Title of Invention	STABLE INTRAVENOUS PREPARATION OF ARTEMISININ' AND ITS DERIVATIVES
Abstract	A process for the manufacture of an injectable antimalarial composition comprising providing (i) an antimalarial active material of general formula (IA) /(IB); Formula (IA) Where R = Oxygen with or without (ii) other antimalarial carrier solvent in solution. Formula VI (iii) 2.5-di-0-methyl-1.4;3.6-dianhydro-D-glucitol having formula VI

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WTO THE PATENTS ACT 1970 ■*.. * ■* COMPLETE SPECIFICATION / ORIGINAL SECTION 10 v ■«* STABLE INTRAVENOUS PREPARATION OF 'ARTEMISININ' AND ITS DERIVATIVES (1) PATEL DINESH SHANTILAL S.V. ROAD, GOREGAON , WEST , MUMBAI - 400104. (2)K.S. PRABHUDAS , MUMBAI - 400 104. The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed : / 26-6-2006 64 |BOM|l999 GRANTED 28 JAN 1999 Field of Invention: "Falciparum Malaria1 is a major parasitic disease and a problem of the major tropical countries of the world. Parasite resistance, to chloroquine and mafloquine, has been rapidly increasing in both degree and prevalence throughout the world. Thus there have been continuous efforts to develop effective chemotherapeutic agents for its treatment. The development of qinghaosu or Artemisinin derivatives, has revolutionized the treatment of such resistant malaria. The present invention relates to a stable preparation of Artemisinin and its derivatives, which are used as anti-malarials and as per specifications and claims. The term 'Artemisinin derivatives' means, its esters - like Artesunate; ethers like Arteether and Artemether and cognate derivatives as well as a solution containing substantial amounts of Artemisinin derivatives which are used as 'Antimalarials' more specifically in cases of 'falciparum malaria'. This invention relates to a novel therapeutic formulation for a parental application which can be used either 'intramuscularly' or 'intravenously'. More particularly it relates to a limpid, stable economically beneficial preparation of'Antimalarial' compounds of Artemisinin derivatives - such as structurally described hereunder AND its composition in 2.5-di-O-methyl-1.4;3.6-dianhydro-D~glucitol as the 'carrier solvent'. 2 STRUCTURE: 1. ARTEMISININ [3R-(3a,5ap,6p,8aP,9a,12p,12aR*)]-Octahydro-3,6,9-trimethyl 3,12-epoxy-l 2H-pyrano{4,3-j]-l ,2-benzodioxepin-10(3 H)-one H3C~ CH3 CH3 2- ARTEMETHER: [3R-(3a,5ap,6p,8aP,9a,10a,12p,12aR*)]-Decahydro-10-methoxy-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin ARTEETHER [3R-(3α,,5αβ,6β,8aβ,9α, 10α, 12β, 12aR*)]-10- Ethoxydecahydro-3,6,9-trimethyl-3,l 2-epoxy-12H-pyrano[4,3-j]-l ,2-benzodioxepin H3C CH3 ARTESUNATE: [3R-(3α,5αβ,6β,8aβ,9α,10α,12β,12aR*)]- Butanedioic acid mono(decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-l ,2~benzodioxepin-10-yl) ester H30 CH3 4 Description of Prior Art: Artemisinin is an excellent antimalarial, approximately equal in potency to Quinine, with a good therapeutic index, except for use on the fetus. The preparation of semi-synthetic derivative thus became necessary as Artemisinin is relatively insoluble in both water and oil. The presently marketed preparations of 'Artemisinin' derivatives, for the treatment of malaria, have often been reported to result in slow action due to poor absorption and pain at site. Development of other oil soluble derivatives has been tried and this has resulted in the preparation of an intramuscular route of administration. These oil soluble derivatives, when given intramuscularly, besides inducing pain at the site, attain low therapeutic levels because of the short life of such derivatives. Thus the efficacy of such products is debatable. The high lipid solubihty of Artemether and Arteether, ensures rapid penetration into CNS and thus is a first line treatment for fatal cerebral malaria caused by 'P.falciparum'. 6 8 dihydroartemisinin-10-succinate derivative of Artemisinin is available as lyophilised' but not as a 'ready-to-use' preparation. This derivative, being water insoluble, requires addition of a weak alkali and water to dissolve the material in the injection. Besides, it has the limitation of being unstable in protic solvent, which again a necessitates a special kit required to be given at the time of use. The kit is a sodium bicarbonate solution OR 5 % dextrose OR 0.9 % saline solution and the same is to be mixed, just prior to its use, to the dry powder filled previously in a sealed vial. It is thus clearly evident that such a preparation would require a special sophisticated technology for the preparation of a sterile, lyophilised formulation. The prepared solution cannot be stored as it decomposes soon on storage. Moreover it is available only for intravenous use to reach a proper therapeutic level. To overcome these difficulties, the compounds which are comparatively stable are prepared but their solubilization requires organic solvents like alcohol, chloroform, which have limited therapeutic use in these type of injectable preparations. Other therapeutic agents of the oil / oil-water type emulsions are often used. The commonly used oils are of natural origin which require special, strict quality check besides there are difficulties faced during manufacturing viz., rancidity, colour formation during sterilization, decomposition of such products as well as difficulty in filtration through milhpore filtration, due to clogging of pores. The difficulty of protecting an active material like Artemisinin derivatives poses further difficulties, as it is very prone to oxidation on heating. / ..7.. SUMMARY OF INVENTION A process for the manufacture of an injectable antimalarial composition comprising providing (i) an antimalarial active material of general formula (IA) / (IB); H3C" H3C" CH3 CH3 CH3 CH3 Formula (IA) Formula (IB) Where R = Oxygen with or without (ii) other antimalarial carrier solvent in solution. Formula VI 2.5-di-0-methyl-1.4;3.6-dianhydro-D-glucitol haying formula VI 7a DETAIL DESCRIPTION OF INVENTION Thus after giving due consideration to all the limitations mentioned above and after thorough study of available literature, we have tried, in our laboratory, various vehicles to solubilise such drugs. Besides even the use of PEG 300, in the above antimalarial intravenous formulations, limits the route of administration to the 'intravenous' type. The present study involves the use of 2.5-di-0-methyl-1.4;3.6-dianhydro-D-glucitol, which is an excellent elegant solvent - overcoming all the difficulties mentioned above in the prior art. The use of 2.5-di-0-methyl-1.4;3.6-dianhydro-D-glucitol as an intravenous vehicle is well documented. The vehicle is very safe for intravenous purpose, maintaining all suitability for antimalarial Artemisinin derivatives. The drugs besides being soluble and safe to inject, attain the concentration range required for schizontocidal action. It also crosses the blood brain barrier and reaches the site of parasitemia. The rapid penetration of a lipid soluble so easy-to-use preparation' of Artemisinin derivatives in 2.5-di-0-methyl-L4;3.6-dianhydro-D-glucitol, is an added advantage and its rapid penetration in the CNS is well elucidated. The drug has a high affinity for homozoin, a storage form of hemin which is retained by the parasite after digestion of haemoglobin, leading to highly selective accumulation of the drug on the parasite. Artemisinin derivatives then decompose in the presence of iron, probably from hemozoin and release the free radicals which kill the parasites. The requirements for a satisfactory solution are - physical & chemical stability with maintenance of activity. This invention meets all the above requirements of a good formulation, with maintenance for good biological activity and its ready-to-use formula. The formulation has been tested for its activity against parasites and all the parasites were eliminated within 24 hours after treatment with Artemisinin derivatives in the above solvent, when tested in vitro. The solution is a limpid liquid, available both as single dose as well as a multiple dose container, to meet the requirements of the medical profession. Essentially Artemisinin and its derivatives solubilize in 2.5-di-O-methyl-1.4;3.6-dianhydro-D-glucitol, leading to a non-toxic, ready-to-use formula for intravenous purpose. The benefits of this invention viz., of these Artemisinin derivatives, over 'prior art' are ; cost effectiveness, easy availability of multiple dose with the added advantage of being very stable as well as non-toxic AND maximum therapeutic use against chloroquine resistant strains of falciparum and cerebral malaria cases. The instant Garaetocytocidal action of one of the derivatives of Artemisinin, is an added advantage for cutting down the transmission of 'falciparum' malaria, which is of epidemiological importance. 9 The invention will be described in greater detail in conjunction with specific examples. In such cases the solution is prepared with thorough stirring. The pH of the solution is measured potentiometrically using glass and saturated calomel electrode. Examples of preferred formulations in accordance with present inventions include but are not limited to the following : EXAMPLE 1 : 53.12 mmol of pure Artemisinin is stirred with 80 ml of 2.5-di-O-methyl-1.4;3.6-dianhydro-D-glucitol in a round bottom flask with controlled temperature at 60° for 1 hour and then cooled to room temperature. The resultant solution is made to 100 ml with 2.5-di-O-methy l-1.4;3.6-dianhydro-D-glucitol. The solution is filtered aseptically through 0.2 Micron filter, filled in amber / white ampoules / vials and sealed. EXAMPLE 2 : a. 53.62 mmol. of pure β Artemether is stirred with 80 ml of 2.5-di-O-methyl-1.4;3.6~dianhydro-D-glucitol in hermetic conditions, in a round bottom flask at 40° C. The solution is stirred slowly for one hour, then cooled to room temperature and made to 100 ml with 2.5-di-0-methyl-1.4;3.6-dwnhydro-D-glucitol The natural pH of the solution is 5.5, measured potentiometrically using glass calomel electrode. The resulting solution is filled aseptically in a brown vial giving a stable therapeutic solution. / 10 b. 53.62 mmol. of a-β Artemether, in the ratio of 80 : 20, is taken in a round bottom flask attached with stirring mechanism and stirred for 1 hour slowly at 40° C, cooled to room temperature and then made to 100 ml with 2.5-di~0-methyl-1.4;3.6-dianhydro-D-glucitol The pH of resulting solution is 5.35. The solution is aseptically filtered through membrane filter 0.2 micron and filled in amber vials. EXAMPLE 3: 48.013 mmol. of p Arteether is dissolved in 2.5-di-0-methyl-L4;3.6-dianhydro-D-glucitol, under hermetic conditions with continuous stirring, for 45 mins. at 40°C. The total volume is made to 100 ml after bringing to room temperature, filtered through millipore 0.2 Micron filter, filled and sealed in amber vial. EXAMPLE 4: 48.0132 mmol. of a-β Arteether in varying ratios of α-β 10:90; 20:80; 30:70; 40:60; 50:50, are taken in a flask containing 80 ml of 2.5-di-O-methyl-1.4;3.6-dianhydro-D-glucitol and stirred using magnetic stirrer at low speed using nitrogen condition for maintaining hennetic atmosphere. The volume of solutions are then made to 100 ml with 2.5-di-0-methyl-1.4;3.6- 11 EXAMPLE 5: 7.8 mmol. of β-Artesunate is mixed with 80 ml of 2.S-di-0-methyl-1.4;3.6-dianhydro-D~glucitol for half an hour at 37° C. The reaction mix is kept under nitrogen atmosphere, allowed to cool to room temperature and then made to 100 ml with 2,5-di-0-methyl-L4;3.6-dianhydro-D-glucitol. The pH of the solution is 5.5 when measured potentiometrically using glass coloured electrode. The solution is stable and clear. The aseptically filtered solution is filtered in amber vials. EXAMPLE 6: The procedure of Example 5 is repeated using 7.8 mmol. of a-β mixture of Artesunate in varying proportions. The resulting stable, clear solution is aseptically filtered, filled and sealed in brown vials. EXAMPLE 7: The procedure of Examples 1 & 2 are repeated using 0.05% Tocopherol as an antioxidant. A stable solution results. EXAMPLE 8: The procedure of Examples 3 & 4 are repeated using 0.05% & 0.1% Tocopherol as an antioxidant. A stable solution results. .. 12.. TABLE - I PERIODICAL STABILITY STUDIES Conditions: 250C ± 2°C / 60% RH ± 5% Eg. No. MATERIAL LIMITS INITIAL 3 months 6 months 9 months 12 months 1. Artemisinin 95%- 105% 100.1% 99.8% 99.5% 99.25% 99.0% 2. A P-Artemether 95%- 105% 98.66% 98.5% 98.25% 98.0% 97.75% B a - P-Artemether (80:20) 95%-105% 101.6% 101.4% 101.2% 101.0% 100.6% 3. P-Arteether 95% -105% 101.2% 100.8% 100.6% 100.5% 100.3% 4. a-P-Arteether (30:70)* 95% - 105% 100.1% 100.0% 99.8% 99.6% 99.3% 5. P-Artesunate 95%-105% 98.99% 98.7% 98.3% 98.0% 97.5% 6. a-P-Artesunate 95%-105% 101.0% 101.0% 100.8% 100.5%1 100.0% 7. With Tocopherol Artemisinin 95% - 105% 100.8% 100.6% 100.5% 100.0% 99.5% a. P-Artemether 95% - 105% 99.0% 99.0% 98.6% 98.2% 97.7% b. a - P-Artemether(80:20) 95%-105% 101.5% 101.5% 101.3% 101.2% 100.5% 8. With Tocopherol (0.05%) P- Arteether 95%-105% 101.4% 101.0% 100.7% 100.3% 100.0% a-P-Arteether (30:70)* With Tocopherol (0.1%) 95% - 105% 101.0% 100.6% 100.3% 100.0% 97.S% P-Arteether a-P-Arteether (30:70)* 95% - 105% 101.4% 101.0% 100.0% 100.1% 99.5% 95% - 105% 100.8% 100.6% 100.2% 100.0% 99.0% * Out of the different formulations prepared in different ratios, stability studies were carried out selectively for the formulations in the ratio of 30:70. 14 TABLE - II ACCELERATED STABILITY STUDIES Conditions: 40°C ± 2°C / 75% RH ± 5% No. MATERIAL LIMITS INITIAL 1 month 2 months 3 months 4 months 5 months 6 months 1. Artemisinin 95%-105% 100.1% 100.0% 99.5% 99.0% 99.0% 98.3% 98.0% 2. a p-Artemether 95% - 105% 98.66% 98.5% b a - P-Artemether (80:20) 95% -105% 101.6% 101.4% 101.2% 101.0% 101.0% 100.5% 100.0% 3. p-Arteether 95%- 105% 101.2% 101.0% 100.8% 100.3% 99.75% 99.4% 99.1% 4. a-P-Arteether (30:70)* 95% - 105% 100.1% 99.75% 99.8% 99.6% 99.0% ' 98.55% 98.3% 5. P-Artesunate 95% -105% 98.99% 98.4% 98.3% 97.65% 97.2% 96.5% 96.4% 6. a-P-Artesunate 95%-105% 101.0% 100.9% 100.8% 100.5%1 100.0% 99.3% 98.5% 7. With Tocopherol Artemisinin 95% -105% 100.8% 100.2% 100.1% 99.7% 99.5% 99.0% I a. P-Artemether 95% -105% 99.0% 98.9% 98.6% 98.2% 97.7% 97.4% 98.2% h. a - P-Artemether (80:20) 95%- 105% 101.5% 101.2% 101. 3% 101.2% . 100.75% 100.2% 97.0% 99.45% 8. With Tocopherol (0.05%) P-Arteether 95%-105% 101.4% 101.0% 100.8% 100.3% 99.6% 99.3% 98.7% a-P-Arteether (30:70)* WittTTocopherol(0.1 %) 95%-105% 101.0% 100.7% 100.3% 100.0% 99.3% 98.65% 98.0% p-Arteether 95%- 105% 101.4% 101.0% 100.7% 100.1% 99.8% 99.35% 98.6% | a-P-Arteether (30:70)* 95%-105% 100.8% 100.6% 100.2% 99.5% 99.0% 98.25% 97.45% | * Out of the different formulations prepared in different ratios, stability studies were carried out sckctivcly for the formulations in the ratio of 30:70. 15 It was noted that the solutions retain their potency at RT for one year when tested by HPLC and slight decrease in potency occurs with high temperature at the end of 6 months. However, the activity can be retained, even at that temperature, by incorporating Tocopherol in the concentration range of 0.1%. The solutions maintain their physical stability also. The loss of potency occurs if hermetic condition is not maintained. 2.5-di-0-methyl-1.4;3.6-dianhydro-D-glucitol has the advantage of ready miscibility with water and thus dilutions in water can be made according to need of anesthetic dose required for the patient. 16 26 JUN 2006 WE CLAIM 1. A process for the manufacture of an injectable antimalarial composition comprising providing (i) an antimalarial active material of general formula (IA) /(IB); Formula (IA) Where R = Oxygen with or without (ii) other antimalarial carrier solvent in solution. Formula VI (iii) 2.5-di-0-methyl-1.4;3.6-dianhydro-D-glucitol having formula VI 17 2. A process as claimed in claim 1, wherein artemisinin derivatives used is selected from artefinic acid, deoxoartemisinin, 10β-n propyl deoxoartemisinin. 3. A process as claimed in any preceding claim, wherein artemisinin or its derivatives is present in amounts of between 5% to 9% (w/v). 4. A process as claimed in claim 3, wherein artemisinin or its derivatives is present in amounts of between 6% to 8% (w/v). 5. A process as claimed in claim 4, wherein the active material used is artesunate which is present in an amount of 6% w/v. 6. A process as claimed in claim 4, wherein the active material used arteether, which is present in an amount of 7.5% w/v. 7. A process as claimed in claim 4, wherein the active material used is artemether, which is present in an amount of 8% w/v. 8. A process as claimed in any preceding claim, wherein optionally antioxidants in amounts of between 0.05% to 0.1% (v/v) are used 9. A process as claimed in claim 8, wherein the antioxidant used is selected from v vitamin E group, preferably tocopherol. 10. A process as claimed in any preceding claim such that the injectable antimalarial composition thus formed is in the form of a limpid liquid. 11. A process as claimed in claim 10, such that the liquid thus formed is packed as single dose or as multiple dose dispensing container. 18 12. A process as claimed in claim 10, such that the liquid thus formed is in the form of a non-toxic, ready-to-use formula for intravenous application. 13. A process for the manufacture of an injectable antimalarial composition substantially hereindescribed with reference to the accompanying examples. Dated this 28th day of January 1999 Dr. Sanchita Ganguli Of S. MAJUMDAR & CO. Applicants' Agent 19

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