FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions of cinacalcet or pharmaceutically acceptable salts thereof. Methods of preparing such compositions are also provided.
BACKGROUND OF THE INVENTION
Cinacalcet is a calcium receptor-active compound which is approved for the treatment of secondary hyperparathyroidism resulting from chronic kidney insufficiency and for the treatment of hypercalcaemia in patients with parathyroid carcinoma. Chemically, Cinacalcet HCI is (R)-N-[l-(l-naphthyl)ethyl]-3-[3- (trifluoromethyl)phenyl]propan-l-amine Hydrochloride and has the following structure:
Commercially, it is available as Sensipar in the USA.
Synthesis of cinacalcet is disclosed in WO 96/12697. The manufacturing process of the most stable polymorphic form I of cinacalcet HCI is disclosed in WO 2007/62147. Marketed tablets with immediate release of the drug are basically described in patent application WO 2005/034928.
WO 2005/034928 reports that calcium receptor-active compounds may be insoluble or sparingly soluble in water, particularly in their non-ionized state. For example, cinacalcet has solubility in water of less than about 1 [mu]g/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. Such limited solubility can reduce the number of formulation and delivery options available for these calcium receptor-active compounds. Limited water solubility can also result in low bioavailability of the compounds.
WO 2005/034928 also discloses a manufacturing process for cinacalcet formulations, indicating several "Critical Process Controls", i.e. parameters such as water level, impeller speed and water spray rate (during granulation), and blend time, tablet press speed, tablet weight, thickness, hardness and friability (during compression) etc. that might be adapted in order to achieve a desired result (i.e. meet the dissolution characteristics according to standards like USP 26/NF 21, chapter 711).
Various techniques have been disclosed in prior art to improve dissolution of cinacalcet.
WO 2005/034928 discloses micronized API. Additionally, it discloses use of specific excipients like microcrystalline cellulose and starch in a particular ratio.
US2012009258 discloses use of an intermediate that is obtainable by jointly compacting cinacalcet and hydrophilising agent, wherein the tablets exhibit in particular a bimodal pore distribution.
US2010168247 discloses a composition comprising a solid composite of cinacalcet in intimate association with at least one carrier prepared by solid solution technique.
WO2014207691 discloses disintegrant free composition of cinacalcet.
WO2014072346 discloses use of 5.1% to 7% by weight of povidone for improved dissolution.

Surprisingly, the inventors of present invention, while working on cinacalcet compositions, found that dissolution aspects may be improved by using low substituted hydroxypropyl cellulose.
SUMMARY OF THE INVENTION
The present specification relates to pharmaceutical compositions of cinacalcet or pharmaceutically acceptable salts thereof and method of preparation of such compositions.
In one aspect, the present specification relates to pharmaceutical compositions of cinacalcet or pharmaceutically acceptable salts thereof comprising low substituted hydroxypropyl cellulose.
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 present specification relates to pharmaceutical compositions of cinacalcet or pharmaceutically acceptable salts thereof and method of preparation of such compositions.
In one aspect, the present specification relates to pharmaceutical compositions of cinacalcet or pharmaceutically acceptable salts thereof comprising low substituted hydroxypropyl cellulose.
The cinacalcet HC1 of the present invention can be in various forms, such as amorphous, crystalline, and mixtures thereof.

Low-substituted hydroxypropyl cellulose is widely used in oral solid-dosage forms. It is primarily used as a binder. Low-substituted hydroxypropyl celluloses is available in various grades for example LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.). The typical content of low-substituted hydroxypropyl cellulose in a formulation is approximately 5-50% by weight.
In one of the embodiments, the present specification relates to pharmaceutical composition of cinacalcet or pharmaceutically acceptable salts thereof comprising low substituted hydroxypropyl cellulose and one or more diluents, one or more additional binder, and optionally a disintegrant.
The pharmaceutical compositions of present specification comprises diluents selected from the group comprising microcrystalline cellulose, silicified MCC, microfine cellulose, lactose, starch, mannitol, sorbitol, dextrates, dextrose, dibasic calcium phosphate.
The diluents are in the range of 30 to 80% by weight of the composition, e.g. in the range of 40 to 70% by weight of the composition, e.g. in the range of 50 to 60% by weight of the composition.
The pharmaceutical compositions of present specification comprises one or more additional binder selected from acacia, guar gum, alginic acid, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hypromellose, carboxymethyl cellulose sodium, polyvinylpyrrolidone.
The binder can be intragranular, intergranular, or mixtures thereof.

Total amount of binder is between 7.1 % to 35% by weight of the composition, e.g. in the range of 10 to 30% by weight of the composition, e.g. in the range of 12 to 25% by weight of the composition, e.g. in the range of 15-20 % by weight of the composition.
The pharmaceutical compositions of present specification may optionally comprise a disintegrant. The suitable disintegrants include but not limited to croscarmellose sodium, carboxymethyl cellulose sodium, crospovidone and sodium starch glycolate. Amount of disintegrant is in the range of 1.0% to 5.0% w/w.
The pharmaceutical compositions of the present specification may further comprise other pharmaceutical ingredients such as lubricants for example magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, hygrogenated vegetable oil, glycerine fumerate and glidants such as colloidal silicon dioxide, and mixtures thereof.
The pharmaceutical compositions of the present specification may further comprise glidants and lubricants in the range of 0.05% to 5% by weight of composition, e.g. in the range of 0.1% to 3% by weight of composition.
The pharmaceutical compositions of the present specification may be coated or uncoated.
The compositions disclosed herein can be in a form chosen from, for example, tablets, capsules, and powders.
The pharmaceutical formulations of the present specification may be prepared by suitable conventional process. For example,

a) Mixing cinacalcet HCI, the binders, a portion of the diluents and optionally disintegrants to form an intragranular phase;
(b) Wet granulating the intragranular phase to form wet granules;
(c) Drying the wet granules;
(d) Sieving & mixing the remaining portions of diluents, glidants, lubricants to form an extragranular phase;
(e) Blending the extragranular phase with the dried granules to form the final blend which is used for production of the tablets.
The pharmaceutical formulations of the present specification were stable during accelerated and long term stability studies.
The following experiments are provided to exemplarily illustrate various aspects of the inventive subject matter presented herein. However, it should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein.

Sr. No. Ingredients Ex.1 Ex.2 Ex.3 Ex.4

%W/W %W/W % W/W % W/W
1 Cinacalcet Hydrochloride 18 18 18 18
2 Lactose monohydrate 19 18 19 18
3 Microcrystalline cellulose 30 30 20 30
4 Low substituted hydroxy Propyl cellulose 10 15 20 13
5 Povidone - 3 5
Granulation
6 Purified water Qs Qs Qs Qs
Extra granular
7 Microcrystalline cellulose 18 7 18 5
8 Povidone - 4 - 6

9
Colloidal silicon dioxide 0.5 0.5 0.5 0.5
10 Magnesium stearate 0.5 0.5 0.5 0.5
Coating
11 Opadry Green 4 4 4 4
12 Purified water Qs Qs Qs Qs
The above composition examples 1 & 3 are prepared by following method: Cinacalcet Hydrochloride mixed with low substituted hydroxypropyl cellulose, lactose and a portion of microcrystalline cellulose. This mixture is granulated with water in rapid mixer granulator. Granules then dried until the LOD of the granules is less than 1-2.5% at 105°C. Dried granules further blended with remaining portion of MCC and colloidal silicon dioxide. The blend is lubricated with magnesium stearate. Lubricated blend further compressed using suitable dies and punches. Compressed. tablets were coated with Opadry green solution until the desired weight is achieved.
The compositions of Example 2 & 4 are prepared by similar process as that of Example 1 & 3; but additionally comprises povidone.
The pharmaceutical compositions of present specification were characterized by dissolution studies compiled in (Table 1)

Test Example Example 1 Example 2
Time (min) Avg % drug release Avg % drug release
5 76.9 43.3
10 89.2 88.8
15 94.6 94.9
20 95.3 95.2
30 97 96.7
45 96.6 96.4

CLAIMS
1) A pharmaceutical composition of cinacalcet or pharmaceutically acceptable salts thereof comprising low substituted hydroxylpropyl cellulose.
2) The pharmaceutical composition according to claim 1, further comprises one or more diluents, one or more additional binder and optionally a disintegrant.
3) The pharmaceutical composition according to claim 2, wherein one or more diluents selected from microcrystallme cellulose, silicified MCC, microfine cellulose, lactose, starch, mannitol, sorbitol, dextrates, dextrose, dibasic calcium phosphate.
4) The pharmaceutical composition according to claim 2, wherein one or more disintegrant selected from croscarmellose sodium, carboxymethyl cellulose sodium, crospovidone and sodium starch glycolate.
5) The pharmaceutical composition according to claim 2, wherein one or more additional binder selected from acacia, guar gum, alginic acid, methylceliulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium, povidone.
6) The pharmaceutical composition according to claim 5, wherein the total amount of binder is more than 7% by weight of the composition.
7) The pharmaceutical composition according to claim 6, wherein the total amount of binder is between 7.1 to 25% by weight of the composition.