Pharmaceutical Composition of Rosuvastatin Calcium

Abstract

The invention relates to pharmaceutical compositions containing rosuvastatin calcium of formula (I) and processes for their manufacture.

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Claims

1. A process for formation of a pharmaceutical formulation comprising a rosuvastatin calcium-containing layer, the process comprising: spray coating an aqueous solution comprising rosuvastatin calcium, a stabilization agent and a first coating polymer onto a tablet, pellet, or granule core to provide the rosuvastatin calcium-containing layer, wherein the stabilization agent is a calcium or magnesium salt of an organic acid.

2. The process as claimed in claim 1 further comprising: coating the tablet, pellet or granule core with a sub-coating layer comprising a second coating polymer.

3. The process as claimed in claim 1 further comprising: optionally coating the tablet, pellet or granule core with a sub-coating layer comprising a second coating polymer; and coating the rosuvastatin calcium-containing layer with an outer coating comprising a third coating polymer.

4. The process as claimed in claim 1 wherein the tablet, pellet or granule core comprises an active ingredient which is not rosuvastatin calcium.

5. The process as claimed in claim 4 wherein the core contains an active ingredient which is not selected from one or more of: niacin or a niacin analogue, a fibrate, metformin, a CETP inhibitor and/or aspirin.

6. The process as claimed in claim 4, wherein the core comprises an active ingredient selected from the group consisting of: sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT-2 inhibitors, aldose reductase inhibitors, phosphodiesterase-5 inhibitors, phosphodiesterase-3 inhibitor, platelet aggregation inhibitors, Factor Xa inhibitors, dipyridamole, peripheral calcium channel blockers, diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, direct thombin inhibitors, coenzyme Q-10, vitamin D1 (ergocalciferol), vitamin D3 (cholecalciferol), GPR40 agonists and antiobesity drugs.

7. The process as claimed in claim 1 wherein the first coating polymer is an HMPC/PEG polymer.

8. (canceled)

9. The process as claimed in claim 1 wherein the stabilization agent is selected from the group consisting of calcium acetate, calcium succinate and calcium fumarate.

10. The process as claimed in claim 9 wherein the stabilization agent is calcium acetate.

11. The process as claimed in claim 3 wherein the first, second and third coating polymers are HMPC/PEG polymers.

12. The process as claimed in claim 1 wherein an outer coating comprises ferric oxide.

13. The process as claimed in claim 1 wherein the rosuvastatin-containing layer comprises rosuvastatin calcium and the first coating polymer in a ratio of between approximately 1:8 to 2:1.

14. The process as claimed in claim 1 wherein the core is a tablet core.

15. The process as claimed in claim 1 wherein the core is a pellet or granule core.

16. The process as claimed in claim 15 wherein the coated pellet or granule core is further processed to form a pharmaceutical product.

17. (canceled)

18. A pharmaceutical formulation comprising a tablet, pellet or granule core, the tablet, pellet or granule core comprising an inner layer coating comprising rosuvastatin calcium and calcium acetate in an HMPC/PEG polymer and an outer layer coating comprising an HMPC polymer and ferric oxide, wherein the inner layer is coated onto the tablet, pellet or granule core by spray coating a solution of rosuvastatin calcium, calcium acetate and an HPMC/PEG polymer in water.

Description

EXAMPLES

[0093] The tablets in the examples described below were coated using a perforated drum coater but other pharmaceutically acceptable coating equipment may also be used.

[0094] The core tablets were capsule shaped and had the following approximate dimensions: 9.8 mm×19.3 mm with a thickness of approximately 8 mm.

[0095] Hereinbelow the term “subcoat” refers to the sub-coating layer, the term “Agent Coat” refers to the rosuvastatin calcium containing layer and the term “top coat” refers to the outercoating layer”.

Example 1

[0096]

TABLE-US-00001 TABLE 1 Example 1 formulation per tab (mg) Core Tablets 1200 Opadry YS-1-10925A 60 Water 740

[0097] The core tablets were coated using a mixture containing Opadry YS-1-10925A and water. Spraying was carried out at a rate of 70 g/min, for 184 minutes, with an inlet temperature of 70-72° C.

Example 2

[0098]

TABLE-US-00002 TABLE 2 per tab (mg) Core Tablets 1200 Opadry II 85F19250 60 Water 740

[0099] The core tablets were coated using a mixture containing Opadry II 85F19250 and water. Spraying was carried out at a rate of 70 g/min, for 160 minutes, with an inlet temperature of 70-73° C.

Example 3

[0100]

TABLE-US-00003 TABLE 3 per tab (mg) Subcoat As Example 1 Agent Coat Subcoated Tablets 1293 Agent 20.8 Opadry YS-1-10925A 166.4 Water 3972.8 Top Coat Agent Coated Tablets 1484 Opadry 03B94523 72.3 Water 891.7

[0101] The coated core tablets were coated using a mixture of the Agent, Opadry YS-1-10925A, and water. Spraying was carried out at a rate of 15 g/min, for 330 minutes, with an inlet temperature of 56.0-61.9° C.

[0102] After the Agent coating was complete, the tablets were coated with a top coat system consisting of Opadry 03B94523 and water. Spraying was carried out at a rate of 15 g/min, for 70 minutes, with an inlet temperature of 60.8-62.5° C.

Example 4

[0103]

TABLE-US-00004 TABLE 4 per tab (mg) Subcoat As example 1 Agent Coat Subcoated Tablets 1293 Agent 20.8 Opadry YS-1-10925A 166.4 Water 3972.8 Top Coat Agent Coated Tablets 1480 Opadry 03B94523 72.3 Water 891.7

[0104] The coated core tablets were coated using a mixture of the Agent, Opadry YS-1-10925A, and water. Spraying was carried out at a rate of 15 g/min, for 342 minutes, with an inlet temperature of 69.1-72.7° C.

[0105] After the Agent coating was complete, the tablets were coated with a top coat system consisting of Opadry 03B94523 and water. Spraying was carried out at a rate of 15 g/min, for 50 minutes, with an inlet temperature of 52.2-58.5° C.

Example 5

[0106]

TABLE-US-00005 TABLE 5 per tab (mg) Subcoat As example 1 Agent Coat Subcoated Tablets 1293 Agent 20.8 Opadry YS-1-10925A 166.4 BHA 0.52 Ethanol USP 4.68 Water 3967.6 Top Coat Agent Coated Tablets 1482 Opadry 03B94523 72.3 Water 891.7

[0107] The coated core tablets were coated using a mixture of the Agent, Opadry YS-1-10925A, BHA-ethanol solution and water. Spraying was carried out at a rate of 15 g/min, for 340 minutes, with an inlet temperature of 58.4-61.0° C.

[0108] After the Agent coating was complete, the tablets were coated with a top coat system consisting of Opadry 03B94523 and water. Spraying was carried out at a rate of 15 g/min, for 65 minutes, with an inlet temperature of 62.0-65.1° C.

Example 6

[0109]

TABLE-US-00006 TABLE 6 per tab (mg) Subcoat As example 1 Agent Coat Subcoated Tablets 1293 Agent 20.8 Opadry YS-1-10925A 166.4 BHA 0.52 Ethanol USP 4.68 Water 3967.6 Top Coat Agent Coated Tablets 1481 Opadry 03B94523 72.3 Water 891.7

[0110] The coated core tablets were coated using a mixture of the Agent, Opadry YS-1-10925A, BHA-ethanol solution and water. Spraying was carried out at a rate of 15 g/min, for 360 minutes, with an inlet temperature of 66.0-73.6° C.

[0111] After the Agent coating was complete, the tablets were coated with a top coat system consisting of Opadry 03B94523 and water. Spraying was carried out at a rate of 15 g/min, for 68 minutes, with an inlet temperature of 57.0-59.1° C.

Example 7

[0112]

TABLE-US-00007 TABLE 7 per tab (mg) Subcoat As example 1 Agent Coat Subcoated Tablets 1285 Agent 20.8 Opadry II 85F19250 166.4 Water 3972.8 Top Coat Agent Coated Tablets 1475 Opadry II 85F94317 72.3 Water 891.7

[0113] The coated core tablets were coated using a mixture of the Agent, Opadry II 85F19250, and water. Spraying was carried out at a rate of 15 g/min, for 307 minutes, with an inlet temperature of 56.5-66.1° C.

[0114] After the Agent coating was complete, the tablets were coated with a top coat system consisting of Opadry II 85F94317 and water. Spraying was carried out at a rate of 15 g/min, for 54 minutes, with an inlet temperature of 59.2-69.9° C.

Example 8

[0115]

TABLE-US-00008 TABLE 8 per tab (mg) Subcoat As example 2 Agent Coat Subcoated Tablets 1285 Agent 20.8 Opadry II 85F19250 166.4 Water 3972.8 Top Coat Agent Coated Tablets 1476 Opadry II 85F94317 72.3 Water 891.7

[0116] The coated core tablets were coated using a mixture of the Agent, Opadry II 85F19250, and water. Spraying was carried out at a rate of 15 g/min, for 330 minutes, with an inlet temperature of 68.0-76.8° C.

[0117] After the Agent coating was complete, the tablets were coated with a top coat system consisting of Opadry II 85F94317 and water. Spraying was carried out at a rate of 15 g/min, for 48 minutes, with an inlet temperature of 65.0-72.6° C.

Example 9

[0118]

TABLE-US-00009 TABLE 9 per tab (mg) Subcoat As example 2 Agent Coat Subcoated Tablets 1285 Agent 20.8 Opadry II 85F19250 166.4 BHA 0.52 Ethanol USP 4.68 Water 3967.6 Top Coat Agent Coated Tablets 1488 Opadry II 85F94317 72.3 Water 891.7

[0119] The coated core tablets were coated using a mixture of the Agent, Opadry II 85F19250, BHA-ethanol solution and water. Spraying was carried out at a rate of 15 g/min, for 290 minutes, with an inlet temperature of 54.9-65.4° C.

[0120] After the Agent coating was complete, the tablets were coated with a top coat system consisting of Opadry II 85F94317 and water. Spraying was carried out at a rate of 15 g/min, for 50 minutes, with an inlet temperature of 64.5-70.5° C.

Example 10

[0121]

TABLE-US-00010 TABLE 10 per tab (mg) Subcoat As example 2 Agent Coat Subcoated Tablets 1285 Agent 20.8 Opadry II 85F19250 166.4 BHA 0.52 Ethanol USP 4.68 Water 3967.6 Top Coat Agent Coated Tablets 1461 Opadry II 85F94317 72.3 Water 891.7

[0122] The coated core tablets were coated using a mixture of the Agent, Opadry II 85F19250, BHA-ethanol solution and water. Spraying was carried out at a rate of 15 g/min, for 330 minutes, with an inlet temperature of 67.8-75.7° C.

[0123] After the Agent coating was complete, the tablets were coated with a top coat system consisting of Opadry II 85F94317 and water. Spraying was carried out at a rate of 15 g/min, for 62 minutes, with an inlet temperature of 66.0-70.3° C.

Example 11

[0124]

TABLE-US-00011 TABLE 11 per tab (mg) Subcoat Core Tablets 1228 Opadry YS-1-10925A 86.4 Water 1065.6 Agent Coat Subcoated Tablets 1310 Agent 10.4 Opadry YS-1-10925A 83.2 Water 1986.4 Top Coat No Top Coat

[0125] The core tablets were coated using a mixture containing Opadry YS-1-10925A and water. Spraying was carried out at a rate of 15 g/min, for 119 minutes, with an inlet temperature of 65.9-68.9° C. Then the coated core tablets were coated using a mixture of the Agent, Opadry YS-1-10925A, and water. Spraying was carried out at a rate of 15 g/min, for 180 minutes, with an inlet temperature of 61.5-68.0° C.

Example 12

[0126]

TABLE-US-00012 TABLE 12 per tab (mg) Subcoat Core Tablets 1228 Opadry YS-1-10925A 111 Water 1369 Agent Coat Subcoated Tablets 1342 Agent 10.4 Opadry YS-1-10925A 83.2 Water 1986.4 Top Coat No Top Coat

[0127] The core tablets were coated using a mixture containing Opadry YS-1-10925A and water. Spraying was carried out at a rate of 15 g/min, for 140 minutes, with an inlet temperature of 59.4-65.0° C. Then the coated core tablets were coated using a mixture of the Agent, Opadry YS-1-10925A, and water. Spraying was carried out at a rate of 15 g/min, for 175 minutes, with an inlet temperature of 62.0-68.1° C.

Example 13

[0128]

TABLE-US-00013 TABLE 13 per tab (mg) Subcoat As example 1 Agent Coat Subcoated Tablets 1293 Agent 20.8 Opadry YS-1-10925A 20.8 Water 4118.4 Top Coat Agent Coated Tablets 1325 Opadry 03B94523 26.7 Water 1041.3

[0129] The coated core tablets were coated using a mixture of the Agent, Opadry YS-1-10925A, and water. Spraying was carried out at a rate of 15 g/min, for 311 minutes, with an inlet temperature of 62.4-70.5° C. After the Agent coating was complete, the tablets were coated with a top coat system consisting of Opadry 03B94523 and water. Spraying was carried out at a rate of 15 g/min, for 60 minutes, with an inlet temperature of 67.0-72.3° C.

Example 14

[0130]

TABLE-US-00014 TABLE 14 per tab (mg) Subcoat As example 1 Agent Coat Subcoated Tablets 1293 Agent 20.8 Opadry YS-1-10925A 83.2 Water 4056 Top Coat Agent Coated Tablets 1385 Opadry 03B94523 26.7 Water 1041.3

[0131] The coated core tablets were coated using a mixture of the Agent, Opadry YS-1-10925A, and water. Spraying was carried out at a rate of 15 g/min, for 306 minutes, with an inlet temperature of 63.3-73.1° C. After the Agent coating was complete, the tablets were coated with a top coat system consisting of Opadry 03B94523 and water. Spraying was carried out at a rate of 15 g/min, for 60 minutes, with an inlet temperature of 54.5-70.8° C.

Example 15

[0132]

TABLE-US-00015 TABLE 15 per tab (mg) Subcoat As example 1 Agent Coat Subcoated Tablets 1293 Agent 20.8 Opadry YS-1-10925A 10.4 Water 4128.8 Top Coat Agent Coated Tablets 1326 Opadry 03B94523 25 Water 975

[0133] The coated core tablets were coated using a mixture of the Agent, Opadry YS-1-10925A, and water. Spraying was carried out at a rate of 15 g/min, for 435 minutes, with an inlet temperature of 66.0-71.7° C. After the Agent coating was complete, the tablets were coated with a top coat system consisting of Opadry 03B94523 and water. Spraying was carried out at a rate of 15 g/min, for 90 minutes, with an inlet temperature of 64.5-68.8° C.

Example 16

[0134]

TABLE-US-00016 TABLE 16 per tab (mg) Subcoat As example 1 Agent Coat Subcoated Tablets 1293 Agent 20.8 Opadry YS-1-10925A 20.8 Water 4118.4 Top Coat Agent Coated Tablets 1335 Opadry 03B94523 25 Water 975

[0135] The coated core tablets were coated using a mixture of the Agent, Opadry YS-1-10925A, and water. Spraying was carried out at a rate of 15 g/min, for 435 minutes, with an inlet temperature of 66.0-74.4° C. After the Agent coating was complete, the tablets were coated with a top coat system consisting of Opadry 03B94523 and water. Spraying was carried out at a rate of 15 g/min, for 85 minutes, with an inlet temperature of 66.5-69.7° C.

Example 17

[0136]

TABLE-US-00017 TABLE 17 per tab (mg) Subcoat As example 1 Agent Coat Subcoated Tablets 1293 Agent 20.8 Opadry YS-1-10925A 31.2 Water 4108 Top Coat Agent Coated Tablets 1349 Opadry 03B94523 25 Water 975

[0137] The coated core tablets were coated using a mixture of the Agent, Opadry YS-1-10925A, and water. Spraying was carried out at a rate of 15 g/min, for 438 minutes, with an inlet temperature of 66.7-71.1° C. After the Agent coating was complete, the tablets were coated with a top coat system consisting of Opadry 03B94523 and water. Spraying was carried out at a rate of 15 g/min, for 95 minutes, with an inlet temperature of 66.0-70.0° C.

Example 18

[0138]

TABLE-US-00018 TABLE 18 per tab (mg) Subcoat As example 1 Agent Coat Subcoated Tablets 1293 Agent 20.8 Opadry YS-1-10925A 20.8 Calcium Acetate 6.6 Water 4118.4 Top Coat Agent Coated Tablets 1335 Opadry 03B94523 25 Water 975

[0139] The coated core tablets were coated using a mixture of the Agent, calcium acetate, Opadry YS-1-10925A, and water. Spraying was carried out at a rate of 15 g/min, for 390 minutes, with an inlet temperature of 66.4-68.0° C. After the Agent coating was complete, the tablets were coated with a top coat system consisting of Opadry 03B94523 and water. Spraying was carried out at a rate of 15 g/min, for 70 minutes, with an inlet temperature of 67.5-73.7° C.

Example 19

[0140]

TABLE-US-00019 per tab (mg) Subcoat As example 1 Agent Coat Subcoated Tablets 1293 Agent 20.8 Opadry YS-1-10925A 20.8 Sodium Hydroxide 0.8 Water 4117.6 Top Coat Agent Coated Tablets 1337 Opadry 03B94523 25 Water 975

[0141] The coated core tablets were coated using a mixture of the Agent, sodium hydroxide solution, Opadry YS-1-10925A, and water. Spraying was carried out at a rate of 15 g/min, for 390 minutes, with an inlet temperature of 67.0-68.5° C. After the Agent coating was complete, the tablets were coated with a top coat system consisting of Opadry 03B94523 and water. Spraying was carried out at a rate of 15 g/min, for 70 minutes, with an inlet temperature of 69.0-75.0° C.

TABLE-US-00020 Moisture Values after Coating and Heating at 50° C. for 24 h in % w/w Example Subcoat Agent Coating Top Coat 1 1.00 N/A N/A 2 1.46 N/A N/A 3 See Example 1 2.17 1.74 4 See Example 1 1.41 1.37 5 See Example 1 2.34 1.89 6 See Example 1 1.38 1.28 7 See Example 2 3.25 3.11 8 See Example 2 2.07 1.96 9 See Example 2 3.60 2.92 10 See Example 2 1.98 1.98 11 0.79 1.26 No Top Coat 12 0.95 1.20 No Top Coat 13 See Example 1 0.78 0.81 14 See Example 1 0.76 0.89 15 See Example 1 0.94 0.90 16 See Example 1 0.86 0.83 17 See Example 1 0.79 0.76 18 See Example 1 0.81 0.97 19 See Example 1 1.34 1.26

[0142] Lactone Formation (% w/w)

[0143] The stability of the formulations of the invention is illustrated by the following stability information.

TABLE-US-00021 Example 3 Example 13 Example 18 Example 19 (labelled as 10 (labelled as (labelled as (labelled as below) 22 below) 27 below) 28 below) 0 month 0.273 0 month 0.060 0 month 0.041 0.055 1 month 0.471 1 month 0.120 1 month 0.058 0.089 3 month 0.848 8 month 0.235 7 month 0.071 0.198