DESC:FIELD OF INVENTION:
The present invention relates to pharmaceutical compositions comprising an anthelmintic agent. The present invention also provides a process of preparing such pharmaceutical compositions and its use in the treatment of anthelmintic infections.

BACKGROUND OF INVENTION:
Praziquantel (PZQ) is recognized worldwide as the primary drug of choice in the treatment of the most common forms of Schistosomiasis (bilharzia) and is recognized as an essential drug by the World Health Organization.

Praziquantel is a broad-spectrum anthelmintic drug and chemically is known as 2-(cyclohexylcarbonyl)-1, 2, 3, 6, 7, 11b-hexahydro-4H-pyrazino [2, 1-a] isoquinolin-4-one.

Praziquantel is indicated for the treatment of infections due to all species of Schistosoma (for example, Schistosoma mekongi, Schistosoma japonicum, Schistosoma mansoni and Schistosoma hematobium) and infections due to the liver flukes such as Clonorchis sinensis and Opisthorchis viverrini.

Praziquantel is commercially available as a 600 mg tablet form for the oral treatment of Schistosome infections and infections due to liver flukes.

The dosage recommended of BILTRICIDE® tablets for the treatment of Schistosomiasis is 20 mg/kg body weight three times a day as a one day treatment, at intervals of not less than 4 hours and not more than 6 hours and the recommended dose for Clonorchiasis and Opisthorchiasis is 25 mg/kg body weight three times a day as a one day treatment, at intervals of not less than 4 hours and not more than 6 hours.

Failures in mass treatment of Schistosomiasis have occurred and have been attributed to the resistance of the parasite to praziquantel. This may be due to the fact that praziquantel therapy is not sufficiently long lasting as a result of the low bioavailability exhibited by praziquantel because of its low water solubility and fast metabolism, and due to the fact that praziquantel is extensively converted into an inactive or considerably less potent compound after oral administration.

This fast metabolism of praziquantel is evidenced by the low effectiveness against younger forms of the above mentioned types of parasites, which being in systemic circulation are less exposed to praziquantel.

In the past researchers have always focused on methods to optimize the low bioavailability exhibited by praziquantel.

“Pharmacokinetic study of praziquantel administered alone and in combination with cimetidine in a single-day therapeutic regimen”, Jung et al., Antimicrob., Agents Chemother. 41 (1997), pp. 1256–1259. This document discloses that a brief therapeutic regimen of praziquantel, reduced to a single day, has been found to be effective for treatment of neurocysticercosis.

“Bioavailability of praziquantel increases with concomitant administration of food”, Castro et al., Antimicrob., Agents Chemother. 44 (2000), pp. 2903–2904. In this document a study was conducted and it was found that after a single oral dose of 1,800 mg of praziquantel, following a high-lipid diet and a high-carbohydrate diet, the maximum levels in plasma increased 243% and 515% and the area under the plasma concentration curve from 0 to 8 hrs increased 180% and 271%, respectively.

“Interaction between grapefruit juice and praziquantel in humans”, Castro et al., Antimicrob., Agents Chemother., 46 (2002), pp. 1614–1616. In this document it was found that after a single oral dose of praziquantel with 250 ml of grapefruit juice, the area under the concentration-time curve and the maximum concentration in plasma of praziquantel were significantly increased.

“Dissolution properties of praziquantel-PVP systems”, El-Arini and Leuenberg, Pharm. Acta Helv., 73 (1998), pp. 89–94, Pharm. In this document, a study was conducted to investigate the dissolution behavior of poorly water-soluble anti-schistosomal drug, praziquantel (PZQ) from co-precipitates (dispersions) and physical mixtures of the drug with polyvinylpyrrolidone (PVP) was characterized.

“Improvement of the in vitro dissolution of praziquantel by complexation with a- , ß- and ?-cyclodextrins” , Becket et al., Int. J. Pharm., 179 (1999), pp. 65–71. This document discusses that the aqueous solubility of praziquantel may be improved by forming inclusion complexes with cyclodextrins.

“Improvement of antischistosomal activity of praziquantel by incorporation into phosphatidylcholine-containing liposomes”, Samanta C. Mourão et al., International Journal of Pharmaceutics, Volume 295, Issues 1–2, 13 May 2005, pp. 157–162. This document discusses the effect of praziquantel against all known species of Schistosomes that infect humans.

“PLGA nanoparticles containing praziquantel: effect of formulation variables on size distribution”, Rubiana M. Mainardes et al., International Journal of Pharmaceutics 290 (2005), pp. 137–144. In this document a study was conducted to investigate the effects of some process variables on the size distribution of nanoparticles, which were prepared by emulsion–solvent evaporation method. In this document the nanoparticles are drug carriers made of poly(D,L-lactide-co-glycolide) acid, which entrap praziquantel active substance.

These studies have described the improvement of dissolution rate or activity of praziquantel using adjuvants, such as ß-cyclodextrin, polyvinylpyrrolidone, nanoparticles and liposomes. Further, these studies demonstrate that the administration of praziquantel concomitant with cimetidine or food increases the levels of praziquantel in the plasma with an improvement in the treatment of the disease.

Although praziquantel is the primary drug of choice in the treatment of Schistosomiasis, its poor solubility has restricted its delivery via the oral route. In spite of its poor solubility, praziquantel is well absorbed across the gastrointestinal tract. However, large doses of praziquantel are required to achieve the adequate concentration at the target sites and to overcome first pass metabolism.

An alternative route of delivery is parenteral formulations. Praziquantel administered by parenteral routes may achieve direct systemic delivery thereby avoiding first pass hepatic metabolism as well as leads to a reduction in the dose required.

Although guidelines recommend that treatments may be selected on the basis of efficacy and tolerability, other factors, such as ease and patient compliance may also influence the treatment decision-making process.

Currently oral route for drug delivery is the preferred choice of patients for the treatment of an infection, as compared to parenteral or any other routes of administration.

Although oral route administration is preferred, large doses of praziquantel are required to achieve the adequate concentration at the target sites, which ultimately leads to increase in the frequency of administration of the tablet dosage form of praziquantel, i. e. approximately three times a day as a one day treatment, at intervals of not less than 4 hours and not more than 6 hours by a patient undergoing the treatment as per his body weight.

In view of the increase in the number of times a day the medication should be taken to achieve the desired results, it is possible that it may result in non-completion of therapy as a result of not taking the medication, leading to the worsening of underlying infection due to such non-compliance, which is especially observed in geriatric and pediatric patients. Therefore, considerable efforts to improve such compliance have been aimed at by simplifying the medication packaging, providing effective medication reminders, improving patient education, and limiting the number of medications prescribed simultaneously. However, such efforts have not been able to completely resolve the drawbacks associated with patient compliance.

Hence, to overcome the issues of patient non-compliance, researchers have attempted to provide sub-curative doses as well as reducing the dosing frequency of praziquantel.

“Randomized comparison of low-dose versus standard-dose praziquantel therapy in treatment of urinary tract morbidity due to Schistosoma haematobium infection”, Charles H. King et al., Am. J. Trop. Med. Hyg, 66(6), 2002, pp. 725–730. In this document random allocation study was carried out to examine the relative efficacy of a 20 mg/kg dose versus a 40 mg/kg dose of praziquantel in control of hematuria and bladder and renal abnormalities associated with S. haematobium infection in an endemic area of Coast Province, Kenya.

“Efficacy of low doses of praziquantel for Schistosoma mansoni and Schistosoma haematobium”, Tayler P et al., J Trop Med Hyg. 1988 Feb, 91(1):13-7. This document discusses the shortage of available information on the impact of low doses of praziquantel was remedied by a trial of 0, 10, 20, 30 and 40 mg kg-1 against double infections of Schistosoma haematobium and S. mansoni in a rural area of Zimbabwe.

“Efficacy of low doses of praziquantel in Taeniasis” , Zbigniew S. Pawlowski, Acta Tropica, Volume 48, Issue 2, December 1990, pp. 83–88. This document discusses experimental studies that suggest that doses of 1 to 5 mg of praziquantel per kg are effective against several intestinal cestodiases.

WO 2001/49269 discloses a sustained-releasing anthelmintic composition, which contains praziquantel as an active ingredient and provides a controlled releasing rate of praziqantel by adequate selection and combination of a polymeric material and a binder.

Therapeutic effect of sub-curative dose praziquantel on Schistosoma mansoni infected mice and resistance to challenge infection after treatment, has been discussed in Ruangyuth Chaiworaporn et al., Vol 36 No. 4 July 2005. In this document concludes that the disadvantage of using sub-curative dose of anthelmintic drug should be carefully observed, especially regarding drug resistance.

Although all the above-mentioned prior art documents disclose several strategies and formulations to overcome the dissolution and patient non-compliance issues, there still exists a need to develop pharmaceutical compositions of praziquantel that alleviates these problems.

OBJECT OF THE INVENTION:
An object of the present invention is to provide pharmaceutical compositions comprising praziquantel and one or more pharmaceutically acceptable excipients having improved dissolution and bioavailability.

Another object of the present invention is to provide pharmaceutical compositions comprising praziquantel to ensure patient compliance.

Yet another object of the present invention is to provide pharmaceutical compositions comprising praziquantel with reduced dose.

Another object of the present invention is to provide a process for preparing pharmaceutical compositions comprising praziquantel and one or more pharmaceutically acceptable excipients.

A further object of the present invention is to provide a method of treating anthelmintic infections, which method comprises administering pharmaceutical compositions comprising praziquantel and one or more pharmaceutically acceptable excipients.

Another object of the present invention is to provide pharmaceutical compositions comprising a praziquantel for use in the treatment of anthelmintic infections.

SUMMARY OF THE INVENTION:
According to one aspect of the present invention, there is provided a pharmaceutical composition comprising praziquantel in the form of particles having an average particle size of less than or equal to about 2000 nm and one or more pharmaceutically acceptable excipients.

According to another aspect of the present invention, there is provided a process of preparing a pharmaceutical composition comprising:
(i) homogenizing praziquantel or R-praziquantel and at least one excipient to produce a homogenized dispersion of praziquantel in the excipient; and
(ii) processing said homogenized dispersion to produce a slurry of nanoparticles of praziquantel having an average particle size of less than or equal to about 2000 nm; and
(iii) processing the slurry to obtain a dosage form.

According to yet another aspect of the present invention, there is provided the use of a pharmaceutical composition comprising praziquantel in the form of particles having an average particle size of less than or equal to about 2000 nm and one or more pharmaceutically acceptable excipients, in the manufacture of a medicament for treating anthelmintic infections in a human being or an animal.

According to yet another aspect of the present invention, there is provided the use of a pharmaceutical composition comprising R- praziquantel in the form of particles having an average particle size of less than or equal to about 2000 nm and one or more pharmaceutically acceptable excipients, in the manufacture of a medicament for treating anthelmintic infections in a human being or an animal.

According to a further aspect of the present invention there is provided a method of treatment of anthelmintic infections in a human being or an animal, by administering a therapeutically effective amount of a pharmaceutical composition comprising praziquantel in the form of particles having an average particle size of less than or equal to about 2000 nm and one or more pharmaceutically acceptable excipients.

According to a further aspect of the present invention there is provided a method of treatment of anthelmintic infections in a human being or an animal, by administering a therapeutically effective amount of a pharmaceutical composition comprising R-praziquantel in the form of particles having an average particle size of less than or equal to about 2000 nm and one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION:
Commercially available praziquantel preparations are prescribed such that they need to be repeatedly administered at regular intervals of not less than 4 hours and not more than 6 hours. If any drug is administered several times, it is difficult to maintain the self-treatment that has been prescribed. Therefore, the patients may find it difficult to keep a track for administration of praziquantel, and there is a high chance that they might miss one or two doses ultimately leading to decrease in the desired anthelmintic effect.

Further, administration of higher number of doses than the required may lead to over dosage or dose dumping. Overdose of praziquantel may lead to resistance and may also result in serious side effects such as pyrexia, headache, vomiting, drowsiness, abdominal pain, diarrhea, eczema etc. depending on individual patients.

Therefore, in order to obtain the desired effect the inventors of the present invention have formulated pharmaceutical compositions comprising praziquantel which can exhibit and maintain the desired effect even by administering it in minimal doses.

More specifically, the inventors of the present invention have formulated pharmaceutical compositions comprising nanosized praziquantel, wherein the dose of praziquantel is reduced significantly.

Furthermore, the pharmaceutical compositions comprising praziquantel of the present invention exhibit increased bioavailability due to enhanced solubility and dissolution properties.

The term “praziquantel” is used in broad sense to include not only “praziquantel” per se but also their pharmaceutically acceptable derivatives thereof. Suitable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable isomers, pharmaceutically acceptable esters, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers and/or pharmaceutically acceptable complexes thereof.

Praziquantel is generally administered as a racemate mixture which essentially implies that it has an equal 1:1 mixture of both enantiomers, namely R-praziquantel and S- praziquantel. R-praziquantel is the active component of praziquantel which acts on worms exhibiting schistosomicidal activity, and S-praziquantel is inactive and may contribute to the unpleasant taste of the drug. Furthermore, R-praziquantel may provide better clinical efficacy than praziquantel at the same dose.

The present invention provides pharmaceutical compositions comprising praziquantel or R-praziquantel or their pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, hydrates, polymorphs, tautomers, anhydrates, complexes thereof and one or more pharmaceutically acceptable excipients.

The pharmaceutical composition, according to the present invention, comprising praziquantel or R-praziquantel, may be administered by various routes of administration such as, but not limited to, oral, parenteral (subcutaneous, intravenous, intramuscular, intradermal, intraperitoneal) or topical and the like.

The pharmaceutical composition, according to the present invention, comprising praziquantel or R-praziquantel, may be provided as, but not limited to, oral, parenteral or topical, dosage forms and the like.

The term "pharmaceutical composition" includes oral dosage forms, such as but not limited to, tablets, soft gelatin capsule, capsules (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, sprinkles microspheres and multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, sprinkles microspheres and multiparticulates) and sprinkles. However, other dosage forms such as liquid dosage forms (liquids, liquid dispersions, suspensions, solutions, emulsions, sprays, spot-on) may also be envisaged under the ambit of the invention.

The term "pharmaceutical composition" includes parenteral dosage forms, such as liquid dosage forms (liquids, liquid dispersions, suspensions, solutions, emulsions), gels, depots, implants (rods, capsules, rings) biodegradable or non-biodegradable microparticles/microspheres etc.

The term "pharmaceutical composition" includes topical dosage forms, such as but not limited to, sprays, solutions, suspensions, ointments, drops, in-situ gel, aerosols, ointments, microspheres, creams, gels, patches, films and the like.

The pharmaceutical composition of the present invention comprising praziquantel or R-praziquantel, in the form of controlled release formulations, lyophilized formulations, delayed release formulations, timed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations.

The pharmaceutical compositions according to the present invention may be used for human and veterinary purposes.

The term “reduced dose” as used herein refers to a therapeutically effective dose of praziquantel or R-praziquantel or their pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, hydrates, polymorphs, tautomers, anhydrates, complexes thereof, which is less than the usual or the conventional dose required to produce the therapeutic effect.

The pharmaceutical compositions, according to the present invention may be administered at least once a day. Preferably, the pharmaceutical compositions are administered once a day or twice a day or thrice a day in a dose which is less than the conventionally administered dose.

The pharmaceutical compositions comprising praziquantel or R-praziquantel, of the present invention may provide a dose of < 25 mg/kg body weight or < 20 mg/kg body weight for once a day or twice a day or thrice a day administration.

Preferably, the present invention provides pharmaceutical compositions comprising praziquantel or R-praziquantel wherein the dose of the praziquantel or R-praziquantel is in a range from about 10 mg/kg body weight to about 15 mg/kg body weight, for administration at least once or twice or thrice a day. Preferably, the total daily dose of praziquantel or R-praziquantel may be less than the conventionally administered daily dose.

Preferably, the present invention provides pharmaceutical compositions comprising praziquantel or R- praziquantel wherein the dose of the praziquantel or R-praziquantel is in a range from about 7.5 mg/kg body weight to about 18 mg/kg body weight for administration at least once or twice or thrice a day.

The term “nanosized” as used herein refers to praziquantel or R-praziquantel particles having an average particle size of less than or equal to about 2000 nm, preferably less than or equal to about 1000 nm. The average particle size may, for example, be measured using laser based particle size analyzer.

Preferably, substantially all particles have an average particle size of less than or equal to about 2000 nm, preferably less than or equal to about 1000 nm. The term average particle size as used herein refers to the average diameter of the particles.

The term “particles” as used herein refers to individual particle of praziquantel or R- praziquantel, or particles of praziquantel or R- praziquantel granules or praziquantel or R-praziquantel compositions and/or mixtures thereof.

The average particle size of the praziquantel or R-praziquantel is preferably above 1 nanometre.

Accordingly, the D90 average particle size of praziquantel or R-praziquantel is not less than or equal to 700 nm, preferably not less than or equal to 300 nm.

Nanosizing leads to increase in the exposure of surface area of praziquantel particles leading to an increase in the rate of dissolution.

The present invention thus provides pharmaceutical compositions comprising praziquantel or R- praziquantel, wherein praziquantel or R-praziquantel particles are in the nanosized range.

The nanoparticles of praziquantel or R-praziquantel may be obtained by any of the process such as but not limited to milling, precipitation and homogenization, high pressure homogenization, spray-freeze drying, supercritical fluid technology, double emulsion/solvent evaporation, PRINT (Particle replication in non-wetting templates), thermal condensation, ultrasonication, spray drying. Preferably, the nanoparticles of the present invention can be obtained by any nanomilling techniques.

Suitable excipients may be used for formulating the pharmaceutical compositions according to the present invention.

Preferably, the nanomilled praziquantel or R-praziquantel is obtained by nanomilling praziquantel or R- praziquantel with at least one of the following : (i) at least one surface stabilizer, (ii) at least one viscosity enhancing agent and (iii) at least one polymer.

Preferably, the present invention provides pharmaceutical compositions comprising nanosized praziquantel or R-praziquantel particles, preferably in the form of a solid dosage forms, such as tablets, granules or sprinkles that may be incorporated in a hard gelatin capsule, sachet or packet or compressed to form tablets. These granules or sprinkles may comprise at least one excipient but not limited to, at least one surface stabilizer, at least one viscosity enhancing agent and at least one polymer and optionally other pharmaceutically acceptable excipients.

Thus, as used herein, the term “sprinkle formulation” includes any formulation that is suitable for oral administration, wherein the formulation is sprinkled upon any consumable item.

Surface stabilizer, according to the present invention, means surfactants or solubilizers that are capable of stabilizing the increased surface charge of the nanomilled drug. Suitable amphoteric, non-ionic, cationic or anionic surfactants may be included as surface stabilizers in the pharmaceutical compositions of the present invention.

Suitable surfactants or solubilizers for use in the pharmaceutical compositions of the present invention may comprise one or more, but not limited to Polysorbates (Tween 80), Sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl dimethyl amine oxide, Docusate sodium, Poloxamers, (Poloxamer 188) Cetyl trimethyl ammonium bromide (CTAB), Polyethoxylated alcohols, Polyoxyethylene sorbitan, Octoxynol, N, N–dimethyldodecylamine–N–oxide, Hexadecyltrimethylammonium bromide, Polyoxyl 10 lauryl ether, Brij, Bile salts (sodium deoxycholate, sodium cholate), Polyoxyl castor oil, Nonylphenol ethoxylate Cyclodextrins, Lecithin, Methylbenzethonium chloride. Carboxylates, Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates, Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated natural oils & fats, Sulphated esters, Sulphated alkanolamides, Alkylphenols, ethoxylated & sulphated, Ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters Polyethylene glycol esters, Anhydrosorbitol ester & it's ethoxylated derivatives, Glycol esters of fatty acids, Carboxylic amides, Monoalkanolamine condensates, Polyoxyethylene fatty acid amides, Quaternary ammonium salts, Amines with amide linkages, Polyoxyethylene alkyl & alicyclic amines, N,N,N,N tetrakis substituted ethylenediamines 2- alkyl 1- hydroxyethyl 2-imidazolines, N -coco 3-aminopropionic acid/ sodium salt, N-tallow 3 -iminodipropionate disodium salt, N-carboxymethyl n dimethyl n-9 octadecenyl ammonium hydroxide, n-cocoamidethyl n-hydroxyethylglycine sodium salt or mixtures thereof.

Preferably, the surfactants may be present in an amount ranging from about 1% to about 10% by weight of the composition.

Viscosity enhancing agents are the excipients that are capable of stabilizing the formulation by increasing the viscosity of the formulation and thus, preventing physical interaction of nanoparticles under the operating conditions employed.

Suitable viscosity enhancing agents for use in the pharmaceutical compositions of the present invention may comprise one or more, but not limited to derivatives of sugars, such as lactose, sucrose, saccharose, hydrolyzed starch (maltodextrin), pharma grade sugar or mixtures thereof.

Preferably, the viscosity enhancing agents may be present in an amount ranging from about 4% to about 20% by weight of the composition.
Suitable polymers for use in the pharmaceutical compositions of the present invention may comprise one or more hydrophilic polymers, but not limited to cellulose derivatives like hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel A15C, Methocel A4M) hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, polyvinylpyrrolidone and carboxymethyl hydroxyethylcellulose; acrylics like acrylic acid, acrylamide, and maleic anhydride polymers, acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum, agar, pectin, carrageenan, gelatin, casein, zein and alginates, carboxypolymethylene, bentonite, magnesium aluminum silicate, polysaccharides, modified starch derivatives and copolymers or mixtures thereof.

Preferably, the polymers may be present in an amount ranging from about 2% to about 10% by weight of the composition.

Suitable channeling agents for use in the pharmaceutical compositions of the present invention, may comprise one or more, but are not limited to sodium chloride, sugars, polyols and the like and mixtures thereof.

Preferably, the channeling agents may be present in an amount ranging from about 1% to about 6% by weight of the composition.

Suitable carriers, diluents or fillers for use in the pharmaceutical compositions of the present invention may comprise one or more, but not limited to lactose (for example, spray-dried lactose, a-lactose, ß-lactose) available under the trade mark Tablettose, various grades of lactose available under the trade mark Pharmatose or other commercially available forms of lactose, lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose (for example, microcrystalline cellulose available under the trade mark Avicel), hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC), methylcellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethyl hydroxyethylcellulose, Non-Pareil Seeds, Sugar Spheres and other cellulose derivatives, starches or modified starches (including potato starch, corn starch, maize starch and rice starch) and mixtures thereof.

Preferably, the carriers, diluents or fillers may be present in an amount ranging from about 15% to about 60% by weight of the composition.

Preferably, glidants, anti-adherents and lubricants are incorporated in the pharmaceutical compositions of the present invention, which may comprise one or more, but not limited to stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, sodium stearyl fumarate or other metallic stearate), talc, waxes (for example, microcrystalline waxes) and glycerides, light mineral oil, PEG, silica acid or a derivative or salt thereof (for example, silicates, silicon dioxide, colloidal silicon dioxide and polymers thereof, crospovidone, magnesium aluminosilicate and/ or magnesium alumino metasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil) , or mixtures thereof.

Preferably, the glidants, anti-adherents and lubricants may be present in an amount ranging from about 0.1% to about 5% by weight of the composition.

Suitable binders may be used in the pharmaceutical compositions of the present invention, which may comprise one or more, but not limited to polyvinyl pyrrolidone (also known as povidone), polyethylene glycol(s), acacia, alginic acid, agar, calcium carragenan, cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, or mixtures thereof.

Preferably, the binders may be present in an amount ranging from about 5% to about 20% by weight of the composition.

Suitable disintegrants may also be present in the pharmaceutical compositions of the present invention, which may comprise one or more, but not limited to hydroxylpropyl cellulose (HPC), low density HPC, carboxymethylcellulose (CMC), sodium CMC, calcium CMC, croscarmellose sodium; starches exemplified under examples of fillers and also carboxymethyl starch, hydroxylpropyl starch, modified starch; crystalline cellulose, sodium starch glycolate; alginic acid or a salt thereof, such as sodium alginate or their equivalents and mixtures thereof.

Preferably, the disintegrants may be present in an amount ranging from about 2% to about 30% by weight of the composition.

The pharmaceutical composition, according to the present invention, may also optionally be coated, but not limited to seal coating, film coating or a combination thereof.

The pharmaceutical compositions may be film coated with, but not limited to, colour mix systems (such as Opadry colour mix systems) and Kollicoat® Protect.

The pharmaceutical compositions may have a seal coat which comprises film forming polymeric materials, such as but not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose, hypromellose, acacia or gelatin, to increase adherence and coherence of the seal coat.

Any suitable pharmaceutically acceptable opacifier may be used in the pharmaceutical compositions of the present invention, preferably titanium dioxide is used.

The pharmaceutical compositions of the present invention may be formulated as a liquid oral dosage form, including but not limited to emulsions, solutions, suspensions, syrups, and elixirs with other suitable pharmaceutically acceptable excipients such as sweeteners, vehicle/wetting agents, coloring agents, flavoring agents, preservatives, viscosity enhancing/thickening agents, and the like or combinations thereof.

Suitable viscosity enhancing/thickening agents which may be used in the pharmaceutical compositions of the present invention, include, but are not limited to methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxy ethyl propyl cellulose, starches (such as maize or corn starch, potato starch, rice starch, tapioca starch, and wheat starch), carboxyvinyl polymers (carbomers such as Carbopol®), carboxymethyl cellulose and salts thereof, microcrystalline cellulose and arabic gum, guar gum, and xanthan gum, and the like or combinations thereof.

Suitable vehicle/wetting agents which may be used in the pharmaceutical compositions of the present invention, include, but are not limited to glycerol, propylene glycol, liquid polyethylene glycols, sorbitol, water and the like or combinations thereof.

Suitable flavouring agents which may be used in the pharmaceutical compositions of the present invention include, but are not limited to cherry, raspberry, pineapple, black currant, strawberry flavour, caramel chocolate flavour, mint cool flavour, fantasy flavour, meat flavours and the like or combinations thereof.

Suitable sweeteners which may be used in the pharmaceutical compositions of the present invention include, but are not limited to, saccharin, aspartame, acesulfame, cyclamate, alitame, a dihydrochalcone sweetener, monellin, neohesperidin, neotame, stevioside and sucralose, pharmaceutically acceptable salts thereof and the like or combinations thereof.

Suitable colouring agents which may be used in the pharmaceutical compositions of the present invention include, but are not limited to quinoline yellow.

Suitable preservatives which may be used in the pharmaceutical compositions of the present invention include, but are not limited to, sodium benzoate, benzoic acid, potassium sorbate, sorbic acid, methyl p-hydroxibenzoate, ethyl p-hydroxibenzoate, propyl p-hydroxibenzoate, butyl p-hydroxibenzoate, sodium methyl p-hydroxibenzoate, sodium ethyl p-hydroxibenzoate, sodium propyl p-hydroxibenzoate, sodium butyl p-hydroxibenzoate, domiphen bromide, sodium propionate, propylene glycol and the like or combinations thereof.

The pharmaceutical compositions, according to the present invention, may further comprise at least one additional active ingredient, such as, but not limited to, ivermecitin, abamectin, pyrantel pamoate, pyrantel embonate, pentostam, albendazole, mebendazole, fenbendazole, mefloquine, moxidectin, febantel, emodepside, mefloquine, artesunate, artemisinin derivatives, niclosamide, levamisole, cimetidine, epsiprantel, oxamniquine, tribendimidine, milbemycin oxime, oxamniquine and combinations thereof.

The pharmaceutical compositions, according to the present invention, may comprise the additional active in a nanosized form.

The pharmaceutical compositions, according to the present invention, may further comprise at least one additional active ingredient, such as, pyrantel pamoate and ivermecitin or combinations thereof, especially for veterinary use.

There is also provided a process for preparing the pharmaceutical compositions of the present invention, which process comprises homogenizing praziquantel or R-praziquantel and at least one excipient to produce a homogenized dispersion of praziquantel or R-praziquantel in the excipient; and milling said homogenized dispersion to produce a slurry of praziquantel or R-praziquantel particles having an average particle size of less than or equal to about 2000 nm.

The present invention also provides a method of treating anthelmintic infections by administering a pharmaceutical composition comprising praziquantel or R-praziquantel for human and veterinary purposes.

The present invention also provides the use of a pharmaceutical composition comprising praziquantel or R- praziquantel for treating anthelmintic infections in human beings and animals.

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

Example 1

Sr. No Ingredients Quantity (mg/Tablet)
API Slurry
1 Praziquantel 300.00 400.00
2 Sodium Lauryl Sulphate 25.00 33.33
3 Docusate Sodium 5.50 7.33
4 Sugar 50.00 66.67
5 Hydroxypropyl methylcellulose 25.00 33.33
6 Purified Water q. s. q. s.
Dry Mix
7 Lactose Monohydrate 187.00 249.34
8 Crospovidone 82.50 110.00
Blending 0.000
9 Crospovidone 62.50 83.33
10 Sodium Chloride 25.00 33.33
11 Silicified Microcrystalline Cellulose 85.25 113.67
Lubrication
12 Magnesium Stearate 2.25 3.00
Total (Uncoated ) 850.00 1133.33
Film Coating
13 Opadry White 17.00 22.67
15 Purified Water q. s. q. s.
Total (Film Coated ) 867.00 1156.00

Process:
Step I: Praziquantel Slurry Preparation
1) Docusate sodium was added to purified water and heated to obtain a clear solution.
2) Hydroxypropyl methylcellulose, sodium lauryl sulphate and sugar were added to the solution obtained in step (1).
3) Praziquantel was added to the solution obtained in step (2) to obtain a homogeneous suspension.
4) The suspension obtained in step (3) was nanomilled to obtain the desired particle size.
Step II: Drug Loading on Dry Mix
5) Lactose monohydrate and crospovidone were pre-sifted and heated to obtain a dry mixed blend.
6) The nanomilled suspension obtained in step (4) was sprayed on the dry mixed blend obtained in step (5).
7) The drug loaded granules obtained in step (6) were dried and sieved to get uniform granules.
Step III: Blending
8) The granules obtained in step (7) were blended with pre-sifted crospovidone, sodium chloride, silicified microcrystalline cellulose.
Step IV: Lubrication and Compression
9) The granules obtained in step (8) were lubricated with pre-sifted magnesium stearate and compressed into tablets.
Step V: Film Coating
10) The tablets obtained in step (9) were film coated with an aqueous dispersion of Opadry White.

Example 2
Sr. No. Ingredients Quantity (mg/Tablet)
API Slurry
1 Praziquantel 300.00
2 Tween 80 30.00
3 Docusate Sodium 5.50
4 Sugar 50.00
5 Hydroxypropyl methylcellulose 25.00
6 Purified Water q. s.
Dry Mix
7 Lactose Monohydrate 182.00
8 Crospovidone 82.50
Blending
9 Crospovidone 62.50
10 Sodium Chloride 25.00
11 Silicified Microcrystalline Cellulose 85.25
Lubrication
12 Magnesium Stearate 2.25
Total (Uncoated ) 850.00
Film Coating
13 Opadry White 17.00
15 Purified Water q. s.
Total (Film Coated ) 867.00

Process:
Step I: Praziquantel Slurry Preparation
1) Docusate sodium was added to purified water and heated to obtain a clear solution.
2) Hydroxypropyl methylcellulose, tween 80 and sugar were added to the solution obtained in step (1).
3) Praziquantel was added to the solution obtained in step (2) to obtain a homogeneous suspension.
4) The suspension obtained in step (3) was nanomilled to obtain the desired particle size.

Step II: Drug Loading on Dry Mix
5) Lactose monohydrate and crospovidone were pre-sifted and heated to obtain a dry mixed blend.
6) The nanomilled suspension obtained in step (4) was sprayed on the dry mixed blend obtained in step (5).
7) The drug loaded granules obtained in step (6) were dried and sieved to get uniform granules.
Step III: Blending
8) The granules obtained in step (7) were blended with pre-sifted crospovidone, sodium chloride, silicified microcrystalline cellulose.
Step IV: Lubrication and Compression
9) The granules obtained in step (8) were lubricated with pre-sifted magnesium stearate and compressed into tablets.
Step V: Film Coating
10) The tablets obtained in step (9) were film coated with an aqueous dispersion of Opadry White.

Example 3
Sr. No. Ingredients Quantity (mg/Tablet)
API Slurry
1 Praziquantel 300.00
2 Poloxamer 188 30.00
3 Docusate Sodium 5.50
4 Sugar 50.00
5 Hydroxypropyl methylcellulose 25.00
6 Purified Water q. s.
Dry Mix
7 Lactose Monohydrate 182.00
8 Crospovidone 82.50
Blending
9 Crospovidone 62.50
10 Sodium Chloride 25.00
11 Silicified Microcrystalline Cellulose 85.25
Lubrication
12 Magnesium Stearate 2.25
Total (Uncoated ) 850.00
V Film Coating
13 Opadry White 17.00
15 Purified Water q. s.
Total (Film Coated ) 867.00
Process:
Step I: Praziquantel Slurry Preparation
1) Docusate sodium was added to purified water and heated to obtain a clear solution.
2) Hydroxypropyl methylcellulose, poloxamer 188 and sugar were added to the solution obtained in step (1).
3) Praziquantel was added to the solution obtained in step (2) to obtain a homogeneous suspension.
4) The suspension obtained in step (3) was nanomilled to obtain the desired particle size.
Step II: Drug Loading on Dry Mix
5) Lactose monohydrate and crospovidone were pre-sifted and heated to obtain a dry mixed blend.
6) The nanomilled suspension obtained in step (4) was sprayed on the dry mixed blend obtained in step (5).
7) The drug loaded granules obtained in step (6) were dried and sieved to get uniform granules.
Step III: Blending
8) The granules obtained in step (7) were blended with pre-sifted crospovidone, sodium chloride, silicified microcrystalline cellulose.
Step IV: Lubrication and Compression
9) The granules obtained in step (8) were lubricated with pre-sifted magnesium stearate and compressed into tablets.
Step V: Film Coating
10) The tablets obtained in step (7) were film coated with an aqueous dispersion of Opadry White.

Example 4
Sr. No. Ingredients Quantity (mg/Tablet) Quantity (mg/Tablet)
API Slurry
1 Praziquantel 300.00 500
2 Poloxamer 188 30.00 49.98
3 Docusate Sodium 5.50 9.16
4 Lactose Monohydrate 50.00 83.29
5 PVP 25.00 41.65
6 Purified Water q. s.
Dry Mix 0.00
7 Lactose Monohydrate 182.00 303.19
8 Crospovidone 82.50 137.44
Blending
9 Crospovidone 62.50 104.12
10 Sodium Chloride 25.00 41.65
11 Silicified Microcrystalline Cellulose 85.25 142.02
Lubrication
12 Magnesium Stearate 2.25 3.75
Total (Uncoated ) 850.00 1416.0
Film Coating
13 Opadry White 17.00 28.00
15 Purified Water q. s. q. s.
Total (Film Coated ) 867.00 1444.00

Process:
Step I: Praziquantel Slurry Preparation
1) Docusate sodium was added to purified water and heated to obtain a clear solution.
2) Poloxamer 188, PVP and lactose monohydrate were added to the solution obtained in step (1).
3) Praziquantel was added to the solution obtained in step (2) to obtain a homogeneous suspension.
4) The suspension obtained in step (3) was nanomilled to obtain the desired particle size.
Step II: Drug Loading on Dry Mix
5) Lactose monohydrate and crospovidone were pre-sifted and heated to obtain a dry mixed blend.
6) The nanomilled suspension obtained in step (4) was sprayed on the dry mixed blend obtained in step (5).
7) The drug loaded granules obtained in step (6) were dried and sieved to get uniform granules.
Step III: Blending
8) The granules obtained in step (7) were blended with pre-sifted crospovidone, sodium chloride, silicified microcrystalline cellulose.
Step IV: Lubrication and Compression
9) The granules obtained in step (8) were lubricated with pre-sifted magnesium stearate and compressed into tablets.
Step V: Film Coating
10) The tablets obtained in step (9) were film coated with an aqueous dispersion of Opadry White.

Example 5
Sr. No. Ingredients Quantity (mg/Tablet)
I API Slurry
1 Praziquantel 300.00 400.00
2 Sodium Lauryl Sulphate 25.00 33.33
3 Docusate Sodium 5.50 7.33
4 Sugar 50.00 66.67
5 Hydroxypropyl methylcellulose 25.00 33.33
6 Purified Water q. s. q. s.
II Dry Mix
7 Sugar Spheres 89.5 119.0
8 Talc 5 6.34
Total (Film Coated ) 500 666

Process:
Step I: Praziquantel Slurry Preparation
1) Docusate sodium was added to purified water and heated to obtain a clear solution.
2) Hydroxypropyl methylcellulose, sodium lauryl sulphate and sugar were added to the solution obtained in step (1).
3) Praziquantel was added to the solution obtained in step (2) to obtain a homogeneous suspension.
4) The suspension obtained in step (3) was nanomilled to obtain the desired particle size.
Step II: Drug Loading on Sugar Spheres
5) The sugar spheres were sprayed with the suspension obtained from step (4).
6) The drug loaded sugar spheres obtained in step (5) were dried and sieved to get uniform pellets.
Step III: Lubrication
7) The drug loaded pellets obtained in step (6) were sifted with talc.
Step IV: Capsule Filling:
8) The pellets obtained in step (7) were filled in capsule shell.

Example 6
Sr. No. Ingredient Quantity (Mg/Tablet)
Nanomilling
1. R-Praziquantel 300.00
2. Sodium Lauryl Sulpate 15.00
3. Hydroxypropylmethylcellulose
50.00
4. Docusate Sodium 5.00
5. Lactose monohydrate 50.00
6. Purified water q.s.
Dry mix
7. Lactose monohydrate 180.00
8. Crospovidone 50.00
Blending & Lubrication
9. Sodium Chloride 60.00
10. Crospovidone 25.00
11. Silicified microcrystalline cellulose 195.00
12. Magnesium Stearate 2.00
Total 932.00

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, Sodium Lauryl Sulpate and lactose were further added and dissolved.
2) R-Praziquantel was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with sodium chloride, crospovidone, silicified microcrystalline cellulose and magnesium stearate and compressed to produce dispersible tablet.

Example 7
Sr. No. Ingredients Quantity (mg/Tablet)
Binder Slurry
1 R-Praziquantel 300.00
2 Cremophor EL 7.50
3 Docusate Sodium 3.75
4 Lactose Monohydrate 37.50
5 Hydroxypropylmethylcellulose 37.50
6. Tween 80 18.75
7 Purified water q.s.
Dry Mix
8 Lactose Monohydrate 180.00
9 Crospovidone 37.50
Blending and Lubrication
10 Crospovidone 50.00
11 Silicified Microcrystalline Cellulose 120.00
12 Magnesium Stearate 2.25
Total 794.75

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, Cremophor EL, tween 80 and lactose were further added and dissolved.
2) R-Praziquantel was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose and magnesium stearate and compressed to produce dispersible tablet.

Example 8
Sr. No. Ingredients Quantity (mg/Tablet)
Binder Slurry
1 Praziquantel 300
3 Docusate Sodium 3.75
4 Lactose Monohydrate 37.50
5 Hydroxypropylmethylcellulose 37.50
6. Tween 80 18.5
7 Purified water q.s.
Dry Mix
8 Lactose Monohydrate 187.5
9 Crospovidone 37.50
Blending and Lubrication
10 Crospovidone 50.00
11 Silicified Microcrystalline Cellulose 100.00
12 Magnesium Stearate 90.00
13 Sodium saccharin 25.00
Total weight 887.25

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, tween 80 and lactose were further added and dissolved.
2) Praziquantel was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose, sodium saccharin and magnesium stearate and compressed to produce dispersible tablet.

Example 9
Sr. No. Ingredients Quantity (mg/ Tablet)
Binder Slurry
1 Praziquantel 300.00
3 Docusate Sodium 4.00
4 Lactose Monohydrate 37.50
5 Hydroxypropylmethylcellulose 37.50
6. Tween 80 18.50
7 Purified water q. s.
Dry Mix
8 Lactose Monohydrate 187.5
9 Crospovidone 37.50
Blending and Lubrication
10 Crospovidone 50.00
11 Silicified Microcrystalline Cellulose 120.00
12 Magnesium Stearate 9
13 Sodium saccharin 22.50
14 Mannitol 7.5
Total 831.5

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, tween 80 and lactose were further added and dissolved.
2) Praziquantel was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose, sodium saccharin, mannitol and magnesium stearate and compressed to produce dispersible tablet.

Example 10
Sr. No. Ingredients Quantity (mg/ Tablet)
Binder Slurry
1 Praziquantel 300.00
3 Cremophor EL 7.50
4 Lactose Monohydrate 37.50
5 Hydroxypropylmethylcellulose 37.50
6. Docusate Sodium 3.75
7. Tween 80 18.50
8 Purified water q. s.
Dry Mix
9 Lactose Monohydrate 187.5
10 Crospovidone 37.50
Blending and Lubrication
11 Crospovidone 60.00
12 Silicified Microcrystalline Cellulose 100.00
13 Magnesium Stearate 9.00
14 Sodium saccharin 22.50
15 Mannitol 7.00
Total 828.25

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, Cremophor EL, tween 80 and lactose were further added and dissolved.
2) Praziquantel was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose, sodium saccharin, mannitol and magnesium stearate and compressed to produce dispersible tablet.

Example 11
Sr. No Ingredient Quantity (mg/ Tablet)
Nanomilling
1. R-Praziquantel 150.00
2. Sodium lauryl sulphate 7.5
3. Hydroxypropylmethylcellulose 25.00
4. Docusate Sodium 2.50
5. Lactose monohydrate 25.00
6. Purified water q.s
Dry mix
7. Lactose monohydrate 90.00
8. Crospovidone 25.00
Blending & Lubrication
9. Sodium Chloride 30.00
10. Crospovidone 13.00
11. Silicified microcrystalline cellulose 95.00
12. Magnesium Stearate 1.00
Total 464.00

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, Sodium lauryl sulphate and lactose were further added and dissolved.
2) R-Praziquantel was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with sodium chloride, crospovidone, silicified microcrystalline cellulose and magnesium stearate and compressed to produce dispersible tablet.

Example 12
Sr. No. Ingredients Quantity (mg/ Tablet)
Binder Slurry
1 R-Praziquantel 150.00
2 Cremophor EL 3.75
3 Docusate Sodium 1.50
4 Lactose Monohydrate 15.0
5 Hydroxypropylmethylcellulose 15.0
6. Tween 80 9.35
7 Purified water qs
Dry Mix
8 Lactose Monohydrate 90.00
9 Crospovidone 15.0
Blending and Lubrication
10 Crospovidone 25.00
11 Silicified Microcrystalline Cellulose 60.00
12 Magnesium Stearate 1.125
Total 385.725

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, Cremophor EL, tween 80 and lactose were further added and dissolved.
2) R-Praziquantel was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose and magnesium stearate and compressed to produce dispersible tablet.

Example 13
Sr. No. Ingredients Quantity (mg/Tablet)
Binder Slurry
1 Praziquantel 150
3 Docusate Sodium 1.50
4 Lactose Monohydrate 15.5
5 Hydroxypropylmethylcellulose 18.750
6. Tween 80 9.25
7 Purified water qs
Dry Mix
8 Lactose Monohydrate 93.75
9 Crospovidone 15.25
Blending and Lubrication
10 Crospovidone 25.00
11 Silicified Microcrystalline Cellulose 50.00
12 Magnesium Stearate 45.00
13 Sodium saccharin 12.50
Total 436.50

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, tween 80 and lactose were further added and dissolved.
2) Praziquantel was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose, sodium saccharin and magnesium stearate and compressed to produce dispersible tablet.

Example 14
Sr. No. Ingredients Quantity (mg/ Tablet)
Binder Slurry
1 Praziquantel 150.00
3 Docusate Sodium 2.00
4 Lactose Monohydrate 15.75
5 Hydroxypropylmethylcellulose 15.75
6. Tween 80 9.25
7 Purified water qs
Dry Mix
8 Lactose Monohydrate 93.75
9 Crospovidone 15.75
Blending and Lubrication
10 Crospovidone 25.00
11 Silicified Microcrystalline Cellulose 60.00
12 Magnesium Stearate 4.5
13 Sodium saccharin 11.25
14 Mannitol 3.75
Total 406.75

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, tween 80 and lactose were further added and dissolved.
2) Praziquantel was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose, sodium saccharin and magnesium stearate and compressed to produce dispersible tablet.

Example 15
Sr. No. Ingredients Quantity (mg /Tablet)
Binder Slurry
1 Praziquantel 300.00
3 Cremophor EL 7.50
4 Lactose Monohydrate 37.50
5 Hydroxypropylmethylcellulose 37.50
6. Docusate Sodium 3.75
7. Tween 80 18.50
8 Purified water qs
Dry Mix
9 Lactose Monohydrate 187.5
10 Crospovidone 37.50
Blending and Lubrication
11 Crospovidone 60.00
12 Silicified Microcrystalline Cellulose 100.00
13 Magnesium Stearate 9.00
14 Sodium saccharin 22.50
15 Mannitol 7.00
Total 828.25

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, Cremophor EL, tween 80 and lactose were further added and dissolved.
2) Praziquantel was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose, sodium saccharin and magnesium stearate and compressed to produce dispersible tablet.

Example 16
Sr. No. Ingredients Quantity
(mg/Tablet) Quantity
(mg/Tablet) Quantity
(mg/Tablet)
Binder Slurry
1 R-Praziquantel 300.00 300.00 300.00
2 Tween 80 18.75 18.75 18.75
3 Docusate Sodium 3.75 3.75 3.75
4 Hydroxy Propyl Methyl Cellulose 37.5 37.50 37.50
5 Lactose Monohydrate 37.5 37.50 37.50
6 Purified water qs qs qs
Dry Mix
7 Lactose Monohydrate 187.5 180.00 180.00
8 Crospovidone 37.50 37.50 37.5
Blending and Lubrication
9 Silicified microcrystalline cellulose 139.62 144.25 140.25
10 Crospovidone 36.75 18.75 18.75
11 Orange Flavour 4.88 7.50 7.50
12 Sunset Yellow Lake 7.75 7.75 11.25
13 Mannitol 75.00 75.00 75.00
14 Saccharin Sodium 22.50 22.50 22.50
15 Magnesium Stearate 9.00 2.25 2.25
Total 918.00 893.00 892.50

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, tween 80 and lactose were further added and dissolved.
2) R-Praziquantel was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose, sodium saccharin, mannitol and magnesium stearate and compressed to produce tablets.

Example 17
Sr. No. Ingredients Quantity (mg/Tablet) Quantity (mg/Tablet)
Binder Slurry
1 R-Praziquantel 300.00 300.00
2 Tween 80 22.50 22.50
3 Docusate Sodium 3.75 3.75
4 Sodium lauryl sulphate 7.50 7.50
5 Hydroxy Propyl Methyl Cellulose 37.50 37.50
6 Lactose Monohydrate 37.50 37.50
7 Purified water qs qs
Dry Mix
8 Lactose Monohydrate 180.00 180.00
9 Crospovidone 37.50 37.50
Blending and Lubrication
10 Silicified microcrystalline cellulose 140.25 140.25
11 Crospovidone 18.75 18.75
12 Orange Flavour 7.50 7.50
13 Sunset Yellow Lake 7.75 11.25
14 Mannitol 75.00 75.00
15 Saccharin Sodium 22.50 22.50
16 Magnesium Stearate 2.25 2.25
Total 900.25 903.75

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, tween 80, Sodium lauryl sulphate and lactose were further added and dissolved.
2) R-Praziquantel was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose, sodium saccharin, mannitol and magnesium stearate and compressed to produce tablets.

Example 18
Sr. No. Ingredients Quantity (mg/Tablet) Quantity (mg/Tablet) Quantity (mg/Tablet)
Binder Slurry
1 Praziquantel 300.00 300.00 300.00
2 Artesunate 25.00 25.00 25.00
3 Tween 80 18.75 18.75 18.75
4 Docusate Sodium 3.75 3.75 3.75
5 Hydroxy Propyl Methyl Cellulose 37.5 37.50 37.50
6 Lactose Monohydrate 37.5 37.50 37.50
7 Purified water qs qs qs
Dry Mix
8 Lactose Monohydrate 187.50 180.00 180.00
9 Crospovidone 37.5 37.50 37.5
Blending and Lubrication
10 Silicified microcrystalline cellulose 139.62 144.25 140.25
11 Crospovidone 36.75 18.75 18.75
12 Orange Flavour 4.88 7.50 7.50
13 Sunset Yellow Lake 7.75 7.75 11.25
14 Mannitol 75.00 75.00 75.00
15 Saccharin Sodium 22.50 22.50 22.50
16 Magnesium Stearate 9.00 2.25 2.25
Total 943.00 918.00 917.50

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, tween 80, and lactose were further added and dissolved.
2) Praziquantel and artesunate was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose, sodium saccharin, mannitol and magnesium stearate and compressed to produce tablets.

Example 19
Sr. No. Ingredients Quantity (mg/Tablet) Quantity (mg/Tablet)
Binder Slurry
1 Praziquantel 300.00 300.00
2 Artesunate 25.00 25.00
3 Tween 80 22.50 22.50
4 Sodium lauryl sulphate 3.75 3.75
5 Docusate Sodium 7.50 7.50
6 Hydroxy Propyl Methyl Cellulose 37.50 37.50
7 Lactose Monohydrate 37.50 37.50
8 Purified water qs qs
Dry Mix
9 Lactose Monohydrate 180.00 180.00
10 Crospovidone 37.50 37.50
Blending and Lubrication
11 Silicified microcrystalline cellulose 140.25 140.25
12 Crospovidone 18.75 18.75
13 Orange Flavour 7.50 7.50
14 Sunset Yellow Lake 7.75 11.25
15 Mannitol 75.00 75.00
16 Saccharin Sodium 22.50 22.50
17 Magnesium Stearate 2.25 2.00
Total 925.25 928.50

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, tween 80, Sodium lauryl sulphate and lactose were further added and dissolved.
2) Praziquantel and artesunate was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose, sodium saccharin, mannitol and magnesium stearate and compressed to produce tablets.

Example 20
Sr. No. Ingredients Quantity (mg/Tablet) Quantity (mg/Tablet) Quantity (mg/Tablet)
Binder Slurry
1 R - Praziquantel 300.00 300.00 300.00
2 Artesunate 25.00 25.00 25.00
3 Tween 80 18.75 18.75 18.75
4 Docusate Sodium 3.75 3.75 3.75
5 Hydroxy Propyl Methyl Cellulose 37.50 37.50 37.50
6 Lactose Monohydrate 37.50 37.50 37.50
7 Purified water qs qs qs
Dry Mix
8 Lactose Monohydrate 187.50 180.00 180.00
9 Crospovidone 37.50 37.50 37.50
Blending and Lubrication
10 Silicified microcrystalline cellulose 139.62 144.25 140.25
11 Crospovidone 36.75 18.75 18.75
12 Orange Flavour 4.88 7.50 7.50
13 Sunset Yellow Lake 7.75 7.75 11.25
14 Mannitol 75.00 75.00 75.00
15 Saccharin Sodium 22.50 22.50 22.50
16 Magnesium Stearate 9.00 2.25 2.25
Total 943.00 918.00 917.50

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, tween 80, and lactose were further added and dissolved.
2) R-Praziquantel and artesunate was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose, sodium saccharin, mannitol and magnesium stearate and compressed to produce tablets.

Example 21
Sr. No. Ingredients Quantity (mg/Tablet) Quantity (mg/Tablet)
Binder Slurry
1 R-Praziquantel 300.00 300.00
2 Artesunate 25.00 25.00
3 Tween 80 22.50 22.50
4 Sodium lauryl sulphate 7.50 7.5
5 Docusate Sodium 3.75 3.75
6 Hydroxy Propyl Methyl Cellulose 37.50 37.5
7 Lactose Monohydrate 37.50 37.5
8 Purified water qs qs
Dry Mix
9 Lactose Monohydrate 180.00 180.00
10 Crospovidone 37.50 37.50
Blending and Lubrication
11 Silicified microcrystalline cellulose 140.25 140.25
12 Crospovidone 18.75 18.75
13 Orange Flavour 7.50 7.50
14 Sunset Yellow Lake 7.75 11.25
15 Mannitol 75.00 75.00
16 Saccharin Sodium 22.50 22.50
17 Magnesium Stearate 2.25 2.25
Total 925.25 928.75

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, tween 80, Sodium lauryl sulphate and lactose were further added and dissolved.
2) R-Praziquantel and artesunate was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose, sodium saccharin, mannitol and magnesium stearate and compressed to produce tablets.

Example 22
Sr. No. Ingredients Quantity (mg/Tablet) Quantity (mg/Tablet) Quantity (mg/Tablet)
Binder Slurry
1 R - Praziquantel 300.00 300.00 300.00
2 Artemether 20.00 20.00 20.00
3 Tween 80 18.75 18.75 18.75
4 Docusate Sodium 3.75 3.75 3.75
5 Hydroxy Propyl Methyl Cellulose 37.50 37.50 37.50
6 Lactose Monohydrate 37.50 37.50 37.50
7 Purified water qs qs qs
Dry Mix
8 Lactose Monohydrate 187.50 180.00 180.00
9 Crospovidone 37.50 37.50 37.50
Blending and Lubrication
10 Silicified microcrystalline cellulose 139.62 144.25 140.25
11 Crospovidone 36.75 18.75 18.75
12 Orange Flavour 4.88 7.50 7.50
13 Sunset Yellow Lake 7.75 7.75 11.25
14 Mannitol 75.00 75.00 75.00
15 Saccharin Sodium 22.50 22.50 22.50
16 Magnesium Stearate 9.00 2.25 2.25
Total 938.00 913.00 912.50

Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, tween 80, and lactose were further added and dissolved.
2) R-Praziquantel and artemether was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose, sodium saccharin, mannitol and magnesium stearate and compressed to produce tablets.

Example 23
Sr. No. Ingredients Quantity (mg/Tablet) Quantity (mg/Tablet)
Binder Slurry
1 R-Praziquantel 300.00 300.00
2 Artemether 20.00 20.00
3 Tween 80 22.50 22.50
4 Sodium lauryl sulphate 7.50 7.50
5 Docusate Sodium 3.75 3.75
6 Hydroxy Propyl Methyl Cellulose 37.50 37.5
7 Lactose Monohydrate 37.50 37.5
8 Purified water qs qs
Dry Mix
9 Lactose Monohydrate 180.00 180.00
10 Crospovidone 37.50 37.5
Blending and Lubrication
11 Silicified microcrystalline cellulose 140.25 140.25
12 Crospovidone 18.75 18.75
13 Orange Flavour 7.50 7.50
14 Sunset Yellow Lake 7.75 11.25
15 Mannitol 75.00 75.00
16 Saccharin Sodium 22.50 22.50
17 Magnesium Stearate 2.25 2.25
Total 920.25 923.75
Process:
1) Docusate sodium was dissolved in water. Hydroxypropylmethylcellulose, tween 80, Sodium lauryl sulphate and lactose were further added and dissolved.
2) R-Praziquantel and artemether was dispersed into the solution obtained in step (1) and nanomilled to obtain a slurry.
3) The slurry obtained in step (2) was sprayed on dry mixture of lactose and crospovidone and granulated.
4) The granules obtained in step (3) were dried, blended and lubricated with crospovidone, silicified microcrystalline cellulose, sodium saccharin, mannitol and magnesium stearate and compressed to produce tablets.

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

It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like. ,CLAIMS:WE CLAIM:

1. A pharmaceutical composition comprising praziquantel in the form of particles having an average particle size of less than or equal to about 2000 nm and one or more pharmaceutically acceptable excipients.

2. A pharmaceutical composition according to claim 1, wherein the praziquantel is in the form of a pharmaceutically acceptable derivative thereof.

3. A pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable derivative thereof is a salt, solvate, complex, hydrate, isomer, ester, tautomer, anhydrate, enantiomer, polymorph or prodrug.

4. A pharmaceutical composition according to claim 3, wherein the enantiomer is R-praziquantel.

5. A pharmaceutical composition according to any one of the preceding claims, wherein the particles have an average particle size of less than or equal to about 1000 nm.

6. A pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is in a dosage amount ranging from about 10 mg/kg body weight to about 15 mg/kg body weight, optionally in a dosage amount ranging from about 7.5 mg/kg body weight to about18 mg/kg body weight.

7. A pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is for once a day, or twice a day or thrice a day administration.

8. A pharmaceutical composition according to any one of the preceding claims, wherein the composition is in an oral or a topical dosage form.

9. A pharmaceutical composition according to claim 8, wherein the composition is in a solid oral dosage form comprising tablet, coated tablet, powders, powders for reconstitution, pellets, beads, mini-tablets, multilayer tablets, bilayered tablets, tablet in tablet, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates, capsules (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, sprinkles, microspheres and multiparticulates), sachets (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, modified release tablets or capsules, effervescent granules, granules, sprinkles microspheres and multiparticulates), or sprinkles.

10. A pharmaceutical composition according to claim 8, wherein the composition is in a liquid oral dosage form comprising emulsions, solutions, suspensions, syrups, or elixirs.

11. A pharmaceutical composition according to claim 8, wherein the composition is in a topical dosage form comprising sprays, solutions, suspensions, ointments, drops, in-situ gels, aerosols, ointments, microspheres, creams, gels, patches or films.

12. A pharmaceutical composition according to any one of the preceding claims, further comprising at least one of the following: at least one surface stabilizer, which is a surfactant or a solubilizer, at least one viscosity enhancing agent and at least one polymer.

13. A pharmaceutical composition according to claim 12, wherein the surface stabilizer is selected from the group comprising: amphoteric surfactants, non-ionic surfactants, cationic surfactants, anionic surfactants and combinations thereof.

14. A pharmaceutical composition according to claim 12 or 13, wherein the surfactant is present in an amount of from about 1% to about 10% by weight of the composition.

15. A pharmaceutical composition according to claim 12, wherein the viscosity enhancing agent is present in an amount of from about 4% to about 20% by weight of the composition.

16. A pharmaceutical composition according to claim 12, wherein the polymer is present in an amount of from about 2% to about 10% by weight of the composition.

17. A pharmaceutical composition according to any one of the preceding claims, further comprising a channeling agent, diluents, fillers, glidants, anti-adherents, lubricants, binders, disintegrants or combinations thereof.

18. A pharmaceutical composition according to claim 8 or 10, further comprising sweeteners, vehicle/wetting agents, coloring agents, flavoring agents, preservatives, viscosity enhancing/thickening agents or combinations thereof.

19. A pharmaceutical composition according to any one of the preceding claims, further comprising at least one additional active ingredient selected from the group comprising: ivermecitin, abamectin, pyrantel pamoate, pyrantel embonate, pentostam, albendazole, mebendazole, fenbendazole, mefloquine, moxidectin, febantel, emodepside, mefloquine, artesunate, artemether, artemisinin derivatives, niclosamide, levamisole, cimetidine, epsiprantel, oxamniquine, tribendimidine, milbemycin, milbemycin oxime, oxamniquine, and combinations thereof.

20. A process of preparing a pharmaceutical composition as claimed in any one of the preceding claims comprising:
(i) homogenizing praziquantel or R-praziquantel and at least one excipient to produce a homogenized dispersion of praziquantel or R-praziquantel in the excipient; and
(ii) processing said homogenized dispersion to produce a slurry of nanoparticles of praziquantelor R-praziquantel having an average particle size of less than or equal to about 2000 nm; and
(iii) processing the slurry to obtain a dosage form.

21. A method of treating anthelmintic infections in a human being or an animal, by administering a therapeutically effective amount of a pharmaceutical composition comprising praziquantel as claimed in any one of the preceding claims, or R-praziquantel as claimed in any one of claims 4 to 20.

22. The use of a pharmaceutical composition comprising praziquantel as claimed in any one of the preceding claims or R- praziquantel as claimed in any one of claims 4 to 20, in the manufacture of a medicament for treating anthelmintic infections in a human being or an animal.

23. A pharmaceutical composition comprising praziquantel as claimed in any one of the preceding claims, or R- praziquantel as claimed in any one of claims 4 to 20, for use in the treatment of anthelmintic infections in a human being or an animal.

24. A method or use according to claim 21, 22 or 23, wherein the pharmaceutical composition is administered at least once a day, optionally twice a day or thrice a day.

25. A method or a use according to claim 21, 22 or 23, wherein the pharmaceutical composition in a dosage amount ranging from about 10 mg/kg body weight to about 15 mg/kg body weight, optionally in a dosage amount ranging from about 7.5 mg/kg body weight to about 18 mg/kg body weight.

26. A pharmaceutical composition substantially as described herein with reference to the examples.

Dated this 14th day of November, 2014

Dr. P. Aruna Sree
(Regn.No.: IN/PA 998)
Agent for the Applicant
Gopakumar Nair Associates