Title of Invention	A PROCESS FOR PREPARING A NEW ANTIOXIDANT FOR TREATMENT OF ACUTE MYOCARDIAL INFARCTION FOR PREVENTION OF REMODELING AND HEART FAILURE
Abstract	A process for preparing a new synergistic antioxidant formulation for treatment of acute myocardial infarction for prevention of remodeling and heart failure comprising mixing the following anti-oxidants in the proportions indicated there against: Coenzyme Q10 (Ubiquinone) - 45 % - 57.5% by wt. Trimetazidine - 30 % - 40.0% by wt. Lovastatin - 1.5% -15% by wt. and the balance if any adding a conventional filler for preparing the tablet or capsule.

Title of Invention

A PROCESS FOR PREPARING A NEW ANTIOXIDANT FOR TREATMENT OF ACUTE MYOCARDIAL INFARCTION FOR PREVENTION OF REMODELING AND HEART FAILURE

Abstract

A process for preparing a new synergistic antioxidant formulation for treatment of acute myocardial infarction for prevention of remodeling and heart failure comprising mixing the following anti-oxidants in the proportions indicated there against: Coenzyme Q10 (Ubiquinone) - 45 % - 57.5% by wt. Trimetazidine - 30 % - 40.0% by wt. Lovastatin - 1.5% -15% by wt. and the balance if any adding a conventional filler for preparing the tablet or capsule.

Full Text	Form 2 THE PATENTS ACT, 1970 COMPLETE SPECIFICATION (SECTION 10) "A process for preparing a new antioxidant formulation for treatment of acute myocardial Infarction for prevention of remodeling and heart failure" Prof. Ram Bahadur Singh, Prof. Adarsh Kumar and Dr. Mohammed Arif, all Indian Citizens of Shiv Niketan, 1st Floor, Flat No. 7,18th Road, Khar West, Mumbai - 400050, Maharashtra, India The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed This invention relates to a process lord preparing a new antioxidant formulation for treatment of acute myocardial infarction for prevention of remodeling and heart failure. Background: Oxidative damage in association with antioxidant deficiency have been observed in patients with AMI. Super oxide and hydroxyl radicals and hydrogen peroxides are important reactive oxygen species in the pathogenesis of cardiac damage resulting remodeling and heart failure among these patients (1-4).Case control studies indicate that there is a deficiency of antioxidant vitamins A,E,C and beta-carotene, CoQ10,lycopene and increased free radical damage in the form of higher thiobarbituric acid reactive substances, MDA and Diane conjugates in patients with AMI and heart failure(l-5).CoQ10 and trimetazidine are potent antioxidant agents which are known to increase the production of ATP and energy in the myocardial cell(3-6). It is possible that antioxidant and bioenergetics activity of these agents may have synergistic effects in patients with AMI because these patients are known to have enormous amount of free radical stress and low level of ATP due to myocardial ischemia. Addition of stations to this combination may further enhance this activity and improve endothelial function which is beneficial in these patients. No other study has examined the role of antioxidants, bioenergetics and stations in combination in patients with AMI and heart failure. The role of Coquito in heart failure and the effect of trimetazidine in coronary artery disease(CAD) are known however the dosages and efficacy are controversial. The object of this invention is to examine the role of this combination of antioxidants in patients with AMI for prevention of remodeling in AMI and in a sub-study to find out whether it is also beneficial and safe in conjunction with statin and thereafter develop a composition for the treatment of AMI and prevention of remodeling and heart failure. To achieve said objective, the present invention provides a process for preparing a new synergistic antioxidant formulation for treatment of acute myocardial infarction for prevention of remodeling and heart failure comprising mixing the following anti-oxidants in the proportions indicated there against: Coenzyme Q10 (Ubiquinone) - 45 % - 57.5% by wt. Trimetazidine - 30 % - 40.0% by wt. Lovastatin - 1.5% -15% by wt. and the balance if any adding a conventional filler for preparing the tablet or capsule. Said filler used is cellulose. The proportions in which the ingredients are mixed in the anti-oxidant composition are as follows: Coenzyme Q10 (Ubiquinone) - 57.14 % by wt. Trimetazidine - 38.1 % by wt. Lovastatin - 4.76% by wt. The proportions in which the ingredients are mixed in the anti-oxidant composition are as follows: Coenzyme Q10 (Ubiquinone) - 45.28% by wt. Trimetazidine - 30.18 % by wt. Lovastatin - 1.9%bywt. Cellulose . - 22.64% by wt The proportions in which the ingredients are mixed in the anti-oxidant composition are as follows: Coenzyme Q10 (Ubiquinone) - 56.25 % by wt. Trimetazidine - 37.5 % by wt. Lovastatin - 6.25 % by wt. The proportions in which the ingredients are mixed in the anti-oxidant composition are as follows: Coenzyme Q10 (Ubiquinone) - 50%bywt. Trimetazidine - 33.3% by wt. Lovastatin - 4.2 % by wt. Cellulose - 12.5% by wt. The invention now will be described with reference to the following examples: Example 1: The test agent ingredients, coenzvmeQlO, trimetazidine and lovastatin were purchased from the market. These ingredients were mixed in the following proportions and capsules prepared were of 52.5mg. CoenzvmeQlO - 30mg Trimetazidine - 20mg Lovastatin - 2.5mg Example 2: The test agent ingredients, coenzyme Q10, trimetazidine and lovastatin were purchased from the market. These ingredients were mixed in the following, proportions and thereafter they were filled in capsules with cellulose. The capsules prepared were of 132.5mg. Coenzyme Q10 - 60mg Trimetazidine - 40mg Lovastatin - 2.5mg Cellulose - 30mg Example 3: The test agent ingredients, coenzyme Q10,trimetazidine and lovastatin were purchased from the market. These ingredients were mixed in the following proportions and thereafter they were filled in capsules. The capsules prepared were of 160.0mg. Coenzyme Q10 - 90mg Trimetazidine - 60mg Lovastatin - lOmg Example 4: The test agent ingredients, coenzyme Q10, trimetazidine and lovastatin were purchased from the market. These ingredients were mixed in the following proportions and thereafter they were filled in capsules with cellulose. The capsules prepared were of 240.Omg. Coenzyme Q10 - 120mg Trimetazidine - 80mg Lovastatin - 10 mg Cellulose - 30mg CLINICAL TRIALS FOR DEVELOPMENT OF PROCESS: The effects of individual ingredients in moderate, higher and in combination were studied by administering coenzyme Ql0+trimetazidine in single and double blind trials with and without control groups for a period of 4 weeks to study their synergistic effects (Tables 1-5). A randomized, double blind trial was conducted in 73 intervention and 71 control group patients of AMI for treatment and prevention of remodeling and heart failure during a follow up of 24 weeks. Results were also calculated after 4 weeks. 1. Effects of individual antioxidants in moderate doses: We administered coenzyme QIO (60 mg/day), trimetazidine (40mg/Day) and lovastatin. (10 mg/day) after randomizing the subjects into three groups (Table 1). There was a modest reduction in TBARS, MDA and Diane conjugates in the coenzyme QIO group, doubtful beneficial effect in the trimetazidine group and no effect in lovastatin group. The changes were nonsignificant. 2. Effects of individual antioxidants in higher doses: Subjects were randomized in to three groups in a double blind fashion. They were administered, coenzyme QIO (120 mg/day) or trimetazidine(80 mg/day) or lovastatin (10 mg/day) in the concerned group for a period of 4 weeks. Treatment with coenzyme QIO was associated with substantial reduction in TBARS, MDA and Diane conjugates and an increase in vitamin E,C and beta-carotene (Table 2). Treatment with trimetazidine also caused substantial changes but slightly lower than coenzyme QIO. Lovastatin had nej:UraLclicet. 3. Effects of two combined antioxidant formulation in higher doses: Subjects were randomized into three groups (after a wash out period of 4 weeks) in a double blind fashion. They were administered coenzyme QIO t trimetazidine. Coenzyme Q l0+lovastatin and trimetazidine + lovastatin. There was a substantial reduction in TBARS, MDA and Diane conjugates and increase in Vitamin E,C and beta carotene indicating that some synergistic effect is possible. 4. Effect of three combined antioxidant formulations in various doses: Subjects were randomized into three groups as given table 4 and were administered various combinations of formulations in a double blind fashion for 4 weeks. High dose combination of coenzyme Q10 (200 mg) +trimetazidine (80 mg) +lovastatin (10 mg) per day showed a marked reduction in TBARS, MDA and Diane conjugates and increase in vitamins E,C and beta carotene but lower compared to high dose combination. Study Methods: Patients of CAD were recruited by giving advertisements in the newspapers that heart disease may be slowed by treatment with antioxidants and antianginal drugs may be stopped in some patients. The diagnosis of CAD was based on available record indicating CAD. The main criteria for inclusion in the study was a serum creatinine level of Subjects and Methods for Final Trial: Clinical trial in patients with AMI were conducted to determine the effective dosage and combinations. Finally, subjects (n- 144) with proven AMI were stratified into anterior or inferior AMI of at the most 72 hours duration and were randomly divided into antioxidant (n=73) and control (n=71) groups by blindly selecting a card. Treatment: The test agent antioxidant coenzyme Q10, trimetazidine and lovastatin are marketed as health products in most industrialized countries and are used for the treatment of heart attack and heart failure and other illnesses indicating that they are safe for human trial. The placebo capsules containing inert fibre were supplied from our laboratory. All patients in the treatment group (group A) were given two capsules twice daily. The placebo capsules (two, twice daily) containing inert fibre were administered to all patients in the placebo group B. The test capsules were identical in shape, size and colour for both groups and were provided to patients in containers marked group A or B that were identical in all other respects. Compliance was monitored by counting the number of capsules returned by the patients from either container, A or B on follow-up visits or on each day during hospitalization. All other advises on treatments were similar in both groups who met for checkup to physician blind to groups. Study Design for Trial in AMI: All the patients with the diagnosis of AMI or unstable angina were randomized to two groups. The study was approved by the ethics committee of human studies in our center. After written informed consent, all patients with the above diagnosis were randomized by the pharmacist to receive either antioxidant capsules or placebo capsules. The physician examining the patients and technicians analyzing the blood were blinded to treatment groups. All patients were asked to select blindly one of the cards, each enclosed in a sealed envelope and marked either group A or B. The intervention group A (n=73) received antioxidant formulation (2 cap twice daily) and the placebo group B (n 71) received inert fibre cellulose (2 cap twice daily, 52.5 mg each) for a period of 4 and 24 weeks. All other treatments such as trinitrates, aspirin, streptokinase, beta blockers, A,C, E inhibitors were administered to both the groups. All patients were followed weekly for 4 weeks and then every 4 weekly for 12 weeks. Clinical, echocardiographic, radiologic and laboratory data were recorded at admission before entry to the study. Hypertension was defined as blood pressure > 140/90 mm/Hg and hypotension as systolic blood pressure 140 mm/Hg systolic and or >90 mm/Hg diastolic with an attempt to maintain blood pressure A blood sample after at least 10 hours of fasting was drawn at entry and then 4, 8 and 12 week of follow up in the morning and was analyzed for blood count, cardiac enzymes, T vitamin, E and C and beta-carotene and thiobarbituric acid reactive substance (TBARS), Diane conjugates and malondialdehyde (MDA) (16-20). Laboratory personnel analyzing the blood were blind to groups. Statistical analysis: The two-sample t-test using one-way analysis of variance and the Z score for proportions were used to measure the statistical significance between the two groups. Turnkeys post-hoc test was also conducted for multiple comparisons. Only a P. Value significant. Data were analyzed on the basis of intention to treat. RESULTS: The new process revealed that a combination of coenzyme QIO (120mg/day)+ trimetazidine (80mg/day) in the given doses due to their synergistic effect was most effective combination. Data were analyzed after dividing the subjects into 2 groups; antioxidant group (n=73)and placebo group(n=71). Antioxidant group showed a significant decline in TBARS,MDA and Diane conjugates and a significant increase in antioxidant vitamins E,C and beta-carotene. Effect on Cardiac Events: After 4 weeks of follow-up on treatment with this new formulation, there was a significant decrease in the total cardiac events including nonfatal myocardial infarction and deaths in the antioxidant group compared to control group (15% vs 30.9%,P arrhythmias and left ventricular dysfunction were not significantly different at entry to the study. However after 4 weeks, CoQ + trimetazidine group showed significant benefit in cardiac events and all other parameters including left ventricular dysfunction (table 7-9 ).The subgroup within group A taking lovastatin showed greater benefit in all these parameters compared to the group not taking lovastatin. Effects on Remodeling: Subgroup having poor ejection fraction showed significant decrease in all the echocardiographic parameters indicating reduction in remodelling compared to the control group. However, antioxidant group as a whole and subjects with low ejection fraction( the control group. No serious adverse effects were observed. The composition prepared according to the process of the present invention results in a synergistic composition. Effective Range of Dosages of Various Agents: Table 5 shows that optimal dosages for reversing oxidative damage in patients with CAD were: coenzyme QIO, 120 mg/day, trimetazidine (80 mg/day) and lovastatin (10 mg/day). It is clear that the effective ranges of doses of these agents in a combination should be: coenzyme Q10,60-120mg/day, trimetazidine, 40-80 mg/day, lovastatin 10-12 mg/day. In mg/kg body weight the dosages could be coenzyme Q10, 2mg, trimetazidine, 1.34 mg and lovastatin, 0.17 mg/day. DISCUSSION : This study shows that the proposed newly processed antioxidant formulation with new dosages was effective and the content have synergistic effects. Treatment with this combined antioxidant formulation containing coenzyme Q10, trimetazidine and in a subgroup in patients with AMI was associated with a significant decline in oxidative damage leading to beneficial effect on angina, arrhythmia's, heart failure and remodeling after 4 and 24 weeks of follow-up in the antioxidant groups compared to control groups (Table 7-10). No published evidence is available to demonstrate the role of antioxidants and stations in-patients with AMI. It is therefore possible that in patients with AMI, with or without low ejection fraction treatment with antioxidants and stations may have reverse oxidative damage due to its potent antioxidant and ATP sparing (bioenergetics) effects and their synergistic activity in our patients. The protective effects were apparent within 4 weeks of therapy with antioxidants indicating that the effect may be on myocardial and coronary artery endothelial function, thrombosis and left ventricular function. The benefit may also be due to anti-inflammatory and membrane stabilizing activity of antioxidants. In case control studies, plasma levels of coenzyme Q10 and vitamin A,K and C, selenium, lycopene, and antioxidant enzymes such as superoxide dismutase, catalase etc. were inversely associated with AMI and heart failure. Deficiency of vitamin E and C and beta-carotene and oxidative damage in the form of high TBARS, malondialdehyde and Diane conjugates were also observed in our study in both the groups indicating that oxidative stress may be an important mechanism of myocardial injury and oxidative damage(21-26). Experimental studies have incriminated reactive oxygen species as primary mediators in the pathogenesis of ischemic, toxic and immunologically mediated in reperfusion myocardial cell injury.(l-4) Overproduction of free radicals by blood borne cells or myocardial cells in presence of poor expression of antioxidant enzymes(5-7) can promote both direct oxidant injury and indirect effects including activation and potentiation of inflammatory mediators. Among characteristics are more leads to chronic inflammation. Cell injury is characterized with first by efflux of adenine metabolites, CPK enzymes and decline in ATP levels and then by cell detachment and cell lysis. The ability of antioxidants to decrease the loss of myocardial function as a result of oxidative injury appears to be due to its antioxidant and anti-inflammatory properties and ATP generation by CoQ10. There is evidence of a synergistic action of coenzyme Q10+ trimetazidine as well as of lovastatin in experimental studies and coenzyme Q10 can spare vitamin E in the tissues on treatment. Antioxidant bioenergetics supplementation in patients with AMI and heart failure might prevent ultimate heart failure. It may interfere with disease progression or it may reverse partial cardiac damage by cell growth and at least it may slow down the deteriorating cardiac function to a more acceptable rate. Antioxidant bioenergetics statin combination may have no ellect on scarred myocardium but can prevent cell dvsfunction. In brief the findings of our trial indicate that the newly processed antioxidant bioenergetics formulation in a new dosage form can reverse oxidative damage, decrease cardiac events, heart failure, angina pectoris, arrhythmia's as well as remodeling and heart failure in patients with failure in patients with AMI. Conclusions: Treatment with newly processed antioxidant and bioenergetics formulation in given dosages due to a synergistic effect reduces oxidative damage and cardiac events, remodeling and heart failure in the treatment group than control group. REFERENCES: 1. Grech ED, Jackson M, Ramsdale DR. Reperfusion injury after acute myocardial infarction. Br Med J 1995;310:477-478. 2. Ceremuzynski L. Hormonal and metabolic reactions evoked by acute myocardial infarction. Circ Res 1981;48:765-776. 3. Singh RB, Niaz MA, Rastogi S, Sharma JP, Kumar R, Bishnoi I, Beegom R. Plasma levels of antioxidant vitamins and oxidative stress in patients with suspected acute myocardial infarction. Acta Cardiol 1994;49:441-452. 4. Zalewski A, Savage M, Goldberg S. Protection of the ischemic myocardium during percutaneous transluminal coronary angioplasty Am J Cardiol 1988;61:54G-60G. 5. Maridonneau-Parini I, Harppey C. Effects of trimetazidine on membrane damage induced by oxygen free radicals in human cells. Br J Clin Pharmacol 1985;20: 148-51. 6. Atar D, Mortensen SA, Flachs H, Herzog WR. Coenzyme Q10 protects ischemic myocardium in an open-chest swine model. Clin Investig 1993;71:S 103-111. 7. Herzog WR, Schlossberg ML, Mortensen SA, Serebruany VL. Dietary supplementation with coenzyme Q10 reduces platelet aggregability in swine Coenzyme Q. Res Biol Med 1995;3:5-8. 8. Serebruany VL, Ordonez JV, Herzog WR. Morten R. Mortensen SA, Folkers K, Gurbel PA. Dietary coenzyme Q10 supplementation alters platelet size and inhibits human Vitronectin (CDSI/CD61) receptor expression. J Cardiocase Pharmacol 1997;29:16-22. 9. Singh RB, Niaz MA. Rastogi V, Rastogi SS. Coenzyme Q in cardiovascular disease. J Assoc Physiol India 1998;48:299-306. lO.Kamikawa T, Kobayashi A, Yamashita T, Hayashi H, Yamasaki N. Effects of coenzyme QIO on exercise tolerance in chronic stable angina pectoris. Am J Cardiol 1985;56:247-257. 1 l.Hofman-Bang C, Rehnqvist N, Swedberg K, Astrom H. Coenzyme QIO as an adjunctive in treatment of congestive heart failure. J Am Coll Cardiol 1992;19(Suppl.)774-776. 12.Kuklinski B, Weissenbacher E, Fahnrich A. Coenzyme QIO and antioxidants in acute myocardial infarction. Mol Aspect Med 1994:15(Suppl.)143-147. 13.Kontush A Reich A, Baum K, Spranger T, Finckh B, Kohlschutter A, Beisiegel U. Plasma ubiquinol is decreased in patients with hyperlipidemia. Atherosclerosis 1997:129:119-126. 14.Yokoyama H, Lingie DM, Crestanello JA, et al. Coenzyme QIO protects coronary endothelial function from ischemia reperfusion injury via an antioxidant effect. Surgery 1996;120:189-196. 15.Baggio G, Gandini R, Plancher AC, Passeri M, Carmosino G. Italian multicenter study on the safety and efficacy of coenzyme QIO as adjunctive therapy in heart failure. Mol Aspects Med 1994;15(Suppl.)287-294. 16.Soja AM, Mortensen SA. Treatment of congestive heart failure with coenzyme QIO illuminated by meta-analysis of clinical trials. Mol Aspects Med 1997:18(Suppl.):159-169. 17.Waters D,Higginson L,Gladstone P et al.Effects of cholesterol lowering on progression of coronary atherosclerosis in women.Circulation, 1995,92:2404-10. Table 3: Effects of two combined antioxidant formulation in higher doses in patients with coronary artery disease Values are means Dosages: Coenzyme Q10, l-2mg/kg body weight, trimetazidine = .67-1.3 mg/kg body weight, lovastatin = .6-1.2 mg/kg body weight. Table 4: Effect of three combined antioxidant formulations in various doses in patients of coronary artery disease. Coenzyme Q10 (120 mg/day) Coenzyme Q10(90 mg/day) Coenzyme Q10 (60mg/day) +Trimetazidine (80 mg/day) +Trimetazidine (60 mg/day) +Trimetazidine (40 mg/day) +Lovastatin (10 mg/day) -t-Lovastatin (10 mg/day) + Lovastatin (10 mg/day) Baseline After 4 week Baseline After 4 week Baseline After 4 week VrtaminE 042 078 041 063 Vitamin C 0.10 0.38 0.10 0.31 Beta-carotene 11.5 25.6 10.8 21.7 TBARS 1.54 1.0 1.55 1.32 MDA 2.88 1.5 2.92 2.31 Diane conjugates 29.6 24.0 29.6 26.0 Benefit +++ ++ Values are means. Table 5: Effective range of dosages of various agents used in the new formulation. Agents Total dose Dosage schedule Content Percentage mg/kg Effective (mg/kg) twice daily per of each agent body range (mg) capsule(mg) per capsule weight (mg/day) Coenzyme Ql0120 60.0 30.0 57.1 2.0 60-120 Trimetazidine 80 40.0 20.0 38.1 1.34 40-80 Lovastatin 10 5.0 2.5 4.8 0.17 10-12 Total Quantity 210 105.0 52 .5 - 100 Table 7: Complications and cardiac events in intervention and placebo groups at 4 weeks. Coenzyme Q Placebo Relative risk (n=73) (n=7l) (95% CI) Complications (0.28-0.80) P value obtained by comparison of intervention and placebo groups by Z score test for proportions. aP- 0.05, bP-0.02 Data are reported as number (%). CI = conlidence interval. Table 8: Changes in biochemical data after 6 months. * = P Table 9: Changes in left ventricular dysfunction on two dimensional echocardiography. Intervention group(n=27) Control group (n=28) Baseline After 6months Baseline After 6 months End diastolic volume (ml)94.2+1.9 90.5+2.0* 97.5+1.9 104.4+2.2 End systolic volume (ml) 52.5+1.5 48.0+1.2* 55.7+1.7 59.7+1.8 Left ventricular wall 12.0+2.0 10.0+1.8 12.8+2.2 13.3+2.3 thickness (mm) Left ventricular mass(g) 236+72 213+61 230+77 255+86* Area of wall thickening at 9.4+3.0 9.1+2.8* 10.1+3.1 13.7+4.2* the site of infarct(m2) Sphericity index 1.61+0.28 1.63+0.30* 1.61+0.32 1.41+0.31 * = P Table 10 : Effect of CoQ10 + trimetazidine + lovastatin in a subgroup of intervention group compared to rest of the patients of intervention group. CoQ 10+Trimetazidine+ (n=37) Baseline CoQ 10+Trimetazidine+ Lovastatin (n=36) Baseline After 4 week After 4 week Peak creatinine 712+H2 45.6+8.6 681+92 36.5+5.8 phosphokinase (IU) Lactic dehydro- 410+58 175+22 404+48 162+21 genase(IU)(3ldor4Ihday) TBARS (pmol/L) 1.87+0.41 0.51+0.11* 1.85+0.38 0.88+0.13 MDA(pmol/L) 2.78+0.43 0.67+0.13* 2.71+0.41 1.10+0.16 Diane conjugates 29.1+4.6 23.1+3.5* 28.5+4.2 25.8+3.8 (OP units) * - P O.05 Table 11: Adverse effects of antioxidant formulation. Manifestations Antioxidant group Control group Hemodialysis No dialysis Hemodialysis No dialysis (n=21) (n=27) (n=24) (n=25 We claim: 1. A process for preparing a new synergistic antioxidant formulation for treatment of acute myocardial infarction for prevention of remodeling and heart failure comprising mixing the following anti-oxidants in the proportions indicated there against: Coenzyme Q10 (Ubiquinone) - 45 % - 57.5% by wt. Trimetazidine - 30 % - 40.0% by wt. Lovastatin - 1.5% -15% by wt. and the balance if any adding a conventional filler for preparing the tablet or capsule. 2. A process as claimed in claim 1 wherein said filler used is cellulose. 3. A process as claimed in claim 1 wherein the proportions in which the ingredients are mixed in the anti-oxidant composition are as follows: Coenzyme Q10 (Ubiquinone) - 57.14 % by wt. Trimetazidine - 38.1% by wt. Lovastatin - 4.76 % by wt. 4. A process as claimed in claim 1 whejein the proportions in which the ingredients are mixed in the anti-oxidant composition are as follows: Coenzyme Q10 (Ubiquinone) - 45.28% by wt. Trimetazidine - 30.18% by wt. Lovastatin - 1.9%by wt. Filler - 22.64% by wt Jayadoc.11552(P-5) 5. A process as claimed in claim 1 wherein the proportions in which the ingredients are mixed in the anti-oxidant composition are as follows: Coenzyme Q10 (Ubiquinone) - 56.25 % by wt. TriMetazidine - 37.5 % by wt. Lovastatin - 6.25 % by wt. 6. A process as claimed in claim 1 wherein the proportions in which the ingredients are mixed in the anti-oxidant composition are as follows: Coenzyme Q10 (Ubiquinone) - 50 % by wt. Trimetazidine - 33.3% by wt. Lovastatin - 4.2 % by wt. Filler - 12.5% by wt. 7. A process for preparing a new antioxidant formulation for treatment of acute myocardial infarction for prevention of remodeling and heart failure substantially as herein described with reference to the foregoing examples. Dated this 26TH day of March, 2001 Jayadoc.11552(P-5)

Full Text

Form 2
THE PATENTS ACT, 1970
COMPLETE SPECIFICATION
(SECTION 10)

"A process for preparing a new antioxidant formulation for treatment of acute myocardial Infarction for prevention of remodeling and heart
failure"
Prof. Ram Bahadur Singh, Prof. Adarsh Kumar and Dr. Mohammed Arif, all Indian Citizens of Shiv Niketan, 1st Floor, Flat No. 7,18th Road, Khar West, Mumbai -
400050, Maharashtra, India

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed

This invention relates to a process lord preparing a new antioxidant formulation for treatment of acute myocardial infarction for prevention of remodeling and heart failure.
Background:
Oxidative damage in association with antioxidant deficiency have been observed in patients with AMI. Super oxide and hydroxyl radicals and hydrogen peroxides are important reactive oxygen species in the pathogenesis of cardiac damage resulting remodeling and heart failure among these patients (1-4).Case control studies indicate that there is a deficiency of antioxidant vitamins A,E,C and beta-carotene, CoQ10,lycopene and increased free radical damage in the form of higher thiobarbituric acid reactive substances, MDA and Diane conjugates in patients with AMI and heart failure(l-5).CoQ10 and trimetazidine are potent antioxidant agents which are known to increase the production of ATP and energy in the myocardial cell(3-6). It is possible that antioxidant and bioenergetics activity of these agents may have synergistic effects in patients with AMI because these patients are known to have enormous amount of free radical stress and low level of ATP due to myocardial ischemia. Addition of stations to this combination may further enhance this activity and improve endothelial function which is beneficial in these patients. No other study has examined the role of antioxidants, bioenergetics and stations in combination in patients with AMI and heart failure. The role of Coquito in heart failure and the effect of trimetazidine in coronary artery disease(CAD) are known however the dosages and efficacy are controversial.
The object of this invention is to examine the role of this combination of antioxidants in patients with AMI for prevention of remodeling in AMI and in a

sub-study to find out whether it is also beneficial and safe in conjunction with statin and thereafter develop a composition for the treatment of AMI and prevention of remodeling and heart failure.
To achieve said objective, the present invention provides a process for preparing a new synergistic antioxidant formulation for treatment of acute myocardial infarction for prevention of remodeling and heart failure comprising mixing the following anti-oxidants in the proportions indicated there against:
Coenzyme Q10 (Ubiquinone) - 45 % - 57.5% by wt.
Trimetazidine - 30 % - 40.0% by wt.
Lovastatin - 1.5% -15% by wt.
and the balance if any adding a conventional filler for preparing the tablet or capsule.
Said filler used is cellulose.
The proportions in which the ingredients are mixed in the anti-oxidant composition are as follows:
Coenzyme Q10 (Ubiquinone) - 57.14 % by wt.
Trimetazidine - 38.1 % by wt.
Lovastatin - 4.76% by wt.
The proportions in which the ingredients are mixed in the anti-oxidant composition are as follows:
Coenzyme Q10 (Ubiquinone) - 45.28% by wt.
Trimetazidine - 30.18 % by wt.
Lovastatin - 1.9%bywt.
Cellulose . - 22.64% by wt

The proportions in which the ingredients are mixed in the anti-oxidant composition are as follows:
Coenzyme Q10 (Ubiquinone) - 56.25 % by wt.
Trimetazidine - 37.5 % by wt.
Lovastatin - 6.25 % by wt.
The proportions in which the ingredients are mixed in the anti-oxidant composition are as follows:
Coenzyme Q10 (Ubiquinone) - 50%bywt.
Trimetazidine - 33.3% by wt.
Lovastatin - 4.2 % by wt.
Cellulose - 12.5% by wt.
The invention now will be described with reference to the following examples:
Example 1:
The test agent ingredients, coenzvmeQlO, trimetazidine and lovastatin were purchased from the market. These ingredients were mixed in the following proportions and capsules prepared were of 52.5mg.
CoenzvmeQlO - 30mg
Trimetazidine - 20mg
Lovastatin - 2.5mg
Example 2:
The test agent ingredients, coenzyme Q10, trimetazidine and lovastatin were purchased from the market. These ingredients were mixed in the following,

proportions and thereafter they were filled in capsules with cellulose. The
capsules prepared were of 132.5mg.
Coenzyme Q10 - 60mg
Trimetazidine - 40mg
Lovastatin - 2.5mg
Cellulose - 30mg
Example 3:
The test agent ingredients, coenzyme Q10,trimetazidine and lovastatin were purchased from the market. These ingredients were mixed in the following proportions and thereafter they were filled in capsules. The capsules prepared were of 160.0mg.
Coenzyme Q10 - 90mg
Trimetazidine - 60mg
Lovastatin - lOmg
Example 4:
The test agent ingredients, coenzyme Q10, trimetazidine and lovastatin were purchased from the market. These ingredients were mixed in the following proportions and thereafter they were filled in capsules with cellulose. The capsules prepared were of 240.Omg.
Coenzyme Q10 - 120mg
Trimetazidine - 80mg
Lovastatin - 10 mg
Cellulose - 30mg

CLINICAL TRIALS FOR DEVELOPMENT OF PROCESS:
The effects of individual ingredients in moderate, higher and in combination were studied by administering coenzyme Ql0+trimetazidine in single and double blind trials with and without control groups for a period of 4 weeks to study their synergistic effects (Tables 1-5). A randomized, double blind trial was conducted in 73 intervention and 71 control group patients of AMI for treatment and prevention of remodeling and heart failure during a follow up of 24 weeks. Results were also calculated after 4 weeks.
1. Effects of individual antioxidants in moderate doses:
We administered coenzyme QIO (60 mg/day), trimetazidine (40mg/Day) and lovastatin. (10 mg/day) after randomizing the subjects into three groups (Table 1). There was a modest reduction in TBARS, MDA and Diane conjugates in the coenzyme QIO group, doubtful beneficial effect in the trimetazidine group and no effect in lovastatin group. The changes were nonsignificant.
2. Effects of individual antioxidants in higher doses:
Subjects were randomized in to three groups in a double blind fashion. They were administered, coenzyme QIO (120 mg/day) or trimetazidine(80 mg/day) or lovastatin (10 mg/day) in the concerned group for a period of 4 weeks. Treatment with coenzyme QIO was associated with substantial reduction in TBARS, MDA and Diane conjugates and an increase in vitamin E,C and beta-carotene (Table 2). Treatment with trimetazidine also caused substantial changes but slightly lower than coenzyme QIO. Lovastatin had nej:UraLclicet.
3. Effects of two combined antioxidant formulation in higher doses:
Subjects were randomized into three groups (after a wash out period of 4 weeks) in a double blind fashion. They were administered coenzyme QIO t

trimetazidine. Coenzyme Q l0+lovastatin and trimetazidine + lovastatin. There was a substantial reduction in TBARS, MDA and Diane conjugates and increase in Vitamin E,C and beta carotene indicating that some synergistic effect is possible. 4. Effect of three combined antioxidant formulations in various doses:
Subjects were randomized into three groups as given table 4 and were administered various combinations of formulations in a double blind fashion for 4 weeks. High dose combination of coenzyme Q10 (200 mg) +trimetazidine (80 mg) +lovastatin (10 mg) per day showed a marked reduction in TBARS, MDA and Diane conjugates and increase in vitamins E,C and beta carotene but lower compared to high dose combination.
Study Methods:
Patients of CAD were recruited by giving advertisements in the newspapers that heart disease may be slowed by treatment with antioxidants and antianginal drugs may be stopped in some patients. The diagnosis of CAD was based on available record indicating CAD. The main criteria for inclusion in the study was a serum creatinine level of Subjects and Methods for Final Trial:
Clinical trial in patients with AMI were conducted to determine the effective dosage and combinations. Finally, subjects (n- 144) with proven AMI were stratified into anterior or inferior AMI of at the most 72 hours duration and were

randomly divided into antioxidant (n=73) and control (n=71) groups by blindly
selecting a card.
Treatment:
The test agent antioxidant coenzyme Q10, trimetazidine and lovastatin are marketed as health products in most industrialized countries and are used for the treatment of heart attack and heart failure and other illnesses indicating that they are safe for human trial. The placebo capsules containing inert fibre were supplied from our laboratory. All patients in the treatment group (group A) were given two capsules twice daily. The placebo capsules (two, twice daily) containing inert fibre were administered to all patients in the placebo group B. The test capsules were identical in shape, size and colour for both groups and were provided to patients in containers marked group A or B that were identical in all other respects. Compliance was monitored by counting the number of capsules returned by the patients from either container, A or B on follow-up visits or on each day during hospitalization. All other advises on treatments were similar in both groups who met for checkup to physician blind to groups.
Study Design for Trial in AMI:
All the patients with the diagnosis of AMI or unstable angina were randomized to two groups. The study was approved by the ethics committee of human studies in our center. After written informed consent, all patients with the above diagnosis were randomized by the pharmacist to receive either antioxidant capsules or placebo capsules. The physician examining the patients and technicians analyzing the blood were blinded to treatment groups. All patients were asked to select blindly one of the cards, each enclosed in a sealed envelope and marked either group A or B. The intervention group A (n=73) received antioxidant formulation (2 cap twice daily) and the placebo group B (n 71)

received inert fibre cellulose (2 cap twice daily, 52.5 mg each) for a period of 4 and 24 weeks. All other treatments such as trinitrates, aspirin, streptokinase, beta blockers, A,C, E inhibitors were administered to both the groups. All patients were followed weekly for 4 weeks and then every 4 weekly for 12 weeks.
Clinical, echocardiographic, radiologic and laboratory data were recorded at admission before entry to the study. Hypertension was defined as blood pressure > 140/90 mm/Hg and hypotension as systolic blood pressure 140 mm/Hg systolic and or >90 mm/Hg diastolic with an attempt to maintain blood pressure A blood sample after at least 10 hours of fasting was drawn at entry and then 4, 8 and 12 week of follow up in the morning and was analyzed for blood count, cardiac enzymes, T vitamin, E and C and beta-carotene and thiobarbituric acid reactive substance (TBARS), Diane conjugates and malondialdehyde (MDA) (16-20). Laboratory personnel analyzing the blood were blind to groups. Statistical analysis:
The two-sample t-test using one-way analysis of variance and the Z score for proportions were used to measure the statistical significance between the two groups. Turnkeys post-hoc test was also conducted for multiple

comparisons. Only a P. Value significant. Data were analyzed on the basis of intention to treat.
RESULTS:
The new process revealed that a combination of coenzyme QIO (120mg/day)+
trimetazidine (80mg/day) in the given doses due to their synergistic effect was
most effective combination. Data were analyzed after dividing the subjects into 2
groups; antioxidant group (n=73)and placebo group(n=71). Antioxidant group
showed a significant decline in TBARS,MDA and Diane conjugates and a
significant increase in antioxidant vitamins E,C and beta-carotene.
Effect on Cardiac Events: After 4 weeks of follow-up on treatment with this new
formulation, there was a significant decrease in the total cardiac events including
nonfatal myocardial infarction and deaths in the antioxidant group compared to
control group (15% vs 30.9%,P arrhythmias and left ventricular dysfunction were not significantly different at
entry to the study. However after 4 weeks, CoQ + trimetazidine group showed
significant benefit in cardiac events and all other parameters including left
ventricular dysfunction (table 7-9 ).The subgroup within group A taking lovastatin
showed greater benefit in all these parameters compared to the group not taking
lovastatin.
Effects on Remodeling:
Subgroup having poor ejection fraction showed significant decrease in all the
echocardiographic parameters indicating reduction in remodelling compared to the
control group. However, antioxidant group as a whole and subjects with low
ejection fraction( the control group. No serious adverse effects were observed.
The composition prepared according to the process of the present invention results in a synergistic composition.

Effective Range of Dosages of Various Agents:
Table 5 shows that optimal dosages for reversing oxidative damage in patients with CAD were: coenzyme QIO, 120 mg/day, trimetazidine (80 mg/day) and lovastatin (10 mg/day). It is clear that the effective ranges of doses of these agents in a combination should be: coenzyme Q10,60-120mg/day, trimetazidine, 40-80 mg/day, lovastatin 10-12 mg/day. In mg/kg body weight the dosages could be coenzyme Q10, 2mg, trimetazidine, 1.34 mg and lovastatin, 0.17 mg/day. DISCUSSION :
This study shows that the proposed newly processed antioxidant formulation with new dosages was effective and the content have synergistic effects. Treatment with this combined antioxidant formulation containing coenzyme Q10, trimetazidine and in a subgroup in patients with AMI was associated with a significant decline in oxidative damage leading to beneficial effect on angina, arrhythmia's, heart failure and remodeling after 4 and 24 weeks of follow-up in the antioxidant groups compared to control groups (Table 7-10). No published evidence is available to demonstrate the role of antioxidants and stations in-patients with AMI. It is therefore possible that in patients with AMI, with or without low ejection fraction treatment with antioxidants and stations may have reverse oxidative damage due to its potent antioxidant and ATP sparing (bioenergetics) effects and their synergistic activity in our patients. The protective effects were apparent within 4 weeks of therapy with antioxidants indicating that the effect may be on myocardial and coronary artery endothelial function, thrombosis and left ventricular function. The benefit may also be due to anti-inflammatory and membrane stabilizing activity of antioxidants. In case control studies, plasma levels of coenzyme Q10 and vitamin A,K and C, selenium, lycopene, and antioxidant enzymes such as

superoxide dismutase, catalase etc. were inversely associated with AMI and heart failure. Deficiency of vitamin E and C and beta-carotene and oxidative damage in the form of high TBARS, malondialdehyde and Diane conjugates were also observed in our study in both the groups indicating that oxidative stress may be an important mechanism of myocardial injury and oxidative damage(21-26).
Experimental studies have incriminated reactive oxygen species as primary mediators in the pathogenesis of ischemic, toxic and immunologically mediated in reperfusion myocardial cell injury.(l-4) Overproduction of free radicals by blood borne cells or myocardial cells in presence of poor expression of antioxidant enzymes(5-7) can promote both direct oxidant injury and indirect effects including activation and potentiation of inflammatory mediators. Among characteristics are more leads to chronic inflammation. Cell injury is characterized with first by efflux of adenine metabolites, CPK enzymes and decline in ATP levels and then by cell detachment and cell lysis. The ability of antioxidants to decrease the loss of myocardial function as a result of oxidative injury appears to be due to its antioxidant and anti-inflammatory properties and ATP generation by CoQ10.
There is evidence of a synergistic action of coenzyme Q10+ trimetazidine as well as of lovastatin in experimental studies and coenzyme Q10 can spare vitamin E in the tissues on treatment. Antioxidant bioenergetics supplementation in patients with AMI and heart failure might prevent ultimate heart failure. It may interfere with disease progression or it may reverse partial cardiac damage by cell growth and at least it may slow down the deteriorating cardiac function to a more acceptable rate. Antioxidant bioenergetics statin combination may have no ellect on scarred myocardium but can prevent cell dvsfunction.
In brief the findings of our trial indicate that the newly processed antioxidant bioenergetics formulation in a new dosage form can reverse

oxidative damage, decrease cardiac events, heart failure, angina pectoris, arrhythmia's as well as remodeling and heart failure in patients with failure in patients with AMI.
Conclusions: Treatment with newly processed antioxidant and bioenergetics formulation in given dosages due to a synergistic effect reduces oxidative damage and cardiac events, remodeling and heart failure in the treatment group than control group.

REFERENCES:
1. Grech ED, Jackson M, Ramsdale DR. Reperfusion injury after acute myocardial infarction. Br Med J 1995;310:477-478.
2. Ceremuzynski L. Hormonal and metabolic reactions evoked by acute myocardial infarction. Circ Res 1981;48:765-776.
3. Singh RB, Niaz MA, Rastogi S, Sharma JP, Kumar R, Bishnoi I, Beegom R. Plasma levels of antioxidant vitamins and oxidative stress in patients with suspected acute myocardial infarction. Acta Cardiol 1994;49:441-452.
4. Zalewski A, Savage M, Goldberg S. Protection of the ischemic myocardium during percutaneous transluminal coronary angioplasty Am J Cardiol 1988;61:54G-60G.
5. Maridonneau-Parini I, Harppey C. Effects of trimetazidine on membrane damage induced by oxygen free radicals in human cells. Br J Clin Pharmacol 1985;20: 148-51.
6. Atar D, Mortensen SA, Flachs H, Herzog WR. Coenzyme Q10 protects ischemic myocardium in an open-chest swine model. Clin Investig 1993;71:S 103-111.
7. Herzog WR, Schlossberg ML, Mortensen SA, Serebruany VL. Dietary supplementation with coenzyme Q10 reduces platelet aggregability in swine Coenzyme Q. Res Biol Med 1995;3:5-8.
8. Serebruany VL, Ordonez JV, Herzog WR. Morten R. Mortensen SA, Folkers K, Gurbel PA. Dietary coenzyme Q10 supplementation alters platelet size and inhibits human Vitronectin (CDSI/CD61) receptor expression. J Cardiocase Pharmacol 1997;29:16-22.
9. Singh RB, Niaz MA. Rastogi V, Rastogi SS. Coenzyme Q in cardiovascular disease. J Assoc Physiol India 1998;48:299-306.

lO.Kamikawa T, Kobayashi A, Yamashita T, Hayashi H, Yamasaki N. Effects
of coenzyme QIO on exercise tolerance in chronic stable angina pectoris.
Am J Cardiol 1985;56:247-257. 1 l.Hofman-Bang C, Rehnqvist N, Swedberg K, Astrom H. Coenzyme QIO as
an adjunctive in treatment of congestive heart failure. J Am Coll Cardiol
1992;19(Suppl.)774-776. 12.Kuklinski B, Weissenbacher E, Fahnrich A. Coenzyme QIO and
antioxidants in acute myocardial infarction. Mol Aspect Med
1994:15(Suppl.)143-147. 13.Kontush A Reich A, Baum K, Spranger T, Finckh B, Kohlschutter A,
Beisiegel U. Plasma ubiquinol is decreased in patients with hyperlipidemia.
Atherosclerosis 1997:129:119-126. 14.Yokoyama H, Lingie DM, Crestanello JA, et al. Coenzyme QIO protects
coronary endothelial function from ischemia reperfusion injury via an
antioxidant effect. Surgery 1996;120:189-196. 15.Baggio G, Gandini R, Plancher AC, Passeri M, Carmosino G. Italian
multicenter study on the safety and efficacy of coenzyme QIO as adjunctive
therapy in heart failure. Mol Aspects Med 1994;15(Suppl.)287-294. 16.Soja AM, Mortensen SA. Treatment of congestive heart failure with
coenzyme QIO illuminated by meta-analysis of clinical trials. Mol Aspects
Med 1997:18(Suppl.):159-169. 17.Waters D,Higginson L,Gladstone P et al.Effects of cholesterol lowering on progression of coronary atherosclerosis in women.Circulation, 1995,92:2404-10.

Table 3: Effects of two combined antioxidant formulation in higher doses in patients with coronary artery disease

Values are means Dosages: Coenzyme Q10, l-2mg/kg body weight, trimetazidine = .67-1.3 mg/kg body weight, lovastatin = .6-1.2 mg/kg body weight.

Table 4: Effect of three combined antioxidant formulations in various doses in patients of coronary artery disease.
Coenzyme Q10 (120 mg/day) Coenzyme
Q10(90 mg/day) Coenzyme Q10 (60mg/day)
+Trimetazidine (80 mg/day)
+Trimetazidine (60 mg/day) +Trimetazidine (40 mg/day)
+Lovastatin (10 mg/day) -t-Lovastatin
(10 mg/day) + Lovastatin (10 mg/day)
Baseline After 4 week Baseline
After 4 week Baseline After 4 week
VrtaminE 042 078 041 063
Vitamin C 0.10 0.38 0.10 0.31
Beta-carotene 11.5 25.6 10.8 21.7
TBARS 1.54 1.0 1.55 1.32
MDA 2.88 1.5 2.92 2.31
Diane conjugates 29.6 24.0 29.6 26.0
Benefit +++ ++
Values are means.

Table 5: Effective range of dosages of various agents used in the new
formulation.
Agents Total dose Dosage schedule Content Percentage mg/kg
Effective
(mg/kg) twice daily per of each agent body
range
(mg) capsule(mg) per capsule weight
(mg/day)
Coenzyme Ql0120 60.0 30.0 57.1 2.0 60-120
Trimetazidine 80 40.0 20.0 38.1 1.34 40-80
Lovastatin 10 5.0 2.5 4.8 0.17 10-12
Total Quantity 210 105.0 52 .5 - 100

Table 7: Complications and cardiac events in intervention and placebo groups at
4 weeks.
Coenzyme Q
Placebo Relative risk
(n=73)
(n=7l) (95% CI)
Complications

(0.28-0.80) P value obtained by comparison of intervention and placebo groups by Z score test for proportions. aP- 0.05, bP-0.02 Data are reported as number (%). CI = conlidence interval.

Table 8: Changes in biochemical data after 6 months.

* = P
Table 9: Changes in left ventricular dysfunction on two dimensional echocardiography.
Intervention group(n=27)
Control group (n=28)
Baseline After 6months Baseline
After 6 months
End diastolic volume (ml)94.2+1.9 90.5+2.0* 97.5+1.9
104.4+2.2
End systolic volume (ml) 52.5+1.5 48.0+1.2* 55.7+1.7
59.7+1.8
Left ventricular wall 12.0+2.0 10.0+1.8** 12.8+2.2
13.3+2.3
thickness (mm)
Left ventricular mass(g) 236+72 213+61** 230+77
255+86*
Area of wall thickening at 9.4+3.0 9.1+2.8* 10.1+3.1
13.7+4.2*
the site of infarct(m2)
Sphericity index 1.61+0.28 1.63+0.30* 1.61+0.32
1.41+0.31
* = P

Table 10 : Effect of CoQ10 + trimetazidine + lovastatin in a subgroup of intervention group compared to rest of the patients of intervention group.
CoQ 10+Trimetazidine+
(n=37) Baseline
CoQ 10+Trimetazidine+
Lovastatin (n=36)
Baseline After 4 week
After 4 week
Peak creatinine 712+H2 45.6+8.6 681+92 36.5+5.8
phosphokinase (IU)
Lactic dehydro- 410+58 175+22 404+48 162+21
genase(IU)(3ldor4Ihday)
TBARS (pmol/L) 1.87+0.41 0.51+0.11* 1.85+0.38 0.88+0.13
MDA(pmol/L) 2.78+0.43 0.67+0.13* 2.71+0.41 1.10+0.16
Diane conjugates 29.1+4.6 23.1+3.5* 28.5+4.2 25.8+3.8
(OP units)
* - P O.05

Table 11: Adverse effects of antioxidant formulation.

Manifestations

Antioxidant group Control group
Hemodialysis No dialysis Hemodialysis

No dialysis

(n=21)

(n=27)

(n=24)

(n=25

We claim:
1. A process for preparing a new synergistic antioxidant formulation for
treatment of acute myocardial infarction for prevention of remodeling and
heart failure comprising mixing the following anti-oxidants in the
proportions indicated there against:
Coenzyme Q10 (Ubiquinone) - 45 % - 57.5% by wt.
Trimetazidine - 30 % - 40.0% by wt.
Lovastatin - 1.5% -15% by wt.
and the balance if any adding a conventional filler for preparing the tablet or capsule.
2. A process as claimed in claim 1 wherein said filler used is cellulose.
3. A process as claimed in claim 1 wherein the proportions in which the
ingredients are mixed in the anti-oxidant composition are as follows:
Coenzyme Q10 (Ubiquinone) - 57.14 % by wt.
Trimetazidine - 38.1% by wt.
Lovastatin - 4.76 % by wt.
4. A process as claimed in claim 1 whejein the proportions in which the
ingredients are mixed in the anti-oxidant composition are as follows:
Coenzyme Q10 (Ubiquinone) - 45.28% by wt.
Trimetazidine - 30.18% by wt.
Lovastatin - 1.9%by wt.
Filler - 22.64% by wt
Jayadoc.11552(P-5)

5. A process as claimed in claim 1 wherein the proportions in which the
ingredients are mixed in the anti-oxidant composition are as follows:
Coenzyme Q10 (Ubiquinone) - 56.25 % by wt.
TriMetazidine - 37.5 % by wt.
Lovastatin - 6.25 % by wt.
6. A process as claimed in claim 1 wherein the proportions in which the
ingredients are mixed in the anti-oxidant composition are as follows:
Coenzyme Q10 (Ubiquinone) - 50 % by wt.
Trimetazidine - 33.3% by wt.
Lovastatin - 4.2 % by wt.
Filler - 12.5% by wt.
7. A process for preparing a new antioxidant formulation for treatment of acute myocardial infarction for prevention of remodeling and heart failure substantially as herein described with reference to the foregoing examples.
Dated this 26TH day of March, 2001

Jayadoc.11552(P-5)

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Patent Number

197787

Indian Patent Application Number

289/MUM/2001

PG Journal Number

41/2007

Publication Date

12-Oct-2007

Grant Date

06-Jan-2006

Date of Filing

28-Mar-2001

Name of Patentee

PROF. RAM BAHADUR SINGH

Applicant Address

SHIV NIKETAN, 1ST FLOOR, FLAT NO.7, 18TH ROAD, KHAR WEST, MUMBAI 400 050, MAHARASHTRA, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	PROF. RAM BAHADUR SINGH	SHIV NIKETAN, 1ST FLOOR, FLAT NO.7, 18TH ROAD, KHAR WEST, MUMBAI - 400 050, MAHARASHTRA, INDIA.
2	PROF. ADARSH KUMAR	SHIV NIKETAN, 1ST FLOOR, FLAT NO.7, 18TH ROAD, KHAR WEST, MUMBAI - 400 050, MAHARASHTRA, INDIA.
3	DR. MOHAMMAD ARIF NIAZ	SHIV NIKETAN, 1ST FLOOR, FLAT NO.7, 18TH ROAD, KHAR WEST, MUMBAI - 400 050, MAHARASHTRA, INDIA.

PCT International Classification Number

N/A

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA