FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13) 1. TITLE OF THE INVENTION:
"A pharmaceutical composition for controlling pregnancy complications by reducing hyperhomocysteinemia and thereof
2. APPLICANT (S)
(a) NAME: WANBURY LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: Plot No.28, 1st floor, Sector 19C, Kopri Road, Vashi,
Navi Mumbai - 400703, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and its use thereof.

Technical Field of Invention:
The present invention relates to a pharmaceutical composition for controlling or reducing the incidence of pregnancy complications in high risk pregnancy comprising folic acid, methylcobalamin and pyridoxine to reduce hyperhomocysteinemia. The present invention also relates to the oral dosage form comprising the said pharmaceutical compositions along with the pharmaceutically acceptable excipients formulated into film coated tablets ,coated pellets in capsules ,minute tablets in capsules, hard gelatin capsules or soft gelatin capsule, more preferably the soft gelatin capsule.
Background of Invention
Pregnancy is full of the most cherishable moments in a woman's life. With every pregnancy there is an associated risk of pregnancy complications. But with high risk pregnancy, the risk of pregnancy complications is much higher. High risk pregnancy is defined as pregnancy above age of 35 years, previous pregnancy with complications, pregnancy with more than one baby, pregnancy with concomitant disease such as diabetes, hypertension. The incidence of high risk pregnancy is rising worldwide.
Clinical management of high risk pregnancy is aimed at controlling pregnancy complications. Two most common approaches practiced in clinical management routinely in this regard are:
• folic acid supplementation in the first trimester in order to prevent (NTD) neural tube defects in the fetus; and
• progesterone supplementation in the first trimester in order to prevent abortion & in the second or third trimester to prevent preterm labour.
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In spite of supplementing folic acid and progesterone, incidence of NTDs & pregnancy complications is on rise in India. Also, incidence of high risk pregnancy is increasing in India, one of the important reasons being late marriages & conceiving at an age over 35 years. Reducing pregnancy complications in such ladies is challenging.
Incidence in India:

NTD (neural tube defects) 8.8 per 1000 births (HIGHEST WORLDWIDE)
Abortion 2 million annually
IUGR(Intrauterine growth restriction) 28.6%
Pre-eclampsia 44.44%
Preterm labour 23.3%
The same implies that:
• Only folic acid deficiency is not the exclusive cause of NTDs.
• Progesterone deficiency is not the only cause behind abortion or preterm labour.
• There is some cause behind NTDs and pregnancy complications which is not treated with folic acid alone and/or progesterone.
In view of rise in the number of high risk pregnancies and pregnancy complications in India, research has focused on finding out the unattended cause behind NTDs & pregnancy complications. The important research finding documented by large number of published studies reveals that Hyperhomocysteinemia is an independent causal factor behind NTDs & pregnancy complications. The causative factors behind hyperhomocysteinemia are folic acid, methylcobalamin and pyridoxine deficiencies.
There are ample references available on the studies associated with hyperhomocysteinaemia and pregnancy complications.
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Curr Drug Metab. 2007 Jan;8(l):17-31; "Hyperhomocysteinaemia: a critical review of old and new aspects" by Herrmann W, Herrmann M, Obeid R. Clinical Chemistry and Laboratory Medicine/Central Laboratory, Saarland University Medical School, 66421 Homburg, Germany, kchwher@uniklinikum-saarland.de
Med Monatsschr Pharm. 2006 Aug;29(8):291-302. "Hyperhomocysteinemia and B-vitamin deficiency. Current clinical aspects"(Article in German) by Herrmann W, Herrmann M, Obeid R. Klinische Chemie/Zentrallabor, Universitatsklinikum des Saarlandes, Homburg. kchwher@uniklinikum-saarland.de
J Nutr. 2006 Jun;136(6 Suppl):1731S-1740S. "The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease" by Refsum H, Nurk E, Smith AD, Ueland PM, Gjesdal CG, Bjelland I, Tverdal A, Tell GS, Nygard O, Vollset SE. Norwegian Institute of Public Health, Oslo, Norway. helga.refsum@physiol.ox.ac.uk
Minerva Ginecol. 2005 Dec;57(6):619-25. "Hyperhomocysteinemia: associated obstetric diabetes and fetal malformations" [Article in Italian] by Rugolo S, Mirabella D, Cantone SM, Giuffrida A. Unita di Ginecologia, Dipartimento di Scienze Microbiologiche e Ginecologiche, Ospedale Santo Bambino, Piazza Torre del Vescovo 2 OSB, 95100 Catania, Italy.
Clin Chem Lab Med. 2005;43(10):1052-7. "Homocysteine, folic acid and vitamin B12 in relation to pre- and postnatal health aspects" by Obeid R, Herrmann W; Department of Clinical Chemistry, Saarland Medical School, Homburg, Germany.
Ginekol Pol. 2004 Apr;75(4):317-25. "Hyperhomocysteinemia and pregnancy complications" [Article in Polish] by Sztenc S.
Eur J Obstet Gynecol Reprod Biol. 2003 Apr 25;107(2):125-34 "Homocysteine, folic acid and B-group vitamins in obstetrics and gynaecology" by de la Calle M, Usandizaga
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R, Sancha M, Magdaleno F, Herranz A, Cabrillo E. Department of Obstetrics and Gynaecology, Hospital La Paz, Paseo de la Castellana n 261,28046 Madrid, Spain.
Am J Clin Nutr. 2001 Aug;74(2):233-41. Am J Clin Nutr. 2001 Aug;74(2): 157-9. "Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians" by Refsum H, Yajnik CS, Gadkari M, Schneede J, Vollset SE, Orning L, Guttormsen AB, Joglekar A, Sayyad MG, Ulvik A, Ueland PM.

Eur J Nutr. 2002 Apr;41(2):68-77. "Hyperhomocysteinemia, and low intakes of folic acid and vitamin B12 in urban North India" by Misra A, Vikram NK, Pandey RM, Dwivedi
M, Ahmad FU, Luthra K, Jain K, Khanna N, Devi JR, Sharma R, Guleria R.
Department of Medicine, All India Institute of Medical Sciences, New Delhi. anoopmisra@hotmail.com
Alt Med Rev 1996;l(4):220-235 "Methionine and Homocysteine Metabolism and the Nutritional Prevention of Certain Birth Defects and Complications of Pregnancy" by Alan L. Miller, N.D. and Gregory S. Kelly, N.D.
Can J Public Health. 2006 Mar-Apr;97(2): 132-5. "Improvements in the status of folate and cobalamin in pregnant Newfoundland women are consistent with observed reductions in the incidence of neural tube defects" by House JD, March SB, Ratnam MS, Crowley M, Friel JK.
Eur J Clin Nutr. 2005 Sep;59(9): 1064-70. "High prevalence of folic acid and vitamin B12 deficiencies in infants, children, adolescents and pregnant women in Venezuela" by Garcia-Casal MN, Osorio C, Landaeta M, Leets I, Matus P, Fazzino F, Marcos E. Instituto Venezolano de Investigaciones Cientificas (IVIC), Carretera Panamericana, Centro de Medicina Experimental, Laboratorio de Fisiopatologia, Caracas, Venezuela.
Eur J Clin Nutr. 2006 Jun;60(6):791-801. Epub 2006 Jan 11. "Low maternal vitamin B(12) status is associated with intrauterine growth retardation in urban South Indians" by
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Muthayya S, Kurpad AV, Duggan CP, Bosch RJ, Dwarkanath P, Mhaskar A, Mhaskar R, Thomas A, Vaz M, Bhat S, Fawzi WW.
Asia Pac J Clin Nutr. 2005; 14(2): 179-81. "Maternal total homocysteine concentration and neonatal size in India" by Yajnik CS, Deshpande SS, Panchanadikar AV, Naik SS, Deshpande JA, Coyaji KJ, Fall C, Refsum H. King Edward Memorial Hospital, Pune, India.
BJOG. 2002 Jul;109(7):784-91. "Relationship between total homocysteine and folate levels in pregnant women and their newborn babies according to maternal serum levels of vitamin B12" by Guerra-Shinohara EM, Paiva AA, Rondo PH, Yamasaki K, Terzi CA, D'Almeida V.Department of Clinical Chemistry and Toxicology, Faculty of Phamaceutical Science, University of Sao Paulo, Brazil.
Eur J Haematol. 2006 Jun;76(6):521-5. Epub 2006 Mar 17. "Cobalamin status during normal pregnancy and postpartum: a longitudinal study comprising 406 Danish women" by Milman N, Byg KE, Bergholt T, Eriksen L, Hvas AM; Department of Obstetrics, Gentofte Hospital, University of Copenhagen, Denmark
Drugs R D. 2004;5(5):259-69. "Oral pyridoxine during pregnancy: potential protective effect for cardiovascular malformations" by Czeizel AE, Puho E, Banhidy F, Acs N. Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary
Indian J Physiol Pharmacol. 2004 Jul;48(3):304-10. "Effect of pyridoxine deficiency on the structural and functional development of hippocampus" by Krishna AP, Ramakrishna T; Department of Physiology, K. S. Hegde Medical Academy, Nithyananda Nagar, Deralakatte, Mangalore-575 018
Z Emahrungswiss. 1996 Dec;35(4):309-17. "The importance of vitamin B 6 for development of the infant and Human medical and animal experiment studies" [Article in
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German] by Gerster H; Abteilung fur Vitaminforschung F. Hoffmann-La Roche AG, Basel, Schweiz
Role of Folic acid-
It is well known that the remethylation pathway of homocysteine degradation produces the amino acid methionine, and is dependent on adequate intake of folic acid and methylcobalamin. Therefore, for treatment of hyperhomocysteinemia, and all the pregnancy complications associated with the same, folic acid supplementation is required. Folic acid supplementation reduces incidence of Neural tube defects (NTDs), which are common birth defects. Also, the relationship of folic acid deficiency with anaemia is well established. Folic acid deficiency is risk factor for intrauterine fetal death, congenital cardiac malformation and other placental diseases (pre-eclampsia, placental abruption) and intrauterine growth restriction - IUGR. Hence, folic acid supplementation will contribute towards reducing these complications. Folic acid 5 mg supplementation in pregnancy is a well established therapy.
Role of Methylcobalamin -
It is well known that the remethylation pathway of homocysteine degradation produces the amino acid methionine, and is dependent on adequate intake of folic acid and methylcobalamin. Therefore, for treatment of hyperhomocysteinemia, and all the pregnancy complications associated with the same, methylcobalamin supplementation is required. Studies suggest that besides folic acid, methylcobalamin has a potential role in NTD risk reduction. Pregnant women with low B12 (methylcobalamin) levels are unable to provide necessary amount of vitamin B12 to their fetuses. Also, vitamin B12 deficiency is often seen in pregnant women. The clinical consequences are the lack of utilization of homocysteine for methionine transformation and presence of neurological abnormalities. Methylcobalamin supplementation alongwith folic acid is contributing to dramatic reductions in NTD rates. Low vitamin B12 levels are also related to anemia & IUGR. Use of methylcobalamin in treatment of anaemia is well known. Also, methylcobalamin supplementation is likely to play an important role in reducing IUGR.
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Role of Pyridoxine Hydrochloride -
It is well known that the trans-sulfuration pathway of homocysteine degradation produces the amino acids cysteine and taurine, and is dependent on adequate intake of vitamin B6. Therefore, for treatment of hyperhomocysteinemia, and all the pregnancy complications associated with the same, besides folic acid and methylcobalamin, pyridoxine supplementation is also required. Protective effect against cardiovascular malformations in fetus is reported with pyridoxine administration. Also, pyridoxine supplementation can prevent nausea and vomiting during pregnancy.
Brands exist in Indian market containing folic acid alone to be used from first trimester of pregnancy itself or in combination with methylcobalamin, pyridoxine along with iron to be used from second trimester of pregnancy. Folic acid, methylcobalamin and pyridoxine deficiencies are commonly seen in pregnant women. To control neural tube defects as well as a range of pregnancy complications such as spontaneous miscarriages, recurrent fetal loss, intrauterine growth retardation (IUGR), pre-eclampsia and intrauterine fetal death, it is essential to treat hyperhomocysteinemia. To treat hyperhomocysteinemia completely, combination of all the three - folic acid, methylcobalamin and pyridoxine hydrochloride is required.
Hence, the pregnancy supplement reducing hyperhomocysteinemia is ideal and innovative approach in controlling pregnancy complications. Such pregnancy supplement is truly the need of time.
Objectives of the Invention:
The main object of the present invention is to provide a pharmaceutical composition comprising folic acid, methylcobalamin and pyridoxine to reduce Hyperhomocysteinemia thereby controlling (reducing the incidence of ) pregnancy complications in high risk pregnancy
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Another object of the present invention is to provide an oral dosage form such as film coated tablets, coated pellets in capsules, minute tablets in capsules, hard gelatin capsules or soft gelatin capsule for the treatment of Hyperhomocysteinemia.
Still another object of the present invention is to provide pharmaceutical composition and formulations to minimize the side effects to control the complications during the pregnancy.
Summary of the Invention:
In accordance with the above objectives, the invention discloses a pharmaceutical composition comprising fixed dose combination of folic acid 5 mg, methylcobalamin 1500 meg and pyridoxine 1.5 mg wherein the methylcobalamin is present in the right dose which can be directly absorbed independent of intrinsic factor thus suitable for the patients having deficiency of intrinsic factor.
Accordingly, the process for the preparation of the said pharmaceutical composition involves mixing the active ingredients in oil base followed by filling it between the two layers of gelatin mass and subsequently drying it under controlled conditions.
The present invention also discloses the oral dosage form comprising pharmaceutical composition along with the pharmaceutically acceptable excipients formulated into film coated tablets, coated pellets in capsules, minute tablets in capsules, hard gelatin capsules or soft gelatin capsules.
As per the available market data, there are many brands available containing folic acid 5 mg or combination of folic acid 5 mg and methylcobalamin 500 meg / 750 meg but there is no a single brand available in Indian or International market having the composition of folinine ( fixed dose combination of folic acid 5 mg, methylcobalamin 1500 meg and pyridoxine 1.5 mg ) Hence, by virtue of composition, the present compositions are novel and unique. Thus, it contains all the active ingredients which are essential to reduce
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hyperhomocysteinemia and control the pregnancy complications in all the nine months of pregnancy.
Detailed Description:
The composition of the present invention describes Folic acid, Methylcobalamin and Pyridoxine Hydrochloride which act together to reduce hyperhomocysteinemia and control pregnancy complications which is essential in all the nine months of pregnancy.
The composition of the invention will thus reduce the incidence of neural tube defects, other congenital defects and will control( reduce incidence of ) a range of pregnancy complications such as spontaneous miscarriage, recurrent fetal loss, IUGR, preeclampsia, placental abruption, intrauterine fetal death, preterm labour.
Therefore, the composition of the invention is the one which offers the right dose combination of folic acid, methylcobalamin and pyridoxine.
Methylcobalamin is present in the stable pharmaceutical composition of the present invention in an amount ranging from 1500 meg to 2250 meg.
Folic acid is present in the stable pharmaceutical composition of the present invention in an amount ranging from 5 mg to 10 mg..
Pyridoxine-Hydrochloride is present in the stable pharmaceutical composition of the present invention in an amount ranging from 1.5 mg to 1.8 mg.
The procedure involves in the preparation of medication by mixing active ingredients Folic acid IP 5 mg ; Methylcobalamin 1500 mcg and Pyridoxine Hydrochloride IP 1.5 mg in an oil base in the first step.
Second step involves preparation of Gelatin mass which is homogenised for 15- 20 minutes. Finally, in the third step, the medication is filled into two layers of gelatin mass
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which is then dried under controlled conditions. The approved colours are used in gelatin shell and appropriate averages of vitamins added to the composition. The product is then packed into primary and secondary packing material.
Folic acid 5 mg, Methylcobalamin 1500 meg and pyridoxine 1.5 mg are the right and clinically established supplemental doses. Methylcobalamin in lower doses shows variable absorption. Also, methylcobalamin absorption depends exclusively on intrinsic factor if lower doses are used. But, 1% of right dose (1500 meg) gets directly absorbed, does not require intrinsic factor. This will ensure better absorption of 1500 meg than 500 mcg/750 meg in patients having deficiency of intrinsic factor.
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We claim:
1. A stable pharmaceutical composition comprising effective amounts of folic acid, methylcobalamin and pyridoxine to reduce hyperhomocysteinemia and control pregnancy complications in high risk pregnancy with minimal or no side effects.
2. The pharmaceutical composition as claimed in claiml, wherein the Methylcobalamin is present in an amount of 1500 meg to 2250 meg.
3. The pharmaceutical composition as claimed in claim 1, wherein the Folic acid is present in an amount of 5 mg to 10 mg..
4. The pharmaceutical composition as claimed in claim 1, wherein the Pyridoxine-Hydrochloride is present in an amount of 1.5 mg to 1.8 mg.
5. The pharmaceutical composition as claimed in claim 1, wherein the said formulation is formulated into specific dosage form using suitable pharmaceutical excipients selected from binding agents , gelling agents, dispersion agents, carrier and solvents.
6. The pharmaceutical composition as claimed in claim 5, wherein the said specific dosage forms are selected from film coated tablets ,coated pellets in capsules ,minute tablets in capsules, hard gelatin capsules or soft gelatin capsule, preferably soft gelatin capsule.
Dated this the 8th day of August, 2007

Dr. P. Aruna Sree Agent for the applicant
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ABSTRACT:
The present invention discloses a pharmaceutical composition for controlling or reducing the incidence of pregnancy complications in high risk pregnancy comprising folic acid, methylcobalamin and pyridoxine to reduce hyperhomocysteinemia.
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