CLIAMS:1. A process for preparing a solid oral pharmaceutical composition of cinacalcet or salts thereof, which process comprises steps of:
(a) preparing a core comprising cinacalcet or salts thereof with one or more pharmaceutically acceptable excipients other than disintegrating agent; and
(b) coating the core with a composition comprising one or more film forming polymers.

2. The process for preparing a solid oral pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipients are selected from diluents, binders, lubricants, film forming polymers or mixtures thereof.

3. The process for preparing a solid oral pharmaceutical composition of claim 3, wherein the ratio of the amount of cinacalcet to diluents in the composition ranges from about 1:0.1 to about 1:1.

4. The process for preparing a solid oral pharmaceutical composition of claim 3, wherein the ratio of the amount of cinacalcet to binder in the composition ranges from about 1:1 to about 1:10.

5. The process for preparing a solid oral pharmaceutical composition of claim 1 or 2 wherein the pharmaceutically acceptable excipients comprise microcrystalline cellulose, polyvinylpyrrolidone, magnesium stearate and hydroxypropyl methylcellulose.

6. A process for preparing a solid oral pharmaceutical composition of cinacalcet or salts thereof comprises steps of:
(a) granulating cinacalcet or salts thereof with one or more pharmaceutically acceptable excipients, which exclude any disintegrating agent;
(b) optionally lubricating the granules obtained in step (a) to form a lubricated blend;
(c) compressing the granules obtained in step (a) or the lubricated blend obtained in step (b) to form a core comprising cinacalcet or salts thereof, and
(d) optionally coating the core obtained in step (c) with a composition comprising one or more film forming polymers.

7. The process for preparing solid oral pharmaceutical composition of claim 1 or 6, wherein the composition is in the form of a tablet, a capsule or granules filed in sachet.

8. A process for preparing tablet of cinacalcet or salts thereof comprises steps of:
(a) preparing plurality of granules comprising cinacalcet or salts thereof with one or more pharmaceutically acceptable excipients, which exclude any disintegrating agent,
(b) compressing the granules obtained in step (a) to form a tablet, and
(c) coating the tablet with a composition comprising one or more film forming polymers.
,TagSPECI:DESCRIPTION

The present invention relates to process of preparing solid oral pharmaceutical compositions comprising cinacalcet or salts thereof. In particular, the present invention relates to process of preparing solid oral pharmaceutical compositions comprising cinacalcet or salts thereof and at least one pharmaceutically acceptable excipient other than disintegrating agent. The invention further relates to a method of treating secondary hyperparathyroidism and hypercalcemia in patients in need thereof by using such compositions.

Calcium receptor-active compounds, especially calcimimetic agents, are small organic molecules that act as allosteric activators of calcium sensing receptors. At the parathyroid cell, they lower the threshold of receptor activation by extra-cellular calcium ions and diminish parathyroid hormone secretion. Cinacalcet is one of the first calcimimetic agents in its class to have reached the marketplace successfully.

Its empirical formula is C22H22F3N.HCl with a molecular weight of 393.9g/mol (hydrochloride salt) and 357.4g/mol (free base). It has one chiral center having an R-absolute configuration. The R-enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity.

Cinacalcet is marketed as a tablet dosage form under the brand name Sensipar® in US and Mimpara® in Europe and both products contains the hydrochloride salt of cinacalcet. Cinacalcet tablets are available in strengths of 30 mg, 60 mg, and 90 mg of cinacalcet as the free base equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively). It is used for the treatment of secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) on dialysis and for hypercalcemia in patients with parathyroid carcinoma and for severe hypercalcemia in patients with primary HPT who are unable to undergo parathyroidectomy.
The hydrochloride salt of cinacalcet is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol and slightly soluble in water. Cinacalcet is described chemically as N-[1-(R)-(-)-(1-naphthyl) ethyl]-3-[3(trifluoromethyl) phenyl]-1-aminopropane hydrochloride and has the following structural formula:

PCT Application Publication No. WO 2008064202 discloses modified-release pharmaceutical formulations comprising cinacalcet.

U.S. Patent Application No. 20080181959 discloses the solid composites of cinacalcet and processes for preparing the solid composites having immediate and controlled-release.

PCT Application No. WO 2013107503 discloses a novel method for producing pharmaceutical compositions of cinacalcet or pharmaceutically acceptable salts thereof in substantially dry powder form, which is suitable for direct compression and for providing improved features of dissolution and compressibility.

U.S. Patent No. 7,829,595 discloses a pharmaceutical composition comprising cinacalcet and at least one pharmaceutically acceptable excipient, wherein the composition has a controlled dissolution profile.

The prior arts suggest that tablets of cinacalcet prepared so far use conventional excipients from general basic category of diluent, binder, disintegrating agent and lubricant.

In the present invention, Inventors have provided an improved composition of cinacalcet or salts thereof by reducing the excipient load, as it is always desirable to reduce the excess load of excipient from the composition, provided its release profile and stability remains unaltered.

Inventors of the present invention have surprisingly found that it is possible to formulate a composition devoid of disintegrating agent that exhibits desired release profile, and more particularly exhibit a similar dissolution profile as compared to currently marketed cinacalcet tablets containing disintegrating agents. Such composition, moreover, may remain stable during the period intended for use.

In one general aspect, there is provided a solid oral pharmaceutical composition comprising:
(a) cinacalcet or salts thereof, and
(b) at least one pharmaceutically acceptable excipient;
wherein the composition is devoid of any disintegrating agent.

In another general aspect, there is provided a tablet comprising:
(a) cinacalcet or salts thereof, and
(b) at least one pharmaceutically acceptable excipient suitable for the preparation of tablets;
wherein the tablet is devoid of any disintegrating agent.

In another general aspect, there is provided a tablet comprising:
(a) cinacalcet or salts thereof;
(b) at least one pharmaceutically acceptable excipient suitable for the preparation of tablets, and
(c) a coating comprising one or more layers comprising one or more film forming polymers;
wherein the tablet is devoid of any disintegrating agent.

In another general aspect, there is provided a tablet comprising:
(a) cinacalcet or salts thereof;
(b) one or more pharmaceutically acceptable excipients selected from the category of diluent, binder, and lubricant suitable for preparing a tablet, and
(c) a coating comprising one or more layers comprising one or more film forming polymers;
wherein the tablet is devoid of any disintegrating agent.

In another general aspect, there is provided a solid oral pharmaceutical composition comprising:
(a) cinacalcet or salts thereof;
(b) microcrystalline cellulose;
(c) polyvinylpyrrolidone;
(d) magnesium stearate, and
(e) a coating comprising one or more layers of hydroxypropyl methyl cellulose; wherein the composition is devoid of any disintegrating agent.

In another general aspect, there is provided a solid oral pharmaceutical composition comprising:
(a) about 5 to 50% w/w of cinacalcet or salts thereof;
(b) about 10 to 60% w/w of microcrystalline cellulose;
(c) about 2 to 12% w/w of polyvinylpyrrolidone;
(d) about 0.1 to 2% w/w magnesium stearate, and
(e) a coating comprising about 0.5 to 4% w/w hydroxypropyl methylcellulose;
wherein the composition is devoid of any disintegrating agent.

In another general aspect, there is provided a solid oral pharmaceutical composition comprising:
(a) 99.18 mg of cinacalcet or salts thereof;
(b) 213.42 mg of microcrystalline cellulose;
(c) 36 mg of polyvinylpyrrolidone;
(d) 5.40 mg of magnesium stearate, and
(e) a coating layer comprising 5 mg of hydroxypropyl methylcellulose;
wherein the composition is devoid of any disintegrating agent.

In another general aspect, there is provided a solid oral pharmaceutical composition of cinacalcet or salts thereof wherein the ratio of the amount of cinacalcet to diluents in the composition ranges from about 1:0.1 to about 1:1.

The diluents may be present either partly intra and partly extragranular or fully in either intragranular or extragranular part of the composition.

In another general aspect, there is provided a solid oral pharmaceutical composition of cinacalcet or salts thereof wherein the ratio of the amount of cinacalcet to binder in the composition ranges from about 1:1 to about 1:10.

One or more pharmaceutically acceptable excipients that may be present in the cinacalcet composition comprises at least one diluent, at least one binder, and at least one lubricant, and optionally at least one film forming polymer in the form of a coating.

The amount of diluent may vary within a range of from about 50 to 90% w/w, preferably 60 to 80% w/w by total weight of the composition.

According to the present invention, the amount of binder may vary within a range of from about 1 to 30% w/w, preferably 1 to 20% w/w, in particular 1 to 10% w/w by weight based on the total weight of the composition.

The amount of lubricant may vary within a range of from about 0.1 to 5% w/w, e.g. 0.5 to 2% w/w by weight based on the total weight of the composition.

The amount of coating may vary from about 1 to 5% w/w, preferably from 1.5 to 2.5% w/w by weight based on the total weight of the composition.

In another general aspect, there is provided a tablet comprising cinacalcet or salts thereof, one or more diluents in a total amount of about 50 to 90% w/w, one or more binders in a total amount of about 1 to 20% w/w, and one or more lubricants in a total amount of about 0.5 to 2% w/w by weight based on the total weight of the tablet; wherein the tablet is devoid of any disintegrating agent.

In another general aspect, the composition releases more than 85% and preferably more than 90% by weight of the initial amount of cinacalcet within 30 minutes when measured using USP type II dissolution apparatus in 900 ml of 0.05N hydrochloric acid at a temperature of about 37°C and at a rotation speed of about 75 rpm.

In another general aspect, there is provided a solid oral pharmaceutical composition which retains at least 90% by weight of the total content of cinacalcet or salts thereof after storing at 40°C and 75% relative humidity over a period of at least 3 months.

In another general aspect, there is provided a process of preparing a solid oral pharmaceutical composition of cinacalcet or salts thereof, which process comprises steps of:
(a) granulating cinacalcet or salts thereof with one or more pharmaceutically acceptable excipients, which exclude any disintegrating agent;
(b) optionally lubricating the granules obtained in step (a) to form a lubricated blend;
(c) compressing the granules obtained in step (a) or the lubricated blend obtained in step (b) to form a core comprising cinacalcet or salts thereof, and
(d) optionally coating the core obtained in step (c) with a composition comprising one or more film forming polymers.

In another general aspect, there is provided a process of preparing tablet of cinacalcet or salts thereof, which process comprises steps of:
(a) preparing plurality of granules comprising cinacalcet or salts thereof with one or more pharmaceutically acceptable excipients, which exclude any disintegrating agent,
(b) compressing the granules obtained in step (a) to form a tablet, and
(c) coating the tablet with a composition comprising one or more film forming polymers.

In another general aspect, there is provided a method for treating secondary hyperparathyroidism and hypercalcemia in patients in need thereof by administering solid oral pharmaceutical composition comprising cinacalcet or salts thereof as substantially described throughout the specification.

The absolute amounts of each excipient and the amounts relative to other excipients are similarly dependent on the desired properties of the tablet and may also be chosen by routine experimentation. For example, the tablet may be chosen to exhibit accelerated and/or delayed release of cinacalcet with or without quantitative control of the release of cinacalcet. Preferably the tablet is chosen to exhibit immediate release of the cinacalcet.

In accordance with the present invention, it has now unexpectedly been found that stable and convenient compositions, such as tablets, comprising cinacalcet which do not contain any disintegrating agent may be obtained.

Thus, with an objective to provide improved formulation of cinacalcet, inventors of the present invention have formulated a solid oral pharmaceutical composition devoid of disintegrating agent that can exhibit desired release profile or a similar dissolution profile compared to the currently marketed cinacalcet tablets containing disintegrating agents.

In an embodiment, the solid oral pharmaceutical composition comprises:
(a) cinacalcet or salts thereof, and
(b) at least one pharmaceutically acceptable excipient;
wherein the composition is devoid of any disintegrating agent.

In another embodiment, the solid oral pharmaceutical composition comprises:
(a) cinacalcet or salts thereof;
(b) one or more pharmaceutically acceptable excipients selected from the category of diluent, binder, and lubricant, and
(c) a coating comprising one or more film forming polymers;
wherein the composition is devoid of any disintegrating agent.

The solid oral pharmaceutical composition of the present invention may be prepared in the form of a tablet, a capsule, a mini-tablet, granules, pellets and a caplet. Particularly preferred for is the tablet.

The solid oral composition of the present invention may be prepared by various methods known to the person skilled in the art, including wet granulation, dry granulation, direct compression and slugging. Particularly preferred method includes wet-granulation followed by compression.

A solid bulk of granulate mass, which is necessary for manufacturing tablets, can be manufactured using two main processes, wet granulation or dry granulation. Tablets may also be manufactured using direct compression. Direct compression relates to the tableting process itself rather than preparation of the starting material.

In wet granulation, components are typically mixed and granulated using a wet binder. The wet granulates are then sieved, dried and optionally ground prior to compressing into tablets. Wet granulation is used extensively in the pharmaceutical industry although it has proven to be a difficult method, mainly because the liquids needed in the granule and tablet manufacturing processes often have an adverse effect on the characteristics of the active pharmaceutical ingredients (APIs) and/or on the end product such as a tablet.

Dry granulation is usually described as a method of controlled crushing of precompacted powders densified by either slugging or passing the material between two counter-rotating rolls.

More specifically, powdered components that may contain very fine particles are typically mixed prior to being compacted to yield hard slugs which are then ground and sieved before the addition of other ingredients and final compression to form tablets. Because substantially no liquids are used in the dry granulation process, the issues related to wet granulation are avoided. Although dry granulation would in many cases appear to be the best way to produce products such as tablets containing APIs, it has been relatively little used because of the challenges in producing the desired kind of granules as well as managing the granulated material in the manufacturing process. Known dry granulation methods, as well as the known issues related to them are well described in scientific articles, such as the review article "Roll compaction / dry granulation: pharmaceutical applications" written by Peter Kleinebudde and published in European Journal of Pharmaceutics and Biopharmaceutics 58 (2004) at pages 317-326.

Direct compression is generally considered to be the simplest and the most economical process for producing tablets. However, it may only be applied to materials that do not need to be granulated before tableting. Direct compression requires only two principal steps; i.e., the mixing of all the ingredients and the compression of this mixture. However, direct compression is applicable to only a relatively small number of substances as the ingredients of the tablets often need to be processed by some granulation technique to make them compressible and/or for improving their homogeneity and flow-ability.

In an embodiment, the process of preparing a solid oral pharmaceutical composition of cinacalcet or salts thereof comprises steps of:
(a) granulating cinacalcet or salts thereof with one or more pharmaceutically acceptable excipients, which exclude any disintegrating agent;
(b) optionally lubricating the granules obtained in step (a) to form a lubricated blend;
(c) compressing the granules obtained in step (a) or the lubricated blend obtained in step (b) to form a core comprising cinacalcet or salts thereof, and
(d) optionally coating the core obtained in step (c) with a composition comprising one or more film forming polymers.

In a further embodiment, the process of preparing tablet of cinacalcet or salts thereof comprises steps of:
(a) preparing plurality of granules comprising cinacalcet or salts thereof with one or more pharmaceutically acceptable excipients, which exclude any disintegrating agent,
(b) compressing the granules obtained in step (a) to form a tablet, and
(c) coating the tablet with a composition comprising one or more film forming polymers.

The inventors of the present invention have also optimized the amount of the excipients those used in formulating cinacalcet solid oral composition. In an embodiment, ratio of the amount of cinacalcet to diluents in the composition ranges from about 1:0.1 to about 1:1. In a further embodiment, ratio of the amount of cinacalcet to binder in the composition ranges from about 1:1 to about 1:10.

The term “cinacalcet” used throughout the specification refers to not only cinacalcet per se, but also its other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof. Particularly, preferred form of cinacalcet is cinacalcet base.

The term 'filler' and the term 'diluent' are herein used interchangeably. Suitable filler/diluent includes, but are not limited to calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, dextrin, dextrose, fructose, lactitol, lactose (e.g. spray-dried lactose, a-lactose, ß-lactose, super tab 11 SD, Tablettose®, various grades of Pharmatose®, Microtose® or Fast-Floe®), methyl cellulose polymers, hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose, carboxy methyl hydroxyethyl cellulose, magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, sorbitol, sucrose, sugar, and xylitol, erythritol and the like.

Suitable binders include, but not limited to microcrystalline cellulose, hydroxymethyl cellulose, gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), waxes, polyethylene glycol, natural and synthetic gums (e.g. acacia, tragacanth, sodium alginate, celluloses, and Veegum), and synthetic polymers such as polymethacrylates, polyvinylpyrrolidone, ethylcellulose, hydroxyethyl cellulose, polyethylene oxide, mixtures thereof and the like.

Suitable lubricants include, but not limited to sodium oleate, sodium stearate, sodium benzoate, sodium stearate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acid, polyethylene glycol, talc, mixtures thereof and the like.

In an embodiment, the solid oral pharmaceutical composition comprises:
(a) cinacalcet or salts thereof;
(b) microcrystalline cellulose;
(c) polyvinylpyrrolidone;
(d) magnesium stearate, and
(d) a coating comprising hydroxypropyl methyl cellulose;
wherein the composition is devoid of any disintegrating agent.

In a further embodiment, the solid oral pharmaceutical composition comprises:
(a) about 5 to 50% w/w of cinacalcet or salts thereof;
(b) about 10 to 60% w/w of microcrystalline cellulose;
(c) about 2 to 12% w/w of polyvinylpyrrolidone;
(d) about 0.1 to 2% w/w magnesium stearate, and
(e) a coating comprising about 0.5 to 4% w/w hydroxypropyl methylcellulose;
wherein the composition is devoid of any disintegrating agent.

In a particularly preferred embodiment, cinacalcet tablet comprises one or more diluents in a total amount of about 50 to 90% w/w, one or more binders in a total amount of about 1 to 20% w/w, and one or more lubricants in a total amount of about 0.5 to 2% w/w by weight based on the total weight of the tablet

In a further embodiment, the solid oral pharmaceutical composition comprises:
(a) 99.18 mg of cinacalcet or salts thereof;
(b) 213.42 mg of microcrystalline cellulose;
(c) 36 mg of polyvinylpyrrolidone;
(d) 5.40 mg of magnesium stearate, and
(e) a coating layer comprising 5 mg of hydroxypropyl methylcellulose;
wherein the composition is devoid of any disintegrating agent.

The solid oral pharmaceutical composition comprising cinacalcet or salts thereof of in accordance with the present invention can be administered for treating secondary hyperparathyroidism and hypercalcemia in patients in need thereof.

The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below.

Example 1: Cinacalcet HCl Tablet
Table 1
Sr. No. Ingredients Qty (mg/tab)
Intragranular
1 Cinacalcet HCl 99.18
2 Polyvinylpyrrolidone 36
3 Microcrystalline cellulose 213.42
4 Purified Water q. s.
Extragranular
5 Lactose 186
6 Magnesium Stearate 5.40
Total wt. of core (mg) 540
7 Opadry Green 15
Total wt. of coated tablet (mg) 555

Process: Microcrystalline cellulose and 50% quantity of polyvinylpyrrolidone were sifted through # 30 sieve and dry mixed. The dry blend was granulated using dispersion of cinacalcet and remaining quantity of polyvinylpyrrolidone in purified water, to form wet mass. Thus formed wet mass was dried in fluidized bed dryer at 60°C till LOD of less than 2% is achieved. Granules were sized through # 20 sieve. Dried and sized granules were mixed for 15 min with extragranular material lactose and lubricated with magnesium stearate in a blender. This lubricated blend was compressed using suitable tooling on compression machine to form tablets. The compressed tablets were coated using opadry green dispersion in water using coating pan.