MXPA06007677A - Pharmaceutical compositions comprising an extract of euphorbia prostrata - Google Patents

Abstract

The invention relates to novel compositions comprising of an extract of the plant Euphorbia prostrata, particularly with pharmaceutically acceptable carrier(s)/base(s), optionally with additional therapeutic agent(s) useful for the treatment of anorectal disease and colonic diseases such as hemorrhoids, fissures, cracks, fistulas, abscesses, inflammatory bowel disease, and the like. The novel compositions possess properties to control inflammation, prevent capillary bleeding and fragility in mammalians, particularly human beings. Process for the preparation of such novel compositions comprising an extract of the plant Euphorbia prostrata and pharmaceutically acceptable carrier(s)/base(s) useful for the treatment of anorectal disease including hemorrhoids, and colonic diseases are also provided. The composition comprise of flavonoidal and phenolic constituents extracted from the plant Euphorbia prostrata that possess anti-inflammatory, analgesic, haemostatic and wound-healing properties.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING AN EXTRACT FROM EUPHORBIA PROSTRATA FIELD OF THE INVENTION The invention relates to novel compositions and a process for the preparation of such compositions, comprising an extract of the plant Euphorbia prostrata useful for the treatment of anorectal diseases, including hemorrhoids and colonic diseases. The novel compositions possess properties to control inflammation, prevent capillary bleeding and brittleness in mammals, particularly in humans. There is also provided use of such compositions for the treatment of anorectal diseases, including hemorrhoids and colonic diseases.

BACKGROUND OF THE INVENTION Among the various anorectal and colonic diseases, hemorrhoids occupy a prominent position and have been the subject of numerous clinical studies. Hemorrhoidal disease is characterized by bleeding, without any pain. Fresh blood spots occur immediately, with defecation. However, pain occurs when hemorrhoids become infected secondarily, or are complicated by thrombosis and anal fissures. Hemorrhoids can be caused by a variety of factors, including hormones, genes, inflammation, infection, constipation, exercise, vascular stasis, diet, tension, physical position in defecation, loss of connective tissue elasticity with age, etc. Bleeding, pain and prolapse are the most widely recognized symptoms (Hyams and Philpot, 1970, Smith, 1987). These may be accompanied by thrombosis, pruritis, edema, etc. Hemorrhoids can be treated through the reduction of inflammation and pain, hemostasis, healing of wounds and protection of vascular walls. Thus, an effective treatment of acute hemorrhoidal attacks should not only provide relief as early as 2-3 days after the start of treatment, but also reduce the recurrence of such attacks. There are several procedures for the treatment of hemorrhoids. The patent application WO8803398 describes surgical bandages for such treatment. Patents have been granted with respect to surgical devices such as European Patent no. 0095142. The Patent of E.U.A. do not. 4,621,635, has been granted for the use of lasers in the treatment of hemorrhoids. Pharmacotherapy techniques and electrochemical techniques for the treatment of hemorrhoids have also been patented in European Patent no. 0091405 and European Patent no. 0116688, respectively. However, the biggest disadvantages of the above are the involvement of medical experts beyond the mere prescription of medicines and the probable hospitalization. Also, some of them are physically and / or psychologically unpleasant in the application for the treatment of such diseases. Several patents (U.S. Patent Nos. 4,160,148, 4,508,728, 4,797,392, 4,518,583 and 5,234,914) have been issued with respect to compositions containing certain agents that cure wounds to provide symptomatic relief, promoting tissue repair, reducing inflammation and encouraging the healing of wounds. Some of them, like the Patents of E.U.A. us. 4,518,583 and 5,234,914, contain antimicrobial agents. These compositions, however, only relieve the symptoms associated with inflammation, such as heat, itching, redness, pain and swelling. Several compositions for the treatment of anorectal diseases (including hemorrhoids) are based on the anesthetic and vasoconstrictor properties of the constituents, but these provide only temporary symptomatic relief. Patents in the United States of America (U.S. Patent Nos. 4,613,498, 4,626,433, 5,166,132, 5,219,880, 5,234,914 and 4,797,392) and Europe (European Patent Nos. 0225832 and 0513442), have been granted with respect to compositions with several constituents, for topical application in the form of suitable and acceptable pharmaceutical carriers, such as salts, ointments, etc., with organic, inorganic or biological active agents. However, these compositions provide only temporary relief and are limited to local application and can not be used for systemic use or oral administration. A topical treatment for hemorrhoidal pain and for sphincter spasms and muscles located in the Gl tract is described in a granted patent (US Patent No. 5,595,753), which includes the amino acid L-arginine in a pharmaceutically acceptable carrier. Another patent of E.U.A. do not. 5,591, 436, has been granted for a composition for a dietary supplement for the treatment of hemorrhoids. The composition comprises 60% to 95% of Indian Barberry in weight; from 4.8% to 38% Nagkesar by weight; and from 0.2% to 2% of Margosa tree leaves by weight. Another patent of E.U.A. do not. 5,562,906, describes the use of bark or berries of the species Xanthoxylum clava herculis L and Xanthoaylum americanum Hill, both of the yellow wood tree family, used for the treatment of hemorrhoids and other membranous and capillary disorders of the veins and the arteries. An improved strength and flexibility of the veins, arteries and their constituent structures is obtained. The flavonoid constituents present in the extract of Euphorbia prostate are reported to have anti-inflammatory properties. Phenolic compounds such as ellagic and gallic acids and tannins are reported to have anti-inflammatory, hemostatic, gastroprotective and wound healing properties.

Other plants containing fiavonoids including apigenin glycosides and luteolin glycosides are arboreal Ixora (Rubiaceae), Bommer hispida (Pteridaceae), Adenocalyma alliaceum (Bignoniaceae), Thalictrum thunbergii (Ranunculaceae), Per / 7 / a frutescens (Labiateae), Chrysanthemum indicum, C. coronarium and Matricaria chamomilla (Compositae), Thymus membranaceus (Labiateae), Digitalis lanata (Scrophulariaceae), Cuminum cyminum and Petroselinum (Umbelliferae). Several species of Euphorbia such as Euphorbia minuta, Euphorbia microphylla, Euphorbia granulata (Euphorbiaceae), contain both apigenin and luteolin. Ellagic acid and other phenolic acids have been reported from different species of Euphorbia. The safety of several components of Euphorbia extract has been reported in the literature. Some of the reports also claim antimutagenic / anticarcinogenic / antigenotoxic properties of the components of Euphorbia extract. A Hindu patent no. 186803 and several other patents (Australia, No. 698407, China, No.CN 1102387C, Europe No. 868914, Russia No. 2174396, South Africa No. 97/2900, South Korea No. 281679, and the United States. No. 5,858,371), have been granted to this applicant for a composition comprising an extract containing Evrinhobia prostrata fiavonoids for the treatment of anorectal and colonic diseases. However, the presence of phenolic compounds that are therapeutically useful for the treatment of anorectal diseases and colonic due to its hemostatic and astringent properties, does not exist in the claimed extract. The extraction procedure claimed in the patent comprises an intermediate step of treating the concentrated extract with hot water (80-90 ° C); which results in the loss of especially the phenolic compounds of the extract, since they are washed with water. It has been surprisingly found by the inventors of the present invention, that the presence of phenolic compounds such as ellagic acid, gallic acid and tannins comprising these acids, make the claimed extract more effective for the treatment of hemorrhoids and other colonic diseases, since phenolic compounds are known mucoprotective agents. The antimicrobial properties of these phenolic compounds also prevent secondary infections accompanied with frequencies with hemorrhoids, fissures, fistulas, etc. The present invention describes an improved process for the preparation of the Euphorbia prostrata extract which results in an improved composition of the extract. The previously essential step of treating the concentrated extract with hot water has been eliminated in the present invention, since it was found that the water-soluble portion contains a substantial amount of phenolic compounds; instead, the wash of the concentrated extract was made directly with a non-polar solvent, where only the waxy materials and the pigments are removed and there is no significant loss of the phenolic compounds, followed by a reextraction of the extract polar wash in an organic solvent with medium polarity followed by distillation, dehydration and finally drying of the extract. The inventors have further investigated, and have found that the novel fiavonoid compounds and phenolic compounds containing the extract of Euphorbia prostrata described in the present invention, exhibit an improved pharmacological response compared to existing compositions employing Euphorbia fiavonoids or other sources. In addition, the method of extracting the extract of Euphorbia prostrata described in the present invention is more cost effective and consumes less time compared to that of existing compositions employing Epahorbia prostrata isolated fiavonoids. The commercial implications of the improved and economical extraction procedure led the inventors to reestablish the pharmacological and toxicological validity of the new extract. The results were surprisingly better than those of the equivalent doses of fiavonoids of the more purified extract of Euphorbia prostrata described above. The present invention provides pharmaceutical compositions for the long-term management of anorectal diseases, including hemorrhoids, and colonic diseases, which are safe and painless to administer, and which have a long-term effectiveness. The compositions of the present invention have improved efficacy and safety and are inexpensive to manufacture.

BRIEF DESCRIPTION OF THE INVENTION An object of the present invention is to provide pharmaceutical compositions for the treatment of anorectal or colonic diseases such as hemorrhoids, fissures, fissures, fistulas, abscesses, inflammatory bowel disease and the like, comprising an extract of the Euphorbia prostate plant containing fiavonoids and phenolic compounds, "" wherein the fiavonoids are apigenin-7-glucoside, 1-4% by weight; luteolin-7-glucoside, 0.3-2% by weight; apigenin, 0.001-0.3% by weight; luteolin, 0.001-0.3% by weight; and cuercetin, 0.001-0.3% by weight; and wherein the phenolic compounds are ellagic acid, 1-15% by weight; gallic acid, 1-12% by weight and tannins, 1-10% by weight, optionally with pharmaceutically acceptable carriers / bases; optionally with additional therapeutic agents; and wherein the pharmaceutical composition comprises the extract of the plant Euphorbia prostrata from about 0.1% to about 99% by weight. It is also an object of the present invention to provide a process for the preparation of an extract of the plant Euphorbia prostrata for the treatment of anorectal or colonic diseases such as hemorrhoids, fissures, cracks, fistulas, abscesses and inflammatory bowel disease. It is a further object of the present invention to provide a process for the preparation of a pharmaceutical composition for the treatment of anorectal or colonic diseases such as hemorrhoids, fissures, fissures, fistulas, abscesses and inflammatory bowel disease, comprising of an extract of the plant Euphorbia prostrata containing fiavonoids and phenolic compounds, where the fiavonoids are 5 apigenin-7 glycoside, 1-4% by weight; luteolin-7-glucoside, 0.3-2% by weight; apigenin, 0.001-0.3% by weight; luteolin, 0.001-0.3% by weight; and cuercetin, 0.001-0.3% by weight; and wherein the phenolic compounds are ellagic acid, 1-15% by weight; gallic acid, 1-12% by weight and tannins, 1-10% by weight, with pharmaceutically acceptable carriers / bases, optionally with additional therapeutic agents, comprising the following steps. to. drying the plant Euphorbia prostrata, b. make a powder from the dried plant, c. extract the coarse dry powder with a polar solvent in a repetitive manner, to form an extract, 15 d. distill the extract, e. wash the concentrated extract with a non-polar organic solvent, and f. drying the washed extract to produce the desired pharmaceutically acceptable extract, capable of being used together with the 0 pharmaceutically acceptable carriers / bases. Still another object of the present invention is to provide a method for using such pharmaceutical compositions for the treatment of Anorectal or colonic diseases such as hemorrhoids, fissures, cracks, fistulas, abscesses, and inflammatory bowel disease. The compositions of the present invention and the method for treating anorectal diseases, including hemorrhoids and colonic diseases using the extract of the plant Euphorbia prostrata, provide long-term effectiveness and low proportions of prolapse.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides compositions that can be administered orally, as well as applied uniformly to the affected region, reduce inflammation, and soothe the sensation of itching and burning associated therewith. from pain associated with hemorrhoids. The invention also significantly reduces bleeding and accelerates tissue regrowth of the affected hemorrhoidal tissue. The invention is useful in the treatment of lesions other than hemorrhoids in the anorectal area and can be formulated into several types of dosage forms. There are no side effects of the use of the composition in humans. In addition, the treatment is not physically or psychologically unpleasant in its administration and / or application. The plant of Euphorbia prostrata (Family: Euphorbiaceae), was identified as being relevant in the study of anorectal and colonic diseases, including hemorrhoids. Euphorbia prostrata is well known in traditional Hindu medicine in the use of asthma treatment, bloody dysentery and sores. Previously, five new compounds were discovered and identified by the inventors in Euphorbia prostrata, namely luteolin, 6-methoxy-cuercetin-glucoside, cuercetin, and glycosides of luteolin and apigenin. Now, two more phenolic compounds, namely, ellagic acid and gallic acid were identified in the extract prepared in a different way, which was found to have an additional therapeutic value for the treatment of hemorrhoids. The compounds of the present invention were standardized to pharmaceutically acceptable specifications in order to ensure reproducibility from batch to batch. The result is the improved extract of Euphorbia prostrata, which is particularly the active ingredient of the present pharmaceutical compositions for the effective treatment of anorectal and colonic diseases. Another unique feature of this extract of Euphorbia prostrata is that it was prepared in such a way that the resulting composition can easily be dispersed in water, due to the presence of many hydrophilic compounds in addition to the fiavonoids. The pharmaceutical composition comprising the extract of Euphorbia prostrata as the active ingredient, comprises fiavonoids and phenolic compounds, of which apigenin-7-glucoside is about 1-4% by weight of the extract, luteolin-7-glucoside is about 0.3-2% by weight of the extract; Apigenin, 0.001-0.3% in weight of the extract; luteolin, 0.001-0.3% by weight of the extract; and cuercetin, 0.001-0.3% by weight of the extract. The extract also comprises 1-15% by weight of ellagic acid, 1-12% by weight of gallic acid, and 1-10% by weight of tannins. In a preferred embodiment of the present invention, there is provided a pharmaceutical composition, wherein the extract preferably comprises apigenin-7-glucoside, 2.5-3.5% by weight; luteolln-7- glucoside, 0.5-1.5% by weight; apigenin, 0.05-0.2% by weight; luteolin, 0.05-0.2% by weight and cuercetin, 0.05-0.2% by weight; ellagic acid, 4-15% in Í0 weight; Gallic acid, 4-12% by weight and tannins, 3-8% by weight. In a further embodiment, the pharmaceutical composition of the present invention further comprises pharmaceutically acceptable carriers / bases selected, non-exclusively, from the group comprising diluents, disintegrants, binders, anti-adherents, glidants, antioxidants, buffering agents, colorants, flavoring agents, coating agents, solvents, viscosifying agents, waxes, wetting agents, emulsifying agents, solubilizers, stabilizers, buffering agents and the like. In one embodiment of the present invention, it was found that 0 Euphorbia prostrata is devoid of any toxic diterpene content such as phorbol or ingenol esters, unlike many other Euphorbia species.

The pharmaceutical compositions of the present invention may also contain additional therapeutic agents from other plants and / or from different pharmacological groups such as anesthetics, vasoconstrictors, protectants, counterirritants, astringents, wound healing agents, antimicrobials, keratolytics, anticholinergics or their salts pharmaceutically acceptable, used either alone or in combinations thereof. Preferably, it would be beneficial to include other agents that cure wounds and antimicrobials, which would result in an improvement in the effectiveness of the composition. Anesthetics include, but are not limited to, benzocaine, diperodon, pramoxine, camphor, dibucaine, phenol, tetracaine, lignocaine, and phenacaine, used either alone or in combinations thereof. The amount of such anesthetics could vary between 0.25% and 25% by weight. Vasopressors include, but are not limited to, ephedrine and phenylephrine, used either alone or in combinations thereof. The amount of such vasoconstrictors can vary between 0.005% and 1.5% by weight. The protectants include, but are not limited to, aluminum hydroxide gel, calamine, cocoa butter, cod liver or shark oil, glycerin in aqueous solution, kaolin, lanolin, mineral oil, starch, white oil, wool alcohol , zinc oxide, vegetable or castor oil, polyethylene glycol and propylene glycol, used either alone or in combinations of them. The amount of such protectants can vary between 5.0% and 88.0% by weight. The counter-irritant includes, in a non-exclusive manner, menthol in aqueous solution. The amount of such a counter-irritant can vary between 0.25-2.5% by weight. The astringents include, but are not limited to, calamine, zinc oxide, witch hazel, bismuthresorcinol compound, bismuth subgalate, Peruvian balm, aluminum chlorhldroxy allantoinate, tannic acid and tannins, used either alone or in combinations thereof. . The amount of such astringents can vary between 0.2% and 60.0% by weight. The tannins can be derived in addition to plants such as Butea monosperma, Butea parvora and Butea frondosa (Family: Leguminosae). Agents that heal wounds include, but are not limited to, vitamin A and vitamin D in an amount between 0.005% and 0.04% by weight. Also the Peruvian balm can be included by weight in an amount between 0.5% and 2.5% by weight. Cod liver oil may also be included in an amount between 1.0% and 6.0% by weight. Antimicrobial agents include, but are not limited to, benzethonium chloride, benzalkonium chloride, boric acid, 8-quinolinol benzoate, secondary amiltricresols, cetylpyridinium chloride, phenol, menthol, chlorothymol, camphor and 8-hydroxyquinoline sulfate, already used be alone or in combinations thereof. The amount of such antimicrobial agents can vary between 0.02% and 40.0% by weight.

Keratolytics include, but are not limited to, aluminum chlorohydroxy allantoinate and resorcinol used either alone or in combinations thereof. The amount of such keratolytics may vary between 0.2% and 3.5% by weight. Anticholinergics include, but are not limited to, atropine or other alkaloids of the solanaceous type, used either alone or in combinations thereof. The amount of such anticholinergics can vary between 0.02% and 0.1% by weight. The pharmaceutical compositions of the present invention can be prepared by dissolving or dispersing the extract in appropriate bases / carriers known in the art. The pharmaceutical composition in different dosage forms can be formulated using excipients and conventional techniques known in the art. The pharmaceutical dosage forms of the present invention can be capsules (hard or soft), tablets (coated or uncoated), ointments, creams, gels, foams, solutions, suspensions, medicated pad, bandage, powder, aerosols, sprays, films , flakes, modified release dosage forms (sustained release, controlled release, delayed release, prolonged release, synchronized release and the like), sublingual dosage forms, wafers, oblong tablets, parenteral dosage forms to infiltrate the site of the injection and the like. The pharmaceutical compositions of the present invention comprise the extract of the Euphorbia prostrata plant from about 0.1% to about 99% by weight. The capsules comprise from 25-300 mg of the Euphorbia prostrata extract, preferably 50-100 mg together with the pharmaceutical excipients. Similarly, tablets can be prepared by dispersing 25-300 mg of the extract of Euphorbia prostrata, preferably 50-100 mg in a suitable carrier, optionally together with other pharmaceutical excipients. The tablets may be coated or uncoated. The cream or ointment comprises 0.1-10% weight / weight, preferably 0.2-5% weight / weight of the Euphorbia prostrata extract. In one embodiment of the present invention, the capsule can be taken, with a maximum of 300 mg of extract per day, together with topical application comprising the same extract and when required. In another embodiment, the granules in easily dispersible and effervescent form are prepared using excipients such as sucrose, mannitol, sodium bicarbonate, citric acid and the like. The cream comprising the Euphorbia prostrata extract is prepared by emulsifying the aqueous phase, which comprises 0.1-10% w / w, preferably 0.2-5% w / w of the extract, together with the appropriate oil phase. Other alternatives can be prepared by formulating the extract in 0.1-10% weight / weight as USP Hydrophilic ointment with absorption base; or water soluble bases such as USNF ointment of Polyethylene glycol; or as water absorbing bases such as hydrophilic USP petrolatum, Lanolin USP; or in hydrocarbon bases such as USP White Petrolatum. The suppository compositions comprise either a hydrophobic or hydrophilic base and include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, polyoxyethylene sorbitan fatty acid esters and polyethylene stearate, polyvinyl alcohol, polyvinyl pyrrolidone. , polyacrylamide, chemically modified starch or a combination of these materials. The foam and the spray bases comprise one or more of aqueous and non-aqueous solvents, propellants, surfactants, suspending agents and stabilizing agents. The medicated pads comprise one or more of the following: Water, glycerin, propylene glycol, alcohol and witch hazel water. In one embodiment of the present invention, there is provided a process for the preparation of a pharmaceutical composition for the treatment of anorectal or colonic diseases such as hemorrhoids, fissures, fissures, fistulas, abscesses and inflammatory bowel disease, comprising an extract of the Euphorbia prostrata plant containing fiavonoids and phenolic compounds, wherein the fiavonoids are apigenin-7-glucoside, 1-4% by weight; luteolin-7-glucoside, 0.3-2% by weight; apigenin, 0.001-0.3% by weight; luteolin, 0.001-0.3% by weight; and cuercetin, 0.001-0.3% or by weight; and wherein the phenolic compounds are ellagic acid, 1-15% by weight; Gallic acid, 1-12% by weight and tannins, 1-10% by weight, with pharmaceutically acceptable carriers / bases, optionally with additional therapeutic agents, comprising the following steps: a. drying the plant Euphorbia prostrata, b. make a powder from the dried plant, or extract the coarse powder dry with a polar solvent in a repetitive manner, to form an extract, d. distill the extract, e. wash the concentrated extract with a non-polar organic solvent, and f. drying the washed extract to produce the desired pharmaceutically acceptable extract, capable of being used together with pharmaceutically acceptable carriers / bases. The polar solvent used in the present invention is non-exclusively selected from acetone, methanol, ethanol, isopropanol, water and the like, used either alone or in combination thereof. The non-polar organic solvent used in the present invention is non-exclusively selected from pentane, hexane, heptane, petroleum ether, chloroform, dichloromethane, dichloroethane or mixtures thereof. In a further embodiment, a method for the preparation of a pharmaceutical composition is provided, wherein the process for making the extract further comprises: a. reextract the washed polar extract in an organic solvento of medium polarity, b. distill the extract, c. dehydrate the extract, and d. drying the extract to produce the desired pharmaceutically acceptable extract, capable of being used together with pharmaceutically acceptable carriers / bases. In the present invention, the medium polarity organic solvent is non-exclusively selected from ethyl acetate, ethyl methyl ketone, butanol or mixtures thereof. The dehydration of the extract is preferably done using a non-exclusively selected dehydrating agent, anhydrous sodium sulfate, fused calcium chloride, potassium aluminosilicate (molecular sieves), and the like, used either alone or in combinations of the same. Dehydration can be done by physical procedures such as gravitational or centrifugal sedimentation, with or without changing the temperature of the extract. In one embodiment of the present invention, there is provided a method of treating anorectal or colonic diseases such as hemorrhoids, fissures, cracks, fistulas, abscesses, inflammatory bowel disease, and the like, which comprises administering an extract of the plant Euphorbia prostrata. containing fiavonoids and phenolic compounds, wherein the fiavonoids are apigenin-7-glucoside, 1-4% by weight; luteoin-7-glucoside, 0.3-2% by weight; apigenin, 0.001-0.3% by weight; luteolin, 0.001-0.3% by weight; and cuercetin, 0.001-0.3% by weight; and where the ellagic acid, 1-15% by weight; gallic acid, 1-12% by weight and tannins, 1-10% by weight, with pharmaceutically acceptable carriers / bases; optionally with additional therapeutic agents. In a further embodiment, the pharmaceutically acceptable carriers / bases used in the present invention are non-exclusively selected from mannitol, lactose, microcrystalline cellulose, calcium dibasic phosphate, maltodextrin, cyclodextrin and the like, used either alone or in combination the same. In another embodiment of the present invention, if the content of fiavonoids and phenolic compounds of the extract obtained by the above method is more than the ranges specified herein, it is standardized by mixing with pharmaceutically acceptable carriers / bases to the desirable range of content. In a further embodiment, the use of an extract of the plant Euphorbia prostrata is provided for the preparation of a pharmaceutical composition for the treatment of anorectal or colonic diseases such as hemorrhoids, fissures, cracks, fistulas, abscesses, inflammatory bowel disease, and the similar. The compositions of the present invention and the method for treating anorectal diseases including hemorrhoids, and colonic diseases using an extract of Euphorbia prostrata, provide long-term effectiveness and low proportions of prolapse. The treatment includes the administration by oral route of a quantity effective of the composition comprising a pharmaceutically acceptable carrier and a mixture of fiavonoids and phenolic compounds extracted from Euphorbia prostrata. The treatment also includes local application to hemorrhoids and anorectal tissues, of an effective amount of the composition comprising a pharmaceutically acceptable carrier and a mixture of fiavonoids and phenolic compounds extracted from Euphorbia prostrata.

Evaluation of the pharmacological activity of the extract Antihemorrhoidal activity The antihemorrhoidal activity of Euphorbia prostrata extract was assessed and compared with a reference drug, diosmin, using a model of the ratio of anorectum: body weight in rats (modified method of Jia et al., 2000). The extract of Euphorbia prostrata (5, 10, 20 and 40 mg / kg, po, 7 days), showed a significant decrease in the anorectic relationship: body weight, as well as inflammation and redness at the site, when compared with control (group treated with carrageenan). Diosmin (50 mg / kg, p.o., 7 days), also significantly decreased the anorectic ratio: body weight in rats (Figure 1). In addition, the individual components of Euphorbia prostrata extract, ie, apigenin-7-glucoside (0.478 mg / kg, po), ellagic acid (1,204 mg / kg, po), and garyic acid (1123 mg / kg, po) after chronic administration (7 days), they also showed an effect (Figure 2). In the histopathological examination of the anorectum, normal animals that were orally administered with 0.5% CMC only showed a layer of Intacta mucosa with prominent mucosal cells and mild leukocyte migration, while the animals treated with carrageenan showed a layer of uneven thick mucosa with broken mucous cells and severe migration of leukocytes, suggesting the presence of significant inflammation. In addition, both the extract of Euphorbia prostrata (10 mg / kg, p.o., 7 days) and diosmin (50 mg / kg, p.o., 7 days), showed an intact mucosal layer with prominent mucous cells and a slight migration of leukocytes.

Anti-inflammatory activity Foot edema induced by carrageenan in rats Carrageenan (1% weight / volume) produces edema of the paw (Winter et al., 1962) in the control group, indicating an inflammatory response. The dose of the extract of Euphorbia prostrata (5, 10, 20 and 40 mg / kg, po) decreased in a dependent and significant way the increase induced by carrageenan in the paw volume compared to the control rats (ED50 15.42- 15.84 mg / kg, po). The onset of the anti-inflammatory effect was rapid and lasted up to 4 hours after the injection of carrageenan. The anti-inflammatory effect of Euphorbia prostrata extract at doses of 20 and 40 mg / kg, was comparable with that of nimesulide (2 mg / kg, p.o.), an NSAID that inhibits preferential cyclooxygenase-2 (COX-2) (Figure 3). In addition, a solution of Euphorbia prostrata extract (0.5-4.0% weight / volume equivalent to 1-8 mg / kg, applied topically in the paw), significantly decreased the increase induced by carrageenan in the paw volume. The topical antiinflammatory effect of Euphorbia prostrata extract (1%) was compared with that of nimesulide (2%) at 60 minutes (Figure 4).

Antinonceptive activity Tremor induced by acetic acid in mice (Koster et al., 1959) The extract of Euphorbia prostrata (2 mg / kg, p.o.) exhibited a maximum antinociceptive effect after 90 minutes of its administration in a time-response study. This effect lasted up to 2 hours after its administration. Nimesulide (2 mg / kg), a reference drug, also significantly decreased the pain threshold in the mice. The extract of Euphorbia prostrata (1, 2, 5 and 10 mg / kg, p.o.), produced a dose-dependent antinociceptive effect in mice (Figure 5). Apigenin-7-glucoside (0.5, 1.0 and 2.0 mg / kg, po) and luteolin-7-glucoside (0.25, 0.5 and 1.0 mg / kg, po), also exhibited a dose-dependent antinociceptive effect in the tests of shivering (Figure 6).

Carrageenan-induced hyperalgesia in rats Carrageenan (1% weight / volume) significantly decreased the paw withdrawal threshold in the paw pressure test (Randall and Selitto, 1957). The extract of Euphorbia prostrata (10, 20 and 40 5 mg / kg, p.o.), significantly increased the paw withdrawal threshold compared to rats treated with carrageenan. Nimesulide (2 mg / kg), a reference drug, also increased paw withdrawal latencies in rats (Figure 7).

T0 Carrageenan-induced pleuritis in rats Pleuritis was induced with carrageenan (2%), using a method reported by Engelhard et al., 1995. A single dose administration of Euphorbia prostrata extract (10, 20 and 40 mg / kg, po), produced a significant inhibition of exudate formation and leukocyte migration and polymorphonuclear monocytes in pleuritis induced by carrageenan. The results are shown in Table 1.

TABLE 1 Effect of Euphorbia prostrata extract (E.p. extract) on cell migration in an animal model of pleuritis * p < 0.05 compared to the control group with carrageenan Hemostatic activity In an incision model of the liver, the topical application of Euphorbia prostrata extract (1% solution, 2% and 4%), significantly reduced the bleeding time compared to the control group (distilled water) . In addition, the reduction in bleeding time observed with the 4% solution of Euphorbia prostrata extract was comparable with that observed with alginic acid (2.5%) (Figure 8).

Extraction activity of the superoxide radical The Euphorbia prostrata extract (25 μg) exhibited a superior superoxide radical purifying activity of 38.70% compared to tocopherol (25 μg), which showed a similar activity of 25.54% (Figure 9).

Activity to heal the wounds The wounds were developed by the skin excision method in rats as described by Vishnu Rao et al., 1996. The extract cream of Euphorbia prostrata (1.75%), showed a healing activity of the significant wounds compared to the placebo cream on Day 4, 8 and 12 in the skin excision model in rats. The results are presented in Table 2 and Table 3.

TABLE 2 Crude examination of wounds in rats TABLE 3 Percent decrease in wound areas in rats or < 0.05 compared to the control group Mechanism of antihemorrhoidal activity of the extract: The extract of Euphorbia prostrata comprises mainly fiavonoids (apigenin-7-giucoside, luteolin-7-glucoside), ellagic acid, gallic acid and tannins. Phenolic compounds are widely distributed in the plant kingdom. The main groups of phenolic compounds are the fiavonoids and phenolic acids. They are one of the main constituents of several medicinal plants that have been used as traditional medicine throughout the world. Interest has recently focused on fiavonoids and fiavonoids due to their broad pharmacological activities. These fiavonoids are well reported for analgesic, anti-inflammatory, antioxidant, antiangiogenic, antiallergic, antiviral and antimutagenic activity (Lin et al., 2001, Fórmica and Regelson, 1995, Fotsis et al., 1997, Wang et al., 1998, Block et al. al., 1998). It is reported that apigenin is a very potent inhibitor of the transcriptional activation of the enzymes COX-2 and NOS (inducible nitric oxide synthase) in RAW 264.7 macrophages activated by lipopolysaccharides. It has further been suggested that the suppression of transcriptional activation of COX-2 and NOS by apigenin may be mediated primarily through KB inhibition. Such a modulation of COX-2 and NOS by apigenin may be important in the prevention of carcinogenesis and inflammation (Liang et al., 1999). In addition, it has also been suggested that the antioxidant property of apigenin-7-glucoside contributes to its anti-inflammatory activity in several animal models (Fuchs and Milbradt, 1993). Della Loggia et al., 1986, also reported that apigenin-7-glucoside and luteolin-7-galactoside show a dose-dependent inhibition of the edema response to croton oil. In the CCI-induced peroxidation, apigenin and luteolin have shown significant antiperoxidative activity in rat liver microsomes (Cholbl et al., 1991). Xagorari et al., 2001, reported that luteolin inhibits tyrosine protein phosphorylation, gene expression measured by nuclear factor KB, and proinflammatory cytokine production in murine macrophages. Ellagic acid, which is one of the main constituents of Euphorbia prostrata extract, was also reported to suppress histamine release mediated by histamine releasers (compound 48/80, dextran and polymyxin B sulfate) in vivo (Bhargava et al. Westfall, 1969). In addition, the anti-inflammatory effects of the fiavonoids include the inhibition of histamine release, the modulation of prostanoid metabolism and antioxidant properties. It is speculated that the analgesic, antiinflammatory and antioxidant activity of several fiavonoid components of Euphorbia prostrata extract (apigenin-7-glucoside, luteolin-7-glucoside) and ellagic acid and / or gallic acid, can contribute to cure the damage to inflammatory tissue in hemorrhoidal conditions. It has been reported that phenolic acids activate the intrinsic coagulation of the blood by activating the Hageman factor and causes a state of hypercoagulability. Although the hypercoagulable state persists as much as 4 hours after i.v. administration, a thrombotic phenomenon has not been reported (Girolami and Cliffton, 1967).

Plant tannins are water-soluble phenolic compounds including hydrolysable and condensed tannins that are present in any food plant. The hydrolysable tannins contain gallotannins or ellagiotariins that provide gallic acid or ellagic acid, respectively with hydrolysis. It is well reported that tannic acid has antimicrobial properties that are associated with the ester bond between gallic acid and other groups of sugars or alcohols (Chung et al., 1993, 1995). From the antihemorrhoidal studies carried out in animals, it is evident that Euphorbia prostrata extract has better efficacy than purified fiavonoids or other constituents alone. The various studies performed on the extract of Euphorbia prostrata are listed below in Figures 1-9. Figure 1: Effect of Euphorbia prostrata extract (E.p. extract) against carrageenan-induced hemorrhoids in rats. Figure 2: Effect of the individual component of the extract of Euphorbia prostrata (extract E.p.) against hemroids induced by carrageenan in rats. Figure 3: Effect of Euphorbia prostrata extract (E.p. extract) against foot edema induced by carrageenan (oral). Figure 4: Effect of Euphorbia prostrata extract (extract E.p.) against foot edema induced by carrageenan (topical). Figure 5: Effect of Euphorbia prostrata extract (E.p. extract) against chemokineption induced by acetic acid in mice.

Figure 6: Effect of the main components of the extract of Euphorbia prostrata (extract E.p.) against the chemolysis induced by acetic acid in mice. Figure 7: Effect of the extract of Euphorbia prostrata (extract E.p.) against the hyperalgesia induced by carrageenan in rats. Figure 8: Effect of the extract of Euphorbia prostrata (extract E.p.) on the bleeding time in the incision model of the liver. Figure 9: Sewage activity of the superoxide radical in vitro of the extract of Euphorbia prostrata (extract E.p.).

Security studies Effect on the central nervous system The effect of the extract of Euphorbia prostrata on the central nervous system was assessed from acute studies of the effect of the appearance and behavior in general of rats and mice, the performance of the mice on a rotating rod, open field behavior in rats, locomotor activity in mice using an actrophotometer, rectal temperature in rats, desperate behavior in forced swimming in mice, sleep time induced by pentobarbitone in mice. Due to the behavior, the extract of Euphorbia prostrata was well tolerated by rats and mice (up to 2000 mg / kg, p.o.), after a single oral administration and after a multiple oral dose administration. (up to 130 mg / kg in mice for 28 days and up to 90 mg / kg in rats for 28 days). In the studies of the mice controlled with diazepam, the extract of Euphorbia prostrata did not (a) alter the general behavior; (b) decreased motor coordination (rotating rod test); (c) decreased motor activity using the actofotometer after oral administration at doses of 100, 200 and 400 mg / kg. In the study of rats controlled with chlorpromazine, the extract of Euphorbia prostrata did not affect the rectal temperature at doses of 100, 200 and 400 mg / kg. In the study of mice controlled with imipramine, the extract of Euphorbia prostrata at doses of 100, 200 and 400 mg / kg, did not alter the desperate behavior with forced swimming after a single oral administration. In addition, the extract of Euphorbia prostrata did not interact with the sleep time induced by pentobarbitone at doses of 100, 200 and 400 mg / kg in mice. In the study of rats controlled with diazepam, the extract of Euphorbia prostrata did not decrease the behavior in open field (ambulatory and rearing behavior) at doses of 100, 200 and 400 mg / kg.

Effect on the cardiovascular system Euphorbia prostrata extract did not cause any change in normal ECG, blood pressure and frequency in rats after a single oral administration of up to 400 mg / kg and after multiple administrations of an oral dose (up to 90 mg / kg in rats for 28 days).

Effect on the respiratory system Daily oral administration of Euphorbia extract prostrata at a dose of 400 mg / kg for 7 days, does not alter the basal insufflation pressure of the trachea in guinea pigs on day 7. 5 Effect on the gastrointestinal system single oral administration of Euphorbia prostrata extract up to 400 mg / kg, does not alter the secretion of basal acid and gastrointestinal integrity after a single administration of up to 400 mg / kg in rats. In O mice, there was no alteration in bowel motility up to 400 mg / kg, p.o., of Euphorbia prostrata extract after 1 hour of a single administration of an oral dose.

Toxicology studies 5 Single-dose toxicity: Euphorbia prostrata extract showed no mortality when administered up to 2000 mg / kg, p.o. in rats and mice. 0 Repeated dose toxicity: Mice: Repeated administration (32.50 mg / kg, 65.0 mg / kg and 130.0 mg / kg, po) of the extract of Euphorbia prostrata for 28 days in mice, did not exhibit mortality (NOEL 130 mg / kg , po).

Rats: Repeated administration (22.50 mg / kg, 45.0 mg / kg and 90.0 mg / kg, p.o.) of the extract of Euphorbia prostrata for 28 days in rats, did not exhibit mortality (NOEL 90 mg / kg, p.o.). In another study, repeated administration of Euphorbia prostrata extract at 428 mg / kg, po, for 14 days, did not produce significant alterations in body weight, organ weight, biochemical and histopathological changes compared to control animals . Guinea Pig: Repeated administration of the Euphorbia extract prostrates up to 300 mg / kg, p.o. to guinea pigs for 14 days, does not produce significant alterations in body weight, organ weight, biochemical and histopathological changes compared to control animals. The examples are given below to illustrate various aspects of the present invention. However, it is not intended to limit the scope of this invention.

EXAMPLES General procedure for manufacturing the extract Qualified professionals collected the plant Euphorbia prostrata from various parts of India. The plant was identified and characterized according to WHO guidelines (WHO / TRM / 91.4, Traditional Medicines Program of the Genova World Health Organization, 1991), and dried under controlled conditions of temperature and humidity. The whole plant was crushed to a coarse powder. The coarse powder was extracted using a polar solvent such as an alkanol or acetone with or without water. The extract was concentrated and washed with a non-polar solvent such as a hydrocarbon or a chlorinated hydrocarbon. The washed extract was further extracted optionally in a polar medium solvent such as ethyl acetate or ethyl methyl ketone. The final extract was optionally dehydrated with a suitable dehydrating agent and dried, either in a tray dryer or in a spray dryer, ground into a powder form, screened to the desired particle size and packed in a suitable container to protect it from moisture.

EXAMPLE 1 The sprayed drug (500 kg) was packed in an S.S.

The extraction was carried out by percolation with 3000 liters of 80% aqueous methanol at about 60 ° C. The procedure was repeated 5 times until the drug was depleted. The aqueous-methanolic extracts were combined and concentrated by distillation. The concentrated extract was washed with 5-10 volumes of hexane to remove the wax and the fatty material. The washed extract was dried completely for several hours at 60 ° C under vacuum. The final extract was ground to a fine powder, sieved to a uniform particle size and packed to protect it from moisture.

EXAMPLE 2 The powdered drug (700 kg) was packed in an S.S. The extraction was carried out by percolation with 4500 liters of methanol at approximately 60 ° C. The procedure was repeated 5 times until the drug was depleted. The methanolic extracts were combined and concentrated by distillation. The concentrated extract was washed with 5-10 volumes of dichloromethane to remove the wax and the fatty material. The washed extract was dried completely for several hours at 60 ° C under vacuum. The final extract was ground to a fine powder, sieved to a uniform particle size and packed to protect it from moisture.

EXAMPLE 3 The powdered drug (350 kg) was packed in an S.S.

The extraction was carried out by percolation with 3000 liters of 80% aqueous acetone at about 50 ° C. The procedure was repeated 5 times until the drug was depleted. The aqueous-acetone extracts were combined and concentrated by distillation. The concentrated extract was washed with 5-10 volumes of hexane to remove the wax and the fatty material. The washed extract was dried completely for several hours at 60 ° C under vacuum. The final extract was ground to a fine powder, sieved to a uniform particle size and packed to protect it from moisture.

EXAMPLE 4 The sprayed drug (500 kg) was packed in an S.S. The extraction was carried out by percolation with 3000 liters of 80% aqueous ethanol at about 60 ° C. The procedure was repeated 5 times until the drug was depleted. The aqueous-ethanolic extracts were combined and concentrated by distillation. The concentrated extract was washed with 5-10 volumes of hexane to remove the wax and the fatty material. The washed extract was extracted again with ethyl acetate. The ethyl acetate extract was dehydrated with anhydrous sodium sulfate and concentrated by distillation. The concentrated extract was dried completely for several hours at 60 ° C under vacuum. The final purified extract was ground to a fine powder, sieved to a uniform particle size and packed to protect it from moisture.

Evaluation procedure of the extract The extract of Euphorbia prostrata from the examples mentioned above was characterized by High Liquid Chromatography Performance (HPLC). HPLC was performed under the following conditions and using a Waters system equipped with M510 pumps and a data station with the Millenium program.

Mobile phase: A linear gradient of Mobile Phase A (2% acetic acid in Water) and Mobile Phase B (2% acetic acid in Acetonitrile) according to the following table: Column: C18 (250X4.6 mm / 5 μm) Flow rate: 1 ml / minute Detector: UV absorbance at 335 nm The chromatogram of the HPLC showed several peaks, the main ones correspond to gallic acid, ellagic acid, luteolin glucoside and apigenin glucoside. The two peaks that correspond to the fiavonoid components of luteolin glucoside and apigenin glucoside were used as the chemical and pharmacological marker for the quantification of the product. A sum of the two peaks was calculated, which corresponds to the standard glycoside apigenin and the measurement was expressed as the total Fiavonoids.

Capsule compositions EXAMPLE 5 Ingredient mg / capsule Extract of Euphorbia prostrata 100.0 Microcrystalline cellulose 200.8 Mannitol 72.0 Talc 3.2 O Sodium glycolate starch 12.0 Colloidal silicon dioxide 12.0 Procedure: 1) Euphorbia prostrata extract, microcrystalline cellulose 5 and mannitol are sieved and mixed. 2) The talc, the sodium starch glycolate and the colloidal silicon dioxide are passed through fine sieves individually, and then mixed. 3) The materials from step 1 and 2 are mixed. 0 4) The material from step 3 is filled into empty hard gelatin capsules at an average filled weight of 400 mg ± 2%. 5) The filled capsules are packed in airtight gaskets.

EXAMPLE 6 Ingredient mg / capsule Extract of Euphorbia prostrata 100.0 5 Microcrystalline cellulose 150.0 Mannitol 65.0 Lactose 50.0 Talcum 3.0 Sodium glycollate starch 17.0 O Colloidal silicon dioxide 15.0 Procedure: 1) The extract of Euphorbia prostrata, the microcrystalline cellulose, the lactose and the mannitol are sifted and mixed. 5 2) Talc, sodium starch glycollate and colloidal silicon dioxide are passed through fine sieves individually, and then mixed. 3) The materials of steps 1 and 2 are mixed. 4) The material from step 3 was filled into empty hard gelatin capsules at an average filled weight of 400 mg ± 2%. 5) The filled capsules are packed in air-tight packages.

AXIS .MPLO 7 Ingredient mg / capsule - Extract of Euphorbia prostrata 100.0 5 Microcrystalline cellulose 50.0 Mannitol 65.0 Lactose 150.0 Talcum 3.0 Sodium glycollate starch 17.0 O Colloidal silicon dioxide 15.0 Procedure: 1) The extract of Euphorbia prostrata, microcrystalline cellulose, lactose and mannitol are sifted and mixed. 5 2) Talc, sodium starch glycollate and colloidal silicon dioxide are passed through fine sieves individually, and then mixed. 3) The materials from step 1 and 2 are mixed. 4) The material from step 3 was filled into empty hard gelatin capsules at an average filled weight of 400 mg ± 2%. 5) The filled capsules are packed in air-tight packages.

EXAMPLE 8 Ingredient mg / capsule Extract of Euphorbia prostrata 100.0 5 Microcrystalline cellulose 175.0 Mannitol 80.0 Talcum 5.0 Sodium glycolate starch 15.0 Colloidal silicon dioxide 25.0 O Procedure: 1) Euphorbia prostrata extract, microcrystalline cellulose and mannitol are sifted and mixed. 2) The talc, the sodium starch glycolate and the colloidal silicon dioxide are passed through fine sieves individually, and then mixed. 3) The materials from step 1 and 2 are mixed. 4) The material from step 3 was filled into empty hard gelatin capsules at an average filled weight of 400 mg ± 2%. 0 5) The filled capsules are packed in air-tight packages.

EXAMPLE 9 Ingredient mg / capsule Extract of Euphorbia prostrata 100.0 Microcrystalline cellulose 135.0 Starch 25.0 Dibasic calcium phosphate 110.0 Talcum 2.0 Magnesium stearate 3.0 Sodium glycollate starch 10.0 Colloidal silicon dioxide 15.0 Procedure: 1) The extract of Euphorbia prostrata, microcrystalline cellulose, starch and dibasic calcium phosphate were sieved and mixed well. 2) Talc, magnesium stearate, sodium starch glycolate and colloidal silicon dioxide are passed through fine sieves individually, and then mixed. 3) The materials from step 1 and 2 are mixed. 4) The material from step 3 is filled into empty hard gelatin capsules at an average filled weight of 400 mg ± 2%.

) The filled capsules are packed in air-tight packages.

EXAMPLE 10 Ingredient mg / capsule Extract of Euphorbia prostrata 100.0 Microcrystalline cellulose 90.0 Lactose 50.0 Starch 122.0 Talcum 3.0 Magnesium stearate 3.0 Croscarmellose sodium 12.0 Colloidal silicon dioxide 20.0 Procedure: 1) The extract of Euphorbia prostrata, the microcrystalline cellulose, the lactose and the starch are sifted and mixed. 2) Talc, magnesium stearate, croscarmellose sodium and colloidal silicon dioxide are passed through fine sieves individually, and then mixed. 3) The materials from step 1 and 2 are mixed. 4) The material from step 3 was filled into empty hard gelatin capsules at an average filled weight of 400 mg 2%. 5) The filled capsules are packed in air-tight packages.

EXAMPLE 11 Ingredient mg / capsule Extract of Euphorbia prostrata 100.0 0 Mannitol 176.0 - Starch 100.0 Talcum 2.0 Croscarmellose sodium 5.0 Sodium glycolate starch 12.0 5 Sodium stearyl fumarate 5.0 Procedure: 1) The extract of Euphorbia prostrata, mannitol and starch are sifted and mixed. 0 2) Talc, croscarmellose sodium, sodium starch glycolate and sodium stearyl fumarate are passed through fine sieves individually, and then mixed. 3) The materials from step 1 and 2 are mixed. 4) The material from step 3 was filled into empty hard gelatin capsules at an average filled weight of 400 mg ± 2%. 5) The filled capsules are packed in air-tight packages.

Compositions of tablets EXAMPLE 12 Uncoated Tablet Ingredient mg / tablet Extract of Euphorbia prostrata 100.0 Microcrystalline cellulose 120.0 Mannitol 80.0 Croscarmellose sodium 10.0 Lactose 66.0 Talcum 4.0 Colloidal silicon dioxide 10.0 Croscarmellose sodium 10.0 Process: 1) The extract of Euphorbia prostrata, microcrystalline cellulose, mannitol, croscarmellose sodium and lactose are sifted and mixed. 2) The material from step 1 is compacted. 3) The compacts from step 2 are passed through a screen and mixed. 4) Talc, colloidal silicon dioxide and croscarmellose sodium are passed through fine sieves and mixed. 5) The material from step 3 is mixed with the material from step 4. 6) The material from step 5 is compressed into tablets at an average weight of 400 mg ± 2%. 7) The tablets are packaged in air-tight packaging.

EXAMPLE 13 Tablet covered with a film Ingredient mg / tablet Composition of the core of the tablet Extract of Euphorbia prostrata 100.0 Microcrystalline cellulose 120.0 Mannitol 80.0 Croscarmellose sodium 10.0 Lactose 66.0 Talcum 4.0 Colloidal silicon dioxide 10.0 Croscarmellose sodium 10.0 Coating composition of the film Hydroxypropyl methylcellulose (E-15) 12.0 Polyethylene glycol 400 (PEG 400) 2.4 Red iron oxide 0.75 Yellow iron oxide 0.50 Titanium dioxide 0.25 Isopropyl alcohol q.s. (lost in processing) Dichloromethane q.s. (lost in processing) Procedure: 1) The extract of Euphorbia prostrata, microcrystalline cellulose, mannitol, croscarmellose sodium and lactose are sifted and mixed. 2) The material from step 1 is compacted. 3) The compacts from step 2 are passed through a screen and mixed. 4) Talc, colloidal silicon dioxide and croscarmellose sodium are passed through fine sieves and mixed. 5) The material from step 3 is mixed with the material from step 4. 6) The material from step 5 is compressed into tablets at an average weight of 400 mg ± 2%. 7) The hydroxypropyl methylcellulose is dispersed in a mixture of isopropyl alcohol and dichloromethane with continuous mixing in a homogenizer. 8) The PEG 400 is added to the previous solution from step 7 and mixed. 9) The red iron oxide, the yellow iron oxide and the titanium dioxide are passed through fine sieves and mixed. 10) The material from step 9 is added to the material from step 8 and mixed for 30 minutes. 11) The cores of the tablets are loaded into the coating pan and coated with the coating solution from step 10 until an average tablet weight gain of -3% is reached. 12) The tablets are dried and packaged in airtight containers.

Cream compositions EXAMPLE 14 Ingredient mg / gm Extract of Euphorbia prostrata 10.0 Propylene glycol 50.0 Titanium dioxide 10.0 Stearic acid 130.0 Cetyl Alcohol 10.0 Isopropyl myristate 60.0 0 Sorbitan stearate 20.0 Methyl paraben 1.5 Propyl paraben 0.3 Corn oil 50.0 Glycerin 50.0 5 Sorbitol solution 30.0 Veegum HV 10.0 Sodium CMC 3.0 Tween 80 15.0 Purified water q.s. nu Procedure: 1) The extract of Euphorbia prostrata, methyl paraben and propyl paraben are dissolved in propylene glycol; the mixture is heated to 55-60 ° C; Titanium dioxide is added to it and it is stirred well. 2) Stearic acid, cetyl alcohol, isopropyl myristate, sorbitan stearate and corn oil are heated to 70 ° -75 ° C. 3) In another container, the solution of sorbitol and Tween 80 are taken. 4) The Veegum HV is hydrated separately in the water. 5) Sodium carboxymethyl cellulose (CMC sodium) is hydrated separately in glycerin. 6) The material from step 4 and step 5 are added to the material from step 3 and heated to 70 ° -75 ° C. 7) The material from step 2 and step 6 is mixed and cooled. 8) When the material from step 7 reaches a temperature of 50 ° -55 ° C, the material from step 1 is added to it. 9) The mixture is allowed to cool to room temperature to obtain the cream.

EXAMPLE 15 Ingredient mg / gm Extract of Euphorbia prostrata 10.0 Propiiengiicol 50.0 Titanium Dioxide 10.0 Solid Paraffin 60.0 Liquid Paraffin 10.0 Isopropyl Myristate 30.0 5 Span 60 20.0 Methyl Paraben 1.5 Propyl Paraben 0.3 Corn Oil 20.0 Glycerin 80.0 10 Sorbitol Solution 50.0 »Veegum HV 20.0 - Tween 80 15.0 Purified water q.s.

Procedure: 1. The extract of Euphorbia prostrata, methyl paraben and propyl paraben are dissolved in propylene glycol; the mixture is heated to 55-60 ° C; Titanium dioxide is added to it and it is stirred well. 2. Hard paraffin, liquid paraffin, isopropyl myristate, Span 60 and Corn oil are heated to 70 ° -75 ° C. 3. Veegum HV is hydrated in purified water; Glycerin, Tween 80 and sorbitol are added; and the mixture is heated to 70 ° -75 ° C. 4. The material from step 2 is added to the material from step 3 with stirring, and the mixture is allowed to cool to 55 ° -60 ° C. 5. The material from step 1 is added to the material from step 4, stirred and allowed to cool to room temperature to obtain the cream.

EXAMPLE 16 Ingredient mg / gm Extract of Euphorbia prostrata 10.0 Propylene glycol 50.0 Titanium dioxide 10.0 Glyceryl monostearate 90.0 Hydrogenated lanolin 30.0 Corn oil 40.0 Simeticone 1.5 Span 60 20.0 Hydroxyethylcellulose 20.0 Glycerin 50.0 Sorbitol 30.0 Sodium CMC 1.5 Propyl paraben 0.3 Methyl paraben 1.5 Tween 80 15.0 Purified water q.s.

Procedure: 1. Extract of Euphorbia prostrata, methyl paraben and propyl paraben are dissolved in propylene glycol; Titanium dioxide is added to it and it is stirred well. 2. Glyceryl monostearate, hydrogenated lanolin, corn oil, simethicone and Span 60 are taken. 3. In fresh purified water, the hydroxyethylcellulose is dissolved; Sorbitol and Tween 80 are added and the mixture is heated to 70-75 ° C. 4. Separately, sodium carboxymethyl cellulose (Sodium CMC) is dispersed in glycerin and added to the material from step 3. 5. The material from step 2 is added to the material from step 3 and allowed to cool with stirring. 6. When a temperature of 50-55 ° C is reached, the material from step 1 is added, stirred and allowed to cool to room temperature to obtain the cream.

EXAMPLE 17 Ingredient mg / gm Extract of Euphorbia prostrata 10.0 Beeswax 50.0 Liquid paraffin 60.0 Corn oil 25.0 Stearic acid 110.0 Cetyl alcohol 10.0 Titanium dioxide 10.0 Propylene glycol 50.0 Methyl paraben 1.5 Propyl paraben 0.3 Glycerin 50.0 Sorbitol solution 30.0 Tween 80 15.0 Purified water q.s.

Procedure: 1. The extract of Euphorbia prostrata, methyl paraben and propyl paraben are dissolved in propylene glycol; Titanium dioxide is added to it and it is stirred well. 2. Beeswax, liquid paraffin, corn oil, stearic acid and cetyl alcohol are heated to 70-75 ° C. 3. Glycerin, sorbitol and Tween 80 are added to purified water and heated to 70 ° -75 ° C. 4. The material from step 2 is added to the material from step 3 and shaken.

. The material from step 1 is added to the material from step 4 and allowed to cool to room temperature to obtain the cream.

EXAMPLE 18 Ingredient mg / gm Extract of Euphorbia prostrata 10.0 Propylene glycol 50.0 Titanium dioxide 10.0 Stearic acid 70.0 Simethicone 1.0 Glyceryl monostearate 60.0 Cetoesteryl alcohol 20.0 Cetyl alcohol 10.0 Sorbitan stearate 20.0 Methyl paraben 1.5 Propll paraben 0.3 Glycerin 50.0 Sorbitol 30.0 Tween 80 15.0 Xanthan gum 10.0 Purified water qs Procedure: 1. The extract of Euphorbia prostrata, methyl paraben and propyl paraben are dissolved in propylene glycol; Titanium dioxide is added to it and it is stirred well. 2. Stearic acid, simethicone, glyceryl monostearate, cetoesteryl alcohol, cetyl alcohol and sorbitan stearate are heated to 70 ° -75 ° C. 3. Glycerin, sorbitol, Tween 80 and purified water are heated to 70 ° -75 ° C. 4. The xanthan gum is dispersed in glycerin and added to the material from step 3. 5. The material from step 2 is added to the material from step 4 and allowed to cool. 6. The material from step 1 is added to the material from step 5 and allowed to cool to room temperature to obtain the cream.

Suppository compositions EXAMPLE 19 Ingredient gm / 10 units Extract of Euphorbia prostrata 0.50 Poiietiienglicoi 4000 (PEG 4000) 3.56 Polyethylene glycol 1000 (PEG 1000) 12.46 Polyethylene glycol 400 (PEG 400) 1.78 Propylene glycol 1.50 Glycerin 0.20 Procedure: 1) PEG 4000, PEG 1000 and PEG 400 are melted together and mixed well. 2) The extract of Euphorbia prostrata dissolves in 0 propylene glycol at 40-45 ° C with constant agitation. 3) The material from step 2 is added to the material from step 1 and mixed well. 4) The material from step 3 is poured into suppository molds and cooled. 5 5) The suppositories thus formed are removed from the molds and packaged in an appropriate manner.

MPLO 20 AXIS 0 Ingredient gm / 10 units Extract of Euphorbia prostate 0.5 Propylene glycol 4.5 Emulsifying wax 9.0 Beeswax 4.0 Span 80 2.0 Procedure: 1) Emulsifying wax and beeswax are melted together and mixed. 2) Span 80 is added to the material from step 1 and mixed. 3) The extract of Euphorbia prostrata is dissolved in propylene glycol at 40-45 ° C with constant agitation. 4) The material from step 3 is added to the material from step 2 and mixed well. 5) The material from step 4 is poured into suppository molds and cooled. 6) The suppositories thus formed are removed from the molds and packaged appropriately.

EXAMPLE 21 Ingredient gm / 10 units Extract of Euphorbia prostate 0.5 Propylene glycol 1.5 Witepsol-45 16.0 Alcohoi ceylic 1.0 Beeswax 1.0 Procedure: 1) Cetyl alcohol, beeswax and Witepsol-45 are fused together. 2) The extract of Euphorbia prostrata is dissolved in propylene glycol at 40-45 ° C with constant agitation. 3) The material from step 2 is added to the material from step 1 and mixed well. T0 4) The material from step 3 is poured into suppository molds and cooled. 5) The suppositories thus formed are removed from the molds and packaged in an appropriate manner.

Evaluation of the clinical efficacy of capsules and cream The effective dose of Euphorbia prostrata extract in nociceptive and inflammatory animal models ranged from 5-20 mg / kg in mice and rats. In addition, the maximum tolerable dose is greater than 2000 mg / kg in mice and rats. Based on the ratio of body surface area to body weight or body weight, the expected dose of Euphorbia prostrata extract for human studies could be between 50-200 mg for a 60 kg human (Paget and Barnes, 1964; Freireich et al., 1966). It was observed that the maximum human therapeutic dose (200 mg for a 60 kg human) is approximately 57 and 112 times lower than the maximum dose used in acute toxicity studies in mice and rats, respectively, calculated based on the ratio of body surface area to body weight.

Results of clinical trials conducted at the Ram hospital Manohar Lohia (RML Hospital) and Lok Nayak Hospital Jay PrakashNaravan (LNJP Hospital), New Delhi (India) Optimum dose, efficacy, safety and tolerability of patient formulations of 50 and 100 mg capsules of Euphorbia extract Prosthesis in hemorrhoidal attacks was evaluated in a double-blind, placebo-controlled, prospective, comparative and randomized study conducted at the RML and LNJP hospiials in New Delhi, India. The duration of the study was 8 months and the protocol therapy was 10 days. A total of 125 patients entered the study, of which 72 patients suffered from grade I hemorrhoids and 53 patients suffered from grade II hemorrhoids. Patients in each category were randomized into 3 treatment groups, ie, ADD, TDB, and BDT (ie, 50 mg capsules, 100 mg, and placebo). All patients were evaluated on day 5 and day 10 of the start of therapy. It was followed up for 3 months. The clinical examination was carried out to qualify the signs and symptoms, that is, proctorrhagia, anal discomfort, pain, anal discharge and proctitis on Day 0, on Day 5 and Day 10. The degree of improvement in ios Individual clinical parameters were also assessed on day 0, Day 5 and Day 10. The number of episodes of bleeding with bowel action and use of analgesics and topical medication as rescue medication, was also assessed on Day 0, Day 5 and on Day 10. For statistical description, all patients were included in the "Intensive to treat" analysis. The Kruskal Wallis test and the Wilcoxan signed ranges test were applied for the qualitative variables and the paired t test and one-way ANOVA for the quantitative analyzes. This study showed that the capsule of 100 mg of the extract of Euphorbia prostrata (TDB) and the 50 mg capsule of Euphorbia prostrata extract (TDA) was generally more effective than the placebo group (TDC) in all parameters of effectiveness of hemorrhoids. All groups tolerated the drugs well and showed minimal side effects. All laboratory parameters were normal to baseline, as well as at the end of therapy in all 3 treatment groups. Previous studies have shown the efficacy and safety of Euphorbia prostrata extract in the treatment of hemorrhoids in an uncontrolled manner. In this study, the extract of Euphorbia prostrata in two doses, that is, 50 and 100 mg, showed good efficacy in the treatment of hemorrhoids. However, clinically, the TDB group (100 mg capsule) showed better results in the total therapeutic evaluation.

In grade I hemorrhoids, certain parameters in the TDA group showed better results. From the analyzes, it was found that of the three treatment groups, the maximum number of patients in the TDB group underwent a 5-day therapy. The prolonged 10-day therapy in the ADT group can be attributed to the best response in some parameters. However, on day 5, in a few evaluation parameters, that is, discomfort and proctorrhagia, complete recovery was found in a maximum number of patients in the TDB group. When the degree of improvement in the signs and symptoms of hemorrhoidal attacks was assessed, the highest number of patients in the TDB group showed a substantial improvement on the day of the assessment, that is, Day 5 and the Day 10. Clinically, the TDB group showed the best decrease in the episodes of bleeding on Day 5 and Day 10. At 3 months of follow-up; both treatment groups, that is, the ADT and TDB groups, were found to be quite effective in terms of non-recurrence of bleeding. It was found that although bleeding occurred in a slightly larger number of patients in the TDB group, no treatment was needed in the higher number of patients in the TDB group than in the ADT group. It can be inferred from this, that the intensity of the sacred was not so severe as to require any interference from the treatment. In grade II hemorrhoids, of all treatment groups, TDB showed the best results in anal discomfort and proctitis on Day 5. In other parameters, ie proctorrhagia, anal discharge and pain with prolapse, both in ADD and TDB, were comparable but better than CDT clinically. Also, on Day 5, TDB proved to be a better drug to cause the complete disappearance of the signs and symptoms of hemorrhoidal attacks. The better results shown by the TDB group on day 5 than on day 10, can be attributed to the fact that of all the treatment groups, the largest number of patients in the TDB groups underwent a 5-day therapy and did not they required a prolonged therapy of 10 days. In the 3-month follow-up analysis, it was found that TDB is better in all aspects. The use of rescue medication in grade I and grade II hemorrhoids was observed in a smaller number of patients in the TDB group at the end of therapy, ie on Day 10. The impact of rescue medication may also explain the best results observed with a lower dose of 50 mg (TDA) compared to a high dose 100 mg (TDB) in few parameters.

Claims (18)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical composition for the treatment of anorectal or colonic diseases such as hemorrhoids, fissures, fissures, fistulas, abscesses, inflammatory bowel disease, and the like, comprising an extract of the plant Euphorbia prostrata containing fiavonoids and phenolic compounds, in where the fiavonoids are apigenin-7-glucoside, 1-4% by weight; luteolin-7-glucoside, 0.3-2% by weight; apigenin, 0.001-0.3% by weight; luteolin, 0.001-0.3% by weight; and cuercetin, 0.001-0.3% by weight; and wherein the phenolic compounds are ellagic acid, 1-15% by weight; Gallic acid, 1-12% by weight and tannins, 1-10% by weight; optionally with additional therapeutic agents; and wherein the pharmaceutical composition comprises the extract of the Euphorbia prostrata plant from 0.1% to 99% by weight.

2. The pharmaceutical composition according to claim 1, further characterized in that the extract comprises apigenin-7-glucoside, 2.5-3.5% by weight; luteolin-7-glucoside, 0.5-1.5% by weight; apigenin, 0.05-0.2% by weight; luteolin, 0.05-0.2% by weight; corcetin, 0.05-0.2% by weight; ellagic acid, 4-15% by weight; Gallic acid, 4-12% by weight; and tannins, 3-8% by weight.

3. - The pharmaceutical composition according to claims 1 and 2, further characterized in that the composition comprises pharmaceutically acceptable carriers / bases.

4. The pharmaceutical composition according to claims 1 to 3, further characterized in that it comprises additional therapeutic agents, selected from astringents, anesthetics, vasoconstrictors, protectants, counterirritants, keratolytics, anticholinergics, wound healing agents and antimicrobial agents, or its pharmaceutically acceptable salts; used either alone or in combination of the same.

5. The pharmaceutical composition according to claim 4, further characterized in that the astringent is selected from calamine, zinc oxide, witch hazel, bismutorresorcinol compound, bismuth subgalate, Peruvian balsam, aluminum chlorohydroxy-5-allantoinate, tannic acid and the similar; used either alone or in combination thereof.

6. The pharmaceutical composition according to claim 4, further characterized in that the anesthetic is selected from benzocaine, diperomon, pramoxine, camphor, dibucaine, phenol, tetracaine, or phenacaine, and the like; used either alone or in combination thereof.

7. The pharmaceutical composition according to claim 4, further characterized in that the vasoconstrictor is selects from ephedrine or phenylephrine, used either alone or in combination thereof.

8. The pharmaceutical composition according to claim 4, further characterized in that the protector is selected from aluminum hydroxide gel, calamine, cocoa butter, cod liver or shark oil, starch, white oil, wool alcohol , zinc oxide, vegetable or castor oil, polyethylene glycol, propylene glycol, and the like; used either alone or in combination thereof.

9. The pharmaceutical composition according to claim 4, further characterized in that the contra-irritant is menthol.

10. The pharmaceutical composition according to claim 4, further characterized in that the keratolytic is selected from aluminum chlorohydroxy allantoinate and resorcinol, used either alone or in combination thereof.

11. The pharmaceutical composition according to claim 4, further characterized in that the anticholinergic is selected from atropine or other alkaloids of the solanaceous type, used either alone or in combination thereof.

12. The pharmaceutical composition according to claim 4, further characterized in that the wound healing agent is selected from vitamin A, vitamin D, Peruvian balsam, cod liver oil and the like; used either alone or in combination thereof.

13. The pharmaceutical composition according to claim 4, further characterized in that the antimicrobial agent is selected from benzethonium chloride, benzalkonium chloride, boric acid, 8-quinolinol benzoate, secondary amyltricresols, cetylpyridinium chloride, phenol, menthol, chlorothymol, camphor and 8-hydroxyquinoline sulfate and the like, used either alone or in combination thereof.

14. The pharmaceutical composition according to claim 1, further characterized in that the composition is in the form of a cream, ointment, solution, spray, foam, suppository, medicated pad, bandage, powder, suspension, film, flake, capsules of oral hard gelatin, soft gelatin capsules, tablets (coated and uncoated), modified release dosage form, liquid, lozenges, buccal or sublingual dosage form, wafers, oblong tablets or parenteral dosage form to be infiltrated at the site of the injection.

15. A process for the preparation of a pharmaceutical composition for the treatment of anorectal or colonic diseases such as hemorrhoids, fissures, cracks, fistulas, abscesses and inflammatory bowel disease, comprising an extract of the plant Euphorbia prostrata containing fiavonoids and phenolic compounds, wherein the fiavonoids are apigenin-7-glucoside, 1-4% by weight; luteolin-7-glucoside, 0.3-2% by weight; apigenin, 0.001-0.3% by weight; luteolin, 0.001-0.3% by weight; and cuercetin, 0.001-0.3% by weight; and where the phenolic compounds are ellagic acid, 1-15% by weight; Gallic acid, 1-12% by weight and tannins, 1-10% by weight, with pharmaceutically acceptable carriers / bases, optionally with additional therapeutic agents, comprising the following steps: a. drying the plant Euphorbia prostrata, b. make a powder from the dried plant, c. extract the coarse dry powder with a polar solvent in a repetitive manner to form an extract, d. distill the extract, e. wash the concentrated extract with a non-polar organic solvent, f. optionally, reextract the washed polar extract in an organic solvento of medium polarity, distill the extract followed by dehydration of the extract, and g. drying the extract to produce the desired pharmaceutically acceptable extract, capable of being used together with pharmaceutically acceptable carriers / bases.

16. The process for the preparation of a pharmaceutical composition according to claim 15, further characterized in that the process for manufacturing the extract further comprises: a. reextract the washed polar extract in an organic solvento of medium polarity, b. distill the extract, c. dehydrate the extract, and d. drying the extract to produce the desired pharmaceutically acceptable extract, capable of being used together with pharmaceutically acceptable carriers / bases.

17. The process for the preparation of a pharmaceutical composition according to claim 15 and 16, further characterized in that the extract comprises apigenin-7-glucoside, 2.5-3.5% by weight; luteolin-7-glucoside, 0.5-1.5% by weight; apigenin, 0.05-0.2% by weight; luteolin, 0.05-0.2% by weight; corcetin, 0.05-0.2% by weight; ellagic acid, 4-15% by weight; Gallic acid, 4-12% by weight; and tannins, 3-8% by weight.

18. The use of an extract of the plant Euphorbia prostrata as defined in claim 1, for the preparation of a pharmaceutical composition for the treatment of anorectal or colonic diseases such as hemorrhoids, fissures, cracks, fistulas, abscesses, inflammatory disease of the intestine, and the like.