FIELD OF THE INVENTION
The invention relates to compositions and process for preparation of such compositions comprising an extract of the plant Euphorbia prostrata useful for the management of chronic venous insufficiency, particularly varicose veins The compositions possess properties to control inflammation, prevent capillary bleeding and fragility in mammals, particularly human beings The invention also provides an animal model for screening efficacy of active component(s), particularly an extract of the plant Euphorbia prostrata, in conditions like varicose veins The compositions of the present invention are useful as a pharmaceutical product or a dietary supplement.
BACKGROUND OF THE INVENTION
Varicose veins are swollen and knotted veins that are both unsightly and uncomfortable Up to about 20% of the adult population has varicose veins and as a result experience discomfort Varicose veins can cause swelling of the legs and feet, and the skin to itch Factors such as prolonged standing or sitting, obesity and pregnancy play a large part in the development of varicosity. Varicose veins can occur in almost any part of the body, however they most often occur in the calf or on the inside of the leg between the groin and the ankle
There are a large number of patients who suffer from problems associated with venous insufficiency Two of the most common manifestations of venous insufficient are varicose veins and hemorrhoids. The prevalence of these two conditions is astonishing In population studies, the prevalence of varicose veins has been reported to be 10-15 percent for men and 20-25 percent for women. In a recent cross-sectional study, the age-adjusted prevalence of varicose veins was 58 percent for men and 48 percent for women The crossroads to the development of varicose veins is the loss of vascular integrity
Varicose veins comprise elongated, protrusive, inoperative, and often spider-like veins, usually occurring in the legs, and frequently occurring after pregnancy Varicose vein is characterized by increased venous and capillary pressures, increased capillary permeability, chronic edema, repeated inflammation, and stasis. Varicosities that occur secondary to obstruction and valvular incompetence of the deep venous system are much more serious because of the associated risk of pulmonary thromboembolism. It has been known in the prior art that various plants, herbs, bushes, and the like, will yield certain beneficial medicinal effects A major component of a safe and effective therapy for varicose veins is the use of botanical and nutritional therapies Several botanical extracts have been shown to improve microcirculation, capillary flow, and vascular tone, and strengthen connective tissue
of the perivascular amorphous substrate The goals of botanical and nutritional support are consistent with the philosophy of treating the cause of a disease Conversely, the bulk of standard treatments for varicose veins are geared towards removing the problem or palliating the disease Additionally, the low compliance associated with treatments such as hydrotherapy, mechanical compression therapy, and diet and lifestyle changes renders oral dietary supplementation an attractive option The use of nutritional and botanical agents for the treatment of hemorrhoids and varicose veins is possibly the missing link to an effective conservative approach to these diseases Early intervention with conservative therapies may prevent time-consuming and expensive complications of varicose veins and hemorrhoids
There exist several procedures for the treatment of varicose veins US patent number 6,210,680 describes a method of treating varicose veins and hemorrhoids comprised of the administration to a patient in need thereof an effective amount of a composition consisting essentially of an isoquinoline alkaloid and a pharmaceutically acceptable carrier US patent number 5,955,085 discloses a method for the treatment of varicose veins for use by one in need of such treatment consisting of the step of administering about 3 to about 12 mg, about three times a day, of xanthoxylum for the duration of said treatment, whereby the xanthoxylum is derived from the bark or berries of a prickly ash tree selected from the group consisting of Xanthoxyllum clava-herculis L. and Xanthoxylum americanum Hill
Another US patent number 5,698,206 describes treatment of varicose veins with compositions containing an effective amount of Sea Kelp, Algae Extract, Panthenol, Jojoba Oil. Calendula Oil, Marigold Extract, Chickweed Extract, Lactic Acid, Carrot Oil, Niacin, Vitamin E, White Willow Extract, Arnica Extract, Horse Chestnut Extract, Red Clover Extract, placed in a carrier oil and used in combination with a patient ingesting a moderate amount of Vitamin C The compositions can be in the form of lotion, cream, gel, or ointment Further, US patent no 7,166,570 has been granted for the use of silk in the treatment of varicose veins A method for treating varicose or spider veins comprising injecting a therapeutically effective amount of a composition comprising silk into the lumen of a varicose or spider vein has been claimed, wherein the silk induces a fibrotic response. Similarly publications US2007003489 and WO2006120469 describe foam comprising a liquid phase and a gas phase for the treatment of varicose vein Yet another US patent no 5,562,906 discloses the use of bark or berries of the species Xanthoxylum clava hercuhs 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
The flavonoidal constituents present in the extract of Euphorbia prostrata (Famil) Euphorbiaceae) are reported to have anti-inflammatory properties The phenolic compounds like ellagic and gallic acids and tannins are reported to have anti-inflammatory, haemostatic, gastro-protective and wound healing properties Other plants containing flavonoids including apigenin glycosides and luteohn glycosides are Ixora arborea (Rubiaceae), Bommena hispida (Ptendaceae), Adenocalymma alhaceum (Bignoniaceae), Thahctrum ihunbergu (Ranunculaceae), Perilla jrutescens (Labiateae), Chtysenthemum indicum, C coronarium and Matricaria chamomilla (Compositae), Thymus membranaceous (Labiateae), Digitalis lanata (Scrophulariaceae), Cuminum cyminum and Petroselmum (Umbelliferae). Several species of Euphorbia like Euphorbia minuta, Euphorbia microphylla, Euphorbia granulata (Euphorbiaceae) contain both apigenin and luteohn Ellagic acid and other phenolic acids have been reported from different species of Euphorbia The safety of various components of the Euphorbia extract has been reported in the literature Some of the reports also claim anti-mutagenic/ anti-carcinogenic/ anti-genotoxic properties of components of Euphorbia extract
The US patent no. 5,858,371 assigned to the applicants of the present invention discloses a pharmaceutical composition for the treatment of anorectal and colonic diseases comprising a pharmaceutically acceptable base and an effective amount of a flavanoid containing extract obtained from the plant Euphorbia prostate The inventors of the present invention have further researched, and have found that the novel flavonoid and phenolic compounds containing extract of Euphorbia prostrata disclosed in the present invention exhibits usefulness for the management including prevention/prophylaxis, amelioration and/or treatment of chronic venous insufficiency, particularly varicose veins Further, the extraction procedure of the disclosed Euphorbia prostrata extract in the present invention is highly cost effective and less time consuming The commercial implications of the improved and economic extraction procedure led the inventors to re-establish the pharmacological and toxicological validity of the new extract. It was surprisingly found that the Euphorbia prostrata extract prepared according to the present invention is very useful in the management of varicose veins
The present invention provides pharmaceutical compositions and methods particularly for the long-term management of varicose veins that are safe and painless to administer and have long-term effectiveness. The compositions of the present invention have improved efficacy and safety and are economical to manufacture.
SUMMARY OF THE INVENTION
An objective of the present invention is to provide composition for the management of chronic venous insufficiency particularly varicose veins comprising of an extract of the plant Euphorbia prostrata as active agent
It is also an objective of the present invention to provide composition for the management of chronic venous insufficiency particularly varicose veins comprising of an extract of the plant Euphorbia prostrata, wherein the extract comprises essentially of flavonoids and phenolic compounds
It is also an objective of the present invention to provide composition for the management of chronic venous insufficiency particularly varicose veins comprising of an extract of the plant Euphorbia prostrata, wherein the extract comprises flavonoids and phenolic compounds, and wherein the flavonoids essentially consist of apigenm-7-glycoside, 0 5 - 8% by weight, luteolin-7-glycoside, 0 05 - 6% by weight; and each of apigenin, luteohn and quercetm, 0.001 - 1% by weight, and wherein the phenolic compounds essentially consist of ellagic acid, 0 05-25% by weight, gallic acid, 0 05 - 25% by weight and tannins, 0 01 - 20% by weight, optionally with one or more excipient(s)
It is also an objective of the present invention to provide composition for the management of chronic venous insufficiency particularly varicose veins comprising of an extract of the plant Euphorbia prostrata optionally with additional therapeutic agent(s)
It is also an objective of the present invention to provide composition for the management of chronic venous insufficiency particularly varicose veins comprising of an extract of the plant Euphorbia prostrata from about 0 01% to about 99 99% by weight of the composition alongwith with one or more excipient(s) from about 0 01% to about 99 99% by weight of the composition
It is also an objective of the present invention to provide process for the preparation of an extract of the plant Euphorbia prostrata for the management of chronic venous insufficiency particularly varicose veins
It is a further objective of the present invention to provide process for the preparation of composition for the management of chronic venous insufficiency particularly varicose veins comprising an extract of the plant Euphorbia prostrata optionally with one or more excipient(s), optionally with additional therapeutic agent(s), comprising the following steps a. drying the plant Euphorbia prostrata under controlled conditions of temperature and humidity,
b. making a powder from the dried plant.
c. extracting the dry coarse powder with a polar solvent repetitively to form an extract,
d. distilling the extract,
e. washing the concentrated extract with a non-polar organic solvent, and
f. drying the washed extract to produce the desired extract capable of being used along with
one or more excipient(s)
Another objective of the present invention is to provide method of using such compositions for the management of varicose veins including prevention/prophylaxis and/or amelioration and/or treatment of such disease/disorder The compositions of the present invention are useful as a pharmaceutical product or a dietary supplement
Yet another objective of the present invention is to develop an animal model for screening efficacy of active component(s), particular!} an extract of the plant Euphorbia prostrata, in conditions like varicose veins
The compositions of the present invention comprising an extract of the plant Euphorbia prostrata possess beneficial properties to control inflammation, prevent capillary bleeding and fragility in disease(s)/disorder(s) such as chronic venous insufficiency particularl) varicose veins, and also provide long-term effectiveness and low prolapse rates of such disease(s)/disorder(s).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides composition for the management of chronic venous insufficiency particularly varicose veins comprising of an extract of the plant Euphorbia prostrata as active agent. The extract useful in the present invention comprises essentially of flavonoids and phenolic compounds. In an embodiment, the extract of the plant Euphorbia prostrata comprises flavonoids essentially consisting of apigenin-7-glycoside, 0.5 - 8% by weight, luteohn-7-glycoside, 0.05 - 6% by weight; and each of apigemn, luteohn and quercetin, 0 001 - 1% by weight; and phenolic compounds essentially consisting of ellagic acid, 0.05-25% by weight, gallic acid, 0.05 - 25% by weight and tannins, 0.01 - 20% by weight, optionally with one or more excipient(s).
In an embodiment, the present invention provides composition for the management of chronic venous insufficiency particularly varicose veins comprising of an extract of the plant Euphorbia prostrata
additionally with at least one another therapeutic agent(s) obtained from a natural, semi-synthetic or synthetic source. In another embodiment, the present invention provides novel composition for the management of chronic venous insufficiency particularly varicose veins comprising of an extract of the plant Euphorbia prostrata from about 0 01% to about 99 99% b\ weight of the composition alongwith one or more excipient(s) from about 0.01%> to about 99 99% b> weight of the composition
The compositions of the present invention can be orally administered as well as uniformly applied to the affected region It reduces inflammation, and soothes the feeling of itching and burning associated with it The invention provides relief from pain associated with varicose veins. There are no side effects from the use of the composition in a subject in need thereof particularly human beings. Further, the composition for management of such disease/disorder is not physically or psychologically unpleasant in its administration and/or application
In a preferred embodiment of the present invention, is provided a pharmaceutical composition, wherein the extract comprises preferably 2 5-3 5% by weight apigenin-7-glycoside, 0 5 1 5% by weight luteolin-7-gIycoside, 0 05 - 0 2% by weight apigenin, luteolin and quercetin, 4 - 15% by weight ellagic acid, 4 - 12% by weight gallic acid and 3 - 8% by weight tannins
The Euphorbia prostrata extract of the present invention is devoid of any substantial amount of toxic diterpene content like phorbol or ingenol esters, unlike man> other species of Euphorbia The pharmaceutical compositions of the present invention may also contain additional therapeutic agents from other plants and/or from different pharmacological groups selected from a group comprising anesthetics, vasoconstrictors, protectants, countenrntants, astringents, wound healing agents, antimicrobials, keratolyses, anticholinergics, and the like or their pharmaceutically acceptable salts, used either alone or in combinations thereof
The 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 The vasoconstrictors include but are not limited to ephednne and phenylephrine, used either alone or in combinations thereof. The amount of such vasoconstrictors may vary between 0 005% and 1 5%o by weight The protectants include but are not limited to aluminum hydroxide gel, calamine, cocoa butter, cod or shark liver oil, glycerin in aqueous solution, kaolin, lanolin, mineral oil, starch, white petroleum, wool alcohol, zinc oxide, vegetable or castor oil, polyethylene glycol and propylene glycol, used either alone or in combinations thereof The amount of such protectants may vary
between 5.0% and 88 0% by weight. The countenrntant includes but is not limited to menthol in
aqueous solution The amount of such counterirritant may vary between 0 25 - 2 5% by weight
The astringents include but are not limited to calamine, zinc oxide, hamamelis water,
bismuthresorcinol compound, bismuth subgallate, Peruvian balsam, aluminium chlorhydrox>
allantoinate, tannic acid and tannins, used either alone or in combinations thereof The amount of
such astringents may vary between 0 2% and 60 0% by weight The tannins additionally ma> be
derived from plants such as Butea monospermy Butea parviflora and Bulea frondoza (Family
Leguminosae). The wound healing agents include but are not limited to vitamin A and vitamin D
in an amount of between 0 005% and 0 04% by weight Also Peruvian balsam can be included b>
weight in an amount of between 0 5% and 2 5% by weight Also cod liver oil can be included in an
amount between 1.0% and 6 0% by weight The antimicrobial agents include but are not limited to
benzethonium chloride, benzalkonium chloride, boric acid, 8-quinolinol benzoate, secondary
amyltricresols, cetylpyridinium chloride, phenol, menthol, chlorothymol, camphor and 8-
hydroxyquinoline sulfate, used either alone or in combinations thereof The amount of such
antimicrobial agents may vary between 0.02% and 40 0% by weight The keratolyses include but
are not limited to aluminium chlorhydroxy allantoinate and resorcinol, used either alone or in
combinations thereof The amount of such keratolyses may vary between 0 2% and 3 5% by
weight. The anticholinergics include but are not limited to atropine or other solanaceous type
alkaloids, used either alone or in combination thereof The amount of such anticholinergics ma>
vary between 0 02% and 0 1% by weight
In an embodiment, the compositions for oral administration comprise about 5 500 ing of the extract of Euphorbiaprostrata, preferably about 10-300 mg along with one or more excipient(s). The composition for topical application such as cream or ointment comprises about 0 01-20% w/w, preferably 0.1 - 15% w/w of the extract of Euphorbia prostrata In an embodiment of the present invention, the method of management of varicose veins and one or more associated disease(s)/disorder(s) comprises administering an oral composition such as tablet or capsule alongwith a topical/transdermal application comprising the Euphorbia prostrata extract, as and when required. In another embodiment, the composition of the present invention may be formulated as granules in readily dispersible and effervescent form by using excipients such as sucrose, mannitol, sodium bicarbonate, citric acid, and the like, or mixtures thereof The cream comprising the extract of Euphorbia prostrata is prepared by emulsifying the aqueous phase, comprising 0.01 - 20% w/w preferably 0 1 - 15% 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 Pol)ethylene glycol ointment USNF, or as water absorbing bases such as Hydrophilic petrolatum USP. Lanolin USP, or in hydrocarbon bases such as White petrolatum USP The Euphorbia prostrata extract containing compositions may comprise either hydrophobic or hydrophilic base and includes cocoa butter, glycennated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, polyoxyethylene sorbitan fatty acid esters and polyethylene stearates, polyvinyl alcohol, polyvinyl pyrrohdone. poly aery lam ide, chemically modified starch or a combination of these materials The foam and spray bases comprises one or more of aqueous and nonaqueous solvents, propellants, surfactants, suspending agents and stabilizing agents The medicated pads comprise one or more of the following- Water, glycerin. propylene glycol, alcohol and Hamamelis water.
In another embodiment of the present invention is provided a process for the preparation of an extract of the plant Euphorbia prostrata for the management of chronic venous insufficiency particularly varicose veins
In another embodiment of the present invention is provided a process for the preparation of composition for the management of chronic venous insufficiency particularly varicose veins comprising an extract of the plant Euphorbia prostrata optionally with one or more excipient(s), optionally with additional therapeutic agent(s), comprising the following steps
a. drying the plant Euphorbia prostrata under controlled conditions of temperature and
humidity,
b. making a powder from the dried plant.
c. extracting the dry coarse powder with a polar solvent repetitively to form an extract,
d. distilling the extract,
e. washing the concentrated extract with a non-polar organic solvent, and
f. drying the washed extract to produce the desired extract capable of being used along with
one or more excipient(s).
The polar solvent useful in the present invention in the process of preparation of Euphorbia prostrata extract 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 The non-polar organic solvent used in the present invention 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 a further embodiment, is provided a process for the preparation of a composition comprising the Euphorbia prostrata extract wherein the process for the manufacture of the extract further comprises of the following steps
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 extract capable of being used along with one or
more excipient(s)
In the present invention, the medium polarity organic solvent is selected from but not limited to a group comprising ethyl acetate, ethyl methyl ketone, butanol, or in combination thereof The dehydration of the extract is preferably done by using a dehydrating agent selected from but not limited to anhydrous sodium sulphate, fused calcium chloride, potassium aluminosilicate (molecular sieves), and the like used either alone or in combination thereof Dehydration ma> be done by physical processes like gravitational or centrifugal settling, with or without changing the temperature of the extract
The compounds of the present invention are standardized to 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 agent of the present pharmaceutical compositions for the effective management of varicose veins Another unique feature of this extract of Euphorbia prostrata is that it is prepared in such a manner that the resulting composition is easilv dispersible in water due to presence of many hydrophihc compounds besides flavonoids
The pharmaceutical compositions of the present invention can be prepared by dissolving or dispersing the extract in appropriate excipient(s) such as suitable base(s)/carner(s) known to the art. The pharmaceutical composition can be formulated into different dosage forms such as oral, topical, transdermal or parenteral compositions using conventional excipients and techniques known to art. Pharmaceutical dosage forms can be capsules (hard or soft), tablets (coated or uncoated), ointments, creams, gels, foams, solutions, suspensions, medicated pad, bandage, powder, aerosols, sprays, film, flakes, modified release dosage forms (sustained release, controlled release, delayed release, prolonged release, timed release, and the like) sublingual dosage forms, wafers, caplets, parenteral dosage forms to be infiltered at the site of the injection, and the like
In a further embodiment, the composition of the present invention comprises one or more excipient(s) selected from but not limited to a group comprising of diluents, dismtegrants binders, anti-adherants, glidants, lubricants, anti-oxidants. buffering agents, colorants, flavoring agents, coating agents, solvents, viscosifymg agents, waxes, wetting agents, emulsifying agents, solubilizers, stabilizers, buffering agents, and the like, used either alone or in combination thereof
In another embodiment, the present invention provides method of using such novel compositions for the management of varicose veins including prevention/prophylaxis and/or amelioration and/or treatment of such disease/disorder Such method comprises administration of an effective composition to a subject in need thereof. The compositions of the present invention are useful as a pharmaceutical product or a dietary supplement
The present invention also provides an animal model for screening efficacy of active component(s), particularly an extract of the plant Euphorbia prostrata, in conditions like varicose veins
The compositions of the present invention comprising an extract of the plant Euphorbia prostrata possess beneficial properties to control inflammation, prevent capillary bleeding and fragility in disease(s)/disorder(s) such as chronic venous insufficiency particular!) varicose veins, and also provide long-term effectiveness and low prolapse rates of such disease(s)/disorder(s).
In another embodiment of the present invention, if the flavonoid and phenolic content of the extract obtained by the methods disclosed herein are more than the ranges specified herein, it is standardized by mixing with suitable quantities of excipient(s) such as carner(s)/base(s) upto the desirable range of the contents
Pharmacological Studies
Pharmacological study was carried out to ascertain the effect of Euphorbia prostrata extract on varicose veins. First, an animal model was developed for the study as follows Wister rats weighing between 180 to 200 g of either sex Rats were anesthetized with Thiopental sodium (25 mg/kg, 1 P ) and the four limbs were ligated on dissection board such that ventral side was facing up The hair over the thigh and femur was depurated and the exposed skin was vertically incised (7-8 mm) The tissues were tweezed apart to expose the femoral vein Femoral vein was identified by the dissection
(towards heart) and color (bluish) of the blood Following identification of femoral vein, 0 2 ml of Thrombovar 3% w/v solution was injected into it against the direction of blood flow using insulin syringe and 30 gauge needle. A blue dog clip was adhered to the site of injection m femoral vein for 1-2 minutes to prevent any leakage of the injected solutions Thereafter, the incision was closed with suture and optionally topical antibiotic solution was applied. 48 hours after the injection, animals were sacrificed with overdose of ketamine (80 mg/kg, I P) and the femoral vein (length 15-20 mm from the point of injection towards toe) was removed The visual changes such as blood clot were recorded and the vein section was stored in 10% formalin solution till further processing The section of femoral vein was stained with haemtoxin and eosm and observed under microscope to confirm the development of the model for conducting the intended study All of the isolated femoral vein segments showed presence of blood clots Femoral vein sections from control rats showed intact structure and no thrombus whereas a single administration of sodium tetradecyl sulphate into femoral vein resulted in thrombosis along the wall and middle of vein Once the model is developed, the intended amount of Euphorbia prostrata extract (calculated as mg/kg) as such or suitably formulated using a carrier/vehicle is administered by a suitable parenteral route such as I P route into the isolated femoral vein segments showing presence of blood clots and the effect is monitored. The Euphorbia prostrata extract is intended to disintegrate/dissolve the blood clots
In a further embodiment, the use of an extract of the plant Euphorbia prostrata for the preparation of a composition for the management of varicose veins is provided
The compositions of the present invention and method for treating varicose veins comprise use of a mixture of flavonoids and phenolic compounds extracted from Euphorbia prostrata plant Preferably the treatment includes administration by oral route an effective amount of composition comprising a mixture of flavonoids and phenolic compounds extracted from Euphorbia prostrata and/or local application to the varicose veins, an effective amount of composition. Examples are provided below to illustrate the various aspects of the present invention. However, they do not intend to limit the scope of the present invention
EXAMPLES
General process of manufacture of 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. Programme Traditional Medicines World Health Organization Geneva, 1991) and was dried under controlled conditions of temperature and humidity The whole plant was ground to coarse
powder The coarse powder was extracted using a polar solvent like an alkanol or acetone with or without water The extract was concentrated and washed with a non-polar solvent like a hydrocarbon or chlorinated hydrocarbon The washed extract was optionally further extracted into a medium polar solvent like ethyl acetate or ethyl meth>l ketone The final extract was optionally dehydrated with a suitable dehydrating agent and dried, either in a tra> drier or in a spray drier, milled to a powder form, sifted to the desired particle size and packed in a suitable container to protect from moisture
Example-1
The powdered drug (500 kg) was packed in a S S extractor The extraction was affected by percolation with 3000 It of 80% aqueous methanol at about 60°C The process was repeated 5 times till the drug was exhausted The aqueous-methanohc extracts were combined and concentrated by distillation The concentrated extract was washed with 5-10 volumes of hexane to remove the wax and fatty material The washed extract was dried completely for several hours at 60°C under vacuum The final extract was milled to a fine powder, sifted for uniform particle size and packed to protect from the moisture
Example-2
The powdered drug (700 kg) was packed in a S.S extractor The extraction was affected b> percolation with 4500 It. of methanol at about 60°C The process was repeated 5 times till the drug was exhausted 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 fatty material. The washed extract was dried completely for several hours at 60°C under vacuum. The final extract was milled to a fine powder, sifted for uniform particle size and packed to protect from the moisture.
ExampIe-3
The powdered drug (350 kg) was packed in a S S extractor The extraction was affected by percolation with 3000 It. of 80% aqueous acetone at about 50°C The process was repeated 5 times till the drug was exhausted. 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 fatty material. The washed extract was dried completely for several hours at 60°C under vacuum The final extract was milled to a fine powder, sifted for uniform particle size and packed to protect from the moisture.
ExampIe-4
The powdered drug (500 kg) was packed in a S.S extractor The extraction was affected by percolation with 3000 It. of 80% aqueous ethanol at about 60°C The process was repeated 5 times till the drug was exhausted 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 fatty material The washed extract was again extracted with ethyl acetate The ethyl acetate extract was dehydrated with anhydrous sodium sulphate and concentrated by distillation The concentrated extract was dried completely for several hours at 60°C under vacuum The final purified extract was milled to a fine powder, sifted for uniform particle size and packed to protect from the moisture
Example-5
The powdered drug (500 kg) was boiled with 2500 It of DM water for 4 hours The aqueous extract was filtered and residue was again boiled with 1500 It of DM water for 2 hours and filtered. The pooled filtered extracts were concentrated using a falling film evaporator and then further dried completely for several hours at 60°C under vacuum The final purified extract was milled to a fine powder, sifted for uniform particle size and packed to protect from the moisture
Process of evaluation of the Extract
The extract of Euphorbia prostrata of the above-mentioned examples was characterized b\ High Performance Liquid Chromatography (HPLC) The HPLC was performed under following conditions and using Waters system equipped with M510 pumps and data station with Millenium software
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
Time (minutes) Mobile Phase'A'% Mobile Phase'B'% Comments
0 90 10 Equilibration
0-2 90 10 Isocratic
2-30 65 35 Linear Gradient
30-35 65 35 Isocratic
35-40 90 10 Linear Gradient
40-45 90 10 Isocratic
Column: Ci8 (250X4.6 mm/5 µM) Flow Rate: 1 ml/min Detector: UV absorbance at 335 nm
The HPLC chromatogram showed a number of peaks, the major ones corresponding to gallic acid, ellagic acid, luteolin glucoside and apigenin glucoside The two peaks corresponding to the flavonoid components luteolin glucoside and apigenin glucoside were used as the chemical and pharmacological marker for quantitation of the product A sum of the two peaks was calculated corresponding to standard apigenin glucoside and the measure was expressed as the Total Flavonoids
Example-6
S.No. Ingredient mg/capsule
1. Euphorbia prostrata extract 100
2. Microcrystalline cellulose 200 8
3. Mannitol 72
4. Talc 3 2
5. Sodium starch glycollate 12
6. Colloidal silicon dioxide 12 Procedure:
i) Euphorbia prostrata extract, microcrystalline cellulose and mannitol were sifted and
mixed together ii) Talc, sodium starch glycollate and colloidal silicon dioxide were passed through fine
sieves individually and then mixed together iii) The materials of step (i) and (n) were mixed iv) The material of step (iii) was filled into empt) hard gelatin capsules at an average fill
weight of 400 mg ± 2% v) The filled capsules were packed in air-tight packages
Example-7
S.No. Ingredient mg/capsule
1. Euphorbia prostrata extract 100
2. Microcrystalline cellulose 150
3. Mannitol 65
4. Lactose 50
5. Talc 3
6. Sodium starch glycollate 17
7. Colloidal silicon dioxide 15
Procedure:
i) Euphorbia prostrata extract, microcrystalline cellulose, lactose and mannitol were sifted
and mixed together ii) Talc, sodium starch glycollate and colloidal silicon dioxide were passed through fine
sieves individually and then mixed together iii) The materials of step (1) and (u) were mixed iv) The material of step (in) was filled into empty hard gelatin capsules v) The filled capsules were packed in air-tight packages
Example-8
S.No. Ingredient mg/capsule
1. Euphorbia prostrata extract 100
2. Microcrystalline cellulose 50
3. Mannitol 65
4. Lactose 150 5 Talc 3

6. Sodium starch glycollate 17
7. Colloidal silicon dioxide 15 Procedure:
i) Euphorbia prostrata extract, microcrystalline cellulose, lactose and mannitol were sifted
and mixed together ii) Talc, sodium starch glycollate and colloidal silicon dioxide were passed through fine
sieves individually and then mixed together iii) The materials of step (I) and (ii) were mixed iv) The material of step (in) was filled into empty hard gelatin capsules at an average fill
weight of400mg± 2% v) The filled capsules were packed in air-tight packages
Example-9
S.No. Ingredient mg/tablet
1 Euphorbia prostrata extract 100
2. Microcrystalline cellulose 120
3. Mannitol 80
4. Croscarmellose sodium 10
5. Lactose 66
6. Talc 4
7. Colloidal silicon dioxide 10
8. Croscarmellose sodium 10 Procedure:
i) Euphorbia prostrata extract, microcrystalline cellulose, mannitol, croscarmellose sodium
and lactose were sifted and mixed together, ii) The material of step (i) was compacted lii) The compacts of step (n) were passed through sieve and mixed iv) Talc, colloidal silicon dioxide and croscarmellose sodium were passed through fine sieve
and mixed together, v) The material of step (in) was mixed with material of step (iv)
vi) The material of step (v) was compressed into tablets at an average weight of 400 mg ± 2% vii) The tablets were packed in air-tight packages
Example-10
S.No. Ingredient mg/tablet
Core tablet composition
1. Euphorbia prostrata extract 100
2. Microcrystalline cellulose 120
3. Mannitol 80
4. Croscarmellose sodium 10
5. Lactose 66
6. Talc 4
7. Colloidal silicon dioxide 10
8. Croscarmellose sodium 10 Film coating composition
9. Hydroxypropyl methylcellulose (E-15) 12
10. Polyethylene glycol 400 (PEG 400) 2 4
11. Iron oxide red 0 75
12. Iron oxide yellow 0 50
13. Titanium dioxide 0 25
14. Isopropyl alcohol q s (lost in processing)
15. Dichloromefhane q s (lost in processing)
Procedure:
i) Euphorbiaprostrata extract, microcrystalline cellulose, mannitol, croscarmellose sodium
and lactose were sifted and mixed together, ii) The material of step (i) was compacted iii) The compacts of step (ii) were passed through sieve and mixed iv) Talc, colloidal silicon dioxide and croscarmellose sodium were passed through fine sieve
and mixed together v) The material of step (ui) was mixed with material of step (iv)
vi) The material of step (v) was compressed into tablets at an average weight of 400 mg ± 2% vii) Hydroxypropyl methylcellulose was dispersed in a mixture of isoprop>l alcohol and
dichloromethane with continuous mixing in homogenizer viii) PEG 400 was added to the above solution of step (vn) and mixed ix) Iron oxide red, iron oxide yellow and titanium dioxide were passed through fine sieve and
mixed, x) The material of step (ix) was added to material of step (viii) and mixed for 30 minutes xi) The core tablets were charged into the coating pan and coated with the coating solution of
step (x) till an average tablet weight gain of -3% was achieved xii) The tablets were dried and packed in air-tight packages
Example-ll
S.No. Ingredient mg/gm
1 Euphorbia prostrata extract 10
2. Propylene glycol 50
3. Titanium dioxide 10
4. Stearic acid 130
5. Cetyl alcohol 10
6. Isopropyl mynstate 60
7. Sorbitan stearate 20
8. Methyl paraben 1.5
9. Propyl paraben 0 3
10. Corn oil 50
11. Glycerin 50
12. Sorbitol solution 30
13. VeegumHV 10
14 Sodium CMC 3
15. Tween80 15
16. Purified water q.s Procedure:
i) Euphorbiaprostrata extract, methyl paraben and propyl paraben were dissolved in propylene
glycol; the mixture heated to 55-60°C, titanium dioxide was added to it and stirred well ii) Stearic acid, cetyl alcohol, isopropyl mynstate. sorbitan stearate, and corn oil were heated
to 70°-75°C iii) In another vessel, sorbitol solution and Tween 80 were taken iv) Veegum HV was separately hydrated in the water
v) Sodium carboxymethyl cellulose (sodium CMC) was separately h>drated in ghcerin vi) The material of step (iv) and step (v) were added to the material of step 3 and heated to
70°-75°C vii) The material of step (u) and step (vi) were mixed and cooled viii) When the material of step (vii) attained a temperature of 50°-55°C, the material of step (i)
was added to it. ix) The mixture was allowed to cool to room temperature to obtain the cream
Exaraple-12
S.No. Ingredient mg/gm
1. Euphorbia prostrata extract 10 0
2. Propylene glycol 50 0
3. Titanium dioxide 10 0
4. Hard paraffin 60 0
5. Liquid paraffin 10 0
6. Isopropyl mynstate 30 0
7. Span 60 20 0
8. Methyl paraben 1 5
9. Propyl paraben 0 3
10. Corn Oil 20 0
11. Glycerin 80 0
12. Sorbitol solution 50 0
13. Veegum HV 20 0
14. Tween 80 15 0
15. Purified water q s
Procedure:
i) Euphorbia prostrata extract, meth\l paraben and propyl paraben were dissolved in
propylene glycol, the mixture heated to 55-60°C. titanium dioxide was added to it and
stirred well ii) Hard paraffin, liquid paraffin, isopropyl mynstate, Span 60, and Corn Oil were heated to
70°-75°C. iii) Veegum HV was hydrated in purified water, glycerin, Tween 80, and sorbitol was added
to it, and the mixture was heated to 70°-75°C iv) The material of step (ii) was added to the material of step (in) with stirring and the mixture
was allowed to cool to 55°-60°C v) The material of step (1) was added to the material of step (iv), stirred, and allowed to cool
to room temperature to obtain the cream
Example-13
S.No. Ingredient mg/gm
1. Euphorbia prostrata extract 10 0
2. Propylene glycol 50 0
3. Titanium dioxide 10 0
4. Stearic acid 70 0
5. Simethicone 1 0
6. Glyceryl monostearate 60 0
7. Cetosteryl alcohol 20.0
8. Cetyl alcohol 10 0
9. Sorbitan stearate 20 0
10. Methyl paraben 1 5
11. Propyl paraben 0 3
12. Glycerin 50 0
13. Sorbitol 30.0
14. Tween 80 15 0
15. Xanthangum 10 0
16. Purified water q s
Procedure:
i) Euphorbia prostrata extract, methyl paraben and propyl paraben were dissolved in
propylene glycol; titanium dioxide was added to it and stirred well ii) Stearic acid, simethicone, glyceryl monostearate, cetosteryl alcohol, cetyl alcohol, and
sorbitan stearate were heated to 70°-75°C iii) Glycerin, sorbitol, Tween 80 and purified water were heated to 70°-75°C iv) Xanthum gum was dispersed in glycerin and added to the material of step (in) v) The material of step (ii) was added to the material of step (iv) and allowed to cool vi) The material of step (1) was added to the material of step (v) and allowed to cool to room
temperature to obtain the cream

We claim:
1. A composition for the management of chronic venous insufficiency particularly varicose veins comprising of an extract of the plant Euphorbia prostrata as active agent from about 0.01% to about 99.99% by weight of the composition, optionally alongvvith one or more excipient(s) from about 0.01% to about 99.99% by weight of the composition and optionally additional therapeutic agent(s), wherein the extract comprises flavonoids and phenolic compounds, and wherein the flavonoids are apigenin-7-glycoside, 0.5 - 8% by weight; luteolin-7-gIycoside, 0.05 - 6% by weight; and each of apigenin, luteolin and quercetin, 0.001 1% by weight; and wherein the phenolic compounds are ellagic acid. 0.05-25%) by weight; gallic acid. 0.05 - 25% by weight and tannins, 0.01 - 20% by weight.
2. A composition according to claim 1, wherein the extract comprises apigenin-7-glycoside, 2.5 - 3.5% by weight; luteolin-7-glycoside, 0.5 1.5% by weight; apigenin. luteolin and quercetin, 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. A composition according to claim 1, wherein the additional therapeutic agent is selected from a group comprising anesthetics, vasoconstrictors, protectants, counterirritants, astringents, wound healing agents, antimicrobials, keratolytics. anticholinergics, or their pharmaceutically acceptable salts, used either alone or in combinations thereof.
4. A process for the preparation of composition according to claim I, optionally with one or more excipient(s), and with additional therapeutic agent(s). comprising of the following steps:
a. drying the plant Euphorbia prostrata under controlled conditions of temperature and humidity.
b. making a powder from the dried plant,
c. extracting the dry coarse powder with a polar solvent repetitively to form an extract,
d. distilling the extract,
e. washing the concentrated extract with a non-polar organic solvent, and
f. drying the washed extract to produce the desired extract capable of being used along
with one or more excipient(s).
5. A process according to claim 3, wherein the polar solvent useful in the process of
preparation of Euphorbia prostrata extract is selected from a group comprising acetone,
methanol, ethanol, isopropanol, water, used either alone or in combination thereof.
6. A process according to claim 3, wherein the non-polar solvent useful in the process of
preparation of Euphorbia prostrata extract is selected from a group comprising pentane.
hexane, heptane, petroleum ether, chloroform, dichloromethane. dichloroethane. used either
alone or in combination thereof.
7. A process for the preparation of a composition comprising the Euphorbia prostrata extract
according to claim 1, wherein the process for the manufacture of the extract further
comprises of the following steps:
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 extract capable of being used along with one
or more excipient(s).
8. A process according to claim 7, wherein the medium polarity organic solvent is selected from a group comprising ethyl acetate, ethyl methyl ketone, butanol, used either alone or in combination thereof.
9. A composition according to claim 1, wherein the pharmaceutically acceptable excipients are selected from a group comprising of diluents, disintegrants, binders, anti-adherants, glidants, lubricants, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, solvents, viscosifying agents, waxes, wetting agents, emulsifying agents, solubilizers, stabilizers, buffering agents, used either alone or in combination thereof.
10. An animal model for screening efficacy of active component(s) according to claim 1. particularly an extract of the plant Euphorbia prostrata, in conditions like varicose veins.
11. The pharmaceutical compositions and process for the preparation of pharmaceutical compositions substantially as herein described and illustrated by the examples.