, lecithin, polyoxyethylene castor oil denvaiixe such as Cremophor RH 40, Cremophor EL (BASF) polyoxyethylene sorbitan tally acid esters, sodium lauryl sulphate, docusate sodium and the like is used as suspendiny agent / surface active agent.
15) A novel pharmaceutical composition as claimed in claim 14 wherein the amount of the surface-active agent and / or solublising agent used in the formulation ranges from 0.5 to 20.0mg, preferably 1.0 to 15.0mg per capsule.
16) A novel pharmaceutical composition as claimed in claims 1 to 15 wherein permeation facilitators are used
17) A novel pharmaceutical composition as claimed in claim 16 wherein the amount of permeation facilitators used ranges from 2.0 to 50.0mg, more preferably 5 () to 30.0mg per capsule.
18) A novel pharmaceutical composition as claimed in claims 1 to 17 wherein the buffering agents used are selected from phthalates, phosphates or mixtures thereof
19)A novel pharmaceutical composition as claimed in claim 18 wherein tlie phthalates used are selected from sodium phthalate; potassium phthalate and phosphates are selected from sodium phosphate, dibasic sodium phosphate, potassium |:)hosphate, dibasic potassium phosphate and mixtures thereof
20) A novel pharmaceutical composition as claimed in claims 18 and 19 wherein the amount of the buffering agent ranges from 0.25 to lO.Omg, preferably 0 5 to 8 (img per capsule.

21) A novel pharmaceutical composition as claimed in claims 1 to 20 wherein the complexing agents used are selected from cyclodextrins such as a, P and y or derivative such as hydroxypropyl - p-cyclodextrine, hydroxymethyl - P-cyclodextrine or mixtures thereof
22) A novel pharmaceutical composition as claimed in claim 21 wherein the amount of the complexing agent used ranges from 1.0 to 20.0 mg, preferably 5.0 to IS.Omg per capsule.
23) A novel pharmaceutical composition as claimed in claims 1 to 22 wherein the antioxidants / preservatives used are selected from butylated hydroxy anisole, butylated hydroxy toluene, salts of p-hydroxy benzoic acid, benzoic acid and its salts and sodium metabisulfite or the mixtures thereof
24) A novel pharmaceutical composition as claimed in claim 23 wherein the amount of the antioxidants / preservatives used ranges from 0.0 Img to 0. 5mg per capsules preferably 0.015 to 0.2mg per capsule.

25) A novel pharmaceutical composition as claimed in claims 1 to 24 wherein flavouring agents are used which are selected from Musk, Lavender oil.
26) A novel pharmaceutical composition as claimed in claim 25 wherein the amount of the flavouring agent used ranges from O.OOlmg to 0. 05mg per capsule , preferably 0.005 mg to 0.02 mg per capsule.
27) A process for the preparation of the novel and Non-invasive pharmaceutical
composition in the form of soft gelatin capsules useful in the treatment of male erectile
dysfunction which comprises preparing gelatin soft gel composition by dissolving
gelatin and hydroxy propyl methlcellulose phthalate in ammonia solution , adding to
the resulting composition a solution containing plasticizers , opacifiers , preservaties
with continuous stirring loading the resulting mass into a capsule forming hopper from
which the desired uniform weight of the mass for the formulation of the shell and from
the medicament hopper from which the desired uniform weight of the medicament
mass comprisiong ofthe inclusion of a complex of Prostaglandin El (Alprostail) with

Cyclodextrin admixed with other solid ingredients dispersed in oily materials, the inclusion having pH in the range of 3.0 to 7.4 being delivered to obtain a homogeneous soft gelatin capsule incorporating the active ingredient and if desired , trimming and polishing the resulting soft gelatin capsule.
28) A process as claimed in claim in claim 27 wherein the amount of Alprostadil in the composition ranges from 0.25 to 2.5mg, more preferably 0.5 to 2.0mg per capsule.
29) A process as claimed in claim 27 to 28 wherein the soft gel shell is made up of materials such as film formers, plasticizers, preservatives, opacifiers and optionally, colouring and flavouring agents .
30) A process as claimed in claim 29 wherein the film formers used are selected from gelatin, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate.
31) A process as claimed in claim 29 and 30 wherein the amount of film formers such as
gelatin and phthalate derivatives used ranges from 50.0 to 150.0mg and 5.0 to 50.0mg
per capsule, more preferably 60.0 to 120.0mg and 10.0 to 40.0mg per capsule
respectively.
32) A process as claimed in claim 29 to 31 wherein Plasticizers such as glycerine and sorbitol or their mixtures are used.
33) A process as claimed in claim 32 wherein the amount of plasticizers used ranges fi'om 5.0 to 60.0mg, more preferably 10.0 to 50.0mg per capsule.
34) A process as claimed in claim31 to 33 wherein the preservatives used are selected from paraben derivatives such as methyl paraben, sodium methyl paraben or mixture thereof
35) A process as claimed in claim 34 wherein the amount of preservatives used ranges from 0.005 to 2.0mg , more preferably 0.01 tol.Omg per capsule .

36) A process as claimed in claim 27 to 35 wherein the colouring agents used are selected from brilliant blue, sunset yellow, quinoline yellow, titanium dioxide or mixtures thereof
37)37. A process as claimed in claim 27 to 36 wherein the amount of colouring agents used ranges from 0.01 to l.Omg per capsule more preferably 0.05 to 0.75mg per capsule.
38) A process as claimed in claims 27 to 37 wherein the oil in the composition used are selected from vegetable origin such as sesame oil, corn oil, maize oil, soybean oil, sunflower oil, arachis oil, gingly oil and the like; animal origin such as fish oil, pig oil, beef oil and the like; esters of straight chain aliphatic oils such as Sunsoft 700 P-2 (Taiho chemical company) Panasete 810 (Nippon oils and Fats); hydrogenated vegetable oils, the hydrophilic gels of poly acrylic acid derivatives such as carbopol 934, carbopol 940 or a mixture thereof
39) A process as claimed in claims 27 to 38 wherein the amount of oil used in the composition used ranges from 50.0 to 250.0 mg , more preferably from 75.0 to 225.Omg per capsule.
40) A process as claimed in claims 27 to 39 wherein materials such as glyceryl monostearate, lecithin, polyoxyethylene castor oil derivative such as Cremophor RH 40, Cremophor EL (BASF) polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulphate, docusate sodium and the like is used as suspending agent / surface active agent.
41) A Process as claimed in claim 40 wherein the amount of the surface-active agent and / or solublising agent used ranges from 0.5 to 20.Omg, preferably 1.0 to 15.Omg per capsule.
42) A process as claimed in claims 27 to 41 wherein the permeation facilitators used are selected from transcutol, lecithin or labrosol or the mixture thereof

43) A process as claimed in claim 42 wherein the amount of permeation facilitators may range from 2.0 to 50.0mg, more preferably 5.0 to 30.0mg per capsule.
44) A process as claimed in claims 27 to 43 wherein the buffering agents used are selected from phthalates, phosphates or mixtures thereof
45) A process as claimed in claim 44 wherein the amount of the buffering agent may ranges from 0.25 to lO.Omg, preferably 0.5 to S.Omg per capsule.
46) A process as claimed in claims 27 to 45 wherein the phthalates are selected from sodium phthalate; potassium phthalate and phosphates are selected from sodium phosphate, dibasic sodium phosphate, potassium phosphate, dibasic potassium phosphate and mixtures thereof
47) A process as claimed in claims 27 to 46 wherein the complexing agents used are selected from cyclodextrins such as a, P and y or derivative such as hydroxypropyl - p-cyclodextrine, hydroxymethyl - p-cyclodextrine or mixtures thereof.
48) A process as claimed in claim 47 wherein the amount of the complexing agent may ranges from 1.0 to 20.0 mg, preferably 5.0 to 15.0mg per capsule.
49) A Process as claimed in claims 27 to 48 wherein the antioxidants / preservatives used are selected from butylated hydroxy anisole, butylated hydroxy toluene, salts of p-hydroxy benzoic acid, benzoic acid and its salts and sodium metabisulfite or the mixtures thereof
50) A process as claimed in claim 49 wherein the amount of antioxidants / preservatives used ranges from 0.01 mg to 0.5mg per capsules preferably 0.015 to 0.2 mg per capsule.
51) A process as claimed in claims 27 to 50 wherein the flavouring agents used are selected from Musk, Lavender oil.

52) A process as claimed in claim 51 wherein the amount of the flavouring agent used
ranges from 0.001 mg to 0. 05 mg per capsule preferably 0.005 mg to 0.02 mg.
53) A novel and non-invasive pharmaceutical composition in the form of a soft gel capsule
useful for the treatment of substantially as herein described with reference to the
Examples 1 to 5.
54) A process for the preparation of a novel and non-invasive pharmaceutical composition
in the form of a soft gel capsule useful for the treatment of substantially as herein
described with reference to the Examples 1 to 5.

Documents:

605-mas-2002-abstract.pdf

605-mas-2002-claims filed.pdf

605-mas-2002-claims granted.pdf

605-mas-2002-correspondnece-others.pdf

605-mas-2002-correspondnece-po.pdf

605-mas-2002-description(complete)filed.pdf

605-mas-2002-description(complete)granted.pdf

605-mas-2002-description(provisional).pdf

605-mas-2002-form 1.pdf

605-mas-2002-form 5.pdf

605-mas-2002-other documents.pdf

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Patent Number

213128

Indian Patent Application Number

605/MAS/2002

PG Journal Number

13/2008

Publication Date

28-Mar-2008

Grant Date

20-Dec-2007

Date of Filing

20-Aug-2002

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	RAMA RAO PENDYALA	NATCO PHARMA LTD, NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD - 500 033,
2	VENKAIAH CHOWDARY NANNAPANENI	NATCO PHARMA LTD, NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD - 500 033,
3	KHADGAPATHI PODILI	NATCO PHARMA LTD, NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD - 500 033,

PCT International Classification Number

A6K 31/557

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA