WO2000044333A2

WO2000044333A2 - Novel injectable antimalarial compositions of artemisinin

Info

Publication number: WO2000044333A2
Application number: PCT/IN2000/000002
Authority: WO
Inventors: Dinesh Shantilal Patel; Shashikant Prabhudas Kurani
Original assignee: Dinesh Shantilal Patel; Shashikant Prabhudas Kurani
Priority date: 1999-01-28
Filing date: 2000-01-03
Publication date: 2000-08-03
Also published as: AU4609200A; WO2000044333A3

Abstract

A novel injectable antimalarial composition comprising from 5 to 9 % (w/v) of an antimalarial active material of general formula (I) where R is selected from oxygen, -OCH3, -OCH2CH3, formula (1) (where X is selected from Na, K and NH4) and -O-COCH2CH2COOY (where Y is selected from Na, K and NH4); optionally in the presence of other antimalarials in solution with 2.5-di-O-methyl-1.4; 3.6-dianhydro-D-glucitol having formula (VI). The composition is in limpid liquid form in ready to use single or multi dose containers for intravenous therapeutic applications.

Description

NOVEL INJECTABLE ANTIMALARIAL COMPOSITIONS OF ARTEMISININ

Field of Invention :

The present invention relates to a novel injectable antimalarial composition of Artemisinin. Particularly the antimalarial composition of the invention is suitable for parental application which can be used either 'intramuscularly' or 'intravenously'. More specifically the invention relates to a limpid, stable economically beneficial composition of Artemisinin and its derivatives. 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 anti-malarials in cases of 'falciparum malaria'.

Artemisinin and its derivatives have the general formula (I)

Formula (I) where R is selected from oxygen, -OCH₃, -OCH₂CH₃,

(where X is selected from Na, K and NH₄) and -O-COCH₂CH₂COOY (where Y is selected from Na, K and NH ) ;

when R is oxygen the compound is Artemisinin, when R is -OCH₃ the compound is Artemether, when R is -O CH₂CH₃ the compound is Arteether, when R is

-O — (O/ — COOX and X is Na the compound is Sodium Artenilate, when R is -O-COCfT₂CH₂COOY and Y is Na the compound is Sodium Artesunate. Artemisinin has the formula [3R-(3 ,5aβ,6β,8aβ,9 ,12β,12aR*)] Octahydro-3,6,9- trimethyl 3,12-epoxy-12H-pyrano{4,3-j]-1 ,2-benzodioxepin-10(3H)-one and the structure of formula II

Formula II

Artemether has the formula [3R-(3α,5aβ,6β,8aβ,9α,10 ,12β,12aR*)]-Decahydro- 10-methoxy-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1 ,2-benzodioxepin and the structure of formula III

Formula III

Arteether has the formula [3R (3α,5aβ,6β,8aβ,9α,10 ,12β,12aR*)]-10- Ethoxydecahydro-3,6,9-trimethyl-3, 12-epoxy-12H-pyrano[4,3-j]-1 ,2- benzodioxepin and the structure of formula IV

Formula IV when R is -OOC-H₂C-CH₂-COOH the compound is Artesunate and the formula is [3R-(3α,5aβ,6β,8aβ,9α, 10α, 12β, 12aR^*)]-Butanedioic acid mono(decahydro-3,6,9- trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1 ,2-benzodioxepin-10-yl) ester and the structure of formula V

Formula V

Background of the invention :

'Falciparum Malaria' is a major parasitic disease and a problem of the major tropical countries of the world. Parasite resistance, to chloroquine and mefioquine, 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. 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.

US Patent No. 5219865 teaches combinations of the malaria therapeutics artemisinine, dihydroartemisinine, arteether, artemether, artesunate or other artemisinine derivatives with one or more of the antimalarials chloroquine, 10-0- methylfloxacrine, quinine, mefloquine, amodiaquine, pyrimethamine, sulfadoxine and primaquine. Synergistic actions are achieved with them on treatment of mammals, including humans, with subcurative doses of the individual substances.

In US Patent No. 5019590 a process for synthesizing oxygen-containing polyoxatetracycle compounds and in particular analogs of the antimalarial agent known as qinghaosu or artemisinin is disclosed. The process employs as a reactant an olefinically unsaturated bicyclic bridging ketone having nonenolizable bridgehead moieties for both of its alpha positions. This ketone is converted to a vinylsilane that is subjected to ozonolytic cleavage of its olefinic bond to yield a member of a family of unique carboxyl/carbonyl-substituted vinylsilanes which may in turn optionally be subjected to a wide range of reactions prior to a final ozonolysis/acidification step which closes the oxygen-containing ring structure. The various intermediates are claimed as aspects of this invention as are novel tetracycles and their use as antimalarials.

US Patent No. 5834505 discussed an antimalarial drug combination for prophylactic treatment or curative treatment of malaria comprises a first component which is a fenozan, that is a cis-fused cyclopenteno-1 ,2,4-trioxane, and a second component which is another antimalarial drug selected from the group consisting of artemisinin, sodium artesunate, chloroquine and mefloquine.

US Patent No. 567733 discloses a synergistic antimalarial composition which comprises the antimalarial agent benflumetol and also an antimalarial agent from the artemisinine group such as artemether. The composition can be formulated into solid dosage forms such as tablets and is useful for the treatment of drug resistant malaria.

The teachings of prior art are related to improved formulation for the treatment of malaria but do not address the problems that the present inventors aims to solve.

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 solubility of Artemether and Arteether, ensures rapid penetration into CNS and thus is a first line treatment for fatal cerebral malaria caused by 'P.falciparum'.

Particularly for the treatment of fatal cerebral malaria there has been a long felt need for a preparation of Artemisinin derivatives that would act fast and attains high therapeutic levels. Obviously, intravenous route of administration was attempted to solve the problem because through the intravenous route the drug can directly reach the site to kill parasites in the brain where P. falciparum has fatal effect. I. M. injection is known to be given for anti-malarials but the limitation of this route is that the availability of the drug to kill parasites is reduced as it takes several hours to reach plasma concentration (Ref : THE LANCET VOL. 341 , MARCH 6, 1993, pp 603-607). In the case I.M. injections there are further limitations in respect of the therapeutic effect. In acute cases the I.M. injection fails to deliver the therapeutic effect within a short period and the patient suffers immensely sometimes resulting in loss of life. Therefore efforts have been made to formulate preparations of artemisinin in IN. form but without much success.

The closest solution to the problem was provided in the form of 8 dihydroartemisinin-10-succinate derivative of Artemisinin which however 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 necessitates the use of a special kit. 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.

Attempts were made to overcome these difficulties. The compounds which are comparatively stable were 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 millipore 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.

The applicants have surprisingly found that the long felt need of an effective injectable, antimalarial formulation especially intravenous may be solved by providing artemisinin or antimalarial artemisinin derivatives in solution with 2.5-di- O-methyl-1.4;3.6-dianhydro-D-glucitol which gives limpid, stable, economically beneficial ready-to-use injectable preparations. It is also found that other anti malarials may be incorporated in the formulation.

Thus according to the present invention there is provided a novel injectable antimalarial composition comprising an antimalarial active material of general formula (I)

Formula (I)

where R is selected from oxygen, -OCH₃, -OCH₂CH₃, -O ( ) — OOX (where X is selected from Na, K and NH ) and -O-COCH₂CH₂COOY (where Y is selected from Na, K and NH ) ; optionally in the presence of other antimalarials in solution with 2.5-di-O-methyl-1.4;3.6-dianhydro-D-glucitol having formula VI

Formula VI

The artemisinin, its derivatives, esters and ethers are selected from compounds known for the purpose and disclosed herein. Other artemisinin derivative such as Artefinic acid, Deoxoartemisinin, 10β-n propyl deoxoartemisinin and others known to have antimalarial effect may also be used. The preferred antimalarial compounds which may be incorporated in addition to the actives according to the invention are selected from mefloquine and quinine.

Artemisinin or its derivatives is present in the formulation in amounts of between 5 to 9 % (w/v). Preferably the active material is present at levels of between 6% to 8% (w/v). the level of the active depends on the specific active used. The most preferred levels are 6% w/v in case of Artesunate, 7.5% w/v in case of Arteethar 8% w/v in case of Artemether in injections and about 50 mg. per tab of artesunate.

The formulation according to the invention optionally comprises antioxidants. The oxidant that are suitable for the purpose of the present invention are selected from vitamin E group. The preferred antioxidant is Tocopherol. The antioxidant is present in the formulation at level of between 0.05% to 0.1% (v/v).

The drugs besides being soluble and safe to inject, attain the concentration range required for schizontocidal action 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-O-methyl-1.4;3.6-dianhydro-D-glucitol, is an added advantage and its rapid penetration in the CNS (Central Nervous System) 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.

2.5-di-O-methyl-1.4;3.6-dianhydro-D-glucitol is commercially available under the trademark Arbasolve (a product of ICI). Artemisinin is available in China in the form of oil and aqueous suspensions for intramuscular injections, tablets, capsules and suppositories. Artemisinin and its derivatives like artemether are also available commercially under the trademark Paluther (Product of Rhone- Poulenc Rorer, France) and Artesunate of Atlantic, Thia (through Martindale, 32^nd Ed.), Rorer, Fr.

The requirements for a satisfactory injectable solution are physical and 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 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 formulations according to the invention may be diluted in water according to need of the dose required for the patient.

To enhance the efficacy of the formulation other known anti-malarials may also be incorporated in the formulation. The benefits of the compositions according to the invention 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 gametocytocidal 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.

The invention will be described in greater detail in conjunction with specific examples. In each case 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-methyl-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-glucitoi 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-O-methyl-1.4;3.6-dianhydro-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.

b. 53.62 mmol. of α-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-O-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 β Arteether is dissolved in 2.5-di-O-methyl-1.4;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 α-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 hermetic atmosphere. The volume of solutions are then made to 100 ml with 2.5-di-O-methyl-1.4;3.6-dianhydro-D-glucitol. The natural pH of solution is 5.5 when measured potentiometrically. The aseptically filtered solution is filled in amber vials.

EXAMPLE 5:

7.8 mmol. of β-Artesunate is mixed with 80 ml of 2.5-di-O-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-O-methyl-1.4;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 α-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.

The Stability of all the above solutions is tested by stability indicating HPLC method under different conditions namely :

i) periodical stability study at room temperature for long periods upto 12 months and the results are demonstrated in Table I ;

ii) accelerated stability study at 40°C / 60% RH - at intervals of 1 month, 2 months 3 months & 6 months and the results are demonstrated in Table

The stability studies were carried out with formulations in the ratio of 30:70. Conclusion :

It was noted that the solutions retain their potency at room temperature 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.

The compounds in all cases remain stable in the conditions mentioned hereinabove and the study on parasites was carried out in vitro. The formulation was tested for its activity against parasites and all the parasites were eliminated within 24 hours after treatment with formulations according to the invention when tested in vitro.

Claims

We Claim :

1. A novel injectable antimalarial composition comprising an antimalarial active material of general formula (I)

Formula (I)

where R is selected from oxygen, -OCH₃, -OCH₂CH₃, -0-7p)V COOX

(where X is selected from Na, K and NH₄) and -O-COCH₂CH₂COOY (where Y is selected from Na, K and NH ) ; optionally in the presence of other antimalarials in solution with 2.5-di-O-methyl-1.4;3.6-dianhydro-D-glucitol having formula VI

Formula VI

2. A novel injectable antimalarial composition as claimed in claim 1, wherein artemisinin derivatives is selected from artefinic acid, deoxoartemisinin, 10β-n propyl deoxoartemisinin.

3. A novel injectable antimalarial composition as claimed in claim 1 or 2, wherein other antimalarials include mefloquine and quinine.

4. A novel injectable antimalarial composition as claimed in any preceding claim, wherein artemisinin or its derivatives is present in amounts of between 5 to 9 %

(w/v).

5. A novel injectable antimalarial composition as claimed in claim 4, wherein artemisinin or its derivatives is present in amounts of between 6% to 8% (w/v).

6. A novel injectable antimalarial composition as claimed in claim 5, wherein the active is artesunate which is present in an amount of 6% w/v.

7. A novel injectable antimalarial composition as claimed in claim 5, wherein the active is arteethar which is present in an amount of 7.5% w/v.

8. A novel injectable antimalarial composition as claimed in claim 5, wherein the active is artemether which is present in an amount of 8% w/v.

9. A novel injectable antimalarial composition as claimed in any preceding claim, further comprising antioxidants in amounts of between 0.05% to 0.1% (v/v).

10. A novel injectable antimalarial composition as claimed in claim 9, wherein the antioxidant is selected from vitamin E group, preferably tocopherol.

11. A novel injectable antimalarial composition as claimed in any preceding claim, which is in the form of a limpid liquid.

12. A novel injectable antimalarial composition as claimed in claim 11 , wherein the liquid is packed as single dose or as multiple dose dispensing container.

13. A novel injectable antimalarial composition as claimed in claim 11 , which is in the form of a non-toxic, ready-to-use formula for intravenous application.

14. A novel injectable antimalarial composition as claimed in claim 13, which is diluted in water according to application requirements.