RAPID DISSOLUTION FORMULATION OF A CALCIUM RECEPTOR-ACTIVE COMPOUND

Abstract

The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a calcium receptor-active compound and at least one pharmaceutically acceptable excipient, wherein the composition has a controlled dissolution profile. The present invention further relates to a method of manufacturing the pharmaceutical composition, as well as a method of treating a disease using the pharmaceutical composition.

Claims

1. A pharmaceutical composition comprising an effective dosage amount of a calcium receptor-active compound and at least one pharmaceutically acceptable excipient, wherein at least one dosage unit of the composition has a dissolution profile in 0.05 N HCl, measured according to a dissolution test conducted in a USP 2 apparatus at a temperature of about 37? C., and at a rotation speed of about 75 r.p.m., which comprises from about 50% to about 125% of a target amount of the calcium receptor-active compound being released from the composition no later than about 30 minutes from the start of the test.

2.-118. (canceled)

Description

EXAMPLES

[0085] Three pharmaceutical formulations with target amounts of 30mg, 60mg, and 90 mg active pharmaceutical ingredient with the following components were prepared:

TABLE-US-00003 30 mg 60 mg 90 mg Tablet Tablet Tablet Weight % Amount Amount Amount (w/w) (mg) (mg) (mg) Cinacalcet HCl 18.367 33.06 66.12 99.18 Pregelatinized starch (Starch 33.378 60.08 120.16 180.24 1500) Microcrystalline cellulose 6.678 12.02 24.04 36.06 (Avicel PH102) Povidone (Plasdone K29/32) 2.044 3.68 7.36 11.04 Crospovidone (Polyplasdone 1.233 2.22 4.44 6.66 XL) Purified Water.sup.1 Microcrystalline cellulose 34.300 61.74 123.48 185.22 (Avicel PH102) Magnesium stearate 0.500 0.90 1.80 2.70 Colloidal silicon dioxide 0.500 0.90 1.80 2.70 (Colloidal anhydrous silica) (Cab-O-Sil M5P) Crospovidone (Polyplasdone 3.000 5.40 10.80 16.20 XL) Core Tablet 100.000 180.00 360.00 540.00 Purified Water.sup.1 Opadry? II (colored 4.000 7.20 14.40 21.60 film former) Purified Water.sup.1 Opadry? Clear (clear film 1.500 2.70 5.40 8.10 former) Carnauba Wax Powder 0.010 0.018 0.036 0.054 Opacode? Ink (Black).sup.2 .sup.1The purified Water was removed during processing. .sup.2Trace quantities of ink were applied to the coated tablet.

[0086] The 30-, 60- and 90-mg tablets were made according to the process flow diagram depicted below.

TABLE-US-00004 Critical Process Equipment Components Unit Operation Controls PMA 800L purified water and granulation.sup.b water level, granulator intra-granular impeller speed, components.sup.a water spray rate ? Comil (In-line) wet mill ? Aeromatic MP6 fluid bed dry ? Quadro Mill 196S dry mill (Comil) ? Gallay tote blender extra-granular pre-blend (650 L) components.sup.c ? Gallay tote blender combine granulation final blend blend time (1000 L) mix A and B and extra-granular mix ? Gallay tote blender magnesium stearate lubrication (1000 L) ? Unipress 27 compression.sup.d tablet press speed, tablet weight, thickness, hardness, friability, disintegration time ? 3 X Vector Hi-Coater pan color coat (Opadry? II), film coating and spray rate, (3 spray guns) delivery clear coat (Opadry? wax exhaust temperature (peristaltic pump) Clear), carnauba Wax ? Ackley ink-based offset Opacode? black print printer .sup.acinacalcet HCl, pregelatinized starch, microcrystalline cellulose, povidone, and crospovidone .sup.bThe granulation step to dry milling step is repeated to generate 2 bowls of wet granulation (Mix A and B). .sup.cExtra-granular components are microcrystalline cellulose, crospovidone, and colloidal silicon dioxide .sup.dTooling dimension is dependent on tablet size and strength, (30 mg; 0.2372 ? 0.3800 oval shape plain, 60 mg; 0.3000 ? 0.4800 modified oval (double radius) plain, 90 mg; 0.3420 ? 0.5480 modified oval (double radius) plain)

[0087] The wet granulation process was conducted in a PMA 800L high-shear granulator with water serving as the granulation fluid. The cinacalcet HCl and the intra-granulation excipients (pregelatinized starch, microcrystalline cellulose, povidone, and crospovidone) were dry-mixed for 1 to 2 minutes with an impeller speed set point at 116?10 rpm, followed by granulation with 30.0% to 36.0% wfw water (based on intra-granular lot size; target was 34.9% wlw) with an impeller speed set point at 116?10 rpm and at a slow or fast chopper speed (target was slow speed). During the granulation process water was delivered at 9.8 ?0.5 kg/min.

[0088] Following granulation, the mixture was wet-milled using an in-line Comil equipped with a 0.375 (0.953 cm) opening screen and an impeller speed set point at 1400?50 rpm. The mixture was then discharged into a fluid-bed dryer.

[0089] After completion of the wet-milling process, the granulation mixture was dried in an Aeromatic MP6 fluid bed dryer with an inlet temperature set point at 70??5? C. When the outlet temperature reached 37? C. to 41? C., samples were taken to determine moisture levels by loss on drying (LOD). The granules were dried until the average moisture levels reached 1.0% to 2.5%.

[0090] The dried granulation mixture was milled through a Ouadro MM 196S (Comil) equipped with a 0.055 (0.140 cm) opening screen at an impeller speed of 1650?50 rpm into a 1000L Gallay tote.

[0091] Except for magnesium stearate, the extra-granular excipients were blended in a 650 L Gallay tote blender for 7?1 minutes at 12?1 rpm. This mixture was further blended with the dry-milled granulation in a 1000 L Galley tote blender for 15?5 minutes at 12?1 rpm, and then for 6?1 minutes at 12?1 rpm after magnesium stearate was added for lubrication.

[0092] The final lubricated blend was compressed into tablets containing 30-, 60-, or 90 mg of the free base equivalent of active cinacalcet HCl using a Unipress 27 tablet press set to a speed of 2000?300 tablets per minute and equipped with a force feeder. Throughout the compression operation, individual tablet weights (target weights of 180, 360, and 540 mg for 30-, 60-, and 90-mg tablets, respectively), the average weight of 10 tablets, tablet hardness and thickness were monitored at pre-determined intervals.

[0093] The color-coating suspension and clear-coating solution were prepared by slowly adding either the Opadry? II (green) or Opadry? Clear into purified water while mixing until uniform (?45 minutes). The color suspension and clear solution deaerated for ?45 minutes before the spraying process began, and were used within a pre-determined time limit.

[0094] Each lot was film-coated with color and clear coats in a Vector Hi-Coater 48 pan. The color-coating suspension was applied onto a moving core tablet bed (pan speed=4 to 7 rpm) and a spray rate of 250?50 grams per minute per 3 guns. The distance between the spray guns and the tablet bed was approximately 8 (20 cm) to 11 (28 cm), and the air volume was 600?200 ft.sup.3 per minute (17.1?5.7 m.sup.3 per minute) with a pan pressure differential maintained between ?0.1 (?0.25 cm) to ?0.3 (?0.76 cm) of water. Supply air temperature was adjusted to 80?10? C. to maintain an exhaust temperature of 41?3? C.

[0095] When the clear-coating application was completed, the heater and the air supply was turned off and the wax was spread evenly over the moving tablet bed (after it reached ?37? C.) with a pan speed of 4 to 7 rpm. The tablets were rotated for 5?1 minutes, and after the supply air and exhaust fan were turned on, the tablets were rotated for an additional 5?1 minutes with a pan speed of 4 to 7 rpm and supply air of 600?200 ft.sup.3 per minute (17.1?5.7 m.sup.3 per minute). The pan was jogged until the tablet bed temperature reached ?30? C.

[0096] An Ackley ink-based offset printer was used to produce 2-sided printed tablets.

[0097] The dissolution profile of the three formulations were measured according the dissolution protocol described in the USP 26/NF 21, chapter 711 using a USP 2 apparatus at a temperature of about 37? C., and at a rotation speed of about 75 r.p.m. The dissolution profile of the formulations in which at least about 75% of the cinacalcet HCl was released from the composition in no later than about 30 minutes from the start of the test is set forth in Table 2.

TABLE-US-00005 TABLE 2 Time (min) 30 mg Tablet 60 mg Tablet 90 mg Tablet 15 85.3 81.9 80.8 30 95.2 93.8 93.4 45 97.7 97.7 97.9 60 98.7 98.8 99.8

[0098] The content uniformity of the three formulations were measured in accordance with USP 26/NF 21, chapter 905, described in detail above. The content uniformity and for each of the three formulations is set forth in Table 3.

TABLE-US-00006 TABLE 3 30 mg Tablet 60 mg Tablet 90 mg Tablet Mean (10 % Mean % Mean % Container tablets) RSD (10 tablets) RSD (10 tablets) RSD 1 (beg.) 98.5 0.8 96.7 1.6 99.7 1.2 5 98.8 0.8 98.5 0.8 100.7 0.9 11 98.5 0.6 98.3 1.0 99.9 0.7 16 98.3 0.8 97.6 1.3 99.9 0.5 22 98.3 1.0 96.3 1.8 100.7 0.9 end 98.0 0.6 95.8 1.9 99.3 0.8