FIELD OF THE INVENTION
The field of the invention relates to pharmaceutical composition of c/s-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methylpropyl)amino]carbonyl]- methyl] -1',2',4'-trioxaspiro[4.5]decane, in combination with piperaquine, and processes for their preparation.
BACKGROUND OF THE INVENTION
Synthetic spiro and dispiro 1,2,4-trixolone derivatives have been found to be very effective in treating malaria. These have been disclosed in U.S. Application No. 2004/0186168, U.S. Patent Nos. 6,486,199 and U.S. 6,825,230. One of the compounds, c/s-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methylpropyl)amino]carbonyl]- methyl] -1',2',4'-trioxaspiro[4.5]decane is the new synthetic artemisinin derivative which can be easily synthesized and is free of any neurotoxicity. It also possesses improved solubility, stability and pharmacokinetic properties over other conventional artemisinin derivatives.
Monotherapy with artemisinin (natural or synthetic) class of drugs might cure the patients within 3 days, however perceiving the potential threat of malarial parasite developing resistance towards otherwise very potent artemisinin class of drugs, WHO had strictly called for an immediate halt to provision of single-drug artemisinin malaria pills. Combination therapy in case of malaria is expected to retard the development of resistance, improve efficacy by lowering recrudescence rate, provide synergistic effect, and increase exposure of the parasite to the drugs.
Artemsinin based combinations are available in the market since a long time. Artemether-lumafentrine (Co-artem®) is the first fixed dose antimalarial combination containing an artemisinin derivative and is known since 1999. This combination has passed extensive safety and efficacy trials and has been approved by more than 70 regulatory agencies. Co-artem® is recommended by WHO as the first line treatment for uncomplicated malaria.
Further available artemisinin based combination includes Artesunate+amodiaquine (Coarsucam®), and dihydroartemisin and piperaquine (Eurartesim®). Unfortunately all the available artemisinin based combinations have complicated dosage regimen making it inconvenient for a patient to adhere completely to the total prescribed duration. For example the dosage regimen of Co-artem® for an adult having body weight of more than 35 kg includes 6 doses for three days. The first dose comprises four tablets initially, second dose comprises four tablets after eight hours, third to sixth doses comprise four tablets twice for another two days; making it a total of 24 tablets. The dosage regimen of Coarsucam® for an adult having body weight of more than 36 kg or age above 14 years includes three doses for three days; each dose comprises two tablets; making it a total of six tablets. The dosage regimen of Eurartesim® for an adult having body weight between 36 -75 kg
include 3 closes for three days, each dose comprise of three tablets, making it a total of nine tablets.
It is evident that the available artemisinin based combinations have a high pill burden on patients as they need to consume too many tablets. This may increase the possibility of missing few doses. This could result in reduced efficacy and may even lead to development of resistance for the drug.
Further all the artemisinin based combinations comprise artemisinin derivative which is conventionally obtained from plant source and is therefore expensive. As the cultivation of the plant material is dependent on many factors including the weather conditions, the supply source thus becomes finite and inconsistent in quality as there are chances of varying yield and potency. This leads to quality inconsistencies and supply constraints. As malaria is more prevalent in developing countries a switch to cheaper and effective medicine is highly desirable.
Piperaquine is a bisquinoline compound that has antimalarial activity against both P. vivax and P. falciparum, including strains of chloroquine resistant P. falciparum. The tolerability, efficacy, pharmacokinetic profile, low cost and longer- acting piperaquine make it a perfect candidate for use in combination the new synthetic artemisinin derivative. The new synthetic artemisinin derivative has a short duration of action whereas piperaquine has a longer duration, thus piperaquine would be present in the circulation in sufficient concentration, even after 2 cycles exposure to new synthetic artemisinin derivative. This would ensure the killing of any parasite remaining after the therapy. Further the smaller t1/2 of new synthetic artemisinin derivative makes it less vulnerable to development of resistance.
The combination of new synthetic artemisinin derivative with piperaquine has been disclosed in the co-assigned applications WO07132438 and WO06123314, and further teachings of these applications have been incorporated herein.
However, there still remains a need in the art to formulate the new synthetic artemisinin derivative in combination with piperaquine into a suitable pharmaceutical composition. Combining the two actives in a single pharmaceutical composition would result in the composition comprising approximately 800 to 1000 mg of active content only. Incorporating this dose into a single unit leaves relatively little room for the optimization of biopharmaceutical and physicochemical properties of a composition. It remains a challenge to the formulators to formulate a large amount of active(s) in a composition which is convenient for patient to swallow while maintain the uniformity of weight and other desirable properties. While formulating the new synthetic artemisinin derivative in combination with piperaquine into a suitable pharmaceutical composition, the inventors came across various obstacles. During development it was determined that the new synthetic artemisinin derivative was very poorly compressible and in order to formulate it into a pharmaceutical composition, large amount of excipients would be required. This would result in a composition which would be difficult to swallow because of its size. The most suitable alternative
would have been wet granulation. Batches fabricated by wet granulation process resulted in good blend flowability, compressibility and satisfactory physical parameters. However, the new synthetic artemisinin derivative was also determined to be highly sensitive to the aqueous media. This was evident from the rapid increase in impurity content.
Further experimentation disclosed that dry processes namely dry granulation or compaction and direct compression were more suitable for formulating the two actives together in a single pharmaceutical composition.
The inventors have now developed pharmaceutical compositions of new synthetic artemisinin derivative in combination with piperaquine which on one hand have a suitable size for ease of swallowing and on the other hand fulfill the requirements of stability.
The term "new synthetic artemisinin derivative" as used herein chemically is c/s-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methylpropyl)amino]carbonyl]-methyl]-1',2',4'-trioxaspiro[4.5]decane.
The term "Active compound I" as used herein includes cis-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-
methylpropyl)amino]carbonyl]- methyl] -1',2',4'-trioxaspiro[4.5]decane, an enantiomer,
diastereomer, or a pharmaceutically acceptable salt thereof.
The pharmaceutically acceptable salts includes; maleate, acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, glycolate, malonate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, methane sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluene sulfonate or undecanoate, in particular maleate.
SUMMARY OF THE INVENTION
In one general aspect there is provided a pharmaceutical composition comprising;
(a) Active compound I maleate;
(b) piperaquine; and
(c) one or more pharmaceutically acceptable excipients, wherein the composition is prepared by a dry process.
In another general aspect, there is provided a pharmaceutical composition comprising;
(a) Active compound I maleate and
(b) piperaquine; wherein the total drug content is present in an amount of from about 25% to about 85% w/w based on the total weight of the composition.
In another general aspect there is provided a pharmaceutical composition comprising;
(a) Active compound I maleate in an amount of from about 5% to about 25%; and
(b) piperaquine in an amount of from about 40% to about 80%, w/w based on the total weight of the composition.
In another general aspect there is provided a pharmaceutical composition comprising;
(a) Active compound I maleate in an amount of from about 5% to about 25%; and
(b) piperaquine in an amount of from about 40% to about 80%; wherein the total drug content does not exceed 85%, w/w based on the total weight of the composition.
In another general aspect there is provided a pharmaceutical composition of Active compound I maleate and piperaquine; wherein the composition has dissolution performance such that, more than 70% w/w of the Active compound I maleate dissolves within 45 minutes, in a pH 4.5 acetate buffer with 2% tween 80, in USP type II apparatus.
In another general aspect there is provided a pharmaceutical composition comprising;
(a) Active compound I maleate and
(b) piperaquine; in a weight ratio of about 1:1 to about 1:10.
In another general aspect there is provided a pharmaceutical composition comprising; Active compound I maleate present in a dose range of about 100 to about 300 mg and piperaquine in a dose range of about 700 to about 850 mg.
In another general aspect there is provided a pharmaceutical composition comprising; Active compound I maleate present in unit dose of 100,150 or 250mg and piperaquine in a unit dose of 750mg.
In another general aspect there is provided a pharmaceutical composition comprising; Active compound I maleate present in unit dose of 100 mg and piperaquine in a unit dose of 750mg.
In another general aspect there is provided a pharmaceutical composition comprising; Active compound I maleate present in unit dose of 150 mg and piperaquine in a unit dose of 750mg.
In another general aspect there is provided a pharmaceutical composition comprising; Active compound I maleate present in unit dose of 200 mg and piperaquine in a unit dose of 750mg.
In another general aspect there is provided a pharmaceutical composition comprising;
(a) Active compound I maleate in an amount of from about 5% to about 25%;
(b) piperaquine in an amount of from about 40% to about 80%;
(c) diluent in an amount of from about 10 to about 40%;
(d) disintegrant in an amount of from about 1 to about 10%; and
(e) lubricant in an amount of from about 1 to about 5%; w/w based on the total weight of the composition.
In another general aspect there is provided a pharmaceutical composition comprising;
(a) Active compound I maleate;
(b) piperaquine;
(c) microcrystalline cellulose as a diluent;
(d) crospovidone as a disintegrant; and
(e) magnesium stearate as a lubricant.
In another general aspect there is provided a pharmaceutical composition comprising;
(a) Active compound I maleate in an amount of from about 5% to about 25%;
(b) piperaquine in an amount of from about 40% to about 80%; and
(c) microcrystalline cellulose in an amount of from about 10% to about 40%; w/w based on the total weight of the composition.
In another general aspect there is provided a pharmaceutical composition comprising the Active compound I maleate and microcrystalline cellulose in a weight ratio of about 1:1 to about 1:5.
The pharmaceutically acceptable excipients may be selected from the group consisting of binders, diluents, glidants/ lubricants, disintegrants, surfactants and coloring agents.
The pharmaceutical composition may be in the form of a tablet and the tablet may optionally be coated.
In another general aspect there is provided a pharmaceutical composition, wherein the composition is processed and stored at a temperature below 27°C and relative humidity 50%.
The dry process may be selected from direct compression or dry granulation.
In another general aspect there is provided a process for the preparation of a pharmaceutical composition, comprising the steps of;
(a) blending Active compound I maleate, piperaquine, and one or more intragranular excipients;
(b) milling, grinding or sieving the blend by roller compaction to form granules;
(c) blending the granules with one or more extragranular excipients; and
(d) compressing the blend into tablets or filling into capsules.
In another general aspect there is provided a process for the preparation of a pharmaceutical composition, comprising the steps of;
(a) blending Active compound I maleate, piperaquine, and 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 tablets or filling into capsules.
In another general aspect there is provided a process for the preparation of a pharmaceutical composition, comprising the steps of;
(a) blending Active compound I maleate, piperaquine, and one or more pharmaceutically acceptable excipients; and
(b) directly compressing the blend into tablets or filling into capsules.
In another general aspect there is provided a process for the preparation of a pharmaceutical composition, comprising the steps of;
(a) granulating a blend of one or more excipients;
(b) drying the excipient granules;
(c) blending excipient granules with Active compound I maleate and piperaquine; and
(d) compressing the blend into tablets or filling into capsules.
The granulation may be dry granulation and the dry granulation may be compaction or slugging. In particular, the dry granulation may be compaction for example, dry roller compaction.
The tablet may be coated with one or more film coating layers.
In another general aspect there is provided a method of treatment of malaria by administering a pharmaceutical composition comprising;
(a) Active compound I maleate;
(b) piperaquine; and
(c) one or more pharmaceutically acceptable excipients, wherein the composition is prepared by a dry process.
In another general aspect there is provided a pharmaceutical composition comprising;
(a) 150mg of Active compound I maleate and
(b) 750mg of piperaquine, wherein the composition is administered once a day for three days.
In another general aspect there is provided a method of treating malaria comprising administering a pharmaceutical composition comprising;
(a) 150mg Active compound I maleate and
(b) 750mg of piperaquine, wherein the composition is administered once a day for three days.
DETAILED DESCRIPTION OF THE INVENTION
The term "Active compound I" as used herein includes cis-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-
methylpropyl)amino]carbonyl]- methyl] -1',2',4'-trioxaspiro[4.5]decane, an enantiomer,
diastereomer, or a pharmaceutically acceptable salt thereof.
The pharmaceutically acceptable salts includes; maleate, acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, glycolate, malonate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, methane sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluene sulfonate or undecanoate, in particular maleate.
The Active compound I maleate may be present in an amount of from about 5% to about 25%, w/w based on the total weight of the composition.
Embodiments of the pharmaceutical composition of the present invention may further include one or more of antimalarial drugs. The antimalarial drugs may include quinine, mefloquine, lumefantrine, sulfadoxine-pyrimethamine, dihydroartimisinin, piperaquine, chloroquine, amodiaquine, proguanil, atovaquone, chloroproguanil, dapsone, fosmidomycin, tetracycline, DB 289 (pafuramidine maleate), clindamycin, their salts and derivatives thereof. In particular, piperaquine, lumefantrine and DB 289 may be used; however piperaquine remains the preferred one.
However, selection of combination as an antimalarial therapy is based on certain attributes. Synthetic artemisinin derivatives exhibit their action by their reaction with the iron in free heme molecules in the malaria parasite with the generation of free radicals leading to cellular destruction. On the other hand bisquinoline derivatives such as piperaquine interfere with the detoxification of haemin in the digestive vacuole of the parasite to non-toxic malaria pigment, so that haemin can generate free radicals and membrane damage follows. The unrelated mode of action of the two drugs would provide improved therapy, and treatment against all stages of parasites including gametocytes. Additionally since, synthetic artemisinin derivatives are very efficacious and highly potent; these would thereby treat the symptoms quickly, exhibiting fast recovery rates. Combination of synthetic artemisinin derivatives and bisquinoline derivatives such as piperaquine provide a short duration of treatment.
Piperaquine of the present invention includes piperaquine phosphate. Piperaquine may be present in an amount of from about 40% to about 80%, w/w based on the total weight of the pharmaceutical composition.
The total drug content of the pharmaceutical composition of the present invention may vary from about 25% to about 85%, in particular may not exceed 85%, w/w based on the total weight of the composition.
The pharmaceutical composition of the present invention comprises Active compound I maleate and piperaquine in a weight ratio of about 1:1 to about 1:10.
The pharmaceutical composition of the present invention comprise Active compound I maleate present in a dose range of about 100 to about 300 mg and piperaquine in a dose range of about 700 to about 850 mg.
The pharmaceutical composition of the present invention comprise Active compound I maleate present in a unit dose of 100,150 or 250 mg and piperaquine in a unit dose of 750 mg.
The pharmaceutical composition of the present invention comprise Active compound I maleate in a unit dose of about 100 mg and piperaquine in a unit dose of about 750 mg.
The pharmaceutical composition of the present invention comprise Active compound I maleate in a unit dose of about 150 mg and piperaquine in a unit dose of about 750 mg
The pharmaceutical composition of the present invention comprise Active compound I maleate in a unit dose of about 200 mg and piperaquine in a unit dose of about 750 mg
The dosage regimen of the present invention includes administering a fixed dose combination of 150mg Active compound I maleate and 750mg of piperaquine once a day for three days.
The dosage regimen of the present invention includes three doses for three days. The first dose is administered immediately on diagnosis, second dose after about 24 hours of first dose and third dose after about 24 hours of second dose.
The dosage regimen of the present invention is suitable for all patients aged from 12 to 65 years and thus eliminates the need for calculating dose based on individual weight parameter. In the existing artemisinin based combinations, the dose is calculated with respect to the individual weight of the patient and in many cases the tablets are scored to adjust the dose. However, the dosage regimen of this combination is surprisingly simple and effective both for patients and for prescribers.
Further it has already been reported that there are chances of developing resistance towards available artemisinins obtained from natural source. In this situation, the introduction of entirely new synthetic artemisinin derivative ensures a remote chance of developing resistance.
Pharmaceutical composition as used herein is selected from a group consisting of tablets or coated tablets, capsules, pellets, pills, granules, powders, and the like, in particular tablet.
The pharmaceutical composition of the present invention may further comprise one or more pharmaceutically acceptable excipients, which include all physiologically inert excipients used in the art for the preparation of pharmaceutical compositions. Examples include binders, diluents, glidants/ lubricants disintegrants, surfactants and coloring agents. The excipients may be used either intragranularly or extragranularly, or both.
Examples of 'binders' include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, agar, tragacanth and sodium alginate.
Examples of 'diluents' include cellulose powdered, microcrystalline cellulose, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, mannitol, sorbitol, sucrose, sugar compressible and sugar confectioners, in particular microcrystalline cellulose. The diluents may be present in an amount from about 10% to about 40% based on the total weight of the composition. Further, the weight ratio of Active compound I maleate to microcrystalline cellulose may vary from about 1:1 to about 1:5.
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 and soy polysaccharides, in particular crospovidone. The disintegrant may be present in an amount from about 1% to about 10% based on the total weight of the composition.
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 and white beeswax, in particular magnesium stearate. The lubricant may be present in an amount from about 1% to about 5% based on the total weight of the composition.
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 tablet may further be coated with one or more functional and/or 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. 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 comprises one or more of plasticizers, glidants or flow regulators, opacifiers and lubricants.
The pharmaceutical acceptable excipients and/or film forming polymers and coating additives may be selected to provide immediate release profile or modified release profile.
Pharmaceutical composition of Active compound I maleate may be prepared by densifying Active compound I maleate and one or more excipients, and processing into pharmaceutical composition. Densification may be carried out using any conventional method known in the art. In particular, granulation orextrusion-spheronization may be used.
In one of the embodiments, oral tablet of Active compound I maleate may be prepared by a process comprising the steps of blending Active compound I maleate and intragranular portion of a 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 a lubricant, disintegrant, and diluent in a double cone blender; and finally compressing into tablets using suitable tooling.
In another embodiment, oral tablet of Active compound I maleate may be prepared by a process comprising the steps of blending Active compound I maleate, intragranular portion of a diluent, lubricant, and disintegrant; compressing the blend in a heavy tabletting press to form slugs; reducing the slugs into granules of suitable size; blending the granules with extragranular portion of a lubricant, disintegrant, and diluent in a double cone blender; and finally compressing into tablets using suitable tooling.
In another embodiment, oral capsule of Active compound I maleate may be prepared by a process comprising the steps of blending Active compound I maleate, intragranular portion of a diluent, lubricant, and disintegrant; passing the blend through a roller compactor to form a compact mass; reducing the compact into granules of a suitable size; blending the granules with extragranular portion of a lubricant in a double cone blender; and finally filling into capsules of a suitable size.
In another embodiment, oral capsule of Active compound I maleate may be prepared by a process comprising the steps of blending Active compound I maleate, intragranular portion of a diluent, lubricant, and disintegrant; compressing the blend in a heavy tabletting press to form slugs; reducing the slugs into granules of a suitable size; blending the granules with extragranular portion of lubricant in a double cone blender; and finally filling into capsules of a suitable size.
In another embodiment, oral tablet of Active compound I maleate may be prepared by a process comprising the steps of blending Active compound I maleate, a diluent, a lubricant and a disintegrant; and directly compressing into tablets using suitable tooling.
In another embodiment, oral capsule of Active compound I maleate may be prepared by a process comprising the steps of blending Active compound I maleate, a diluent, and a lubricant; and filling the blend into capsules of a suitable size.
In yet another embodiment, tablets prepared by any of the above described processes 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 a fluidized bed processor; or dip coating. Alternatively, coating can also be performed using a hot melt technique.
The coating layers over the tablet may be applied as a solution/dispersion of coating components in a suitable solvent. Examples of solvents used for preparing a solution/dispersion of the coating ingredients include methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water or mixtures thereof.
The pharmaceutical composition of the present invention is processed and stored at a temperature below 27°C and relative humidity 50%.
The invention described herein is further illustrated by the following example, which should not be construed as limitation the scope of the invention.
Example 1:
(Table Removed)
Procedure:
1. Active compound I maleate, piperaquine phosphate and intragranular portion of microcrystalline cellulose and crospovidone were sieved through sieve BSS # 44 and mixed together.
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 and compacts were sifted through sieve BSS # 18 to form granules.
4. Extragranular portion of microcrystalline cellulose and crospovidone were sieved through sieve BSS # 44 and blended with the granules of step 3.
5. Extragranular portion of magnesium stearate were sieved through sieve BSS # 44 and blended with the blend of step 4, in a double cone blender for about 5 minutes.
6. The blend of step 5 was compressed using suitable size punches to obtain compressed tablets.
7. The tablets as obtained from step 6 were coated with Opadry® using conventional coating techniques and weight built of up to 2.5 %w/w.
Table 1: Percentage (%w/w) of In vitro drug release of Active compound I maleate, from example 1, in USP II apparatus (media: 2% tween 80 in water, 900ml, 75 rpm)
(Table Removed)
*The in vitro drug release (%w/w) should not be less than 70 % (Q) of the labeled amount dissolved in 45 minutes.
A Phase II, double bind, parallel group, randomized, dose finding study was performed to determine the safety and efficacy of three dose levels (50, 100 and 200mg) of Active compound I maleate administered for three days in patients with uncomplicated P. falciparum malaria. Preliminary data showed that the mean parasite clearance time for the patient on 50mg was 52 hours and all the 3 patients who were followed up for 28 days showed reappearance of parasites. Patients receiving 100mg had a parasite clearance time of 46.6 hours and 5 of total 6 patients showed reappearance of parasites. Patients receiving 200mg had a parasite clearance time of 30.4 hours and 4 out of 5 patients showed adequate clinical and parasitological response (ACPR) at day 28. Only 1 patient showed reappearance of parasites. The results obtained so far indicate that Active compound I maleate was a short-acting drug and produced rapid clearance of parasites. The relatively high rate of recrudescence with Active compound I maleate three days monotherapy highlighted the need to combine the drug with long acting drug.
Piperaquine phosphate was chosen as a partner drug and a Phase I double blind, randomized, parallel group, placebo controlled study was conducted in young healthy male subjects to investigate the safety, tolerability and pharmacokinetic profile of Active compound I maleate and piperaquine phosphate after co-administration of multiple oral doses. The study comprised of three cohorts. Cohort I received oral daily dose of 100 mg of Active compound I maleate and 750 mg of piperaquine phosphate, Cohort II received oral daily dose of 200 mg of Active compound I maleate and 750 mg of piperaquine phosphate and Cohort III received oral daily dose of 200 mg of Active compound I maleate and 1000 mg of piperaquine phosphate. All the three doses were administered once daily for three days in each cohort. No drug related adverse event was observed up to dose levels of 200mg Active compound I maleate and 750 mg of piperaquine phosphate. However somnolence and vomiting were reported in dose level of 200 mg Active compound I maleate and 1000 mg of piperaquine phosphate. Systemic exposures to Active compound I maleate after repeated dosing was not appreciably different to that after single dose, hence no accumulation was observed for Active compound I maleate upon 3 days repeated dosing
of Active compound I maleate - piperaquine phosphate combination. Exposures of Active compound I maleate increased in a dose proportional manner upon doubling the dose from 100 mg to 200mg, when the dose of piperaquine phosphate was kept constant (Table 2).
Table 2: Geometric mean pharmacokinetic parameters of Active compound I following multiple oral co-administration of Active compound I maleate and piperaquine phosphate to young healthy male subjects (n=6).
(Table Removed)
Comparative Bioavailability Study of fixed dose combination of Active compound I maleate 150mg + piperaquine phosphate 750 mg and Co-pack formulations.
A single-dose, two-treatment, parallel design study comparing the bioavailability of fixed dose combination tablets of Active compound I maleate 150mg + piperaquine phosphate 750 mg with co-administered Active compound I maleate 150mg and piperaquine phosphate 750 mg was conducted as an open label, balanced, randomized, single-dose, two-treatment, parallel design in 36 healthy, adult, human, male subjects under fasting conditions. The pharmacokinetic parameters are presented in Tables 3 and 4. The results of this study suggested that the pharmacokinetics of Active compound I remained unaltered when administered in fixed dose combination with piperaquine phosphate as compared to their co-administration as individual tablets.
Table 3: Geometric mean pharmacokinetic parameters of Active compound I following administration of fixed dose combination (FDC) and co-pack formulations of Active compound I maleate and piperaquine phosphate to young healthy male subjects.
(Table Removed)
FDC: Fixed dose combination tablet of Active compound I maleate 150mg and piperaquine phosphate 750mg as one tablet (n=16), Co-pack: Three Active compound I maleate 50mg tablets and one piperaquine phosphate 750mg tablet as individual tablets (n=17), AUCo-i = AUC 0 to last measurable concentration (sampling upto 96 h).
Table 4: Geometric mean pharmacokinetic parameters of piperaquine following administration of fixed dose combination (FDC) and co-pack formulations of Active compound I maleate and piperaquine phosphate to young healthy male subjects.
(Table Removed) FDC: Fixed dose combinationlablet of Active compound I maleate 150mg and piperaquine phosphate 750mg as one tablet
(n=16), Co-pack: Three Active compound I maleate 50mg tablets and one piperaquine phosphate 750mg tablet as individual tablets (n=17), AUCo-t = AUC 0 to last measurable concentration (sampling upto 96 h).
While several particular compositions have been described, it will be apparent that various modifications and combinations of the compositions detailed in the text can be made without departing from the spirit and scope of the invention.

We Claim:
Claim 1: A pharmaceutical composition comprising:
(a) 150mg of Active compound I maleate and
(b) 750mg of piperaquine, wherein the composition is administered once a day for three days.
Claim 2: The pharmaceutical composition according to claim 1, wherein the first dose of the composition is administered immediately on diagnosis, the second dose after about 24 hours of first dose and third dose after about 24 hours of second dose.
Claim 3: The pharmaceutical composition according to claim 1, wherein the composition is selected from a group consisting of tablet, capsule, pill, granule and powder.
Claim 4: The pharmaceutical composition according to claim 3, wherein the composition is a tablet.
Claim 5: The pharmaceutical composition according to claim 4, wherein the tablet is coated with one or more functional and or non-functional coating layers comprising film-forming polymers and coating additives.
Claim 6: The pharmaceutical composition according to claim 1, wherein the composition further comprises pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants/ lubricants, disintegrants, surfactants and coloring agents.
Claim 7: A method of treating malaria comprising administering a pharmaceutical composition comprising;
(a) 150mg Active compound I maleate and
(b) 750mg of piperaquine, wherein the composition is administered once a day for three days.
Claim 8: A pharmaceutical composition comprising of Active compound I maleate and piperaquine and process of preparation thereof, as described and illustrated in the examples herein.