We Claim:
1. Pharmaceutical composition comprising cinacalcet and its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, wherein the composition is free of binder.
2. Pharmaceutical composition comprising cinacalcet and its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, wherein the composition comprises 5-10% w/w by weight of binder.
3. Pharmaceutical composition as claimed in Claim 1 and 2, wherein one or more
pharmaceutical excipients are selected from diluents, disintegrants, lubricants, glidants
and combinations thereof.
4. Pharmaceutically acceptable salts of cinacalcet as claimed in Claim 1 and 2, are selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, benzoic acid, butyric acid, maleic acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, methane-sulfonic acid.
5. Binders as claimed in claim 2, are selected from povidone, dihydroxy propyl cellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin and combinations thereof.
6. Pharmaceutical composition of claim 1 and 2, may be in the form of tablet, capsule or sachet dosage form.
7. Pharmaceutical composition of claim 1, 2 and 6, wherein the composition is prepared by direct compression, wet granulation and dry granulation.
8. Pharmaceutical composition as claimed in Claim 1 and 2, is film coated tablet.

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PHARMACEUTICAL COMPOSITIONS OF
CINACALCET
FIELD OF THE INVENTION
The present invention relates to pharmaceutical composition of calcimimetic compounds. More specifically the present invention relates to pharmaceutical composition of cinacalcet and its pharmaceutically acceptable salts.
BACKGROUND OF THE INVENTION
Cinacalcet is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor
to activation by extracellular calcium. It is approved as hydrochloride salt in 2004 under the
trademark of Sensipar® in USA and Mimpara® in Europe and is available as film-coated
tablets. Cinacalcet hydrochloride is used to treat secondary hyperparathyroidism as a
consequence of chronic renal failure. In addition, the substance is approved for the treatment
of hypercalcaemia in patients with parathyroid carcinoma. Chemically cinacalcet
hydrochloride is N- [ 1 -(R)-(-)-( 1 -naphthyl)ethyl] -3 - [3 -(trifluoromethyl)phenyl] -1 -
aminopropane hydrochloride and structurally cinacalcet hydrochloride is
Cinacalcet hydrochloride is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol and slightly soluble in water. Cinacalcet has a solubility in water of less than about 1 |ag/mL at neutral pH. The solubility of cinacalcet can reach about 1.6 mg/mL when the pH ranges from about 3 to about 5. However, when the pH is about 1, the solubility decreases to about 0.1 mg/mL. Due to poor solubility of cinacalcet there is need to develop improved formulations of cinacalcet. Following patents/applications discloses various formulations/process for preparing improved formulations of cinacalcet:
US 7,829,595 patent discloses improved formulation of cinacalcet using specific ratios of excipients. Diluent in the range of from about 45% to about 85% by weight, binder from about 1% to about 5% by weight and disintegrant from about 1% to about 10% by weight. Diluents disclosed in this patent are starch, micrcrystalline cellulose, dicalcium phosphate, lactose,

sorbitol, mannitol, sucrose, methyl dextrins. Binders disclosed in this patent are povidone, hydroxypropyl methylcellulose, dihydroxy propylcellulose, and sodium carboxylmethylcellulose. Disintegrants disclosed in this patent are crospovidone, sodium starch glycolate, croscarmellose sodium, and mixtures of any of the foregoing. In addition to these, the composition also contains lubricant and glidant. The specific formulation contains binder in the range of about 1% to about 5% and the formulation release cinacalcet about 50% to about 125% in 30 minutes time.
US 20080181959 patent application discloses composition of cinacalcet, wherein the composition comprises solid composite of cinacalcet in intimate association with at least one polymer selected from consisting of povidone, poloxamer, hydroxypropyl methylcellulose, polyethylene glycol, copovidone, copolymers of methacrylate, copolymers of methacrylic acid, and mixtures thereof. This patent application also discloses process for preparing solid composite comprising: combining cinacalcet, at least one carrier, and at least one liquid solvent to form a solution; and removing the solvent to obtain a solid composite of the cinacalcet and the at least one carrier.
US20110287065 patent application discloses stable nanoparticulate cinacalcet composition comprising: (a) particles of cinacalcet or a pharmaceutically acceptable salt thereof, having an effective average particle size of less than about 2000 nm; and (b) at least one surface stabilizer.
US 20120009258 patent application discloses an intermediate, obtainable by jointly compacting (i) crystalline cinacalcet or a pharmaceutically acceptable salt thereof, with (ii) a hydrophilising agent like polysaccharides, such as hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC, especially sodium and calcium salts), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC); polyvinyl pyrrolidone, polyvinyl alcohol, polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone/vinyl acetate copolymers (such as Kollidon VA64, BASF), polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic.RTM., BASF), and mixtures of the polymers mentioned. This application further discloses that the intermediate is milled, sieved and mixed with extragranular excipients.

US 20120270949 patent application discloses cinacalcet intermediate prepared by melt-processing cinacalcet with matrix former of hydrophilic polymers with a weight-average molecular weight of 1,000 g/mol to 150,000 g/mol like polysaccharides, such as hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone, polyvinyl alcohol, polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone/vinyl acetate copolymers (such as Kollidon.RTM. VA64, BASF), polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic.RTM., BASF), and mixtures of the polymers mentioned. Cinacalcet intermediate further comprising disintegrant and wicking agent. This patent application discloses that cinacalcet is used as non-micronized form.
WO2013107503 patent application discloses process for preparation of cinacalcet compositions, wherein the process containing the steps of preparing a core composition involving mixing of Cinacalcet particles having a particle size distribution -d(90) value of less than 150 pm together with at least one diluent sieving the core composition to obtain overall particle size profile of less than 355 pm, separately selecting filler materials to have a bulk density of ranging from 350 to 650 g/1, and mixing the same with the core composition in substantially dry conditions such that bulk density of the overall composition is greater than 400 g/1.
CA2818565 patent application discloses cinacalcet composition for use in capsule or sprinkle formulation, wherein the composition comprising cinacalcet is admixed with at least about 2% w/w to about 5% w/w of silicon dioxide. This formulation will not stick to the capsule shells and gives good uniformity of drug from the dosage form.
WO2014029953 patent application discloses cinacalcet composition prepared by hot melt
extrusion process with a pharmaceutically acceptable polymer, wherein the polymer is water
soluble polymer or water insoluble polymer. 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. 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.
All the above patents/application discloses various formulations of cinacalcet using different technologies like hot melt granulation/extrusion, solid composite, mixing of cinacalcet with diluents etc. All these process requires use of melting process, which are tedious as well as increase production time and ultimately product cost will increase. Hence, there is a need to develop simple cinacalcet formulations, which are manufactured by routine techniques with low cost. Hence, the present inventors developed a simple formulation of cinacalcet without use of any tedious process.
SUMMARY OF THE INVENTION
In one embodiment of the present invention provides pharmaceutical composition comprising cinacalcet and its pharmaceutically acceptable salts and at least one or more pharmaceutically acceptable excipients, wherein the composition is free of binder.
In another embodiment of the present invention provides pharmaceutical composition of comprising cinacalcet and its pharmaceutically acceptable salts and at least one or more

pharmaceutically acceptable excipients, wherein the composition comprises binder 5% -10% by weight relative to the total weight of the composition.
In another embodiment of the present invention, process for preparing pharmaceutical composition of cinacalcet and its pharmaceutically acceptable salts.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides pharmaceutical composition of cinacalcet and its pharmaceutically acceptable salts, comprising one or more pharmaceutically acceptable excipients, wherein the composition is free of binder.
Pharmaceutically acceptable salts of cinacalcet are selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, benzoic acid, butyric acid, maleic acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, methane-sulfonic acid. Preferable the salt is Hydrochloric acid.
The term "free" means less than 1% w/w by weight, specifically less than 0.5% w/w by weight and more specifically 0% w/w by weight of binder.
The present invention also provides pharmaceutical composition of cinacalcet and its pharmaceutically acceptable salts, comprising one or more pharmaceutically acceptable excipients, wherein the composition comprises binder 5% - 10% by weight of total weight of the composition.
The one or more pharmaceutically acceptable excipients are preferably selected from the group consisting of diluents, disintegrants, lubricants, glidants and combinations thereof.
Suitable diluents used according to the present invention may be selected from microcrystalline cellulose, mannitol, lactose, starch, calcium hydrogen phosphate, sorbitol, sucrose, dicalcium phosphate and combinations thereof.
Suitable binders used according to the present invention may be selected from the group consisting of povidone, dihydroxy propyl cellulose, sodium carboxy methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin and combinations thereof.

Suitable disintegrants used according to the present invention may be selected from the group consisting of sodium starch glycolate, crospovidone, low substituted hydroxypropyl cellulose, croscarmellose sodium, carmellose calcium, croscarmellose potassium, silicified microcrystalline cellulose, and combinations thereof.
Suitable lubricants used according to the present invention may be selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, talc and combinations thereof.
Suitable glidants used according to the present invention may be selected from the group consisting of calcium phosphate tribasic, powdered cellulose, colloidal silicon dioxide, magnesium oxide, magnesium silicate, magnesium trisilicate, talc and combinations thereof.
The pharmaceutical compositions disclosed herein can be in the form chosen from, for example, tablets, capsules, and powders. The tablet dosage form are coated with film-coating polymers.
Film-coating polymers used according to the present invention may be selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, hydroxyl ethyl cellulose and combination thereof.
A preferred composition, according to the invention, comprises:
Cinacalcet hydrochloride 10 to 40% by weight;
at least one diluent 40 to 85% by weight;
at least one disintegrant 1 to 10% by weight;
at least one lubricant 0.05 to 2% by weight; and
optionally at least one glidant; wherein the percentage by weight is relative to the total weight of the composition.
Another preferred composition, according to the invention, comprises:
Cinacalcet hydrochloride 10 to 40% by weight;
at least one diluent 40 to 85% by weight;
at least one binder 5 to 10% by weight;
at least one disintegrant 1 to 10% by weight;

at least one lubricant 0.05 to 2% by weight; and
optionally at least one glidant; wherein the percentage by weight is relative to the total weight of the composition.
In another embodiment, the present invention provides a process for preparing pharmaceutical composition of cinacalcet hydrochloride.
The pharmaceutical compositions are prepared by techniques known by the skilled person in the art like direct compression or wet granulation or dry granulation.
Direct compression technique generally involves blending all ingredients in a blender for suitable time till to achieve blend uniformity and compressing into tablets of suitable size and shape.
Wet granulation technique generally involves utilization of solvents for preparation of granules. This process generally has the steps of mixing active ingredient with diluent, optionally disintegrant, binder, granulating this mixture either by aqueous or non-aqueous granulation, drying the granulate, optionality sieving dried granules and blending dried granules with optionally further diluent, disintegrant, optionally glidant and lubricated with lubricant.
Suitable solvents used according to the present invention for preparation of wet granulation are selected from water, isopropyl alcohol, methylene chloride and combinations thereof.
Dry granulation is another technique which doesn't use any solvents for preparation of granules. This process generally has the steps of mixing active ingredient with diluent, optionally disintegrant, binder, slugging and de-slugging and blending with optionally disintegrant, optionally diluent, optionally glidant, and finally lubricating with lubricant.
Reference will now be made to the following examples which are not intended to limit the invention. To the contrary, it will be appreciated that various alternatives, modifications, and equivalents may be included within the spirit and scope of the invention.
Example 1:

Manufacturing process:
1) Sifted Cinacalcet hydrochloride, pregelatinized starch, microcrystalline cellulose, crospovidone and colloidal silicon dioxide through 20 mesh sieve
2) Loaded step 1 ingredients in V-cone blender and blended for 20 minutes
3) Added magnesium stearate to blend of step 2 and blended for 5 minutes
4) Final blend of step 3 is compressed into tablets
5) Tablets are coated with film-coating polymer
Example 2:
Manufacturing process:
1) Sifted Cinacalcet hydrochloride, pregelatinized starch, microcrystalline cellulose, povidone, crospovidone and colloidal silicon dioxide through 20 mesh sieve
2) Loaded step 1 ingredients in V-cone blender and blended for 20 minutes

3) Added magnesium stearate to blend of step 2 and blended for 5 minutes
4) Final blend of step 3 is compressed into tablets
5) Tablets are coated with film-coating polymer
Example 3:
Manufacturing process:
1) Sifted and collected separately Cinacalcet hydrochloride, pregelatinized starch, microcrystalline cellulose, hydroxypropyl methylcellulose, crospovidone and colloidal silicon dioxide through 20 mesh sieve
2) Loaded part quantity of pregelatinized starch, part quantity of microcrystalline cellulose, part quantity of crospovidone and hydroxypropyl methylcellulose in rapid mixer granulator and granulated using purified water
3) Wet granules of step 2 are milled through comill equipped with 2mm screen
4) Sized granules of step 3 are dried in fluid bed dryer
5) Dried granules of step 4 were sized
6) Blended dried granules of step 5 with part quantity of pregelatinized starch, part quantity of microcrystalline cellulose, part quantity of crospovidone and colloidal silicon dioxide in blender for 15 minutes
7) Added magnesium stearate to blend of step 6 and blended for 5 minutes

8) Final blend of step 7 is compressed into tablets
9) Tablets are coated with film-coating polymer
In-vitro dissolution for the tablets of Example 1, 2 & 3 were conducted using USP Type II, 0.05 HC1, 75 rpm, 900ml. Results of the same are given below:
From the above data it is evident that the tablets prepared according present inventions releases more than 90% of cinacalcet in 30 minutes.