CLIAMS:We Claim:
1. A pharmaceutical composition comprising
a) from about 10% to about 40% by weight of Cinacalcet hydrochloride having particle size d90less than 25 µm;
b) from about 10% to about 40% by weight of microcrystalline cellulose;
c) from about 15 % to about 55 % by weight of lactose or dicalcium phosphate dihydrate or combination thereof;
d) from about 1% to about 5% by weight of hydroxypropyl cellulose;
e) from about 0.01% to about 3% by weight of croscarmellose sodium or sodium starch glycolate;
f) from about 0.5% to about 2.5% by weight of talc; and
g) from about 0.5% to about 2.5% by weight of sodium stearyl fumarate or hydrogenated castor oil; wherein the percentage by weight is relative to the total weight of the composition.
2. The composition according to claim 1, further coated with seal coating followed by film coating.
3. The composition according to claim 1, wherein croscarmellose sodium or sodium starch glycolate is present extragranularly.
4. The pharmaceutical composition of claim 1, wherein the composition is prepared by direct compression or dry granulation or wet granulation process.
5. The pharmaceutical composition of claim 1, wherein the composition is used for primary hyperparathyroidism, secondary hyperparathyroidism and parathyroid carcinoma.
6. A pharmaceutical composition comprising
a) from about 10% to about 40% by weight of Cinacalcet hydrochloride having particle size d90less than 25 µm;
b) from about 10% to about 40% by weight of microcrystalline cellulose;
c) from about 15 % to about 55 % by weight of lactose or dicalcium phosphate dihydrate ;
d) from about 1% to about 5% by weight of hydroxypropyl cellulose;
e) from about 0.01% to about 3% by weight of croscarmellose sodium or sodium starch glycolate;
f) from about 0.5% to about 2.5% by weight of talc; and
g) from about 0.5% to about 2.5% by weight of sodium stearyl fumarate or hydrogenated
castor oil; wherein the percentage by weight is relative to the total weight of the composition, wherein the release of Cinacalcet hydrochloride from said composition is not less than about 85% in 30 minutes when tested in USP type 2 (paddle) apparatus with 900 ml of 0.05 N HCL as the dissolution medium at 37°C, at 75 rpm paddle speed.
7. A method for producing a pharmaceutical composition of Cinacalcet or pharmaceutically acceptable salts thereof, comprising the steps of:
a) Dry mixing the Cinacalcet hydrochloride, microcrystalline cellulose and lactose in rapid mixer granulator (RMG).
b) Dissolving hydroxypropyl cellulose in purified water by continuous stirring to prepare binder solution.
c) Adding binder solution (b) to the dry mix (a) to achieve wet mass of the desired consistency.
d) Drying the wet mass (c) and pass the dried granules through the appropriate sieve.
e) Adding lactose, croscarmellose sodium and talc to the sifted granules (d) and mix.
f) Lubricating the mix (e) with sodium stearyl fumarate.
g) Compressing the lubricated blend (f) to obtain tablets.
h) Coating the tablets (g) with seal coat followed by film coat.
,TagSPECI:COMPLETE SPECIFICATION
TITLE
A NOVEL STABLE PHARMACEUTICAL COMPOSITION COMPRISING CINACALCET HYDROCHLORIDE

FIELD OF THE INVENTION
The present invention relates to a novel stable pharmaceutical composition of Cinacalcet or pharmaceutically acceptable salts thereof as active ingredient comprising one or more pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION
Cinacalcet hydrochloride is commercially available as Sensipar® in US market and Mimpara® in Europe market. Cinacalcet N-[1-(R)-(-)-(1-Naphthyl)ethyl]-3-[3(trifluoromethyl)phenyl]-1- aminopropane has the following chemical structure:

Cinacalcet is described in US 6,211,244 B1. The approved indications of said active ingredient are for the treatment of secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) on dialysis, for the treatment of hypercalcemia in patients with Parathyroid Carcinoma and for the treatment of severe hypercalcemia in patients with primary HPT who are unable to undergo parathyroidectomy.
US 7,829,595 B2 describes calcium receptor-active compounds, especially Cinacalcet known with its hardly soluble nature in water and soluble behavior in some organic solvents. It was also reported that cinacalcet has solubility in water of less than about 1 µg/ml at neutral pH, while this value can reach up to 1.6 mg/ml when the pH ranges from about 3 to 5. Further, describes rapid dissolution formulation of Cinacalcet hydrochloride, wherein the composition has a dissolution profile in 0.05N HCI from about 50% to about 125% of a target amount of the calcium receptor-active compound being released from the composition no later than 30 minutes.

US 7,829,595 B2 further discloses rapid dissolution formulation of Cinacalcet hydrochloride by wet granulation by controlling the particle size of the granules such as to obtain the above mentioned dissolution profile.
US 2011/0136915 A1 discloses a Cinacalcet formulation with the concentration of disintegrant in the range of 1 % to 10% by weight relative to the total weight of the composition.
US 2012/0270949 A1 discloses Cinacalcet formulations obtained by melt granulation method.
US 2012/0009258 A1 discloses Cinacalcet formulations obtained by jointly compacting Cinacalcet and hydrophilising agent to form flakes (as intermediate) and further screening and granulating the obtained flakes which are further compressed into solid dosage form.
US 2011/0287065 A1 discloses a Cinacalcet composition having an overall particle size distribution of less than 2000 nm in order to achieve better solubility and bioavailability.
US 2010/0168247 A1 discloses immediate and controlled release pharmaceutical formulations of Cinacalcet obtained by 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.
WO 2013/107503 A1 discloses Cinacalcet formulations obtained by direct compression method.
Thus, there is still unmet need to develop a pharmaceutical composition comprising Cinacalcet hydrochloride which is cost effective and stable composition with acceptable dissolution profile.

SUMMARY OF THE INVENTION
The present invention relates to a stable pharmaceutical composition comprising at least one calcium receptor-active compound.
The present invention relates to a stable pharmaceutical composition comprising Cinacalcet or its pharmaceutically acceptable salts thereof.
The present invention relates to a stable pharmaceutical composition comprising Cinacalcet hydrochloride and one or more pharmaceutically acceptable excipients.
In one aspect present invention provides to a stable oral rapid dissolution pharmaceutical composition comprising Cinacalcet hydrochloride and one or more pharmaceutically acceptable excipients.
In yet another aspect the present invention provides a stable pharmaceutical composition comprising Cinacalcet hydrochloride having particle size distribution d0.9 less than 35 µm, preferably d0.9 less than 30 µm, most preferably d0.9 less than 25 µm.
In yet another aspect the present invention provides a method of manufacturing the stable pharmaceutical composition comprising Cinacalcet hydrochloride and one or more pharmaceutically acceptable excipients.
In yet another aspect the present invention provides a stable pharmaceutical composition comprising Cinacalcet hydrochloride that has a stable dissolution profile.
In yet another aspect the present invention provides a stable pharmaceutical composition comprising therapeutically effective amount of Cinacalcet hydrochloride and pharmaceutically acceptable excipients.
In yet another aspect the present invention provides a rapid dissolution composition of Cinacalcet hydrochloride, wherein the in-vitro dissolution release profile matches with the commercially available Cinacalcet hydrochloride tablet formulation i.e. Sensipar®.
In yet another aspect the present invention provides a rapid dissolution composition of Cinacalcet hydrochloride, for the treatment of secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) on dialysis, for the treatment of hypercalcemia in patients with Parathyroid Carcinoma and for the treatment of severe hypercalcemia in patients with primary HPT who are unable to undergo parathyroidectomy.

BRIEF DESCRIPTION OF THE DRAWING
Fig. 1 Graphical representation of dissolution profile of formulation prepared according to Example 4 and reference product Sensipar® 90 mg in 900 ml, 0.05 N HCl, at 75 RPM, Apparatus USP Type II (Paddle).

Fig. 2 Graphical representation of dissolution profile of formulation prepared according to Example 4 and reference product Sensipar® 90 mg in 900 ml, 0.1 N HCl, at 75 RPM, Apparatus USP Type II (Paddle).

Fig. 3 Graphical representation of dissolution profile of formulation prepared according to Example 4 and reference product Sensipar® 90 mg in 900 ml, Acetate Buffer pH 4.5, at 75 RPM, Apparatus USP Type II (Paddle).

Fig. 4 Graphical representation of dissolution profile of formulation prepared according to Example 4 and reference product Sensipar® 90 mg in 900 ml, Phosphate Buffer pH 6.8, at 75 RPM, Apparatus USP Type II (Paddle).

BRIEF DESCRIPTION OF THE TABLE
Table 1: Provides multimedia comparative dissolution profiles of Sensipar® 90 mg versus Cinacalcet Tablets 90 mg as per composition of Example 4 in 900 ml, Apparatus USP Type II (Paddle), 75 RPM, at 37 ± 0.5°C.

Table 2: Cinacalcet hydrochloride Tablets 90 mg packed in HDPE Bottle with Purified cotton finished product analysis data-initial and on stability.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel stable pharmaceutical composition comprising of Cinacalcet hydrochloride and other pharmaceutically acceptable excipients.
The composition of the present invention can be formulated as solid compositions for oral administration in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads, or mini-tablets. Preferably, the composition is in the form of tablets.
The term "Cinacalcet hydrochloride", as used herein, includes crystalline or amorphous Cinacalcet hydrochloride.
The term "composition" as used herein refers to equivalents thereof, including but not limited to: cores, coated cores, pellets, micro-pellets, pills, compressed tablets, granules, spheres, capsules and the like.
The phrase "therapeutically effective amount", as used herein, means a dosage that is sufficient to provide the specific pharmacological response for which the Cinacalcet hydrochloride is being administered.
The term "tablet" is intended to encompass compressed pharmaceutical dosage forms of all shape and size, whether coated or uncoated.
A novel stable pharmaceutical composition of the present invention may comprise one or more pharmaceutically acceptable excipients which include, but are not limited to binders, diluents, disintegrants, lubricants, glidants, coating agents, plasticizers, coloring agent, viscosity enhancers, and the like.
An embodiment of the present invention covers all the commercially available strengths of Cinacalcet hydrochloride rapid dissolution composition i.e. 30mg, 60mg and 90mg.
Binders used include, but not limited to acacia, alginic acid, carbomer copolymer, copovidone, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, glucose (liquid), guar gum, hydroxypropyl cellulose, maltose, methylcellulose, polyethylene oxide, polyvinylpyrrolidone, starch, or sodium carboxymethyl cellulose and the like.
Diluents include, but not limited to microcrystalline cellulose (MCC), silicified MCC, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide or combination thereof.
Disintegrants which include, but not limited to croscarmellose sodium, cross-povidone, sodium starch glycolate, starch and its derivatives, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose and the like.
Lubricants which include, but not limited to sodium stearyl fumarate, hydrogenated castor oil, stearic acid and its salts.
Glidants which include, but not limited to colloidal silicon dioxide, talc, tribasic calcium phosphate, magnesium oxide and magnesium silicate and the like.
Plasticizers which include but not limited to polyethylene glycol, triethyl citrate, tributyl citrate, glycerin, dibutyl sebacate, triacetin and diethylphthalate.
Viscosity enhancers which include but not limited to carboxymethylcellulose calcium, carboxymethylcellulose sodium, ceratonia, hydroxypropyl methylcellulose, acacia, agar, alginic acid and like.
Coloring agents which include but not limited to FD &C dyes, D&C dyes or lake forms of these dyes.
The tablets may optionally be coated with a film coat, which provides an aesthetic appeal or can also provide some functional role such as moisture protection, taste masking etc. Coating agents include, but not limited to polyvinyl alcohol, hydroxypropyl methylcellulose, carboxymethyl cellulose and like.
Preferably coating is carried out using coating agents such as Opadry®. Preferred Opadry® are Opadry® Clear 00B29074 which contains hypromellose, polyethylene glycol / macrogol, Opadry II Green 32K11479 which contains hypromellose, lactose monohydrate, titanium dioxide, triacetin, FD&C Blue #2/ indigo carmine aluminum lake, yellow iron oxide,
Solvents that may be used for coating include purified water.
In one embodiment, the composition herein can be formed by any known process, such as high wet shear granulation, low wet shear granulation, fluid bed granulation, rotary granulation, extrusion-spheronization, dry granulation, roller compaction, and the like. Preferably, the composition herein is formed by wet granulation method.

In another embodiment, the composition herein comprises:
(a) from about 10% to about 40% by weight of a Cinacalcet hydrochloride having particle size distribution d0.9 less than 35 µm, preferably d0.9 less than 30 µm, most preferably d0.9 less than 25 µm.;
(b) from about 10% to about 85% by weight of at least one diluent or combination thereof;
(c) from about 1% to about 5% by weight of at least one binder; and
(d) from about 0.01% to about 5% by weight of at least one disintegrant; wherein the percentage by weight is relative to the total weight of the composition.
(e) The compositions can further comprise from about 0.05% to about 5% by weight, relative to the total weight of the composition, of additives chosen from glidants, and lubricants.
(f) The composition can additionally comprise seal and/or film coating from about 1% to about 3% by weight of coating material, relative to the total weight of the composition.
In yet another embodiment, the composition herein comprises:
(a) from about 10% to about 40% by weight of a Cinacalcet hydrochloride;
(b) from about 10% to about 85% by weight of microcrystalline cellulose or lactose or combination thereof.
(c) from about 1% to about 5% by weight of hydroxypropyl cellulose;
(d) from about 0.01% to about 5% by weight of croscarmellose sodium; wherein the percentage by weight is relative to the total weight of the composition.
(e) The compositions can further comprise from about 0.05% to about 5% by weight, relative to the total weight of the composition, of talc and sodium stearyl fumarate.
(f) The composition can additionally comprise seal and/or film coating from about 1% to about 3% by weight of coating material Opadry®, relative to the total weight of the composition.
In yet another embodiment, the present invention also relates to a process of preparing a composition comprising Cinacalcet hydrochloride wherein the process comprises:
a) Sifting Cinacalcet hydrochloride and all the excipients through appropriate sieve.
b) Dry mixing the intra granular materials in rapid mixer granulator (RMG).
c) Dissolve binder in purified water by stirring for preparing binder solution.
d) Add binder solution (c) to the dry mix (b) to achieve wet mass of the desired consistency.
e) Drying the wet mass (d) and passing the dried granules through the appropriate sieve.
f) Adding the extra granular materials to the sifted & milled granules (e) and mixing.
g) Lubricating the mix (f) with lubricant.
h) Compressing the lubricated blend (g) with desired punches & dies.
i) The compressed tablets can be further seal and/or film coated by mixing Opadry® in purified water under continuous stirring and coating the uncoated tablets in coating pan until the desired weight is achieved.
In yet another embodiment, the present invention relates to a stable Cinacalcet hydrochloride composition when subjected to a 40 ± 2ºC / 75 ± 5% RH stability conditions for 3 months.
In yet another embodiment, the present invention relates to a Cinacalcet hydrochloride composition having dissolution profile of not less than 85% of drug release from the composition within 30 minutes.
The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

EXAMPLES

Example 1
Sr. No. Ingredients Rationale Input
Qty. per tablet in mg
INTRA-GRANULAR MATERIALS
1. Cinacalcet Hydrochloride having particle size d90 less than 25 µm API 99.180
2. Microcrystalline cellulose (Avicel PH 101) Diluent 173.820
3. Lactose Monohydrate (Pharmatose 200 M) Diluent 126.000
BINDER SOLUTION
4. Hydroxy Propyl cellulose (Klucel LF) Binder 12.000
5. Purified water* Granulating
Fluid Qs.
EXTRA-GRANULAR MATERIALS
6. Lactose Monohydrate (Super Tab 30GR) Diluent 121.500
7. Croscarmellose sodium (Ac-Di-Sol) Disintegrant 3.000
8. Talc (Luzenac) Glidant 9.000
LUBRICATION MATERIAL
9. Hydrogenate castor oil Lubricant 7.500
Theoretical Weight of core Tablet 552.000
SEAL COATING MATERIAL
10. Opadry Clear (00B29074) Coating agent 6.000
11. Purified water* Solvent Qs
FILM COATING MATERIAL
12. Opadry II Green (32K11479) Coating agent 12.000
13. Purified water* Solvent QS
Theoretical Weight of coated Tablet 570.000

Manufacturing Procedure
A formulation as shown in example 1 was prepared as follows:
1.0 Sifting:
1.1 Sift Cinacalcet hydrochloride along with Microcrystalline cellulose (Avicel PH 101) through #40 seive.
1.2 Sift materials of step 1.1 along with Lactose Monohydrate (Pharmatose 200 M) through # 40 seive.
1.3 Sift Lactose Monohydrate (Super Tab 30GR), Croscarmellose sodium (Ac-Di-Sol) &Talc through # 40 seive.
1.4 Sift Hydrogenate castor oil through # 60 seive.
2.0 Granulation & Drying:
2.1 Load the sifted materials of step 1.2 in Rapid Mixer Granulator & mix the materials for
10min.
2.2 Dissolve Hydroxy Propyl cellulose (Klucel LF) in desired quantity of purified water and
granulate the step 2.1 blended materials in RMG.
2.3 Dry the above wet mass in dryer.
3.0 Milling:
3.1 Pass the dried granules through #30 seive.
3.2 Mill the sifted granules by using 1.5mm & 1.0mm screen.
3.3 Pass the milled granules through #30 seive.
4.0 Prelubrication & Lubrication:
4.1 Load the sifted granules of step 3.3 & sifted prelubrication materials of step 1.3 into blender
& mix for 20min.
4.2 Add step 1.4 sifted material into blender & lubricate for 5min.
5.0 Compression:
5.1 Compress the lubricated blend with desired punches & dies.
6.0 COATING PROCESS:
6.1 Seal Coating:
6.1.1 Mix the Opadry clear in Purified water and stir.
6.1.2 Coat the core tablets in coating pan to achieve the desired weight.
Film Coating:
6.2.1 Mix the Opadry II green in Purified water and stir.
6.2.2 Film coat the seal coated tablets to achieve the desired.

Example 2
Sr. No. Ingredients Rationale Input
Qty. per tablet
in mg
INTRA-GRANULAR MATERIALS
1. Cinacalcet Hydrochloride having particle size d90 less than 25 µm API 99.180
2. Microcrystalline cellulose (Avicel PH 101) Diluent 173.820
3. Lactose Monohydrate (Pharmatose 200 M) Diluent 122.000
BINDER SOLUTION
4. Povidone K-30 Binder 16.000
5. Purified water* Granulating
Fluid Qs.
EXTRA-GRANULAR MATERIALS
6. Lactose Monohydrate (Super Tab 30GR) Diluent 118.200
7. Croscarmellose sodium (Ac-Di-Sol) Disintegrant 3.000
8. Talc (Luzenac) Glidant 9.000
LUBRICATION MATERIAL
9. Sodium Stearyl Fumarate (Pruv) Lubricant 10.800
Theoretical Weight of core Tablet 552.000
SEAL COATING MATERIAL
10. Opadry Clear (00B29074) Coating agent 6.000
11. Purified water* Solvent Qs
FILM COATING MATERIAL
12. Opadry II Green (32K11479) Coating agent 12.000
13. Purified water* Solvent QS
Theoretical Weight of coated Tablet 570.000

Manufacturing Procedure
A formulation as shown in example 2 was prepared as follows:
1.0 Sifting:
1.1 Sift Cinacalcet hydrochloride along with Microcrystalline cellulose (Avicel PH 101) through #40 seive.
1.2 Sift materials of step 1.1 along with Lactose Monohydrate (Pharmatose 200 M) through # 40 seive.
1.3 Sift Lactose Monohydrate (Super Tab 30GR), Croscarmellose sodium (Ac-Di-Sol) &Talc through # 40 seive.
1.4 Sift Sodium Stearyl Fumarate (Pruv)through # 60 seive.
2.0 Granulation & Drying:
2.1 Load the sifted materials of step 1.2 in Rapid Mixer Granulator & mix the materials for
10min.
2.2 Dissolve Povidone K-30 in desired quantity of purified water and
granulate the step 2.1 blended materials in RMG.
2.3 Dry the above wet mass in dryer.
3.0 Milling:
3.1 Pass the dried granules through #30 seive.
3.2 Mill the sifted granules by using 1.5mm & 1.0mm screen.
3.3 Pass the milled granules through #30 seive.
4.0 Prelubrication & Lubrication:
4.1 Load the sifted granules of step 3.3 & sifted prelubrication materials of step 1.3 into blender
& mix for 20min.
4.2 Add step 1.4 sifted material into blender & lubricate for 5min.
5.0 Compression:
5.1 Compress the lubricated blend with desired punches & dies.
6.0 COATING PROCESS:
6.1 Seal Coating
6.1.1 Mix the Opadry clear in Purified water and stir.
6.1.2 Coat the core tablets in coating pan to achieve the desired weigh
6.2 Film Coating:
6.2.1 Mix the Opadry II green in Purified water and stir.
6.2.2 Film coat the seal coated tablets to achieve the desired.

Example 3
Sr. No. Ingredients Rationale Input
Qty. per tablet
in mg
INTRA-GRANULAR MATERIALS
1. Cinacalcet Hydrochloride having particle size d90 less than 25 µm API 99.180
2. Microcrystalline cellulose (Avicel PH 101) Diluent 173.820
3. Dicalacium phosphate dihydrate (Ditab) Diluent 122.000
BINDER SOLUTION
4. Hydroxy Propyl cellulose (Klucel LF) Binder 12.000
5. Purified water* Granulating
Fluid Qs.
EXTRA-GRANULAR MATERIALS
6. Lactose Monohydrate (Super Tab 30GR) Diluent 122.200
7. Sodium starch glycolate (Type -A) Disintegrant 3.000
8. Talc (Luzenac) Glidant 9.000
LUBRICATION MATERIAL
9. Sodium Stearyl Fumarate (Pruv) Lubricant 10.800
Theoretical Weight of core Tablet 552.000
SEAL COATING MATERIAL
10. Opadry Clear (00B29074) Coating agent 6.000
11. Purified water* Solvent Qs
FILM COATING MATERIAL
12. Opadry II Green (32K11479) Coating agent 12.000
13. Purified water* Solvent QS
Theoretical Weight of coated Tablet 570.000

Manufacturing Procedure
A formulation as shown in example 3 was prepared as follows:
1.0 Sifting:
1.1 Sift Cinacalcet hydrochloride along with Microcrystalline cellulose (Avicel PH 101) through #40 seive.
1.2 Sift materials of step 1.1 along with Dicalacium phosphate dihydrate (Ditab) through # 40 seive.
1.3 Sift Lactose Monohydrate (Super Tab 30GR), Sodium starch glycolate (Type-A) &Talc through # 40 seive.
1.4 Sift Sodium Stearyl Fumarate (Pruv) through # 60 seive.
2.0 Granulation & Drying:
2.1 Load the sifted materials of step 1.2 in Rapid Mixer Granulator & mix the materials for
10min.
2.2 Dissolve Hydroxy Propyl cellulose (Klucel LF) in desired quantity of purified water and
granulate the step 2.1 blended materials in RMG.
2.3 Dry the above wet mass in dryer.
3.0 Milling:
3.1 Pass the dried granules through #30 seive.
3.2 Mill the sifted granules by using 1.5mm & 1.0mm screen.
3.3 Pass the milled granules through #30 seive.
4.0 Prelubrication & Lubrication:
4.1 Load the sifted granules of step 3.3 & sifted prelubrication materials of step 1.3 into blender
& mix for 20min.
4.2 Add step 1.4 sifted material into blender & lubricate for 5min.
5.0 Compression:
5.1 Compress the lubricated blend with desired punches & dies.
6.0 COATING PROCESS:
6.1 Seal Coating:
6.1.1 Mix the Opadry clear in Purified water and stir.
6.1.2 Coat the core tablets in coating pan to achieve the desired weight.
6.2 Film Coating:
6.2.1 Mix the Opadry II green in Purified water and stir.
6.2.2 Film coat the seal coated tablets to achieve the desired.

Example 4
Sr. No. Ingredients Rationale Input
Qty. per tablet
in mg
INTRA-GRANULAR MATERIALS
1. Cinacalcet Hydrochloride having particle size d90 less than 25 µm API 99.180
2. Microcrystalline cellulose (Avicel PH 101) Diluent 173.820
3. Lactose Monohydrate (Pharmatose 200 M) Diluent 126.000
BINDER SOLUTION
4. Hydroxy Propyl cellulose (Klucel LF) Binder 12.000
5. Purified water* Granulating
Fluid Qs.
EXTRA-GRANULAR MATERIALS
6. Lactose Monohydrate (Super Tab 30GR) Diluent 118.200
7. Croscarmellose sodium (Ac-Di-Sol) Disintegrant 3.000
8. Talc (Luzenac) Glidant 9.000
LUBRICATION MATERIAL
9. Sodium Stearyl Fumarate (Pruv) Lubricant 10.800
Theoretical Weight of core Tablet 552.000
SEAL COATING MATERIAL
10. Opadry Clear (00B29074) Coating agent 6.000
11. Purified water* Solvent Qs
FILM COATING MATERIAL
12. Opadry II Green (32K11479) Coating agent 12.000
13. Purified water* Solvent QS
Theoretical Weight of coated Tablet 570.000
1. * Processing solvent. Not present in the final

Manufacturing process
A formulation as shown in example 4 was prepared as follows:
1.0 Sifting:
1.1 Sift Cinacalcet hydrochloride along with Microcrystalline cellulose (Avicel PH 101) through #40 seive.
1.2 Sift materials of step 1.1 along with Lactose Monohydrate (Pharmatose 200 M) through # 40 seive.
1.3 Sift Lactose Monohydrate (Super Tab 30GR), Croscarmellose sodium (Ac-Di-Sol) &Talc through # 40 seive.
1.4 Sift Sodium Stearyl Fumarate (Pruv) through # 60 seive.
2.0 Granulation & Drying:
2.1 Load the sifted materials of step 1.2 in Rapid Mixer Granulator & mix the materials for
10min.
2.2 Dissolve Hydroxy Propyl cellulose (Klucel LF) in desired quantity of purified water and
granulate the step 2.1 blended materials in RMG.
2.3 Dry the above wet mass in dryer.
3.0 Milling:
3.1 Pass the dried granules through #30 seive.
3.2 Mill the sifted granules by using 1.5mm & 1.0mm screen.
3.3 Pass the milled granules through #30 seive.
4.0 Prelubrication & Lubrication:
4.1 Load the sifted granules of step 3.3 & sifted prelubrication materials of step 1.3 into blender
& mix for 20min.
4.2 Add step 1.4 sifted material into blender & lubricate for 5min.
5.0 Compression:
5.1 Compress the lubricated blend with desired punches & dies.
6.0 COATING PROCESS:
6.1 Seal Coating:
6.1.1 Mix the Opadry clear in Purified water and stir.
6.1.2 Coat the core tablets in coating pan to achieve the desired weight.
6.2 Film Coating:
6.2.1 Mix the Opadry II green in Purified water and stir.
6.2.2 Film coat the seal coated tablets to achieve the desired.

Comparison of in-vitro dissolution profile:
The tablets of Cinacalcet hydrochloride prepared as per the composition of example 4 were subjected to multimedia dissolution studies.

Table 1: Provides multimedia comparative dissolution profiles of Sensipar® 90 mg versus Cinacalcet Tablets 90 mg as per composition of Example 4 in 900 ml, Apparatus USP Type II (Paddle), 75 RPM, at 37 ± 0.5°C.
Dissolution Media 0.05 M HCl 0.1 M HCl Acetate Buffer pH4.5 Phosphate Buffer pH6.8
Sensipar® 90 mg Composition of Example 4 Sensipar® 90 mg Composition of Example 4 Sensipar® 90 mg Composition of Example 4 Sensipar® 90 mg Composition of Example 4
Time (Min) % Drug Release % Drug Release % Drug Release % Drug Release
10 80.2 76.8 64.6 63.2 97.4 89.2 28.6 25.6
15 88.1 86.9 73.6 71.8 97.0 90.5 29.4 25.7
20 92.6 91.6 78.7 76.9 96.8 90.7 30.0 25.8
30 96.7 96.9 85.6 83.5 96.8 90.6 30.8 26.3
45 99.1 100.3 90.9 89.3 96.8 90.8 32.2 26.6
F2 85.0 85.0 59.0 68.0

Table 2: Cinacalcet hydrochloride Tablets 90 mg packed in HDPE Bottle with Purified cotton finished product analysis data-initial and on stability.

Storage Condition: 40 ± 2ºC / 75 ± 5% RH
Test Intervals 0 month 1 month 2 months 3 months
Tests Specification Limits (Initial)
Description
Green colored, oval-shaped, biconvex, film coated tablets, debossed with “C” on one side and with “15” on the other side. Complies Complies Complies Complies
Water content
Not more than 6.5% w/w 3.8% w/w 3.7% w/w 3.9% w/w 3.8% w/w
Dissolution
Not less than 75% (Q) of labelled amount of Cinacalcet is dissolved in 30 minutes. Min: 103.1%
Max: 104.6%
Avg: 103.5% Min: 92.9%
Max: 94.4%
Avg: 93.4% Min: 95.7%
Max: 96.7%
Avg: 96.1% Min: 93.6%
Max: 94.8%
Avg: 94.2%
Assay
Each film coated tablet contains Cinacalcet… 90 mg equivalent to Cinacalcet hydrochloride 99 mg Not less than 90.0% and not more than 110% of the label claim.

(Not less than 81.0 mg and not more than 99.0 mg of Cinacalcet per tablet) 99.9 %

89.89 mg 99.2%

89.3 mg 100.9%

90.8 mg 101.3%

91.2 mg
Related Substances

Highest unknown impurity

Total impurities

Not more than 0.2%

Not more than 2.0% ND

ND BDL

BDL 0.08%

0.08% 0.07%

0.07%
Microbial limit test
1) Total aerobic Microbial count
2) Total combined yeast/moulds count
3) Specified microorganism – Escherichia coil
Not more than 1000 CFU/g

Not more than 100 CFU/g

Should be absent/g
10 CFU/g

<10 CFU/g

Absent NA NA
<10 CFU/g

<10CFU/g

Absent
Remarks Passes Passes Passes Passes
Where, ND = Not Detected, BDL = Below Disregard Limit