DESC:COMPOSITIONS AND COMBINATIONS COMPRISING EUPHORBIA PROSTRATA AND ISPAGHULA HUSK

FIELD OF THE INVENTION

The present invention provides a pharmaceutical combination comprising Euphorbia Prostrata and Ispaghula husk. The combination and compositions of present invention are suitable for the treatment of piles, haemorrhoids, haemorrhoids during pregnancy, anal fissures, and/or anal fistula.

BACKGROUND OF THE INVENTION

Euphorbia Prostrata is a small, prostrate, annual green herb widely distributed globally and used as antihemorrhoidal, anti-inflammatory, analgesic, hypolipidemic, antidiabetic, antidiarrheal, antiasthmatic and for various skin diseases. Among the various anorectal and colonic diseases, piles and haemorrhoids occupy a prominent position and has been the subject of numerous clinical studies. In patients with piles, constipation further aggravate piles which would tend to bleeding and impaired wound healing. 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 are certain other medical conditions that worsen the haemorrhoids such as anal fistulas and piles. There is a need to counter the problem associated with haemorrhoids, anal fissures, anal fistulas, that make piles treatment more complicated. Further, there is also a need of a treatment for piles and haemorrhoids during pregnancy that is effective and safe.

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.

The present invention provides a pharmaceutical compositions and combination comprising Euphorbia Prostrata and Ispaghula husk that are more efficacious and safer. The present invention further provides use of compositions and combinations of the invention for the treatment of piles, haemorrhoids including haemorrhoids during pregnancy, anal fissures, and/or anal fistula. The present invention further provides safe and effective dosing schedules for the compositions and combinations of the invention.

OBJECTIVE OF THE INVENTION

The Main objective of the present invention is to provide a pharmaceutical combination comprising Euphorbia Prostrata and Ispaghula husk.

Another objective of the present invention is to provide compositions and combinations comprising substantially pure Euphorbia Prostrata extract, wherein said extract has a controlled particle size that provides improved dissolution profile of Euphorbia Prostrata.

Another objective of the present invention is to provide dosing schedules for the compositions and combinations of the invention for the treatment of piles, haemorrhoids including haemorrhoids during pregnancy, anal fissures, and/or anal fistula.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a pharmaceutical combination comprising:
- Euphorbia Prostrata, and
- Ispaghula husk.

Another aspect of the present invention provides a pharmaceutical combination comprising:
- about 10 – about 500 mg Euphorbia Prostrata,
- about 1 – about 5 g Ispaghula husk, and
- optionally, one or more pharmaceutically acceptable excipients;
wherein the combination is effective in the treatment of piles, haemorrhoids including haemorrhoids during pregnancy, anal fissures, and/or anal fistula.

Another aspect of the present invention provides a pharmaceutical combination comprising:
- about 100 mg Euphorbia Prostrata, and
- about 3.5 g Ispaghula husk;
wherein the combination is administered orally for 14 days for the treatment of piles and haemorrhoids.

Another aspect of the present invention provides a pharmaceutical fibre composition comprising:
- about 10 – about 500 mg Euphorbia Prostrata,
- about 1 – about 5 g Ispaghula husk, and
- optionally, one or more pharmaceutically acceptable excipients.

According to another aspect, the composition or combinations of the present invention comprise 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.

According to another aspect, the composition or combinations of the present invention comprise dry extract of the Euphorbia Prostrata, wherein said dry extract of Euphorbia Prostrata contains flavonoids and phenolic compounds, wherein total flavonoids are 3.0% to 8.5% by weight calculated as apigenin-7-glycoside; and wherein the total phenolic compounds are 12.0% to 45.0% by weight calculated as gallic acid.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a pharmaceutical combination comprising: Euphorbia Prostrata and Ispaghula husk.

The present invention also provides a pharmaceutical fibre composition comprising: Euphorbia Prostrata, Ispaghula husk, and optionally, 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 ascribed 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 “oral composition” pharmaceutical formulation” or “dosage form” or “pharmaceutical formulation” or “formulation” 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, powder, fibre, granules, suspensions, syrups, elixirs, and solutions.

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, the group comprising of diluent(s), disintegrants(s), binder(s), anti-adherant(s), glidant(s), opacifier(s), buffering agent(s), colorant(s), flavoring agent(s), coating agent(s), solvent(s), viscosifying agent(s), wax(s), wetting agent(s), emulsifying agent(s), solubilizer(s), stabilizer(s), filler(s), bulking agent(s), thickener(s), colorant(s), stabilizer(s), preservative(s), lubricant(s), chelating agent(s), pH adjusting agent(s), antioxidant(s), humectant(s), osmotic agent(s), vehicle(s), and mixture thereof.

In one embodiment, the present invention describes a Combination/ composition of cream using a hydrophobic cream base. A combination/composition 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).

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 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 bases may be sufficient to bring the mixture to the desired pH range.

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 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.

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 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, microcrystalline cellulose, sodium starch glycolate, 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, aluminium 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.

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 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), Hydroxypropyl methyl cellulose, Methyl hydroxyethyl cellulose, Ethylcellulose, Povidone, Opadry, and the like.

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 oral formulations may be included.

In one embodiment, the present invention provides a pharmaceutical combination comprising:
- about 10 – about 500 mg Euphorbia Prostrata, and
- about 1 – about 5 g Ispaghula husk.

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

In another embodiment, the present invention provides a pharmaceutical combination comprising:
- about 10 – about 500 mg Euphorbia Prostrata,
- about 10 – about 1000 mg Calcium dobesilate, and
- about 1 – about 5 g Ispaghula husk.

In another embodiment, the present invention provides a pharmaceutical combination comprising:
- Euphorbia Prostrata,
- optionally, one or more additional pharmaceutically active agents, and
- Ispaghula husk;
wherein the combination is effective in the treatment of piles, haemorrhoids including haemorrhoids during pregnancy, anal fissures, and/or anal fistula.

In another embodiment, the present invention provides a pharmaceutical combination comprising:
- about 100 mg Euphorbia Prostrata, and
- about 3.5 g Ispaghula husk;
wherein the combination is administered orally for 14 days for the treatment of piles and haemorrhoids.

In another embodiment, the present invention provides a pharmaceutical combination comprising about 1% w/w to about 70% w/w Euphorbia prostrata; about 5% w/w to about 60% w/w of Ispaghula husk; about 0.01% w/v to about 20% w/v Emollient, and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients selected from the group comprising:
(a) about 0.01% w/v to about 5% w/v of preservative(s);
(b) about 0.01% w/v to about 25% w/v of Penetration enhancer(s);
(c) about 0.01% w/v to about 70% w/v of one or more pharmaceutically excipients.

In another embodiment, the present invention provides a pharmaceutical combination comprising about 1% w/w to about 70% w/w Euphorbia prostrata; about 5% w/w to about 60% w/w of Ispaghula husk; about 0.01% w/v to about 20% w/v Emollient, and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients selected from the group comprising:
(a) about 0.01% w/v to about 5% w/v of preservative(s);
(b) about 0.01% w/v to about 25% w/v of Penetration enhancer(s);
(c) about 0.01% w/v to about 10% w/v of Emulsifier(s);
(d) about 0.01% w/w to about 30% w/w of Humectant(s);
(e) about 0.01% w/v to about 70% w/v of one or more pharmaceutically excipients.

In another embodiment, the combination of the invention is to be administered orally once daily or twice daily. In one embodiment, the combination of the invention is to be administered simultaneously or sequentially in any order.

Another embodiment of the present invention provides a pharmaceutical fibre composition comprising:
- about 10 – about 500 mg Euphorbia Prostrata,
- optionally, one or more additional pharmaceutically active agents, and
- about 1 – about 5 g Ispaghula husk, and
- optionally, one or more pharmaceutically acceptable excipients.

Another embodiment of the present invention provides a pharmaceutical fibre composition comprising:
- about 10 – about 500 mg Euphorbia Prostrata,
- about 10 – about 1000 mg Calcium dobesilate,
- about 1 – about 5 g Ispaghula husk, and
- optionally, one or more pharmaceutically acceptable excipients.

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.

In patients with piles, constipation aggravates piles which tends to cause bleeding, impaired wound healing. It is observed that combination of Euphorbia Prostrata along with Ispaghula husk works synergistically in the treatment of piles. Both molecules have shown strength of evidence in piles, haemorrhoids including haemorrhoids during pregnancy, anal fissures, and/or anal fistula.

According to a further aspect, the composition or combinations of the present invention comprise substantially pure Euphorbia Prostrata extract, wherein said extract has a controlled particle size that provides safe and effective amount of Euphorbia Prostrata.

In one another embodiment, the particle size 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 pharmaceutical combination or composition of Euphorbia, wherein the pH of the combination is in the range of 3 to 8.

In another embodiment, the present invention provides a pharmaceutical combination or composition of Euphorbia, wherein the pH of the combination is in the range of 4 to 7.

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

In another embodiment, the present invention provides a combination or composition of Euphorbia, wherein the viscosity of the combination is in the range of 50000 cps to 400000 cps.

In another embodiment, the present invention provides a combination or composition of Euphorbia wherein the viscosity of the combination is in the range of 100000 cps to 200000 cps.

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).

In another embodiment, a bottle of 210gm comprising Euphorbia Prostrata and Ispaghula husk
• Catering to a 14-day treatment regimen
• 100 mg dry extract of Euphorbia Prostrata and 3.5 g Ispaghula husk is given as single dose.

In another embodiment, the present invention provides a process for the preparation of combination or composition of Euphorbia comprising the steps of:
1. dispensing all the materials and proceeding with Preparation of Preservative phase;
2. Preservative phase - taking batch quantity of purified water, adding emulsifier under stirring, allow to stir to form clear solution. Then heating to 40 – 50°C, and adding preservative and followed by addition of another preservative under stirring. Continue heating to 65 -75°C under stirring, ensure clear solution is formed;
3. oil phase - taking oil phase ingredients penetration enhancer/absorption promoters, emollient, viscosity modifier, and heating this phase to 65 – 75°C then ensuring clear liquid is formed;
4. Emulsification – adding oil phase as obtained in step 3 & step 2 under homogenization at 5000 rpm and homogenize for 30 min;
5. adding the active ingredient extract to humectant/lubricant under stirring and allow to stir to form uniform dispersion. Then adding second active ingredient hulk under stirring, allow to stir to form uniform viscous dispersion is formed, followed by addition of the prepared drug phase to step 4 under homogenization at 5000 rpm and homogenize for 30 min;
6. cooling the bulk as obtained in step 5 under stirring to reach room temperature, then mixing the bulk for about 30 min and further Packing the bulk in approved packaging material and then Store in cool and dry place at temperature not exceeding 30°C.

One or more additional pharmaceutical agents to be included in the compositions and combinations of the invention include calcium dobesilate, diosmin, Docusate sodium, pain relievers such as diclofenac, ibuprofen, acetaminophen, steroids such as hydrocortisone, or combinations thereof.

In another embodiment, the dry extract of the Euphorbia Prostrata contains flavonoids and phenolic compounds, wherein total flavonoids are 3.0% to 8.5% by weight calculated as apigenin-7-glycoside; and wherein the total phenolic compounds are 12.0% to 44.0% by weight calculated as gallic acid.

In another embodiment, the dry extract of the Euphorbia Prostrata contains 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.

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: Pharmaceutical Composition of Euphorbia Prostrata and Isphagula husk

S. No. Ingredient Quantity (%w/w)
1 Euphorbia Prostrata 1.00
2 Ispaghula husk 35.00
3 Propylene glycol 17.00
4 Liquid paraffin 5.00
5 Isopropyl Myristate 3.00
6 PEG 100 Stearate 3.00
7 Cetostearyl alcohol 5.00
8 Methyl Paraben 0.2
9 Propyl Paraben 0.05
10 Purified water 30.75
Total 100.00

Process:
1. dispensing all the materials and proceeding with Preparation of Preservative phase;
2. Preservative phase - taking batch quantity of purified water, adding PEG 100 Stearate under stirring, allow to stir to form clear solution. Then heating to 40 – 50°C, and adding methyl paraben and followed by addition of propyl prarben under stirring. Continue heating to 65 -75°C under stirring, ensure clear solution is formed;
3. oil phase - taking oil phase ingredients Isopropyl myristate, liquid paraffin, cetostearyl alcohol and heating this phase to 65 – 75°C then ensuring clear liquid is formed;
4. Emulsification – adding oil phase as obtained in step 3 & step 2 under homogenization at 5000 rpm and homogenize for 30 min;
5. adding euphorbia prostrata extract to propylene glycol under stirring and allow to stir to form uniform dispersion. Then adding Ispaghula hulk under stirring, allow to stir to form uniform viscous dispersion is formed, followed by addition of the prepared drug phase to step 4 under homogenization at 5000 rpm and homogenize for 30 min;
6. cooling the bulk as obtained in step 5 under stirring to reach room temperature, then mixing the bulk for about 30 min and further Packing the bulk in approved packaging material and then Store in cool and dry place at temperature not exceeding 30°C.

The Pharmaceutical composition of the 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 – 8.00 5.50 5.98 5.78
Assay of Euphorbia Prostrata Extract 90.0% to 110.0% of label claim 99.95 101.1 100.8
Viscosity (cps) 100000 – 200000 157050 168586 149780

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

,CLAIMS:WE CLAIM:
1. A pharmaceutical combination comprising:
- Euphorbia Prostrata,
- Ispaghula husk and optionally, one or more pharmaceutically acceptable excipients.

2. The pharmaceutical combination as claimed in claim 1, wherein the combination comprising
(a) about 10 mg to about 500 mg of dry extract of Euphorbia Prostrata,
(b) about 1g to about 5 g Ispaghula husk, and
one or more pharmaceutically acceptable excipients;

3. The pharmaceutical combination as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients selected form diluent(s), disintegrate(s), binder(s), anti-adherant(s), glidant(s), opacifier(s), buffering agent(s), colorant(s), flavoring agent(s), coating agent(s), solvent(s), viscosifying agent(s), wax(s), wetting agent(s), emulsifying agent(s), solubilizer(s), stabilizer(s), filler(s), bulking agent(s), thickener(s), colorant(s), stabilizer(s), preservative(s), lubricant(s), chelating agent(s), pH adjusting agent(s), antioxidant(s), humectant(s), osmotic agent(s), vehicle(s), and mixture thereof.

4. The pharmaceutical combination as claimed in claim 1, wherein dry extract of Euphorbia Prostrata containing flavonoids and phenolic compounds, wherein total flavonoids are 3.0% to 8.5% by weight calculated as apigenin-7-glycoside; and wherein the total phenolic compounds are 12.0% to 45.0% by weight calculated as gallic acid.

5. The pharmaceutical combination as claimed in claim 1, wherein combination comprising additional pharmaceutical agents include calcium dobesilate, diosmin, Docusate sodium, pain relievers such as diclofenac, ibuprofen, acetaminophen, steroids such as hydrocortisone, or combinations thereof.

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

7. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical formulations in the form of oral solid or liquid formulation.

8. The pharmaceutical combination as claimed in claim 7, wherein oral administration is in the form of capsules, tablets, oral films, powder, fibre, granules, suspensions, syrups, elixirs, and solutions.

9. The pharmaceutical combination as claimed in claim 1, wherein said combination is administered once or twice daily.

10. The pharmaceutical combination as claimed in claim 1, wherein the combination comprising about 10 mg to about 500 mg of Euphorbia Prostrata and about 1g to about 5 g Ispaghula husk, is effective in the treatment of piles, haemorrhoids, haemorrhoids during pregnancy, anal fissures, and/or anal fistula.

Dated this, 23th Day of May, 2024 For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer