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Title:
PHARMACEUTICAL COMPOSITIONS COMPRISING CINACALCET HYDROCHLORIDE AND ONE OR MORE BINDERS
Document Type and Number:
WIPO Patent Application WO/2019/034981
Kind Code:
A1
Abstract:
The invention relates to a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient. The invention also relates to the pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof having a particle size distribution D 90 equal to or less than 20 µm, D 50 equal to or less than 10 µm, and D equal to or less than 5 µm and one or more and binders in an amount of 0.9% w/w or less, relative to the total weight of composition, wherein the composition is not free of binder and that the total amount of binder does not exceed 0.9%w/w relative to the total weight of the composition.

Inventors:
SATHE, Dhananjay (202/A-1, Golden Park L.B.S. Marg,,Panchpakhadi, Thane, Maharashtra 1, 400601, IN)
PIMPLE, Srikant (B101, Vastushree Pearl Near Kinara Hotel,,Paud Road, Kothrud, Pune, Maharashtra 8, 411038, IN)
MAURYA, Pravin Kumar (Survey No.139/3 Flat No. 112, 1st Floor Aquamarina,Shinde Wasti Road, Behind Escon Temple, Ravet, Kivale, Pune, Maharashtra 1, 412101, IN)
Application Number:
IB2018/056084
Publication Date:
February 21, 2019
Filing Date:
August 13, 2018
Export Citation:
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Assignee:
UNICHEM LABORATORIES LTD (Unichem Bhavan, Prabhat Estate Off. S. V. Road,,Jogeshwari , Mumbai, Maharashtra 2, 400102, IN)
International Classes:
A61K31/00; A61K31/135; A61K31/137
Foreign References:
US7829595B22010-11-09
US20110287065A12011-11-24
US20110295037A12011-12-01
CN102885792A2013-01-23
Attorney, Agent or Firm:
KHURANA & KHURANA, ADVOCATES & IP ATTORNEYS (E-13, UPSIDC Site-IV, Behind-Grand Venice,Kasna Road, Greater Noida, National Capital Region, Uttar Pradesh 0, 201310, IN)
Download PDF:
Claims:
We Claim:

1. A pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient(s).

2. A pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and one or more binder(s) in an amount of about 0.9% w/w or less, relative to the total weight of the composition, and optionally a pharmaceutically acceptable excipient(s), wherein the composition is not free of binder.

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is selected from the group consisting of granules, pellets, micro-pellets, spheres, cores, coated cores, pills, compressed tablets, mini tablets, layered tablets, beads, particles and capsules.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is in the form of compressed tablets.

5. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipient(s) is selected from the group consisting of a diluent, a disintegrant, a binder, a lubricant, and a glidant.

6. The pharmaceutical composition according to claim 2 or 5, wherein the binder is selected from the group consisting of polyvinylpyrrolidone; polyethylene glycol; cross-linked polyvinylpyrrolidone; cellulose derivatives including hydroxymethyl cellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, ethyl cellulose, hydroxylethylcellose, and hydroxypropylmethylcellulose; sucrose; alginic acid; sodium alginate; carbomer; cottonseed oil; dextrin; dextrose; guar gum; hydrogenated vegetable oil type I; magnesium aluminium silicate; maltodextrin; maltose; polydextrose; polyethylene oxide; stearic acid; zein or combination thereof; said binder being preferably povidone and / or pregelatinized starch.

7. The pharmaceutical composition according to claim 2 or 6, wherein the pharmaceutical composition comprises povidone as a binder from about 0.35% w/w to about 0.9% w/w, relative to total weight of the composition.

8. The pharmaceutical composition According to claim 2 or 6, wherein the pharmaceutical composition comprises pregelatinized starch as a binder from about 0.35% w/w to about 0.9% w/w, relative to total weight of the composition.

9. The pharmaceutical composition according to any of the preceding claims, wherein the diluents is selected from the group consisting of but not limited to microcrystalline cellulose, microfine cellulose, powdered cellulose, lactose, dibasic calcium phosphate, tribasic calcium phosphate, starch, pregelatinized starch, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, dextrates, dextrin, dextrose, kaolin, maltodextrin, mannitol, sucrose, methyl dextrin and sorbitol or combination thereof; said diluent being preferably microcrystalline cellulose.

10. The pharmaceutical composition according to any of the preceding claims, wherein the disintegrant is selected from the group consisting of but not limited tocarboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, polacrilin potassium, sodium alginate and sodium starch glycolate or combination thereof; said disintegrant being preferably crospovidone.

11. The pharmaceutical composition according to any one of the preceding claims, wherein the lubricant is selected from the group consisting of but not limited tomagnesium stearate, aluminium stearate, sucrose stearate, stearic acid, talc, fumaric acid, palmitic acid, sodium stearyl fumarate, glyceryl monostearate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols or combination thereof; said lubricant being preferably magnesium stearate.

12. A process of preparing a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof according to any one of the preceding claims, comprising the steps of:

a) sifting cinacalcet or pharmaceutically acceptable salts thereof, binder(s) and pharmaceutical acceptable excipient(s);

b) mixing the sifted ingredients of step a) into rapid mixer granulator (RMG);

c) granulating the dry mixed material obtained in step b) with purified water;

d) drying the granules obtained in step c) in fluid bed dryer (FBD)until the loss on drying (LOD) ranging from 2.0 - 4.0 % w/w is achieved;

e) sifting the dried granules of step d) through sieve of mesh 30# ASTM and mixing; f) lubricating the granules and compressing into the tablets, and optionally coating the tablets.

13. A pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof having a particle size distribution D90 equal to or less than 20 μηι, D50 equal to or less than 10 μηι, and D10 equal to or less than 5 μηι and one or more pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof having a particle size distribution D90 equal to or less than 20 μηι, D50 equal to or less than 10 μηι, and Di0 equal to or less than 5 μιη and one or more binders in an amount of about 0.9% w/w or less, relative to the total weight of the composition.

15. The pharmaceutical composition according to claim 13 or 14, wherein the cinacalcet or pharmaceutically acceptable salts thereof has a particle size distribution D90 ranging from about 12 μηι -20 μηι, D50 ranging from about 5 μιη - 10 μηι and D10 ranging from about 2 μηι - 5 μηι.

16. The pharmaceutical composition according to any of the preceding claims, used for treating hyperparathyroidism, parathyroid carcinoma, hypercalcemia in a patient in need thereof.

Description:
PHARMACEUTICAL COMPOSITIONS COMPRISING CINACALCET

HYDROCHLORIDE AND ONE OR MORE BINDERS.

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients. Particularly the present invention relates to a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and one or more binders in an amount 0.9% w/w or less, relative to the total weight of composition. The present invention also relates to process for preparation of composition comprising cinacalcet or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Cinacalcet is calcimimetic drug which acts by allosteric activation of the calcium-sensing receptor and it is indicated for the treatment of secondary hyperparathyroidism and for the treatment of hypercalcemia in patients with parathyroid carcinoma.

The IUPAC name for cinacalcet is, (R)-N-[l-(l-naphthyl)ethyl]-3-[3- (trifluoromethyl)phenyl]propan-l -amine, is described in US patent no 6211244. The hydrochloride salt of cinacalcet is described chemically as N-[l-(R)-(-)-(l-naphthyl)ethyl]-3- [3(trifluoromethyl)phenyl]-l-aminopropane hydrochloride and has the following structural formula:

Cinacalcet hydrochloride is currently available in the market as tablet for oral use under the brand name Sensipar ® in USA and Mimpara ® inEurope market.

US7829595 and US9375405by Amgen, disclose cinacalcet composition containing a binder in an amount from about 1% to about 5% of total weight of composition. Inventive step and novelty of US7829595 and US9375405is limited only to the attributes claimed i.e. l-5%w/wof binder. Presence of colloidal silicon dioxide is an important and critical attribute of the composition claimed by US 7829595.

IN2250/CHE/2014 patent application by Appcure Labs, discloses a pharmaceutical composition comprising cinacalcet and its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, wherein the composition is free of binder. Though it discloses the composition to be free of binder, it does disclose the composition comprising a binder in the range from 5%-10% by weight relative to the total weight of the composition. Moreover, the invention discloses that 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, however, the specification is devoid of the experimental data, reproducibility and working of such a composition, excluding composition containing 0% w/w by weight of the binder. Thus, there is no teaching for the preparation of cinacalcet composition that contains binder at a lower concentration, especially less than 1% w/w of the composition. Furthermore product profile is always vulnerable to several factors and binder concentration is one of the most critical factor that determines attributes of dissolution and hence subsequent bioavailability. Thus the specification is inadequate and does not to enable or support the claims having binder from 0.1% to 1% w/w of composition. Further, the composition comprising combination of binders is not disclosed in this invention. The specification is silent on dissolution profile, stability, shelf life and the bioequivalence of the product of invention. Specification is inadequate as it does not describe similarity factor in comparison with the innovator composition. Further there is ambiguity if the compositions described by this application are bioequivalent. The composition that exhibits f2 more than 50% would not necessarily be bioequivalent. Therefore this invention is more relevant for the composition which is free of binder or which comprises much higher amount of 5-10% w/w by weight of binder relative to the total weight of the composition.

US20150306049 patent application by K.H.S. Pharma Holding GMBH, discloses a pharmaceutical composition of cinacalcet, wherein the composition comprises from 15 to 50% by weight cinacalcethydrochloride, from 30 to 80% by weight of one or more fillers and from 5.1% to 7% by weight of one or more binders. The specific formulation contains high percentage of binder that ismore than 5% w/w to the total weight of total composition. US20150328172 patent application bySynthon BV, discloses a pharmaceutical composition of cinacalcet, wherein the composition comprises a therapeutically effective dose of cinacalcet hydrochloride in an amount from 45% to 55% by weight;

from 30% to 50% of pregelatinized starch by weight based on the total weight of the composition; at least one binder in an amount of from 1 % to 5% by weight based on the total weight of the composition; a disintegrant in an amount of from 1 % to 10% by weight based on the total weight of the composition; a lubricant and a glidant in a total amount of from 0.05% to 5% by weight based on the total weight of the composition, and wherein the cinacalcet hydrochloride has a D 90 equal to or less than 30 μηι.

US2016143863 patent application by Jubilant Life Sciences Ltd., discloses an immediate release pharmaceutical composition, comprising from about 10 to 60% by weight cinacalcet or its pharmaceutically acceptable salts; from about 20.0 to 80.0% by weight of one or more diluents; and from about 1.0% to 8.0% by weight of one or more binders; wherein the immediate release pharmaceutical composition is substantially free of disintegrating agent.

IN35/CHE/2014 patent application by Hetero Labs Limited, discloses a binder free immediate release tablet composition comprising cinacalcet and one or more pharmaceutically acceptable excipients. This patent application also discloses that the invention is free of particular binders listed in the embodiment of IN35/CHE/2014 which are present in the range from 1% to 10% of the total composition. The patent application does not disclose any illustrative example of composition containing less than 1% binder.

WO2015136329PCT application by Abdi Ibrahim Ilac discloses a binder free pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salt thereof and at least one or more excipients, the composition is prepared by wet granulation. The application discloses that the composition is free of binding agent; specifically the composition does not contain polyvinylpyrrolidone or copovidone.

Binder free compositions produce weak bonding during granulation and it affects the dissolution profile and hence bioavailability of the product. Also use of more than 5% binder in the composition results in the risk of over-granulation and of tablet hardening during storage over a longer time. Moreover the presence of binder in a formulation in higher quantity also requires the addition of (strong) disintegrants for rapid dissolution. Hence there is unmet need to provide a more stable, reproducible, cost effective and bioequivalent composition comprising cinacalcethydrochloride..

OBJECT OF THE INVENTION

The main object of the present invention to provides a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and one or more binders in an amount of 0.9% w/w or less relative to the total weight of composition, wherein the composition is not free of binder and that the total amount of binder does not exceed 0.9% w/w relative to the total weight of the composition.

Yet another main object of the present invention to provide a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and one or more binders in an amount of 0.9% w/w or less, preferably about 0.7% w/w or less, more preferably about 0.4 % w/w or less, relative to the total weight of the composition.

Yet another object of the present invention is to provide a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and povidone in an amount of 0.9% w/w or less, preferably about 0.7% w/w or less, more preferably about 0.4 % w/w or less, relative to the total weight of the composition.

Yet another object of the present invention is to provide a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and multiple binders such that the total weight of the binder or concentration of binder is less than 0.9% w/w or less, preferably about 0.7% w/w or less relative to the total weight of the composition.

Yet another object of the present invention is to provide a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and povidone in an amount of 0.9% w/w or less, preferably about 0.7% w/w or less, more preferably about 0.4 % w/w or less, relative to the total weight of the composition and pregelatinized starch in an amount of 0.9% w/w or less, preferably about 0.7% w/w or less, more preferably about 0.4% w/w or less, relative to the total weight of the composition such that the total amount of binder does not exceed 0.9%w/w relative to the total weight of the composition.

Yet another object of the present invention is to provide a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and preferably povidone present in an amount of about 0.4 % w/w or less and pregelatinized starch present in an amount of about 0.4 % w/w or less, still more preferably povidone present in an amount of about 0.35 % w/w and pregelatinized starch present in an amount of about 0.35 % w/w relative to the total weight of the composition.

Yet another object of the present invention is to provide a process for preparing pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and one or more binders. The process can be selected from wet granulation, dry granulation, direct compression and compaction method.

SUMMARY OF THE INVENTION

In an aspect, the present invention relates to a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient.

In one aspect, the present invention provides a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and one or more binders in an amount of 0.9% w/wor less relative to the total weight of composition, wherein the composition is not free of binder and that the total amount of binder does not exceed 0.9% w/w relative to the total weight of the composition.

In another aspect, the present invention provides a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and povidone in an amount of 0.9% w/w or less, preferably about 0.7% w/w or less, more preferably about 0.4 % w/wor less, relative to the total weight of the composition.

In yet another aspect, the present invention provides a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and povidone in an amount of 0.9% w/w or less, preferably about 0.7% w/w or less, more preferably about 0.4 % w/wor less, relative to the total weight of the composition and pregelatinized starch in an amount of 0.9% w/w or less, preferably about 0.7% w/w or less, more preferably about 0.4 % w/wor less, relative to the total weight of the composition such that the total amount of binder does not exceed 0.9% w/w relative to the total weight of the composition.

In another aspect, the present invention provides the pharmaceutical composition of cinacalcet, wherein the composition comprises cinacalcet hydrochloride. Another aspect of the present invention provides a process for preparation of the pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.

In yet another aspect, the present invention provides a process for preparing pharmaceutical composition of the present invention, the process comprising:

a) mixing cinacalcet or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients;

b) granulating the mixture obtained in step a);

c) drying the granules obtained in step b) followed by blending, lubrication and compression; and

d) optionally coating the dosage form obtained in step c). BRIEF DESCRIPTION OF THE DRAWING

Features and advantages of the subject matter of the present invention as disclosed herein will become clearer from the detailed description of an embodiment thereof, with reference to the attached drawing, given purely by way of an example, in which:

Figure 1 is a flow chart for process for manufacturing of cinacalcet tablets 30 mg, 60 mg and 90 mg.

Figure 2 is a graph depicting a comparative dissolution profile of Reference - [Sensipar ] cinacalcet tablets 30 mg and Test - cinacalcet tablets 30 mg as per one of the embodiment of the present invention.

Figure 3 is graph depicting a comparative dissolution profile of Reference - [Sensipar ® ] Cinacalcet tablets 60 mg and Test - cinacalcet tablets 60 mg as per one of the embodiment of the present invention.

Figure 4 is a graph depicting a comparative dissolution profile of Reference - [Sensipar®]cinacalcet tablets 90 mg and Test - cinacalcet tablets 90 mg as per one of the embodiment of the present invention.

Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments. DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. The term "Cinacalcet" refers to cinacalcet in the form of any pharmaceutically acceptable salts or derivativesthereof, including polymorphs, hydrates, solvates or amorphous forms, preferably cinacalcet is used in cinacalcet hydrochloride salt form, more preferably cinacalcet is used in micronized cinacalcet hydrochloride salt form in the formulation of the present invention.

The term "composition" or 'pharmaceutical composition" or "dosage form" as used herein interchangeably includes solid dosage forms such as but not limited to granules, pellets, micropellets, spheres, cores, coated cores, pills, compressed tablets, mini tablets, layered tablets, beads, particles, capsules and the like, meant for oral administration.

The term "pharmaceutically acceptable" as used herein means that which is useful in

preparing a pharmaceutical composition that is generally safe and non-toxic.

The term "excipient" means a pharmacologically inactive compound such as a diluent, a disintegrant, a lubricant, a glidant, a binder comprised in a pharmaceutical product. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for human use. Reference to an excipient includes both one and more than one such excipients.

The term "tablet" is intended to encompass compressed pharmaceutical dosage forms of all shape and size, whether coated or uncoated.

The term "binder" as used herein means a substance that helps bind the active ingredient and other excipients together in a tablet. Binder ensures that tablets and granules can be formed having desired and required mechanical strength.

The term "not free of binder" as used herein means that the amount of binder present in the composition of the present invention is more than 0%.

The term "stable and reproducible" as used herein means that the composition is stable when stored at stability conditions as per ICH stability guidelines as well as it is stable during shelf life of the product. The process described herein produces a stable and bioequivalent formulation repeatedly.

The term "bioequivalent" as used herein means that a formulation that has the same pharmacologic potency and bioavailability as another formulation containing same active agent at the same dose. Two products or formulations containing the same active ingredient are bioequivalent if their rates and extents of absorption i.e., bioavailability are the same.

The term "micronization" means the production of particles having particle size distribution D90 equal to or less than 20 μηι, D50 equal to or less than 10 μηι, and D10 equal to or less than 5 μπι.

The term "reference" as used herein means the drug identified by the FDA as the drug product upon which an applicant relies in seeking approval of its Abbreviated New Drug Application

(ANDA).

The term "ASTM" as used herein means American Society for Testing and Materials.

The term "RH" as used herein means Relative humidity.

The term "LOD" as used herein means Loss on drying.

The term 'similarity factor' or '£2' as used herein refers to one way of comparing dissolution profiles of two different products. This model-independent mathematical approach compares the dissolution profile of the two products: test and reference or two strengths. Tests are recommended to be performed under the same test conditions. The dissolution time points for both the profiles should be the same. An f2 value of 50 or greater (50-100) ensures sameness or equivalence of two curves, and thus performance of the two products, in-vitro.

The present invention in a preferred embodiment provides a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and one or more binders in an amount of 0.9% w/w or less, relative to the total weight of the composition, wherein the composition is not free of binder. Inventors of the present invention surprisingly found that a composition comprising cinacalcethydrochloride and one or more binders in an amount of less than 0.9% w/w of total weight of the composition results into the stable, reproducible and bioequivalent product.

In one of the preferred embodiment, the pharmaceutical composition comprises cinacalcet hydrochloride as a preferred pharmaceutically acceptable salt of cinacalcet.

In a preferred embodiment, the pharmaceutical composition comprises micronized cinacalcet hydrochloride as a preferred pharmaceutically acceptable salt of cinacalcet.

In another preferred embodiment, the pharmaceutical composition of the present invention comprises cinacalcet hydrochloride crystal form I.

In an embodiment, micronized cinacalcet hydrochloride in accordance with the present invention is usually obtained by milling. In an embodiment, the milling is performed by using milling apparatus such as but not limited to ball mill, jet mill, pin mill, classifier mill, cross beater mill, disk mill, mortar grinder and rotor mill or any combination thereof.

In a preferred embodiment, the present invention relates to a tablet composition comprising a therapeutically effective dose of cinacalcet hydrochloride having particle size distribution D90 equal to or less than 20 μιη, preferablyD 90 ranging from about 12 μηι -20 μηι,Ο50 equal to or less than 10 μηι, preferably D50 ranging from about 5 μηι - 10 μηι and D10 equal to or less than 5 μηι, preferablyDio ranging from about 2 μηι - 5 μηι.

In an embodiment, the particle size of cinacalcet hydrochloride can be measured by techniques such as Malvern Mastersizer and a like.

In an embodiment, the present invention provides an oral dosage forms comprising cinacalcet hydrochloride and at least one pharmaceutically acceptable excipient(s).

In an embodiment, the present invention can be formulated in the form of solid dosage forms selected from but not limited to granules, pellets, micro-pellets, spheres, cores, coated cores, pills, compressed tablets, mini tablets, layered tablets, beads, particles, capsules and the like. In a preferred embodiment, the present invention can be formulated into immediate release tablets.

In an embodiment, the present invention provides the pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and one or more binders in an amount of 0.9% w/w or less, relative to the total weight of the composition, wherein the composition is not free of binder.

In an embodiment, the present invention provides the pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and one or more binders in an amount of 0.9% w/w or less, preferably about 0.7% w/w or less, more preferably about 0.4 % w/wor less, relative to the total weight of the composition.

In an embodiment, the present invention provides the pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and one binder in an amount of 0.9% w/w or less, relative to the total weight of the composition, wherein the composition is not free of binder. In a preferred embodiment, the present invention provides the pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and povidone in an amount of 0.9% w/w or less, preferably about 0.7% w/w or less, more preferably about 0.4 % w/wor less, relative to the total weight of the composition.

In an embodiment, the present invention provides the pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and multiple binders such that total weight of the binder or concentration of binder is less than 0.9% w/w or less, preferably about 0.7% w/w or less relative to the total weight of the composition.

In another embodiment the present invention provides the pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and povidone present in an amount of 0.9% w/w or less, preferably about 0.7% w/w or less, more preferably about 0.4 % w/wor less, relative to the total weight of the composition and pregelatinized starch in an amount of 0.9% w/w or less, preferably about 0.7% w/w or less, more preferably about 0.4 % w/wor less, relative to the total weight of the composition, such that the total amount of binder does not exceed 0.9%w/w relative to the total weight of the composition.

In an embodiment, the oral dosage form further comprises one or more of the following excipients such as but not limited to binders, disintegrants, glidants, lubricants, diluents, sweeteners, thickening agents, preservatives, flavoring agents, plasticizers and coloring agent or any combinations thereof.

Diluents or fillers include but are not limited to microcrystalline cellulose, microfine cellulose, powdered cellulose, lactose, dibasic calcium phosphate, tribasic calcium phosphate, starch, pregelatinized starch, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, dextrates, dextrin, dextrose, kaolin, maltodextrin, mannitol, sucrose, methyl dextrin and sorbitol or any combination thereof.

In a preferred embodiment of the present invention diluents used is microcrystalline cellulose, pregelatinized starch or any combination thereof.

The composition of the present invention preferably comprises from about 50 % to about 90% of one or more diluents by weight based on the total weight of the composition.

Binders include but are not limited to, polyvinylpyrrolidone (povidone, PVP); polyethylene glycol (PEG); cross-linked polyvinylpyrrolidone; cellulose derivatives including hydroxymethyl cellulose, hydroxypropylcellulose, carboxy- methylcellulose sodium, ethyl cellulose, hydroxylethylcellose, and hydroxypropylmethylcellulose; sucrose; alginic acid or sodium alginate; carbomer; cottonseed oil; dextrin; dextrose; guar gum; hydrogenated vegetable oil type I; magnesium aluminium silicate; maltodextrin; maltose; polydextrose; polyethylene oxide stearic acid and zein or combination thereof.

One or more binders are preferably used in an amount of from about 0.2 % to about0.7 %by weight based on the total weight of the composition.

A preferred binder is povidone or various commercially available grades thereof.

Disintegrants include, but are not limited to carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, polacrilin potassium, sodium alginate and sodium starch glycolate or any combination thereof.

Disintegrants are preferably used in an amount of from about 0.5 % to about 6.0 % by weight based on the total weight of the composition.

A preferred disintegrant is crospovidone.

Lubricants include, but are not limited to magnesium stearate, aluminium stearate, sucrose stearate, stearic acid, talc, fumaric acid, palmitic acid, sodium stearyl fumarate, glyceryl monostearate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols or combination thereof.

Lubricants are preferably used in an amount of from about 0.1% to about 2.0% by weight based on the total weight of the composition.

In an embodiment of the present invention the pharmaceutically acceptable excipients to be used in accordance with the present invention can be used only intragranularly, only extragranularly or both.

In one of the preferred embodiment, the tablet of the present application optionally be coated with a film coat, which provides an aesthetic appeal. Film coat also provides moisture protection, taste masking etc.

Film coating material suitable for present application include but not limited to polyvinyl alcohol, hydroxypropyl methylcellulose,carboxymethyl cellulose and like. Preferably the coating is carried out using coating agents for example Opadry®. Preferred Opadry® isOpadry II Green which contains hypromellose, titanium dioxide, lactose monohydrate,triacetin, yellow iron oxide, FD&C Blue #21 indigo carmine aluminum lake. In yet another embodiment, the present invention provides a stable cinacalcet hydrochloride composition when subjected to 40±2°C/ 75±5% RH accelerated stability condition.

In an embodiment of the invention, the pharmaceutical compositions as described herein may be prepared by processes known to a person having ordinary skill in the art of pharmaceutical technology such as direct compression, wet granulation, dry granulation or melt granulation. In one embodiment the present invention provides a process for preparation of a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the process comprises steps of:

a) mixing cinacalcet or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients;

b) granulating the mixture obtained in step a);

c) drying the granules obtained in step b) followed by blending, lubrication and compression; and

d) optionally coating the dosage form obtained in step c).

In one embodiment the present invention provides a process of preparing a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salts thereof according to any one of the preceding claims, comprising the steps of:

a) sifting cinacalcet or pharmaceutically acceptable salts thereof, binder(s) and pharmaceutical acceptable excipient(s);

b) mixing the sifted ingredients of step a) into rapid mixer grinder (RMG);

c) granulating the dry mixed material obtained in step b) with purified water;

d) drying the granules obtained in step c) in fluid bed dryer (FBD)until the loss on drying (LOD) ranging from 2.0 - 4.0 % w/w is achieved;

e) sifting the dried granules of step d) through sieve of mesh 30# ASTM and mixing;

f) lubricating the granules and compressing into the tablets; and optionally coating the tablets.

In a preferred embodiment the present invention provides a process for preparation of a pharmaceutical composition comprising cinacalcet or pharmaceutically acceptable salt thereof by wet granulation process, wherein the process comprises the steps of:

a) sifting cinacalcet hydrochloride, one or more diluent, one or more binders through # 40 sieve; b) sifting a disintegrant through # 30 sieve;

c) transferring the sifted ingredients of step a) and b) in rapid mixer granulator (RMG) and mixing for 10 minutes to prepare dry mix;

d) granulating the dry mix of step c) with purified water;

e) drying the granules obtained in step d) in fluid bed dryer (FBD) to achieve the required loss on drying (LOD) ranging from 2.0-4.0 % w/w is achieved;

f) sifting the dried granules of step e) through # 30 ASTM sieve using vibrosifter and mixing from 10 minutes;

g) lubricating the sifted granules of step f)to obtain lubricated blend;

h) compressing the lubricated blend of step g) to obtain tablets; and

i) optionally coating the compressed tablets of step h).

In an embodiment, the pharmaceutical composition of the present invention comprises about 30 mg to about 90 mg cinacalcet as a free base.

In one of the preferred embodiment the pharmaceutical composition comprises about33mg to about 99 mg of cinacalcet hydrochloride equivalent to the free base.

In yet another embodiment, the composition of the present invention is useful for the treatment of at least one disease selected from hyperparathyroidism, parathyroid carcinoma, hypercalcemia in a patient in need thereof.

EXAMPLES

The present invention will be described in more detail by way of the following illustrative examples. It should be understood, however, that the present invention or the examples provided herein below are not limited to the specific details, components, conditions described in these examples, and the scope of the present invention is not limited thereto.

Example 1:

Composition comprising 30 mg, 60 mg, and 90 mg of Cinacalcet Hydrochloride and preparation of tablet dosage form there from:

Table 1 : Composition comprising 30 mg, 60 mg, and 90 mg of Cinacalcet Hydrochloride

Sr. Ingredients Quantity (mg/Tab)

No. 30 mg 60 mg 90 mg

Core Tablet

Dry Mix 1 Cinacalcet Hydrochloride 33.06 * 66.12 99.18"""

2 Pregelatinized Starch 0.65 1.3 1.95

3 Microcrystalline Cellulose 135.66 271.32 406.98

4 Crospovidone 9.08 18.16 27.24

5 Povidone K29/30 0.65 1.3 1.95

Granulating Agent

6 Purified water q.s q.s q.s

Lubrication

7 Magnesium Stearate 0.9 1.8 2.7

Total theoretical weight of core tablet (mg) 180 360 540

Film Coating

8 Opadry Green 5.4 10.8 16.2

9 Purified water q.s. q.s q.s

Total theoretical weight of coated tablet (mg) 185.4 370.8 556.2

33.06 mg of Cinacalcet Hydrochloride is equivalent to 30 mg Cinacalcet;

66.12 mg of Cinacalcet Hydrochloride is equivalent to 60 mg Cinacalcet and

* ** 99.18 mg of Cinacalcet Hydrochloride is equivalent to 90 mg Cinacalcet

Manufacturing Procedure:

a) All the ingredients as per unit formula were dispensed maintaining the temperature less than

25°C and RH less than 50%.

b) Cinacalcet Hydrochloride and Microcrystalline Cellulose were co sifted through mesh 40#

ASTM.

c) Pregelatinized Starch and Povidone K-29/32 were co sifted through 40# ASTM.

d) Crospovidone was sifted through 30# ASTM.

e) Sifted ingredients of step b), c) and d) were transferred into RMG & mixed for 10 minutes. f) The contents of step e) were granulated with purified water.

g) The granules of step f) were dried in FBD till the desired LOD (2.0 - 4.0 % w/w) was achieved.

h) Dried granules were passed through mesh 30# ASTM.

i) The sifted granules were transferred into blender and mixed for 10 min at 16 rpm.

j) The content of step i) was lubricated using sifted Magnesium Stearate (mesh 40# ASTM) for 3 min at 16 rpm.

k) The lubricated blend was compressed into tablets for all strengths.

1) The punch dimensions for 30 mg strength, 9.70 x 6.10 mm oval shape, standard concave. m) The punch dimensions for 60 mg strength, 12.40 x 7.80 mm oval shape, standard concave, n) The punch dimensions for 90mg strength, 14.20 x 8.90mm oval shape, standard concave, o) Film coating solution: Opadry Green was dispersed in purified water under continuous stirring for 45 min.

p) The compressed tablets were coated using coating solution.

Example 2

Composition comprising 30 mg, 60 mg, and 90 mg of Cinacalcet Hydrochloride and preparation of tablet dosage form there from:

Table 2: Composition comprising 30 mg, 60 mg, and 90 mg of Cinacalcet Hydrochloride

Manufacturing procedure:

a) Cinacalcet hydrochloride, microcrystalline cellulose, pregelatinized Starch 1500, crospovidone and povidone were sifted through # 40 sieve.

b) the above sifted ingredients were transferred in rapid mixer granulator (RMG) and mixed. c) Granulation was carried out with purified water.

d) The wet mass was dried in Fluid bed dryer to achieve the LOD of NMT 2% w/w.

e) The dried granules of step d) were sifted through # 30 sieve.

f) The sifted granules were lubricated by using sodium stearyl fumarate. g) The lubricated blend was compressed using specified punch.

h) The compressed tablets were coated using Opadry II Green coating solution.

Example 3

Micronization of Cinacalcet Hydrochloride:

Micronization of cinacalcet hydrochloride was carried out by Jet Milling. Particle size of micronized cinacalcet hydrochloride was measured with Malvern Mastersizer. Micronized cinacalcet hydrochloride was found to have particle size distribution D90 equal to or less than 20 μηι, D50 equal to or less than 10 μιη, and D10 equal to or less than 5 μιη as can be seen below Table 1 showing the particle size distribution of different batches of the micronized cinacalcet hydrochloride.

Table 3 : Particle size distribution of different batches of the micronized cinacalcet hydrochloride

Comparison of in-vitro dissolution profile:

The tablets of cinacalcet hydrochloride prepared as per the composition of Example 1 were subjected to dissolution studies.

Table 4:Provides comparative dissolution profiles of Sensipar® 30mg, 60mg &90 mg (RLD)herein referred as 'reference' versus cinacalcet tablets 30mg, 60mg &90 mg as per composition of Example l,herein referred to as 'test'in 900 ml 0.05 N HC1, apparatus USP type II (Paddle), 75 RPM, at 37 ± 0.5°C.

Table 4: Dissolution data of cinacalcet tablets 30mg, 60mg and 90mg [Reference vs Test]

Method Time Cinacalcet Cinacalcet tablets Cinacalcet tablets

points tablets 30mg 60mg 90mg

imirmtesfi Reference Test Reference Test Reference Test

Paddle, 10 86 78 84 80 84 77

75 rpm, 15 93 85 90 87 90 84

900 mL, 20 97 88 95 90 94 87

0.05N 30 101 93 97 94 98 91

HC1 45 103 96 99 98 99 95

F2 value 54.61 72.1 5 59.73

Stability data:

Table 5, Table 6andTable 7:Provides initial 1M, 2M, 3M & 6M accelerated stability data of cinacalcet tablets30mg, 60mg and 90 mg as per composition of example 1 packed in HDPE container.

Table 5: Accelerated stability data of cinacalcet tablets 30mg [Test product-HDPE pack]

40°C/ 75%RH

Sr. Parameters Limits Initial

1M 2M 3M 6M

Light green Light green

coloured, film coloured,

coated, oval film coated,

shaped tablets oval shaped

tablets Com Compl Compli Compl

1. Description debossed with

debossed plies ies es ies '257' on one side with '257' on

and 'U' on other one side and

side. 'U' on other

side.

NLT 75%(Q) of

the labelled

amount of

2. 96 94 98 90 90

% Dissolution Cinacalcet is

dissolved in 45

min.

3. Related substances (%)

Any individual

a. unspecified NMT 0.20% 0.06 0.06 0.06 0.06 0.06

impurity

Total Impurities

(Sum of all the

b. individual NMT O.60% 0.06 0.06 0.06 0.06 0.06

impurities>0.05 Between 90% to

4. Assay 110% of label 99.9 98.7 99.7 101.3 98.0

claim

Table 6: Accelerated stability data of cinacalcet tablets 60mg [Test product-HDPE pack]

Table 7: Accelerated stability data of cinacalcet tablets 90mg [Test product-HDPE pack]

Sr. Parameters Limits Initial 40°C/ 75%RH

1M 2M 3M 6M

Light green Light green

coloured, film coloured, film

coated, oval coated, oval

shaped tablets Compile Compile Compile

1. Description shaped tablets Complies

debossed with debossed with s s s

'259' on one

'259' on one side

side and 'U' on

and 'U' on other other side. side.

NLT 75%(Q) of

the labelled

% Dissolution amount of

2. 95 97 90 92 94

Cinacalcet is

dissolved in 45

min.

3. Related substances (%)

Any individual

a. unspecified NMT 0.20% 0.06 0.06 0.07 0.06 0.06 impurity

Total

Impurities

(Sum of all

b. NMT O.60% 0.06 0.06 0.07 0.06 0.06 the individual

impurities>0.0

Between 90% to

4. Assay 110 % of label 101.1 100.3 100.1 98.2 96.5 claim

Table 8: Bioequivalence Summary Table of Cmax:

Treatment Ratio 90%CI

Test product 90 mg

89.88 ( 81.37, 99.28)

REFERENCE Product 90mg

Table 9: Bioequivalence Summary Table of AUC 0-t

Treatment Ratio 90%CI

Test product 90 mg

89.85 (83.52, 96.67)

REFERENCE Product

Table 10: Bioequivalence Summary Table of AUC 0-inf

Treatment Ratio 90%CI

Test product 90 mg

90.04 (83.89, 96.63)

REFERENCE Product