The present invention relates to oral dosage forms of artemisinin derivative compound 'A' and piperaquine comprising taste masked resinates of Artemisinin derivative compound 'A1 and piperaquine, and the process of preparation thereof.
Malaria, the most common parasitic disease of humans, remains a major health and economic burden in most tropical countries. However, the discovery of Artemisinin (qinghaosu), a naturally occurring endoperoxide sesquiterpene lactone isolated from the plant Artemisia annua was the major breakthrough in the malaria treatment and a number of its precursors, metabolites and semi synthetic derivatives have also shown to possess promising antimalarial properties. Artemisinin derivatives (such as dihydroartemisinin, artesunate, artemether, arteether) have been used in conjunction with piperaquine to have a long half-life. Our co-pending patent application 1278/DEL/2006 discloses use of combination of Artemisinin derivative compound 'A' and piperaquine as a novel and effective treatment for malaria. Further our published PCT application WO 06123314 discloses conventional tablet dosage form of Artemisinin derivative compound 'A' and piperaquine.
Use of conventional tablets, no doubt, is the most preferred dosage form for administration of wide variety of drugs to produce systemic effects. However, many patients have difficulty in swallowing conventional tablets. This is particularly the case with pediatric and geriatric patients; mentally ill and developmental^ disabled patients and patients who are uncooperative. It is estimated that 50% of the population experience difficulties with the conventional dosage forms, with the possible consequence of the prescribed product not being taken and thus causing a major impact on the efficacy of the treatment (H. Seager, 1998, J. Pharm. Pharmacol. 50, 375-382). For these groups of patients, rapid-disintegrating tablets, rapid-disintegrating films, effervescent tablets, chewable tablets, chewing gums, suspensions, sprinkle granules, powder for reconstitution and the like, are available as alternative dosage forms. These dosage forms, due to their ease of administration and pleasant taste may encourage patients to adhere to daily medication regimens and, therefore, provide better patient compliance. Further, these offer the convenience of a readily administered dosage form, which can be taken anywhere and anytime.
Most of these dosage forms disintegrate in the oral cavity and the drug comes in close contact with the taste buds, until swallowed. After swallowing, it is expected that there

remains a minimal or no residue in the mouth. A further critical requirement is that of a pleasant taste inside the mouth, especially if the drug is bitter in taste. So there remains a need to formulate such dosage forms with taste masking/taste enhanced properties.
Prior art cites many approaches to mask the bitter taste of drugs which include coating of tablets or pellets by resins, enteric polymers or combinations thereof, preparation of suspension, complexation of drugs with polymers or with ion-exchange resins, encapsulating the drug into microparticles or granules, modifying the particle size distribution of drug, use of sweeteners and the like. Among these, complexation of an active drug with an ion exchange resin particle is a well-known technique as disclosed in U.S. Patent Nos. 2,990,332 and 4,221,778.
As taught in the prior arts, there are mainly two processes, batch and continuous (column), for complexing a drug with an ion exchange resin particle. In the batch process, the dispersion/solution of ion exchange resin particles is prepared using a solvent, to which drug is mixed at room/elevated temperature for a sufficient period of time to obtain the necessary loading. In the continuous process, a chromatography column or like can be used, to which certain amount of the ion-exchange resin particles slurried with water or any other solvent are loaded. Dispersion/solution of the drug is prepared using a solvent and passed through the column. The end point of the drug loading can be determined by analyzing the active ingredient concentration of the effluent or by simply measuring the pH changes. Choice of solvent for a particular drug, for both batch and continuous processes, however remains a critical step for preparing a stable resinate.
artemisinin derivative compound 'A' and pipraquine suffer from the problem of bitter taste just like most of the other antimalarials and thus there remains a need to formulate dosage forms of artemisinin derivative compound 'A' and pipraquine, with taste masking.
We have now found that a taste masked oral dosage form of Artemisinin derivative compound 'A' and piperaquine can be formulated, by preparing cation-exchange resinates of Artemisinin derivative compound 'A' and piperaquine. Further we have also found that a stable resinate of Artemisinin derivative compound 'A' can be prepared

using hydrocarbon solvents, whereas a stable resinate of the piperaquine can be prepared using organic solvents.
Hence in one general aspect there is provided a taste masked oral dosage form of Artemisinin derivative compound 'A' and piperaquine comprising cation-exchange resinates of Artemisinin derivative compound 'A' and piperaquine.
In another general aspect there is provided a stable cation-exchange resinate of Artemisinin derivative compound 'A' comprising Artemisinin derivative compound 'A' and cation-exchange resin, wherein the resinate is prepared using hydrocarbon solvent.
In another general aspect there is provided a stable cation-exchange resinate of the Artemisinin derivative compound 'A' comprising Artemisinin derivative compound 'A' and cation-exchange resin, wherein the resinate is prepared using normal saturated alkane solvent.
In another general aspect there is provided a stable cation-exchange resinate of the Artemisinin derivative compound 'A' comprising Artemisinin derivative compound 'A' and polacrillin potassium resin, wherein the resinate is prepared using n-heptane solvent.
In another general aspect there is provided a stable cation-exchange resinate of the piperaquine comprising piperaquine and cation-exchange resin, wherein the resinate is prepared using an organic solvent.
In another general aspect there is provided a stable cation-exchange resinate of the piperaquine comprising piperaquine and cation-exchange resin, wherein the resinate is prepared using alcohol solvent.
In another general aspect there is provided a stable cation-exchange resinate of the piperaquine comprising piperaquine and polacrillin potassium resin, wherein the resinate is prepared using isopropyl alcohol solvent.
In another general aspect there is provided a process of preparing a stable cation-exchange resinate of the Artemisinin derivative compound 'A' comprising the steps of; adding Artemisinin derivative compound 'A', cation-exchange resin and optionally one

or more pharmaceutically acceptable excipients to the hydrocarbon solvent to form a dispersion/solution, mixing for a sufficient period of time at room/elevated temperature to obtain the necessary loading, removing the solvent to form a solid residue, and finally drying and sizing the residue to form Artemisinin derivative compound 'A' resinate.
In another general aspect there is provided a process of preparing a stable cation-exchange resinate of the pipraquine comprising the steps of; adding piperaquine, cation-exchange resin, and optionally one or more pharmaceutically acceptable excipients to the organic solvent to form a dispersion/solution, mixing for a sufficient period of time at room/elevated temperature to obtain the necessary loading, removing the solvent to form a solid residue, and finally drying and sizing the residue to form piperaquine resinate
In another general aspect there is provided a rapid disintegrating solid oral dosage form of Artemisinin derivative compound 'A' and piperaquine comprising cation-exchange resinates of Artemisinin derivative compound 'A' and piperaquine; microcrystalline cellulose and croscarmellose sodium.
In another general aspect, there is provided a process of a preparing rapid disintegrating solid oral dosage form of Artemisinin derivative compound 'A' and piperaquine comprising the steps of; mixing cation-exchange resinates of Artemisinin derivative compound 'A' and piperaquine with microcrystalline cellulose and croscarmellose sodium, optionally with one or more pharmaceutically acceptable excipients and directly compressing into a solid oral dosage form.
In another general aspect, there is provided a method of treating malaria in mammals by administering a taste masked oral dosage form of Artemisinin derivative compound 'A1 and piperaquine comprising cation-exchange resinates of Artemisinin derivative compound 'A' and piperaquine.
The term "rapid disintegrating" as used herein is intended for dosage forms that completely disperse in water in a short period of less than about three minutes to form a solution, or non-gritty suspension or slurry when placed either in water or in the oral cavity.

The term "stable" as used herein refers to percentage degradation of Artemisinin derivative compound 'A' and piperaquine not more than 5% of the initial value, after storage at 40°C and 75% relative humidity, for three months.
While formulating the taste masked oral dosage form of Artemisinin derivative compound 'A' and piperaquine, we have discovered that cation-exchange resinates of Artemisinin derivative compound 'A' and piperaquine results in the complete taste masking amongst the other conventional taste masking techniques. Further, while formulating the cation-exchange resinates of Artemisinin derivative compound 'A' and piperaquine, we have discovered that the stable cation exchange resinate of Artemisinin derivative compound 'A1 and piperaquine can be prepared using particular solvent(s). Amongst the various solvents, we have discovered that a stable cation exchange resinate of Artemisinin derivative compound 'A' can be prepared using hydrocarbon solvent whereas a stable cation exchange resinate of piperaquine can be prepared using organic solvent.
Using hydrocarbon and organic solvents to prepare cation-exchange resinates of artemisinin derivative compound 'A' and piperaquine, the resinates obtained were found to be stable as shown below in Table I.
Table 1: Results of the stability study conducted on Artemisinin derivative compound 'A' and piperquine resinate

(Table Removed)

The term "hydrocarbon solvent" as used herein includes any solvent consisting of carbon and hydrogen molecules, wherein the number of carbon atoms ranges from C5-C2o These solvents may be selected from any of the aliphatic hydrocarbons (saturated or unsaturated, normal, branched or cyclic), aromatic hydrocarbons (with one or more aromatic rings optionally substituted with alkyl side chains), in particular saturated aliphatic hydrocarbon such as alkanes. One or more hydrocarbon solvent may be used to prepare resinates of artemisinin derivative compound 'A'. Examples of the aliphatic hydrocarbons include n-pentane, n-hexane, n-heptane, and the like, and that of the aromatic hydrocarbons include benzene, toluene, xylene, naphthalene, isoparaffins, cycloparaffins, and the like, in particular n-heptane.
The term "organic solvent" as used herein includes any solvent such as ether, alcohol, aldehydes, ketone, hydrocarbon, ester, amide, amine, in particular alcohol. One or more organic solvent may be used to prepare resinates of piperaquine. Examples of alcohols include isopropyl alcohol, ethanol, n-butanol, octanol and the like, in particular isopropyl alcohol.
An ion exchange resin is an ionic, or charged, compound which has binding sites that can bind to an ionic drug. Either a cation or an anion exchange resin can be used depending on whether the drug to be bound is acidic or basic. A basic drug binds to a cation exchange resin which is negatively charged and have anionic binding sites and an acidic drug binds to an anion exchange resin which is positively charged and have cationic binding sites. Conjugation between the drug and the ion exchange resin result from the ionic bonds between oppositely charged species because of their mutual electrostatic attraction. The conjugation of a drug with an ion exchange resin forms a composition known as a "drug-resin complex" or "drug-resin conjugate" or "resinate".
When such resinates are administered through the gastrointestinal tract, the attached drug is released by the ion exchange reaction with the counter ions in the stomach and intestine. Artemisinin derivative compound 'A' and piperaquine are basic drugs, hence cation-exchange resins may be used to form their respective resinates. These resinates provide taste masking and can also be designed to provide controlled/sustained release of the drugs.

Cation exchange resins may include a wide range of synthetic cation exchange resins with different polymeric matrices which may further be cross-linked. Suitable cation exchange resins of the present invention are commercially available under the trade names Amberlite™ and Duolite™ from Rohm and Haas Co. and Dowex™ from the Dow Chemical Co. The resin may be used in acid form or in the form of a salt with an alkali metal such as sodium or potassium. The Amberlite™ may be Amberlite™ IRP88 (Polacrilin potassium), Amberlite™ IRP64 (Polacrilex resin), Amberlite™ IRP69 (Sodium polystyrene sulfonate), in particular Amberlite™ IRP88 (Polacrilin potassium), which is hereby acting both as taste masking agent and disintegrant. The drug: resin ratio of the present invention may vary from about 1:0.1 to 1:5, in particular 1:1. Further, the amount of drug that can be loaded onto the resin particles may range from about 1 % to about 90% w/w.
In one of the embodiment, the stable cation-exchange resinate of Artemisinin derivative compound 'A1 may be prepared by a process comprising the steps of: adding Artemisinin derivative compound 'A', cation-exchange resin, and optionally one or more pharmaceutically acceptable excipients to the hydrocarbon solvent to form a dispersion/solution, mixing for a sufficient period of time at room/elevated temperature to obtain the necessary loading, removing the solvent to form a solid residue, and finally drying and sizing the residue to form artemisinin derivative compound 'A' resinate.
In another embodiment, the stable cation-exchange resinate of Artemisinin derivative compound 'A' may be prepared by a process comprising the steps of: adding Artemisinin derivative compound 'A', optionally one or more pharmaceutically acceptable excipients to the hydrocarbon solvent to form a dispersion/solution as a mobile phase, loading the cation-exchange resin on to a stationary phase, passing the mobile phase over a stationary phase with/without pressure, collecting the fractions, removing the solvent to form a solid residue, and finally drying and sizing the residue to form Artemisinin derivative compound 'A' resinate.
In another embodiment, the stable cation-exchange resinate of piperaquine may be prepared by a process comprising the steps of: adding piperaquine, cation-exchange resin and optionally one or more pharmaceutically acceptable excipients to the organic solvent to form a dispersion/solution, mixing for a sufficient period of time at
room/elevated temperature to obtain the necessary loading, removing the solvent to
form a solid residue, and finally drying and seizing the residue to form piperaquine resinate.
In another embodiment, the stable cation-exchange resinate of piperaquine may be prepared by a process comprising the steps of: adding piperaquine, optionally one or more pharmaceutically acceptable excipients to the organic solvent to form a dispersion/solution as a mobile phase, loading the cation-exchange resin on to a stationary phase, passing the mobile phase over a stationary phase with/without pressure, collecting the fractions, removing the solvent to form a solid residue, and finally drying and seizing the residue to form piperaquine resinate.
The term "stationary phase" and "mobile phase" as used herein have general meanings as in chromatographic systems.
For removing the solvents, techniques such as evaporation with or without the use of heat source, lyophilization, centrifugation, spray drying, and filtration with or without vacuum or combinations thereof may be employed. The drug-resin complex thus formed is washed with an appropriate solvent to insure removal of any unbound drug or by-products. The complexes are usually air-dried in trays.
Since both the drugs artemisinin derivative compound 'A' and piperaquine carry the same ionic charge, these may be conjugated with a single resin, without one significantly displacing the other, and without retarding the initial availability of either drug.
The term "Artemisinin derivative compound 'A'" as used herein means c/s-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'methylpropyl)amino]carbonyl]methyl] 1', 2', 4'-trioxaspiro[4.5] decane and includes its free base as well as pharmaceutically acceptable salts thereof. Suitable salts of Artemisinin derivative compound 'A' include but are not limited to, acid addition salts, such as those made with maleic, malonic, succinic, fumaric, malic, tartaric, citric, methylsulfonic, hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfomc, benezenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid; salts made with saccharin, preferably with maleic acid. It further includes all individual enantiomers,

diastereomers, racemates, and other isomers of those compounds wherein such structural variations are possible Additionally it also includes all polymorphs and solvates, such as hydrates and those formed with organic solvents, of these compounds.
The term "piperaquine" includes its free base as well as pharmaceutically acceptable salts thereof. Suitable salts of piperaquine include but are not limited to, acid addition salts, such as those made with phosphoric, maleic, malonic, succinic, fumaric, malic, tartaric, citric, methylsulfonic, hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, acetic, propionic, glycolic, lactic pyruvic, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid; salts made with saccharin, preferably with phosphoric acid. It further includes all individual enantiomers, diastereomers, racemates, and other isomers of those compounds wherein such structural variations are possible. Additionally it also includes all polymorphs and solvates, such as hydrates and those formed with organic solvents, of these compounds.
Stable resinates prepared above may be processed into any suitable oral dosage forms such as rapid-disintegrating tablets, rapid-disintegrating films, effervescent tablets, chewable tablets, chewing gums, suspensions, sprinkle granules, powder for reconstitution and the like, using one or more of pharmaceutically acceptable excipients, as and when desirable. These oral dosage forms may be prepared by using any of the conventional technologies such as freeze drying, spray drying, tablet molding, vacuum drying and sublimation techniques, comminuting, mixing, melting, sizing, filling, drying, molding, immersing, coating, dry or wet granulation, direct compression, extrusion-spheronization etc. However, as Artemisinin derivative compound 'A' is a moisture-sensitive drug, in formulating solid oral dosage forms, direct compression or dry granulation techniques remain the preferred ones.
The term "pharmaceutically acceptable excipients" as used herein may include any physiologically inert additive used in the pharmaceutical art of dispensing. Examples may include carrier materials, surface stabilizers, structure imparting excipients, thickening agents, suspending agents, neutralizing agents, anti-foaming agents,
effervescent agents, fillers/diluents, disintegrants/superdisintegrants,
10

lubricants/glidants, surfactants, binders, sweetening agents, flavoring agents, coloring agents, preservatives, and the like.
The resinate may be carried in a carrier material, which forms a porous network or matrix. The carrier may be any water-soluble or water-dispersible material that is capable of forming a rapidly disintegrating network. Examples of substances that may be used as carrier materials include, but are not limited to gelatin, glycine, mannitol, hydrolyzed dextrose, dextran, dextrin, maltodextrin, alginates, hydroxyethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, corn-syrup solids, pectin, carrageenan, agar, chitosan, locust bean gum, xanthan gum, guar gum, acacia gum, tragacanth, conjac flower, rice flower, wheat gluten, sodium starch glycolate, soy fiber protein, potato protein, papain or horseradish peroxidase, and mixtures thereof.
Surface stabilizers physically adhere to the surface of the drug but do not chemically bond to or interact with it. The surface stabilizer is adsorbed on the surface of the drug while the individually adsorbed molecules of the surface stabilizer are essentially free of intermolecular cross-linkages. Accordingly, one or more surface stabilizers can be employed in the dosage form of the present invention.
Examples of structure-imparting water-soluble or water-dispersible excipients include, but are not limited to, a sugar (such as sucrose, lactose, glucose, mannose and the like), a sugar alcohol (such as mannitol, sorbitol, xylitol, erythritol, lactitol, maltitol and the like), a starch or modified starch (such as corn starch, potato starch, maize starch and the like), natural polymers or synthetic derivatives of a natural polymer (such as gelatin, xanthan gum, carrageenan, alginates, dextran, maltodextran and the like) and the like or mixtures thereof.
Examples of thickening agents include, but are not limited to, natural gums (such as acacia, xanthan gum and the like), a high molecular weight cross-linked acrylic acid carbomer [such as Carbopol™ 980, Carbopol™ 974P (Carbomer 934P), Carbopol™ 940 (all trade names of B.F. Goodrich & Co.)] and mixtures thereof.
Suspending agents help the drug and resins to remain uniformly distributed in a suspension and thus maintain content uniformity of the active substance in suspension.
Examples of suspending agents include, but are not limited to, propylene glycol, polyethylene glycol, glycerin and mixtures thereof.
Neutralizing agents in the context of the present invention shift the equilibrium concentration of a solubilized weakly basic drug and drive the drug to favor complexing with a weakly acidic ion-exchange resin. The equilibrium concentration is shifted since a neutralizing agent is used to remove excess solubilized hydrogen ions present in the suspension as a result of using various acidic components (such as an acidic resin, an acidic carrier material, an acidic thickening agent and the like). Examples of neutralizing agent include, but are not limited to, sodium carbonate, potassium carbonate, ammonium carbonate, and mixtures thereof.
Examples of anti-foaming agents include, but are not limited to, simethicone and mixtures thereof.
Examples of effervescent agents include effervescent combinations of an organic acid and a carbonate or bicarbonate. Useful acids include: citric, tartaric, malic, fumaric, adipic, succinic and the like and acid salts and anhydrides thereof. Acid salts may also include sodium dihydrogen phosphate, disodium dihydrogen pyrophosphate, acid citrate salts, sodium acid sulfite and the like. While the food acids can be those indicated above, acid anhydrides of the above-described acids may also be used. Carbonate sources include dry solid carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate, amorphous calcium carbonate and mixtures thereof.
Examples of fillers/diluents include, but are not limited to, calcium disulfate, calcium trisulfate, calcium carbonate, microcrystalline cellulose, lactose monohydrate, lactose anhydrous, sucrose, rnannitol, sorbitol, calcium phosphate dibasic, calcium phosphate tribasic kaolin, calcium silicate, maltodextrin, sugar alcohols such as xylitol, erythritol, sorbitol and rnannitol various starches and modified starches and mixtures thereof.
Examples of disintegrants/superdisintegrants include, but are not limited to, sodium carboxymethyl cellulose, low-substituted hydroxypropylcellulose L-HPC), sodium starch
glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked
polyvinyl pyrrolidone, croscarmellose sodium, natural, modified or pregelatinized starch, microcrystalline cellulose, gums especially guargum, alginic acid or salts thereof and mixtures thereof.
Examples of lubricants include, but are not limited to, colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, silica gel and mixtures thereof.
The surfactant may be selected from anionic, cationic or non-ionic surface-active agents or surfactants. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate, and sulfate ions such as sodium lauryl sulfate (SLS), sodium laurate, dialkyl sodium sulfosuccinates particularly bis-(2-ethylhexyl) sodium sulfosuccinate, sodium stearate, potassium stearate, sodium oleate and the like. Suitable cationic surfactants include those containing long chain cations, such as benzalkonium chloride, bis-2-hydroxyethyl oleyl amine or the like. Suitable non-ionic surfactants include polyoxyethylene sorbitan fatty acid esters, fatty alcohols such as lauryl, cetyl and stearyl alcohols; glyceryl esters such as the naturally occurring mono-, di-, and tri-glycerides; fatty acid esters of fatty alcohols; polyglycolized glycerides such as Gelucire; polyoxyethylene-polyoxypropylene block co-polymer such as Poloxamer and other alcohols such as propylene glycol, polyethylene glycol, sorbitan, sucrose, cholesterol, and mixtures thereof.
Examples of binders include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, microcrystalline cellulose, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, carboxyvinyl polymers like carbomers and mixtures thereof.
Sweetening agents, flavoring agents and mixtures thereof used in the present invention are selected from those which are pharmaceutically acceptable, compatible with the attributes of an oral dosage formulation and adequately mask the slight acidic taste of cationic exchange resin (polacrillin potassium) to below the taste threshold. Examples of sweetening agents include, but are not limited to, any natural or artificial sweetener
(such as glucose, dextrose or fructose and the like or mixtures thereof, when not used
as a carrier; saccharin and its various salts, maltodextrin, cyclamate, aspartame, acesulfame-K and its sodium and calcium salts and the like or mixtures thereof; sucrose or sucralose; sugar alcohols such as sorbitol, mannitol, xylitol and the like or mixtures thereof) and mixtures thereof.
Examples of flavoring agents include, but are not limited to, any natural or synthetic flavoring liquid (such as volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins and extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof, including, but not limited to, spearmint, peppermint, lemon, caramel, banana, vanila, orange, grape, lime or grapefruit citric oils or apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot, or other mint or fruit flavor essences), an aldehyde or ester (such as benzaldehyde (cherry, almond), citral, a-citral (lemon, lime), neral, beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanal (green fruit), 2-dodedenal (citrus, mandarin) and mixtures thereof.
Examples of coloring agents include, but are not limited to, any pharmaceutically acceptable natural or synthetic dyes such as Red 30 ferric oxide, titanium dioxide, Lake of Tartrazine, Lake of Quinoline Yellow, Lake of Sunset Yellow and Lake of Erythrosine, Lack of Carmosine Ponceau, Allura Red and mixtures thereof.
Examples of preservatives include, but are not limited to, potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid (such as butylparaben, alcohols such as ethyl or benzyl alcohol), phenolic compounds (such as phenol) or quartemary compounds (such as benzalkonium chloride), and mixtures thereof.
In another embodiment, the oral dosage form of Artemisinin derivative compound 'A' and piperaquine may be prepared by a process comprising the steps of; mixing the cation-exchange resinates of Artemisinin derivative compound 'A' and piperaquine, with one or more pharmaceutically acceptable excipients, and finally formulating into suitable oral dosage form.
In another embodiment, the rapid disintegrating oral dosage form of Artemisinin derivative compound 'A' and piperaquine may be prepared by a process comprising the steps of; mixing cation-exchange resinates of Artemisinin derivative compound 'A' and piperaquine with microcrystalline cellulose, croscarmellose sodium and one or more pharmaceutically acceptable excipients, compressing the blend with appropriate tooling into suitable sized tablets, and optionally coating with one or more layers of film forming polymer(s) and coating additive(s).
In the present invention resins are complexed with Artemisinin derivative compound 'A' and piperaquine, which are incorporated in matrix of rapid disintegrating tablets. The resin used herein is performing the dual function of taste masking and further acting as an aid in disintegration along with conventionally used disintegrants. Moreover, since both the drugs are bitter in taste, separately making the resinates of each of these provide the benefit of complete taste masking, and further minimizing the risk of incompatibility, if any
Examples of film-forming polymers include ethylcellulose, hydroxypropyl methylcellulose,
hydroxypropylcellulose, methylcellulose, carboxymethyl cellulose,
hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit ®; and the like. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used.
Coating additives may be selected from the group comprising of plasticizers, coloring agents, lubricants/glidants, and the like.
Specific examples of plasticizers include triethylcitrate, acetylated triacetin, tributylcitrate, glyceroltributyrate, monoglyceride, rape oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethyl phthalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, and the like.
Coating may be performed by applying film forming polymer(s) with or without other pharmaceutically inert excipients, as solution/suspension using any conventional coating technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor; dip coating or compression coating.
The invention is further illustrated by the following examples, which is for illustrative purpose only and should not be construed as limiting the scope of the invention in any way.
Example 1 Artemisinin derivative compound 'A' maleate resinate

Example
Artemisini derivative compound 'A' maleate resinate
(Table Removed)
Procedure:
1. A 32.83% w/v dispersion of polacrillin potassium resin was prepared in n-
heptane by stirring for 15 minutes.
2. Artemisinin derivative compound 'A' was sifted through #44 BSS.
3. The sifted Artemisinin derivative compound 'A' of step 2, was added to the
dispersion of step 1 under continuous stirring
4. The stirring was continued for another 4-5 hours.
5. The dispersion of step 4 was filtered to separate the resinate.
6. The filtered wet mass of step 5 was dried in a vacuum oven.
7. The dried resinate of step 6 was sifted through #30 BSS.
8. The sifted resinate was again dried in fluidized bed dryer till the n-heptane
content is not more than 1500 ppm.
9. The dried Artemisinin derivative compound 'A' maleate resinate was kept in triple
laminated pack.

Piperaquine phosphate resinate
(Table Removed)

Procedure:
1. A 29% w/v dispersion of polacrillin potassium resin was prepared in isopropyl
alcohol by stirring for 15 minutes.
2. Piperaquine phosphate was sifted through #36 BSS.
3. The sifted piperaquine phosphate of step 2 was added to the dispersion of step 1
under continuous stirring.
4. The stirring was continued for another 4-5 hours.
5. The dispersion of step 4 was filtered to separate the resinate.
6. The filtered wet mass of step 5 was dried in a vacuum oven.
7. The dried resinate of step 6 was sifted through #22 BSS.
8. The sifted resinate was again dried in fluidized bed dryer till the isopropyl alcohol
content is not more than 5000 ppm.
9. The dried piperaquine phosphate resinate was kept in triple laminated pack.
Rapid disintegrating tablet
(Table Removed)
Procedure:
1 Artemisinin derivative compound 'A' maleate resinate and Piperaquine phosphate resinate were sifted through #22 BSS.
2. Microcrystalline cellulose, microcrystalline cellulose and sodium
carboxymethylcellulose, and crosscarmellose sodium were sifted through #44
BSS.
3. Aspartame, orange flavor and vanilla flavor were sifted through #60 BSS.
4. Materials form steps 1, 2 and 3 were mixed for 30 minutes.
5 Colloidal silicon dioxide and magnesium stearate were sifted through #44 BSS.
6. Mixture of step 4 was blended with mixture of step 5 for 5 minutes.
7. The blend of step 6 was compressed into tablets in a tablet compression
machine
Examples 2-5
(Table Removed)
In-vitro Dissolution study
In-vitro drug releases from the tablets prepared as per the compositions of examples 2-4 as given above, was determined by dissolution for ARTEMISININ DERIVATIVE COMPOUND 'A' USP II dissolution apparatus at 75 rpm, in 0.1 N HCI 900ml for 30 min and piperaquine using USP II dissolution apparatus at 75 rpm, in 0.01N HCI 900ml for 30 minutes. The results of the dissolution study are presented below in Table 2.
Table 2: In-vitro drug release (%w/w) at 30 minutes

(Table Removed)

Stability data
The tablets of example 1, were stored at 40° C and 75% relative humidity for a period of 3 months, and analyzed for Artemisinin derivative compound 'A1 and piperquine contents and related substances using validated in house HPLC analytical method. The results of the analysis are represented below in Table 3.

Table 3: Results of the stability study conducted on tablets of Example 1.
(Table Removed)

WE CLAIM:
1. A taste masked oral dosage form of Artemisinin derivative compound 'A' and piperaquine comprising cation-exchange resinates of Artemisinin derivative compound 'A' and piperaquine.
2. The taste masked oral dosage form of claim 1, wherein the dosage form is
selected from the group consisting of rapid-disintegrating tablets, rapid-
disintegrating films, effervescent tablets, chewable tablets, chewing gums,
suspensions, sprinkle granules and powder for reconstitution.
3. The taste masked oral dosage form of claim 2, wherein the dosage form
comprises cation exchange resinates of Artemisinin derivative compound 'A' and
piperaquine; microcrystalline cellulose and croscarmellose sodium.
4. The taste masked oral dosage form of any of the preceding claims, further
comprises one or more pharmaceutically acceptable excipients selected from the
group consisting of carrier materials, surface stabilizers, structure imparting
excipients, thickening agents, suspending agents, neutralizing agents, anti-
foaming agents, effervescent agents, fillers/diluents,
disintegrants/superdisintegrants, lubricants/glidants, surfactants, binders, sweetening agents, flavoring agents, coloring agents and preservatives.
5. A stable cation-exchange resinate of Artemisinin derivative compound 'A' comprising Artemisinin derivative compound 'A' and cation-exchange resin, wherein the resinate is prepared using hydrocarbon solvent selected from the group consisting of aliphatic hydrocarbons (saturated or unsaturated, normal, branched or cyclic) or aromatic hydrocarbons (with one or more aromatic rings optionally substituted with alkyl side chains).
6. The stable cation-exchange resinate of
Artemisinin derivative compound 'A' of claim 5, wherein the aliphatic hydrocarbon is selected from the group consisting of n-pentane, n-hexane and n-heptane.
7. A stable cation-exchange resinate of piperquine comprising piperquine and cation-exchange resin, wherein the resinate is prepared using organic solvent selected from the group consisting of ether, alcohol, aldehydes, ketone, hydrocarbon, ester, amide and amine.

8. The stable cation-exchange resinate of piperaquine of claim 7, wherein the
alcohol is selected from the group consisting of isopropyl alcohol, ethanol, n-
butanol and octanol.
9. The stable cation exchange resinates of any of the preceding claims, wherein
the cation exchange resins is selected from the group consisting of polacrilin
potassium, polacrilex resin and sodium polystyrene sulfonate.

10. The stable cation exchange resinates of any of the preceding claims, wherein
the drug: resin ratio may vary from about 1:0.1 to about 1:5.
11. The process of preparing a stable cation-exchange resinate of Artemisinin
derivative compound 'A' of claim 5, wherein the resinate is prepared by a
process comprising the steps of; adding Artemisinin derivative compound 'A',
cation-exchange resin and optionally one or more pharmaceutically acceptable
excipients to the hydrocarbon solvent to form a dispersion/solution, mixing for a
sufficient period of time at room/elevated temperature to obtain the necessary
loading, removing the solvent to form a solid residue, and finally drying and
sizing the residue to form Artemisinin derivative compound 'A' resinate.
12. The process of preparing a stable cation-exchange resinate of pipraquine of
claim 7, wherein the resinate is prepared by a process comprising the steps of;
adding pipraquine, cation-exchange resin, and optionally one or more
pharmaceutically acceptable excipients to the organic solvent to form a
dispersion/solution, mixing for a sufficient period of time at room/elevated
temperature to obtain the necessary loading, removing the solvent to form a
solid residue, and finally drying and sizing the residue to form pipraquine
resinate.
13. A taste masked oral dosage form of Artemisinin derivative compound 'A' and
piperaquine comprising cation-exchange resinates of Artemisinin derivative
compound 'A' and piperaquine, and process of preparation thereof, as described
and illustrated in the examples herein.