DESC:

TOPICAL COMPOSITIONS COMPRISING EUPHORBIA PROSTRATA

FIELD OF THE INVENTION

The present invention provides a topical composition of Euphorbia Prostrata, comprising one or more pharmaceutically active agent, wherein said composition is suitable for the treatment of 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. Among the various anorectal and colonic diseases, haemorrhoids occupy a prominent position and has been the subject of numerous clinical studies. Haemorrhoidal disease is characterized by bleeding, without any pain. Fresh blood spots occur immediately, on defecation. However, pain occurs when the haemorrhoids are secondarily infected, or complicated by thrombosis and anal fissures. There exist several procedures for the treatment of haemorrhoids. 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 a still a need for more efficacious compositions, combinations, and dosing schedules for the treatment of haemorrhoids and to counter the problem associated with anal fissures, anal fistulas that make haemorrhoids treatment more complicated and is also safe and effective during pregnancy.

An anal fissure is a tear in the epithelial lining of the anal canal. Although this is an extremely common condition. 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. Soaking in warm water for 10 to 20 minutes several times a day, especially after bowel movements, can help relax the sphincter and promote healing. Nitroglycerin is generally considered the medical treatment of choice when other conservative measures fail. However, it caused side effects that may include headache, which can be severe. Other solutions are use of Botulinum toxin type A injection to paralyze the anal sphincter muscle and relax spasms. Medications, such as Nifedipine can help relax the anal sphincter. These medications may be taken orally or applied externally and may be used when nitroglycerin is not effective or causes significant side effects. Surgery is last option in chronic anal fissure and anal fistula that is resistant to other treatments.

Hence, it is important to evaluate the efficacy of Euphorbia Prostrata in the management of fissures and fistulas because of its broad spectrum of actions, covering the patho-physiological process involved in fissure progression. Based on aforesaid, present invention is focussed to work on the formulations of Euphorbia Prostrata alone or in combination with one or more active ingredients that are sufficient for the treatment of anal fissures, anal fistulas and none the less, haemorrhoids and other related conditions.

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 standing and walking increase the pressure in the veins of the lower body. For many people, varicose veins and spider veins are simply a cosmetic concern. For other people, varicose veins can cause aching pain and discomfort. Sometimes varicose veins lead to more-serious problems. Currently available treatment involves self-care measures or procedures done by a health care provider to close or remove veins. The present invention is further focussed to work on the formulations of Euphorbia Prostrata alone or in combination with one or more active ingredients that are sufficient for the treatment varicose veins.

There is therefore a strong need felt in the art for compositions and dosing schedules of Euphorbia Prostrata alone or in combination with other active agents for the treatment of haemorrhoids in particular, haemorrhoids during pregnancy, anal fissures, anal fistula, and varicose veins that are safe and effective. The present invention provides a topical composition comprising Euphorbia Prostrata dry extract that provides effective and safe amounts of Euphorbia Prostrata at specific site of action for the treatment of haemorrhoids in particular, haemorrhoids during pregnancy, anal fissures, anal fistula, and varicose veins. The present invention further provides safe and effective dosing schedules for the topical compositions of the invention. The topical compositions of the invention may further comprise one or more another active agent.

OBJECTIVE OF THE INVENTION
The principal objective of the present invention is to provide a topical composition of Euphorbia Prostrata, and one or more pharmaceutically acceptable excipients, and optionally comprising one or more pharmaceutically active agent.

Another objective of the present invention is to provide a process for preparation of said topical composition comprising substantially pure Euphorbia Prostrata extract, wherein said extract has a controlled particle size that provides effective and safe amount of Euphorbia Prostrata at specific site of action, and wherein said topical composition optionally comprises one or more pharmaceutically active agent.

Another objective of the present invention is to provide dosing schedules for the topical compositions of the invention for the effective and safe treatment of anal fissures, anal fistula, varicose veins, and haemorrhoids including haemorrhoids during pregnancy.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a topical composition comprising a therapeutically effective amount of Euphorbia Prostrata and one or more pharmaceutically acceptable excipients.

In one aspect, the present invention provides a topical composition comprising:
- a therapeutically effective amount of Euphorbia Prostrata;
- one or more additional pharmaceutically active agents; and
- one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a topical composition comprising:
- a therapeutically effective amount of Euphorbia Prostrata;
- lidocaine;
- one or more pharmaceutically acceptable excipients.

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

In another aspect, the present invention provides 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,
wherein the composition is a cream or a gel.

In another aspect, the present invention provides a topical composition comprising substantially pure Euphorbia Prostrata extract, wherein said extract has a controlled particle size that provides safe and effective amount of Euphorbia Prostrata at specific site of action and wherein said topical composition optionally comprises one or more pharmaceutically active agents.

In another aspect, the present invention provides a topical composition comprising dry extract of Euphorbia Prostrata, wherein the particle size of dry extract of Euphorbia Prostrata is d10 is not more than 10 µm; d50 is not more than 100 µm and d90 is not more than 350 µm.

In another aspect, the present invention provides a topical composition comprising a therapeutically effective amount of Euphorbia Prostrata; one or more pharmaceutically acceptable excipients, and optionally one or more pharmaceutically active agents, wherein the composition is effective in the treatment of anal fissures, anal fistula, varicose veins, haemorrhoids including haemorrhoids during pregnancy.

In another aspect, the present invention provides a topical composition comprising:
- a therapeutically effective amount of Euphorbia Prostrata;
- one or more pharmaceutically acceptable excipients,
wherein the composition is applied at least twice daily and after each act of defecation for 14 days for the treatment of haemorrhoids during pregnancy.

In another aspect, the present invention provides a topical composition comprising:
- a therapeutically effective amount of Euphorbia Prostrata;
- one or more pharmaceutically acceptable excipients,
wherein the composition is applied at least twice daily for 3 months for the treatment of varicose veins.

In another aspect, the present invention provides a topical composition comprising:
- a therapeutically effective amount of Euphorbia Prostrata;
- optionally one or more additional pharmaceutically active agents; and
- one or more pharmaceutically acceptable excipients,
wherein the composition is applied at least twice daily and after each act of defecation for 6 weeks for the treatment of anal fissures or anal fistula.

In another aspect, the present invention provides a topical composition comprising:
- a therapeutically effective amount of Euphorbia Prostrata;
- lidocaine; and
- one or more pharmaceutically acceptable excipients,
wherein the composition is applied at least twice daily and after each act of defecation for 6 weeks for the treatment of anal fissures or anal fistula.

In another aspect, the present invention provides a topical composition comprising:
- about 100 mg dry extract of Euphorbia Prostrata;
- about 3%w/w lidocaine;
- about 1%w/w diltiazem; and
- one or more pharmaceutically acceptable excipients,
wherein the composition is effective for the treatment of anal fissures or anal fistula.

In another aspect, the present invention provides a topical composition comprising:
- about 100 mg dry extract of Euphorbia Prostrata;
- about 3%w/w lidocaine;
- about 1%w/w diltiazem; and
- one or more pharmaceutically acceptable excipients,
wherein the composition is a topical gel and is applied at least twice daily and after each act of defecation for 6 weeks for the treatment of anal fissures or anal fistula.

In another aspect, the present invention provides a 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.

In other aspect, the present invention provides a topical 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 topical composition comprising a therapeutically effective amount of Euphorbia Prostrata; 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 “formulation” or “pharmaceutical formulation” or “topical composition” pharmaceutical formulation” or “dosage form” or “pharmaceutical formulation” or “formulation” 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, composition is a cream or a gel.

The term “pharmaceutically acceptable” refers to what is physiologically well tolerated by mammals or humans.

The term “excipient” or “pharmaceutically acceptable excipients” means a pharmacologically inactive component. As pharmaceutical excipients have various functions and contribute to the pharmaceutical formulation in many different ways, e.g., solubilisation, dilution, thickening, stabilization, and preservation. The properties that are commonly considered when formulating an active drug substance include bioavailability, ease of manufacture, ease of administration, and stability of the dosage form. Due to the varying properties of the active drug substance to be formulated, dosage forms typically require pharmaceutical excipients that are uniquely tailored for the active drug substance in order to achieve advantageous physical and pharmaceutical properties.

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 one embodiment, the present invention describes a topical cream formulation using a hydrophobic cream base. A topical formulation in hydrophobic cream base is particularly advantageous as it provides an emollient action and soothes the skin. 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)

In another embodiment, the present invention describes a topical gel formulation using a gel base. A topical formulation in gel base is particularly advantageous as it provides a hydrant action and soothes the skin. Extract of Euphorbia Prostrata is mixed with gelling agent or mixture of gelling agent(s) to form a topical gel. Gelling agents are the gel-forming agents when dissolved in a liquid phase as a colloidal mixture forms a weakly cohesive internal structure. They are organic hydrocolloids or hydrophilic inorganic substances.

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), poly(N-isopropylacrilamide), poly(N-isopropylacrilamide) monomer crosslinked with N,N'-methylenebisacrylamide, polyethylene glycol (PEG)-conjugated- poly(N-isopropylacrilamide), poly(hydroxyethylmethacrylate)- conjugated- poly(N-isopropylacrilamide), poly(N-isopropylacrilamide)-block-poly(methyl methacrylate)-(poly (acrylic acid)), polyvinylacetal diethylaminoacetate, poly(2-hydroxyethylmethacrylate-co-2-(diisopropylamino)ethyl methacrylate), Poly(2-hydroxyethyl methacrylate), gelatine methacrylate (GelMA), PLGA-PEG-PLGA triblock copolymer hydrogels, poly(ethylene glycol) acrylate, poly(ethylene glycol) diacrylate, poly(ethylene glycol) methacrylate, polycaprolactone-polylactic acid, hydroxyethyl methacrylate-methacrylic acid, Polyvinyl alcohol (PVA) and Polyvinylpyrrolidone (PVP), poly(amino acids), methyl methacrylate cross-linked poly (vinyl alcohol), Polyglycolic acid-polycaprolactone-polyethylene glycol-polycaprolactone-polyglycolic acid (PGA-PCL-PEG-PCL-PGA), polylactic acid-polycaprolactone-polyethyleneglycol-polycaprolactone-polylactic acid (PLA-PCL-PEG-PCL-PLA), poly(N-isopropylacrylamide)-poly(ethylene glycol)- poly(e-caprolactone), poly (N,N-diethylacrylamide) and poly (N-isopropylacrylamide), poly (N-n-propylacrylamide), ethylene vinyl acetate polymer , polyalkyl cyanoacrylate, hydroxypropyl methacrylate mixture of tocopheryl acetate:medium-chain triglycerides, polyoxyethylene hydrogenated castor oil, 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, Isopropyl Myristate, Diethylene glycol monoethyl ether, 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 or diethylene glycol monoethyl ether. 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, diethylene glycol monoethyl ether, 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, Dipalmitoylphosphatidyl choline (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), dilinoleoylphosphatidyl choline (DLPC), two myristoyl lecithin, Dipalmitoylphosphatidyl choline (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, cetostearyl alcohol, 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, sodium thiosulfate, sodium bisulfite, acetone sodium bisulfite, gentisic acid, gentisic acid ethanolamide, sodium formaldehyde sulfoxylate, thiourea, butylated hydroxyanisole, butylated hydroxy toluene, esters of gallic acid, ascorbic acid, salts of ascorbic acids such as ascorbyl palmitate, tartaric acid, citric acid, fumaric acid, malic acid, sodium ascorbate, retinoids and derivatives of vitamin A, acetylcysteine, thioglycerol, sodium metabisufite, sodium sulphite, sodium pyrosulphate, methionine, glutamine, thiamine, propyl gallate, vitamin C, lutein, beta-carotene, Vitamin E and its derivatives e.g. Vitamin E TPGS and/or combinations thereof

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.

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

In another embodiment, the present invention provides a topical composition comprising:
- a therapeutically effective amount of Euphorbia Prostrata;
- one or more additional pharmaceutically active agents; and
- one or more pharmaceutically acceptable excipients.

One or more additional pharmaceutical agents to be included in the 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.

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

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

In another embodiment, the present invention provides a topical composition comprising about 1% w/w Euphorbia Prostrata; and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a pharmaceutical composition comprising dry extract of Euphorbia Prostrata, wherein the particle size distribution of dry extract of Euphorbia Prostrata, i.e., 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 present invention provides a topical composition comprising a therapeutically effective amount of Euphorbia Prostrata; and one or more pharmaceutically acceptable excipients, wherein the composition 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 topical composition comprising:
- a therapeutically effective amount of Euphorbia Prostrata;
- one or more pharmaceutically acceptable excipients,
wherein the composition is applied at least twice daily and after each act of defecation for 14 days for the treatment of haemorrhoids during pregnancy.

In another embodiment, the present invention provides a topical composition comprising:
- a therapeutically effective amount of Euphorbia Prostrata;
- one or more pharmaceutically acceptable excipients,
wherein the composition is applied at least twice daily for 3 months for the treatment of varicose veins.

In another embodiment, the present invention provides a topical composition comprising:
- a therapeutically effective amount of Euphorbia Prostrata;
- optionally one or more additional pharmaceutically active agents; and
- one or more pharmaceutically acceptable excipients,
wherein the composition is applied at least twice daily and after each act of defecation for 6 weeks for the treatment of anal fissures or anal fistula.

In another embodiment, the present invention provides a topical composition comprising:
- a therapeutically effective amount of Euphorbia Prostrata;
- lidocaine; and
- one or more pharmaceutically acceptable excipients,
wherein the composition is applied at least twice daily and after each act of defecation for 6 weeks for the treatment of anal fissures or anal fistula.

In another embodiment, the present invention provides a topical composition comprising:
- about 100 mg dry extract of Euphorbia Prostrata;
- about 3%w/w lidocaine;
- about 1%w/w diltiazem; and
- one or more pharmaceutically acceptable excipients,
wherein the composition is effective for the treatment of anal fissures or anal fistula.

In another embodiment, the present invention provides a topical composition comprising:
- about 100 mg dry extract of Euphorbia Prostrata;
- about 3%w/w lidocaine;
- about 1%w/w diltiazem; and
- one or more pharmaceutically acceptable excipients,
wherein the composition is a topical gel and is applied at least twice daily and after each act of defecation for 6 weeks for the treatment of anal fissures or anal fistula.

In another embodiment, the present invention provides a topical composition of Euphorbia, wherein the pH of composition is in the range of 3 to 7.

In another embodiment, the present invention provides a topical composition of Euphorbia, wherein the pH of composition is in about 5±1.

In another embodiment, the present invention provides a topical composition of Euphorbia, wherein the viscosity of the composition is in the range of 30000 cps to 70000 cps.

In another embodiment, the present invention provides a topical composition of Euphorbia, wherein the viscosity of the composition is in the range of 40000 cps to 60000 cps.

In another embodiment, the present invention provides a topical composition of Euphorbia, wherein the assay of the Euphorbia Prostrata Extract is about 90.0% to 110.0% of label claim.

In another embodiment, the present invention provides a topical composition of Euphorbia, wherein the assay of the other pharmaceutical active agent is about 90.0% to 110.0% of label claim.

In another embodiment, the dosing schedules for the pharmaceutical combination are as follows:
1. The topical composition of the invention 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 of the invention 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 of the invention 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 of the invention is applied at least twice daily and after each act of defecation for 6 weeks, and the oral composition is provided as one tablet twice daily for eight weeks, for the treatment of anal fistula.

It is observed that Diltiazem that acts as a calcium channel blocker works by relaxing the anal sphincter muscle which allows blood to flow to the lining of the anus which in turn alleviates pain and allows stool to pass more easily. On other hand, Lidocaine is a local anaesthetic of the amide that provides local anaesthesia by nerve blockade and stabilizing the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anaesthetic action. Also, Lidocaine acts as sodium channel block and shorten the action potential of myocardial cell that also helps in treating anal fissures. Meanwhile, Euphorbia Prostrata work on wound healing. Hence the combination of above three drugs, i.e., Euphorbia Prostrata along with Lidocaine and Diltiazem in a specific concentration act as a sufficient, effective, and safe solution to treat anal fissures and anal fistula along with haemorrhoids.

Further, it is known that haemorrhoids are one of the pathogenic processes that implicates stagnation and stasis of blood in the vascular plexuses of the prolapsed anal cushions. During pregnancy and post-delivery the prevalence of haemorrhoids is around 40% and increases in the due course of progression. Pregnancy results into increased pressure on the pelvic veins and the strain on the rectal veins during delivery. Increased progesterone and estrogen hormones during pregnancy can weaken the veins and lead to haemorrhoids. Other risk factors such as constipation (a predominant symptom during pregnancy), obesity, and a sedentary lifestyle can also contribute to developing haemorrhoids during pregnancy with symptoms like bleeding, pain, itching irritation and swelling.

It is also known that Varicose veins (VV) are twisted, enlarged, and superficial in appearance on the lower extremities and are a part of the chronic venous insufficiency syndrome. The associated signs and symptoms include aching, heavy legs, swelling, brownish-yellow shiny skin discoloration near the affected veins redness, dryness, itchiness of areas of skin, termed stasis dermatitis or venous eczema, muscle cramps, abnormal bleeding or healing time for injuries in the affected area, lipoderma to sclerosis or shrinking skin near the ankles, restless legs syndrome, atrophie blanche, or white, scar-like formations. The major complications are edema, skin pigmentation, lower-limb ulcers. Prior art treatment options include drugs that are venotonic, and surgical measures including sclerotherapy, micro-sclerotherapy, laser surgery, endovenous ablation therapy and endoscopic vein surgery.

In another embodiment, the present invention provides a topical 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.

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.

In another embodiment, the present invention provides a method for preparation of topical composition, preferably gel or cream composition comprising substantially pure dry extract of Euphorbia Prostrata, and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a method for preparation of topical composition, preferably gel or cream composition comprising substantially pure dry extract of Euphorbia Prostrata, Lidocaine or its pharmaceutically acceptable salt, and Diltiazem or its pharmaceutically acceptable salts.

In another embodiment, the present invention provides a topical composition comprising dry extract of Euphorbia Prostrata wherein said extract is substantially free of heavy metals selected from lead (Pb), cadmium (Cd), mercury (Hg) and arsenic (As).

In another embodiment, it is observed that the combination of Euphorbia Prostrata along with Diltiazem and Lidocaine have shown strength of evidence in wounds healing and muscle relaxation respectively.

While selected embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. 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:

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

Process:
Preparation of oily phase:
i) filtering corn oil through nylon cloth of mesh size #160;
ii) emulsifying wax, sorbitan stearate, butylated hydroxyanisole, propyl gallate were mixed with corn oil of step (i), followed by heating at 70-75 °C;

Preparation of aqueous phase:
iii) sifting Veegum HV through sieve of mesh size #40 and dispersing in purified water under continuous stirring;
iv) filtering Sorbitol solution and polysorbate through nylon cloth of mesh size #160 and mixed with step (iii) under continuous stirring;
v) Sifting sodium carboxymethyl cellulose through sieve of mesh size #20, filtering glycerine through nylon cloth of mesh size #160;
vi) mixing filtered glycerine with sifted sodium carboxymethyl cellulose as obtained in the step (v) followed by mixing with step (iv) under continuous stirring maintaining the quantity with purified water to obtain the bulk;
vii) maintaining the temperature of the bulk to 70-75 °C.

Preparation of Drug, i.e., Euphorbia Prostrata phase:
viii) filtering propylene glycol through nylon cloth of mesh size #160 and heating to temperature of 60-65 °C;
ix) sifting Euphorbia Prostrata dry extract, propyl paraben, methyl paraben through sieve of mesh size #40 and sifting titanium dioxide through sieve of mesh size #100;
x) mixing sifted material as obtained in step (ix) with filtered propylene glycol.

Preparation of cream:
xi) mixing the oily phase and aqueous phase together which are maintained at a temperature of 70-75 °C, and cooling the emulsion so obtain to 50-55 °C; and
xii) adding propylene glycol and homogenize the bulk for 10 minutes, and cooling the emulsion (cream) so obtain to 20-25 °C, followed by packing.

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%

Process:
1. filtering corn oil through nylon cloth of mesh size #160;
2. dissolving the active ingredient in the ethanol/propylene glycol/diethylene glycol monoethyl ether/lauryl alcohol mixture;
3. adding oil and carbomer thoroughly dispersed in the hydro-alcoholic solution under mechanical stirring at room temperature at a suitable speed ensuring good homogenization of the formulation while avoiding lumps formation and air entrapment;
4. adding triethanolamine under stirring to form the emulsion (cream) followed by packing.

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

Process:
1. sifting active agents through appropriate sieve;
2. filtering propylene glycol and glycerol through nylon cloth of mesh size #160 and heating to temperature of 60-65oC;
3. adding Euphorbia Prostrata dry extract and propyl gallate to form Euphorbia Prostrata phase;
4. dissolving Sorbic acid and polysorbate into Purified water;
5. adding diltiazem hydrochloride, lidocaine hydrochloride, and Euphorbia Prostrata phase;
6. mixing with soaked polymers (Polycarbophil and Carbomer 934P);
7. adding sodium hydroxide to adjust the pH and kept the mixture to gel followed by packing.

Example 4: Cream composition of Euphorbia Prostrata and Lidocaine

Ingredient Amount (%w/w)
Euphorbia Prostrata 1.00
Lidocaine 3.00
Diethylene glycol monoethyl ether 10.00
Propylene glycol 10.00
Liquid paraffin 5.00
Isopropyl Myristate 5.00
PEG 100 Stearate 3.00
Cetostearyl alcohol 5.00
Methyl Paraben 0.2
Propyl Paraben 0.05
Purified water 57.75

Process:
1. dispensing all the ingredients and preparing a preservative phase - taking batch quantity of purified water, and further adding PEG 100 Stearate under stirring, allow to stir to form clear solution. Then heating to 40 – 50°C, and adding methyl paraben, followed by addition of propyl paraben under stirring. Continue heating to 65 -75°C under stirring, ensure clear solution is formed;
2. Preparation of oil phase: Taking oil phase ingredients Isopropyl myristate, liquid paraffin, cetostearyl alcohol and heat this phase to 65 – 75°C. Ensuring clear liquid is formed;
3. Emulsification: Adding oil phase as obtain in the above steps under homogenization at 5000 rpm and homogenize for 30 min;
4. Preparation and Addition of Drug phase: to Diethyleneglycol monoethyl ether adding propylene glycol under stirring, ensuring homogenous clear solution is formed. Then adding lidocaine API under stirring and allow to stir to form clear solution. Then adding Euphorbia Prostrata Extract under stirring, allow to stir to form uniform dispersion. Adding the prepared drug phase to step 4 under homogenization at 5000 rpm and homogenize for 30 min;

5. Cooling the bulk of step 5 under stirring to reach room temperature. Then mixing the bulk for about 30 min, followed by Packing the bulk in approved packaging material and Storing in cool and dry place at temperature not exceeding 30°C.

Pharmaceutical composition of present invention was subjected to stability study and results are as follows:
Tests Specifications Condition/ Time point
Initial 40°C/75%RH – 6M 30°C/75%RH – 6M
Description Pale brown to brownish color cream should be free from lumps and phase separation Pale brown cream free from lumps and phase separation Pale brown cream free from lumps and phase separation Pale brown cream free from lumps and phase separation
pH 3.00 – 7.00 5.00 5.30 4.90
Assay of Euphorbia Prostrata Extract 90.0% to 110.0% of label claim 99.80 100.9 99.5
Assay of Lidocaine 90.0% to 110.0% of label claim 99.90 99.2 100.5
Viscosity (cps) 30000 – 70000 54000 49980 55650

From the above table, it is evident that the topical composition of Euphorbia is stable.

,CLAIMS:WE CLAIM:

1. A topical composition comprising a therapeutically effective amount of dry extract of Euphorbia Prostrata, one or more additional pharmaceutically active agents and one or more pharmaceutically acceptable excipient(s).

2. The topical composition as claimed in claim 1, wherein the topical composition in the form of solution, suspension, gel, in-situ gel, cream, ointment or lotion.

3. The topical composition as claimed in claim 1, wherein the dry extract of Euphorbia Prostrata having particle size of d90 is not more than 350 µm.

4. The topical composition as claimed in claim 1, wherein said additional pharmaceutically active agent is 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.

5. The topical composition as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients is selected from the group comprising 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.

6. The topical composition as claimed in claim 1, wherein the composition comprising:
(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 0.01% w/w to about 25% w/w of solubilizing agent(s),
(f) about 0.01% w/w to about 10% w/w of viscosity modifier(s);
(g) about 0.01% w/w to about 20% w/w of buffering agent(s);
(h) about 0.0001% w/v to about 5.0% w/v of preservative (s); and purified water.

7. The topical composition as claimed in claim 1, wherein the composition is applied at least twice daily and after each act of defecation for 14 days for the treatment of haemorrhoids during pregnancy.

8. The pharmaceutical composition as claimed in claim 1, wherein the composition is applied at least twice daily for 3 months for the treatment of varicose veins.

9. The pharmaceutical composition as claimed in claim 4, wherein the composition is applied at least twice daily and after each act of defecation for 6 weeks for the treatment of anal fissures or anal fistula.

10. A topical composition comprising about 100 mg dry extract of Euphorbia Prostrata; about 3%w/w lidocaine; about 1%w/w diltiazem; and one or more pharmaceutically acceptable excipients, wherein the composition is effective for the treatment of anal fissures or anal fistula.

Dated this, 20th Day of May 2024 For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer