DESC:FIELD OF THE INVENTION

The present invention provides a suppository composition comprising Euphorbia Prostrata and one or more pharmaceutically acceptable excipients, wherein said composition is suitable for the treatment of haemorrhoids, haemorrhoids during pregnancy, anal fissures, anal fistula, and varicose veins. Further, the present invention also relates to the process of preparation of said composition.

BACKGROUND OF THE INVENTION

Euphorbia Prostrata is a small, prostrate, annual green herb widely distributed globally and used as anti-haemorrhoidal, anti-inflammatory, analgesic, hypolipidemic, antidiabetic, antidiarrheal, anti-asthmatic, and for various skin diseases. Among the various anorectal and colonic diseases, haemorrhoids occupy a prominent position and has been the subject of numerous clinical studies. Haemorrhoidal disease is characterized by bleeding, without any pain. Fresh blood spots occur immediately, on defecation. However, pain occurs when the haemorrhoids are secondarily infected, or complicated by thrombosis and anal fissures. There exist several procedures for the treatment of haemorrhoids.

Various topical and oral dosages form are known for promoting healing and for relieving the discomfort caused by diseases of the anus. However, a location of the ailment within the anal/rectal canal and the complex physiology of the anorectal region presents several unique problems in terms of physically distributing medication to the injured area and for maintaining a suitable concentration of the medication for the required treatment time.

A simple application of medication in the form of topical cream/gel/ointment into the anal/rectal canal is generally inadequate and is an unsuccessful method of therapy because the medication is too quickly dissipated from the treated area. Such application is also aesthetically and hygienically undesirable. The most popular method of applying medication within the anal canal is from a transportive medium capable of dispensing the medication uniformly to the region of the anal canal for a predetermined period of time.

Therefore, there is a strong need felt in the art to develop a composition of Euphorbia Prostrata which is retained in the affected area for sufficient time and release the drug locally. The local release of drug is helpful in treatment of haemorrhoids in particular, haemorrhoids during pregnancy, anal fissures, anal fistula, and varicose veins. The present invention provides a suppository composition comprising Euphorbia Prostrata that provides effective and safe amounts of Euphorbia Prostrata at specific site of action. The suppository compositions of the invention may further comprise one or more active agent.

OBJECTIVE OF THE INVENTION

Main objective of the present invention is to provide a suppository composition comprising Euphorbia Prostrata, and one or more pharmaceutically acceptable excipients.

Another objective of the present invention is to provide a suppository composition comprising Euphorbia Prostrata, and one or more pharmaceutically acceptable excipients.

Another objective of the present invention is to provide a process for the preparation of the suppository composition comprising Euphorbia Prostrata.

Another objective of the present invention is to provide a suppository composition comprising Euphorbia Prostrata with increased safety and efficacy.

Another objective of the present invention is to provide a method for preparation of suppository composition comprising Euphorbia Prostrata, wherein Euphorbia Prostrata has a controlled particle size that provides safe & effective amount of Euphorbia Prostrata at site of action.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a suppository composition comprising a therapeutically effective amount of Euphorbia Prostrata; and one or more pharmaceutically acceptable excipients.

The one aspect of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of Euphorbia Prostrata and Lidocaine, wherein the pharmaceutical composition is administered in the form of suppository.

Another aspect, of the present invention is to provide a suppository composition comprising a therapeutically effective amount of Euphorbia Prostrata, Lidocaine and one or more pharmaceutically acceptable excipients.

Another aspect, of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of Euphorbia Prostrata, Lidocaine, Phenylephrine and one more pharmaceutically acceptable excipient.

Another aspect, of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of Euphorbia Prostrata, Lidocaine, Phenylephrine and one more pharmaceutically acceptable excipient, wherein the pharmaceutical composition is administered in the form of suppository.

Another aspect, of the present invention is to provide a pharmaceutical combination comprising a therapeutically effective amount of Euphorbia Prostrata, Lidocaine and one or more anesthetics agents, wherein the pharmaceutical combination is administered in the form of suppository.

Another aspect, of the present invention is to provide a pharmaceutical combination comprising a therapeutically effective amount of Euphorbia Prostrata, Lidocaine and Phenylephrine, wherein the pharmaceutical combination is administered in the form of suppository.

Another aspect, of the present invention is to provide a suppository composition comprising a therapeutically effective amount of Euphorbia Prostrata, Lidocaine, optionally one or more additional pharmaceutical active agents and one or more pharmaceutically acceptable excipients.

Another aspect, of the present invention is to provide a suppository composition comprising a therapeutically effective amount of Euphorbia Prostrata, Lidocaine, optionally one or more anesthetics agents and one or more pharmaceutically acceptable excipients.

Another aspect, of the present invention is to provide a suppository composition comprising a therapeutically effective amount of Euphorbia Prostrata, Lidocaine, optionally Phenylephrine and one or more pharmaceutically acceptable excipients.

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

Another aspect, of the present invention is to provide a suppository composition comprising dry extract of Euphorbia Prostrata, wherein the Euphorbia Prostrata is having a particle size of d10 not more than 50 µm; d50 not more than 150 µm and/or d90 is not more than 250 µm.

Another aspect, of the present invention is to provide a suppository composition comprising Euphorbia Prostrata, wherein the Euphorbia Prostrata is having a particle size of d10 not more than 50 µm, d50 not more than 150 µm and/or d90 is not more than 250 µm.

Another aspect, of the present invention is to provide a suppository composition comprising a therapeutically effective amount of Euphorbia Prostrata, one or more pharmaceutically acceptable excipients, and optionally one or more additional pharmaceutically active agents, wherein the composition is effective for the treatment of anal fissures, anal fistula, varicose veins, haemorrhoids including haemorrhoids during pregnancy.

Another aspect, of the present invention is to provide a suppository composition comprising a therapeutically effective amount of Euphorbia Prostrata, one or more pharmaceutically acceptable excipients, wherein the composition is administered at least once daily for 14 days for the treatment of haemorrhoids during pregnancy.

Another aspect, of the present invention is to provide a suppository composition comprising a therapeutically effective amount of Euphorbia Prostrata, one or more pharmaceutically acceptable excipients, wherein the composition is administered at least twice daily and after each act of defecation for 14 days for the treatment of haemorrhoids during pregnancy.

Another aspect, of the present invention is to provide a suppository composition comprising a therapeutically effective amount of Euphorbia Prostrata, one or more pharmaceutically acceptable excipients, wherein the composition is administered at least twice daily for 3 months for the treatment of varicose veins.

Another aspect, of the present invention is to provide a suppository composition comprising a therapeutically effective amount of Euphorbia Prostrata, optionally one or more additional pharmaceutically active agents; and one or more pharmaceutically acceptable excipients, wherein the composition is administered at least twice daily and after each act of defecation for 6 weeks for the treatment of anal fissures or anal fistula.

Another aspect, of the present invention is to provide a suppository composition comprising a therapeutically effective amount of Euphorbia Prostrata, lidocaine and one or more pharmaceutically acceptable excipients, wherein the composition is administered at least twice daily and after each act of defecation for 6 weeks for the treatment of anal fissures or anal fistula.

Another aspect, of the present invention is to provide a suppository composition comprising a therapeutically effective amount of Euphorbia Prostrata, Lidocaine, Phenylephrine and one or more pharmaceutically acceptable excipients, wherein the composition is administered at least twice daily and after each act of defecation for 6 weeks for the treatment of anal fissures or anal fistula.

Another aspect, of the present invention is to provide a suppository composition comprising about 5% w/w of Euphorbia Prostrata; about 10% w/w of liquid paraffin, about 5% w/w of PEG 100 stearate, about 40% w/w of cocoa butter, about 40% w/w of hard fat; optionally one or more pharmaceutically acceptable excipients, wherein the composition is effective for the treatment of anal fissures or anal fistula.

Another aspect, of the present invention is to provide a suppository composition comprising about 5% w/w of Euphorbia Prostrata, about 2% w/w of Lidocaine, about 8% w/w of liquid paraffin, about 5% w/w of PEG 100 stearate, about 40% w/w of cocoa butter, about 40% w/w of hard fat, optionally one or more pharmaceutically acceptable excipients, wherein the composition is administered at least twice daily and after each act of defecation for 6 weeks for the treatment of anal fissures or anal fistula.

Another aspect, of the present invention is to provide a suppository composition comprising about 5% w/w of Euphorbia Prostrata, about 2% w/w of lidocaine, about 0.25% w/w of Phenylephrine , about 7.75% w/w of liquid paraffin, about 5% w/w of PEG 100 stearate, about 40% w/w of cocoa butter, about 40% w/w of hard fat, optionally one or more pharmaceutically acceptable excipients, wherein the composition is administered at least twice daily and after each act of defecation for 6 weeks for the treatment of anal fissures or anal fistula.

Another aspect, of the present invention is to provide a pharmaceutical combination comprising:
a suppository composition comprising Euphorbia Prostrata and one or more pharmaceutically acceptable excipients, and
an oral composition comprising Euphorbia Prostrata and one or more pharmaceutically acceptable excipients.

Another aspect, of the present invention is to provide a suppository composition comprising Euphorbia Prostrata and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are selected from the group comprising suppository base, emulsifiers, sucrose fatty acid esters, stabilizers, isotonic agents, viscosity-adjusting agents, preservatives, chelating agents, antioxidants, buffering agents or combinations thereof.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objectives and advantages of the inventions will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a suppository composition comprising a therapeutically effective amount of Euphorbia Prostrata and one or more pharmaceutically acceptable excipients.

As used in this specification, the singular forms “a”, “an”, and “the” include plural references unless the context dictates otherwise. Thus, for example, a reference to “a method” or “a process” includes one or more methods, one or more processes, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

As used herein the term “about” in reference to a numerical value means that variations of 10% above or below the numerical value are within the range ascribed to the specified value.

As used herein the term “Euphorbia Prostrata”, “extract of Euphorbia Prostrata”, “pure extract of Euphorbia Prostrata” as used herein synonymously include the Extract obtained from the plant Euphorbia Prostrata.

The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug (e.g., Euphorbia Prostrata), which is sufficient to elicit an appreciable biological response when administered to the patient. It will be appreciated that the precise therapeutic dose will depend on the age and condition of the patient, the nature of the condition to be treated and will be at the ultimate discretion of the attendant physician.

The term “formulation” or “pharmaceutical formulation” or “suppository composition” “pharmaceutical formulation” or “dosage form” or “pharmaceutical formulation” or “formulation” as used herein synonymously include the pharmaceutical formulations, which is in the form of suppository.

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

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

In an embodiment, the present invention provides a suppository composition comprising about 0.1% w/w to about 30% w/w of Euphorbia prostrata, about 1% w/w to about 30% w/w of emollient and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provide a suppository composition comprising a therapeutically effective amount of Euphorbia Prostrata one or more one or more anesthetics agents and one or more pharmaceutically acceptable excipients; wherein the one or more anesthetics agent is selected from the group comprising procaine, amethocaine, cocaine, benzocaine, tetracaine, lidocaine, phenylephrine , prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, etidocaine, desflurane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, xenon, benzyl alcohol, ethanol, ketamine, thiopental, propofol, fentanyl, remifentanil, midazolam, one or more opioids and combinations thereof.

According to another embodiment, the present invention provides a suppository composition comprising extract of Euphorbia prostrata and one or more pharmaceutically acceptable excipients, wherein the composition is used for the treatment of anal fissures, anal fistula, varicose veins, haemorrhoids including haemorrhoids during pregnancy.

According to another embodiment, the present invention provides a suppository composition comprising about 0.1% w/w to about 30% w/w of Euphorbia prostrata, about 1% w/w to about 30% w/w of emollient, about 1% w/w to about 20% w/w of emulsifier and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a suppository composition comprising about 1% w/w to about 10% w/w of Euphorbia prostrata, about 5% w/w to about 25% w/w of emollient, about 2% w/w to about 10% w/w of emulsifier, about 5% w/w to about 99% w/w of suppository base and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a suppository composition comprising about 1% w/w to about 10% w/w of Euphorbia prostrata, about 0.5% w/w to about 10% w/w of Lidocaine, about 1% w/w to about 20% w/w of emollient and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a suppository composition comprising about 1% w/w to about 10% w/w of Euphorbia prostrata, about 0.5% w/w to about 10% w/w of Lidocaine, about 1% w/w to about 20% w/w of emollient, about 1% w/w to about 10% w/w of emulsifier and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a suppository composition comprising about 1% w/w to about 10% w/w of Euphorbia prostrata, about 0.5% w/w to about 10% w/w of Lidocaine, about 1% w/w to about 20% w/w of emollient, about 1% w/w to about 10% w/w of emulsifier, about 5% w/w to about 90% w/w of suppository base and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a suppository composition comprising about 1% w/w to about 10% w/w of Euphorbia prostrata, about 0.01% w/w to about 5% w/w of phenylephrine, about 05% w/w to about 10% w/w of lidocaine, about 1% w/w to about 10% w/w of emollient and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a suppository composition comprising about 1% w/w to about 10% w/w of Euphorbia prostrata, about 0.01% w/w to about 5% w/w of phenylephrine, about 0.5% w/w to about 10% w/w of lidocaine, about 1% w/w to about 10% w/w of emollient, about 1% w/w to about 10% w/w of emulsifier and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provide a suppository composition comprising about 1% w/w to about 10% w/w of Euphorbia prostrata, about 0.5% w/w to about 10% w/w of Lidocaine , about 0.01% w/w to about 5% w/w of Phenylephrine , about 1% w/w to about 10% w/w of emollient, about 1% w/w to about 10% w/w of emulsifier, about 5% w/w to about 90% w/w of suppository base and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a suppository composition comprising about 1% w/w to about 10% w/w of Euphorbia prostrata, about 5% w/w to about 25% w/w of liquid paraffin and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a suppository composition comprising about 1% w/w to about 10% w/w of Euphorbia prostrata, about 5% w/w to about 25% w/w of liquid paraffin, about 2% w/w to about 10% w/w of PEG 100 Stearate and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a suppository composition comprising about 0.1% w/w to about 30% w/w of Euphorbia prostrata, about 5% w/w to about 25% w/w of liquid paraffin, about 2% w/w to about 10% w/w of PEG 100 Stearate, about 5% w/w to about 99% w/w of suppository base selected from the group comprising cocoa butter, hard fat or combinations thereof and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a suppository composition comprising about 0.1% w/w to about 30% w/w of Euphorbia prostrata, about 0.5% w/w to about 10% w/w of Lidocaine, about 1% w/w to about 30% w/w of liquid paraffin and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a suppository composition comprising about 0.1% w/w to about 30% w/w of Euphorbia prostrata, about 0.5% w/w to about 10% w/w of Lidocaine, about 1% w/w to about 30% w/w of liquid paraffin, about 1% w/w to about 20% w/w of PEG 100 Stearate and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provide a suppository composition comprising about 0.1% w/w to about 30% w/w of Euphorbia prostrata, about 0.5% w/w to about 10% w/w of Lidocaine , about 1% w/w to about 30% w/w of liquid paraffin, about 1% w/w to about 20% w/w of PEG 100 Stearate, about 5% w/w to about 90% w/w of suppository base selected from the group comprising Cocoa butter, Hard Fat or combinations thereof and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a suppository composition comprising about 0.1% w/w to about 30% w/w of Euphorbia prostrata, about 0.5% w/w to about 10% w/w of Lidocaine, about 0.01% w/w to about 5% w/w of Phenylephrine, about 1% w/w to about 30% w/w of Liquid paraffin and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a suppository composition comprising about 0.1% w/w to about 30% w/w of Euphorbia prostrata, about 0.5% w/w to about 10% w/w of Lidocaine, about 0.01% w/w to about 5% w/w of Phenylephrine, about 1% w/w to about 30% w/w of Liquid paraffin, about 1% w/w to about 20% w/w of PEG 100 Stearate and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a suppository composition comprising about 0.1% w/w to about 30% w/w of Euphorbia prostrata, about 0.5% w/w to about 10% w/w of Lidocaine, about 0.01% w/w to about 5% w/w of Phenylephrine , about 1% w/w to about 30% w/w of Liquid paraffin, about 1% w/w to about 20% w/w of PEG 100 Stearate, about 5% w/w to about 90% w/w of suppository base selected from the group comprising Cocoa butter, Hard Fat or combinations thereof and one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a suppository composition comprising Euphorbia Prostrata, wherein the suppository is in the shape of conical, cylindrical or globular.

According to another embodiment, the present invention provides a suppository composition comprising Euphorbia prostrata characterised in that the composition comprises from 0.1 to 10g based upon the weight of the suppository composition.

According to another embodiment, the present invention provides a suppository composition comprising Euphorbia prostrata characterised in that the composition comprises from 1 to 5g based upon the weight of the suppository composition.

According to another embodiment, the present invention provides a suppository composition comprising Euphorbia prostrata characterised in that the composition comprises 2g based upon the weight of the suppository composition.

According to another embodiment, the present invention provides a suppository composition comprising Euphorbia Prostrata, wherein the composition is suitable for administration through rectum, vagina, or urethra route.

According to another embodiment, the present invention provides a suppository composition comprising Euphorbia Prostrata, wherein a suppository designed for use as a rectal suppository wherein the suppository is having a length in the range from about 1-7 cm and diameter of about 0.1 to 2 cm.

According to another embodiment, the present invention provides a suppository composition comprising Euphorbia Prostrata, wherein the euphorbia prostrata is dispersed or dissolved in the suitable base.

According to another embodiment, the dosing schedules for the synergistic pharmaceutical combination are as follows:
The suppository composition is administered at least twice daily and after each act of defecation for 14 days, and the oral composition is administered once daily for 14 days, for the treatment of haemorrhoids including haemorrhoids during pregnancy.
The suppository composition is administered at least twice daily for 3 months and the oral composition is administered as one tablet twice daily for first month followed by one tablet once or twice daily for next 3 months, for the treatment of varicose veins.
The suppository composition is administered at least twice daily and after each act of defecation for 6 weeks, and the oral composition is administered as one tablet twice daily for six weeks, for the treatment of anal fissures.
The suppository composition is administered at least twice daily and after each act of defecation for 8 weeks, and the oral composition is provided as one tablet twice daily for 8 weeks, for the treatment of anal fistula.

According to another embodiment, the suppository composition and the oral composition are to be administered sequentially in any order with or without a time gap.

According to another embodiment, the present invention provides a synergistic pharmaceutical combination comprising:
suppository composition comprising Euphorbia Prostrata, and one or more pharmaceutically acceptable excipients; and
an oral composition comprising 100 mg dry extract of Euphorbia Prostrata, and one or more pharmaceutically acceptable excipient; wherein the combination is effective in the treatment of anal fissures, anal fistula, varicose veins, haemorrhoids including haemorrhoids during pregnancy.

According to another embodiment, the present invention provides a synergistic pharmaceutical combination comprising:
suppository composition comprising Euphorbia Prostrata, and one or more pharmaceutically acceptable excipients, and
an oral composition comprising 100 mg dry extract of Euphorbia Prostrata, 500 mg calcium dobesilate, and one or more pharmaceutically acceptable excipient,
wherein the suppository composition is administered at least twice daily for 3 months and the oral composition is administered as one tablet twice daily for first month followed by one tablet once or twice daily for next 2 months, for the treatment of varicose veins.

According to another embodiment, the present invention provides a synergistic pharmaceutical combination comprising:
suppository composition comprising Euphorbia Prostrata; about 2%w/w lidocaine, optionally one or more pharmaceutically active agents, and one or more pharmaceutically acceptable excipients, and
an oral composition comprising 100 mg dry extract of Euphorbia Prostrata, 500 mg calcium dobesilate, and one or more pharmaceutically acceptable excipient,
wherein the suppository composition is administered at least twice daily and after each act of defecation for 6 weeks, and the oral composition is administered as one tablet twice daily for six weeks, for the treatment of anal fissures.

According to another embodiment, the present invention provides a synergistic pharmaceutical combination comprising:
suppository composition comprising Euphorbia Prostrata; about 2%w/w lidocaine, optionally one or more pharmaceutically active agents, and one or more pharmaceutically acceptable excipients, and
an oral composition comprising 100 mg dry extract of Euphorbia Prostrata, 500 mg calcium dobesilate, and one or more pharmaceutically acceptable excipient,
wherein the suppository composition is administered at least twice daily and after each act of defecation for 8 weeks, and the oral composition is administered as one tablet twice daily for 8 weeks, for the treatment of anal fistula.

According to another embodiment, the present invention provides a synergistic pharmaceutical combination comprising:
a. suppository composition comprising Euphorbia Prostrata; about 2%w/w lidocaine; about 0.25% w/w of phenylephrine; optionally one or more pharmaceutically active agents, and one or more pharmaceutically acceptable excipients, and
b. an oral composition comprising 100 mg dry extract of Euphorbia Prostrata, 500 mg calcium dobesilate, and one or more pharmaceutically acceptable excipient,
wherein the suppository composition is administered at least twice daily and after each act of defecation for 6 weeks, and the oral composition is administered as one tablet twice daily for six weeks, for the treatment of anal fissures.

According to another embodiment, the present invention provides a synergistic pharmaceutical combination comprising:
a. suppository composition comprising Euphorbia Prostrata; about 2%w/w lidocaine; about 0.25% w/w of phenylephrine; optionally one or more pharmaceutically active agents, and one or more pharmaceutically acceptable excipients, and
b. an oral composition comprising 100 mg dry extract of Euphorbia Prostrata, 500 mg calcium dobesilate, and one or more pharmaceutically acceptable excipient,
wherein the suppository composition is administered at least twice daily and after each act of defecation for 8 weeks, and the oral composition is administered as one tablet twice daily for 8 weeks, for the treatment of anal fistula.

According to another embodiment, the present invention provides a suppository composition, wherein the said composition completely disintegrates within 60 minutes after administration.

According to another embodiment, the present invention provides a suppository composition, wherein the said composition completely disintegrates within 30 minutes after administration.

According to another embodiment, the present invention provides a suppository composition comprising euphorbia prostrata and one or more pharmaceutically active excipients, wherein the one or more pharmaceutically active excipients are selected from the group comprising suppository base, emulsifiers, sucrose fatty acid esters, stabilizers, isotonic agents, viscosity-adjusting agents, preservatives, chelating agents, antioxidants, buffering agents or combinations thereof.

Suitable suppository base/ emollient includes, without limitation, cocoa butter, Hard fat, palm oil, coconut oil, lard; waxes, such as lanolin and vasoline, fatty acids, such as, oleic, stearic, and lauric acids, polyethylene glycols or mixtures of mono, di, and triglycerides of fatty acids of C10 to C20 chain length.

Suitable fatty base includes, without limitation, olive oil, soyabean oil, vegetable oil, hydrogenated castor oil, other hydrogenated fatty acids, petrolatum, various forms of paraffin, liquid paraffin, stearic acid and oleic acid, polyethylene glycol 1,000-8,000; cocoa butter, NF (fat obtained from the roasted seed of Theobroma cacao); Suppocire AI, A, B, C, D, AS2, BS2, AT, AS2X, BS2X, CS2X (Semi-synthetic glycerides- Multipurpose vehicles), Suppocire AIM, AM, BM, BCM, CM, DM (Semi-synthetic glycerides- Low Reactivity Vehicles), Suppocire AIML, AML, BML (Semi-synthetic glycerides- Low Reactivity Vehicles Compatible With Large Amounts Of Powders), Suppocire AP, BP, CP, DP (Saturated polyglycolysed glycerides- Absorption Enhancers), Suppocire NA0, NAI10, NA10, NAS10, NA15, NAIS10, NCS10 (Semi-synthetic glycerides- Low Reactivity Vehicles), Suppocire NAI, NAI 25A, NA 35, NAI50, NA50, NAS40, NAS50, NAS55, NAIS90, (Semi-synthetic glycerides- Large Scale Production Vehicles), Suppocire NAI 25, NA, NB, NC, ND, NAL, NBL, NAX, NBX, NCX (Semi-synthetic glycerides-Multipurpose vehicles), Suppocire AIX (semi-synthetic glycerides with ethoxylated fatty acid esters containing 95% mono, di and triglycerides and 5% polysorbate 65); Ovicure WL2944, WL3264, WL 3460 (Semi-synthetic glycerides- Vehicles for Vaginal Pessaries); Witepsol H5 (Hydrogenated Coco-Glycerides), Witepsol H12 (Hydrogenated Coco-Glycerides), Witepsol H 15 (Hydrogenated Coco-Glycerides), Witepsol H19 (Hydrogenated Coco-Glycerides + Glyceryl Ricinoleate), Witepsol H175, Witepsol H185 (Hydrogenated Coco-Glycerides ), Witepsol H32 (Hydrogenated Coco-Glycerides), WitepsolH35 (Hydrogenated Coco-Glycerides), Witepsol H37 (Hydrogenated Coco-Glycerides). Witepsol W25 (Hydrogenated Coco-Glycerides), Witepsol W31 (Hydrogenated Coco-Glycerides), Witepsol W32 (Hydrogenated Coco-Glycerides), Witepsol W35 (Hydrogenated Coco-Glycerides), Witepsol W45 (Hydrogenated Coco-Glycerides), Witepsol S51 (Hydrogenated Coco-Glycerides + Ceteareth-25 + Glyceryl Ricinoleate), Witepsol S52, Witepsol S55 (Hydrogenated Coco-Glycerides + Ceteareth-25 + Bees Wax), Witepsol S58 (Hydrogenated Coco-Glycerides + Ceteareth-25 + Glyceryl Ricinoleate), Witepsol E75 (Hydrogenated Coco-Glycerides + Bees Wax), Witepsol E76 (Hydrogenated Coco-Glycerides), Witepsol E85 (Hydrogenated Coco-Glycerides), MASSA ESTARINUM 299 (Hydrogenated Coco-Glycerides), MASSA ESTARINUM B (Hydrogenated Coco-Glycerides), Massa Estarinum BC (Hydrogenated Coco-Glycerides + Glyceryl Ricinoleate), Massa Estarinum C (Hydrogenated Coco-Glycerides), Massa Estarinum E (Hydrogenated Coco-Glycerides + Ceteareth-25 + Bees Wax), Softisan 378 (Hydrogenated Coco-Glycerides); Pharmazol™ and/or combinations thereof.

Suitable emulsifiers include, without limitation, non-ionic surfactants, anionic surfactants, cationic surfactants and amphoteric surfactants or mixtures thereof. Suitable nonionic surfactants may comprise sorbitan fatty acid esters, glycerol fatty acid esters, glycerol, decaglycerin fatty acid esters, polyglycerin fatty acid esters, propylene glycol fatty acid esters, pentaerythritol fatty acid esters, PEG 100 Stearate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyethylene glycol fatty acid esters, sucrose fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene phytosterols, polyoxyethylene phytostanols, polyoxyethylene polyoxypropylene glycol, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene lanolin, polyoxyethylene lanolin alcohol, beeswax derivatives, polyoxyethylene alkylamines and polyoxyethylene fatty acid amides and/or combinations thereof.

Suitable anionic surfactants may comprise alkyl sulfates, polyoxyethylene alkyl ether sulfates, N-acylamino acid or salts thereof, and polyoxyethylene alkyl ether phosphates and/or combinations thereof. Suitable cationic surfactants may comprise alkyl ammonium salts and alkylbenzyl ammonium salts and/or combinations thereof. Suitable amphoteric surfactants may comprise betaine acetate and lecithin and/or combinations thereof.

Suitable sucrose fatty acid esters include, without limitation, sugar esters are monoesters, diesters, triesters constituted of sucrose and one or more fatty acids and/or combinations thereof.

Suitable stabilizers include, without limitation, amino acids or salts thereof, proteins and sugars. Specifically, amino acids include basic amino acids such as arginine and lysine, as well as acidic amino acids such as glutamic acid and aspartic acid; proteins include gelatin, casein and albumin; and sugars include disaccharides such as sucrose and maltose, as well as sugar alcohols such as mannitol and sorbitol.

Suitable buffering agent(s) include, without limitation, phosphate buffer, acetate buffer, citrate buffer, succinate buffer, borate buffers, tris HCl and amino acids such as glycine, aspartate, histidine, cysteine, tyrosine, phenylalanine, proline, arginine, threonine, serine, valine, isoleucine, lycine, and glutamine. The particular concentration of the buffer will differ, depending on the specific agent employed.

Suitable isotonic agents include, without limitation, sodium chloride and potassium chloride, antiseptics typified by paraoxybenzoic acid esters such as methyl paraoxybenzoate and propyl paraoxybenzoate and/or combinations thereof.

Suitable viscosity-adjusting agents include, without limitation, glycerol, propylene glycol, polymeric polyols, such as, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 6000), microcrystalline wax, beeswax, butylene glycol, paraffin, cetyl palmitate sodium stearate, triethylene glycol, collagen, dextrans such as dextran 70, water soluble proteins such as gelatin, polyvinyl alcohols, polyvinylpyrrolidones, cellulose derivatives, carbomers, gums such as gellan gum, xanthan gum, guar gum, chitosan, alginic acid and its salts, xyloglucan, pectin, hyaluronic acid-agar, carrageenan, shellac, and hyaluronic acid derivatives, dextrans, polyvinyl alcohol, polyacrylic acids, povidone such povidone K90, and polysaccharides such as hyaluronic acid and its salts and chondroitin sulfate and its salts, or combinations thereof.

Suitable preservatives include, without limitation, benzalkonium chloride (BAC), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, benzyl alcohol, ethanol, phenylmercury nitrate, phenylmercury acetate, thiomerosal, merthiolate, phenylmercuryborate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, butyl-p-hydroxybenzoate, chlorobutanol, sorbic acid, polyquaternary ammonium compounds, ascorbic acid, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), benzoic acid, citric acid, edetic acid, parabens, phenol, propyl gallate, sodium bisulfite, sodium sulfite, chlorocresol, cresol, dehydroacetic acid, phenol, potassium benzoate, potassium sorbate, sodium dehydroacetate, sodium propionate, thymol, butylparaben, ethylparaben, methylparaben, methylparaben sodium, propylparaben, propylparaben sodium, thimerosal and the various salt forms for these compounds, or combinations thereof.

Suitable chelating agents, includes, without limitation, ethylenediaminetetraacetic acid and metal salts thereof, such as disodium edetate, trisodium edetate, tetrasodium edetate, sodium citrate, or mixtures thereof.

Suitable antioxidants includes, without limitation, sodium thiosulfate, sodium bisulfite, sodium metalbisulfite, acetone sodium bisulfite, gentisic acid, gentisic acid ethanolamide, sodium formaldehyde sulfoxylate, thiourea, butylated hydroxyanisole, butylated hydroxy toluene, hypophosphorous acid, monothioglycerol, esters of gallic acid, ascorbic palmitate, ascorbic acid, salts of ascorbic acids such as ascorbyl palmitate, tartaric acid, citric acid, fumaric acid, malic acid, sodium ascorbate, retinoids and derivatives of vitamin A, acetylcysteine, thioglycerol, sodium metabisufite, sodium sulphite, sodium pyrosulphate, methionine, glutamine, thiamine, propyl gallate, vitamin C, lutein, beta-carotene, Vitamin E and its derivatives e.g. Vitamin E TPGS and/or combinations thereof.

According to another embodiment, the present invention provides a suppository composition comprising extract of Euphorbia prostrata, and one or more pharmaceutically acceptable excipients; wherein the composition is used for the treatment of anal fissures, anal fistula, varicose veins, haemorrhoids including haemorrhoids during pregnancy.

According to another embodiment, the present invention provides a process of preparation of a suppository composition comprising extract of Euphorbia prostrata, wherein said process comprises:
taking one or more suppository base followed by melting it on higher temperature;
adding Euphorbia prostrata in the suppository base as obtained in step (a) under constant stirring/homogenization;
optionally adding one or active agents in mixture as obtained in step (b) under constant stirring/homogenization;
pouring the bulk as obtained in step (c) into appropriate mould/pre-formed shells;
allowing to cool to form suppository;
storing in cool and dry place at temperature not exceeding 25°C.

According to another embodiment, the present invention provides a process of preparation of a suppository composition comprising extract of Euphorbia prostrata, wherein said process comprises the steps of:
dispensing one or more suppository base selected from the group of hard fat, cocoa butter, PEG 100 sterate and liquid paraffin into appropriate vessel followed by heating at 50? to 70? under stirring till it completely melts;
adding Euphorbia Prostrata under continues stirring/homogenization for suitable time;
pouring the bulk as obtained in step (b) into appropriate mould/pre-formed shells followed by cooling to form suppository;
storing in cool and dry place at temperature not exceeding to 25?.

According to another embodiment, the present invention provides a process of preparation of a suppository composition comprising extract of Euphorbia prostrata, wherein said process comprises the steps of:
dispensing one or more suppository base selected from the group of hard fat, cocoa butter, PEG 100 sterate and liquid paraffin into appropriate vessel followed by heating at 50? to 70? under stirring till it completely melts;
adding Euphorbia Prostrata under continues stirring/homogenization for Suitable time followed by addition of lidocaine under continues stirring/homogenization for suitable time;
pouring the bulk as obtained in step (b) into appropriate mould/pre-formed shells followed by cooling to form suppository;
storing in cool and dry place at temperature not exceeding to 25?.

According to another embodiment, the present invention provides a process of preparation of a suppository composition comprising extract of Euphorbia prostrata, wherein said process comprises the steps of:
dispensing one or more suppository base selected from the group of hard fat, cocoa butter, PEG 100 sterate and liquid paraffin into appropriate vessel followed by heating at 50? to 70? under stirring till it completely melts;
adding Euphorbia Prostrata under continues stirring/homogenization for suitable time followed by addition of lidocaine and Phenylephrine under continues stirring/homogenization for suitable time;
pouring the bulk as obtained in step (b) into appropriate mould/pre-formed shells followed by cooling to form suppository;
storing in cool and dry place at temperature not exceeding to 25?.

Another embodiment of the present invention is to provide a suppository composition comprising extract of Euphorbia prostrata, wherein the composition may be given once daily, twice daily, thrice daily, 4 times a day, 5 times a day, or at appropriate interval, with or without food.

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

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

EXAMPLES

The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below:

Example 1: Suppository composition of Euphorbia Prostrata

Ingredient %w/w mg/ 2g Suppository
Euphorbia Prostrata 5.00 100.00
Liquid paraffin 10.00 200.00
PEG 100 Stearate 5.00 100.00
Cocoa butter 40.00 800.00
Hard Fat 40.00 800.00
Total 100.00 2.00 g

Process:
Dispensing: Dispensing all the materials as per Bill of Material;
Melting of Bases: Taking hard fat, cocoa butter, PEG 100 Stearate and liquid paraffin into appropriate vessel and heating this to 50 - 70°C under stirring. Ensue phase is completely melted;
Addition of active: adding Euphorbia Prostrata to the bulk as obtained in step 2 under stirring/homogenization and continuing stirring/homogenization for suitable time;
Moulding & sealing: Pouring the bulk as obtained in step 3 into appropriate mould/pre-formed shells, followed by allowing to cool to form suppository. Then inspect visually mould/preformed shells for suppository formation. Sealing the preformed shells with appropriate sealing machine or packing suppositories in approved packing;
Storage: Storing in cool and dry place at temperature not exceeding 25°C.

Example 2: Suppository composition of Euphorbia Prostrata

Ingredient %w/w mg/ 2g Suppository
Euphorbia Prostrata 5.00 100.00
Lidocaine 2.00 40.00
Liquid paraffin 8.00 160.00
PEG 100 Stearate 5.00 100.00
Cocoa butter 40.00 800.00
Hard Fat 40.00 800.00
Total 100.00 2.00 g

Process:
Dispensing: Dispensing all the materials as per Bill of Material;
Melting of Bases: Taking hard fat, cocoa butter, PEG 100 Stearate and liquid paraffin into appropriate vessel and heating this to 50 - 70°C under stirring. Ensue phase is completely melted;
Addition of actives/key ingredients: adding Euphorbia Prostrata to the bulk as obtained in step 2 under stirring/homogenization followed by Allowing to stir/homogenize for suitable time. Then adding lidocaine under stirring/homogenization. Allowing to stir/homogenize for suitable time;
Moulding & sealing: Pouring the bulk as obtained in step 3 into appropriate mould/pre-formed shells. Then allowing to cool to form suppository. Then inspect visually mould/preformed shells for suppository formation. Sealing the preformed shells with appropriate sealing machine or pack suppositories in approved packing;
Storage: Storing in cool and dry place at temperature not exceeding 25°C.

Example 3: Suppository composition of Euphorbia Prostrata
Ingredient %w/w mg/ 2g Suppository
Euphorbia Prostrata 5.00 100.00
Lidocaine 2.00 40.00
Phenylephrine 0.25 5.00
Liquid paraffin 7.75 155.00
PEG 100 Stearate 5.00 100.00
Cocoa butter 40.00 800.00
Hard Fat 40.00 800.00
Total 100.00 2.00 g

Process:
Dispensing: Dispensing all the materials as per Bill of Material;
Melting of Bases: Taking hard fat, cocoa butter, PEG 100 Stearate and liquid paraffin into appropriate vessel and heat this to 50 - 70°C under stirring. Ensue phase is completely melted;
Addition of actives/key ingredients: adding Euphorbia Prostrata to the bulk as obtained in step 2 under stirring/homogenization followed by adding lidocaine under stirring/homogenization and further adding phenylephrine under stirring/homogenization, Continuing stirring/homogenization for suitable time;
Moulding & sealing: Pouring the bulk as obtained in step 3 into appropriate mould/pre-formed shells, then allow to cool to form suppository. Then inspect visually mould/preformed shells for suppository formation. Sealing the preformed shells with appropriate sealing machine or packing suppositories in approved packing;
Storage: Storing in cool and dry place at temperature not exceeding 25°C.

Example 4: Suppository composition of Euphorbia Prostrata
Ingredient mg/Unit
Euphorbia Prostrata Extract 20.00
Lidocaine 60.00
Colloidal Silicon Dioxide 40.00
Titanium Dioxide 35.00
Witepsol E 85 500.00
Witepsol W 45 1345.00
Total 2.00g

Process:
Dispensing: Dispensing all the materials as per Bill of Material;
Melting of bases: Taking batch quantity of witepsol E 85 and witepsol W 45 and heat to suitable temperature to melt hard fats. Ensure clear liquid is formed;
Addition of actives:
adding Lidocaine to the liquid as obtained in step 2 under stirring, allowing to stir to form clear liquid;
adding colloidal silicon dioxide to the clear liquid as obtained in step 3a) under stirring, allowing to stir to form uniform dispersion;
adding euphorbia prostrata extract to the dispersion as obtained in step 3b) under stirring, allowing to stir to form uniform dispersion;
Further adding titanium dioxide under stirring, allowing to stir to form uniform dispersion. Then further homogenize the bulk at 3000 – 5000 rpm for suitable time;
Cooling the bulk as obtained in step 3 d) under stirring to reach desired temperature;
Filling the bulk in preformed shells and allowing to cool to room temperature followed by sealing the suppositories;
Storing in cool and dry place at temperature not exceeding 25°C.

Suppository composition of the present invention are subjected to the stability study at 40°C/75%RH and 30°C/75%RH for three months. The stability results are as follows:

Tests Specifications Condition/ Time point
Initial 40°C/75%RH – 3M 30°C/75%RH – 3M
Total Phenolics by UV Between 12.6 – 44.0% 23.26 23.67 23.87
Total Flavonoids by HPLC Between 3.15% - 8.25% 3.66 3.90 3.86
Assay of Lidocaine 90.0% - 110.0% of label claim 99.6 105.4 102.6

From the above table, it is evident that the suppository composition of the present invention is stable during storage at 30°C to 40°C at 75%RH. Further, the composition is disintegration time of the suppository composition is determined and the results are as follows:
Tests Specifications Condition/ Time point
Initial 40°C/75%RH – 3M 30°C/75%RH – 3M
Disintegration time Less than 60 min 27 min 11 sec 20 min 05 sec 24 min 21 sec
,CLAIMS:We Claim:

1. A suppository composition comprising a therapeutically effective amount of Euphorbia Prostrata, and one or more pharmaceutically acceptable excipients.

2. The suppository composition as claimed in claim 1, wherein the pharmaceutical composition further comprising Lidocaine.

3. The suppository composition as claimed in claim 2, wherein the composition further comprises one or more additional pharmaceutical active agents.

4. The suppository composition as claimed in claim 1, wherein the Euphorbia Prostrata is having a particle size of d10 not more than 50 µm; d50 not more than 150 µm and/or d90 is not more than 250 µm.

5. The suppository composition as claimed in claim 1, wherein the suppository composition comprising about 5% w/w of Euphorbia Prostrata; about 10% w/w of liquid paraffin, about 5% w/w of PEG 100 stearate, about 40% w/w of cocoa butter, about 40% w/w of hard fat; optionally one or more pharmaceutically acceptable excipients.

6. The suppository composition as claimed in claim 1, wherein the suppository composition comprising about 5% w/w of Euphorbia Prostrata; about 2% w/w of Lidocaine, about 8% w/w of liquid paraffin, about 5% w/w of PEG 100 stearate, about 40% w/w of cocoa butter, about 40% w/w of hard fat; optionally one or more pharmaceutically acceptable excipients

7. The suppository composition as claimed in claim 1, wherein the suppository is in the shape of conical, cylindrical or globular.

8. The suppository composition as claimed in claim 1, wherein the suppository is having a length in the range from about 1-7 cm and diameter of about 0.1 to 2 cm.

9. A synergistic pharmaceutical combination comprising:
a. suppository composition comprising Euphorbia Prostrata, and one or more pharmaceutically acceptable excipients; and
b. an oral composition comprising 100 mg dry extract of Euphorbia Prostrata, and one or more pharmaceutically acceptable excipient; wherein the combination is effective in the treatment of anal fissures, anal fistula, varicose veins, haemorrhoids including haemorrhoids during pregnancy.

10. A synergistic pharmaceutical combination comprising:
i. suppository composition comprising Euphorbia Prostrata, and one or more pharmaceutically acceptable excipients; and
ii. an oral composition comprising 100 mg dry extract of Euphorbia Prostrata, 500 mg calcium dobesilate, and one or more pharmaceutically acceptable excipient;
wherein the suppository composition is administered at least twice daily for 3 months and the oral composition is administered as one tablet twice daily for first month followed by one tablet once or twice daily for next 2 months, for the treatment of varicose veins.

Dated this, 09th Day of January, 2024
For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer