WO2014029953A1

WO2014029953A1 - Hot melt extruded (hme) pharmaceutical composition of cinacalcet

Info

Publication number: WO2014029953A1
Application number: PCT/GB2013/000347
Authority: WO
Inventors: Shrinivas Madhukar Purandare; Geena Malhotra
Original assignee: Cipla Ltd
Current assignee: Cipla Ltd
Priority date: 2012-08-21
Filing date: 2013-08-16
Publication date: 2014-02-27
Anticipated expiration: 2015-02-21

Description

Hot Melt Extruded (HME) Pharmaceutical Composition of Cinacalcet

The present invention relates to a hot-melt extruded pharmaceutical composition comprising a calcimimetic drug. The invention also relates to processes for the preparation of the said pharmaceutical composition and its use for the treatment and/or prevention of hyperparathyroidism.

Various factors are responsible or contribute to the efficacy of a drug. Amongst such factors solubility, bioavailability and lipophilicity are the three parameters that are closely interconnected. Lipophilic drugs have higher affinity to their respective target receptors and therefore the solubility increases which in turn results in the increment of its bioavailability. The drawback to this fundamental is that lipophilic drugs tend to have a higher molecular weight thus affecting their absorption and amounting to decreased solubility. So either the drug is more soluble and less lipophilic which in turn makes it less bioavailable or a drug can be more lipophilic and less soluble which also makes it less bioavailable which ultimately proves that there are very few cases where bioavailability can be increased. This principle applies to over 40% of present potential actives.

Cinacalcet belongs to the class of naphthalenes and phenylpropylamines and is a calcimimetic drug used in the treatment of hyperparathyroidism in chronic kidney disease especially for those who require dialysis. It functions by reducing the calcium levels caused by increasing the sensitivity of calcium receptors to extracellular calcium. Cinacalcet is chemically known as [(lR)-l-(naphthalen-l-yl)ethyl]({3-[3-(trifluoromethyl)phenyl]propyl})amine and its chemical structure is as follows:-

Cinacalcet is a type II calcimimetic (i.e. it mimics the action of calcium on tissues). It binds to the transmembrane region of the calcium-sensing receptor, which leads to a different structural configuration that is more sensitive to serum calcium. Unlike vitamin D sterols, cinacalcet does not increase serum calcium levels; therefore, adverse effects associated with hypercalcemia can be avoided. Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with increase in parathyroid hormone (PTH) levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary hyperparathyroidism are to lower levels of PTH, calcium and phosphorus in the blood, in order to prevent progressive bone diseases and the systemic consequences of disordered mineral metabolism. In CKD patients on dialysis with uncontrolled secondary HPT, reductions in PTH are associated with a favorable impact on bone-specific alkaline phosphatase (BALP), bone turnover and bone fibrosis. Cinacalcet reduces calcium levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium.

The calcium-sensing receptors on the surface of the chief cell of the parathyroid gland are the principal regulators of parathyroid hormone secretion (PTH). Cinacalcet directly lowers parathyroid hormone levels by increasing the sensitivity of the calcium sensing receptors to activation by extracellular calcium, resulting in the inhibition of PTH secretion. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.

Further, cinacalcet is well absorbed orally but the absorption and bioavailability depends on the food intake of the patient and it gets affected by fed-fast conditions. Cinacalcet has been proved to be better absorbed when administered with food or just after a meal as compared to fasting conditions.

Studies have proven that the mean (90% confidence intervals) AUC (infinity) following high and low fat meals was increased by 68% and 50% respectively, relative to fasting. The difference in mean AUC_max between high and low fat meals was small (12%) and the mean T_max of cinacalcet was prolonged in fasting (6 hours) subjects than high (4 hours) and low fat (3.5 hours) fed subjects. The mean ti/^eta was similar between treatment conditions.

Cinacalcet is commercially available as Sensipar^® in the United States of America and Mimpara^® in Europe for secondary hyperparathyroidism in chronic kidney disease, hypercalcemia in parathyroid carcinoma, severe hypercalcemia in patients with primary hyperparathyroidism and cannot undergo parathyroidectomy. The recommended daily dose of cinacalcet is 30 mg and goes up to 120 mg daily depending on the severity of the condition. WO 2011047837 discloses an intermediate formed by melt processing crystalline cinacalcet or any one of its pharmaceutically accepted salts with a matrix former or any other excipients. However, it is a very well known phenomenon that amorphous form of drug is always more suited than the crystalline counterpart of the drug due to an increased amount of energy associated, increased surface area as well as enhanced bioavailability.

WO 2008027522 discloses immediate and controlled release solid composites of cinacalcet. Further this application also claims a method for preparing a solid composite of cinacalcet by hot melt extrusion. However, this application neither discloses details about the process of hot melt extrusion nor exemplifies it.

WO 2005034928 discloses an immediate release pharmaceutical composition comprising cinacalcet having a controlled dissolution profile. The tablets contain cinacalcet in a micronized form with an active ingredient content of about 18%. The tablets need to be administered with meals or shortly after meals, because the bioavailability is increased by 50% to 80% with concomitant food intake. However, micronization of cinacalcet is accompanied, by some disadvantages such as undesirable low fluidity. The micronized active ingredient may lead to non-uniform drug distribution within the pharmaceutical formulation to be pressed. Further, due to increase of the surface area during micronization, oxidation of the drug may occur.

WO 2007124465 discloses a stable anti-irritant emulsion formulation of cinacalcet in the form of an injectable.

WO 2008064202 discloses modified release formulations containing cinacalcet and their methods of preparation. Modified or sustained release dosage forms are commonly used for special purposes; however, immediate-release dosage forms are always desirable or preferred.

WO 2010034497 discloses cinacalcet formulations in the form of tablets with bimodal pore size and pH adjusters so as to increase its solubility and stability.

WO 2011146583 discloses a cinacalcet formulation with increased solubility wherein cinacalcet is nanosized below 200 nm.

WO 2012071535 discloses hard shell capsules containing a granular powder formulation of Cinacalcet which can be sprinkled on and mixed with food or drinks and then administered orally to the pediatric patients

All the above citations do mention various forms of cinacalcet formulations such as nanosized, modified release, controlled release and various methods of making them more soluble and more bioavailable. But there still exists a need to develop and formulate a cinacalcet formulation which alleviates the shortcomings of the prior art.

The object of the present invention is to provide a pharmaceutical composition of cinacalcet having improved solubility.

Another object of the present invention is to provide a cinacalcet formulation which has higher bioavailability.

Yet another object of the present invention is to provide a cinacalcet formulation which can be preferably administered without food. One more object of the present invention is to provide a pharmaceutical composition of cinacalcet having improved stability.

Another object of the present invention is to provide a process for preparing the pharmaceutical composition comprising cinacalcet.

Another object of the present invention is to provide a method for treatment and/or prevention of secondary hyperparathyroidism, hypercalcemia in patients with parathyroid carcinoma, severe hypercalcemia in patients with primary hyperparathyroidism by administering a pharmaceutical composition comprising cinacalcet.

Another object of the present invention is to provide a use of the pharmaceutical composition comprising cinacalcet in the manufacture of a medicament for treating secondary hyperparathyroidism, hypercalcemia in patients with parathyroid carcinoma, severe hypercalcemia in patients with primary hyperparathyroidism.

According to one aspect of the present invention there is provided a pharmaceutical composition comprising cinacalcet and at least one pharmaceutically acceptable polymer. Preferably, the pharmaceutical composition is a hot melt extruded pharmaceutical composition. Preferably, the composition comprises one or more suitable pharmaceutically acceptable excipients.

Advantages associated with pharmaceutical compositions of the present invention include providing cinacalcet formulations with higher solubility, stability and/or bioavailablity. Pharmaceutical compositions of the present invention may also be administered to patients without food.

According to a further aspect of the present invention, there is provided a process for preparing a pharmaceutical composition of the present invention, wherein the process comprises hot melt extrusion of the cinacalcet polymer blend to form extrudates and optionally mixing it with one or more pharmaceutically acceptable excipients.

According to another aspect of the present invention, there is provided a method for the treatment of secondary hyperparathyroidism, hypercalcemia in patients with parathyroid carcinoma, severe hypercalcemia in patients with primary hyperparathyroidism comprising administering a pharmaceutical composition of the present invention to a subject in need thereof.

According to another aspect of the present invention, there is provided the use of a pharmaceutical composition of the present invention in the manufacture of a medicament for treating secondary hyperparathyroidism, hypercalcemia in patients with parathyroid carcinoma, severe hypercalcemia in patients with primary hyperparathyroidism.

According to another aspect of the present invention, there is provided a pharmaceutical composition of the present invention for use in the treatment of secondary hyperparathyroidism, hypercalcemia in patients with parathyroid carcinoma, severe hypercalcemia in patients with primary hyperparathyroidism.

Cinacalcet is very soluble in its amorphous form when taken orally but the main drawback is that it tends to convert to its stable crystalline form. Absorption of Cinacalcet also depends on the fasting condition of the patient. If the patient is well fed and the dose is administered with the meal or right after the meal, the absorption is optimal but the contrary results in minimal absorption. Therefore, the time lapse between the drug administration and food intake plays a major role in the absorption and bioavailability patterns of cinacalcet.

The inventors of the present invention have found that the solubility, bioavailability as well as stability of cinacalcet was greatly improved when cinacalcet was formulated using hot melt technology. Hot melt extrusion enables the drug to have exceptional absorption and solubility and minimizes its dependence on the food intake of the patient. The inventors made sure that the extruded form of cinacalcet can be taken by the patients at any time of the day without having an effect on its bioavailability.

Thus, the present invention provides a pharmaceutical composition comprising cinacalcet with a polymeric carrier and optionally one or more pharmaceutically acceptable excipients by hot melt technology.

The term "Cinacalcet" is used in broad sense to include not only "Cinacalcet free base" per se but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable esters, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.

The term "salt" as used herein, refers to salts derived from inorganic or organic acids.

Examples of suitable salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, carbonates, bicarbonates, hydrobromide, hydroiodide, 2-hydr xy-ethanesulfonate, lactate, maleate, mandelate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 2-phenylpropionate, picrate, pivalate, propionate, salicylate, succinate, sulfate, nitrates, tartrate, sulfonates, thiocyanate, tosylate, mesylate, and undecanoate. Preferably, the cinacalcet salt used is hydrochloride or methanesulphonate.

The term "extrudates" as used herein refers to solid product solutions, solid dispersions and glass solutions of Cinacalcet with one or more polymers and optionally pharmaceutically acceptable excipients.

The term "pharmaceutically acceptable" mentioned throughout the specification would be applied to a carrier, diluent or excipient which is compatible with the actives as employed. The term "administration without food" mentioned throughout the specification means that the patient need not necessarily take the pharmaceutical composition of the present invention with meals.

Cinacalcet can be present in crystalline or amorphous form or a combination thereof. Preferably, the pharmaceutical compositions of the present invention, provide cinacalcet in an amorphous form.

The process of hot melt extrusion is carried out in the conventional extruders as known to a person skilled in the art.

Typically, the melt-extrusion process comprises the steps of preparing a homogeneous melt of one or more drugs, the polymer and the excipients, and cooling the melt until it solidifies.

Melting usually involves heating above the softening point of the polymer. The preparation of the melt can take place in a variety of ways. The mixing of the components can take place before, during or after the formation of the melt.

Usually, the melt temperature is in the range of about 50° C to about 200° C.

Suitable extruders include single screw extruders, intermeshing screw extruders or else multiscrew extruders, preferably twin screw extruders, which can be co-rotating or counter- rotating and, optionally, be equipped with kneading disks.

The extrudates can be in the form of beads, granulates, tubes, strands or cylinders and these can be further processed into any desired shape.

The cinacalcet compositions of the invention generally comprise at least one pharmaceutically acceptable water soluble and/or insoluble polymer or combination thereof and optionally one or more pharmaceutically acceptable excipients.

The cinacalcet compositions of the present invention can be administered to a subject via any conventional means including, but not limited to, orally, rectally, ocularly, parenterally (e.g., intravenous, intramuscular, or subcutaneous), intracisternally, intravaginally, intraperitoneally, locally (e.g., powders, ointments or drops), or as a buccal or nasal spray.

Moreover, the extrudates/granules of cinacalcet of the present invention may be formulated into any suitable dosage form, including but not limited to liquid dispersions, gels, aerosols, ointments, creams, controlled release formulations, lyophilized formulations, tablets, capsules, immediate release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations.

The cinacalcet compositions may be formulated for parenteral injections (e.g., intravenous, intramuscular, or subcutaneous), oral administration in solid, liquid, or aerosol forms, foams (vaginal, rectal), vaginal, rectal, ocular, local (powders, ointments or drops), buccal, intracistemal, intraperitoneal, or topical administration, and the like.

Solid dosage forms are preferably in the form of tablets, coated tablets, powders, powders for reconstitution, pellets, beads, mini-tablets, film coated 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, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini- tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, modified release tablets or capsules, effervescent granules, granules, and microspheres, multiparticulates) and sprinkles and the like,

Liquid dosage forms according to the present invention for oral administration include pharmaceutically acceptable emulsions, liquid dispersions, sprays, solutions, suspensions, syrups, dry syrup and elixirs. Water soluble polymers or hydrophilic polymer which may be used in the pharmaceutical composition of the present invention, include, but are not limited to, polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer (Soluplus), homopolymers and co-polymers of N-vinyl lactams, especially homopolymers and co-polymers of N- vinyl pyrrolidone e.g. polyvinylpyrrolidone (PVP), co-polymers of PVP and vinyl acetate, co-polymers of N-vinyl pyrrolidone and vinyl acetate (Copovidone) or vinyl propionate, dextrins such as grades of maltodextnn, cellulose esters and cellulose ethers, high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and co-polymers of ethylene oxide, propylene oxide, hydroxypropyl methylcellulose (HPMC, also known as hypromellose), hydroxypropylcellulose (HPC), methylcellulose, carmellose (carboxymethylcellulose), hydroxyethylcellulose (HEC), hydroxymethylcellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, xanthan gum, sodium alginate, ammonium alginate, polyethylene oxide, potassium alginate, calcium alginate, propylene glycol alginate, alginic acid, polyvinyl alcohol, povidone, carbomer, guar gum, locust bean gum, potassium pectate, potassium pectinate, polysaccharide, polyalkyleneglycol, starch and derivatives cross linked homopolymers and copolymers of acrylic acid and the like or mixtures thereof.

Water insoluble polymers or hydrophobic which may be used in the pharmaceutical composition of the present invention, include, but are not limited to, acrylic copolymers, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic acid esters, ammonio methyacrylate copolymer, methyacrylic acid copolymers, methacrylic acid-acrylic acid ethyl ester copolymer, methacrylic acid esters neutral copolymer, polyvinyl acetate, waxes, such as, beeswax, carnauba wax, microcrystalline wax, candelilla wax, spermaceti, montan wax, hydrogenated vegetable oil, lecithin, hydrogenated cottonseed oil, hydrogenated tallow, paraffin wax, shellac wax, petrolatum, ozokerite, and the like, as well as, synthetic waxes, e. g., polyethylene, and the like; fatty acids such as, stearic acid, palmitic acid, lauric acid, eleostearic acids, and the like; fatty alcohols, such as, lauryl alcohol, cetostearyl alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol; fatty acid esters, such as, glyceryl monostearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate and glyceryl behenate; vegetable oil, such as, hydrogenated castor oil; mineral oil and the like or mixtures thereof.

Water-swellable polymers for use in the pharmaceutical composition of the present invention may comprise one or more, polyethylene oxide having a molecular weight of 100,000 to 8,000,000; poly (hydroxy alkyl methacrylate) having a molecular weight of from 30,000 to 5,000,000; poly (vinyl) alcohol, having a low acetal residue, which is cross-linked with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization of from 200 to 30,000; a mixture of methyl cellulose, cross- linked agar and carboxymethyl cellulose; a water-insoluble, water-swellable copolymer produced by forming a dispersion of a finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, butylene or isobutylene cross-linked with from 0.001 to 0.5 moles of saturated cross-linking agent per mole of maleic anhydride in the copolymer; Carbopol^® carbomer which is as acidic carboxy polymer having a molecular weight of 450,000 to 4,000,000; Cyanamer^® polyacrylamides; cross-linked water swellable indene- maleic anhydride polymers; Goodrich^® polyacrylic acid having a molecular weight of 80,000 to 200,000; starch graft copolymers; Aqua Keeps^® acrylate polymer polysaccharides composed of condensed glucose units such as diester cross-linked polyglucan, and the like; Amberlite^® ion exchange resins; Explotab^® sodium starch glycolate; Ac-Di-Sol^® croscarmellose sodium and the like or mixtures thereof.

Other pharmaceutically acceptable excipients may include, but are not limited to, plasticizers, disintegrating agents, lubricants, glidants, diluents, binders, chelating agents, coating agents and the like or mixtures thereof. Plasticizers reduce the viscosity of the polymer melt and thereby allow for lower processing temperature and extruder torque during hot melt extrusion. They further decrease the glass transition temperature of the polymer.

Plasticizers which may be used in the pharmaceutical composition of the present invention, include, but are not limited to propylene glycol, polysorbates such as sorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan monoisostearate; citrate ester type plasticizers like triethyl citrate, citrate phthalate; propylene glycol; glycerin; polyethylene glycol (low & high molecular weight); triacetin; dibutyl sebacate, tributyl sebacate; dibutyltartrate, dibutyl phthalate, glycerol palmitosterate and the like or mixtures thereof. The plasticizers may be present in an amount of from about 5 to 20 % of polymer in the composition.

Suitable disintegrating agents which may be used in the pharmaceutical composition of the present invention, include, but are not limited to hydroxyl propyl cellulose, dihydroxyypropyl cellulose, sodium carboxy methyl cellulose, carboxy methyl cellulose, calcium carboxy methyl cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, carboxymethyl starch, hydroxylpropyl starch, potato starch, maize starch, alginic acid or a salt, modified starches, calcium silicates, low substituted hydroxy- propylcellulose and the like or mixtures thereof. The disintegrating agents may be present in an amount of from about 0.5 to 20 % w/w. Suitable lubricants, anti-adherents and glidants which may be used in the pharmaceutical composition of the present invention, include, but are 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), and the like or mixtures thereof.

The lubricants and glidants may be present in an amount of from about 0.05 to 1 % w/w.

Suitable diluents or bulking agents which may be used in the pharmaceutical composition of the present invention, include, but are not limited to microcrystalline cellulose, silicified microcrystalline cellulose, lactose, calcium phosphate, starch, dicalcium phosphate,sorbitol/mannitol, sucrose/methyl dextrins, saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, lactose, dextrose, sucrose, fructose, maltose, mannitol, erythritol, sorbitol, xylitol, lactitol, and the like or mixtures thereof.

Suitable binders may include, one or more of, but not limited to polyvinyl pyrrolidone (also known as povidone), polyethylene glycol, acacia, alginic acid, agar, calcium carragenan, cellulose derivative such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, copovidone, starches, and the like or any other pharmaceutically acceptable substances with cohesive properties, or any combination thereof.

Suitable chelating agents include, one or more of, but not limited to ethylenediaminetetraacetic acid (EDTA), disodium EDTA and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives thereof, and sodium desoxycholate and the like or mixtures thereof.

The pharmaceutical composition, may also optionally be coated, i.e. seal coated and/or enteric coated and/or film coated. Preferably, the pharmaceutical composition may be seal coated and finally film coated or it may be seal coated and further enteric coated.

Optionally, pharmaceutical compositions of the invention may be film coated. Preferably, the film coating polymer may be present in an amount from about 2 to 10 % w/w.

Alternatively, there is a seal coat between the core containing cinacalcet, and an enteric coat. The seal coat can comprise one or more pharmaceutically acceptable film-forming polymers and pharmaceutically acceptable excipients(s). The seal coat provides a smooth base for the application of the enteric coat, prolongs the resistance of the core to the acidic conditions, improves stability by minimizing the interaction between drug in the core and the enteric polymer in the enteric layer from coming into direct contact with each other; and also improves stability of drug from light exposure. The smoothing function of the separating coat is purely mechanical, the objective of which is to improve the coverage of the enteric coat and to avoid thin spots in it, caused by bumps and irregularities on the core.

The seal coat can comprise film forming polymeric materials, such as but not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose, hypromellose, acacia, gelatin to increase adherence and coherence of the seal coat. The seal coating polymer/plasticizer may be present in an amount of from about 0.05 to 1 % w/w.

Optionally, an enteric coat is present over the seal coat. The enteric coat comprises of materials such as, but not limited to, neutralized methacrylic acid copolymer such as, EUDRAGIT L 30 D- 55, EUDRAGIT L 100-55, EUDRAGIT S 100, EASTACRYL 30D, KOLLICOAT MAE 30 DP, KOLLICOAT MAE 100 P; cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate and combinations thereof.

Further, the pharmaceutical composition according to the present invention may further comprise at least one additional active ingredient. The additional active ingredient may be another calcium receptor-active compound, or it may be an active ingredient having a different therapeutic activity. Examples of such additional active ingredients include, for example, vitamins and their analogs, such as vitamin D and analogs thereof, antibiotics, and cardiovascular agents..

The process for preparing the pharmaceutical composition of the invention can comprise forming a powder blend, which melts on passage through a heated barrel of an extruder, to form a molten solution product and is then subsequently cooled to form an extrudate.

Alternatively, the extrudate is cut into pieces after solidification and can be further processed into suitable dosage forms.

In an alternative process, the present invention may further be allowed to form granules which may be compressed to form tablets, powders, powders for reconstitution, pellets, beads, mini- tablets, film coated 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, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, modified release tablets or capsules, effervescent granules, granules, and microspheres, multiparticulates) and sprinkles and the like.

This process involves heating the polymer(s) to soften it, without melting it, and mixing the active ingredient(s) with the polymer(s) to form granules.

The process can be carried out in the same type of extrusion apparatus as the hot melt extrusion process, except that the product is not extruded through the extrusion nozzle of the apparatus.The present invention also provides a method of treating secondary hyperparathyroidism, hypercalcemia in patients with parathyroid carcinoma, severe hypercalcemia in patients with primary hyperparathyroidism which method comprises administration of a therapeutically effective amount of a pharmaceutical composition of the present invention.

The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention:- Example 1

Process

1) Propylene glycol was adsorbed on microcrystalline cellulose

. 2) Cinacalcet, Polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer (Soluplus^®) and propylene glycol were mixed with the blend obtained in step (1) 3) The mixture obtained in step (2) was subjected to hot melt extrusion.

4) The extrudates obtained in step (3) were further milled and sized which was followed by addition of microcrystalline cellulose, crospovidone and further lubricated with magnesium stearate.

5) The lubricated mixture obtained in step (4) was compressed to form a tablet which was seal

coated with hydroxypropyl methyl cellulose and finally film coated with Opadry II.

Example 2

Process

1) Propylene glycol was adsorbed on microcrystalline cellulose

2) Cinacalcet, Polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer (Soluplus^®) and propylene glycol were mixed with the blend obtained in step (1) 3) The mixture obtained in step (2) was subjected to hot melt extrusion.

5) Lubricated granules/extrudates which were obtained in step (4) were filled in capsules made of Gelatin /Hydroxy propyl methyl cellulose, Carrageenan

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. 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 a "cosolvent" refers to a single cosolvent or to combinations of two or more cosolvents, and the like

Claims

1. A pharmaceutical composition comprising cinacalcet or its salt, solvate, derivative, hydrate, anhydrate, enantiomer, polymorph, prodrug or complex and at least one pharmaceutically acceptable polymer.

2. A pharmaceutical composition according to claim 1 wherein cinacalcet is in its free base form, or in a salt form optionally selected from cinacalcet hydrochloride, or cinacalcet methanesulphonate.

3. A pharmaceutical composition according to claim 1 or 2 wherein the composition is a hot melt extruded pharmaceutical composition.

4. A pharmaceutical composition according to claims 1, 2 or 3 wherein the cinacalcet is in an amorphous form.

5. A pharmaceutical composition according to any preceding claim, wherein the at least one pharmaceutically acceptable polymer is a water soluble polymer and /or a water swellable polymer and/or a water insoluble polymer.

6. A pharmaceutical composition according to claim 5, wherein the water soluble polymer is selected from Polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer, homopolymers and co-polymers of N-vinyl lactams, co-polymers of PVP and vinyl acetate, copolymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate, dextrins, cellulose esters and cellulose ethers, high molecular polyalkylene oxides, propylene oxide, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, xanthan gum, sodium alginate, ammonium alginate, polyethylene oxide, potassium alginate, calcium alginate, propylene glycol alginate, alginic acid, polyvinyl alcohol, povidone, carbomer, guar gum, locust bean gum, potassium pectate, potassium pectinate, polysaccharide, polyalkyleneglycol, starch and derivatives cross linked homopolymers and copolymers of acrylic acid.

7. A pharmaceutical composition according to claim 5 or 6, wherein the water insoluble polymer is selected from ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic acid esters, ammonio methyacrylate copolymer, methyacrylic acid copolymers, methacrylic acid-acrylic acid ethyl ester copolymer, methacrylic acid esters neutral copolymer, polyvinyl acetate, waxes, such as, beeswax, carnauba wax, microcrystalline wax, candelilla wax, spermaceti, montan wax, hydrogenated vegetable oil, lecithin, hydrogenated cottonseed oil, hydrogenated tallow, paraffin wax, shellac wax, petrolatum, ozokerite, synthetic waxes, fatty acids, fatty alcohols, fatty acid esters, glyceryl monostearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitm, cetyl esters wax, glyceryl palmitostearate and glyceryl behenate; vegetable oil, such as, hydrogenated castor oil, mineral oil.

8. A pharmaceutical composition according to claim 5, 6 or 7 wherein the water swellable polymer is selected from polyethylene oxide, poly (vinyl) alcohol, formaldehyde, glutaraldehyde, carbopol, cyanamer, polyacrylamides, cross-linked water swellable indene- maleic anhydride polymers, acrylate polymer, ion exchange resins; explotab, sodium starch glycolate, ac-di-sol' croscarmellose sodium.

9. A pharmaceutical composition according to any preceding claim, further comprising one or more pharmaceutically acceptable excipients.

10. A pharmaceutical composition according to claim 9, wherein the one or more pharmaceutically acceptable excipients are selected from plasticizers, disintegrating agents, lubricants, glidants, diluents, anti-adherents, binders, chelating agents.

11. A pharmaceutical composition according to claim 10, wherein the composition comprises at least one plasticiser, optionally selected from propylene glycol; polysorbates such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monoisostearate; citrate ester type plasticizers such as triethyl citrate, citrate phthalate; glycerin; polyethylene glycol (low and high molecular weight); triacetin; dibutyl sebacate, tributyl sebacate; dibutyltartrate, dibutyl phthalate, glycerol palmitosterate and/or mixtures thereof.

12. A pharmaceutical composition according to claim 10 or 11, further comprising at least one disintegrating agent, optionally selected from hydroxyl propyl cellulose, dihydroxyypropyl cellulose, sodium carboxy methyl cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, potato starch, maize starch, modified starches, calcium silicates, substituted hydroxy- propylcellulose and/or mixtures thereof.

13. A pharmaceutical composition according to claim 10, 11 or 12, further comprising at least one lubricant/glidant, optionally selected from stearic acid; stearic acid esters, derivatives or salts, glyceryl behenate, glycerol fumarate, hydrogenated vegetable oil, talc, colloidal silicon dioxide, and/or mixtures thereof.

14. A pharmaceutical composition according to any one of claims 10 to 13, further comprising at least one diluent/bulking agent optionally selected from microcrystalline cellulose; silicified microcrystalline cellulose; lactose; calcium phosphate; starch; dicalcium phosphate; sorbitol/mannitol; sucrose; methyl dextrins; monosaccharides; disaccharides; polysaccharides; sugar alcohols such as arabinose, lactose, dextrose, sucrose, fructose and maltose; mannitol; erythritol; sorbitol; xylitol; lactitol; and/or mixtures thereof.

15. A pharmaceutical composition according to any one of claims 10 to 14, further comprising at least one binder, optionally selected from methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose, polyvinylpyrrolidone, gelatin, gum arabic, polyvinyl alcohol, pullulan, starch, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, alginate, cellulose derivatives, and/or mixtures thereof.

16. A pharmaceutical composition according to any one of claims 10 to 15, further comprising at least one chelating agent, optionally selected from ethylenediaminetetraacetic acid (EDTA), disodium EDTA and/or derivatives thereof, citric acid and/or derivatives thereof, niacinamide and/or derivatives thereof, sodium desoxycholate and/or derivatives thereof, and/or mixtures thereof.

17. A pharmaceutical composition according to any preceding claim, wherein the composition is in the form of a tablet, coated tablet, powders, powders for reconstitution, pellets, beads, mini-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, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, modified release tablets or capsules, effervescent granules, granules, and microspheres, multiparticulates) and sprinkles.

18. A process for preparing a pharmaceutical composition according to any one of claims 1 to 17, wherein the process comprises hot melt extrusion of the cinacalcet polymer blend to form extrudates and optionally mixing it with one or more pharmaceutically acceptable excipients.

19. A process according to claim 18, wherein the process comprises preparing a homogeneous melt of cinacalcet, at least one polymer and optionally one or more pharmaceutically acceptable excipients, extruding the melt and cooling the melt until it solidifies.

20. A process according to any one of claim 18 or 19, wherein the hot melt is formed at a temperature from about 50°C to 200°C.

21. A process according to any one of claims 18 to 20, wherein cinacalcet, at least one polymer and optionally, one or more pharmaceutically acceptable excipients are processed to form a powder blend which melts on passage through the heated barrel of an extruder, to form a molten solution product and is then subsequently cooled to form an extrudate.

22. A process according to any one of claims 18 to 21, wherein the process further comprises forming the extrudates as beads, granulates, tubes, strands and/or cylinders.

23. A pharmaceutical composition according to any one of claims 1 to 17, further comprising at least one additional active pharmaceutical ingredient selected from vitamins and their analogues, such as vitamin D and analogues thereof, antibiotics, and cardiovascular agents.

24. A pharmaceutical composition according to any one of claims 1 to 17, for use in treatment of secondary hyperparathyroidism, hypercalcemia in patients with parathyroid carcinoma, or severe hypercalcemia in patients with primary hyperparathyroidism.

25. Use of a pharmaceutical composition according to any one of claims 1 to 17 in the manufacture of a medicament for the treatment of secondary hyperparathyroidism, hypercalcemia in patients with parathyroid carcinoma, or severe hypercalcemia in patients with primary hyperparathyroidism.

26. A method of treating secondary hyperparathyroidism, hypercalcemia in patients with parathyroid carcinoma, or severe hypercalcemia in patients with primary hyperparathyroidism, wherein the method comprises administering a pharmaceutical composition according to any one of claims 1 to 17 to a subject in need thereof.

27. A pharmaceutical composition as substantially described herein, with reference to any one of the examples.

28. A process for preparing a pharmaceutical composition as substantially described herein, with reference to any one of the examples.