DESC:FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising oyster peptide and PDE5 Inhibitor or salts thereof, its process of preparation and method of use of said pharmaceutical composition.

More particularly the present invention relates to a pharmaceutical composition for oral administration comprising combination of oyster peptide and PDE5 Inhibitor or salts thereof, its process of preparation and its use for the treatment of adult patients with erectile dysfunction (ED).

BACKGROUND OF THE INVENTION
Oysters, the most cultured shellfish worldwide, are an important marine biological resource to humans. The chemical composition of oysters is (based on dry flesh weight) as follows: protein (39.1%–53.1%); glycogen (21.6%–38.9%); and fat (7.8%–8.7%).

Methods commonly used for protein extraction include salting out, enzymatic hydrolysis and organic solvent-or/and pH-based protocols.

The most abundant amino acids in oysters are taurine (Tau), glycine (Gly), alanine (Ala), aspartic acid (Asp), glutamic acid (Glu) and proline (Pro). Moreover, since eight essential amino acids account for a high proportion of the total amino acid content of oysters (around 40%), oysters are a complete source of protein.

Oyster peptides (OPs) are obtained by applying peptide molecular biotechnology to oysters processing. OPs are easily absorbed by the organism to exert their bioactivities and completely retain their intrinsic nutrients such as vitamins, trace elements and Tau. In recent years, OPs have been described to have multiple potential bioactivities, such as antioxidant, antimicrobial, antihypertensive, sexual reproductive promoting, anti-inflammatory, anticancer, antimelanogenic, anti-wrinkle, anti-fatigue, anticoagulant, antithrombotic and osteogenic.

Oyster peptides have a demonstrated role in promoting reproduction by effectively increasing the expression of key regulatory proteins in the androgen production pathway, which leads to higher serum testosterone levels and enhanced male sexual function.

Oysters are an excellent source of zinc and contain a higher amount per serving than any other food. Because oysters are rich in zinc, they may help maintain healthy levels of dopamine to enhance sexual function.

A phosphodiesterase type 5 inhibitor (PDE5 inhibitor) is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying various tissues. These drugs dilate the corpora cavernosa of the penis, facilitating erection with sexual stimulation, and are used in the treatment of erectile dysfunction (ED). Examples of PDE5 inhibitors are Sildenafil and Tadalafil.

Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methyl piperazine citrate and has the following structural formula:

(Formula I)

Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7.

Sildenafil citrate Tablet, Oral was first approved by U.S. FDA on Mar 27, 1998 under the brand name VIAGRA for Viatris Specialty LLC it is available in Eq 25mg Base, Eq 50mg Base & Eq 100mg Base strengths. The product is indicated for the treatment of erectile dysfunction.

Tadalafil is designated chemically as pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)­2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-
and has the following structural formula:

(Formula II)

Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C22H19N3O4 representing a molecular weight of 389.41.

It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol.

Tadalafil Tablet, Oral was first approved by U.S. FDA on Nov 21, 2003 under the brand name CIALIS for Eli Lilly and Co. it is available in 2.5mg, 5mg, 10mg, 20mg strengths. The product is indicated for the treatment of erectile dysfunction, benign prostatic hyperplasia and erectile dysfunction and benign prostatic hyperplasia.

To date, no pharmaceutical composition for oral administration comprising combination of Oyster peptides and PDE5 Inhibitor or salt thereof are known. In view of this pharmaceutical composition for oral administration comprising combination of Oyster peptides and PDE5 Inhibitor or salt thereof are desirable over presently available solid dosage forms, as they would offer better and enhanced therapeutic action, better patient compliance and convenience.

The inventors of the present invention surprisingly found that a pharmaceutical composition for oral administration comprising combination of Oyster peptides and PDE5 Inhibitor or salt thereof can be manufactured without using costly and tedious formulation manufacturing instruments.

The inventors of the present invention surprisingly found that a pharmaceutical composition for oral administration comprising combination of Oyster peptides and PDE5 Inhibitor or salt thereof exhibit qualities such as but not limited to high therapeutic efficiency, minimum side effects, storage stability, ready to use composition, easy administration, and better patient compliance and have a significant advance over the available solid dosage forms of PDE5 Inhibitor or salt thereof or Oyster peptides and fulfills the long felt need to provide synergistic composition. As PDE5 Inhibitor or salts thereof and Oyster peptide having different mechanism of action in the treatment of Erectile Dysfunction (ED) combination of both the actives (API) produces synergistic action without any side effects.

Further, a pharmaceutical composition for oral administration comprising combination of Oyster peptides and PDE5 Inhibitor or salt thereof is indicated for the treatment of adult patients with Erectile Dysfunction (ED).

OBJECTIVES OF THE INVENTION
The main objective of the present invention is to develop a pharmaceutical composition comprising oyster peptide and PDE5 Inhibitor(s) or salts thereof, for oral administration.

Another objective of the present invention is to develop a pharmaceutical composition for oral administration comprising oyster peptide and PDE5 Inhibitor(s) or salts thereof and its process of preparation and its use for the treatment of adult patients with Erectile Dysfunction (ED).

SUMMARY OF THE INVENTION
The present invention discloses a pharmaceutical composition, comprising: a) oyster peptide; b) PDE5 Inhibitor(s) or salts thereof; and c) one or more pharmaceutically acceptable excipient.

In a feature of the present invention, the oyster peptide is present in an amount of from about 0.1% to about 40% by weight with respect to total weight of the pharmaceutical composition.

In a feature of the present invention, the PDE5 Inhibitor(s) or salts thereof is present in an amount of from about 1.0% to about 50% by weight with respect to total weight of the pharmaceutical composition.

The present invention also discloses a pharmaceutical composition, comprising: a) 0.1-40% w/w of oyster peptide; b) 1.0-50% PDE5 Inhibitor(s) or salts thereof; b) 30-90% w/w of at least one diluent; c) 0.5%-30% w/w of a binder; d) 0.1-20% w/w of a surfactant; e) 0.1-5% w/w of a lubricant; f) optionally, 1%-15% w/w of a disintegrant; and g) a pharmaceutically acceptable excipient; wherein said composition is optionally coated.

In a feature of the present invention, the pharmaceutically acceptable excipient is selected from the group consisting of diluents or filler, disintegrants, binders, solubilizing agent, surfactant, absorption enhancer, bioadhesive agents or mucoadhesion promoting agent, polymers or release modifying agent, carriers, plasticiser, penetration enhancer, bases, lubricant, glidant, acidic agent, basic agent, chelators, sweeteners, flavoring agent, pH regulating agent, preservatives, antioxidants, coloring agents, solvents, taste masking agent, antifoaming agents, flow agents and opacifiers, antiadherent, stabilizing agent, antistatic agent, viscosity adjuster and coating agent.

In a feature of the present invention, the composition is in the form of tablet, capsule, granule, pellet, bead, sachet or powder.

In a feature of the present invention, the composition is prepared by a manufacturing process selected from a group comprising of solvent casting, solvent evaporation, hot-melt extrusion, semisolid casting, rolling, direct compression, dry granulation, wet granulation, spray granulation and extrusion-spheronization.

The present invention also discloses a process of preparing pharmaceutical composition, comprising the step of admixing the PDE5 Inhibitor(s) or salts thereof and oyster peptide along with one or more excipient selected from a group consisting of diluents or filler, disintegrants, binders, solubilizing agent, surfactant, absorption enhancer, bioadhesive agents or mucoadhesion promoting agent, polymers or release modifying agent, carriers, plasticiser, penetration enhancer, bases, lubricant, glidant, acidic agent, basic agent, chelators, sweeteners, flavoring agent, pH regulating agent, preservatives, antioxidants, coloring agents, solvents, taste masking agent, antifoaming agents, flow agents and opacifiers, antiadherent, stabilizing agent, antistatic agent, viscosity adjuster and coating agent.

DETAILED DESCRIPTION OF THE INVENTION
The term "composition" or "pharmaceutical composition" or "pharmaceutical composition for oral administration" as used herein synonymously include dosage forms such as a tablet, capsule, powder, granules, pellets, caplets, pills, soft gelatin capsules, mini tablets, solution, syrup, suspension, emulsion, elixir or the like.

The term “composition”, as in pharmaceutical composition, is intended to encompass a drug product(s) comprising combination of oyster peptide and PDE5 Inhibitor(s) or salts thereof and other inert ingredient(s) (pharmaceutically acceptable excipients).

The present invention relates to a pharmaceutical composition comprising oyster peptide and PDE5 Inhibitor(s) or salts thereof, for oral administration and at least one pharmaceutically acceptable excipient.

The term “PDE5 Inhibitor(s)” is used in broad sense to include not only “PDE5 Inhibitor” per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, prodrugs thereof.
PDE5 inhibitor(s) are selected from but not limited to Sildenafil or salt thereof, Tadalafil or salt thereof or combination thereof.

The term “oyster peptide” is used in broad sense to include a small molecular collagen peptide, it is extracted from fresh oyster or natural dried oyster by special treatment(s)/technology.

The term “Pharmaceutically acceptable salts” or “salt thereof” as used herein, includes those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, which are well known in the art.

Pharmaceutically acceptable salts include, but are not limited to, any of the salts or cocrystals of PDE5 Inhibitor(s) selected from citrate, hydrochloride, hydrobromide, sulphate, phosphate, maleate, formate, acetate, nitrate, mesylate, succinate, benzoate or the like.

The term “stable” as used herein, refers to any composition comprising a drug having sufficient physical and chemical stability at the time of manufacturing of the composition and during shelf life.

The term "treating" or "treatment" refers to obtaining desired pharmacological and/or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder or delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.

"Pharmaceutically acceptable excipient(s)" are components that are added to the pharmaceutical composition other than the active ingredients oyster peptide and PDE5 Inhibitor(s) or salts thereof. Excipients may be added to facilitate manufacture, enhance stability, enhance product characteristics, enhance patient acceptability etc. Pharmaceutically acceptable excipient(s) includes, but not limited to, diluents or filler, disintegrants, binders, solubilizing agent, surfactant, absorption enhancer, bio-adhesive agents or muco-adhesion promoting agent, polymers or release modifying agent, carriers, plasticizer, penetration enhancer, bases, lubricant, glidant, acidic agent, basic agent, chelators, sweeteners, flavoring agent, pH regulating agent, preservatives, antioxidants, coloring agents, solvents, taste masking agent, antifoaming agents, flow agents and opacifiers, anti-adherent, stabilizing agent, antistatic agent, viscosity adjuster and coating agent and any other excipient known to the art for making pharmaceutical composition.

The term "substantially", for example, when used in terms such as "substantially pure", please understand that in the context of the present invention, it refers specifically to individual compositions /active (API) compounds, etc. Wherein the term “substantially pure oyster peptide” used, comprises oyster peptide having more than 50 percent purity, specifically more than 80 percent purity, more specifically more than 90 percent purity and furthermore specifically comprises more than 95 percent purity by weight.

In one embodiment, an invention provides a pharmaceutical composition comprising oyster peptide and PDE5 Inhibitor(s) or salts thereof, for oral administration.

In one embodiment, an invention provides a pharmaceutical composition for oral administration comprising:
a) Oyster peptide; and
b) PDE5 Inhibitor(s) or salts thereof; and
c) One or more suitable pharmaceutically acceptable excipient.

In one embodiment, an invention provides a pharmaceutical composition for oral administration comprising:
a) Substantially pure Oyster peptide;
b) PDE5 Inhibitor(s) or salts thereof; and
c) One or more suitable pharmaceutically acceptable excipient.

In another embodiment, an invention also relates to a process of preparation of a pharmaceutical composition for oral administration comprising oyster peptide and PDE5 Inhibitor(s) or salts thereof.

The pharmaceutically acceptable excipients are selected from the group consisting of diluents or filler, disintegrants, binders, solubilizing agent, surfactant, absorption enhancer, bio-adhesive agents or muco-adhesion promoting agent, polymers or release modifying agent, carriers, plasticizer, penetration enhancer, bases, lubricant, glidant, acidic agent, basic agent, chelators, sweeteners, flavoring agent, pH regulating agent, preservatives, antioxidants, coloring agents, solvents, taste masking agent, antifoaming agents, flow agents and opacifiers, antiadherent, stabilizing agent, antistatic agent, viscosity adjuster and coating agent and any other excipient known to the art for making pharmaceutical composition.

The examples of diluent or filler according to present invention include but not limited to group comprising of citric acid, mannitol, carboxymethyl cellulose (carmellose), calcium hydrogen phosphate, sodium carboxymethyl cellulose (carmellose sodium), hydroxypropyl cellulose, corn starch, potato starch, microcrystalline cellulose, anhydrous lactose, lactose monohydrate and the mixtures thereof.

The diluents according to present invention may be present in an amount from about 10% to about 95% by weight with respect to total weight of the pharmaceutical composition, preferably 30% to 90% w/w.

The examples of disintegrants according to present invention include but not limited to group comprising of croscarmellose sodium, croscarmellose potassium, carboxymethyl cellulose, chitosan, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, starch, sodium starch glycolate, light anhydrous silicic acid, low substituted hydroxypropylcellulose, lactose, sucrose, starch, silicified microcrystalline cellulose, polarcilin potassium, crosslinked polyvinylpyrrolidone, ethyl hydroxyethyl cellulose, modified cellulose gum; moderately cross-linked starch, modified starch, hydroxylpropyl starch and pregelatinized starch; calcium alginate, sodium alginate, alginic acid, chitosan, colloidal silicon dioxide, docusate sodium, guar gum, agar, locust bean, karaya, pectin and tragacanth, magnesium aluminium silicate, polyvinylpyrrolidone or mixture thereof.

The disintegrants according to present invention may be present in an amount from about 1%-15% by weight with respect to total weight of the pharmaceutical composition.

The examples of binders according to present invention include but not limited to group comprising of microcrystalline cellulose, alginic acid, potato starch, corn starch, wheat starch, ethyl cellulose, gelatin, cellulose-based polymers like methylcellulose, ethylcellulose, hydroxylated derivatives, hydroxyethyl cellulose, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, dihydroxy propylcellulose, hypromellose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetosuccinate, acrylic polymers and polyethylene glycols, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, copovidone, sodium starch glycolate, starch, trehalose, flurane, sucrose, D-mannitol, sodium alginate, cellulose gum, pregelatinized starch, guar gum, pullulan, gum arabic, bentonites, sugars, invert sugars, polyvinyl pyrrolidone, polyacrylamides, polyvinyloxoazolidone, polyvinyl alcohols, or mixture thereof.

The binders according to present invention may be present in an amount from about 0.5%-30% by weight with respect to total weight of the pharmaceutical composition.

The examples of solubilizing agents or solubility enhancer according to present invention include but not limited to group comprising of cyclodextrin and/or its derivatives, 2-Hydroxypropyl-beta-cyclodextrin (Kleptose), polyethylene glycol, polyvinylpyrrolidone, dextran, sugars such as sucrose, lactose or dextrose, mannitol, sorbitol or lactitol, sodium chloride or mixture thereof.

The examples of surfactants according to present invention include but not limited to group comprising of cationic, anionic, nonionic or amphoteric agents, polysorbate, sodium lauryl sulphate, polyoxyethylene, polyoxypropylene glycol, the monooleate, the monolaurate, the monopalmitate, the monostearate, the trioleate, the tristearate or any other ester of polyoxyethylenated sorbitan, glycerides of polyoxyethylenated fatty acids, poloxamers, ethylene oxide/propylene oxide block copolymers, lecithin, stearyl alcohol, cetearyl alcohol, cholesterol, polyoxyethylenated castor oil, fatty alcohol polyoxyethylenated ethers, and polyoxyethylenated stearates, cetyl alcohol, spans and tweens, ethoxylated oils, including ethoxylated castor oils, such as cremophor or mixture thereof.

The surfactants according to present invention may be present in an amount from about 0.1%-20% by weight with respect to total weight of the pharmaceutical composition.

The examples of absorption enhancer according to present invention include but not limited to group comprising of sodium lauryl sulphate, sodium caprate or chitosans, and also P-glycoprotein (P-gp) inhibitors, such as polysorbates, sorbitan esters, poloxamer block copolymers, PEG-35 castor oil, PEG-40 hydrogenated castor oil, caprylocaproyl macrogol-8 glycerides, PEG-8 caprylic/capric glycerides, dioctyl sulfosuccinate, polyethylene lauryl ether, ethoxydiglycol, propylene glycol mono-di-caprylate, glycerol monocaprylate, glyceryl fatty acids (C8-C18) ethoxylated, oleic acid, linoleic acid, glyceryl caprylate/caprate, glyceryl monooleate, glyceryl monolaurate, caprylic/capric triglycerides, ethoxylated nonylphenols, PEG-(8-50) stearates, olive oil PEG-6 esters, triolein PEG-6 esters, lecithin, d-alpha tocopheryl polyethylene glycol 1000 succinate, polycarbonate, sodium glycocholate, sodium taurocholate, cyclodextrins, citric acid, sodium citrate, triacetin, combinations thereof or the like.

The examples of bioadhesive agents or mucoadhesion promoting agents according to present invention include but not limited to group comprising of carbomers, sodium carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, gelatine, guar gum, polyethylene oxide, and dextran, carbopol 934 P, methocel, polycarbophil, sodium hyaluronate and other natural or synthetic bioadhesives, cellulose derivatives such as modified cellulose gum and, more particularly, methyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose, starch derivatives such as modified starch, sodium starch glycolate and, more particularly, moderately cross-linked starch; acrylic polymers, polyvinylpyrrolidone; polyethylene oxide (PEO), chitosan (poly-(D-glucosamine); natural polymers such as gelatin, sodium alginate, pectin; scleroglucan; xanthan gum; poly co-(methylvinyl ether/maleic anhydride); and crosscarmellose (e.g. crosscarmellose sodium) or mixture thereof.

The examples of polymers or release modifying agent include but not limited to cellulosic polymers, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), methylcellulose (MC), powdered cellulose such as microcrystalline cellulose, cellulose acetate, sodium carboxymethylcellulose, calcium salt of carboxymethylcellulose, ethylcellulose; alginates, gums such as guar and xanthan gums; cross-linked polyacrylic acid derivatives such as Carbomers available in various molecular weight grades; carageenan; polyvinyl pyrrolidone and its derivatives such as crospovidone; polyethylene oxides; and polyvinyl alcohol, glyceryl monostearate, mixtures of glyceryl monostearate and glyceryl monopalmitate, glycerylmonooleate, a mixture of mono, di and tri-glycerides, glycerylmonolaurate, glyceryl behenate, paraffin, white wax, long chain carboxylic acids, long chain carboxylic acid esters and long chain carboxylic acid alcohols. Suitable pH-sensitive enteric polymers include cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic monoester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer or mixture thereof.

The examples of carriers according to present invention include but not limited to group comprising of mannitol, carbohydrates, e.g., sugars, such as lactose, and sugar alcohols, such as mannitol, sorbitol and xylitol; pharmaceutically-acceptable inorganic salts, such as sodium chloride. Water soluble carrier particles (poly)saccharides like hydrolysed dextran, dextrin, alginates and may also comprise the weakly acidic, and/or weakly acidic buffer forming materials such as citric acid and/or sodium citrate, insoluble or sparingly soluble in water, such as dicalcium phosphate anhydrate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium carbonate, and barium sulphate; starch and pre-gelatinised starch; bioadhesive and mucoadhesive materials, such as polyvinylalcohol, polyvinylpyrrolidine, crosslinked polyvinylpyrrolidone and croscarmellose sodium and other polymers, such as microcrystalline cellulose, hydroxypropyl cellulose, water, buffer, saline, buffered saline, dextrose solution, propylene glycol, polyethylene glycols, miglyol or mixtures thereof.

The examples of plasticizers according to present invention include but not limited to group comprising of polyalkylene oxides, such as polyethylene glycols, polypropylene glycols, polyethylene-propylene glycols, organic plasticizers with low molecular weights, such as glycerol, glycerol monoacetate, diacetate or triacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol, sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate, fatty acid esters, such as glyceryl oleate, polyalcohols, sorbitan esters, citric acid esters, polyvinyl alcohol, polyvinyl methyl ether, triacetin; mannitol, xylitol, and sorbitol or mixtures thereof.

The examples of penetration enhancers according to present invention include but not limited to group comprising of bile salts, such as sodium cholate, sodium glycocholate, sodium glycodeoxycholate, taurodeoxycholate, sodium deoxycholate, sodium lithocholate chenocholate, chenodeoxycholate, ursocholate, ursodeoxy-cholate, hyodeoxycholate, dehydrocholate, glycochenocholate, taurochenocholate, and taurochenodeoxycholate; sodium dodecyl sulfate (SDS), dimethyl sulfoxide (DMSO), N-lauroyl sacrcosine, sorbitan monolaurate, stearyl methacrylate, N-dodecylazacycloheptan-2-one, N-dodecyl-2-pyrrolidinone, N-dodecyl-2-piperidinone, 2-(1-nonyl)-1,3-dioxolane, N-(2-methoxymethyl)dodecylamine, N-dodecylethanolamine, N-dodecyl-N-(2-methoxymethyl)acetamide, 1-N-dodecyl-2-pyrrolidone-5-carboxylic acid, 2-pentyl-2-oxo-pyrrolidineacetic acid, 2-dodecyl-2-oxo-1-pyrrolidineacetic acid, 2-dodecyl-2-oxo-1-pyrrolidineacetic acid, 1-azacylioheptan-2-one-dodecylacetic acid, menthol, propylene glycol, glycerol monostearate, sorbitol monolaurate, glycerol dilaurate, tocopherol acetate, phosphatidyl choline, glycerol, polyethyleneglycol, monoglycerides, diglycerides, triglycerides, lecithin, tween surfactants, sorbitan surfactants, sodium lauryl sulfate; salts and other derivatives of saturated and unsaturated fatty acids, surfactants, bile salt analogs, derivatives of bile salts, inclusion compounds, such as cyclodextrins and caged molecules; coloring agents; and flavors, cyclodextrin derivatives like hydroxypropyl, hydroxyethyl, glucosyl, maltosyl, ß-cyclodextrin maltotriosyl derivatives, ?-cyclodextrin maltotriosyl derivatives or mixtures thereof.

The examples of bases according to present invention include but not limited to group comprising of hydrophilic bases include, for example, polyethylene glycol, polyvinylpyrrolidone, D-mannitol, D-sorbitol, xylitol, lactose, white sugar, maltose anhydrous, D-fructose, dextran, glucose, polyoxyethylene curing It may be at least one selected from the group consisting of castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan higher fatty acid ester, citric acid, tartaric acid, glycine, ß-alanine, lysine hydrochloride and meglumine or mixture thereof.

The examples of lubricant according to present invention include but not limited to group comprising of calcium stearate, magnesium stearate, Sodium stearyl fumarate, fumaric acid, calcium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, colloidal silica, sucrose fatty acid esters, stearic acid, zinc stearate, hydrogenated vegetable oil, mineral oil, glyceryl behenate, polyoxyethylene glycols, sodium benzoate, dimethicone or liquid paraffin, or mixture thereof.

The lubricant according to present invention may be present in an amount from about 0.1% to about 10% by weight with respect to total weight of the pharmaceutical composition, preferably 0.1-5% w/w.

The examples of glidant according to present invention include but not limited to group comprising of colloidal silica, pyrogenic silica, hydrated sodium silicoaluminate, magnesium stearate, sodium stearyl fumarate, fumed silica (colloidal silicon dioxide), starch, talc, calcium phosphate tribasic, powdered cellulose, magnesium oxide; magnesium silicate, magnesium trisilicate, stearic acid, calcium stearate or mixture thereof.

The examples of basic agents according to present invention include but not limited to group comprising of potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, arginine carbonate, glycine carbonate or lithium carbonate, calcium carbonate, ammonium carbonate, L-lysine carbonate, sodium glycine carbonate, sodium carbonates of amino acids, anhydrous sodium perborate, effervescent perborate, sodium perborate monohydrate, sodium percarbonate, sodium dichloroisocyanurate, sodium hypochlorite, calcium hypochlorite, tris, tartrate, acetate, phosphate or mixture thereof.

The examples of chelators according to present invention include but not limited to group comprising of ethylene diamine tetra acetic acid (EDTA), proteins, polysaccharides, polynucleic acids, glutamic acid, histidine, organic diacids, polypeptides, phytochelatin, hemoglobin, chlorophyll, humic acid, phosphonates, transferrin, desferrioxamine, and combinations thereof.

The examples of sweeteners according to present invention include but not limited to group comprising of dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, saccharose, glucose, maltose, galactose, and artificial sweeteners, such as acesulfame potassium, sodium saccharin, cyclamates, sucralose, sodium saccharinate, neohesperidine dihydrochalcone, monoammonium glycyrrhizinate, Thaumatic, dextrose, invert sugar, fructose, Stevia Rebaudiana (Stevioside); sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Also contemplated are hydrogenated starch hydrolysates and the synthetic sweetener Acesulfame, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof, and natural intensive sweeteners, or mixture thereof.

The examples of flavoring agent according to present invention include but not limited to group comprising of fruit flavor, peppermint flavor, lemon, lemon-lime, orange, sour cherry, flavor of mint, honey lemon, vanilla, citrus oil, grapefruit grape, menthol, cranberry, vanilla berry, bubble gum, cherry, alpha-citral, beta-citral, decanal, aldehyde C-8, aldehyde C-9, aldehyde C-12, and volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. mint oils, cocoa, and citrus oils such as lemon, orange, grape, lime, cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil, grapefruit and fruit essences including apple, pear, peach, strawberry, raspberry, plum, pineapple, apricot or other fruit flavors or mixture thereof.

The examples of pH regulating agent according to present invention include but not limited to group comprising of hydrochloric acid, fumarate, citrate, phosphate, carbonate, tartrate, acetate, amino acid, citric acid and sodium citrate or potassium citrate, sodium hydroxide, monoethanolamine, diethanolamine, sodium bicarbonate or potassium bicarbonate, sodium phosphate, tartaric acid, propionic acid, lactic acid, maleic acid, succinic acid, phosphoric acid, boric acid, succinic acid/monosodium succinate, glycine/sodium glycine, malic acid/sodium malate, phosphoric acid/sodium phosphate, fumaric acid/sodium fumarate, monosodium phosphate/disodium phosphate, and boric acid/sodium borate and monosodium glutamate or mixture thereof.

The examples of the preservatives according to present invention include but not limited to group comprising of phenethyl alcohol, benzyl alcohol, p-hydroxybenzoate esters, chlorobutanol, dehydroacetic acid, sorbic acid or mixtures thereof.

The examples of the antioxidants according to present invention include but not limited to group comprising of butylated hydroxytoluene (BHT), hydrogen sulfite, ascorbic acid, sodium ascorbate, erythorbic acid, sodium nitrite, propyl gallate (PG), butylhydroxyanisol (BHA), sodium bisulfite, sodium pyrosulfite, citric acid, and edetate sodium, Sodium bicarbonate, sodium citrate, sodium citrate, sodium metabisulfate, sodium tartrate, sodium sulphite, sodium metabisulphite, Sodium sulfate, potassium metabisulphite, potassium, bisulphite, potassium sulphite, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole, thiols (e.g., aurothioglucose, dihydrolipoic acid, propylthiouracil, thioredoxin, glutathione, glutathione peroxidase or peroxidase catalase, cysteine, cystine, cystamine, thiodipropionic acid), sulphoximines (e.g., buthionine-sulphoximines, homo-cysteine-sulphoximine, buthionine-sulphones, and penta-, hexa- and heptathionine-sulphoximine), metal chelators (e.g, .alpha.-hydroxy-fatty acids, palmitic acid, phytic acid, lactoferrin, lactic acid, and malic acid, humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTA, and DTPA), vitamins (e.g., vitamin E, vitamin C, ascorbyl palmitate, Mg ascorbyl phosphate, and ascorbyl acetate), phenols (e.g., butylhydroxytoluene, butylhydroxyanisole, ubiquinol, nordihydroguaiaretic acid, trihydroxybutyrophenone), benzoates (e.g. coniferyl benzoate), uric acid, mannose, selenium (e.g., selenium-methionine), stilbenes (e.g. stilbene oxide and trans-stilbene oxide), superoxide dismutase (SOD) or mixtures thereof.

The examples of the coloring agents according to present invention include but not limited to group comprising of carmine, caramel, ß-carotene, titanium oxide, talc, riboflavin sodium phosphate, hydrogenated starch hydrolysate, food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors are dyes, their corresponding lakes, and certain natural and derived colorants, yellow aluminum lake natural pigments (examples: beta-carotene, chlorophyll, and colcothar), water-insoluble lake pigments (examples: aluminum salts of the above water-soluble edible tar pigments), water-soluble edible tar pigments (examples: edible pigments such as food red No. 2, food red No. 3, food yellow No: 4, food yellow No. 5, food blue No. 1, and food blue No. 2), blue lake, titanium dioxide, natural coloring agents such as grape skin extract, beet red powder, annato, carmine, turmeric, paprika or mixtures thereof.

The examples of solvents according to present invention include but not limited to group comprising of aqueous or inert organic solvents or inorganic acids, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic solvents, aromatic solvents, heterocyclic solvents, and mixtures thereof. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl ethyl ketone, methylene chloride, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water, hydrochloric acid (HCl), aqueous solvents containing inorganic salts (such as sodium chloride, calcium chloride, and the like), and mixtures thereof (such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol) or mixture thereof.

The examples of taste masking agent according to present invention include but not limited to group comprising of ionic exchange resins including a water-insoluble organic or inorganic matrix material having covalently bound functional groups that are ionic or capable of being ionized under appropriate conditions. The organic matrix may be synthetic (e.g., polymers or copolymers or acrylic acid, methacrylic acid, sulfonated styrene or sulfonated divinylbenzene) or partially synthetic (e.g., modified cellulose or dextrans). The inorganic matrix may be, for example, silica gel modified by the addition of ionic groups. Most ion exchange resins are cross-linked by a crosslinking agent, such as divinylbenzene, sodium bicarbonate, cyclodextrin inclusion compounds, adsorbates or mixture thereof.

The examples of anti-foaming agents according to present invention include but not limited to group comprising of certain alcohols (cetostearyl alcohol), insoluble oils (castor oil), stearates, polydimethylsiloxanes and other silicones derivatives, ether and glycols or mixture thereof.

The examples of flow agents and opacifiers according to present invention include but not limited to group comprising of such as the oxides of magnesium, aluminum, silicon, titanium or mixture thereof

The examples of antiadherent according to present invention include but not limited to group comprising of talc, corn starch, colloidal silica, DL-leucine, sodium lauryl sulphate, stearates or mixture thereof.

The examples of stabilizing agent according to present invention include but not limited to group comprising of tocopherol, cyclodextrin tetrasodium edetate, nicotinamide, thermo-setting gels such as pectin, carageenan, and gelatin, yellow ferric oxide, red ferric oxide, black iron oxide or mixture thereof.

The examples of antistatic agents according to present invention include but not limited to group comprising of micronized or nonmicronized talc, colloidal silica, treated silica or precipitated silica or mixtures thereof.

The examples of viscosity adjusters according to present invention include but not limited to group comprising of alginate, carrageenan, hydroxypropyl methyl cellulose, locust bean gum, guar gum, xanthan gum, dextran, gum arabic, gellan gum or mixtures thereof.

The examples of coating agents according to present invention include but not limited to a film coating agent or the like. for example, an opadry film coating agents or film coating agent known in the prior art for pharmaceutical dosage form.

In another embodiment, there is provided a method of using a pharmaceutical composition for oral administration comprising oyster peptide and PDE5 Inhibitor(s) or salts thereof for the treatment of adult patients with Erectile Dysfunction (ED).

In another embodiment, the pharmaceutical composition, comprising: a) 0.1-40% w/w of oyster peptide; b) 1.0-50% PDE5 Inhibitor(s) or salts thereof; b) 30-90% w/w of at least one diluent; c) 0.5%-30% w/w of a binder; d) 0.1-20% w/w of a surfactant; e) 0.1-5% w/w of a lubricant; f) Optionally, 1%-15% w/w of a disintegrant; and g) a pharmaceutically acceptable excipient; wherein said composition is optionally coated.

The process of manufacturing pharmaceutical composition according to present invention involves admixing Oyster Peptide and PDE5 Inhibitor(s) along with one or more pharmaceutically acceptable excipient selected from the group consisting of diluents or filler, disintegrants, binders, solubilizing agent, surfactant, absorption enhancer, bio-adhesive agents or muco-adhesion promoting agent, polymers or release modifying agent, carriers, plasticizer, penetration enhancer, bases, lubricant, glidant, acidic agent, basic agent, chelators, sweeteners, flavoring agent, pH regulating agent, preservatives, antioxidants, coloring agents, solvents, taste masking agent, antifoaming agents, flow agents and opacifiers, antiadherent, stabilizing agent, antistatic agent, viscosity adjuster and coating agent.

The novel pharmaceutical composition according to present invention were evaluated for appearance, average weight, thickness, hardness, disintegration time, assay, dissolution, moisture content and were found to be within the specifications.

The pharmaceutical composition of the present invention is packaged in suitable airtight containers and moisture proof packs. The novel pharmaceutical composition of the present invention preferably packaged into the strip, blister, bottle or sachet.

EXAMPLES

Example 1:
Sr. No Ingredient Weight
(mg/tablet) % w/w
1 Sildenafil 140.48 25.2
2 Oyster Peptide 120.00 21.6
3 Dibasic Calcium Phosphate Anhydrous 48.52 8.7
4 Microcrystalline Cellulose 101 65.00 11.7
5 Microcrystalline Cellulose 102 103.00 18.5
6 Hydroxypropyl Cellulose-L 10.00 1.8
7 Sodium Lauryl Sulfate 7.00 1.2
8 Sodium Starch Glycolate 22.00 4.0
9 R-Somalt 20.00 3.6
10 Magnesium Stearate 4.00 0.7
11 Purified Water q.s q.s
Core tablet weight 540.00
12 Novomix Blue 16.20 3.0
Coated tablet weight 556.20 100.00

Manufacturing Process:
1. All raw materials were dispensed accurately;
2. Sift Sildenafil, Dibasic calcium phosphate anhydrous, Microcrystalline cellulose 101, Hydroxypropyl cellulose-L and Sodium Starch Glycolate through sieve 40#;
3. Sift Sodium Lauryl Sulfate through sieve 60#;
4. The blend of step 2 was mixed with blend of step 3;
5. Binder addition: Weigh required quantity of purified water (binder) and carry out granulation;
6. Spraying was done using sprays;
7. Drying was done in FBP, Loss on Drying (LOD) was checked;
8. Material from FBP unloaded and passed through sieve no.30#;
9. Prelubricarion: Microcrystalline cellulose 102, Oyster peptide, R-Somalt and Sodium starch glycolate, was sifted through sieve no.40# and pre-lubricated with dried granules;
10. Lubrication: Magnesium stearate was sifted through sieve no.60# and lubricated with dried granules of step 9; and
11. Compression: Blend was compressed using 11.50 x 8.2mm diamond shape punch;
12. Film Coating: Core tablets were coated using Novomix 20098 Blue in a suitable coating machine.

Stability Data (Example 1):
Sr No Test Parameter Specification Initial 3M 6M 3M 6M 3M 6M
40oC±2oC/75±5 % RH 30oC±2oC/75±5 % RH 25oC±2oC/60±5 % RH
1. Moisture Content NMT 5.0% w/w 2.65 2.70 2.80 2.87 2.85 2.75 2.72
2. Assay 90.0% to 110% of label claim 101.70 101.30 99.59 101.20 101.00 100.89 100.68
3. Dissolution
0.01 N HCl, 900mL, 100rpm, USP type-I (basket) Limit: 15min : NLT 80% (Q) 91.0 93.0 90.0 91.0 89.0 93.0 92.0
NMT: Not more than, M: Months, NLT: Not less than, Mins: Minutes

Example: 2:
Sr. No Ingredient Weight
(mg/tablet) % w/w
1 Sildenafil 140.48 25.2
2 Oyster Peptide 10.00 1.8
3 Lactose monohydrate 200 M 116.52 21.0
4 Microcrystalline Cellulose 102 240.00 43.1
5 Hydroxypropyl Cellulose-L 5.00 0.9
6 Sodium Lauryl Sulfate 4.00 0.7
7 R-Somalt 20.00 3.6
8 Magnesium Stearate 4.00 0.7
9 Purified Water q.s q.s
Core tablet weight 540.00
10 Novomix Blue 16.20 3.0
Coated tablet weight 556.2 100.00

Manufacturing Process:
1. All raw materials were dispensed accurately;
2. Sift Sildenafil, Lactose monohydrate 200 M and Hydroxypropyl cellulose-L through sieve 40#;
3. Binder addition: Weigh required quantity of purified water (binder) and carry out granulation;
4. Spraying was done using sprays;
5. Drying was done in FBP, Loss on Drying (LOD) was checked;
6. Material from FBP unloaded and passed through sieve no.30#;
7. Pre-lubrication: Microcrystalline cellulose 102, Oyster peptide, R-Somalt and Sodium lauryl sulfate, was sifted through sieve no.40# and pre-lubricated with dried granules;
8. Lubrication: Magnesium stearate was sifted through sieve no.60# and lubricated with dried granules of step 7; and
9. Compression: Blend was compressed using 11.50 x 8.2 mm diamond shape punch;
10. Film Coating: Core tablets were coated using Novomix Blue in a suitable coating machine.

Stability Data (Example 2):
Sr No Test Parameter Specification Initial 3M 6M 3M 6M 3M 6M
40oC±2oC/75±5 % RH 30oC±2oC/75±5 % RH 25oC±2oC/60±5 % RH
1. Moisture Content NMT 5.0% w/w 2.80 2.92 2.82 3.55 3.22 3.20 3.15
2. Assay 90.0% to 110% of label claim 99.58 99.91 99.88 99.91 99.89 99.90 99.87
3. Dissolution
0.01 N HCl, 900mL, 100rpm, USP type-I (basket) Limit: 15min : NLT 80% (Q) 92.0 91.0 90.0 90.0 89.0 89.0 88.0
NMT: Not more than, M: Months, NLT: Not less than, Mins: Minutes

Example 3:
Sr. No Ingredient Weight
(mg/tablet) % w/w
1 Sildenafil 70.24 25.2
2 Oyster Peptide 60.00 21.6
3 Dibasic Calcium Phosphate Anhydrous 24.26 8.7
4 Microcrystalline Cellulose 101 32.50 11.7
5 Microcrystalline Cellulose 102 51.50 18.5
6 Hydroxypropyl Cellulose-L 5.00 1.8
7 Sodium Starch Glycolate 11.00 4.0
8 Sodium Lauryl Sulfate 3.50 1.2
9 R-Somalt 10.00 3.6
10 Magnesium Stearate 2.00 0.7
11 Purified Water q.s. q.s.
Core tablet weight 270.00
12 Novomix Blue 8.10 3.0
Coated tablet weight 278.10 100.00

Manufacturing Process:
1. All raw materials were dispensed accurately;
2. Sift Sildenafil, Dibasic calcium phosphate anhydrous, Microcrystalline cellulose 101, Hydroxypropyl cellulose-L and Sodium Starch Glycolate through sieve 40#;
3. Sift Sodium Lauryl Sulfate through sieve 60#;
4. The blend of step 2 was mixed with blend of step 3;
5. Binder addition: Weigh required quantity of purified water (binder) and carry out granulation;
6. Spraying was done using sprays;
7. Drying was done in FBP, Loss on Drying (LOD) was checked;
8. Material from FBP unloaded and passed through sieve no.30#;
9. Prelubricarion: Microcrystalline cellulose 102, Oyster peptide, R-Somalt and Sodium starch glycolate, was sifted through sieve no.40# and pre-lubricated with dried granules;
10. Lubrication: Magnesium stearate was sifted through sieve no.60# and lubricated with dried granules of step 9; and
11. Compression: Blend was compressed using 11.50 x 8.2mm diamond shape punch;
12. Film Coating: Core tablets were coated using Novomix 20098 Blue in a suitable coating machine.

Stability Data (Example 3):
Sr No Test Parameter Specification Initial 3M 6M 3M 6M 3M 6M
40oC±2oC/75±5 % RH 30oC±2oC/75±5 % RH 25oC±2oC/60±5 % RH
1. Moisture Content NMT 5.0% w/w 2.02 2.88 2.70 2.34 2.20 3.10 3.00
2. Assay 90.0% to 110% of label claim 100.54 99.98 100.80 102.50 101.50 101.29 101.00
3. Dissolution
0.01 N HCl, 900mL, 100rpm, USP type-I (basket) Limit: 15min : NLT 80% (Q) 93.0 92.0 91.0 92.0 91.0 93.0 92.0
NMT: Not more than, M: Months, NLT: Not less than, Mins: Minutes ,CLAIMS:1. A pharmaceutical composition, comprising:
a) oyster peptide; and
b) PDE5 Inhibitor(s) or salts thereof; and
c) one or more pharmaceutically acceptable excipient.

2. The pharmaceutical composition as claimed in claim 1, wherein the oyster peptide is present in an amount of from about 0.1% to about 40% by weight with respect to total weight of the pharmaceutical composition.

3. The pharmaceutical composition as claimed in claim 1, wherein the PDE5 Inhibitor(s) or salts thereof is present in an amount of from about 1.0% to about 50% by weight with respect to total weight of the pharmaceutical composition.

4. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of diluents or filler, disintegrants, binders, solubilizing agent, surfactant, absorption enhancer, bioadhesive agents or mucoadhesion promoting agent, polymers or release modifying agent, carriers, plasticiser, penetration enhancer, bases, lubricant, glidant, acidic agent, basic agent, chelators, sweeteners, flavoring agent, pH regulating agent, preservatives, antioxidants, coloring agents, solvents, taste masking agent, antifoaming agents, flow agents and opacifiers, antiadherent, stabilizing agent, antistatic agent, viscosity adjuster and coating agent.

5. The pharmaceutical composition as claimed in claims 1-4, comprising:
a) 0.1-40% w/w of oyster peptide;
b) 1.0-50% PDE5 Inhibitor(s) or salts thereof
b) 30-90% w/w of at least one diluent;
c) 0.5%-30% w/w of a binder;
d) 0.1-20% w/w of a surfactant;
e) 0.1-5% w/w of a lubricant;
f) Optionally, 1%-15% w/w of a disintegrant; and
g) a pharmaceutically acceptable excipient
wherein said composition is optionally coated.

6. A pharmaceutical composition as claimed in claim 1, wherein composition is in the form of tablet, capsule, granule, pellet, bead, sachet or powder.

7. The pharmaceutical composition as claimed in claim 1, wherein the composition is prepared by a manufacturing process selected from a group comprising of solvent casting, solvent evaporation, hot-melt extrusion, semisolid casting, rolling, direct compression, dry granulation, wet granulation, spray granulation and extrusion-spheronization.

8. A process of preparing pharmaceutical composition as claimed in claim 1, comprising the step of admixing the PDE5 Inhibitor(s) or salts thereof and oyster peptide along with one or more excipient selected from a group consisting of diluents or filler, disintegrants, binders, solubilizing agent, surfactant, absorption enhancer, bioadhesive agents or mucoadhesion promoting agent, polymers or release modifying agent, carriers, plasticiser, penetration enhancer, bases, lubricant, glidant, acidic agent, basic agent, chelators, sweeteners, flavoring agent, pH regulating agent, preservatives, antioxidants, coloring agents, solvents, taste masking agent, antifoaming agents, flow agents and opacifiers, antiadherent, stabilizing agent, antistatic agent, viscosity adjuster and coating agent.