DESC:SYNERGISTIC PHARMACEUTICAL COMBINATIONS OF EUPHORBIA PROSTRATA

FIELD OF THE INVENTION
The present invention provides a synergistic pharmaceutical combination comprising a topical composition comprising Euphorbia Prostrata and an oral composition comprising Euphorbia Prostrata, wherein said topical and oral compositions comprises one or more pharmaceutical acceptable excipients and optionally one or more other active agent. Moreover, the combination and compositions of present invention are suitable for haemorrhoids, haemorrhoids during pregnancy, anal fissures, anal fistula, and varicose veins.

BACKGROUND OF THE INVENTION
Euphorbia Prostrata is a small, prostrate, annual green herb widely distributed globally and used as anti-haemorrhoidal, anti-inflammatory, analgesic, hypolipidemic, antidiabetic, antidiarrheal, antiasthmatic, and for various skin diseases. Haemorrhoidal disease is characterized by bleeding, without any pain, on defecation. However, pain occurs when the haemorrhoids are secondarily infected, or complicated by thrombosis and anal fissures. There are few prior art literature reports that disclose use of pharmaceutical compositions comprising dry extract of Euphorbia Prostrata for the treatment of haemorrhoids but there is still a need of compositions, dosage forms, combinations, dosage schedules that are more efficacious than existing options for the treatment of haemorrhoids, anal fissures, anal fistulas that make haemorrhoids treatment more comprehensive and is also safe and effective during pregnancy.

An anal fissure is a tear in the epithelial lining of the anal canal. Fissures may be delineated as acute versus chronic and typical versus atypical. An anal fistula is a small tunnel that develops between the end of the bowel and the skin near the opening of the bottom (anus). It’s usually caused by an infection near the anus, which results in a collection of pus (abscess) in the nearby tissue. When the pus drains away, it can leave a small channel behind. Conservative treatment like using stool softeners, increasing intake of fibre and fluids, Nitroglycerin, use of Botulinum toxin type A injection, Nifedipine. These medications may be taken orally or applied externally and may cause significant side effects. Surgery is last option in chronic anal fissure and anal fistula.

Varicose veins are twisted, enlarged veins. Any vein that is close to the skin’s surface (superficial) can become varicosed. Varicose veins most commonly affect the veins in the legs. That’s because prolonged standing and walking increase the pressure in the veins of the lower body. Varicose veins can cause aching pain and discomfort. Sometimes varicose veins lead to more-serious problems. Currently available options involve self-care measures or procedures done by a health care provider to close or remove veins.

The present invention provides a synergistic pharmaceutical combination of different compositions or dosage forms comprising Euphorbia Prostrata that is more efficacious and safe. The present invention further provides use of combinations of the invention for the treatment of haemorrhoids including haemorrhoids during pregnancy, anal fissures, anal fistula, and varicose veins. The present invention further provides safe and effective dosing schedules for the combinations of the invention. The compositions may further comprise one or more other active agent.

OBJECTIVES OF THE INVENTION
The principal objective of the present invention is to provide a synergistic pharmaceutical combination comprising a topical composition of Euphorbia Prostrata and an oral composition comprising Euphorbia Prostrata.

Another objective of the present invention is to provide a synergistic pharmaceutical combination of the present invention which is effective for haemorrhoids including haemorrhoids during pregnancy, anal fissures, anal fistula, and/or varicose veins.

Another objective of the present invention is to provide a synergistic pharmaceutical combination which is safe and provide effective dosing schedules.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a synergistic pharmaceutical combination comprising:
- a topical composition comprising Euphorbia Prostrata, and
- an oral composition comprising Euphorbia Prostrata.

According to one more aspect, the present invention provides a synergistic pharmaceutical combination comprising:
- a topical composition comprising about 1% w/w dry extract of Euphorbia Prostrata, optionally one or more additional pharmaceutically active agents, and one or more pharmaceutically acceptable excipients, and
- an oral composition comprising about 100 mg Euphorbia Prostrata, optionally one or more additional pharmaceutically active agents, and one or more pharmaceutically acceptable excipients;
wherein the topical composition is a cream or a gel and the oral composition is a capsule or a tablet.

According to a further aspect, the synergistic pharmaceutical combination of the present invention is effective in the treatment of haemorrhoids including haemorrhoids during pregnancy, anal fissures, anal fistula, and/or varicose veins.

According to a further aspect, the present invention provides a synergistic pharmaceutical combination comprising:
- a topical composition comprising Euphorbia Prostrata and one or more pharmaceutically acceptable excipients, and
- an oral composition comprising Euphorbia Prostrata and one or more pharmaceutically acceptable excipients;
wherein the topical composition is applied at least twice daily and after each act of defecation for 14 days, and the oral composition is administered once daily for 14 days, for the treatment of haemorrhoids including haemorrhoids during pregnancy.

According to a further aspect, the present invention provides a synergistic pharmaceutical combination comprising:
- a topical composition comprising Euphorbia Prostrata and one or more pharmaceutically acceptable excipients, and
- an oral composition comprising Euphorbia Prostrata and one or more pharmaceutically acceptable excipients;
wherein the topical composition is applied at least twice daily for 3 months and the oral composition is administered as one tablet twice daily for first month followed by one tablet once or twice daily for next two months, for the treatment of varicose veins.

According to a further aspect, the present invention provides a synergistic pharmaceutical combination comprising:
- a topical composition comprising Euphorbia Prostrata and one or more pharmaceutically acceptable excipients, and
- an oral composition comprising Euphorbia Prostrata and one or more pharmaceutically acceptable excipients;
wherein the topical composition is applied at least twice daily and after each act of defecation for 6 weeks, and the oral composition is administered as one tablet twice daily for six weeks, for the treatment of anal fissures.

According to a further aspect, the present invention provides a synergistic pharmaceutical combination comprising:
- a topical composition comprising Euphorbia Prostrata and one or more pharmaceutically acceptable excipients, and
- an oral composition comprising Euphorbia Prostrata and one or more pharmaceutically acceptable excipients;
wherein the topical composition is applied at least twice daily and after each act of defecation for 8 weeks, and the oral composition is provided as one tablet twice daily for 8 weeks, for the treatment of anal fistula.

According to a further aspect, the present invention provides a synergistic pharmaceutical combination comprising:
- a topical composition comprising Euphorbia Prostrata, one or more additional pharmaceutically active agents selected from lidocaine, diltiazem, or combination thereof, and one or more pharmaceutically acceptable excipients, and
- an oral composition comprising Euphorbia Prostrata, calcium dobesilate, and one or more pharmaceutically acceptable excipients;
wherein the combination is effective in the treatment of haemorrhoids including haemorrhoids during pregnancy, anal fissures, anal fistula, and/or varicose veins.

In other aspect, the present invention provides a topical composition and an oral composition comprising dry extract of the Euphorbia Prostrata, optionally with one or more pharmaceutically active agent, wherein said dry extract of the Euphorbia Prostrata containing flavonoids and phenolic compounds, wherein total flavonoids are 3.0 % -8% mg by weight calculated as apigenin-7-glycoside; and wherein the total phenolic compounds are 15-45% by weight calculated as gallic acid, along with one or more pharmaceutically acceptable excipient; and wherein the pharmaceutical composition comprises extract of the plant Euphorbia Prostrata from about 0.1 % to about 95% by weight.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a synergistic pharmaceutical combination comprising: a topical composition comprising Euphorbia Prostrata, and an oral composition comprising Euphorbia Prostrata.

The present invention provides a synergistic pharmaceutical combination comprising: a topical composition comprising therapeutically effective amount of Euphorbia Prostrata, optionally one or more additional pharmaceutically active agents, and one or more pharmaceutically acceptable excipients; and an oral composition comprising therapeutically effective amount of Euphorbia Prostrata, optionally one or more additional pharmaceutically active agents, and one or more pharmaceutically acceptable excipients.

As used in this specification, the singular forms “a”, “an”, and “the” include plural references unless the context dictates otherwise. Thus, for example, a reference to “a method” or “a process” includes one or more methods, one or more processes, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

As used herein the term “about” in reference to a numerical value means that variations of 10% above or below the numerical value are within the range described to the specified value.

The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug (e.g., Euphorbia Prostrata), which is sufficient to elicit an appreciable biological response when administered to the patient. It will be appreciated that the precise therapeutic dose will depend on the age and condition of the patient, the nature of the condition to be treated and will be at the ultimate discretion of the attendant physician.

The term “topical composition”, “topical formulation” or “topical dosage form” or as used herein synonymously include the pharmaceutical formulations in a form suitable for topical administration such as but not limited to include solution, suspension, gel, gel forming suspension (in-situ gels), cream, ointment, lotion, or any other suitable dosage form meant for topical application. Preferably, topical composition is a cream or a gel. The term “oral composition”, “oral formulation” or “oral dosage form” as used herein synonymously include the pharmaceutical formulations in a form suitable for oral administration including oral solid and liquid administration such as but not limited to include capsules, tablets, oral films, fibre, granules, sachets, ampoules, suspensions, syrups, elixirs, and solutions preferably tablet. The oral composition includes immediate release, fast release, orally disintegrating, extended release, modified release, delayed release, pulsed release formulations and the like.

The term “excipient” or “pharmaceutically acceptable excipients” means a pharmacologically inactive component. In regard to topical compositions, suitable “pharmaceutically acceptable excipients” include, without limitation, hydrophobic cream base(s), gelling agent(s), viscosity modifier(s), lipid(s), emulsifier(s), co-emulsifier(s), surfactant(s), solubilizing agent(s), humectant(s), pH adjusting agent(s), antimicrobial agent(s), buffering agent(s), antioxidant(s), chelating agent(s), stabilizer(s), preservative(s), solvent(s), co-solvent(s), or combinations thereof. In regard to oral compositions, suitable “pharmaceutically acceptable excipients” include, without limitation, diluent/filler, binder, disintegrant, glidant, surfactant, extended release or delayed release excipients, pH modifier, anti-oxidant, preservative, lubricant, flavoring agent, plasticizer, colorant, opacifier, carrier, and like.

In one embodiment, the present invention describes a topical cream formulation using a hydrophobic cream base. Extract of Euphorbia Prostrata is mixed with hydrophobic cream base or mixture of hydrophobic cream base(s), selected from following classes such as Oleaginous bases, Absorption bases, Water removable base and water-soluble base and mixture thereof. ‘Oleaginous Bases’ are also termed as Hydrocarbon bases. On application to the skin, have an emollient effect and as occlusive dressing, can remain on the skin for prolonged periods of time without drying out. ‘Absorption Bases’ are of two types: (i) those that permit the incorporation of aqueous solutions resulting in the formation of water-in-oil emulsions, (ii) those that are water-in-oil emulsions (i.e., emulsion bases) and permit the incorporation of additional quantities of aqueous solutions. ‘Water-Removable Bases’ are oil-in-water emulsions resembling creams in appearance. Because the external phase of the emulsion is aqueous, they are easily washed from skin and are often called “water-washable” bases. ‘Water-Soluble Bases’ do not contain oleaginous components. They are completely water-washable and often referred to as “greaseless” Because they soften greatly with the addition of water; large amounts of aqueous solutions are not effectively incorporated into these bases. They mostly are used for the incorporation of solid substances.

Suitable hydrophobic cream base(s) include but are not limited to Hydrocarbons such as Liquid petrolatum (mineral oil, liquid paraffin, paraffin oil), White petrolatum (petroleum jelly, Vaseline), Yellow petrolatum (petroleum jelly) Squalane (perhydrosqualene, spinacane); Silicones such as Liquid polydimethylsiloxanes (dimethicone, silastic, medical grade silicone oil); Alcohols such as Lauryl alcohols (1-dodecanol, dodecyl alcohols), Myristyl alcohols (tetradecanol, tetradecyl alcohols), Cetyl alcohols (hexadecanol, ethal, palmityl alcohols), Stearyl alcohols (stenol, cetosteryl alcohols), Oleyl alcohols (ocenol) Sterols; sterol esters: Lanolin (hydrous wool fat, lanum), Anhydrous lanolin (wool fat, anhydrous lanum, agnin), Semi synthetic lanolin’s; Carboxylic Acids such as Lauric acid, Myristic acid, palmitic acid, stearic acid, oleic acid Esters; polyesters: Cholesterol esters (stearate), Ethylene glycol monoesters, Propylene glycol monoesters, Glyceryl monoesters, Glyceryl monostearate, Sorbitol monoesters, Sorbitain monoesters, Sorbitol diesters, Sorbitan polyesters (spans, arlacels), Glyceryl tristearate, Lard, Almond oil, Corn oil, Caster oil, Cottonseed oil, Olive oil, Soyabean oil, Hydrogenated oils, Sulfated oils, Isopropyl myristate, Isopropyl palmitate. Ethers; polyethers: Polyethylene-polypropylene glycols (pluronics), or combinations thereof.

In another embodiment, the present invention describes a topical gel formulation using a gel base. Extract of Euphorbia Prostrata is mixed with gelling agent or mixture of gelling agent(s) to form a topical gel. The gel is an aqueous gel or an emulgel. The aqueous gel is pure water based, emulgel contains both water and lipid and/or hydrophobic liquid/semisolid.

Suitable gelling agent(s) include, without limitation, synthetic, semisynthetic, natural gelling agents, or mixtures thereof. Examples include but not limited to gellan gum, xanthan gum, guar gum, chitosan, alginic acid and its salts, xyloglucan, pectin, hyaluronic acid-agar, carrageenan, shellac, and hyaluronic acid derivatives, cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyl ethyl cellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 6000), carboxymethyl cellulose, carboxymethylcellulose, hydroxypropylmethyl cellulose, a carboxyvinyl polymer such as polycarbophil, cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross- linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), Polyvinyl alcohol (PVA) and Polyvinylpyrrolidone (PVP), or combinations thereof. The gelling agent(s) may be present in an amount of about 0.05% w/w to about 50% w/w.

Suitable solubilizing agents include, without limitation, emulsifier, co-emulsifiers, surfactants, lipids, organic liquids/semi-solids, cyclic oligosaccharides/cyclodextrins, phospholipids, or mixtures thereof. The solubilizing agent(s) may be employed in an amount ranging from about 0.01% w/w to about 25% w/w of the pharmaceutical formulation.

As used herein, the term “emulsifier” and “co-emulsifier” represents suitable agents that aids emulsification and surfactants that may be included in the formulations of the invention. Suitable emulsifiers, co-emulsifiers, and surfactants include, without limitation, ionic, non-ionic, amphiphilic, amphoteric emulsifiers, co-emulsifiers, and surfactants such as sodium docusate, sodium lauryl sulfate, naturally occurring phospholipids extracted from egg yolk or soybean, synthetic phosphatidyl cholines or purified phosphatidyl cholines from vegetable origin, hydrogenated derivatives can also be used, such as phosphatidylcholine hydrogenated (egg) and phosphatidylcholine hydrogenated (soya), poloxamers, polysorbates, alkylaryl polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, poloxamines, polyoxyethylene stearates, polyoxyethylene sorbitan fatty acid esters or sorbitan fatty acid esters, derivatives of tocopherol such as tocopherol PEG succinate, long chain fatty acids such as oleic acid, stearic acid, palmitic acid, bile acids such as cholic acid and deoxycholic acid or surface active derivatives and polyoxyls. Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly (propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly (ethylene oxide)). Polysorbates are oily liquids derived from ethoxylated sorbitan esterified with fatty acids. Cyclodextrins are composed of 5 or more a-D-glucopyranoside units linked together at position 1 and 4. Polyoxyls are a mixture of mono- and diesters of stearate and polyoxyethylene diols. Preferred embodiments include but are not limited to poloxamer 188 (such as Pluronic® F-68) and poloxamer 407 (such as Pluronic® F127); polysorbate 20, polysorbate 60, polysorbate 80, tyloxapol, Brij® 35, Brij® 78, Brij® 98 and Brij® 700, Span® 20, Span® 40, Span® 60, Span® 80; and polyoxylspolyoxyl 40 stearate, polyoxyl 30 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 hydrogenated castor oil; Hydrogenated Castor oil (or PEG (40 Hydrogenated Castor Oil) (HCO-40) or combinations thereof. In preferred embodiment, the surfactant includes, without limitation non-ionic surfactants such as Kolliphore EL (Cremophor EL), Cremophor RH 40, Cremophor RH 60, d-a-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, Softigen 767, and mono- and di-fatty acid esters of PEG 300, 400, or 1750, and combinations thereof. When present, emulsifier(s), co-emulsifier(s), and/or surfactant(s) may be employed in an amount ranging from about 0.005% w/w to about 25% w/w of the pharmaceutical formulation.

Suitable lipid(s) include, without limitation, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, sunflower oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, medium-chain triglycerides of coconut oil, palm seed oil, a medium chain triglyceride such as Miglyol™ 812 or 810 or triacetin, and combinations thereof. As used herein, the term “lipid” in the formulations is any pharmaceutically acceptable oil, preferably a triglyceride. The lipid may also be a propylene glycol diester or monoglyceride (such as acetylated monoglyceride). The lipid can also be a mixture of one or more of these lipids. The amount of lipid in the formulations of the present invention can vary depending on the total overall volume of the formulation and the concentration of the other components. The lipid(s) may be employed in an amount ranging from about 5%w/w to about 50% w/w.

Suitable organic liquids/semi-solids include, without limitation, waxes such as beeswax, carnauba wax, polawax, Candelilla wax etc., veegum, d-a-tocopherol, oleic acid, vegetable oils, ethyl oleate, propylene glycol, and polyethylene glycol, transcutol, isopropyl myristate, glycerine, medium-chain mono- and di- glycerides, diethylene glycol, glyceryl monostearate, and combinations thereof. When present, organic liquids/semi-solids may be employed in an amount ranging from about 0.01% w/w to about 25% w/w of the pharmaceutical formulation.

Suitable cyclic oligosaccharides/cyclodextrins include, without limitation, a-cyclodextrin, ß-cyclodextrin, hydroxypropyl-ß-cyclodextrin, and sulfobutylether-ß-cyclodextrin, cyclodextrins-2-HP25, ionically charged (e.g. anionic) ß-cyclodextrins with or without a butyrated salt (Captisol®), hydroxypropyl-gamma-cyclodextrin, gamma cyclodextrin, and combinations thereof. When present, a cyclodextrin may be employed in an amount ranging from about 0.01% w/w to about 25% w/w of the pharmaceutical formulation, preferably from about 0.01% w/w to 10% w/w of the pharmaceutical formulation.

Suitable phospholipids include, without limitation, hydrogenated soy phosphatidyl choline, distearoyl phosphatidyl glycerol, l-a-dimyristoylphosphatidylcholine, l-a-dimyristoyl phosphatidyl glycerol, and combinations thereof. of the present invention may further comprise synthetic phospholipids comprised following one or more: hydrogenated soybean lecithin, Dipalmitoylphosphatidylcholine (DOPC), 1,2-Dimyristoyl-sn-glycero-3-phosphorylethanolamine (DMPEA), 1,2-Dipalmitoyl-sn-glycero-3-phosphorylethanolamine (DPPE), two myristoyl Phosphatidylserine, 1,2-Distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE), dilinoleoyl phosphatidyl choline (DLPC), two myristoyl lecithin, Dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine, distearoylphosphatidylcholine, and their polyethylene glycol derivative. When present, phospholipid(s) may be employed in an amount ranging from about 0.01% w/w to about 10% w/w of the pharmaceutical formulation.

Suitable humectant(s) and viscosity modifier(s) include, without limitation, glycerol, propylene glycol, polymeric polyols, such as, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 6000), butylene glycol, triethylene glycol, collagen, dextrans such as dextran 70, water soluble proteins such as gelatin, polyvinyl alcohols, polyvinylpyrrolidones, cellulose derivatives, carbomers, gums such as gellan gum, xanthan gum, guar gum, chitosan, alginic acid and its salts, xyloglucan, pectin, hyaluronic acid-agar, carrageenan, shellac, and hyaluronic acid derivatives, dextrans, polyvinyl alcohol, polyacrylic acids, povidone such povidone K90, and polysaccharides such as hyaluronic acid and its salts and chondroitin sulfate and its salts, or combinations thereof. The viscosity modifiers may be present in an amount of about 0.05% w/w to about 10 % w/w.

Suitable buffering agent(s) include, without limitation, phosphate buffer, acetate buffer, citrate buffer, succinate buffer, borate buffers, tris HCl and amino acids such as glycine, aspartate, histidine, cysteine, tyrosine, phenylalanine, proline, arginine, threonine, serine, valine, isoleucine, lycine, and glutamine. The particular concentration of the buffer will differ, depending on the specific agent employed. When present, the buffering agent(s) is preferably used in an amount of about 0.01% w/w to about 20% w/w, preferably about 0.05% w/w to about 10% w/w of the pharmaceutical formulation.

The formulations of the present invention may include a preservative. In some embodiments, the preservative is an “antimicrobial agent” that inhibits the growth of microorganisms such as bacteria and fungi (molds and yeast). Suitable preservative includes, without limitation, benzalkonium chloride (BAC), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, benzyl alcohol, ethanol, phenylmercury nitrate, phenylmercury acetate, thiomerosal, merthiolate, phenylmercuryborate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, butyl-p-hydroxybenzoate, chlorobutanol, sorbic acid, polyquaternary ammonium compounds, ascorbic acid, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), benzoic acid, citric acid, edetic acid, parabens, phenol, propyl gallate, sodium bisulfite, sodium sulfite, chlorocresol, cresol, dehydroacetic acid, phenol, potassium benzoate, potassium sorbate, sodium dehydroacetate, sodium propionate, thymol, butylparaben, ethylparaben, methylparaben, methylparaben sodium, propylparaben, propylparaben sodium, thimerosal and the various salt forms for these compounds, or combinations thereof. When present, the preservative(s) may be used in an amount of about 0.0001% w/v to about 5.0% w/v of the pharmaceutical formulation.

Suitable chelating agents, includes, without limitation, ethylenediaminetetraacetic acid and metal salts thereof, such as disodium edetate, trisodium edetate, tetrasodium edetate, sodium citrate, or mixtures thereof. When present, the chelating agent(s) may be added in an amount of about 0.001% w/w to about 5.0% w/w of the pharmaceutical formulation.

Suitable antioxidants includes, without limitation, ascorbic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, citric acid, malic acid, lactic acid, benzenesulfonic acid, oxalic acid, triphenylacetic acid, 1-hydroxy-2-naphthoic acid, 3-hydroxy-2-naphthoic acid, sodium ascorbate, alpha-tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, gentisic acid (2,5-dihydroxy benzoic acid), acetyl cysteine, ascorbyl palmitate, cysteine, dithiothreitol, thioglycerol, thiourea, caffeic acid, propyl gallate, ferulic acid, sodium pyrosulfite, edetic acid, edetate salts, 2, 6-di-tert-butyl p-cresol, gallic acid and esters thereof, nordihydroguaiaretic acid, guaiacol ester, tea polyphenol, curcumin, chlorogenic acid, methionine, proline, biflavonoids, superoxide dismutase, silymarin, grape skin/seed extract, melanin, rosemary extract, sodium sulfite, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, tert-butylhydroquinone, thiourea, methionine, sodium citrate, magnesium ascorbyl phosphate, sodium ascorbyl phosphate, 3,4-dihydroxybenzoic acid, butylated hydroxybenzoic acid and salts thereof, erythorbic acid and sodium salts thereof, sorbic acid and salts thereof, sodium formaldehyde sulfoxylate, glutathione, lipoic acid, dihydroxy fumaric acid, and the like.

The pH adjusting agent is typically an organic or inorganic acid or an organic or inorganic base preferably selected from the group of potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, ammonia, tertiary sodium phosphate, diethanolamine, ethylenediamine, N-methylglucamine, L-lysine, hydrochloric acid, phosphoric acid, or mixtures thereof, preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or basic pH adjusting agents are added to adjust the formulation to the target pharmaceutically acceptable pH range. Hence, it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

Suitable solvent(s) includes, without limitation, an aqueous or a non-aqueous solvent such as purified water, water for injection, bacteriostatic water for injection, sterile water, isotonic saline water, buffered aqueous solution, ethanol, glycerin, propylene glycol, or combinations thereof. Solvent(s) is present in an amount of about 10% w/w to about 90% w/w of the pharmaceutical formulation.

Suitable co-solvent(s) include, without limitation, organic or inorganic solvents solvents selected from but not limited to monohydric or polyhydric alcohols including ethanol, isopropyl alcohol, polyethylene glycol (PEG), propylene glycol (PG), sorbitol, glycerine, acetone, benzyl alcohol, dimethyl sulfoxide, N-methyl-2-pyrrolidone, glycofurol, solketal, glycerol formal, or combinations thereof. When present, cosolvent(s) may be employed in an amount ranging from about 0.01% w/w to about 50% w/w of the pharmaceutical formulation or equivalent weight conversion based on the density of the co-solvent.

Suitable diluents/fillers include, without limitation, microcrystalline cellulose, silicified microcrystalline cellulose, sugar alcohol selected from but not limited to alditols, polyols, mannitol, meglumine, xylitol, isomalt, sorbitol, lactitol, pentitol, arabitol, ribitol, galactitol, erythritol, glycerol, and the like, Carbohydrate selected from but not limited to monosaccharides, oligosaccharides, polysaccharides, dextrins, maltodextrin, pullulan, arabinose, dextrose, dextrates, lactose, sucrose, sucralose, saccharin, fructose, maltose, trehalose, psicose, tagatose, sorbose, cellulose derivatives, cellobiose, starches, modified starches, sucrose fatty acid esters, and the like, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, kaolin, calcium sulfate, and combinations thereof. When present, a filler may be employed in an amount ranging from about 1% to about 80% by weight of the pharmaceutical formulation.

Suitable binders include, without limitation, polyvinylpyrrolidone (PVP), e.g., PVP K30 or PVP K90, polyethylene glycols (PEG), e.g., PEG 4000, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, both preferably of medium to high viscosity, e.g. viscosity grades 3 or 6 cps, copovidone, maltodextrins, pregelatinized starch, cellulose and their derivatives including microcrystalline cellulose, acacia, alginic acid, tragacanth, gelatin, liquid glucose; starch and their derivatives including corn starch; hydrocolloids; sugars; ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, and hydroxyethyl cellulose, carboxymethyl cellulose, sodium alginate, used either alone or combinations. When present, a binder may be employed in an amount ranging from about 0.1% to about 20%, by weight of the pharmaceutical formulation.

Suitable disintegrants include, without limitation, cellulose and their derivatives including low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone, starch and modified starches such as corn starch, cross-linked sodium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium starch glycolate, crosslinked CMC (Ac-Di-Sol), Sodium carboxymethyl starch ion-exchange resins, formalin-casein, used either alone or combinations thereof. When present, a disintegrant may be employed in an amount ranging from about 0.1% to about 20%, by weight of the pharmaceutical formulation.

Suitable lubricants include, without limitation, zinc stearate, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, colloidal silica, sodium lauryl sulfate, aluminum or calcium silicate, stearic acid, cutina, PEG 4000-8000, talc and combinations thereof. When present, a lubricant may be employed in an amount ranging from about 0.01% to about 10%, preferably from about 0.1% to about 5%, by weight of the pharmaceutical formulation,

Suitable glidants include, without limitation, colloidal silicon dioxide (e.g., Aerosil 200), magnesium trisilicate, powdered cellulose, starch, talc and combinations thereof. When present, a glidant may be employed in an amount ranging from about 0.01% to about 10%, preferably from about 0.1% to about 5%, by weight of the pharmaceutical formulation.

Suitable extended release or delayed release excipients include, without limitation, hydrophilic or hydrophobic agents comprise one or more of polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, a fatty acid, a fatty acid ester, an alkyl alcohol, a wax, xanthan gum, gellan gum, shellac, rosin, zein (prolamine from corn), povidone, kollidon SR (polyvinyl acetate and povidone), a poly(meth)acrylate, poly(ethylene oxide), polyuronic acid salts, cellulose ethers, xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan gum locust bean gum, alkali metal salts of alginic acid or pectic acid, sodium alginate, potassium alginate, ammonium alginate, polyethylene oxide, carbomer homopolymer, hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methyl cellulose, carboxyvinyl polymers, polymerized gelatin, shellac, methacrylic acid copolymer type C NF, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate, hydrogenated castor oil, stearic acid, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and acrylic acid polymers and copolymers like methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate with copolymers of acrylic and methacrylic acid esters (Eudragit NE, Eudragit RL, Eudragit RS) and the like. Polymer may be used from 0.1- 50% by weight of the formulation, preferably 10-50% by weight of the formulation.

Suitable coating agents according to present invention may be selected from immediate release, extended release, or delayed release coatings but not limited to, Shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hyroxylpropyl cellulose, hyroxypropyl methylcellulose (HPMC), acrylates, phthalates, and Zein (a corn protein derivative), Hydroxyproply methyl cellulose, Methyl hydroxyethyl cellulose, Ethylcellulose, Povidone, Opadry, and the like.

In another embodiment, one or more additional components used in topical formulations and oral formulations may be included.

In another embodiment, the present invention provides synergistic pharmaceutical combination comprising: a topical composition comprising about 1%w/w Euphorbia Prostrata; and an oral composition comprising about 100 mg dry extract of Euphorbia Prostrata and optionally one or more additional active agents.

In another embodiment, the present invention provides a topical composition comprising about 1%w/w Euphorbia Prostrata or about 100 mg dry extract of Euphorbia Prostrata and optionally one or more additional active agents; and an oral composition comprising about 100 mg dry extract of Euphorbia Prostrata and optionally one or more additional active agents.

In another embodiment, the dry extract of Euphorbia Prostrata is having particle size d10 is not more than 10 µm; d50 is not more than 100 µm and d90 is not more than 350 µm. In another embodiment, the dry extract of Euphorbia Prostrata is substantially free of heavy metals selected from lead (Pb), cadmium (Cd), mercury (Hg) and arsenic (As).

One or more additional pharmaceutical agents to be included in the topical compositions of the invention include lidocaine, benzocaine, dibucaine, diltiazem, nefidipine, nitroglycerine, bethanecol, zinc oxide, pain relievers such as diclofenac, ibuprofen, acetaminophen, steroids such as hydrocortisone, phenylephrine, pramoxine, diosmin, or combinations thereof. One or more additional pharmaceutical agents to be included in the oral compositions of the invention include calcium dobesilate, diosmin, Docusate sodium, Ispaghula husk, pain relievers such as diclofenac, ibuprofen, acetaminophen, steroids such as hydrocortisone, or combinations thereof.

In another embodiment, the present invention provides a topical composition comprising a therapeutically effective amount of Euphorbia Prostrata, lidocaine; optionally diltiazem, and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a topical composition comprising about 1%w/w or 100 mg dry extract of Euphorbia Prostrata, about 3%w/w lidocaine; optionally about 2%w/w diltiazem; and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides an oral composition comprising about 100 mg dry extract of Euphorbia Prostrata and 500 mg of calcium dobesilate.

In another embodiment, the dosing schedules for the synergistic pharmaceutical combination are as follows:
1. The topical composition is applied at least twice daily and after each act of defecation for 14 days, and the oral composition is administered once daily for 14 days, for the treatment of haemorrhoids including haemorrhoids during pregnancy.
2. The topical composition is applied at least twice daily for 3 months and the oral composition is administered as one tablet twice daily for first month followed by one tablet once or twice daily for next 2 months, for the treatment of varicose veins.
3. The topical composition is applied at least twice daily and after each act of defecation for 6 weeks, and the oral composition is administered as one tablet twice daily for six weeks, for the treatment of anal fissures.
4. The topical composition is applied at least twice daily and after each act of defecation for 8 weeks, and the oral composition is provided as one tablet twice daily for 8 weeks, for the treatment of anal fistula.

In another embodiment, the topical composition and the oral composition are to be administered sequentially in any order with or without a time gap.

In another embodiment, the present invention provides a synergistic pharmaceutical combination comprising:
- a topical composition comprising about 1% w/w dry extract of Euphorbia Prostrata, and one or more pharmaceutically acceptable excipients; and
- an oral composition comprising 100 mg dry extract of Euphorbia Prostrata, and one or more pharmaceutically acceptable excipient;
wherein the combination is effective in the treatment of anal fissures, anal fistula, varicose veins, haemorrhoids including haemorrhoids during pregnancy.

In another embodiment, the present invention provides a synergistic pharmaceutical combination comprising:
- a topical composition comprising about 1% w/w dry extract of Euphorbia Prostrata, and one or more pharmaceutically acceptable excipients; and
- an oral composition comprising 100 mg dry extract of Euphorbia Prostrata, 500 mg calcium dobesilate, and one or more pharmaceutically acceptable excipient;
wherein the topical composition is applied at least twice daily for 3 months and the oral composition is administered as one tablet twice daily for first month followed by one tablet once or twice daily for next 2 months, for the treatment of varicose veins.

In another embodiment, the present invention provides a synergistic pharmaceutical combination comprising:
- a topical composition comprising about 1% w/w dry extract of Euphorbia Prostrata; about 3%w/w lidocaine, optionally about 1%w/w diltiazem, and one or more pharmaceutically acceptable excipients; and
- an oral composition comprising 100 mg dry extract of Euphorbia Prostrata, 500 mg calcium dobesilate, and one or more pharmaceutically acceptable excipient;
wherein the topical composition is applied at least twice daily and after each act of defecation for 6 weeks, and the oral composition is administered as one tablet twice daily for six weeks, for the treatment of anal fissures.

In another embodiment, the present invention provides a synergistic pharmaceutical combination comprising:
- a topical composition comprising about 1% w/w dry extract of Euphorbia Prostrata; about 3%w/w lidocaine, optionally about 1%w/w diltiazem, and one or more pharmaceutically acceptable excipients; and
- an oral composition comprising 100 mg dry extract of Euphorbia Prostrata, 500 mg calcium dobesilate, and one or more pharmaceutically acceptable excipient;
wherein the topical composition is applied at least twice daily and after each act of defecation for 8 weeks, and the oral composition is administered as one tablet twice daily for 8 weeks, for the treatment of anal fistula.

In another embodiment, the present invention provides dry extract of the Euphorbia Prostrata containing flavonoids and phenolic compounds, wherein total flavonoids are about 4% by weight calculated as apigenin-7-glycoside; and wherein the total phenolic compounds are about 20% by weight calculated as gallic acid, along with one or more pharmaceutically acceptable excipient; and wherein the pharmaceutical composition comprises extract of the plant Euphorbia Prostrata from about 0.1 % to about 95% by weight.

While selected embodiments of the present invention have been shown and described herein, it should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

EXAMPLES
The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below:

Topical Compositions

Example 1: Cream composition of 1% w/w of Euphorbia Prostrata
Ingredients Amount (in mg)
Euphorbia Prostrata 10
Propylene Glycol IP 50.00
Methyl paraben IP 1.50
Propyl Paraben IP 0.30
Titanium dioxide 10.00
Emulsifying wax 170.00
Sorbitan Stearate 20.00
Corn oil 100.00
Butylated Hydroxyanisole 0.029
Propyl Gallate IP 0.029
Glycerine IP 50.00
Sorbitol solution (70% non-crystallizing) IP 30.00
Veegum HV 10.50
Sodium carboxymethyl cellulose 3.15
Polysorbate 80 15.00
Purified water q.s

Example 2: Cream composition comprising 1% w/w of Euphorbia Prostrata and 3% w/w of Lidocaine
Ingredients Amount (%w/w)
Euphorbia Prostrata 1%
Lidocaine 3%
Diethylene glycol monoethyl ether 6.0%
Propylene glycol 6.0%
Ethanol 45-80%
Water q.s
Carbomer 2-5%
Corn oil 40-60%
Triethanol amine 0.29%
Lauryl alcohol 1-2%

Example 3: Gel composition comprising 100mg of Euphorbia Prostrata, 3% w/w of Lidocaine, and 2% w/w of Diltiazem
Ingredients Amount (w/w)
Euphorbia Prostrata 100mg
Lidocaine 3%
Diltiazem 2%
Glycerol 12-15%
Propylene glycol 5-10%
Polycarbophil 1-5%
Carbomer 974P 1-4%
Butylated Hydroxyanisole 1-5%
Propyl Gallate 1-5%
Sorbic acid 1-10%
Sodium hydroxide 1-10%
Polysorbate 80 1-10%
Purified water q.s

Oral Compositions

Example 4: Tablet composition of dry extract of Euphorbia Prostrata
Ingredients Amount (in mg)
Euphorbia Prostrata extract 100
Mannitol IP 348.85
Microcrystalline cellulose IP+IH 41.00
Pregelatinized starch 5.50
Purified water Lost in processing
Croscarmellose sodium 10.00
Glyceryl Behenate 3.00
Colloidal silicon dioxide 3.00
Magnesium stearate IP+IH 1.65
Crospovidone 37.00
Coating-I
Opadry II (white) 13.75
Purified water Lost in processing
Coating-II
Opadry (Green) 19.73
Purified water Lost in processing

Example 5: Tablet composition of dry extract of Euphorbia Prostrata and Calcium Dobesilate Monohydrate
Ingredients Amount (in mg)
Euphorbia Prostrata extract 100
Clacium Dobesilate Monohydrate 500
Starch (Maize) 50
Microcrystalline cellulose IP+IH 65.5
Croscarmellose sodium 30.00
Crospovidone 30.00
Sodium metabisufite 0.50
Purified water Lost in processing
Croscarmellose sodium IP 20.00
Crospovidone IP+IH 40.00
Maize Starch IP 50.00
Colloidal Silicon dioxide 5.00
Magnesium stearate 9.00
Film Coating
200 series (white) 22.50
Purified water Lost in processing
Coating-II
Opadry 200 (Green) 23.00
Purified water Lost in processing

CLINICAL STUDIES:
CASE 1: Efficacy and Safety of combination of tablet (Euphorbia prostrata 100 mg) and Cream (Euphorbia prostrata 1% w/w) in the management of hemorrhoids during pregnancy.

Tab (Oral): (Euphorbia Prostrata 100 mg); 100 mg once daily for 14 days, and Cream (Topical): (Euphorbia Prostrata 1% w/w); To be applied locally at least twice daily and after each act of defecation for 14 days.

Table 1: Demographic characteristics of the patients.
Parameter Number of patients (n=100)
Age (years), mean (SD) 24.1 (3.8)
Weight (kg), mean (SD) 61.2 (12.2)
Height (Ft), mean (SD) 5.3 (0.3)
Systolic blood pressure (mm Hg), mean (SD) 117.4 (7.8)
Diastolic blood pressure (mm Hg), mean (SD) 74.9 (8.5)
Pulse rate (per min), mean (SD) 79.4 (8.9)
Pregnancy trimester
Second
Third (n=99)
58 (58.6)
41 (41.4)
Type of haemorrhoids
Internal
Internal and external
75 (75.0)
25 (25.0)
Administration of laxatives 15 (15.0)
Treatment type
Combination of Euphorbia prostrata 100 mg tablets plus Euphorbia prostrata cream 1% w/w till 2 weeks
Additional Euphorbia prostrata 100 mg tablets (till 4 weeks);
Additional Euphorbia prostrata cream (till 4 weeks)
100 (100.0)
13 (13.0)
15 (15.0)
Data presented as n (%), unless otherwise specified.
N=100, unless otherwise specified.

Table 2: Changes in haemorrhoidal symptoms from baseline to follow-up of 8 weeks
Duration Baseline 1 week 2 weeks 4 weeks 8 weeks P-value
Per rectal bleeding
Mean score (SD) 1.0 (0.5) 0.5 (0.5) 0.1 (0.3) 0.1 (0.2) - <0.001
Mean change from baseline - -0.5 (0.5) -0.9 (0.5) -1.0 (0.5) -1.0 (0.5) <0.001
Mean score (%) - 49.1 86.8 95.3 100.0 -
Pain at defecation
Mean score (SD) 1.5 (0.8) 1.1 (0.6) 0.7 (0.4) 0.6 (0.4) 0.3 (0.4) <0.001
Mean change from baseline - -0.3 (0.4) -0.7 (0.6) -0.9 (0.7) -1.1 (0.8) <0.001
Mean score (%) - 24.3 49.3 59.9 77.6 -
Itching
Mean score (SD) 1.2 (0.5) 0.6 (0.5) 0.4 (0.5) 0.1 (0.3) 0.0 (0.2) <0.001
Mean change from baseline - -0.6 (0.4) -0.8 (0.5) -1.1 (0.4) -1.2 (0.5) <0.001
Mean score (%) - 50.8 64.1 85.9 96.9 -
Exudates
Mean score (SD) 0.11 (0.3) 0.05(0.2) 0.03(0.1) 0.01(0.1) 0 <0.001
Mean change from baseline - -0.06(0.2) -0.08 (0.2) -0.10 (0.3) -0.11 (0.3) <0.001
Mean score (%) - 54.5 72.7 90.9 100.0 -
Swelling
Mean score (SD) 0.8 (0.7) 0.5 (0.5) 0.3 (0.4) 0.2 (0.4) 0.1 (0.3) <0.001
Mean change from baseline - -0.3 (0.4) -0.5 (0.6) -0.6 (0.6) -0.7 (0.7) <0.001
Mean score (%) - 34.5 59.5 72.6 84.5 -
Data presented as mean (SD), unless otherwise specified.

Results as observed in Table 2:
1. There is observed significant mean reduction of scores from baseline at subsequent follow-up visits (from 1 week to 8 weeks’ follow-up) in different symptoms like per rectal bleeding, pain during defecation, itching, exudation, and swelling (p<0.001)
2. The mean score of per rectal bleeding and pain at defecation showed a significant reduction at each visit (86.6% and 49.3% [2 weeks], 95.3% and 59.9% [4 weeks], 100% and 77.6% [8 weeks])
3. The mean pain score at defecation, itching, exudates, and swelling showed a significant reduction of 77.6%, 96.9%, 100%, and 84.5% at 8 weeks (p<0.001)

Table 3: Profile of overall improvement in disease (as per patient)
Assessment 2 weeks /(N = 100),
No % Post-partum (N = 100),
No %
Excellent 27 27.0 75 75.0
Good 65 65.0 25 25.0
Fair 08 08.0 - -
Poor - - - -

Results as observed in Table 3: After 2 weeks, >90% of the patients and after 30 days post-delivery, 100% showed good to excellent improvement in the disease.

Table 4: Profile of overall improvement in disease (as per physician)
Assessment 2 weeks/(N = 100), No % Post-partum/(N = 100), No %
Excellent 44 44.0 96 96.0
Good 51 51.0 04 04.0
Fair 05 05.0 - -
Poor - - - -

Results as observed in Table 4:
1. After 2 weeks as per the physician’s evaluation, 95.0% of the patients showed good to excellent improvement in the disease and after 30 days post-delivery, 100.0% good to excellent improvement in the disease
2. None of the patients required retreatment
3. None of the patients reported any adverse events.
4. No anomalies in infants and no relationship between the study drug with infants’

CASE 2: Efficacy and Safety of combination of tablet (Euphorbia prostrata 100 mg plus Calcium Dobesilate 500 mg) and Cream (Euphorbia prostrata 1% w/w) in the treatment of varicose veins.

Tab (Oral): (Euphorbia Prostrata 100 mg + Calcium Dobesilate 500 mg); 1 tablet twice daily for first month. Followed by, one tablet once or twice daily for next 2 months (As per clinical condition) (Total for 3 months), AND Cream (Topical): (Euphorbia Prostrata 1 % w/w) to be applied locally with standard dressing (as applicable) at affected area at-least twice daily for 3 months.

Table 5: Demographic characteristics
Parameter No. of Patients (#N=104)
Age [years], mean (SD) 47.0 (13.5)
Height [feet], mean (SD) (n=101) 5.5 (0.3)
Weight [kg], median (range) (n= 103) 72.0 (14.7)
BMI [kg/m2], mean (SD) (n= 100) 26.6 (4.7)
Sex (%), (n= 102) - Male
Female 48 (47.1)
54 (52.9)
Vital signs
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Pulse rate (per min) 120.6 (11.6)
77.9 (8.7)
80.4 (9.0)
Co-morbidities
Diabetes
Hypertension
Any other 8 (7.7)
6 (5.8)
2 (1.9)
Prolonged standing 58 (56.9)
Data presented as n (%), unless otherwise specified. #N=104, unless otherwise specified. BMI, body mass index; SD, standard deviation.

Table 6: Change in VVSymQ scores for symptoms.
Parameters Baseline 1 month 2 months 3 months
Pain in legs
Mean score (SD) 4.2 (1.1) 2.3 (1.3) 2.4 (1.2) 1.3 (1.0)
Mean difference from baseline; p-value - -1.2 (0.8);
0.001 -1.7 (0.9);
0.001 -2.9 (1.1);
0.001
Percentage change from baseline - 28.9 41.9 69.2
Swelling (around tortuous vein)
Mean score (SD) 3.5 (1.5) 2.6 (1.3) 2.3 (1.2) 1.5 (1.1)
Mean difference from baseline; p-value - -0.8 (0.8);
0.001 -1.2 (0.9);
0.001 -2.0 (1.2);
0.001
Percentage change from baseline - 24.0 35.0 57.8
Tingling
Mean score (SD) 2.9 (1.5) 2.3 (1.4) 2.1 (1.2) 0.9 (1.0)
Mean difference from baseline; p-value - -0.6 (0.9);
0.001 -0.9 (0.9);
0.001 -2.0 (1.5);
0.001
Percentage change from baseline (%) - 21.1 29.3 68.0
Numbness in legs
Mean score (SD) 2.9 (1.6) 2.4(1.5) 1.8 (1.2) 1.0 (1.0)
Mean difference from baseline; p-value - -0.5 (0.7);
0.001 -1.2 (1.0);
0.001 -2.0 (1.4);
0.001
Percentage change from baseline (%) - 18.5 39.4 67.1
Itching around veins
Mean score (SD) 3.0 (1.5) 2.2 (1.4) 1.4 (1.1) 0.8 (1.0)
Mean difference from baseline; p-value - -0.8 (0.9);
0.001 -1.6 (1.2);
0.001 -2.2 (1.5);
0.001
Percentage change from baseline (%) - 25.9 53.2 74.1
Cramps at night
Mean score (SD) 3.3 (1.4) 2.6 (1.5) 2.1 (1.3) 1.1 (1.0)
Mean difference from baseline; p-value - -0.7 (0.9);
0.001 -1.2 (1.0);
0.001 -2.1 (1.2);
0.001
Percentage change from baseline (%) - 20.9 36.8 65.0
Edema (whole leg)
Mean score (SD) 3.1 (1.7) 2.5 (1.6) 2.1 (1.3) 1.4 (1.2)
Mean difference from baseline; p-value - -0.6 (0.9);
0.001 -0.9 (0.9);
0.001 -1.7 (1.2);
0.001
Percentage change from baseline (%) - 19.0 29.7 53.9
Data presented as n (%), unless otherwise specified. #N=104, unless otherwise specified. BMI, body mass index; SD, standard deviation.
Leg circumference (Cm)
Cm (SD) (n=79)
34.0 (12.6) (n=79)
33.5 (13.0) (n=76)
33.1 (12.3) (n=76)
32.4 (12.1)
Mean difference from baseline; p-value§ - -0.5 (1.1);
0.001 -1.7 (1.5);
0.001 -2.4 (2.1);
0.001
Percentage change from baseline (%) - 1.6 4.7 6.9

Results as obtained in Table 6:
1. Post-treatment, at 1-month, 2-month and 3-month follow-up, mean pain scores in the legs showed a significant fall of 28.9%, 41.9%, and 69.2%, respectively, from baseline.
2. Post-treatment, at 1-month, 2-month, and 3-month follow-up, the mean swelling score showed a significant fall of 24.0%, 35.0%, and 57.8%, respectively, from baseline.
3. Post-treatment, at 1-month, 2-month, and 3-month follow-up, mean tingling scores showed a significant fall of 21.1%, 29.3%, and 68.0%, respectively, from baseline.
4. After treatment, at 1-month, 2-month, and 3-month follow-ups, the mean score of numbness in legs and itching around veins showed a significant fall of 18.5% and 25.9%, 39.4% and 53.2%, 67.1% and 74.1%, respectively.
5. Significant improvement in mean scores of cramps at night, edema (whole leg) and changes in mean leg circumference at each follow up visits from baseline, were observed (P=0.001).

Table 7: Change in other symptoms of varicose veins
Parameters Baseline 1 month 2 months 3 months
Skin color† (n=102)
46 (45.1) (n=102)
46 (45.1) (n=97)
38 (39.2) (n=96)
26 (27.1)a
Changes in skin pigmentation (mean [SD])§
Mean score (SD) (n=48)
2.6 (1.4) (n=48)
2.1 (1.0) (n=48)
1.7 (1.0) (n=48)
0.7 (0.9)
Mean difference from baseline; p-value - -0.5 (0.6);
0.001 -0.9 (0.8);
0.001 -1.9 (1.1);
0.001
Percentage change from baseline (%) - 19.5 35.9 72.3
Number of ulcer (mean [SD])§
Mean score (SD) (n=12)
1.9 (1.1) (n=12)
1.3 (1.2) (n=12)
0.5 (0.7) (n=12)
0.2 (0.4)
Mean difference from baseline;
p-value - -0.6 (1.0);
0.069 -1.4 (1.1);
0.001 -1.8 (1.1);
0.001
Percentage change from baseline (%) - 30.2 74.0 91.1
Size of venous ulcer (cm)†
0 (Complete heal)
< 2
> 2 (n=12)
-
6 (50.0)
6 (50.0) (n=12)
2 (16.7)
5 (41.7)
5 (41.7) (n=12)
5 (41.7)b
2 (16.7)
5 (41.7) (n=12)
7 (58.3)c
2 (16.7)
3 (25.0)
Patients with presence of any of the following†
Thread veins
Spider veins
Superficial Telangiectasia (n=93)
51 (54.8)
37 (39.8)
14 (15.1) (n=89)
48 (53.9)
34 (38.2)
11 (12.4) (n=89)
48 (53.9)
33 (37.1)
11 (12.4) (n=87)
47 (54.0)
33 (37.9)
10 (11.5)
Patients with lipodermatosclerosis† (n=104)
16 (15.4) (n=102)
15 (14.7) (n=100)
14 (14.0) (n=101)
13 (12.9)
Data presented as n (%), unless otherwise specified. #N=104, unless otherwise specified.
a, P=0.008; b, P=0.04; c, P=0.007. SD, standard deviation.
Statistical tests used: †, Chi-square test; §, Student ‘t’ test

Results as obtained in Table 7:
1. Significant improvement in mean scores of other symptoms of varicose veins, such as changes in skin pigmentation at each follow up visits from baseline, were observed (P=0.001).
2. At 3-month follow-up, the proportion of patients who had changes in skin color (27.1%) significantly reduced from the baseline (45.1%) (P=0.008).
3. The average number of ulcers significantly improved at the 3-month follow-up from baseline (mean change: -1.8; P=0.0001).
4. Among 12 patients with venous ulcers at baseline, 41.7% (P=0.04) and 58.3% (P=0.007) of patients were completely healed at the end of 2-month and 3-month follow-ups, respectively.
5. There was no significant change in the proportion of patients with thread veins/spider veins/superficial Telangiectasia, lipodermatosclerosis from baseline to the end of 3-month follow-up.

Table 8: Profile of overall improvement in disease at the end of study (3 months)
Parameter No. of patients
(#N=104)
As per physician
Residual varicosities, (n=101)
Complications present, (n=102)
Recurrence at 6 months, (n=67)
83 (82.2)
2 (2.0)
1 (1.5)
As per patients
Not at all noticeable
Slightly noticeable
Moderately noticeable
Very noticeable
Extremely noticeable
2 (1.9)
7 (6.7)
41 (39.4)
48 (46.2)
6 (5.8)
Data presented as n (%). #N=104, unless otherwise specified.

Results as obtained in Table 8 above:
1. As per physician assessment, 82.2% of patients were diagnosed with residual varicosities, 2.0% of patients with complications, and 1.5% of patients had recurrence at 6 months.
2. As per patients’ assessment, 91.4% of patients showed moderately to a highly noticeable improvement in the disease.

Table 9: Profile of treatment assessment (as per Patient)
Assessment V2 (1 month)
(N=104) V3 (2 month)
#(N=101) V4 (3 month)
#(N=101)
No % No % No %
Excellent 03 02.9 06 05.9 18 17.8
Good 41 39.4 71 70.3 73 72.3
Fair 47 45.2 23 22.8 09 08.9
Poor 13 12.5 01 01.0 01 01.0

Results: As per patients, 42.3%, 76.2%, and 90.1% of patients had good to the excellent improvement of treatment at 1-month, 2-month, and 3-month follow-up, respectively.

Table 10: Profile of treatment assessment (as per Physician)
Assessment V2 (1 month) (N=104) V3 (2 month) #(N=101) V4 (3 month) #(N=101)
No % No % No %
Excellent 03 02.9 09 08.9 52 51.5
Good 64 61.5 79 78.2 46 45.5
Fair 35 33.7 12 11.9 02 02.0
Poor 02 01.9 01 01.0 01 01.0

Results:
1. As per physicians, at the end of 1-month, 2-month, and 3-month follow-up, 64.4%, 87.1%, and 97.0% of patients, respectively, had good to excellent improvement in treatment.
2. None of the patients reported any adverse events.
,CLAIMS:WE CLAIM:
1. A synergistic pharmaceutical combination comprising:
- a topical composition comprising dry extract of Euphorbia Prostrata; and
- an oral composition comprising dry extract Euphorbia Prostrata.

2. The synergistic pharmaceutical combination as claimed in claim 1, wherein the topical composition and the oral composition are to be administered sequentially in any order with or without a time gap.

3. The synergistic pharmaceutical combination as claimed in claim 1, wherein
- a topical composition comprising about 1% w/w dry extract of Euphorbia Prostrata, optionally one or more additional pharmaceutically active agents, and one or more pharmaceutically acceptable excipients; and
- an oral composition comprising about 100 mg dry extract of Euphorbia Prostrata, optionally one or more additional pharmaceutically active agents, and one or more pharmaceutically acceptable excipients.

4. The synergistic pharmaceutical combination as claimed in claim 1, wherein the topical composition is a cream or a gel and the oral composition is a capsule or a tablet.

5. The synergistic pharmaceutical combination as claimed in claim 1, wherein the combination is effective for haemorrhoids including haemorrhoids during pregnancy, anal fissures, anal fistula, and/or varicose veins.

6. The synergistic pharmaceutical combination as claimed in claim 1, wherein the topical composition comprises additional pharmaceutical agents selected from lidocaine, benzocaine, dibucaine, diltiazem, nefidipine, nitroglycerine, bethanecol, zinc oxide, pain relievers such as diclofenac, ibuprofen, acetaminophen, steroids such as hydrocortisone, phenylephrine, pramoxine, diosmin, or combinations thereof.

7. The synergistic pharmaceutical combination as claimed in claim 3, wherein the oral composition comprises additional pharmaceutical agents selected from calcium dobesilate, diosmin, docusate sodium, ispaghula husk, pain relieving agents such as diclofenac, ibuprofen, acetaminophen, steroids, or combinations thereof

8. The synergistic pharmaceutical combination as claimed in claim 1, wherein the topical composition comprises:
(a) about 0.1 % w/w to about 95% w/w of dry extract of Euphorbia Prostrata,
(b) about 0.05 % w/w to about 50% w/w of gelling agent(s),
(c) about 10% w/w to about 90% w/w of one or more solvent(s),
(d) about 0.01% w/w to about 50% w/w of one or more co-solvent(s),
(e) about 0.05% w/w to about 90% w/w of one or more solubilizing agent(s),
(f) about 0.01% w/w to about 20% w/w of one or more buffering agent(s),
(g) about 0.0001% w/v to about 5.0% w/v of one or more preservatives (s), and
purified water.

9. The synergistic pharmaceutical combination as claimed in claim 1, wherein the oral composition comprises:
(a) about 0.1 % w/w to about 95% w/w of dry extract of Euphorbia Prostrata
(b) about 1 % w/w to about 80% w/w of diluent/filler(s);
(c) about 0.1% w/w to about 20% w/w of one or more binder(s);
(d) about 0.1% w/w to about 20% w/w of one or more disintegrant(s); and
(e) about 0.01% w/w to about 10% w/w of lubricant(s), and
(f) about 0.01% w/w to about 10% w/w of glidant(s)

10. The synergistic pharmaceutical combination as claimed in claim 2, wherein the dry extract of Euphorbia Prostrata is having d90 particle size of not more than 350 µm.

Dated this, 22th Day of May, 2024
For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer