WO2005023304A2

WO2005023304A2 - Antimalarial compositions and manufacturing process thereof

Info

Publication number: WO2005023304A2
Application number: PCT/GB2004/003748
Authority: WO
Inventors: Geena Malhotra; Amar Lulla
Original assignee: Cipla Ltd
Current assignee: Cipla Ltd
Priority date: 2003-09-04
Filing date: 2004-09-03
Publication date: 2005-03-17
Anticipated expiration: 2006-03-04
Also published as: WO2005023304A3; ZA200602031B; AP2006003557A0; BRPI0413767A

Abstract

A pharmaceutical composition for treating malaria includes at least one artenisinin or a salt or derivative thereof, and at least one quinoline or a salt or derivative thereof, as a combined preparation, for simultaneous or separate use in the treatment of malaria. In preferred embodiments, bilayer tablets are formulated comprising artesunate + amodiaquine, artesunate + chloroquine or artesunate + mefloquine.

Description

ANTIMALARIAL COMPOSTTTONS AND PROCESS THEREOF

Technical Field

The present invention relates to pharmaceutical combinations comprising antimalarial compositions such as artemisinin, quinoline and their derivatives. In particular, the present invention is concerned with pharmaceutical formulations comprising combinations of artemisinin, quinoline and their derivatives, useful particularly in the prophylaxis and treatment of protozoal infections; particularly, malaria.

Background and Prior art

Human malaria is caused by four species of obligate intracellular protozoa of the genus Plasmodium.

Malaria, caused by four species of Plasmodium, of which Plasmodium falciparum is the most dangerous, remains the world's most devastating human parasitic infection.

Each Plasmodium species causes a characteristic illness and shows distinguishing morphological features in blood smears: (1) P. falciparum causes malignant tertian malaria, the most dangerous form of human malaria. By invading erythrocytes of any age, this species can produce a devastating parasitemia, sequestration of infected erythrocytes, in the peripheral microvasculature, hypoglycemia, hemolysis, and shock with multiorgan failure. Delay in the treatment until after demonstration of parasitemia may lead to a fatal outcome even after the peripheral blood is free of parasites. If treated early, the infection usually responds within 48 hours to appropriate therapy. (2) P. vivax causes benign tertian malaria. (3) P. ovale causes a rare malarial infection with a periodicity and relapses similar to those of P. vivax, but is milder.

Antimalarials can be categorized by the stage of the parasite that they affect and the clinical indication for their use. Some drugs have more than one type of antimalarial activity. Nearly all antimalarial drugs were developed because of their action against asexual erythrocytic forms of malarial parasites that cause clinical illness. Efficacious, rapidly acting drugs in this category include chloroquine, quinine, quinidine, mefloquine, atovaquone, and the artemisinin compounds. Yet, due to the continuing spread of increasingly drug-resistant and multidrug-resistant strains of P. falciparum, no single agent successfully controls infections with these parasites. Instead, use of two or more antimalarial agents with complementary properties is recommended.

Artemisinin is a sesquiterpene lactone endoperoxide derived from the weed qing hao (Artemisia annua), also called sweet wormwood or annual wormwood. Chinese scientists had extracted and crystallized the major antimalarial ingredient, qinghaosu, now known as artemisinin. They synthesized three derivatives with greater antimalarial potency than artemisinin itself namely, dϊhydroartemisinin, artemether and artesunate, the water-soluble hemisuccinate salt of dihydroartemisinin.

Artemisinin compounds are the most rapidly acting, effective and safe drugs for the treatment of severe malaria, including infections due to chloroquine and multidrug-resistant strains of P. falciparum. Although artemisinin and its derivatives can be used as single agents, infections can often relapse.

Hence, the present invention relates to a combination of antimalarial agents and more specifically permits desirable antimalarial therapy while preventing or delaying the development of resistance.

The use of combinations of different antimalarials is known in malarial chemotherapy. In the prior art, various combination antimalarials are reported for delaying the development of resistance.

US patent no. 5,219,865 describes combination therapy of artesunate with quinine and its derivatives. The patent relates to combinations of the malaria therapeutics artemisinine, dihydroartemisinine, arteether, artemether, artesunate or other artemisinine derivatives with one or more of the antimalarial chloroquine, 10-o-methylfloxacrine, quinine, mefloquine, amodiaquine, pyrimethamine, sulfadoxine and primaquine but there is not sufficient disclosure of a pharmaceutical product/composition of the said composition by way of any example or process. EP patent no. 0,362,810 describes combination therapy of artesunate with quinidine and its derivatives. This patent relates to a new and improved antimalarial composition and a method of treating malaria which employs a combination with, on the one hand, one of the antimalarial agents artemisinine, dihydroartemisinine, arteether, artemether, artesunate and on the other hand, quinidine and optionally mefloquine and their pharmaceutically acceptable salts.

A combination of Amodiaquine and tetracycline and a combination of Pyrimethamine and Sulphadoxine has already been used in treatment of P. falciparum malaria in Thiland. (Reported in "Tropical Diseases Research, seventh programme report" Chapter-2; malaria, published by WHO).

It has now been found, surprisingly, that combinations of artemisinin and/or its above mentioned derivatives with the known malaria therapeutics like chloroquine, mefloquine, amodiaquine and the pharmaceutically utilizable salts thereof show a synergistic action.

The present combination of antimalarials which is described in more detail hereinafter permits the desired malaria treatment, specifically both for prophylaxis and for therapy, and prevents or delays the development of resistance.

We are unaware of any pharmaceutical composition of the combination of the present invention as a fixed dose combination (two drugs combined in one tablet). The compositions being sold to date are in the form of kits wherein each drug has to be taken as a separate tablet.

Objectives

The object of the present invention is to provide a pharmaceutical product comprising at least one artemisinin or its salts or derivatives thereof and at least one quinoline or its salts or derivatives thereof, preferably a chloroquinoline, or its salts or derivatives thereof as a combined preparation, for simultaneous or separate use in the treatment of malaria. Accordingly, it is an object of the present invention to provide fixed dose combination of antimalarial agents which specifically permits antimalarial therapy while preventing or delaying the development of resistance.

It is another object of the present invention to provide a process for the manufacture of a fixed dose combination comprising at least one artemisinin or its salts or derivatives thereof and at least one quinoline or its salts or derivatives thereof as a combined preparation in suitable pharmaceutically acceptable carriers.

Summary of the invention

The present invention provides a pharmaceutical product comprising at least one artemisinin or its salts or derivatives thereof and at least one quinoline or its salts or derivatives thereof as a combined preparation, for simultaneous or separate use in the treatment of malaria.

Detailed Description

It will be appreciated from the above, that the respective therapeutic agents of the combined preparation can be administered simultaneously, either in the same or different pharmaceutical formulations or separately. If there is separate administration, it will also be appreciated that the subsequently administered therapeutic agents should be administered to a patient within a time scale so as to achieve, or more particularly optimize, the above referred to advantageous synergistic therapeutic effect of a combined preparation as present in a pharmaceutical product according to the present invention.

Also compliance to the treatment is crucial to ensure treatment effectiveness and prevent future resistance. When combination is provided as two separate drugs, patients might take only one of the two drugs or fail to complete the whole course. The protection against resistance is also lost if one drug is taken without the other. To optimize the patient compliance it is therefore very advantageous to provide patients with fixed dose combinations rather than separate tablets. Also, according to the present invention, there is provided a pharmaceutical formulation comprising at least one artemisinin or its salts or derivatives thereof and at least one quinoline or its salts or derivatives thereof, for use in the treatment of malaria, together with a pharmaceutically acceptable carrier or excipient thereof.

Also, according to the present invention, there is provided the use of at least one artemisinin or its salts or derivatives thereof and at least one quinoline or its salts or derivatives thereof, in the manufacture of a medicament for use in the treatment of malaria.

In the pharmaceutical products or formulations according to the present invention, artemisinin and derivatives suitably includes dihydroartemisinin, arteether, artemether, and artesunate, the water- soluble hemisuccinate salt of dihydroartemisinin or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. Preferably the derivative employed according to the present invention is artesunate.

Artesunate is the water-soluble hemisuccinate salt of dihydroartemisinin, namely, Butanedioic acid mono-[3R,5aS, 6R,8aS,9R,10R,12R,12aR)-decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3- j]-l,2-benzodioxepin-10-yl] ester. As mentioned above a pharmaceutically acceptable salt thereof may be used.

Artesunate, semi-synthetic derivative of artemisinin, has been used in the treatment of malaria. Artesunate is active in typical blood schizonticides in all forms of malaria. It has a peroxide bond, which breaks up inside the parasite, forming singlet oxygen as well as free radicals. Both exert a direct cytotoxic effect on the cells, which forms the essential part of the mechanism of action of artesunate and explains its rapid effect as well as its efficacy.

Following oral administration, artesunate is rapidly absorbed and reaches Cmax within 45 to 90 minutes. The product is metabolized in the liver by hydrolysis, giving rise to dihydroartemisinin which is also effective against malaria by the same mechanism of action. Elimination half-life of the drug is approximately 2 to 4 hours. Suitably in pharmaceutical products or formulations according to the present invention, the quinoline is selected from the group consisting of chloroquine, mefloquine, amodiaquine, and primaquine or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

Artesunate is preferably given in a dose of about 50 mg. Amodiaquine is preferably given in a dose of about 153 mg for the treatment of malaria, chloroquine is preferably given in a dose of about 150 to 600 mg for the treatment of malaria, mefloquine is preferably given in a dose of about 250 mg for the treatment of malaria, while primaquine is preferably given in a dose of about 7.5 mg

Amodiaquine hydrochloride is 4-[(7-cUoro-4-quinolinyl)amino]-2-[(diethylamino)-methyl]-phenol dihydrochloride, dihydrate.

Amodiaquine is a 4-aminoquinoline antimalarial with action similar to chloroquine and is effective against both chloroquine sensitive as well as chloroquine resistant strains of plasmodium falciparum.

Upon administration it is readily absorbed from the gastrointestinal tract (GIT). Amodiaquine is rapidly converted in the liver to its active metabolite desethylamodiaquine. The plasma elimination half life of desethylamodiaquine is varied from 1 to 10 days or more.

The present invention further provides a method of administering to a subject in need of treatment a pharmaceutical product or formulation substantially as hereinbefore described.

Artesunate is poorly stable in water and hence it is difficult to formulate a solid dosage form using water in the binder. Hence it would generally be directly compressed in order to form a solid dosage form. Amodiaquine on the other hand is not directly compressible and hence would generally be granulated using a wet binder. These formulation problems make it difficult to formulate a single layered tablet wherein both the drugs are mixed together. Also since amodiaquine has poor flow properties and is required in a large dose, which makes it difficult to formulate capsules by dry mixing both the drugs. Capsules can be formed by way of granulating both the drugs separately and then filling the capsules. The granules of at least one artemisinin or its salts or derivative is preferably obtained by dry granulating the said artemisinin along with suitable diluents and lubricants to form slugs that are then, preferably, subjected to milling. The granules of at least one quinoline or its salts or derivative are preferably obtained by wet granulating the said quinoline with suitable excipients.

Hence the present invention also encompasses a bilayer tablet formulation which can typically be administered to patients and permits or achieves delivery of pharmaceutically active agents effective for the treatment of a specific pathology to be treated, and as such is particularly suited for the treatment of malaria.

The present invention further provides use of at least one artemisinin or its salts or derivatives thereof and at least one quinoline or its salts or derivatives thereof, in the manufacture of a medicament for the treatment of malaria. Such a medicament according to the present invention comprises a formulation substantially as herein described, and in particular a bilayer formulation, typically a bilayer tablet formulation substantially as hereinafter further described.

The terms 'artemisinin and quinoline' are used in the entire specification and claims in a broad sense to include not only 'artemisinin and quinoline' per se but also their pharmaceutically available salts or derivatives thereof.

In a preferred embodiment of the present invention, a pharmaceutical formulation comprises a bilayer system including the pharmaceutically active agents effective for the treatment of malaria. More particularly, a bilayer formulation according to the present invention comprises a first layer comprising at least one artemisinin or its salts or derivatives thereof and further comprising other pharmaceutical excipients and a second layer comprising at least one quinoline or its salts or derivatives thereof; forming a pharmaceutically stable preparation.

The pharmaceutical formulations according to the present invention are preferably in the form of tablets, but it is also possible to use other preparations, such as capsules. A tablet according to the present invention comprises a combination of materials, including for example one or more polymers, diluents and optionally glidants and lubricants. The above materials are combined with drugs to achieve beneficial characteristics of the present invention.

The bilayer tablet according to the present invention comprises two layers which may be prepared by using standard methods of tablet preparation i.e. wet granulation or dry granulation and/or direct compression method.

The diluent or bulking agent should be selected to provide an increase in tablet size. The skilled person can utilize known methods to select a bulking agent, which provides hardness, friability and disintegration time required for pharmaceutical advantage. The preferred diluent is lactose, starch and/or microcrystalline cellulose. The most desired form of lactose and microcrystalline cellulose could be selected based on desired dissolution, content uniformity, hardness, and friability and disintegration time. The skilled person can use known techniques to achieve the desired physical properties.

The skilled person may further select appropriate binders using known methods. Most preferably, the binders used are starch, lactose, dicalcium phosphate, mannitol, microcrystalline cellulose; however, other appropriate binders may be selected. Various forms of starch are appropriate for formulations, including pregelatinized starch.

The skilled person may also include appropriate disintegrants in the tablet. Most preferably, the disintegrants used are microcrystalline cellulose, sodium starch glycollate, starch, croscarmellose sodium, hydroxypropyl cellulose, etc.

A tablet formulation according to the present invention may also include a hydrophobic lubricant. The skilled person can select an appropriate lubricant to prevent sticking and picking of the tablets to the compression tooling. Suitable lubricants include talc, fatty acids, and salts of fatty acids, mineral oil, colloidal silicon dioxide and hydrogenated vegetable oils. An example of a suitable fatty acid material is stearic acid or its magnesium salt. The most preferred lubricant is magnesium stearate. The first layer of tablet containing artemisinin or its salts or derivatives in the formulation according to the present invention may comprise about 5 to 50 % of artemisinin or its salts or derivatives, about 50 to 90 % binder/diluents, about 2 to 10% disintegrant and about 0.2 to 2 % of a lubricant.

Preferably, the first layer of tablet containing artemisinin or its salts or derivatives in the formulation according to the present invention comprises about 5 to 50% of artesunate, about 50 to 90 % lactose, about 2 to 10% croscarmellose sodium and about 0.2 to 2 % of a lubricant.

The second layer of tablet containing quinoline or its salts or derivatives in the formulation according to the present invention may comprise about 35 to 85% of quinoline or its salts or derivatives, about 5 to 40 % binder/diluent, about 1 tolO % disintegrant and about 0.2 to 2 % of a lubricant.

Preferably, the second layer of tablet containing quinoline or its salts or derivatives in the formulation according to the present invention comprises about 35 to 85 % of amodiaquine hydrochloride, about 5 to 40 % starch or microcrystalline cellulose, about 1 to 10 % pregelatinized starch or sodium starch glycollate and about 0.2 to 2 % of a lubricant.

According to another aspect of the invention there is provided a process for preparing a pharmaceutical product, or a pharmaceutical formulation, or a medicament substantially as hereinbefore described. Suitably such a process comprises providing at least one artemisinin or its salts or functional derivatives thereof and at least one quinoline or its salts or derivatives thereof, and formulating at least one artemisinin or its salts or its derivatives, and at least one quinoline or its salts or derivatives thereof. Suitably such a process comprises providing a bilayer pharmaceutical formulation, typically in tablet form.

Substantially as hereinbefore described the tablets of the present invention comprise bilayered tablets, of which a first layer comprising artesunate may be prepared by mixing artesunate with diluents and binders. The resulting mixture may then be blended and mixed with disintegrants, glidants and a lubricant. The resulting mixture may then be compressed using a standard rotary tablet press.

Preferably a second layer comprising a quinoline, such as amodiaquine, is prepared by mixing amodiaquine with diluents, blending well and wet granulated with binders and then sized and mixed with a lubricant followed by compressing. The second layer may alternatively be prepared by using direct compression or fluid bed granulation processes to achieve homogenous distribution of a drug within the formulation. The tablets may further be coated using suitable coating materials.

The tablets of the invention are orally administered in the amounts necessary to achieve a particular blood level. An optimum dosage size may be determined by observing the therapeutic results achieved and the side effects encountered and/or by blood serum analysis.

Thus, in the preferred embodiment, the invention provides a pharmaceutical composition or formulation which comprises a combination of artemisinin or a salt or derivative thereof in combination with a quinoline or a salt or derivative thereof as a single dosage form in combination with one or more pharmaceutically acceptable carriers or excipients. Advantageously, the single dosage form is an oral dosage form, preferably a tablet or a capsule. The tablet is most preferably a bilayer tablet, each layer containing an amount of a respective one of the active ingredients.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.

The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention. Examples Example-I

Example-II

Example-Ill

Procedure:

A first layer comprising artesunate was prepared by mixing artesunate with the diluents, blended well and mixed with the lubricant and compressed. A second layer comprising amodiaquine was prepared by mixing amodiaquine with diluents. The resulting mixture was then blended and wet granulated. The granulate was then sized through a sieve of optimum mesh, mixed with the lubricant. The resulting mixture was then compressed using a standard rotary tablet press. The bilayer tablet so formed was then coated.

Claims

1. A pharmaceutical stable product comprising (i) at least one artemisinin or a salt or derivative thereof, and at least one quinoline or a salt or derivative thereof, as a combined preparation, for simultaneous or separate use in the treatment of malaria.

2. A pharmaceutical formulation comprising (i) at least one artemisinin or a salt or derivative thereof, and at least one quinoline or a salt or derivative thereof, together with a pharmaceutically acceptable carrier or excipient thereof.

3. A pharmaceutical product according to claim 1, or a pharmaceutical formulation according to claim 2, wherein said artemisinin is selected from the group consisting of artemisinin per se, dihydroartemisinin, arteether, artemether, and artesunate, the water-soluble hemisuccinate salt of dihydroartemisinin or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

4. A product or formulation according to claim 3, wherein said artemisinin derivative is artesunate.

5. A pharmaceutical product or formulation according to any one of claims 1 to 4, wherein said quinoline is selected from the group consisting of chloroquine, mefloquine, amodiaquine, and primaquine or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

6. A pharmaceutical product or formulation according to claim 5, wherein said quinoline is amodiaquine, preferably amodiaquine hydrochloride.

7. A pharmaceutical product or formulation according any one of claims 1 to 6, which comprises an oral drug delivery form which may be a tablet or a capsule.

8. A pharmaceutical product or formulation according to claim 7, wherein said delivery form is tablet, preferably a bilayer tablet.

9. A pharmaceutical product or formulation according to any one of claims 6 to 8, which 5 comprises a bilayer system comprising a first layer comprising at least one artemisinin or a salt or derivative thereof and a second layer comprising at least one quinoline or a salt or derivative thereof.

10. A pharmaceutical product or formulation according to claim 9, wherein the first layer 10 comprises substantially 5 to 50 % artemisinin or its salts or derivatives, substantially 50 to 90 % binder/diluents, substantially 2 to 10% disintegrant and substantially 0.2 to 2 % of a lubricant.

11. A pharmaceutical product or formulation according to claim 10, wherein the first layer comprises substantially 5 to 50% of artesunate, substantially 50 to 90 % lactose, substantially 2 to

15 10% croscarmellose sodium and substantially 0.2 to 2 % of a lubricant.

12. A pharmaceutical product or formulation according to claim 10, wherein the binder and/or diluent are selected from lactose and microcrystalline cellulose.

20 13. A pharmaceutical product or formulation according to any one of claims 9 to 12, wherein the second layer comprises substantially 35 to 85 % quinoline or its salts or derivatives, substantially 5 to 40 % binder/diluent, substantially 1 to 10 % disintegrant and substantially 0.2 to 2 % of a lubricant.

25 14. A pharmaceutical product or formulation according to claim 13, wherein the second layer comprises substantially 35 to 85 % of amodiaquine hydrochloride, substantially 5 to 40 % starch or microcrystalline cellulose, substantially 1 to 10 % pregelatinized starch or sodium starch glycollate and substantially 0.2 to 2 % of a lubricant.

30 15. A pharmaceutical product or formulation according to claim 13, wherein the binder/diluent is selected from starch, lactose, dicalcium phosphate, mannitol and microcrystalline cellulose.

16. A pharmaceutical product or formulation according to claim 10 or 13, wherein the disintegrant is selected from microcrystalline cellulose, sodium starch glycollate, starch, croscarmellose sodium and hydroxypropyl cellulose. 5

17. A pharmaceutical product or formulation according to claim 10 or 13, wherein the lubricant is selected from talc, fatty acids, and salts of fatty acids, mineral oil, colloidal silicon dioxide and hydrogenated vegetable oils.

10 18. A pharmaceutical product or formulation according to any one of claims 9 to 17, wherein the bilayer tablet is coated.

19. A process for preparing a pharmaceutical product or formulation according to any preceding claim, comprising (a) precompressing a first layer comprising at least one artemisinin or its salts or

15 derivatives followed by compressing with the precompressed layer (b) a second layer comprising granules of at least one quinoline or its salts or derivatives along with (a).

20. A process according to claim 19, wherein the first layer comprises artesunate, and is prepared by blending artesunate with diluents and binders, disintegrants, glidants, lubricant and

20 compressing the resulting mixture.

21. A process according to claim 19 or 20, wherein the second layer comprises a quinoline, such as amodiaquine, and is prepared by wet granulating amodiaquine with suitable excipients.

25 22. A process according to claim 19, wherein the two layers are prepared by using direct compression or wet granulation or dry granulation processes.

23. A pharmaceutical product or formulation according to claim 7, wherein said delivery form is capsule. 30

24. A pharmaceutical product or formulation according to claim 23, wherein the capsule comprises at least one artemisinin or a salt or derivative thereof, and at least one quinoline or a salt or derivative thereof, together with a pharmaceutically carrier or excipient thereof.

5 25. A process for preparing a pharmaceutical product or formulation according to claim 24, which process comprises granulating the or each artemisinin or its salt or derivative, and the or each quinoline or its salt or derivative separately and then filling in capsules.

26. A process according to claim 25, wherein the granules of the or each artemisinin or its salt 10 or derivative is obtained by dry granulating the said artemisinin along with suitable diluents and lubricants to form slugs which are then subjecting to milling.

27. A process according to claim 25 or 26, wherein the granules of the or each quinoline or its salt or derivative is obtained by wet granulating the said quinoline with suitable excipients.

15 28. A method of treating a disease in a subject in need of treatment, which method comprises administering to the subject a pharmaceutical product or formulation according to any of claims 1 to 18, 23 or 24.

20 29. A method according to claim 28, wherein the disease is malaria.

30. A pharmaceutical composition comprising a therapeutically effective amount of at least one artemisinin or a salt or derivative thereof, and at least one quinoline or a salt or derivative thereof, for use in the treatment of malaria, together with a pharmaceutically acceptable carrier or excipient.

25 31. Use of at least one artemisinin or a salt or derivative thereof, and at least one quinoline or a salt or derivative thereof, in the manufacture of a medicament for the treatment of malaria.