Specification
FIELD OF THE INVENTION
The present invention relates to topical pharmaceutical compositions comprising dry extract of Euphorbia species or drug or active agent with pharmaceutically acceptable excipient(s) and process(s) for the preparation of such compositions useful for the treatment of anorectal disease such as hemorrhoids, fissures, cracks, fistulas, abscesses and the like. Further, the pharmaceutical compositions of the present invention provides for the administration of a therapeutically and/or prophylactically effective amount of the Euphorbia species wherein the compositions possess properties to control inflammation, prevent capillary bleeding and fragility in mammalians, particularly human beings. Preferably the compositions of the present invention are in the form of dusting powders, emulsions, suspensions, sprays, oils, ointments, aerosol ointments, greasy ointments, creams, pastes, gels, foams or solutions, transdermal therapeutic systems and the like. The present invention also provides and prophylactic and/or therapeutic methods of using such compositions for the treatment of anorectal 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, on defecation. However, pain occurs when the hemorrhoids are secondarily infected, or 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, strain, physical stance in defecation, loss of connective tissue elasticity with age etc. The symptoms most widely recognized are bleeding, pain and prolapse (Hyams and Philpot, 1970; Smith, 1987). These may be accompanied by thrombosis, pruritis, edema etc. Hemorrhoids can be treated through reduction of inflammation and pain, hemostasis, wound healing 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 initiation of the treatment, but also reduce the recurrence of such attacks.
There exist several procedures for the treatment of hemorrhoids. PCT publication WO8803398 discloses surgical dressings for such treatment. Patents have been granted in respect of surgical devices such as European patent no. 0095142, US patent no. 4,621,635 has been granted for the use of lasers in the treatment of hemorrhoids. The techniques of cryopharmacotherapy and electrochemical techniques for treatment of hemorrhoids have also been patented vide European patent no. 0091405 and European patent no. 0116688, respectively. However, the biggest
drawbacks of the above are the involvement of medical experts beyond mere prescription of medicines and probable hospitalization. Also, some of them are physically and/or psychologically unpleasant in application for treating such diseases.
Several patents (US patent nos. 4,160,148, 4,508,728, 4,797,392, 4,518,583 and 5,234,914) have been granted in respect of compositions containing certain wound healing agents to provide symptomatic relief, by promoting tissue repair, reducing inflammation and encouraging wound healing. Some of them like US patent nos. 4,518,583 and 5,234,914 contain antimicrobial agents. These compositions, however, only relieve symptoms associated with inflammation, like heat, itching, redness, pain and swelling. A number of compositions for the treatment of anorectal diseases (including hemorrhoids) are based on the anesthetic and vasoconstrictive properties of the constituents, but these provide only temporary symptomatic relief.
Patents in the USA (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 patents nos. 0225832 and 0513442) have been granted in respect of compositions with varying 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. None of the above said patents disclose Euphorbia and further these compositions provide only temporary relief and are limited to local application and cannot be used for systemic use or oral administration.
A topical treatment for hemorrhoidal pain and for spasms of the sphincters and muscles located in the GI tract is disclosed in a granted patent (U.S. patent no. 5,595,753), which includes amino acid L-arginine in a pharmaceutically acceptable carrier. Another U.S. patent no. 5,591,436 has been granted for a composition for dietary supplement for the treatment of hemorrhoids. The composition comprises 60% to 95% Indian Barberry by weight; 4.8% to 38% Nagkesar by weight; and 0.2% to 2% Margosa tree leaves by weight. Another U.S. patent no. 5,562,906 discloses the use of bark or berries of the species Xanthoxylum clava herculis L and Xanthoxylum americanum Hill, both of the yellow wood tree family, are employed for the treatment of hemorrhoids and other membrane and capillary disorders of the veins and arteries. Improved strength and flexibility of the veins, arteries and their constituent structures is obtained.
Chinese patent CN101116692 discloses a drug combination and a preparation method comprising snake retreat, euphorbia, agkistrodon, citrus tangerine, centipede, corner cream and
selfheal ball. The drug combination can be used for treating breast hyperplasia, in particular treating mammary lumps and endosperm nucleus. Chinese patent CN1623587 discloses a Chinese medicine in the form of cream or ointment for treating psoriasis, acne, wart, etc is prepared from 7 Chinese-medicinal materials including sun euphorbia herb, toad venom, corydalis tuber, realga, vaseline, etc. Its advantages are high curative effect and no recurrence. Chinese patent CN 14593 04 discloses a health-care and face-beautifying product in the form of cream or aerosol for treating tinea, sore and rough skin is prepared from more than 10 Chinese medicinal materials including euphorbia herb as main component and egg white which is fetched by special immersion method of fresh egg. Chinese patent CN 1363378 discloses a medicine in the form of tablet, ointment, cream of spray for treating flat wart and dermatopathy is prepared from sun euphorbia herb as primary raw material. Its advantages include high curative effect (98% for effective rate). Chinese patent CN1413612 discloses a medicine "Meihening" in the form of cream or powder for treating tuberculosis, especially drug-resistant tuberculosis is prepared from fischer euphorbia root, giant typhonium herb, sun euphorbia herb, etc. Its advantages are short course of treatment and low cost. Chinese patent CN 1220829 discloses a Chinese-medicinal cream for preventing and treating bark disease of fruit tree is prepared from such Chinese-medicinal materials as fischer euphorbia root, tobacco leaf, rhubarb, phellodendron barkand cnidium fruit through immersing extraction in oil for 100-200 hr, heating to 80-120 deg.C, filtering, heating oil to 100-150 deg.C, dissolvig rosin in it, mixing and cooling, and features high effect to rot, dry not, etc with effective rate up to more than 95%. Japanese patent application JP9071527 relates to a skin preparation for external use having excellent moisture-retaining and emollient actions on the horny layer of the skin and resistant to discoloration with time. Japanese patent application JP9030927 relates to a skin preparation for external use, having a moisture-retaining effect, an effect for preventing and improving skin roughness, and an effect for preventing and improving the formation of skin wrinkles, and excellent in a skin aging-preventing effect. Japanese patent application JP8268859 relates to a cosmetic containing a plant extract and stearyl glycyrrhetinate or epsi -aminocaproic acid and excellent in a wrinkle-preventing and improving effect. Japanese patent application JP8175954 relates to a skin cosmetic containing a plant selected from among Euphorbia lathyris, leaf mustard and madder or its extract as an active component and having excellent effect to suppress the wrinkling and pigmentation of the skin.
An Indian 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 U.S., No. 5,858,371) have been granted to the present applicant for a composition comprising a flavonoid containing extract of Euphorbia prostrata for treatment of anorectal and colonic diseases. Recently a US patent 7,371,412 has been granted to the applicants of the present invention for a composition 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 such as hemorrhoids, fissures, cracks, fistulas, abscesses and the like.
The inventors with expenditure of intellectual effort and careful experimentation have prepared topical pharmaceutical compositions of Euphorbia species preferably Euphorbia prostrata for the long-term management of anorectal diseases including hemorrhoids that are safe and painless to administer and have long-term effectiveness. The topical compositions of the present invention when applied locally at the site of the action aid in ameliorating the pain, thus avoiding the entry of the drug in the systemic circulation, thereby reducing the associated deleterious side effects. The compositions of the present invention have improved efficacy and safety and are economical to manufacture.
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide topical pharmaceutical compositions for the treatment of anorectal disease such as hemorrhoids, fissures, cracks, fistulas, abscesses and the like comprising dry extract of Euphorbia species or drug or active agent with pharmaceutically acceptable excipient(s); wherein the pharmaceutical composition comprise dry extract of Euphorbia species from about 0.1% to about 99% by weight. It might be emphasized that the phrase "anorectal disease" anywhere in the specification relates to disease such as hemorrhoids, fissures, cracks, fistulas, abscesses and the like.
The phrase 'dry extract of Euphorbia species or drug or active agent' as herein described anywhere in the specification comprises flavonoids from about 3% to about 9% by weight, phenolic compounds from about 10% to about 50% by weight and other compounds from about 41% to about 87% by weight and the like or mixtures thereof. The 'dry extract of Euphorbia species or drug or active agent' as herein described is prepared by drying the plant of various Euphorbia species under controlled conditions of temperature and humidity, making a powder from the dried plant, extracting the dry coarse powder with a polar solvent repetitively to form an extract, distilling the extract, optionally washing the concentrated extract with a non-polar organic solvent, optionally re-extracting the concentrated extract with a medium polarity organic
solvent and drying the washed extract to produce the desired pharmaceutically acceptable extract.
It is another objective of the present invention to provide a topical pharmaceutical composition for the treatment of anorectal disease comprising dry extract of Euphorbia species or drug or active agent comprising flavonoids, phenolic compounds and other compounds, wherein the flavonoids are selected from but not limited to apigenin-7-glycoside, 1 - 5% by weight; luteolin-7-glycoside, 0.3 - 4% by weight; and apigenin, luteolin and quercetin, 0.01 - 1% by weight and the like; and wherein the phenolic compounds are selected from but not limited to ellagic acid, 1-15% by weight; gallic acid, 1 - 12% by weight and tannins, 1 - 10% by weight and the like with pharmaceutically acceptable excipient(s).
It is another objective of the present invention to provide topical pharmaceutical compositions for the treatment of anorectal disease such as hemorrhoids, fissures, cracks, fistulas, abscesses and the like comprising the dry extract of Euphorbia species or drug or active agent selected from but not limited to a group comprising E. adnechlora, E. amygdaloides, E. clarkeana, E. condylocarpa, E. discolor, E. dracunculoides, E. dulcis, E. formosa, E. formosana, E. geniculata, E. granulata, E. hirta, E. hypercifolia, E. jaxartica, E. kaleniczenkii, E. lanata, E. larica, E. lucida, E. lunulata, E. macroceras, E. minuta, E. oblongifolia, E. palustris, E. retusa, E. scripta, E. serpeusmicrofilia, E. splendens, E. steppoosa, E. stricta, E. terracina, E. thymifolia, E. tinctoria, E. verrucosa, E. vigultosa, E. virgata, E. wallichi, E. prostrata and the like or mixtures used alone or in combination thereof.
It is yet another objective of the present invention to provide topical pharmaceutical compositions for the treatment of anorectal disease such as hemorrhoids, fissures, cracks, fistulas, abscesses and the like comprising the dry extract of Euphorbia species or drug or active agent wherein the dry extract is substantially devoid of diterpene esters, either inherently or by selective extraction and processing of the extract selected from but not limited to a group comprising E. cyparissias, E. helioscopia, E. lathyris, E. magalanta, E. paralias, E. seguieriana, E. tirucalli, E. peplus, and the like or mixtures used alone or in combination thereof.
It is a preferred objective of the present invention to provide topical pharmaceutical compositions for the treatment of anorectal disease such as hemorrhoids, fissures, cracks, fistulas, abscesses and the like comprising the dry extract of Euphorbia species or drug or active agent wherein the dry extract is of E. prostrata. The plant Euphorbia prostrata (Family:
Euphorbiaceae) was identified as being relevant in the study of venous diseases, including hemorrhoids. Euphorbia prostrata is well known to the Indian traditional medicine in the use of treatment for asthma, bloody dysentery, and sores.
It is also an objective of the present invention to provide process for the preparation of an extract of the plant of Euphorbia species for the treatment of venous disease.
It is an objective of the present invention to provide process for the preparation of topical pharmaceutical composition for the treatment of anorectal disease comprising dry extract of Euphorbia species or drug or active agent comprising flavonoids and phenolic compounds, wherein the flavonoids are selected from but not limited to apigenin-7-glycoside, 1 - 5% by weight; luteolin-7-glycoside, 0.3 - 4% by weight; and apigenin, luteolin and quercetin, 0.01 - 1% by weight and the like; and wherein the phenolic compounds are selected from but not limited to ellagic acid, 1-15% by weight; gallic acid, 1 - 12% by weight and tannins, 1 - 10% by weight and the like with pharmaceutically acceptable excipient(s) as herein described, comprising of the following steps:
i) drying the extract to produce the desired pharmaceutically acceptable extract, ii) mixing the dried extract obtained from step (i) with pharmaceutically acceptable excipient(s), iii) formulating the mixture obtained in step (ii) into a topical pharmaceutical composition.
Yet another objective of the present invention is to provide method of using such pharmaceutical compositions for the treatment of anorectal diseases.
The compositions of the present invention and method for treating anorectal diseases using dry extract of Euphorbia prostrata provides long-term effectiveness and low prolapse rates.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compositions that can be topically administered. The invention provides relief from pain associated with hemorrhoids. The invention also significantly reduces bleeding and accelerates tissue re-growth in the affected hemorrhoidal tissue. The invention is useful in the treatment of lesions, other than hemorrhoids in the anorectal area and can be formulated in several types of topical compositions. There are no side effects from the use of the composition in human beings.
In the context of the present invention the term or the phrase "dry extract of Euphorbia species or drug or active agent" has been used interchangeably.
In an embodiment of the present invention, is provided a topical pharmaceutical composition, comprising dry extract of Euphorbia species or drug or active agent with pharmaceutically acceptable excipient(s); wherein the pharmaceutical composition comprises dry extract of Euphorbia species from about 0.1% to about 99% by weight. It might be emphasized that the phrase "anorectal disease" anywhere in the specification relates to disease such as hemorrhoids, fissures, cracks, fistulas, abscesses and the like.
The phrase 'dry extract of Euphorbia species or drug or active agent' as herein described anywhere in the specification comprises flavonoids from about 3% to about 9% by weight, phenolic compounds from about 10% to about 50% by weight and other compounds from about 41% to about 87% by weight and the like or mixtures thereof. The 'dry extract of Euphorbia species or drug or active agent' as herein described is prepared by drying the plant of various Euphorbia species under controlled conditions of temperature and humidity, making a powder from the dried plant, extracting the dry coarse powder with a polar solvent repetitively to form an extract, distilling the extract, optionally washing the concentrated extract with a non-polar organic solvent, optionally re-extracting the concentrated extract with a medium polarity organic solvent and drying the washed extract to produce the desired pharmaceutically acceptable extract.
In another embodiment of the present invention, is provided a topical pharmaceutical composition for the treatment of anorectal diseases comprising dry extract of Euphorbia species or drug or active agent comprising flavonoids, phenolic compounds and other compounds, wherein the flavonoids are selected from but not limited to apigenin-7-glycoside, 1 - 5% by weight; luteolin-7-glycoside, 0.3 - 4% by weight and the like; and apigenin, luteolin and quercetin, 0.01 - 1% by weight and the like; and wherein the phenolic compounds are selected from but not limited to ellagic acid, 1-15% by weight; gallic acid, 1 - 12% by weight and tannins, 1 -10% by weight and the like with pharmaceutically acceptable excipient(s).
In an embodiment of the present invention, the dry extract of Euphorbia species or drug or active agent is selected from but not limited to a group comprising E. adnechlora, E. amygdaloides, E. clarkeana, E. condylocarpa, E. discolor, E. dracunculoides, E. dulcis, E. formosa, E. formosana, E. geniculata, E. granulata, E. hirta, E. hypercifolia, E. jaxartica, E. kaleniczenkii, E. lanata, E. larica, E. lucida, E. lunulata, E. macroceras, E. minuta, E. oblongifolia, E. palustris, E. retusa, E. scripta, E. serpeusmicrofilia, E. splendens, E. steppoosa, E. stricta, E. terracina, E.
thymifolia, E. tinctoria, E. verrucosa, E. vigultosa, E. virgata, E. wallichi, E. prostrata and the like or mixtures used alone or in combination thereof.
In another embodiment of the present invention, the dry extract of Euphorbia species or drug or active agent is substantially devoid of diterpene esters, either inherently or by selective extraction and processing of the extract selected from but not limited to a group comprising E. cyparissias, E. helioscopia, E. lathyris, E. magalanta, E. paralias, E. seguieriana, E. tirucalli, E. peplus, and the like or mixtures used alone or in combination thereof.
In a preferred embodiment of the present invention, the dry extract of Euphorbia species or drug or active agent is E. prostrata. The plant Euphorbia prostrata (Family: Euphorbiaceae) was identified as being relevant in the study of venous diseases, including hemorrhoids. Euphorbia prostrata is well known to the Indian traditional medicine in the use of treatment for asthma, bloody dysentery, and sores.
The pharmaceutical composition into different topical compositions can be formulated using pharmaceutically acceptable excipient(s) and techniques known to art. Pharmaceutical dosage forms of the present invention can be in the form of dusting powders, emulsions, suspensions, sprays, oils, ointments, greasy ointments, aerosol ointments, creams, pastes, gels, foams or solutions, transdermal therapeutic systems, and other compositions suitable for topical administration. The compositions of the present invention are applied topically to the anorectal area to obtain relief from the above mentioned symptoms of hemorrhoids, fissures, cracks, fistulas, abscesses and the like. The administration of the topical composition is dependent on the particular symptom to be treated wherein the administration may be applicable to any or all of the regions of the anorectal area including the perianal area or portion of the skin and buttocks immediately surrounding the anus, the modified anal skin area of the anal canal and the mucous membrane of the rectum. The compositions are applied topically to the involved area until the symptoms are relieved. The compositions are administered once or several times over the course of a single day. The administration is continued for as many days as are necessary to relieve the condition being treated.
The topical compositions as well as methods for their preparation are well established in the art (Niedner, R., and Ziegenmeyer, J. (1997) Dermatika. Therapeutischer Einsatz, Pharmakologie und Pharmazie. Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, Germany; Gennaro, A.L. and Gennaro, A.R. (2000) Remington: The Science and Practice of Pharmacy, 20th Ed.,
Lippincott Williams & Wilkins, Philadelphia, PA; Niazi, S. K. (2004) Handbook of Pharmaceutical Manufacturing Formulations, CRC Press, Boca Raton, FL). The pharmaceutical carriers and/or excipients suitable for topical administration are preferably according to the invention conventional carriers and/or excipients known to the skilled person.
In an embodiment of the invention, the topical pharmaceutical preparation of the invention is in the form of a semi-solid. Well known examples which may be mentioned are, in particular, ointments (e.g. solution ointment, suspension ointment), creams, gels or pastes.
The term "gel", as used herein, refers to a colloidal system in which a porous network of interconnected particles is distributed throughout the volume of a liquid medium. 'Gels' are solid, jelly-like materials which both by weight and volume are mostly liquid in composition exhibiting densities similar to liquids, however have the structural properties of a solid. In an embodiment, the gels are in the form of one or more cross-linked water-swellable (hydrophilic) gel-forming polymers such as polysaccharides or polyacrylic acid derivatives. The said hydrophilic gels are termed as 'hydrogels'. Hydrogels may comprise more than 99% water. The water bound in such a hydrogel does not evaporate fast when applied to the skin. This results in prolonged contact of water with the skin which, in turn, results in an improved susceptibility for the uptake of active ingredients present in the hydrogel, thus increased penetration through the skin. Typically, such gel- forming polymers have an average molecular weight of 1000 to 50000 Dal ton, preferably of 1000 to 30000 Dal ton. The 'hydrogel' may alternatively be characterized by its flow behavior such as by its viscosity coefficient as determined by the flow models of Bingham, Casson, Herschel-Bulkley and Ostwald, respectively, all of them well known in the art (see, e.g. Gosh, T.K. et al. (1997) Transdermal and topical drug delivery systems. CRC Press, Boca Raton, FL, USA; Fairclough, J.P.A., and Norman A.I. (2003) Annu. Rep. Prog. Chem., Sect. C: Phys. Chem. 99, 243-276). In another preferred embodiment, the hydrogel comprises one or more gel-forming polymers in a total amount of 0.1% to 15% (w/w) based on the total weight of the hydrogel. The gel-forming polymers used in the present invention are selected from but not limited to naturally occurring polymers, synthetic polymers or mixtures used either alone or in combination thereof. Preferably one or more gel-forming polymers are selected from but not limited to group comprising cellulose derivatives, polyacrylic acid derivatives, and gums mixtures used either alone or in combination thereof. The cellulose derivatives as gel-forming polymers are selected from but not limited to methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, and carboxymethyl cellulose, sodium carboxymethylcellulose
and the like or mixtures thereof. Examples of polyacrylic acid derivatives are selected from but not limited to polyacrylic acid, polymethylacrylate, and polyethylacrylate and the like or mixtures thereof. Examples of gums are selected from but not limited to agar, alginic acid, glucomannan, arabic gum, sodium alginate, tragacanth and the like or mixtures thereof.
In an embodiment, the compositions are in the form of emulsions. Emulsions are in general mixtures prepared from two mutually insoluble components wherein the first substance (the dispersed phase) is dispersed (i.e. distributed) in the second (the continuous phase). Emulsions form as a result of proper selection and manipulation of mixing conditions of the two mutually insoluble components. The most common type of emulsions is in which an aqueous component and a lipophilic component are employed and are frequently referred to as oil-in-water and water-in-oil emulsions known in the art. Oil-in-water emulsions comprise the lipophilic phase which is dispersed in the aqueous phase, while water-in-oil emulsions comprise the aqueous phase which is dispersed in the lipophilic phase. Emulsions require at least one, and frequently a combination of several emulsifying agents in order to achieve a desirable balance of emulsification, viscosity, stability and appearance. The said emulsifying agents facilitate the dispersal of one immiscible phase into the other and assist in stabilizing the emulsion. In an embodiment of the invention, the topical composition is an oil-in-water emulsion. 'Oil-in- water emulsion', as used herein in the entire specification relates to formulations composed of small droplets of a lipid phase (e.g., an oil) dispersed in a continuous aqueous phase. In general, oil-in-water emulsions are more comfortable and pharmaceutically/cosmetically acceptable as compared to water-in-oil emulsions (such as an ointment) as they are less greasy when applied on the skin and more easily washed off when using water. By employing such an oil-in-water emulsion the penetration of active agents such as the dried extract of the Euphorbia species of the present invention through the skin is improved as compared to formulations having only an aqueous phase, since the presence of a lipid phase is assumed to aid in crossing the hydrophobic core of biological membranes. In an embodiment the preferred oil-in- water-emulsions of the invention are selected from but not limited to the group comprising creams, lotions, and balms which primarily differ with regard to their respective viscosities. A cream is a semi-solid emulsion, having a medium viscosity, lotion is a low- to medium- viscosity preparation intended for application to unbroken skin, balm (also referred to as liniment) has a similar viscosity as a lotion but unlike a lotion a balm is applied with friction that is a liniment is always rubbed in. In another embodiment, the oil-in-water emulsions used according to the invention comprises one or more emulsifiers selected from but not limited to a group comprising sorbitan esters (also
referred to as Span®), polyoxyethylene sorbitan esters (also referred to as polysorbates; Tween®), and glyceryl esters or mixtures used alone or in combination thereof. Examples of sorbitan esters include inter alia sorbitan monooleate, sorbitan monostearate, sorbitan monolaurate, sobitan trioleate, and sorbitan tristearate or mixtures thereof. Examples of polyoxyethylene sorbitan esters include polyethylene glycol (PEG) sorbitan esters such as inter alia PEG-(5)-sorbitan monooleate, PEG-(4)-sorbitan monostearate, PEG-(4)-sorbitan monolaurate, PEG-sobitan trioleate, and PEG-sorbitan tristearate or mixtures thereof. Examples of glyceryl esters include inter alia glyceryl monostearate, glyceryl monolaurate, and glyceryl tristearate or mixtures thereof. Other emulsifiers that can be used in the present invention include inter alia lecithin, cholesterol, phosphatidyl glycerols, alkyl alcohols, poloxamers (also referred to as Pluronic®/Synperonic®), poloxamin (also referred to as Tetronic®), sodium laurylsulfate, sodium cetylstearylsulfate, and potassium oleate. The nature of an emulsion such as water-in-oil emulsion or oil-in- water emulsion depends on the volume fraction of both phases and on the type of emulsifier. Generally, the Bancroft rule applies: emulsifiers and emulsifying particles tend to promote dispersion of the phase in which they do not dissolve very well i.e. the phase in which an emulsifier is more soluble constitutes the continuous phase. Thus, for the preparation of oil-in-water emulsions water-soluble emulsifiers are preferred.
In another embodiment, the topical compositions are administered as ointments. These may be anhydrous and contain as base the paraffins which are suitable for topical use and are liquid at body temperature, especially low-viscosity paraffin, also the said natural or partially synthetic fats, e.g. coconut fatty acid triglyceride; hardened oils, e.g. hydrogenated peanut or castor oil; fatty acid partial esters of glycerol, e.g. glycerol monostearate and distearate; silicones, e.g. polydimethylsiloxanes, e.g. hexamethyldisiloxane or octamethyltrisiloxane; and, for example, the fatty alcohols mentioned in connection with the hydrous creams and increasing the water uptake capacity, and sterols, wool waxes, other emulsifiers and/or other additives.
In an embodiment of the present invention the cream or ointment comprises 0.1-10% w/w, preferably 0.2-5% w/w of the extract of Euphorbia species. In an embodiment of the present invention, a capsule may be taken, subject to a maximum of 300 mg of extract per day, along with topical application comprising the same extract, as and when required. The cream comprising the dry extract of Euphorbia species is prepared by emulsifying the aqueous phase, comprising 0.1-10% w/w preferably 0.2-5% w/w of the extract, along with a suitable oleaginous phase. Other alternatives can be prepared by formulating the extract in 0.1-10% w/w as
Hydrophilic ointment USP with absorption bases; or water soluble bases such as Polyethylene glycol ointment USNF; or as water absorbing bases such as Hydrophilic petrolatum USP, Lanolin USP; or in hydrocarbon bases such as White petrolatum USP.
In an embodiment, the compositions are applied in the form of pastes. The paste has the advantage that in addition to covering and sticking to the treated tissue, it is easier to apply than thinner ointments which are difficult even to keep on the fingers. The paste is applied locally well up into the anal canal to cover the treated tissue, one to four times daily, as needed. In preparing the desired pharmaceutical form of the present compositions, various additives, diluents and adjuvants can be utilized. These illustratively include perfumes, essential oils, surfactants, ointment type bases, higher fatty acids, propellants', thickening agents, humectants, silicone-type fluids and solid diluents as is known in the art.
In another embodiment, the compositions of the present invention can be administered as aerosol ointments. These topical aerosol compositions enhance the therapeutic action of an ointment by producing a sustained cooling effect which provides fast relief from pain and itching as well as a tendency to shrink swollen, inflamed tissue in advance of the slower action of any medication present in the ointment. In an embodiment, the ingredients present in an aerosol container includes the dried alcoholic extract of Euphorbia species, petroleum jellies, oils, volatile liquids, thickening agents, surfactants, and dispersed solids known to one skilled in art. The ointment may additionally comprise adjuvants such as fragrances, corrosion inhibitors, preservatives, and coloring agents known to one skilled in art. In a preferred embodiment, the oils used in the aerosol ointment are selected from but not limited to a group comprising mineral oils, silicone oils, vegetable oils such as corn oil, safflower oil, soya oil, cod liver oil, shark liver oil, synthetic oils such as isopropyl myristate, butyl stearate and dimethyl sebacate and the like or mixtures used alone or in combination thereof. Volatile organic liquids boiling below about 250°C may be used as partial or complete replacements of the oils, to provide an ointment component that dries to leave a non-greasy, non-oily residue. The polydimethyl cyclosiloxanes having 3 to 5 silicone atoms are particularly useful, because of their low potential to cause irritation. In an embodiment, the thickening agents are selected from but not limited to a group comprising mineral waxes such as paraffin and microcrystalline waxes, animal and vegetable waxes such as beeswax, wool wax, spermaceti and bayberry wax, synthetic waxes such as hydrogenated caster oil, glyceryl monostearate, cetyl palmitate and cetyl alcohol; polymers such as polyethylene and polyisobutylene and metallic soaps such as aluminum distearate and the like or mixtures used alone or in combination thereof. The thickening agent(s) present in the ointment are sufficient
which when expelled from an aerosol device, deposits as a solid or semi-solid ointment. The aerosol ointments of the present composition may additionally comprise water in the form of a water-in-oil emulsion. Water can act as a solvent or a dispersion medium with a low evaporation rate so that less residue remains on the skin. In another embodiment, the water-in-oil emulsion ointment comprises emulsifying agents such as a water-soluble and an oil-soluble emulsifier. Oil-soluble emulsifiers are selected from but not limited to a group comprising the di- and tri-ethanoxy esters of lauric, myristic, palmitic and stearic acids, and the di and tri-ethanoxy ethers of lauryl alcohol, cetyl alcohol, oleyl alcohol, lanolin alcohols, glyceryl monostearate and the like used alone or in combination thereof. Water-soluble emulsifiers used in the present context are selected from but not limited to a group comprising decylethanoxy esters and ethers of the above acids and alcohols; water-soluble soaps, such as potassium palmitate; anionic surfactants, such as sodium lauryl sulfate, sodium lauroyl sarcosinate and sodium stearoyl lactate; amphoteric surfactants, such as the sodium salts of the imidazoline monocarboxyl stearyl derivative and the imidazoline dicarboxyl coconut derivative; and cationic surfactants, such a cetyl trimethylammonium bromide. Alternatively the ointment ingredients used in the preparation of the aerosol composition can be an oil-in-water emulsion. One skilled in art may make various modifications to finally arrive to an aerosol ointment wherein the ointment ingredients are in the form of oil-in-water emulsion. When water is included in the composition, it is sometimes beneficial to include ethyl alcohol or isopropyl alcohol. Humectants, such as propylene glycol, glycerine or sorbitol may also be used. Preservatives, such as sorbic acid, methyl paraben and propyl paraben may be included. Also, corrosion inhibitors, such as sodium benzoate, may be used.
The preparation of the ointments compositions of this invention are known in the art. In general the ingredients are combined and heated with stirring until all ingredients have dissolved, excluding ingredients that are not soluble or are heat sensitive. These are added after the ointment has cooled sufficiently. The ointment is stirred while cooling. It is dosed into the aerosol containers at a temperature above its flow temperature.
In yet another embodiment, the topical compositions of the present invention may additionally comprise other active agents selected from but not limited to a group comprising local anesthetics and/or their salts, vasoconstrictors, protectants, counterirritant, astringents, wound healing agents, antimicrobial agents and anticholinergics. The local anesthetics and/or their salts are selected from but not limited to group comprising benzocaine, diperodon, pramoxine,
camphor, dibucaine, phenol, tetrtacaine, lignocaine and phenacaine and the like or mixtures thereof. The vasoconstrictors are selected from but not limited to group comprising ephedrine, phenylephrine, phenylephrine and/or their salts and the like or mixtures thereof. The protectants are selected from but not limited to group comprising aluminum hydroxide gel, calamine, cocoa butter, cod or shark liver oil, glycerin in aqueous solution, kaolin, lanolin, mineral oil, starch, white petrolatum, wool alcohol, zinc oxide, vegetable or castor oil, polyethylene glycol and propylene glycol and the like or mixtures thereof. The counterirritant includes but is not limited to menthol in aqueous solution. The astringents are selected from but not limited to group comprising calamine, zinc oxide, hamamelis water, bismuthresorcinol compound, bismuth subgallate, peruvian balsam, aluminium chlorhydroxy allantoinate, tannic acid and tannins and the like or mixtures thereof. The tannins additionally may be derived from plants such as Butea monosperma (Family: Leguminosae) Butea parvifiora and Butea frondoza. The wound healing agents include but not limited to vitamin A and vitamin D. Peruvian balsam, cod liver, live yeast cell derivative can be included in the composition. The antimicrobial agents are selected from but not limited to group comprising benzethonium chloride, benzalkonium chloride, boric acid, 8-quinolinol benzoate, secondary amyltricresols, cetylpyridinium chloride, phenol, menthol, chlorothymol, camphor and 8-hydroxyquinoline sulfate and the like or mixtures thereof. The keratolyses include but are not limited to aluminium chlorhydroxy allantoinate and resorcinol and the like or mixtures thereof. The anticholinergics include but are not limited to atropine or other solanaceous type alkaloids, either alone or in combination.
In a further embodiment, is provided a process for the preparation of a topical pharmaceutical composition wherein the process for the manufacture of the extract comprises: a. re-extracting the washed polar extract in a medium polarity organic solvent, b. distilling the extract, c. dehydrating the extract, and d. drying the extract to produce the desired pharmaceutically acceptable extract followed by pulverization of the dry drug extract and capable of being used along with pharmaceutically acceptable carrier(s)/base(s).
In an embodiment, the polar solvent(s) used in the present invention for the process of preparation of extract of the plant Euphorbia species is selected from but not limited to a group comprising acetone, methanol, ethanol, isopropanol, water, and the like used either alone or in combination thereof. In a further embodiment, the non-polar organic solvent(s) used in the present invention for the process of preparation of extract of the plant Euphorbia prostrata is selected from but not limited to a group comprising pentane, hexane, heptane, petroleum ether,
chloroform, dichloromethane, dichloroethane, and the like used either alone or in combination thereof. In an embodiment the medium polarity organic solvent(s) is selected from but not limited to ethyl acetate, ethyl methyl ketone, butanol, and the like used either alone or in combination thereof.
In an embodiment of the present invention, is provided a process for the preparation of a topical
pharmaceutical composition for the treatment of anorectal or colonic disease such as
hemorrhoids, fissures, cracks, fistulas, abscesses and inflammatory bowel disease comprising dry
extract of Euphorbia species with pharmaceutically acceptable excipient(s) as herein described,
comprising of the following steps:
i) drying the extract to produce the desired pharmaceutically acceptable extract,
ii) mixing the dried extract obtained from step (i) with pharmaceutically acceptable excipient(s),
iii) formulating the mixture obtained in step (ii) into a topical pharmaceutical composition.
Pre-Clinical study:
A) Anti-inflammatory activity of dry extract of Euphorbia prostrata preparation on topical application:
Animal model used in the present study was Carageenan-induced paw edema in rat. Wistar rats weighing 1.50 to 250g were used for the study. Drugs used were Carrageenan type-IV, Indomethacin, Nimesulide and dry extract of Euphorbia prostrata preparation (0.5, 1,2 and 4 %) in DMSO.
Procedure: Carrageenan-induced paw edema was induced in Wistar rats as described by Winter et al., (1962). A 1% w/v solution of carrageenan (0.1 m) in water was injected in right paw of rats. The dry extract of Euphorbia prostrata preparation was dissolved in DMSO and applied (0.05 mJ) topically by rubbing for 15s on the right paw 30 min before carrageenan injection. The left paw was served as control (saline). Edema was measured at 15, 30, 60, 90, 120, 150, 180, 210 and 240 min after carrageenan challenge by using mercury plethysmograph. Nimesulide (2 %) was used as reference drug to compare the anti-inflammatory effect of test compound dry extract of Euphorbia prostrata.
Calculation of ED50 (Anti-inflammatory} value: Percent edema inhibition was calculated % Edema inhibition= edema (control)-edema (drug treated) × 100
edema (control) % Edema inhibition was plotted against log dose and ED50 value calculated from slope.
Statistical analysis: Results were expressed as mean±SEM. Percentage edema (%increase in paw volume) was subjected to analysis of variance (one-way ANOVA) followed by Duncan's multiple comparison test. P<0.05 was considered statistically significant.
Results: Carrageenan (1%) produced significant increase in paw volume in control group, indicating inflammatory response. Nimesulide (2%) produced significant anti-inflammatory effect as compared to control group (P
Documents
Application Documents
| # |
Name |
Date |
| 1 |
112-DEL-2009-Form-5 (8-1-2010).pdf |
2011-08-21 |
| 2 |
112-DEL-2009-Form-3 (8-1-2010).pdf |
2011-08-21 |
| 3 |
112-del-2009-form-2.pdf |
2011-08-21 |
| 4 |
112-DEL-2009-Form-2 (8-1-2010).pdf |
2011-08-21 |
| 5 |
112-del-2009-form-1.pdf |
2011-08-21 |
| 6 |
112-del-2009-drawings.pdf |
2011-08-21 |
| 7 |
112-DEL-2009-Drawings (8-1-2010).pdf |
2011-08-21 |
| 8 |
112-del-2009-description (provisional).pdf |
2011-08-21 |
| 9 |
112-DEL-2009-Description (Complete) (8-1-2010).pdf |
2011-08-21 |
| 10 |
112-del-2009-correspondence-others.pdf |
2011-08-21 |
| 11 |
112-DEL-2009-Correspondence-Others (8-1-2010).pdf |
2011-08-21 |
| 12 |
112-DEL-2009-Claims (8-1-2010).pdf |
2011-08-21 |
| 13 |
112-DEL-2009-Abstract (8-1-2010).pdf |
2011-08-21 |
| 14 |
112-del-2009-Form-18-(11-01-2013).pdf |
2013-01-11 |
| 15 |
112-del-2009-Form-13-(21-11-2017).pdf |
2017-11-21 |
| 16 |
112-DEL-2009-Form 13-211117.pdf |
2017-11-28 |
| 17 |
112-DEL-2009-Form 1-211117.pdf |
2017-11-28 |
| 18 |
112-DEL-2009-FER.pdf |
2018-01-15 |
| 19 |
112-DEL-2009-OTHERS-060718.pdf |
2018-07-10 |
| 20 |
112-DEL-2009-Other Patent Document-060718.pdf |
2018-07-10 |
| 21 |
112-DEL-2009-Form 3-060718.pdf |
2018-07-10 |
| 22 |
112-DEL-2009-Form 1-060718.pdf |
2018-07-10 |
| 23 |
112-DEL-2009-Examination Report Reply Recieved-060718.pdf |
2018-07-10 |
| 24 |
112-DEL-2009-Drawing-060718.pdf |
2018-07-10 |
| 25 |
112-DEL-2009-Claims-060718.pdf |
2018-07-10 |
| 26 |
112-DEL-2009-HearingNoticeLetter.pdf |
2018-08-07 |
| 27 |
112-DEL-2009-OTHERS-310818.pdf |
2018-09-06 |
| 28 |
112-DEL-2009-OTHERS-250918.pdf |
2018-10-03 |
| 29 |
112-DEL-2009-OTHERS-250918-.pdf |
2018-10-03 |
| 30 |
112-DEL-2009-Correspondence-250918.pdf |
2018-10-03 |
| 31 |
112-DEL-2009-Claims-250918.pdf |
2018-10-03 |
| 32 |
112-DEL-2009-OTHERS-260520.pdf |
2020-06-05 |
| 33 |
112-DEL-2009-Other Patent Document-260520.pdf |
2021-10-03 |
| 34 |
112-DEL-2009-Form-6-260520.pdf |
2021-10-03 |
Search Strategy
| 1 |
112tkdldocument_12-01-2018.pdf |
| 2 |
112search_12-01-2018.pdf |