Title of Invention	PHARMACEUTICAL COMPOSITION COMPRISING MISOPROSTOL FOR VAGINAL SUPPOSITORY DOSAGE FORM AND PROCESS FOR PREPARATION THEREOF
Abstract	This invention relates to pharmaceutical composition of Misoprostol for suppository dosage form and method of preparation thereof. It gives synergistic effect in the gynecological problems, including cervical ripening, labor induction, mid-trimester terminations and postpartum hemorrhage. Oily based suppository form prepared by dissolving 0.02% (w/w) pure Misoprostol or 0.2% (w/w) Isopropyl Myristate, 2.0% (w/w) Cholesterol with heating. Melting q.s. Palm Karnel oil at 40˚C, adding drug solution in it, the mass is filled in ovule. PEG based suppository form is prepared by dissolving 0.02% (w/w) pure Misoprostol or 0.2% (w/w) stabilized Misoprostol in 5.0% (w/w) Polyethylene Glycol 200; adding 0.1 (w/w) Polysorbate 80 with constant stirring, nitrogen bubbling; Melting PEG 1540 and q.s. Polyethylene Glycol 6000 at 45˚C, adding drug solution with constant stirring; filling the ovule with the solution.

Title of Invention

PHARMACEUTICAL COMPOSITION COMPRISING MISOPROSTOL FOR VAGINAL SUPPOSITORY DOSAGE FORM AND PROCESS FOR PREPARATION THEREOF

Abstract

This invention relates to pharmaceutical composition of Misoprostol for suppository dosage form and method of preparation thereof. It gives synergistic effect in the gynecological problems, including cervical ripening, labor induction, mid-trimester terminations and postpartum hemorrhage. Oily based suppository form prepared by dissolving 0.02% (w/w) pure Misoprostol or 0.2% (w/w) Isopropyl Myristate, 2.0% (w/w) Cholesterol with heating. Melting q.s. Palm Karnel oil at 40˚C, adding drug solution in it, the mass is filled in ovule. PEG based suppository form is prepared by dissolving 0.02% (w/w) pure Misoprostol or 0.2% (w/w) stabilized Misoprostol in 5.0% (w/w) Polyethylene Glycol 200; adding 0.1 (w/w) Polysorbate 80 with constant stirring, nitrogen bubbling; Melting PEG 1540 and q.s. Polyethylene Glycol 6000 at 45˚C, adding drug solution with constant stirring; filling the ovule with the solution.

Full Text	FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. "PHARMACEUTICAL COMPOSITION COMPRISING MISOPROSTOL FOR VAGINAL SUPPOSITORY DOSAGE FORM AND PROCESS FOR PREPARATION THEREOF." 2. (a) LINCOLN PHARMACEUTICALS LIMITED (b) NATIONALITY: an Indian company (c) Nirav Complex, Opp. Navrang High School, Naranpura, Ahmedabad - 380 014. Gujarat, India. The following specification particularly describes the invention and the manner in which it is to be performed. l The present invention relates to pharmaceutical composition comprising Misoprostol for vaginal suppository dosage form and process for preparation thereof. The objective of the present invention is to provide pharmaceutical composition using active pharmaceutical ingredient Misoprostol for cervical ripening, labor induction, mid-trimester terminations of pregnancy. One another objective of the present invention is to provide Misoprostol composition for the vaginal suppository (ovules) dosage form to counteract postpartum hemorrhage. Another objective of the present invention is to provide the Misoprostol composition for the vaginal suppository dosage form with higher efficacy, quick onset of action due to enhanced absorption as well as faster disintegration and faster dissolution than the conventional misoprostol formulation. PRIOR ART: Misoprostol is used for obstetric and gynecological problems or gynecological dysfunction to the human body. Misoprostol is effective drug for the treatment of such problems, with low cost and easy administeration by vaginal route. 2 Misoprostol is an analog of Prostaglandin El. Prostaglandin are naturally occurring fatty acids produced by many tissues in the body. Prostaglandin El causes myometrial contractions by interacting with specific receptors on myometrial cells. This interaction results in a cascade of events, including a change in calcium concentration, thereby initiating muscle contraction. By interacting with prostaglandin receptors, Misoprostol causes the cervix to soften and the uterus to contract, resulting in the expulsion of the uterine contents. Misoprostol is relatively metabolically resistant, and thus has prolonged action. Misoprostol regimen begins with the vaginal administration of 800 ug of Misoprostol. Misoprostol has also been shown effective in treating postpartum hemorrhage and early pregnancy failure. In the beginning of early 1990s, Misoprostol alone was used as a method of terminating early pregnancies. A growing body of evidence has now shown that Misoprostol can be used as a single agent to induce early abortion. Mesoprostol is a low cost drug. It is stable at ambient temperature and hence does not require refrigeration for storage. Due to this stable 3 nature, there is an ease in transportation of the product. These characteristic of misoprostol enhances its significance as medication for absortion. Nearly every measure of adequacy of labor induction was significantly better with Misoprostol, including time from induction to delivery and lack of necessity for oxytocin. Patent Application No. 020607 is based on delayed release oral tablet of Diclofenac Sodium and Misoprostol. The dosage form contains 0.2 mg Misoprostol and 50 mg or 75 mg of Diclofenac Sodium. Patent Application No. 019268 is based on oral tablet of Misoprostol. The dosage form is prepared by using 0.1 mg or 0.2 mg Misoprostol drug. Patent Application No. 076095 is based on oral tablet of Misoprostol. The dosage form is prepared by using 0.1 mg or 0.2 mg Misoprostol drug. China patent application No. 00123869 describes, suppository for treating cervical erosion and vaginitis. The suppository is prepared by using five Chinese medicinal material including Cortex Phellodendri, Rhizoma Zedoariae, pofygoni avicularis herba, alumen and pricklyash and through the processes pulverizing Chinese medicinal materials in to fine powder, heating the mixture of glycerin, gelatin and distilled water in water bath to 4 dissolve into medium, mixing the hot medium, the medicinal materials and honey, molding, cooling naturally, packing and disinfecting. This is good medicine of preventing and treating cervical erosion, vaginitis and other diseases of women. Patent no. WO 00/09134 is claiming use of Misoprostol or Misoprostol acid for preparing of a pharmaceutical product applied to be topically to the clitoris or/and the vagina in order to cure sexual dysfunction in women. The use of Misoprostol and its acids in the form of various galenic preparations (solutions, ointments, endourethral sticks, systems of controlled-transdermal absorption). The pharmaceutical product is prepared in combination with other vasodilatory drugs as alprostadil for the synergistic action, as well as "passage accelerators" used normally in pharmaceutical technology to increase absorption of drugs through the skin or mucosa. Pharmaceutical product using Misoprostol or its acid is also prepared in combination with cyclodextrin or other substances to retard the undesired effects of the drug or prolong their pharmaceutical action. US patent no. 6,664,290 relates to a method of limiting postpartum hemorrhage comprising administering orally a single effective dose of misoprostol to a woman during the third stage of the labor. 5 At present Misoprostol is available as oral tablets of strength 100 ug and 200 \xg. Misoprostol is available in tablet dosage form is also administered in female vagina, two to four tablets are required at a time for vaginal insertion. Tablet wetted with water is administered in vagina. There may be chances of non dissolution of tablet in the vagina. After the administration of tablet, other excipients present in the tablet may not dissolve in vagina and may come out of it giving ugly feeling. To over come from such drawbacks, there is need to prepare a novel composition of Misoprostol. Pharmaceutical formulations of Misoprostol are widely available in market for the treatment of stomach ulcers. The above mentioned prior art and other market search shows that, at present Misoprostol is available in tablet dosage form comprising one or more pharmaceutical excipients and/or drugs in the treatment of male erectile dysfunction, gastric and duodenal ulcers, female sexual dysfunction and hepto biliary diseases. In the present invention of pharmaceutical composition containing misoprostol is in the form of for suppository (ovule) and, is administered through the. vaginal route. Pharmaceutical composition of misoprostol as prepared as in the present invention is having good efficacy, quick onset of 6 action due to enhanced absorption because of synergistic effect of other excipients, faster disintegration and faster dissolution. The present pharmaceutical composition is used for cervical ripening, labor induction and to counteract postpartum hemorrhage. In the preparation process of pharmaceutical composition for suppository dosage form, the use of other pharmaceutical ingredients in addition to misoprostol gives synergistic effect in enhancing of drug absorption in systemic circulation, which results into rapid onset of action. Isopropyl myristate and cholesterol enhances the absorption of misoprostol through vaginal walls. Moreover, in the said invention Misoprostol composition prepared for the suppository dosage form administered through vaginal route, imparts several advantages over conventional dosage forms. Suppository form (i) melts at body temperature, (ii)easy to use, (iii)ability and flexibility to deliver the drug with different release rates, (iv) required less frequent doses, (v) easily removable if needed (vi) can be administered in unconscious patients. Comparative analysis has been carried out between the Misoprostol composition for suppository dosage form of the present invention and Misoprostol Tablets (X) as presently available dosage form in the market. Comparative disintegration study has been carried out. Results are 7 mentioned in the table given below and are compared by plotting the graph of Formulation Vs Disintegration time in minutes. The graph is annexed as in figure 1. Drug Formulation Disintegration Time (Minutes) Misoprostol Oral Tablets 10 Minutes Misoprostol in oily base Suppository dosage form. 3 Minutes Misoprostol in Polyethylene Glycol base(water soluble) Suppository dosage form. 5 Minutes From the above results it is concluded that the Misoprostol suppository in Oily Base and Suppository in Aqueous Base require less time for disintegration than Oral tablets of Misoprostol. Faster disintegration occurs in Misoprostol leads to faster dissolution, that results into rapid site specific onset of action over existing oral dosage form of Misoprostol. Comparative analysis on application of Presently invented Misoprostol composition Vs conventional tablet for the various treatments: DOSAGE FORM TERMINATION OF PREGNANCY INDUCTION OF LABOR POSTPARTUM HAEMORRHAG E 8 Oral Tablets - * + Suppository in Oily base +++ Aft* +++ Suppositoryy in Aqueous Base ++ ** ++ Note: Less Effective: (-) Good: () Effective: (+) Better: () More Effective: (++) Best: (**) Most Effective: (+++) Above analysis shows that the conventional tablets are comparatively less effective than presently invented pharmaceutical composition of Misoprostol for the treatment of termination of pregnancy, induction of labor, postpartum hemorrhage. Detail Description of the invention: The present invention of pharmaceutical composition of Misoprostol for suppository dosage form and method of preparation thereof is described as following. In the said invention the pharmaceutical composition of misoprostol is prepared by using the active pharmaceutical ingredient misoprostol, other pharmaceutical excipients such as Isopropyl Myristate as penetration enhancer, Propylene Glycol as solvent, Cholesterol as a surfactant, Fractionated Palm karnel oil as suppository (ovule) base, Polyethylene Glycol 200, Polyethylene Glycol 1540, Polyethylene Glycol 6000 as base, 9 Polysorbate 80 as surfactant. The use of such pharmaceutical ingredients provide good efficacy and stability to the dosage form. In the present invention, pharmaceutical composition of Misoprostol is prepared in Oily base suppositories (ovules) and PEG (Polyethylene Glycol) base suppositories (ovules) dosage forms. Use of Isopropyl Myristate and Cholesterol in the preparation of misoprostol pharmaceutical composition enhances the absorption of the drug in systemic circulation, which will result into rapid onset of action in cervical ripening, labor induction and postpartum hemorrhage. The use of Palm Karnel Oil in the preparation of composition is locally non irritant, chemically inert and stable, compatible with drug, shrink slightly on cooling, melting and solidifying over a narrow temperature range, is a best lubricant, do not produce rancidity over a time, no polymerization. The pharmaceutical composition of Misoprostol comprises active pharmaceutical ingredient Misoprostol in the range between 0.002% to 0.12% w/w or stabilized diluted Misoprostol in the range between 0.02% to 1.2% w/w. Presently invented pharmaceutical composition of Misoprostol is composed of the following active pharmaceutical ingredient and other excipients. 10 1. Pharmaceutical composition of Misoprostol in oily base suppository (ovules) dosage form:- (I) In case of pure Misoprostol drug: Ingredients Quantity (w/w) Misoprostol 0.02% Isopropyl Myristate 5.0% Propylene Glycol 5.0% Cholesterol 2.0% Fractionated Palm Karnel oil (Suppocire) quantity sufficient. (II) In case of stabilized diluted Misoprostol: Ingredients Quantity (w/w) Misoprostol (1:10) 0.2% Isopropyl Myristate 5.0% Propylene Glycol " 5.0% Cholesterol 2.0% Fractionated Palm Kernel oil (Suppocire) quantity sufficient 2. Pharmaceutical composition of Misoprostol in PEG based suppository (Ovules) dosage form: 11 (I) Incase of pure Misoprostol drug: Ingredient Quantity (W/W) Misoprostol 0.02% Polyethylene Glycol 200 5.0% Polysorbate 80 0.1% Polyethylene Glycol 1540 and Polyethylene Glycol 6000 (base) quantity sufficient (II) Incase of stabilized diluted Misoprostol: Ingredient Quantity (W/W) Misoprostol (1:10) 0.2% Polyethylene Glycol 200 5.0% Polysorbate 80 0.1% Polyethylene Glycol 1540 and Polyethylene Glycol 6000 (base) quantity sufficient 1. Process for the preparation of pharmaceutical dosage composition of Misoprostol for oily base suppository (ovule) dosage forms: (I) In case of pure Misoprostol drug: Batch size: 25 kgs.(5000 suppositories) i) Preparation of Misoprostol solution: 12 Take required quantity of Misoprostol and dissolve in 1.25 Kgs.(5% w/w) of Propylene glycol. To the above add 0.5 kg.(2%w/w) of cholesterol and 1.25 kgs.of Isopropyl myristate after bringing their temperature to 40°C + 2°C. it) Preparation of suppository base: Take weighed quantity of fractionated palm karnel oil (suppocire). Heat it at to 40°C ± 2°C. The mass will melt. Hi) Prearation of the filling mass:- Add i) to ii) with constant stirring and keeping the temperature of the mass 40°C + 2°C.Stirr to mix both the parts. iv) Preparation of suppositories by melt mouldins method: The melted filling mass of iii) is poured into a suppository mould. After pouring into tightly clamped mould, the suppository and mould are allowed to cool at or below 25 °C + 2°C.The size of the mould is kept in such a way that it forms a suppository weighing 5grams + 5%. Then the mould is opened and suppository are removed. v) Packing and storage: 13 Suppositories are packaged in either partitioned boxes or in a blister of aluminum foil and PVC-polyethylene film. Store the suppository at or below 25°C. In case of stabilized-diluted Misoprostol drug: Batch size: 25 kgs.(5000 suppositories) i) Preparation of Misoprostol dispersion:- Take required quantity of diluted Misoprostol(l:10) and disperse it into 1.25 kg.(5%w/w) of propylene glycol by stirring both together. Then add 1.25 kg.(5%w/w)of isopropyl Myristate and 0.5Kg.(2%w/w) of cholesterol after bringing their temperature to 40° C± 2°C. ii) Preparation of suppository base:- Take weighed quantity of fractionated palm karnel oil (suppocire). Heat it at to 40°C ± 2°C. The mass will melt. Hi) Prearation of the fillins mass:- Add i) to ii) with constant stirring and keeping the temperature of the mass 40°C + 2°C.Stirr to mix both the parts. iv) Preparation of suppositories by melt mouldins method: 14 The melted filling mass of iii)is poured into a suppository mould. After pouring into tightly clamped mould, the suppository and mould are allowed to cool at or below 25°C + 2°C.The size of the mould is kept in such a way that it forms a suppository weighing 5grams + 5%.Then the mould is opened and suppository are removed. v) Packing and storage: Suppository are packaged in either partitioned boxes or in a blisters of aluminum foil and PVC-poly-ethylene film. Store the suppository at or below 25°C. 2 Process for the preparation of pharmaceutical dosage composition of Misoprostol for PEG based suppository (ovule) dosage forms: (I) In case of pure Misoprostol drug: Batch size: 25 kgs.(5000 suppositories) i) Preparation of Misoprostol solution: Take required quantity of Misoprostol and dissolve in 1.25 Kgs.(5% w/w) of Polyethylene glycol-200. To the above add 0.025 kg.(0.1%w/w) of Polysorbate-80 with constant stirring and nitrogen bubbling. 15 ii) Preparation of suppository base : Take weighed quantity of Polyethylene glycol 1540 and Polyethylene glycol- 6000 in suitable proportion. Mix them and melt by heating upto 45°C± 2° C with constant stirring. iii) Prearation of the fillins mass:- Add i) to ii) with constant stirring and keeping the temperature of the mass 40°C ± 2°C.Stirr to mix both the parts. iv) Preparation of suppositories by melt moulding method: The melted filling mass of iii) is poured into a suppository mould. After pouring into tightly clamped mould, the suppository and mould are allowed to cool at or below 25°C ± 2°C.The size of the mould is kept in such a way that it forms a suppository weighing 5grams + 5%. Then the mould is opened and suppository are removed. v) Packing and storage: Suppositories are packaged in either partitioned boxes or in a blister of aluminum foil and PVC-polyethylene film. Store the suppository at or below 25°C. Incase of stabilized-diluted Misoprostol drug: 16 Batch size: 25 kgs.(5000 suppositories) Preparation of Misoprostol dispersion:- Take required quantity of diluted Misoprostol (1:10) and disperse it into 1.25 kg.(5%w/w) of Polyethylene glycol-200 by stirring both together. Then add 0.025 kg.(0.1 %w/w) of Polysorbate-80 with constant stirring and nitrogen bubbling. Preparation of suppository base:- Take weighed quantity of Polyethylene glycol 1540 and Polyethylene glycol- 6000 in suitable proportion. Mix them and melt by heating upto 45°C± 2° C with constant stirring. Prearation of the fillins mass:- Add i) to ii) with constant stirring and keeping the temperature of the mass 40°C + 2°C.Stirr to mix both the parts. Preparation of suppositories by melt moulding method: The melted filling mass of iii) is poured into a suppository mould. After pouring into tightly clamped mould, the suppository and mould are allowed to cool at or below 25 °C ± 2°C.The size of the mould is kept in such a way that it forms a 17 suppository weighing 5grams + 5%. Then the mould is opened and suppository are removed. v) Packing and storage: Suppositories are packaged in either partitioned boxes or in a blister of aluminum foil and PVC-polyethylene film. Store the suppository at or below 25°C. References: 1. A comparison of two regimens of intravaginal Misoprostol for termination of second trimester pregnancy: a randomized comparative trial. [Hum Reprod. 2000 Mar;15(3):709-12.] [PMID: 10686224] 2. Comparative study of intravaginal Misoprostol with gemeprost as an abortifacient in second trimester missed abortion. [Aust N Z J Obstet Gynaecol. 1997 Aug; 37(3):331-4.] [PMID: 9325520] 3. A preliminary study of cutaneous blood flow associated with postpartum use of oral Misoprostol. [J Obstet Gynaecol Can. 2004 Dec;26(12): 1073-6.] [PMID: 15607043] 4. Vaginal Misoprostol in managing premature rupture of membranes. [East Mediterr Health J. 2002 M-Sep;8(4-5):515-20.] [PMID: 15603033] 5. A randomized comparison of oral Misoprostol and vaginal prostaglandin E2 tablets in labour induction at term [BJOG: An International Journal of Obstetrics & Gynaecology Volume 111 Issue 5 Page 436 - May 2004] 6. A randomized double-blind study of vaginal Misoprostol Vs dinoprostone for cervical ripening and labour induction in prolonged pregnancy. [Singapore Med J. 1997 Jul;38(7):292-4] [PMID: 9339095] 7. Non-pregnant patients" preference for delivery route. [Int Urogynecol J Pelvic Floor Dysfunct. 2004 Sep-Oct;15(5):308-12. Epub 2004 Sep-Oct] [PMID: 15580415] 8. Experience with intravaginal Misoprostol in the management of intra-uterine fetal death. [Afr J Med Med Sci. 2004 Jun;33(2): 105-8] [PMID: 15565925 ] 9. A randomized controlled trial of laminaria, oral Misoprostol, and vaginal Misoprostol before abortion. [Obstet Gynecol. 1999 May;93(5 Pt l):766-70.] [PMID: 10912983] 19 10. Experience with intravaginal Misoprostol in the management of intra-uterine fetal death. [Afr J Med Med Sci. 2004 Jun;33(2): 105-8.] [PMID: 15565925] 11. The effect of a pill inserter on vaginal Misoprostol dosing. [J Matern Fetal Med. 2001 Oct;10(5):332-4.] [PMID: 11730497] 12. Misoprostol: an old drug, new indication , Journal of post graduate medicine - Drug Review: 2002, Vol. 48, Department of Clinical Pharmacology, Seth G. S. Medical College and K. E. M Hospital, Parel, Mumbai - 400 012, India. 20 We claim, 1. Pharmaceutical composition comprising Misoprostol for vaginal suppository dosage form and process for preparation thereof, wherein; the Misoprostol composition is comprising of active pharmaceutical ingredient Misoprostol 0.002%(w/w) to 0.12%(w/w) as pure drug or 0.02%(w/w) to 1.2%(w/w) as stabilized or diluted drug, other pharmaceutical excipients such as 5.0%(w/w) Isopropyl Myristate, 5.0%(w/w) Propylene Glycol, 2.0%(w/w) Cholesterol, quantity sufficient Fractionated Palm karnel oil, 5.0%(w/w) Polyethylene Glycol 200, Polyethylene Glycol 1540, quantity sufficient Polyethylene Glycol 6000, 0.1%(w/w) Polysorbate 80. 2. Pharmaceutical composition comprising Misoprostol as claimed in claim 1 wherein oily based suppository (ovules) forms are comprised of 0.02%(w/w) Misoprostol as pure drug or 0.2%(w/w) as stabilized diluted form, 5.0%(w/w) Isopropyl Myristate, 5.0%(w/w) Propylene Glycol, 2.0%(w/w) Cholesterol, quantity sufficient Fractionated Palm karnel oil. 3. Pharmaceutical composition comprising Misoprostol as claimed in claim 1 wherein aqueous based suppository (ovules) forms are 21 comprised of 0.2%(w/w) Misoprostol as stabilized diluted drug or 0.02%(w/w) as pure drug form, 5.0%(w/w) Polyethylene Glycol 200, 0.1%(w/w) Polysorbate 80, Polyethylene Glycol 1540 and quantity sufficient Polyethylene Glycol 6000. 4. Pharmaceutical composition comprising Misoprostol for vaginal suppository dosage form and process for preparation thereof as claimed in claim 1 wherein the Misoprostol is used in the range from 0.002% to 0.12% (w/w) or 0.02% to 1.2% (w/w) as stabilized diluted form. 5. A process for preparation of pharmaceutical composition of Misoprostol for suppository (ovules) dosage form as claimed in claim 1 wherein oily base suppository (ovule) form is prepared by dissolving 0.02% (w/w) Misoprostol drug in pure form or 0.2%(w/w) as stabilized diluted form into the solvent 5.0% (w/w) propylene glycol; further adding 5.0% (w/w) Isopropyl Myristate and 2.0%) (w/w) cholesterol with little heating; preparing oily phase by melting quantity sufficient fractionated Palm Kernel oil at 40°C; mixing above prepared drug solution into the oily phase with constant stirring; filling the mass solution into suppository 22 (ovule) mould and sealed by machine; cooling the ovules at 25°C temperature and packing. 6. A process for preparation of pharmaceutical composition of Misoprostol for suppository (ovules) dosage form as claimed in claim 1 wherein aqueous (water soluble) base suppository (ovule) form is prepared by dissolving 0.02% (w/w) Misoprostol as pure drug/0.2%(w/w) as stabilized diluted form into 5.0% (w/w) polyethylene glycol 200; adding 0.1% (w/w) Polysorbate 80 in the said solution with constant stirring and nitrogen bubbling; aqueous base is prepared by melting the blend of polyethylene glycol 1540 and quantity sufficient polyethylene glycol 6000 at 45°C; adding the aqueous base with the drug solution with constant stirring; filling the mass solution into suppository (ovule) mould and sealed by machine; cooling the ovules at 25°C temperature and packing it. 7. Pharmaceutical composition comprising Misoprostol for vaginal suppository dosage form as claimed in claim 1 has higher efficacy, provides quick onset of action due to enhanced absorption because of presence of synergistic effect in the gynecological problems such as cervical ripening, labor 23 induction, mid-trimester terminations of pregnancy and postpartum hemorrhage. 8. Pharmaceutical composition comprising Misoprostol for vaginal suppository dosage form and process for preparation thereof as substantially herein described with the foregoing description and drawing. Dated this on 19th day of January 2005. Dr. Rajeshkumar H. Acharya Advocate & Patent agent For and on behalf of the applicant.

Full Text

FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. "PHARMACEUTICAL COMPOSITION COMPRISING MISOPROSTOL FOR VAGINAL SUPPOSITORY DOSAGE FORM AND PROCESS FOR PREPARATION THEREOF."
2. (a) LINCOLN PHARMACEUTICALS LIMITED
(b) NATIONALITY: an Indian company
(c) Nirav Complex, Opp. Navrang High School,
Naranpura, Ahmedabad - 380 014.
Gujarat, India.
The following specification particularly describes the invention and the
manner in which it is to be performed.

l

The present invention relates to pharmaceutical composition comprising Misoprostol for vaginal suppository dosage form and process for preparation thereof.
The objective of the present invention is to provide pharmaceutical composition using active pharmaceutical ingredient Misoprostol for cervical ripening, labor induction, mid-trimester terminations of pregnancy.
One another objective of the present invention is to provide Misoprostol composition for the vaginal suppository (ovules) dosage form to counteract postpartum hemorrhage.
Another objective of the present invention is to provide the Misoprostol composition for the vaginal suppository dosage form with higher efficacy, quick onset of action due to enhanced absorption as well as faster disintegration and faster dissolution than the conventional misoprostol formulation. PRIOR ART:
Misoprostol is used for obstetric and gynecological problems or gynecological dysfunction to the human body. Misoprostol is effective drug for the treatment of such problems, with low cost and easy administeration by vaginal route.
2

Misoprostol is an analog of Prostaglandin El. Prostaglandin are naturally occurring fatty acids produced by many tissues in the body. Prostaglandin El causes myometrial contractions by interacting with specific receptors on myometrial cells. This interaction results in a cascade of events, including a change in calcium concentration, thereby initiating muscle contraction.
By interacting with prostaglandin receptors, Misoprostol causes the cervix to soften and the uterus to contract, resulting in the expulsion of the uterine contents. Misoprostol is relatively metabolically resistant, and thus has prolonged action.
Misoprostol regimen begins with the vaginal administration of 800 ug of Misoprostol. Misoprostol has also been shown effective in treating postpartum hemorrhage and early pregnancy failure.
In the beginning of early 1990s, Misoprostol alone was used as a method of terminating early pregnancies. A growing body of evidence has now shown that Misoprostol can be used as a single agent to induce early abortion.
Mesoprostol is a low cost drug. It is stable at ambient temperature and hence does not require refrigeration for storage. Due to this stable
3

nature, there is an ease in transportation of the product. These characteristic of misoprostol enhances its significance as medication for absortion.
Nearly every measure of adequacy of labor induction was significantly better with Misoprostol, including time from induction to delivery and lack of necessity for oxytocin.
Patent Application No. 020607 is based on delayed release oral tablet of Diclofenac Sodium and Misoprostol. The dosage form contains 0.2 mg Misoprostol and 50 mg or 75 mg of Diclofenac Sodium.
Patent Application No. 019268 is based on oral tablet of Misoprostol. The dosage form is prepared by using 0.1 mg or 0.2 mg Misoprostol drug.
Patent Application No. 076095 is based on oral tablet of Misoprostol. The dosage form is prepared by using 0.1 mg or 0.2 mg Misoprostol drug.
China patent application No. 00123869 describes, suppository for treating cervical erosion and vaginitis. The suppository is prepared by using five Chinese medicinal material including Cortex Phellodendri, Rhizoma Zedoariae, pofygoni avicularis herba, alumen and pricklyash and through the processes pulverizing Chinese medicinal materials in to fine powder, heating the mixture of glycerin, gelatin and distilled water in water bath to
4

dissolve into medium, mixing the hot medium, the medicinal materials and honey, molding, cooling naturally, packing and disinfecting. This is good medicine of preventing and treating cervical erosion, vaginitis and other diseases of women.
Patent no. WO 00/09134 is claiming use of Misoprostol or Misoprostol acid for preparing of a pharmaceutical product applied to be topically to the clitoris or/and the vagina in order to cure sexual dysfunction in women. The use of Misoprostol and its acids in the form of various galenic preparations (solutions, ointments, endourethral sticks, systems of controlled-transdermal absorption). The pharmaceutical product is prepared in combination with other vasodilatory drugs as alprostadil for the synergistic action, as well as "passage accelerators" used normally in pharmaceutical technology to increase absorption of drugs through the skin or mucosa. Pharmaceutical product using Misoprostol or its acid is also prepared in combination with cyclodextrin or other substances to retard the undesired effects of the drug or prolong their pharmaceutical action.
US patent no. 6,664,290 relates to a method of limiting postpartum hemorrhage comprising administering orally a single effective dose of misoprostol to a woman during the third stage of the labor.
5

At present Misoprostol is available as oral tablets of strength 100 ug and 200 \xg. Misoprostol is available in tablet dosage form is also administered in female vagina, two to four tablets are required at a time for vaginal insertion. Tablet wetted with water is administered in vagina. There may be chances of non dissolution of tablet in the vagina. After the administration of tablet, other excipients present in the tablet may not dissolve in vagina and may come out of it giving ugly feeling. To over come from such drawbacks, there is need to prepare a novel composition of Misoprostol.
Pharmaceutical formulations of Misoprostol are widely available in market for the treatment of stomach ulcers.
The above mentioned prior art and other market search shows that, at present Misoprostol is available in tablet dosage form comprising one or more pharmaceutical excipients and/or drugs in the treatment of male erectile dysfunction, gastric and duodenal ulcers, female sexual dysfunction and hepto biliary diseases.
In the present invention of pharmaceutical composition containing misoprostol is in the form of for suppository (ovule) and, is administered through the. vaginal route. Pharmaceutical composition of misoprostol as prepared as in the present invention is having good efficacy, quick onset of
6

action due to enhanced absorption because of synergistic effect of other excipients, faster disintegration and faster dissolution. The present pharmaceutical composition is used for cervical ripening, labor induction and to counteract postpartum hemorrhage. In the preparation process of pharmaceutical composition for suppository dosage form, the use of other pharmaceutical ingredients in addition to misoprostol gives synergistic effect in enhancing of drug absorption in systemic circulation, which results into rapid onset of action. Isopropyl myristate and cholesterol enhances the absorption of misoprostol through vaginal walls.
Moreover, in the said invention Misoprostol composition prepared for the suppository dosage form administered through vaginal route, imparts several advantages over conventional dosage forms. Suppository form (i) melts at body temperature, (ii)easy to use, (iii)ability and flexibility to deliver the drug with different release rates, (iv) required less frequent doses, (v) easily removable if needed (vi) can be administered in unconscious patients.
Comparative analysis has been carried out between the Misoprostol composition for suppository dosage form of the present invention and Misoprostol Tablets (X) as presently available dosage form in the market. Comparative disintegration study has been carried out. Results are
7

mentioned in the table given below and are compared by plotting the graph of Formulation Vs Disintegration time in minutes. The graph is annexed as in figure 1.

Drug Formulation Disintegration Time (Minutes)
Misoprostol Oral Tablets 10 Minutes
Misoprostol in oily base Suppository dosage form. 3 Minutes
Misoprostol in Polyethylene Glycol base(water soluble) Suppository dosage form. 5 Minutes
From the above results it is concluded that the Misoprostol
suppository in Oily Base and Suppository in Aqueous Base require less
time for disintegration than Oral tablets of Misoprostol. Faster
disintegration occurs in Misoprostol leads to faster dissolution, that results
into rapid site specific onset of action over existing oral dosage form of
Misoprostol.
Comparative analysis on application of Presently invented Misoprostol composition Vs conventional tablet for the various treatments:

DOSAGE FORM TERMINATION
OF
PREGNANCY INDUCTION OF LABOR POSTPARTUM
HAEMORRHAG
E
8

Oral Tablets - * +
Suppository in Oily base +++ Aft* +++
Suppositoryy in Aqueous Base ++ ** ++
Note: Less Effective: (-) Good: (*)
Effective: (+) Better: (**)
More Effective: (++) Best: (***)
Most Effective: (+++)
Above analysis shows that the conventional tablets are comparatively less effective than presently invented pharmaceutical composition of Misoprostol for the treatment of termination of pregnancy, induction of labor, postpartum hemorrhage. Detail Description of the invention:
The present invention of pharmaceutical composition of Misoprostol for suppository dosage form and method of preparation thereof is described as following.
In the said invention the pharmaceutical composition of misoprostol is prepared by using the active pharmaceutical ingredient misoprostol, other pharmaceutical excipients such as Isopropyl Myristate as penetration enhancer, Propylene Glycol as solvent, Cholesterol as a surfactant, Fractionated Palm karnel oil as suppository (ovule) base, Polyethylene Glycol 200, Polyethylene Glycol 1540, Polyethylene Glycol 6000 as base,
9

Polysorbate 80 as surfactant. The use of such pharmaceutical ingredients provide good efficacy and stability to the dosage form.
In the present invention, pharmaceutical composition of Misoprostol is prepared in Oily base suppositories (ovules) and PEG (Polyethylene Glycol) base suppositories (ovules) dosage forms.
Use of Isopropyl Myristate and Cholesterol in the preparation of misoprostol pharmaceutical composition enhances the absorption of the drug in systemic circulation, which will result into rapid onset of action in cervical ripening, labor induction and postpartum hemorrhage. The use of Palm Karnel Oil in the preparation of composition is locally non irritant, chemically inert and stable, compatible with drug, shrink slightly on cooling, melting and solidifying over a narrow temperature range, is a best lubricant, do not produce rancidity over a time, no polymerization.
The pharmaceutical composition of Misoprostol comprises active pharmaceutical ingredient Misoprostol in the range between 0.002% to 0.12% w/w or stabilized diluted Misoprostol in the range between 0.02% to 1.2% w/w.
Presently invented pharmaceutical composition of Misoprostol is composed of the following active pharmaceutical ingredient and other excipients.
10

1. Pharmaceutical composition of Misoprostol in oily base suppository (ovules) dosage form:-
(I) In case of pure Misoprostol drug:
Ingredients Quantity (w/w)
Misoprostol 0.02%
Isopropyl Myristate 5.0%
Propylene Glycol 5.0%
Cholesterol 2.0%
Fractionated Palm
Karnel oil (Suppocire) quantity sufficient.
(II) In case of stabilized diluted Misoprostol:
Ingredients Quantity (w/w)
Misoprostol (1:10) 0.2%
Isopropyl Myristate 5.0%
Propylene Glycol " 5.0%
Cholesterol 2.0%
Fractionated Palm
Kernel oil (Suppocire) quantity sufficient
2. Pharmaceutical composition of Misoprostol in PEG based
suppository (Ovules) dosage form:
11

(I) Incase of pure Misoprostol drug:
Ingredient Quantity (W/W)
Misoprostol 0.02%
Polyethylene Glycol 200 5.0%
Polysorbate 80 0.1%
Polyethylene Glycol 1540 and Polyethylene Glycol 6000 (base) quantity sufficient
(II) Incase of stabilized diluted Misoprostol:
Ingredient Quantity (W/W)
Misoprostol (1:10) 0.2%
Polyethylene Glycol 200 5.0%
Polysorbate 80 0.1%
Polyethylene Glycol 1540 and
Polyethylene Glycol 6000 (base) quantity sufficient 1. Process for the preparation of pharmaceutical dosage composition
of Misoprostol for oily base suppository (ovule) dosage forms: (I) In case of pure Misoprostol drug:
Batch size: 25 kgs.(5000 suppositories)
i) Preparation of Misoprostol solution:
12

Take required quantity of Misoprostol and dissolve in 1.25 Kgs.(5% w/w) of Propylene glycol. To the above add 0.5 kg.(2%w/w) of cholesterol and 1.25 kgs.of Isopropyl myristate after bringing their temperature to 40°C + 2°C.
it) Preparation of suppository base:
Take weighed quantity of fractionated palm karnel oil (suppocire). Heat it at to 40°C ± 2°C. The mass will melt.
Hi) Prearation of the filling mass:-
Add i) to ii) with constant stirring and keeping the temperature of the mass 40°C + 2°C.Stirr to mix both the parts.
iv) Preparation of suppositories by melt mouldins method:
The melted filling mass of iii) is poured into a suppository mould. After pouring into tightly clamped mould, the suppository and mould are allowed to cool at or below 25 °C + 2°C.The size of the mould is kept in such a way that it forms a suppository weighing 5grams + 5%. Then the mould is opened and suppository are removed.
v) Packing and storage:
13

Suppositories are packaged in either partitioned boxes or in a blister of aluminum foil and PVC-polyethylene film. Store the suppository at or below 25°C.
In case of stabilized-diluted Misoprostol drug: Batch size: 25 kgs.(5000 suppositories)
i) Preparation of Misoprostol dispersion:-
Take required quantity of diluted Misoprostol(l:10) and disperse it into 1.25 kg.(5%w/w) of propylene glycol by stirring both together. Then add 1.25 kg.(5%w/w)of isopropyl Myristate and 0.5Kg.(2%w/w) of cholesterol after bringing their temperature to 40° C± 2°C.
ii) Preparation of suppository base:-
Take weighed quantity of fractionated palm karnel oil (suppocire). Heat it at to 40°C ± 2°C. The mass will melt.
Hi) Prearation of the fillins mass:-
Add i) to ii) with constant stirring and keeping the temperature of the mass 40°C + 2°C.Stirr to mix both the parts.
iv) Preparation of suppositories by melt mouldins method:
14

The melted filling mass of iii)is poured into a suppository mould. After pouring into tightly clamped mould, the suppository and mould are allowed to cool at or below 25°C + 2°C.The size of the mould is kept in such a way that it forms a suppository weighing 5grams + 5%.Then the mould is opened and suppository are removed. v) Packing and storage:
Suppository are packaged in either partitioned boxes or in a blisters of aluminum foil and PVC-poly-ethylene film. Store the suppository at or below 25°C. 2 Process for the preparation of pharmaceutical dosage composition
of Misoprostol for PEG based suppository (ovule) dosage forms: (I) In case of pure Misoprostol drug:
Batch size: 25 kgs.(5000 suppositories)
i) Preparation of Misoprostol solution:
Take required quantity of Misoprostol and dissolve in 1.25 Kgs.(5% w/w) of Polyethylene glycol-200. To the above add 0.025 kg.(0.1%w/w) of Polysorbate-80 with constant stirring and nitrogen bubbling.
15

ii) Preparation of suppository base : Take weighed quantity of Polyethylene glycol 1540 and Polyethylene glycol- 6000 in suitable proportion. Mix them and melt by heating upto 45°C± 2° C with constant stirring.
iii) Prearation of the fillins mass:-
Add i) to ii) with constant stirring and keeping the temperature of the mass 40°C ± 2°C.Stirr to mix both the parts.
iv) Preparation of suppositories by melt moulding method:
The melted filling mass of iii) is poured into a suppository mould. After pouring into tightly clamped mould, the suppository and mould are allowed to cool at or below 25°C ± 2°C.The size of the mould is kept in such a way that it forms a suppository weighing 5grams + 5%. Then the mould is opened and suppository are removed.
v) Packing and storage:
Suppositories are packaged in either partitioned boxes or in a blister of aluminum foil and PVC-polyethylene film. Store the suppository at or below 25°C.
Incase of stabilized-diluted Misoprostol drug:
16

Batch size: 25 kgs.(5000 suppositories) Preparation of Misoprostol dispersion:-
Take required quantity of diluted Misoprostol (1:10) and
disperse it into 1.25 kg.(5%w/w) of Polyethylene glycol-200
by stirring both together. Then add 0.025 kg.(0.1 %w/w) of
Polysorbate-80 with constant stirring and nitrogen bubbling.
Preparation of suppository base:-
Take weighed quantity of Polyethylene glycol 1540 and
Polyethylene glycol- 6000 in suitable proportion. Mix them
and melt by heating upto 45°C± 2° C with constant stirring.
Prearation of the fillins mass:-
Add i) to ii) with constant stirring and keeping the
temperature of the mass 40°C + 2°C.Stirr to mix both the
parts.
Preparation of suppositories by melt moulding method:
The melted filling mass of iii) is poured into a suppository
mould. After pouring into tightly clamped mould, the
suppository and mould are allowed to cool at or below 25 °C ±
2°C.The size of the mould is kept in such a way that it forms a
17

suppository weighing 5grams + 5%. Then the mould is opened and suppository are removed. v) Packing and storage:
Suppositories are packaged in either partitioned boxes or in a blister of aluminum foil and PVC-polyethylene film. Store the suppository at or below 25°C.
References:
1. A comparison of two regimens of intravaginal Misoprostol for termination of second trimester pregnancy: a randomized comparative trial. [Hum Reprod. 2000 Mar;15(3):709-12.] [PMID: 10686224]
2. Comparative study of intravaginal Misoprostol with gemeprost as an abortifacient in second trimester missed abortion. [Aust N Z J Obstet Gynaecol. 1997 Aug; 37(3):331-4.] [PMID: 9325520]
3. A preliminary study of cutaneous blood flow associated with postpartum use of oral Misoprostol. [J Obstet Gynaecol Can. 2004 Dec;26(12): 1073-6.] [PMID: 15607043]

4. Vaginal Misoprostol in managing premature rupture of membranes. [East Mediterr Health J. 2002 M-Sep;8(4-5):515-20.] [PMID: 15603033]
5. A randomized comparison of oral Misoprostol and vaginal prostaglandin E2 tablets in labour induction at term [BJOG: An International Journal of Obstetrics & Gynaecology Volume 111 Issue 5 Page 436 - May 2004]
6. A randomized double-blind study of vaginal Misoprostol Vs dinoprostone for cervical ripening and labour induction in prolonged pregnancy. [Singapore Med J. 1997 Jul;38(7):292-4] [PMID: 9339095]
7. Non-pregnant patients" preference for delivery route. [Int Urogynecol J Pelvic Floor Dysfunct. 2004 Sep-Oct;15(5):308-12. Epub 2004 Sep-Oct] [PMID: 15580415]
8. Experience with intravaginal Misoprostol in the management of intra-uterine fetal death. [Afr J Med Med Sci. 2004 Jun;33(2): 105-8] [PMID: 15565925 ]
9. A randomized controlled trial of laminaria, oral Misoprostol, and vaginal Misoprostol before abortion. [Obstet Gynecol. 1999 May;93(5 Pt l):766-70.] [PMID: 10912983]
19

10. Experience with intravaginal Misoprostol in the management of
intra-uterine fetal death. [Afr J Med Med Sci. 2004 Jun;33(2): 105-8.]
[PMID: 15565925]
11. The effect of a pill inserter on vaginal Misoprostol dosing. [J Matern
Fetal Med. 2001 Oct;10(5):332-4.] [PMID: 11730497]
12. Misoprostol: an old drug, new indication , Journal of post graduate
medicine - Drug Review: 2002, Vol. 48, Department of Clinical
Pharmacology, Seth G. S. Medical College and K. E. M Hospital,
Parel, Mumbai - 400 012, India.
20

We claim,
1. Pharmaceutical composition comprising Misoprostol for vaginal suppository dosage form and process for preparation thereof, wherein; the Misoprostol composition is comprising of active pharmaceutical ingredient Misoprostol 0.002%(w/w) to 0.12%(w/w) as pure drug or 0.02%(w/w) to 1.2%(w/w) as stabilized or diluted drug, other pharmaceutical excipients such as 5.0%(w/w) Isopropyl Myristate, 5.0%(w/w) Propylene Glycol, 2.0%(w/w) Cholesterol, quantity sufficient Fractionated Palm karnel oil, 5.0%(w/w) Polyethylene Glycol 200, Polyethylene Glycol 1540, quantity sufficient Polyethylene Glycol 6000, 0.1%(w/w) Polysorbate 80.
2. Pharmaceutical composition comprising Misoprostol as claimed in claim 1 wherein oily based suppository (ovules) forms are comprised of 0.02%(w/w) Misoprostol as pure drug or 0.2%(w/w) as stabilized diluted form, 5.0%(w/w) Isopropyl Myristate, 5.0%(w/w) Propylene Glycol, 2.0%(w/w) Cholesterol, quantity sufficient Fractionated Palm karnel oil.
3. Pharmaceutical composition comprising Misoprostol as claimed in claim 1 wherein aqueous based suppository (ovules) forms are
21

comprised of 0.2%(w/w) Misoprostol as stabilized diluted drug or 0.02%(w/w) as pure drug form, 5.0%(w/w) Polyethylene Glycol 200, 0.1%(w/w) Polysorbate 80, Polyethylene Glycol 1540 and quantity sufficient Polyethylene Glycol 6000.
4. Pharmaceutical composition comprising Misoprostol for vaginal suppository dosage form and process for preparation thereof as claimed in claim 1 wherein the Misoprostol is used in the range from 0.002% to 0.12% (w/w) or 0.02% to 1.2% (w/w) as stabilized diluted form.
5. A process for preparation of pharmaceutical composition of Misoprostol for suppository (ovules) dosage form as claimed in claim 1 wherein oily base suppository (ovule) form is prepared by dissolving 0.02% (w/w) Misoprostol drug in pure form or 0.2%(w/w) as stabilized diluted form into the solvent 5.0% (w/w) propylene glycol; further adding 5.0% (w/w) Isopropyl Myristate and 2.0%) (w/w) cholesterol with little heating; preparing oily phase by melting quantity sufficient fractionated Palm Kernel oil at 40°C; mixing above prepared drug solution into the oily phase with constant stirring; filling the mass solution into suppository
22

(ovule) mould and sealed by machine; cooling the ovules at 25°C temperature and packing.
6. A process for preparation of pharmaceutical composition of Misoprostol for suppository (ovules) dosage form as claimed in claim 1 wherein aqueous (water soluble) base suppository (ovule) form is prepared by dissolving 0.02% (w/w) Misoprostol as pure drug/0.2%(w/w) as stabilized diluted form into 5.0% (w/w) polyethylene glycol 200; adding 0.1% (w/w) Polysorbate 80 in the said solution with constant stirring and nitrogen bubbling; aqueous base is prepared by melting the blend of polyethylene glycol 1540 and quantity sufficient polyethylene glycol 6000 at 45°C; adding the aqueous base with the drug solution with constant stirring; filling the mass solution into suppository (ovule) mould and sealed by machine; cooling the ovules at 25°C temperature and packing it.
7. Pharmaceutical composition comprising Misoprostol for vaginal suppository dosage form as claimed in claim 1 has higher efficacy, provides quick onset of action due to enhanced absorption because of presence of synergistic effect in the gynecological problems such as cervical ripening, labor
23

induction, mid-trimester terminations of pregnancy and postpartum hemorrhage. 8. Pharmaceutical composition comprising Misoprostol for vaginal suppository dosage form and process for preparation thereof as substantially herein described with the foregoing description and drawing.
Dated this on 19th day of January 2005.

Dr. Rajeshkumar H. Acharya
Advocate & Patent agent
For and on behalf of the applicant.

Documents:

75-mum-2005-cancelled pages(17-10-2007).pdf

75-mum-2005-claims(granted)-(17-10-2007).doc

75-mum-2005-claims(granted)-(17-10-2007).pdf

75-mum-2005-correspondence(17-10-2007).pdf

75-mum-2005-correspondence(ipo)-(13-09-2007).pdf

75-mum-2005-drawing(24-01-2005).pdf

75-mum-2005-form 1(24-01-2005).pdf

75-mum-2005-form 18(8-01-2007).pdf

75-mum-2005-form 2(granted)-(17-10-2007).doc

75-mum-2005-form 2(granted)-(17-10-2007).pdf

75-mum-2005-form 26(24-01-2005).pdf

75-mum-2005-form 3(24-01-2005).pdf

75-mum-2005-form 5(24-01-2005).pdf

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Patent Number

214054

Indian Patent Application Number

75/MUM/2005

PG Journal Number

13/2008

Publication Date

28-Mar-2008

Grant Date

25-Jan-2008

Date of Filing

24-Jan-2005

Name of Patentee

LINCOLN PHARMACEUTICALS LIMITED

Applicant Address

NIRAV COMPLEX, OPP. NAVRANG HIGH SCHOOL, NARANPURA, AHMEDABAD - 380014.

Inventors:

#	Inventor's Name	Inventor's Address
1	PATEL RAJNI GULABDAS	NIRAV COMPLEX, OPP. NAVRANG HIGH SCHOOL, NARANPURA, AHMEDABAD - 380014.
2	MODI KUNAL BHADRESHBHAI	NIRAV COMPLEX, OPP. NAVRANG HIGH SCHOOL, NARANPURA, AHMEDABAD - 380014.
3	PATIL GOPALKRISHNA RANGNATH	NIRAV COMPLEX, OPP. NAVRANG HIGH SCHOOL, NARANPURA, AHMEDABAD - 380014.
4	AGRAWAL SANJAY KRISHNA	NIRAV COMPLEX, OPP. NAVRANG HIGH SCHOOL, NARANPURA, AHMEDABAD - 380014.

PCT International Classification Number

A61K9/02 A61K31/202

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA