Technical field of invention
The technical field of the present invention relates to a stabilized antimalarial oral solid dosage forms comprising Spiro or dispiro 1,2,4-trioxalones, or their pharmaceutically acceptable salts, prodrugs and analogues; and process of preparation thereof.
Background of the invention
Malaria, the most common parasitic disease of humans, remains a major health and economic burden in most tropical countries. Large areas of Central and South America, Hispaniola (Haiti and the Dominican Republic), Africa, the Middle East, the Indian subcontinent, Southeast Asia, and Oceania are considered as malaria-risk areas. It leads to a heavy toll of illness and death especially amongst children and pregnant women. According to the World Health Organization, it is estimated that the disease infects about 400 million people each year, and around two to three million people die from malaria every year. There are four kinds of malaria parasites that infect human: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovate and Plasmodium malariae.
Malaria spreads from one person to another by the bite of a mosquito, Anopheles gambiae, which serves as vector. When a mosquito sucks the blood of human, sporozoites are transfused into the human body together with saliva of the mosquito. The sporozoites enter into the hepatocytes, reproduce asexually and finally enter into the bloodstream. The parasites continue to multiply inside the red blood cells, until they burst and releases large numbers of merozoites. This process continues, destroying a significant number of blood cells and causing the characteristic paroxysm ("chills and fever") associated with the disease. In the red blood cells some of the merozoites become male or female gametocytes. These gametocytes are ingested by the mosquito when it feeds on blood. The gametocytes fuse in the vector's gut, sporozoites are produced and are migrated to the vector's salivary glands.
The clinical symptoms of malaria are generally associated with the bursting of the red blood cells causing an intense fever associated with chills that can leave the infected individual exhausted and bedridden. More severe symptoms associated with repeat infections and/or infection by Plasmodium falciparum include anaemia, severe headaches, convulsions, delirium and, in some instances, death.
Quinine, an antimalarial compound that is extracted from the bark of cinchona tree, is one of the oldest and most effective Pharmaceuticals in existence. Chloroquine and Mefloquine are the synthetic analog of quinine developed in the 1940's, which due to their effectiveness, ease of manufacture, and general lack of side effects, became the drugs of choice. The downside to quinine and its derivatives is that they are short-acting and have bitter taste. Further they fail to prevent disease relapses and are also associated with side effects commonly known as 'Chinchonism syndrome' characterized by nausea, vomiting,
dizziness, vertigo and deafness. However in recent years, with the emergence of drug-resistant strains of parasites and insecticide-resistant strains of mosquito vectors, the treatment or control of malaria is becoming difficult with these conventional drugs.
Malarial treatment further progressed with the discovery of Artemisinin (qinghaosu), a naturally occurring endoperoxide sesquiterpene lactone isolated from the plant Artemisia annua (Meshnick et al., 1996; Vroman et al. 1999; Dhingra et al., 2000) and a number of its precursors, metabolites and semisynthetic derivatives which have shown to possess antimalarial properties. The antimalarial action of artemisinin is due to its reaction with the iron in free heme molecules in the malaria parasite with the generation of free radicals leading to cellular destruction. This has initiated a substantial effort to elucidate its molecular mechanism of action (Jefford, 1997; Gumming et al., 1997) and to identify novel antimalarial peroxides (Dong and Vennerstrom, 2001).
Although the clinically useful semi synthetic artemisinin derivatives are rapid acting and potent antimalarial drugs, they have several disadvantages including recrudescence, neurotoxicity, (Wesche et al., 1994) and metabolic instability. (White, 1994). A fair number of these compounds are quite active in vitro, but most suffer from low oral activity. (White, 1994; van Agtmael et al., 1999).
Thus there exists a need in the art to identify new peroxide antimalarial agents, especially those which are easily synthesized, are devoid of neurotoxicity, and which possess improved solubility, stability and pharmacokinetic properties. Following that many synthetic antimalarial 1,2,4-trioxanes (Cumming et al., 1996; Jefford, 1997), 1,2,4,5-tetraoxanes (Vennerstrom et al., 2000), and other endoperoxides have been prepared. Various patents/* applications assigned to Medicines for Malaria Venture, MMV viz; US 2004/0186168, US 6,486,199 and US 6,825,230, disclose means and method for treating malaria using Spiro or dispiro 1,2,4-trioxolanes. The present invention relates to solid dosage forms of the various antimalarial compounds disclosed in these patents/ applications, hereinafter referred to as active compound.
Active compound, representing various Spiro and dispiro 1,2,4- trioxolane derivatives possess excellent potency, efficacy against Plasmodium parasites, and a lower degree of neurotoxicity, in addition to their structural simplicity and ease of synthesis. Furthermore, these compounds have half lives conductive to treatment of malaria which are believed to permit short-term treatment regimens comparing favorably to other artemisinin-like drugs. In general, the therapeutic dose of trioxolane may range between about 0.1-1000 mg/kg/day, with between about 1-100 mg/kg/day being preferred. The foregoing doses may be administered as a single dose or may be divided into multiple doses for administration. The compositions may be administered once to several times daily. For malaria prevention, a typical dosing schedule could
be, for example, 2.0-1000 mg/kg weekly beginning 1-2 weeks prior to malaria exposure taken up until 1-2 weeks post-exposure.
However, in spite of many advantages there are certain limitations which grounds for many formulation related difficulties, the first among being their susceptibility to degradation in presence of moisture that may results in reduced shelf lives. And another is their bitter taste, which can result in poor compliance of the regimen or selection of another, possibly less effective, therapeutic agent.
We have now discovered that a stable antimalarial oral solid dosage form comprising active compound can be prepared by controlling the water content below a certain critical limit. Further the bitter taste can be masked by applying a film coating layer to the solid dosage form.
SUMMARY OF INVENTION
In one aspect it provides a stable antimalarial oral solid dosage form of active compound comprising:
(a) active compound; and
(b) one or more pharmaceutically acceptable excipients;
wherein the water content of the dosage form is not more than (NMT) 6.5% w/w.
In another aspect it provides, a stable antimalarial oral solid dosage form of active compound, which is formulated using a dry or non-aqueous process.
In another aspect there is provided, a process for the preparation of a stable antimalarial oral solid dosage form of active compound comprising the steps of:
(a) blending active compound, with one or more intragranular excipients;
(b) granulating the blend by roller compaction or slugging;
(c) blending the granules with one or more extragranular excipients;
(d) compressing the blend into tablet or filling into capsule; and
(e) optionally applying one or more film coating layers to the tablet.
In another aspect there is provided, a process for the preparation of a stable antimalarial oral solid dosage form of active compound comprising the steps of:
(a) blending active compound, and one or more pharmaceutically acceptable excipients;
(b) directly compressing into tablet or filling into capsules; and
(c) optionally applying one or more film coating layers to the tablet.
In another aspect there is provided, a process for the preparation of a stable antimalarial oral solid dosage form of active compound comprising the steps of:
(a) blending active compound, with one or more intragranular excipients;
(b) granulating the blend with non-aqueous granulating fluid;
(c) blending the granules with one or more extragranular excipients;
(d) compressing the blend into tablet or filling into capsule; and
(e) optionally applying one or more film coating layers to the tablet.
In another aspect there is provided, a process for the preparation of a stable antimalarial oral solid dosage form of active compound comprising the steps of:
(a) granulating a blend of one or more excipients using water alone or mixture with other solvents as
granulating fluid;
(b) drying the excipient granules;
(c) blending excipient granules with active compound as such, or active compound comprising
granules prepared using one or more non-aqueous granulating fluids;
(d) compressing the blend into tablet or filling into capsule; and
(e) optionally applying one or more film coating layers to the tablet.
In another aspect there is provided, a method of prophylaxis or treatment of malaria in mammals, by administering to the said mammal a stable antimalarial oral solid dosage form of active compound comprising:
(a) active compound; and
(b) one or more pharmaceutically acceptable excipients;
wherein the water content of the dosage form is NMT 6.5% w/w.
In another aspect there is provided, a method of prophylaxis or treatment of malaria in mammals, by administering to the said mammal a stable antimalarial oral solid dosage form of active compound, which is formulated using a dry or non-aqueous process.
In yet another aspect the stable antimalarial oral solid dosage form of active compound as described above may further comprise one or more other antimalarial drugs.
The other antimalarial drugs may include Quinine, Mefloquine, Lumefantrine, Sulfadoxine-pyrimethamine, Dihydroartimisinin, Piperaquine, Chloroquine, Amodiaquine, Proguanil, Atovaquone, Chloroproguanil, Dapsone, Fosmidomycin, Tetracycline, DB 289, Clindamycin, their salts and derivatives thereof. In particular, Piperaquine, Lumefantrine and DB 289 may be used.
In another aspect there is provided, a stable antimalarial oral solid dosage form of active compound comprising:
(a) active compound;
(b) at least one other antimalarial drug selected from Lumefantrine, Piperaquine or DB 289; and
(c) one or more pharmaceutically acceptable excipients.
The details of one or more embodiments are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is not limited to particular process steps and materials disclosed herein, but are extended to equivalents thereof as would be recognized by those ordinarily skilled in the relevant arts. It should also be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.
The term "stable" as used herein refers to chemical stability of active compound in solid dosage forms against decomposition occurring during shelf life due to hydrolysis, wherein NMT 5% w/w total related substances are formed on storage at 40 ± 2°C and 75 ± 5% relative humidity over a period of 6 months.
The term "solid dosage form" as used herein includes conventional solid dosage forms such as tablets, capsules, pills, granules, powders, and the like. In particular, the solid dosage form is tablet.
The present invention provides stable antimalarial oral solid dosage forms of active compound, by using excipients having low water content and manufactured using dry or non-aqueous formulation processes.
It has been observed through exhaustive experimentation that when active compound was formulated into various dosage forms including liquid as well as solid dosage forms, it gets degraded by hydrolysis, which may be due to the water associated with the excipients or added during the course of processing. It was also noticed that the liquid oral dosages forms such as aqueous syrups, suspensions or solutions having desired shelf life could not be successfully prepared. Further on preparing solid oral dosage forms of active compound, using techniques involving use of water such as wet granulation or spray drying or extrusion-spheronization resulted in dosage forms with wavering stability results. However, acceptable stability results were obtained when solid dosage forms were formulated using appropriate excipients with low water content and a process in which water is absent such as dry granulation, direct compression or non-aqueous granulation. In case where excipients are granulated using water, the excipient granules
may be dried appropriately before blending with active compound as such or with active compound containing granules, and processed into solid dosage forms of acceptable stability.
The role of excipients and water content was evaluated by conducting compatibility studies of active compound with various excipients, in different proportions and evaluating the extent of degradation by forced degradation at 60°C over the period of 2 weeks and at 50°C for 4 weeks. The water content was analyzed using Karl Fischer method and the total related substances (%w/w) were determined by HPLC method. The results of the study are represented below in Table 1.
The study clearly Indicates the importance of the use of excipients having low water or moisture content in stabilizing solid dosage forms of active compound. In the present invention, we have discovered that use of excipients having water content less has 6.5% w/w and particularly less than 2% w/w surprisingly increases the stability of Active compound, and would thus provide reasonably long shelf lives. Excipients such as higher amount of starch were found to be incompatible with active compound. Further lactose was also found to be incompatible due to degradation by other mechanisms such as Maillard reaction & DCP was not preferred due to increase in RS at 60°C. Microcrystalline Cellulose, however gave the most satisfactory results.
Active compound covers various Spiro and dispiro trioxolanes derivatives having antimalarial activity and prepared by the any of the known process, disclosed in US 2004/0186168, US 6,486,199 and US 6,825,230. These trioxolanes are relatively sterically hindered on at least one side of the trioxolane heterocycle which provides better in vivo activity, especially with respect to oral administration. Particularly, Spiro and dispiro 1,2,4-trioxolanes derivatives possess excellent potency and efficacy against Plasmodium parasites, and a lower degree of neurotoxicity. They are structurally simple, easy, inexpensive to synthesize, and can be used effectively alone or in conjuction with other antimalarials.
Active compound includes free form of the compounds referred to herein as well as their pharmaceutically acceptable salts, solvates, esters, enantiomers, diastereomers, polymorphs, metabolites, prodrugs and analogues, e.g. cis-Adamantane-2-spiro-3'-8'-[[[(2'-amino2'methylpropyl)amino]carbonyl]methyl]1l,2',4'-trioxaspiro[4.5]decane hydrogen maleate. Active compound constitute from about 5% to about 60% w/w of the solid dosage form. In particular, it may constitute from about 8% to about 50% w/w of solid dosage form.
The stable antimalarial oral solid dosage forms of the present invention may further comprise one or more pharmaceutically acceptable excipients, which include all physiologically inert excipients used in the art for preparation of solid dosage forms. Examples include binders, diluents, glidants/ lubricants disintegrants, surfactants, coloring agents, and the like. The excipients may be used either intragranularly or extragranularly or both. The weight ratio of active compound and excipients in the dosage forms may vary from about 1:1 to about 1:30.
Examples of 'Binders' include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, agar, tragacanth, sodium alginate, and the like.
Examples of 'Diluents' include cellulose powdered, microcrystalline cellulose, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, mannitol, sorbitol, sucrose, sugar compressible, sugar
confectioners and the like.
Examples of 'Disintegrants' include clays, celluloses, alginates, gums, cross-linked polymers (such as cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose), sodium starch glycolate, low-substituted hydroxypropyl cellulose, soy polysaccharides, and the like.
Examples of 'Lubricants' or 'Glidants' include talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, magnesium carbonate, magnesium oxide, calcium silicate, microcrystalline cellulose, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, sodium laurylsulfate, sodium stearyl fumarate, and hydrogenated vegetable oils, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax and the like.
Examples of 'Surfactants' include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in sweetener compositions. These include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides for example glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene -polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, and palmitoyl carnitine.
The 'coloring agents' include any FDA approved colors for oral use.
The solid dosage forms may further be coated with one or more non-functional layers comprising film-forming polymers, and other coating additives.
Examples of 'film-forming polymers' include cellulose derivatives such as ethyl cellulose, hydroxypropyl
methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose,
hydroxymethylcellulose, hydroxyethylcellulose, partially hydrolyzed polyvinyl alcohol, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit ® RL and RS; and the like.
Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating.
The 'coating additives' include plasticizers, glidants or flow regulators, opacifiers and lubricants.
Pharmaceutical acceptable excipients and/ or film forming polymers and coating additives may be selected to provide conventional immediate release profile or modified release profile of active compound.
Solid dosage forms of active compound may be prepared by densifying active compound and one or more excipients, and processing into solid dosage forms. Densification may be carried out using any conventional method known in the art. In particular, granulation or extrusion-speronization may be used.
In one of the embodiments, the stable oral antimalarial tablet of active compound may be prepared by a process comprising the steps of blending active compound, intragranular portion of diluents, lubricant, and disintegrant; passing the blend through a roller compactor to form a compact mass; reducing the compact into granules of suitable size; blending the granules with extragranular portion of lubricant, disintegrant and filler in double cone blender; and finally compressing into tablet using suitable tooling.
In another embodiment, the stable oral antimalarial tablet of active compound may be prepared by a process comprising the steps of blending active compound, intragranular portion of diluents, lubricant, and disintegrant; compressing the blend in heavy tabletting press to form slugs; reducing the slugs into granules of suitable size; blending the granules with extragranular portion of lubricant, disintegrant and filler in double cone blender; and finally compressing into tablet using suitable tooling.
In another embodiment, the stable oral antimalarial capsule of active compound may be prepared by a process comprising the steps of blending active compound, intragranular portion of diluent, lubricant, and disintegrant; passing the blend through a roller compactor to form a compact mass; reducing the compact into granules of suitable size; blending the granules with extragranular portion of lubricant, disintegrant and diluent in double cone blender; and finally filling into capsule of suitable size.
In another embodiment, the stable oral antimalarial capsule of active compound may be prepared by a process comprising the steps of blending active compound, intragranular portion of diluents, lubricant, and disintegrant; compressing the blend in heavy tabletting press to form slugs; reducing the slugs into granules of suitable size; blending the granules with extragranular portion of lubricant, disintegrant and filler in double cone blender; and finally filling into capsule of suitable size.
In another embodiment, the stable oral antimalarial tablet of active compound may be prepared by a process comprising the steps of blending active compound, diluents, lubricant and disintegrant; and directly compressing into tablet using suitable tooling.
In another embodiment, the stable oral antimalarial capsule of active compound may be prepared by a process comprising the steps of blending active compound, diluent, lubricant and disintegrant; and filling into capsule of suitable size.
In another embodiment, the stable oral antimalarial tablet of active compound may be prepared by a process comprising the steps of blending active compound, intragranular portion of diluent, and disintegrant; wet granulating the blend with non aqueous granulating fluid or solution/dispersion of pharmaceutically acceptable excipients in the non-aqueous granulating fluid; drying and reducing the granules to a suitable size, blending the granules with extragranular portion of lubricant, disintegrant and diluent in double cone blender; and finally compressing into tablet using suitable tooling.
In yet another embodiment, the stable oral antimalarial capsule of active compound may be prepared by a process comprising the steps of blending active compound, intragranular portion of diluent, and disintegrant; wet granulating the blend with non aqueous granulating fluid or solution/dispersion of pharmaceutically acceptable excipients in the non-aqueous granulating fluid; drying and reducing the granules to a suitable size, blending the granules with extragranular portion of lubricant, disintegrant and diluent in double cone blender; and finally filling into capsule of suitable size.
Examples of 'non-aqueous granulating fluid' include organic solvents such as methanol, ethanol, IPA, dichloromethane, acetone, and the like.
In another embodiment, tablets prepared by any of the above described process may further be coated with film forming polymers and one or more coating additives, using techniques well known in the art such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating. Alternatively, coating can also be performed using hot melt technique whenever possible
The coating is applied to the tablets as solution/ dispersion of coating components in a suitable solvent. The solvents for the coating solution may be selected from amongst water, organic solvent and mixtures thereof. The organic solvents include lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and n-butyl alcohol; lower alkanones such as acetone; acetonitrile; chloroform; and methylene chloride.
In another embodiment, one or more other antimalarial drug selected from amongst Piperaquine, Lumefantrine and DB 289 may be incorporated in the blend comprising active compound, in any of the embodiments above.
In order to further illustrate the present invention and the advantages thereof, the following specific examples are given with the understanding that these examples are intended only to be illustrations without serving as a limitation on the scope of the present invention.
(Table Remove)
Procedure:
1. Active compound and intragranular portion of microcrystalline cellulose were sieved through sieve
BSS# 44 and mixed together in Double cone blender to form a uniform blend.
2. To the blend of step 1, intragranular portion of sifted Magnesium stearate was added and
blended for about 5 minutes.
3. The blend of step 2 was compacted in a roller compactor and was sifted through sieve BSS # 22
to form granules.
4. Extragranular portion of microcrystalline cellulose, croscarmellose sodium and magnesium
stearate were sieved through sieve BSS # 44 & blended with the granules of step 3
5. The blend of step 4 was compressed using suitable size punches to obtain compressed tablets.
6. The tablets as obtained from step 5, were coated with Opadry® using conventional coating
techniques
The tablets prepared as per the Example 1 were subjected to stability studies at 25°C/ RH 60%, 30°C/ RH 65% and 40°C/ RH 75% over a period of 6 months, as represented in Table 2. Similarly, the results of the % of In Vitro drug release analyzed at predetermined time periods, represented as Table 3.
Table 2: % total related substances (%w/wl.

' % Total Related Substance should NMT than 5%
Table 3: % In vitro drug release In USP II apparatus (media: 2% tween 80 in water. 900ml 75. rpm. in 45 min)

*The in vitro drug release (%w/w) should NLT 70 % (Q) of the labeled amount is dissolved in 45 minutes.
As evident from the above studies, the tablets prepared by the process of the present invention in which water is absent had shown to possess acceptable shelf stability
(Table Remove)
Procedure:
1. Active compound, microcrystalline cellulose, croscarmellose sodium and magnesium stearate were
sifted through sieve BSS# 44.
2. Siftedactive compound, microcrystalline cellulose, and croscarmellose sodium were mixed in Double
cone blender for about 15 minutes to form a uniform blend.
3. To the blend of step 2, sifted magnesium stearate was added and mixed for about 5 minutes.
4. The blend obtained in step 3 was directly compressed using suitable size capsule shape punches to
obtain compressed tablets.
Particular formulations have been described above, it will be apparent that various modifications and combinations of the formulations detailed in the text can be made without departing from the spirit and scope of the invention. For example although the tablet dosage form has been prepared, other conventional solid dosage forms like capsule can also be prepared using the similar compositions.

WE CLAIM:
1. A stable oral solid dosage form of active compound comprising:
(a) active compound (as disclosed herein); and
(b) one or more pharmaceutically acceptable excipients;
wherein the water content of the dosage form is NMT 6.5% w/w.

2. The stable solid dosage form according to claim 1, wherein active compound includes
pharmaceutically acceptable salts, solvates, esters, enantiomers, diastereomers, polymorphs,
metabolites, prodrugs and analogues of Active compound.
3. The stable solid dosage form according to claim 2, wherein active compound is cis-Adamantane -
2 - spiro - 3' - 8' - [[[(2'-amino 2' methylpropyl) amino] carbonyl] methyl] 1', 2', 4' - trioxaspiro [4.5]
decane hydrogen maleate.
4. The stable solid dosage form according to claims 1-3, wherein the active compound constitutes
from about 5 to 60% w/w of the solid dosage form.
5. The stable solid dosage form according to claims 1-4, wherein the pharmaceutically acceptable
excipients are selected from amongst binders, diluents, glidants/ lubricants, disintegrants,
surfactants and coloring agents.
6. The stable solid dosage form according to claims 1-5, wherein the composition further comprises
one or more other antimalarial drugs selected from amongst quinine, mefloquine, lumefantrine,
sulfadoxine-pyrimethamine, dihydroartimisinin, piperaquine, chloroquine, amodiaquine, proguanil,
atovaquone, chloroproguanil, dapsone, fosmidomycin, tetracycline, clindamycin, and DB 289.
7. The stable solid dosage form according to claims 1-6, wherein the solid dosage form may be
coated with one or more non-functional coating layers comprising film-forming polymers.
8. The stable solid dosage form according to claims 1-7, wherein the solid dosage form is selected
from amongst tablet, capsule, pill, granule and powder.
9. The stable solid dosage form according to claims 1-8, wherein the dosage form is prepared by a
process comprising the steps of:
(a) blending active compound, with one or more intragranular excipients;
(b) granulating the blend by roller compaction;
(c) blending the granules with one or more extragranular excipients; and
(d) compressing the blend into tablet or filling into capsule.
10. The stable solid dosage form according to claims 1-8, wherein the dosage form is prepared by a
process comprising the steps of:
(a) blending active compound, with one or more intragranular excipients;
(b) granulating the blend by slugging;
(c) blending the granules with one or more extragranular excipients; and
(d) compressing the blend into tablet or filling into capsule.
11. The stable solid dosage form according to claims 1-8, wherein the dosage form is prepared by a
process comprising the steps of:
(a) blending active compound, one or more pharmaceutically acceptable excipients, and
(b) directly compressing the blend into tablet or filling into capsule;
12. The stable solid dosage form according to claims 1-8, wherein the dosage form is prepared by a
process comprising the steps of:
(a) blending active compound, one or more intragranular excipients;
(b) wet granulating the blend with non aqueous granulating fluid ;
(c) drying and reducing the granules to a suitable size;
(d) blending the granules with one or more extragranular excipients; and
(e) compressing into tablet or filling into capsules.
13. The stable solid dosage form according to claims 1-12, wherein the tablet is further coated with
one or more non-functional coating layers, by a process comprising the steps of:
(a) preparing a solution/dispersion of film forming polymers and coating additives and
(b) layering on the tablets.
14. A method of prophylaxis or treatment of malaria in mammals by administering to the said
mammal a stable oral solid dosage form of active compound (as disclosed herein) comprising:
(a) active compound; and
(b) one or more pharmaceutically acceptable excipients;
wherein the water content of the dosage form is NMT 6.5% w/w of the final formulation.
15. A method of prophylaxis or treatment of malaria in mammals by administering to the said
mammal a stable oral solid dosage form of active compound (as disclosed herein), which is
formulated using a dry or non-aqueous process.
16. A stable oral solid dosage form of active compound and a process of its preparation as described
and illustrated in the examples herein.