Pharmaceutical composition comprising rosuvastatin and ezetimibe and a preparation method thereof

Abstract

The invention relates to a pharmaceutical composition comprising the active ingredients rosuvastatin of formula I, with the systematic name (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe of formula II, with the systematic name (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one or its pharmaceutically acceptable salts, esters, hydrates or solvates, as well as a preparation method of this pharmaceutical composition. The weight ratio of the layers is 1:2 to 2:1. ##STR00001##

Claims

1. A two-layer oral tablet comprising: (a) rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates; (b) ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates; wherein the tablet comprises one ezetimibe layer and one rosuvastatin layer; wherein said ezetimibe layer comprises a granulate and an extragranulate phase; wherein the granulate comprises ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates; wherein the extragranulate phase comprises stearic acid or its acceptable salts as a glidant at a concentration of 0.15 to 0.5% by weight, including the limit values, relative to the weight of the ezetimibe layer, and at least one further pharmaceutically acceptable excipient comprising a filler, a binder, or a disintegrant; and wherein said rosuvastatin layer consists of rosuvastatin or its pharmaceutically acceptable salt, ester, hydrate or solvate, and at least one pharmaceutically acceptable excipient, wherein said pharmaceutically acceptable excipient(s) are non-basic, and wherein the rosuvastatin layer does not contain a basic excipient.

2. The two-layer oral tablet according to claim 1, wherein the stearic acid or its acceptable salts comprise magnesium stearate, calcium stearate, or aluminum stearate.

3. The two-layer oral tablet according to claim 1, wherein the weight ratio of the ezetimibe layer and rosuvastatin layer is in the range from 1:2 to 2:1, including the limit values.

4. The two-layer oral tablet according to claim 1, wherein the granulate of the ezetimibe layer comprises ezetimibe or its pharmaceutically acceptable salt, ester, hydrate or solvate, and at least one pharmaceutically acceptable excipient comprising a filler, a binder, a disintegrant, or a surfactant.

5. The two-layer oral tablet according to claim 1, wherein the granulate of the ezetimibe layer is free of microcrystalline cellulose and wherein the extragranulate layer comprises microcrystalline cellulose.

6. The two-layer oral tablet according to claim 1, wherein the extragranular phase of the ezetimibe layer comprises microcrystalline cellulose, at a concentration of up to 10.5% by weight, including the limit values, relative to the weight of the ezetimibe layer.

7. The two-layer oral tablet according to claim 1, wherein the ezetimibe layer comprises: a filler or a combination of fillers comprising lactose, glucose, calcium carbonate, calcium phosphate, starch, or sugar alcohols; a binder or a combination of binders comprising water-soluble polymers or water-soluble cellulose derivatives, said water-soluble cellulose derivatives comprising methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose or hydroxypropyl methylcellulose; a disintegrant or a combination of disintegrants comprising sodium salt of croscarmellose, sodium salt of carboxymethyl starch, crospovidone, or alginates; or a surfactant or a combination of surfactants comprising block copolymers of ethylene oxide and propylene oxide, alkyl sulphates, alkyl aryl sulfonates, polyethylene glycols, or polysorbates.

8. The two-layer oral tablet according to claim 1, wherein the at least one pharmaceutically acceptable non-basic excipient in the rosuvastatin layer consists of: a filler or a combination of fillers comprising lactose or its monohydrate, glucose, cellulose, starch, or sugar alcohols; a binder or a combination of binders comprising polyvinylpyrrolidone, microcrystalline cellulose, water-soluble cellulose, or sugar alcohols; a disintegrant or a combination of disintegrants comprising sodium salt of croscarmellose, sodium salt of carboxymethyl starch, crospovidone or alginates; a glidant or a combination of glidants comprising colloidal silicon dioxide, maize starch, talc, polyethylene oxide, sodium stearyl fumarate, or stearic acid or its acceptable salts; or any combination thereof.

9. The two-layer oral tablet according to claim 1, wherein the tablet contains 10 mg of ezetimibe or the corresponding amount of its pharmaceutically acceptable salt, ester, hydrate or solvate, and 5 to 45 mg of rosuvastatin or the corresponding amount of its pharmaceutically acceptable salt, ester, hydrate or solvate.

10. A method of preparation of a two-layer oral tablet comprising rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, and pharmaceutically acceptable excipients, and consisting of one ezetimibe layer and one rosuvastatin layer, wherein the method comprises the steps a) to e): a) ezetimibe or its pharmaceutically acceptable salt, together with at least one first pharmaceutically acceptable excipient which is other than microcrystalline cellulose, is granulated with the use of water as a wetting agent, b) the obtained granules of ezetimibe are mixed with at least one second pharmaceutically acceptable excipient, the at least one second pharmaceutically acceptable excipient being a glidant, which is stearic acid or its acceptable salts, at a concentration of 0.15 to 0.5% by weight, including the limit values, relative to the weight of the ezetimibe layer, and at least one other pharmaceutically acceptable excipient selected from a group comprising a filler, a binder and a disintegrant; c) rosuvastatin or its pharmaceutically acceptable salt, is mixed together with at least one pharmaceutically acceptable excipient, said excipient(s) being non-basic, wherein the rosuvastatin layer does not contain a basic excipient, d) the obtained tableting blend of ezetimibe and rosuvastatin is compressed into two-layer tablets, e) coating is optionally applied onto the obtained two-layer tablets.

11. The method according to claim 10, wherein the at least one first pharmaceutically acceptable excipient in step a) is selected from a group comprising a filler, a binder, a disintegrant, a surfactant or any combinations thereof.

12. The method according to claim 10, wherein the mixture of ezetimibe with at least one first pharmaceutically acceptable excipient in step a) is wetted with the use of water and the obtained mixture is processed into granulate by means of fluid granulation.

13. The method according to claim 10, wherein the at least one second pharmaceutically acceptable excipient in step b) in the extragranular phase is magnesium stearate, calcium stearate or aluminum stearate.

14. The method according to claim 10, wherein the second pharmaceutically acceptable excipients in step b) in the extragranular phase comprise microcrystalline cellulose, contained in a total concentration of up to 10.5% by weight, including the limit values, relative to the weight of the ezetimibe layer; or the second pharmaceutically acceptable excipients are free of microcrystalline cellulose.

15. The method according to claim 10, wherein the at least one pharmaceutically acceptable non-basic excipient in step c) is selected from a group comprising: a filler or a combination of fillers, selected from the group comprising lactose or its monohydrate, glucose, cellulose and its derivatives, starch, and sugar alcohols; a binder or a combination of binders selected from a group comprising polyvinylpyrrolidone, microcrystalline cellulose, water-soluble cellulose derivatives, and sugar alcohols; a disintegrant or a combination of disintegrants selected from a group comprising sodium salt of croscarmellose, sodium salt of carboxymethyl starch, crospovidone, and alginates; a glidant or combination of glidants, selected from a group comprising colloidal silicon dioxide, maize starch, talc, polyethylene oxide, sodium stearyl fumarate, and stearic acid or its acceptable salts; and any combination thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1: The dissolution profile of releasing of ezetimibe from a two-layer tablet according to the invention (example 13) as compared to the tablet of Comparative Example A

(2) FIG. 2: The dissolution profile of releasing of ezetimibe from a two-layer tablet according to the invention (example 13) as compared to the tablet of Comparative Example C

EXAMPLES

(3) The embodiment examples below are only provided to illustrate and to explain the invention and are not in any case intended to restrict the protection scope, which is only delimited by the wording of the patent claims. Any other modifications of the composition or production methods are possible if they are implemented in line with maintaining the stability of the composition and the dissolution profile of both the active substances.

(4) Examples of a Stable Formulation of the Ezetimibe Layer

(5) In all the Examples 1 to 6 the tableting blend for the ezetimibe layer was prepared by wet granulation with water as the granulating wetting agent.

Example 1

(6) TABLE-US-00001 Composition Substance name Function (mg/tbl) Granulate Ezetimibe active 10.0 ingredient Lactose monohydrate filler 141.0 Sodium salt of croscarmellose disintegrant 12.0 Sodium lauryl sulphate surfactant 4.0 Povidone 25 binder 8.0 Extragranular phase Microcrystalline cellulose filler, binder 20.0 Sodium salt of croscarmellose disintegrant 4.0 Magnesium stearate glidant 1.0 Layer - total: 200.0

Example 2

(7) TABLE-US-00002 Composition Substance name Function (mg/tbl) Granulate Ezetimibe active 10.0 ingredient Lactose monohydrate filler 137.0 Sodium salt of carboxymethyl disintegrant 14.0 starch Sodium stearyl sulphate surfactant 4.0 Hydroxypropyl binder 8.0 methylcellulose (Methocel E5) Extragranular phase Microcrystalline cellulose filler, binder 20.4 Sodium salt of carboxymethyl disintegrant 6.0 starch Magnesium stearate glidant 0.6 Layer - total: 200.0

Example 3

(8) TABLE-US-00003 Composition Substance name Function (mg/tbl) Granulate Ezetimibe active 10.0 ingredient Mannitol filler 141.0 Sodium salt of croscarmellose disintegrant 12.0 Sodium lauryl sulphate surfactant 4.0 Povidone 25 binder 8.0 Extragranular phase Microcrystalline cellulose filler, binder 20.7 Sodium salt of croscarmellose disintegrant 4.0 Calcium stearate glidant 0.3 Layer - total: 200.0

Example 4

(9) TABLE-US-00004 Composition Substance name Function (mg/tbl) Granulate Ezetimibe active 10.0 ingredient Lactose monohydrate filler 161.4 Sodium salt of croscarmellose disintegrant 12.0 Sodium lauryl sulphate surfactant 4.0 Hydroxypropyl binder 8.0 methylcellulose (Methocel E5) Extragranular phase Microcrystalline cellulose filler, binder — Sodium salt of croscarmellose disintegrant 4.0 Aluminum stearate glidant 0.6 Layer - total: 200.0

Example 5

(10) TABLE-US-00005 Composition Substance name Function (mg/tbl) Granulate Ezetimibe active 10.0 ingredient Mannitol filler 141.0 Sodium salt of croscarmellose disintegrant 12.0 Sodium lauryl sulphate surfactant 4.0 Povidone 25 binder 8.0 Extragranular phase Microcrystalline cellulose filler, binder 20.0 Sodium salt of croscarmellose disintegrant 4.0 Stearic acid glidant 1.0 Layer - total: 200.0

Example 6

(11) TABLE-US-00006 Composition Substance name Function (mg/tbl) Granulate Ezetimibe active 10.0 ingredient Lactose monohydrate filler 161.0 Sodium salt of croscarmellose disintegrant 12.0 Sodium lauryl sulphate surfactant 4.0 Povidone 25 binder 8.0 Extragranular phase Microcrystalline cellulose filler, binder — Sodium salt of croscarmellose disintegrant 4.0 Magnesium stearate glidant 1.0 Layer - total: 200.0
Examples of a Stable Formulation of the Rosuvastatin Layer

(12) In all the Examples 7 to 12 the tableting blend for the rosuvastatin layer was prepared by direct mixing.

Example 7

(13) TABLE-US-00007 Composition Substance name Function (mg/tbl) Rosuvastatin layer Rosuvastatin calcium salt active 41.6 ingredient Lactose monohydrate filler, binder 244.0 Microcrystalline cellulose filler, binder 94.0 Colloidal silicon dioxide glidant 2.4 Sodium salt of croscarmellose disintegrant 12.0 Magnesium stearate glidant 6.0 Layer - total: 400.0

Example 8

(14) TABLE-US-00008 Composition Substance name Function (mg/tbl) Rosuvastatin layer Rosuvastatin calcium salt active 41.6 ingredient Lactose monohydrate filler, binder 244.0 Microcrystalline cellulose filler, binder 94.0 Talc/talcum powder glidant 2.4 Sodium salt of croscarmellose disintegrant 12.0 Magnesium stearate glidant 6.0 Layer - total: 400.0

Example 9

(15) TABLE-US-00009 Composition Substance name Function (mg/tbl) Rosuvastatin layer Rosuvastatin calcium salt active 41.6 ingredient Mannitol filler, binder 244.0 24Microcrystalline cellulose filler, binder 94.0 Colloidal silicon dioxide glidant 2.4 Sodium salt of croscarmellose disintegrant 12.0 Aluminum stearate glidant 6.0 Layer - total: 400.0

Example 10

(16) TABLE-US-00010 Composition Substance name Function (mg/tbl) Rosuvastatin layer Rosuvastatin calcium salt active 41.6 ingredient Mannitol filler, binder 240.0 Microcrystalline cellulose filler, binder 94.0 Colloidal silicon dioxide glidant 2.4 Sodium salt of carboxymethyl disintegrant 16.0 starch Calcium stearate glidant 6.0 Layer - total: 400.0

Example 11

(17) TABLE-US-00011 Composition Substance name Function (mg/tbl) Rosuvastatin layer Rosuvastatin calcium salt active 20.8 ingredient Lactose monohydrate filler, binder 122.0 Microcrystalline cellulose filler, binder 47.0 Colloidal silicon dioxide glidant 1.2 Sodium salt of croscarmellose disintegrant 6.0 Magnesium stearate glidant 3.0 Layer - total: 200.0

Example 12

(18) TABLE-US-00012 Composition Substance name Function (mg/tbl) Rosuvastatin layer Rosuvastatin calcium salt active 10.4 ingredient Lactose monohydrate filler, binder 61.0 Microcrystalline cellulose filler, binder 23.5 Colloidal silicon dioxide glidant 0.6 Sodium salt of croscarmellose disintegrant 3.0 Magnesium stearate glidant 1.5 Layer - total: 100.0
Stable Formulation of a Two-Layer Tablet Comprising an Ezetimibe Layer and a Rosuvastatin Layer

Examples 13-15

(19) TABLE-US-00013 Composition (mg/tbl) Substance name Example 13 Example 14 Example 15 Ezetimibe layer according to according to according to Example 1 Example 1 Example 1 Rosuvastatin layer according to according to according to Example 7 Example 11 Example 12 Tablet core - total: 600.0 400.0 300.0 Coating layer Hydroxypropyl 10.45 6.97 5.23 methylcellulose Polyethylene glycol 6000 1.50 1 0.75 Titanium dioxide 1.20 0.8 0.6 Talc 1.80 1.2 0.9 Red iron oxide 0.05 — — Yellow iron oxide — 0.03 — Tablet - total: 615.0 410.0 307.48

(20) Abrasion, determined using the method according to the European Pharmacopoeia, was less than 0.2% for Examples 13-15.

(21) During the dissolution test, more than 90% by weight of the declared amount of ezetimibe was released from the tablets after 30 minutes:

(22) TABLE-US-00014 Example Example Test 13 Example 14 15 Disintegration time of the two- 3 min 4 min 3 min layer tablet Released ezetimibe after 30 min 98.3% 94.7 97.6% (% by weight, average value of 10 tablets) Released ezetimibe after 30 min 96.5% 90.7% 94.3 (% by weight, minimum measured value of 10 tablets) Released rosuvastatin after 30 min 97.6% 99.6% 99.6% (% by weight, average value of 10 tablets) Released rosuvastatin after 30 min 95.6% 98.3% 95.7% (% by weight, minimum measured value of 10 tablets)

(23) TABLE-US-00015 Test Example 13 Example 14 Example 15 Content of ezetimibe after the 10.2 mg     10.1 mg    10.2 mg production, average value of 10 (9.9-10.3 mg)    (10.0-10.2 mg) (9.9-10.2 mg) tablets (minimum and maximum measured value) Content of rosuvastatin after the 40.2 mg     20.1 mg    10.2 mg production, average value of 10 (39.3-40.4 mg)     (19.8-20.2 mg) (9.8-10.3 mg) tablets (minimum and maximum measured value)

Examples 16-18

(24) TABLE-US-00016 Composition (mg/tbl) Substance name Example 16 Example 17 Example 18 Ezetimibe layer according to according to according to Example 2 Example 4 Example 5 Rosuvastatin layer according to according to according to Example 8 Example 11 Example 12 Tablet core - total: 600.0 400.0 300.0 Coating layer Hydroxypropyl 10.45 6.97 5.23 methylcellulose Polyethylene glycol 6000 1.50 1 0.75 Titanium dioxide 1.20 0.8 0.6 Talc 1.80 1.2 0.9 Red iron oxide 0.05 — — Yellow iron oxide — 0.03 — Tablet - total: 615.0 410.0 307.48

(25) Abrasion, determined using the method according to the European Pharmacopoeia, was less than 0.2% for Examples 16-18.

(26) TABLE-US-00017 Example Example Test 16 Example 17 18 Disintegration time of the two- 3 min 3 min 4 min layer tablet Released ezetimibe after 30 min 96.2% 93.4 97.1% (% by weight, average value of 10 tablets) Released ezetimibe after 30 min 86.5% 85.3% 93.2% (% by weight, minimum measured value of 10 tablets) Released rosuvastatin after 30 min 97.1% 97.1% 97.5% (% by weight, average value of 10 tablets) Released rosuvastatin after 30 min 96.3% 93.1% 96.7% (% by weight, minimum measured value of 10 tablets)

Examples 19-21

(27) TABLE-US-00018 Composition (mg/tbl) Substance name Example 19 Example 20 Example 21 Ezetimibe layer according to according to according to Example 1 Example 3 Example 6 Rosuvastatin layer according to according to according to Example 9 Example 11 Example 12 Tablet core - total: 600.0 400.0 300.0 Coating layer Hydroxypropyl 10.45 6.97 5.23 methylcellulose Polyethylene glycol 6000 1.50 1 0.75 Titanium dioxide 1.20 0.8 0.6 Talc 1.80 1.2 0.9 Red iron oxide 0.05 — — Yellow iron oxide — 0.03 — Tablet - total: 615.0 410.0 307.48

(28) Abrasion, determined using the method according to the European Pharmacopoeia, was less than 0.2% for Examples 19-21.

(29) TABLE-US-00019 Test Example 19 Example 20 Example 21 Disintegration time of the two- 5 min 3 min 4 min layer tablet Released ezetimibe after 30 min 96.2% 98.2% 97.4% (% by weight, average value of 10 tablets) Released ezetimibe after 30 min 86.5% 95.8% 90.9% (% by weight, minimum measured value of 10 tablets) Released rosuvastatin after 30 97.1% 97.4% 98.2% min (% by weight, average value of 10 tablets) Released rosuvastatin after 30 96.3% 94.7% 96.4% min (% by weight, minimum measured value of 10 tablets)

COMPARATIVE EXAMPLES

(30) In all the Comparative Examples A to D, the tableting blend for the ezetimibe layer was prepared in the same way as in Examples 1 to 6, i.e. by means of wet granulation with water as the granulation wetting agent, and the tableting blend for the rosuvastatin layer was prepared in the same way as in Examples 7 to 12, i.e. by means of direct mixing. After the compression, coating was applied onto the two-layer tablets in the same way as in Example 13.

Comparative Example A—Magnesium Stearate Contents 1% by Weight and 1.5% by Weight

(31) TABLE-US-00020 Composition A1 Composition A2 Substance name (mg/tbl) (mg/tbl) Ezetimibe granulate: Ezetimibe 10.0 10.0 Lactose monohydrate 140.0 139.0 Sodium salt of croscarmellose 12.0 12.0 Sodium lauryl sulphate 4.0 4.0 Povidone 25 8.0 8.0 Extragranular phase: Microcrystalline cellulose 20.0 20.0 Sodium salt of croscarmellose 4.0 4.0 Magnesium stearate 2.0 3.0 Ezetimibe layer—total: 200.0 200.0 Rosuvastatin layer: Rosuvastatin calcium salt 41.6 41.6 Lactose monohydrate 244.0 244.0 Microcrystalline cellulose 94.0 94.0 Colloidal silicon dioxide 2.4 2.4 Sodium salt of croscarmellose 12.0 12.0 Magnesium stearate 6.0 6.0 Rosuvastatin layer—total: 400.0 400.0 Tablet—total: 600.0 600.0

(32) TABLE-US-00021 Comparative Comparative Test Example A1 Example A2 Disintegration time of the two-layer tablet 4 min 5 min Released ezetimibe after 30 min 84.7% 81.1% (% by weight, average value of 10 tablets)

(33) TABLE-US-00022 Comparative Comparative Test Example A1 Example A2 Released ezetimibe after 30 min 79.1% 77.3% (% by weight, minimum measured value of 10 tablets) Released rosuvastatin after 30 97.1% 97.4% min (% by weight, average value of 10 tablets) Released rosuvastatin after 30 96.3% 94.7% min (% by weight, minimum measured value of 10 tablets)

(34) The dissolution profiles of tablet A2 and the tablet in accordance with Example 13 are shown in FIG. 1.

Comparative Example B—Ratio of Layers 1:3 and 3:1

(35) TABLE-US-00023 Composition B1 Composition B2 Substance name (mg/tbl) (mg/tbl) Ezetimibe granulate: Ezetimibe 10.0 10.0 Lactose monohydrate 90.5 224.8 Sodium salt of croscarmellose 8.0 16.0 Sodium lauryl sulphate 2.7 5.3 Povidone 25 5.3 10.6 Extragranular phase: Microcrystalline cellulose 13.3 26.6 Sodium salt of croscarmellose 2.7 5.3 Magnesium stearate 0.6 1.3 Ezetimibe layer—total: 133.1 299.9 Rosuvastatin layer:

(36) TABLE-US-00024 Composition B1 Composition B2 Substance name (mg/tbl) (mg/tbl) Rosuvastatin calcium salt 41.6 10.4 Lactose monohydrate 244.0 61.0 Microcrystalline cellulose 94.0 23.5 Colloidal silicon dioxide 2.4 0.6 Sodium salt of croscarmellose 12.0 3.0 Magnesium stearate 6.0 1.5 Rosuvastatin layer-total: 400.0 100.0 Tablet-total: 533.1 399.9

(37) Abrasion, determined using the method according to the European Pharmacopoeia, was 4% for composition B1 and 6% for composition B2.

(38) TABLE-US-00025 Comparative Comparative Test Example B1 Example B2 Content of ezetimibe after the 10.2 mg 10.1 mg production (average value of  (9.3-10.6 mg)  (9.1-10.7 mg) 10 tablets, minimum and maximum measured value) Content of rosuvastatin after the 39.9 mg 40.2 mg production (average value of (37.6-42.4 mg) (38.0-42.7 mg) 10 tablets, minimum and maximum measured value)

Comparative Example C—Microcrystalline Cellulose in the Intragranular Phase of the Ezetimibe Layer

(39) TABLE-US-00026 Composition Substance name Function (mg/tbl) Granulate Ezetimibe active ingredient 10.0 Lactose monohydrate filler 131.0 Microcrystalline cellulose filler, binder 10.0 Sodium salt of croscarmellose disintegrant 12.0 Sodium lauryl sulphate surfactant 4.0 Povidone 25 binder 8.0 Extragranular phase Microcrystalline cellulose filler, binder 20.0 Sodium salt of croscarmellose disintegrant 4.0 Magnesium stearate glidant 1.0 Layer - total: 200.0 Rosuvastatin layer Rosuvastatin calcium salt active ingredient 41.6 Lactose monohydrate filler, binder 244.0 Microcrystalline cellulose filler, binder 94.0 Colloidal silicon dioxide glidant 2.4 Sodium salt of croscarmellose disintegrant 12.0 Magnesium stearate glidant 6.0 Layer - total: 400.0

(40) TABLE-US-00027 Comparative Test Example C Disintegration time of the two-layer tablet 7 min Released ezetimibe after 30 min 82.6% (% by weight, average value of 10 tablets) Released ezetimibe after 30 min (% by weight, 77.3% minimum measured value of 10 tablets) Released rosuvastatin after 30 min 98.2% (% by weight, average value of 10 tablets) Released rosuvastatin after 30 min (% by weight, 96.4 minimum measured value of 10 tablets)

(41) The dissolution profile of releasing of ezetimibe was measured and compared to the dissolution profile of the tablet in accordance with Example 13 and 21. The dissolution profile of the tablet in accordance with Comparative Example C and the tablet in accordance with Example 13 and 21 are shown in FIG. 2.

Comparative Example D—Stabilization of the Rosuvastatin Layer with Calcium Hydrogen Phosphate

(42) TABLE-US-00028 Composition Substance name (mg/tbl) Ezetimibe granulate: Ezetimibe 10.0 Lactose monohydrate 141.0 Sodium salt of croscarmellose 12.0 Sodium lauryl sulphate 4.0 Povidone 25 8.0 Extragranular phase: Microcrystalline cellulose 20.0 Sodium salt of croscarmellose 4.0 Magnesium stearate 1.0 Ezetimibe layer - total: 200.0 Rosuvastatin layer: Rosuvastatin calcium salt 41.6 Lactose monohydrate 224.0 Calcium hydrogen phosphate 20 Microcrystalline cellulose 94.0 Colloidal silicon dioxide 2.4 Sodium salt of croscarmellose 12.0 Magnesium stearate 6.0 Rosuvastatin layer - total: 400.0 Coating layer: Hydroxypropyl methylcellulose 10.45 Polyethylene glycol 6000 1.50 Titanium dioxide 1.20 Talc 1.80 Red iron oxide 0.05 Yellow iron oxide — Tablet - total: 615.0

(43) Two-layer tablets according to Comparative Example D, stabilized with calcium hydrogen phosphate, and two-layer tablets according to Example 13 were exposed to a stability test at the conditions of 40° C. and 75% relative humidity for 6 months. The results show that the two-layer tablet according to the invention is as stable as the two-layer tablet stabilized with calcium hydrogen phosphate.

(44) TABLE-US-00029 Comparative Test Example 2 Example 13 Total contents of impurities of 0.06% <0.05% ezetimibe (average value of 10 tablets, (<0.05-0.06%) (<0.05-0.06%) minimum and maximum measured value) Total contents of impurities of 0.28% 0.31 rosuvastatin (average value of 10 0.20-0.32   (0.24-0.37%) tablets, minimum and maximum measured value)
Methods Used

(45) Unless specified otherwise, methods according to Ph. Eur (European Pharmacopoeia) were used.

(46) Variability of the Contents of the Active Ingredients, Uniformity of the Contents, Abrasion, Disintegration Time, Strength

(47) according to Ph. Eur (European Pharmacopoeia)
Dissolution Measurements A device with stirrers according to Ph. Eur. (European Pharmacopoeia) 900 ml, phosphate buffer, having pH 7.0±0.05 with 0.5% of sodium lauryl sulphate, 75 rpm HPLC chromatography with a column detector with a UV or PDA detector, column Kinetex 2.6μ, C18, 30×4.60 mm or its equivalent, mobile phase 0.1% of phosphoric acid:methanol (42:58 v/v), solvent acetonitrile:water (60:40, v/v), detection 242 nm
Stability stability test, storage at the conditions of 40° C. and 75% relative humidity for 6 months gradient elution method on HPLC chromatography with a UV (PDA) detector, column Gemini C6-Phenyl, 3 μm, 150×4.6 mm or its equivalent, mobile phase 1.0 ml of phosphoric acid per 1000 ml of water (constituent A) and methanol (constituent B) in the gradient program as specified in the table below, detection 245 nm

(48) TABLE-US-00030 Time Constituent A Constituent B (min) (% v/v) (% v/v) 0 45 55 11.0 40 60 14.0 25 75 19.0 25 75 19.5 45 55 23.0 45 55
Uniformity, Variability of the Contents HPLC chromatography with a column thermostat and UV detector, column Gemini C6-Phenyl, 3 μm, 150×4.6 mm (Phenomenex) or its equivalent, mobile phase 0.085% of phosphoric acid:methanol (35:65, v/v), detection 245 nm.