SOLID ORAL PHARMACEUTICAL COMPOSITION

Abstract

A solid oral pharmaceutical composition is disclosed, which comprises: a first active ingredient, which is pitavastatin or a pharmaceutically acceptable salt thereof; a second active ingredient, which is ezetimibe or a pharmaceutically acceptable salt thereof; and at least one excipient, including a diluent, a stabilizing agent, a disintegrant, a binding agent, a sweetener, a lubricant, a glidant, a flavor, a coloring agent or a combination thereof.

Claims

1. A solid oral pharmaceutical composition, comprising: a first active ingredient, which is pitavastatin or a pharmaceutically acceptable salt thereof; a second active ingredient, which is ezetimibe or a pharmaceutically acceptable salt thereof; and at least one excipient, including a diluent, a stabilizing agent, a disintegrant, a binding agent, a sweetener, a lubricant, a glidant, a flavor, a coloring agent or a combination thereof.

2. The solid oral pharmaceutical composition of claim 1, wherein the first active ingredient is pitavastatin calcium.

3. The solid oral pharmaceutical composition of claim 1, wherein the second active ingredient is ezetimibe.

4. The solid oral pharmaceutical composition of claim 1, wherein a loading of the first active ingredient in a unit dosage form is in a range from

0. 5 mg to 5 mg.

5. The solid oral pharmaceutical composition of claim 1, wherein a loading of the second active ingredient in a unit dosage form is in a range from 5 mg to 20 mg.

6. The solid oral pharmaceutical composition of claim 1, wherein the excipient includes the stabilizing agent, which is magnesium oxide, magnesium aluminometasilicate, potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium hydroxide, calcium carbonate, ammonium hydroxide, diethanolamine or a combination thereof.

7. The solid oral pharmaceutical composition of claim 1, wherein the excipient includes the stabilizing agent, which is citric acid, acetic acid, tartaric acid, lactic acid, sodium phosphate monobasic or a combination thereof.

8. The solid oral pharmaceutical composition of claim 1, which is a tablet.

9. The solid oral pharmaceutical composition of claim 8, which is a single layered tablet, wherein the single layered tablet comprises the first active ingredient, the second active ingredient and the excipient.

10. The solid oral pharmaceutical composition of claim 8, which is a double layered tablet, wherein one layer of the double layered tablet comprises the first active ingredient and the excipient, and the other layer of the double layered tablet comprises the second active ingredient and the excipient.

11. The solid oral pharmaceutical composition of claim 1, which is a capsule, wherein the capsule comprises a first tablet and a second tablet, the first tablet comprises the first active ingredient and the excipient, and the second tablet comprises the second active ingredient and the excipient.

12. The solid oral pharmaceutical composition of claim 1, which is a capsule, wherein the capsule comprises a first granule and a second granule, the first granule comprises the first active ingredient and the excipient, and the second granule comprises the second active ingredient and the excipient.

13. The solid oral pharmaceutical composition of claim 1, which is a capsule, wherein the capsule comprises a first pellet and a second pellet, and the first pellet comprises: a first core; a first drug-containing layer disposed on the first core and comprising the first active ingredient and the excipient; and a first protection layer disposed on the first drug-containing layer and comprising a polymer.

14. The solid oral pharmaceutical composition of claim 13, wherein the polymer is povidone.

15. The solid oral pharmaceutical composition of claim 13, wherein the excipient comprised in the first drug-containing layer is the stabilizing agent, which is magnesium oxide, magnesium aluminometasilicate, potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium hydroxide, calcium carbonate, ammonium hydroxide, diethanolamine or a combination thereof.

16. The solid oral pharmaceutical composition of claim 15, wherein the stabilizing agent is magnesium oxide.

17. The solid oral pharmaceutical composition of claim 1, which is a capsule, wherein the capsule comprises a first pellet and a second pellet, and the second pellet comprises: a second core; a second drug-containing layer disposed on the second core and comprising the second active ingredient and the excipient; and a second protection layer disposed on the second drug-containing layer and comprising a polymer.

18. The solid oral pharmaceutical composition of claim 17, wherein the polymer is povidone.

19. The solid oral pharmaceutical composition of claim 17, wherein the excipient comprised in the second drug-containing layer is the stabilizing agent, which is citric acid, acetic acid, tartaric acid, lactic acid, sodium phosphate monobasic or a combination thereof.

20. The solid oral pharmaceutical composition of claim 17, wherein the stabilizing agent is citric acid.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIG. 1 is a schematic diagram showing a solid oral pharmaceutical composition according to Example 1 of the present disclosure.

[0035] FIG. 2 is a schematic diagram showing a solid oral pharmaceutical composition according to Example 2 of the present disclosure.

[0036] FIG. 3 is a schematic diagram showing a solid oral pharmaceutical composition according to Example 3 of the present disclosure.

[0037] FIG. 4 is a schematic diagram showing a solid oral pharmaceutical composition according to Example 4 of the present disclosure.

[0038] FIG. 5 is a schematic diagram showing a solid oral pharmaceutical composition according to Example 5 of the present disclosure.

[0039] FIG. 6 is a cross-sectional view showing a first or second pellet according to Example 5 of the present disclosure.

DETAILED DESCRIPTION OF EMBODIMENT

[0040] Different embodiments of the present invention are provided in the following description. These embodiments are meant to explain the technical content of the present invention, but not meant to limit the scope of the present invention. A feature described in an embodiment may be applied to other embodiments by suitable modification, substitution, combination, or separation.

[0041] It should be noted that, in the present specification, when a component is described to have an element, it means that the component may have one or more of the elements, and it does not mean that the component has only one of the element, except otherwise specified.

[0042] Moreover, in the present specification, the ordinal numbers, such as “first” or “second”, are used to distinguish a plurality of elements having the same name, and it does not means that there is essentially a level, a rank, an executing order, or an manufacturing order among the elements, except otherwise specified. A “first” element and a “second” element may exist together in the same component, or alternatively, they may exist in different components, respectively. The existence of an element described by a greater ordinal number does not essentially means the existent of another element described by a smaller ordinal number.

[0043] Herein, except otherwise specified, when it comes to feature A “or” or “and/or” feature B, it refers to the presence of A alone, B alone, or A and B exist at the same time. When it comes to feature A “and” feature B, it means that A and B exist at the same time. The term “comprise”, “include”, “have”, or “contain” means including but not limited thereto.

[0044] Moreover, in the present specification, a value may be interpreted to cover a range within ±10% of the value, and in particular, a range within ±5% of the value, except otherwise specified; a range may be interpreted to be composed of a plurality of subranges defined by a smaller endpoint, a smaller quartile, a median, a greater quartile, and a greater endpoint, except otherwise specified.

[0045] Different embodiments of the present disclosure are provided in the following description. These embodiments are meant to explain the technical content of the present disclosure, but not meant to limit the scope of the present disclosure.

[0046] Unless otherwise specified, in the following preparation examples, examples and comparative examples, the temperature is shown by Celsius, the parts and percentages are shown by weight. The relationship between parts by weight and parts by volume is like the relationship between kilograms and liters.

Dissolution Methods and Assay

[0047] Dissolution medium such as 0.1N HCl, phosphate buffer (pH 4.5) and phosphate buffer (pH 6.8) were prepared following USP Method. 0.3% Tween 80 was added into the medium to help solubilize the active ingredients. Dissolution conditions were summarized as in the following. Dissolution samples were analyzed by HPLC method.

[0048] Apparatus: USP apparatus II (Paddle Method) with sinkers.

[0049] Medium: 0.1N HCl, Phosphate Buffer (pH 4.5) or Phosphate Buffer (pH 6.8)

[0050] Volume: 900 mL

[0051] Temperature: 37±0.5° C.

[0052] Filter: 10 μm HDPE full flow filter tips

[0053] Sampling Volume: 10 mL

[0054] Sampling Times: 5, 10, 15, 20, 30 and 45 minutes

EXAMPLE 1: SINGLE LAYERED TABLE

Component

[0055] Pitavastatin Calcium (10 mg), Ezetimibe (50 mg), Lactose monohydrate (629 mg), Microcrystalline Cellulose (MCC) (308 mg), Sodium Lauryl Sulfate (SLS) (10 mg), Sodium Starch Glycolate (SSG) (90 mg), Crospovidone (30 mg), Magnesium Stearate (8 mg) and Povidone (45 mg), 95% Alcohol (18 mg), and purified water (72 mg). Alcohol and water were evaporated during the drying process.

Manufacturing Process

[0056] Pitavastatin calcium, ezetimibe, lactose, microcrystalline cellulose (MCC), sodium lauryl sulfate (SLS), sodium starch slycolate (SSG) and povidone were discharged into a suitable container separately. A binding solution made of 45 mg povidone dissolved in 18 mg of alcohol and 72 gm water was prepared.

[0057] The pitavastatin calcium and ezetimibe were first mixed with SLS, MCC and SSG which have been passed through 30 mesh sieve by Comil and the mixture was rotated 100 times. The mixture was discharged with lactose. All materials were transferred into a granulator and mixed by the high shear mixer for 7 min (impeller 215 rpm).

[0058] After pre-mixing, the binder solution was added to the higher mixer, followed by granulating with Chopper 3400 rpm (impeller 215 rpm). The wet granules were dried at 40 to 60° C. The dried granules were mixed with sieved crospovidone and magnesium stearate for the final blending.

[0059] Tablets were compressed by rotatory tableting machine, and the schematic diagram of the target tablet 10 is shown in FIG. 1, wherein the weight of the target tablet was 300 mg±15 mg per unit and the hardness of final tablets was controlled within 8 to 11 kp. In addition, each tablet comprises about 2 mg of pitavastatin calcium and about 10 mg of ezetimibe.

[0060] The obtained tablets were tested with aforesaid dissolution test, and the results are shown in the following Table 1 and Table 2.

TABLE-US-00001 TABLE 1 % Released into 0.1 N HCl with 0.3% Tween 80 at sampling time (min) Drug 5 mm 10 min 15 mm 30 mm 45 min Pitavastatin Ca 79% 84% 86% 89% 90% Ezetimibe 56% 70% 77% 86% 91%

TABLE-US-00002 TABLE 2 % Released into phosphate buffer (pH 6.8) with 0.3% Tween 80 at sampling time (min) Drug 5 mm 10 mm 15 min 30 min 45 min Pitavastatin Ca 69% 90% 95% 97% 98% Ezetimibe 54% 77% 86% 94% 96%

EXAMPLE 2: DOUBLE LAYERED TABLE

Component of Pitavastatin Calcium Layer

[0061] Pitavastatin Calcium (24 mg), Lactose monohydrate (732 mg), Microcrystalline Cellulose (732 mg), Magnesium Oxide (96 mg), Sodium

[0062] Starch Glycolate (192 mg), Crospovidone (76.8 mg), Magnesium Stearate (9.6 mg) and Povidone (57.6 mg), 95% Alcohol (57.6 mg), and Water (57.6 mg). Alcohol and water were evaporated during the drying process.

Component of Ezetimibe Layer

[0063] Ezetimibe (120 mg), Lactose monohydrate (720 mg), Microcrystalline Cellulose (950.4 mg), Sodium Lauryl Sulfate (24 mg), Sodium Starch Glycolate (38.4 mg), Magnesium Stearate (9.6 mg) and Povidone (57.6 mg), 95% Alcohol (57.6 mg), and Water (57.6 mg). Alcohol and water were evaporated during the drying process.

Preparation of Pitavastatin Calcium Granules

[0064] Pitavastatin calcium, lactose monohydrate, microcrystalline cellulose, magnesium oxide (MgO), sodium starch glycolate, crospovidone, magnesium stearate and povidone were discharged into a suitable container separately. A binding solution was prepared by dissolving 57.6 gm povidone in a solution made of 57.6 gm alcohol and 57.6 gm water.

[0065] A geometric dilution method was used herein. The pitavastatin calcium was first mixed with MgO, part of MCC and part of SSG after passing through 30 mesh sieve by Comil. All materials for mixing were rotated by drum mixer for 100 times. Lactose which was delumped through 30 mesh sieve by comil was discharged. All materials were transferred into a granulator and mixed using the high shear mixer for 7 min (impeller 215 rpm).

[0066] Then, the granulation was performed by turning on the impeller (215 rpm) and chopper (3,400 rpm). The binder solution was added into the granulator within 2 min in a planetary mixer for 3 minutes. The wet granules were dried at 50° C. in a try dryer until the water content of the granules was below 2.0% (measured as loss on drying at 105° C. for 15 min by IR Moisture Analyzer).

[0067] After drying, the dry granules were mixed with the rest of MCC, rest of SSC and crospovidone together by drum mixer with 300 times. For lubrication, the mixture granules were mixed with magnesium stearate by drum mixer with 60 times.

Preparation of Ezetimibe Granules

[0068] Ezetimibe, lactose monohydrate, microcrystalline cellulose, sodium lauryl sulfate, sodium starch glycolate, magnesium stearate and povidone were discharged into a container separately. A binding solution was prepared by dissolving 57 gm povidone in a solution made of 57 gm alcohol and 57 gm water.

[0069] The ezetimibe was first mixed with SLS, SSG and part of MCC after passing through 30 mesh sieve by Comil 032R and all materials for mixing were rotated by drum mixer for 100 times. Lactose which was delumped through 30 mesh sieve by comil was discharged. All materials were transferred into a granulator and mixed using the high shear mixer for 7 min (impeller 215 rpm).

[0070] Then, the granulation was performed by turning on the impeller (215 rpm) and chopper (3,400 rpm). The binder solution was added to the granulator within 2 min in a planetary mixer for 3 minute. The wet granules were dried at 50° C. in a tray dryer until the water content of the granules was below 2.0% (measured as loss on drying at 105° C. for 15 min by IR Moisture Analyzer).

[0071] After drying, the dry granules were mixed with the rest of MCC together by drum mixer with 300 times. For lubrication, the mixture granules were mixed with magnesium stearate by drum mixer with 60 times.

[0072] The obtained pitavastatin calcium granules and ezetimibe granules were compressed into double layered tablets using a double-side rotatory tableting machine. The schematic diagram of the target tablet is shown in FIG. 2, and the target tablet comprises: a pitavastatin calcium layer 11 and an ezetimibe layer 12. The target weight per unit was 320 mg±16 mg, and the hardness of tablet was controlled within 9 to 13 kp. In addition, each tablet comprises about 2 mg of pitavastatin calcium and about 10 mg of ezetimibe.

[0073] The obtained tablets were tested with aforesaid dissolution test, and the results are shown in the following Table 3 and Table 4.

TABLE-US-00003 TABLE 3 % Released into 0.1 N HCl with 0.3% Tween 80 at sampling time (min) Drug 5 mm 10 mm 15 min 30 min 45 min Pitavastatin Ca 81% 87% 89% 86% 89% Ezetimibe 30% 56% 67% 79% 83%

TABLE-US-00004 TABLE 4 % Released into Phosphate Buffer (pH 6.8) with 0.3% Tween 80 at sampling time (min) Drug 5 min 10 mm 15 mm 30 min 45 min Pitavastatin Ca 90% 96% 97% 99% 100% Ezetimibe 42% 72% 80% 88%  91%

EXAMPLE 3: TABLES IN ONE CAPSULE

Component of Pitavastatin Calcium Tablet

[0074] Pitavastatin Calcium (10 mg), Lactose monohydrate (454 mg), Pregelatinized Starch (54 mg), Magnesium Aluminometasilicate (11 mg), Magnesium Stearate (3 mg) and Hydroxypropyl Methylcellulose (HPMC) (9 mg), 95% Alcohol (40 mg), and Water (40 mg). Alcohol and water were evaporated during the drying process.

Component of Ezetimibe Tablet

[0075] Ezetimibe (50 mg), Lactose monohydrate (190 mg), Microcrystalline Cellulose (190 mg), Sodium Lauryl Sulfate (10 mg), Pregelatinized Starch (50 mg), Magnesium Stearate (3 mg) and Hydroxypropyl Methylcellulose (8 mg), 95% Alcohol (37 mg) and Water (37 mg). Alcohol and water were evaporated during the drying process.

[0076] The pitavastatin calcium granules and the ezetimibe granules were prepared by the similar method described in Example 2.

[0077] The obtained pitavastatin calcium granules were compressed into single layer tablets using a rotatory tableting machine. The target weight per unit was 120 mg±6 mg, and the hardness of tablet was controlled within 4 to 6 kp. In addition, the obtained ezetimibe granules were compressed into single layer tablets using a rotatory tableting machine. The target weight per unit was 100 mg±5 mg, and the hardness of tablet was controlled within 3 to 6 kp. Then, the obtained pitavastatin calcium tablet and the obtained ezetimibe table were inserted into one gelatin capsule manually. The schematic diagram of the obtained capsule is shown in FIG. 3, wherein the obtained capsule comprises: a pitavastatin calcium tablet 11a, an ezetimibe tablet 12a and a capsule 13. In addition, each capsule comprises about 2 mg of pitavastatin calcium and about 10 mg of ezetimibe.

EXAMPLE 4: GRANULES IN ONE CAPSULE

[0078] The pitavastatin calcium granules and the ezetimibe granules prepared in Example 2 were directly inserted into one gelatin capsule manually. The schematic diagram of the obtained capsule is shown in FIG. 4, wherein the obtained capsule comprises: pitavastatin calcium granules 11b, ezetimibe granules 12b and a capsule 13. In addition, each capsule comprises about 2 mg of pitavastatin calcium and about 10 mg of ezetimibe.

EXAMPLE 4: PELLETS IN ONE CAPSULE

[0079] In the present example, the pitavastatin calcium pellet and the ezetimibe pellet respectively have the structure shown in FIG. 6. As shown in FIG. 6, the active ingredient pellet used in the present example comprises: a core 21; a drug-containing layer 22 disposed on the core 21 and covering the whole surface of the core 21; and a protection layer 23 disposed on the drug-containing layer 22 and covering the whole surface of the drug-containing layer 22. In the present example, the core 21 is a sphere, and the drug-containing layer 22 is a layer comprising pitavastatin calcium or ezetimibe.

Preparation of Pitavastatin Calcium Pellet

Drug-Containing Layer

[0080] Pitavastatin calcium (9 mg) was mixed and dispersed homogeneously with mannitol (24 mg), povidone (8 mg), magnesium oxide (2 mg), sodium lauryl sulfate (2 mg) in purified water. The mixture was stirred and homogenized until the suspension has no aggregations.

Protection Layer

[0081] Mannitol (47 mg), povidone (15 mg), talc (27 mg) and iron oxide yellow (0.5 mg) were mixed in purified water.

[0082] The fluidized bed equipment was used for pellet coating. After adding sugar balls (using sucrose as raw material spheres) into the preheated equipment, when the product temperature was above 35° C., the formulated suspension for the drug-containing layer was used to proceed the coating process of the drug-containing layer. In the subsequent coating process, the inlet gas temperature and the inlet gas volume were adjusted to control the product temperature to not exceed 60° C. After the coating process of the drug-containing layer, the formulated suspension for the protection layer was used to proceed the coating process of the protection layer. The coating process of the protection layer was continuously performed after the previous coating operation until the suspension of the protection layer was exhausted. After the coating process, the obtained pellets were dried, and about 2 mg of the pitavastatin calcium pellets were inserted into a capsule.

Preparation of Ezetimibe Pellet

Drug-Containing Layer

[0083] Ezetimibe (36 mg) was mixed and dispersed homogeneously with mannitol (80 mg), povidone (27 mg), anhydrous citric acid (0.4 mg), sodium lauryl sulfate (0.4 mg) in water. The mixture was stirred and homogenized until the suspension has no aggregations.

Protection Layer

[0084] Mannitol (38 mg), povidone (13 mg), talc (15 mg) and sodium lauryl sulfate (7 mg) were mixed in purified water.

[0085] The fluidized bed equipment was used for pellet coating. After adding sugar balls (using sucrose as raw material spheres) into the preheated equipment, when the product temperature was above 35° C., the formulated suspension for the drug-containing layer was used to proceed the coating process of the drug-containing layer. In the subsequent coating process, the inlet gas temperature and the inlet gas volume were adjusted to control the product temperature to not exceed 60° C. After the coating process of the drug-containing layer, the formulated suspension for the protection layer was used to proceed the coating process of the protection layer. The coating process of the protection layer was continuously performed after the previous coating operation until the suspension of the protection layer was exhausted. After the coating process, the obtained pellets were dried. About 10 mg of the ezetimibe pellets were inserted into the capsule comprising about 2 mg of the pitavastatin calcium pellets.

[0086] The schematic diagram of the composition comprising the pitavastatin calcium pellets and the ezetimibe pellets prepared in the present example is shown in FIG. 5, wherein the composition comprises: pitavastatin calcium pellets 11c, ezetimibe pellets 12c and a capsule 13. In addition, each capsule comprises about 2 mg of pitavastatin calcium and about 10 mg of ezetimibe.

[0087] The obtained capsules were tested with aforesaid dissolution test. The dissolution medium used herein respectively is medium containing 0.1 N HCl with 0.3% Tween 80, phosphate buffer (pH 4.5) with 0.3% Tween 80 and phosphate buffer (pH 6.8) with 0.3% Tween 80. The results are shown in the following Table 5 to Table 7.

TABLE-US-00005 TABLE 5 % Released into 0.1 N HCl with 0.3% Tween 80 at sampling time (min) Drug 5 min 10 min 15 min 20 min 30 min 45 min Pitavastatin Ca 90% 99% 100% 100% 100%  99% Ezetimibe 71% 95%  99% 100% 101% 101%

TABLE-US-00006 TABLE 6 % Released into Phosphate Buffer (pH 4.5) with 0.3% Tween 80 at sampling time (min) Drug 5 min 10 min 15 min 20 min 30 min 45 min Pitavastatin Ca 82% 100% 102% 102% 102% 102% Ezetimibe 64%  99% 103% 104% 105% 105%

TABLE-US-00007 TABLE 7 % Released into Phosphate Buffer (pH 6.8) with 0.3% Tween 80 at sampling time (min) Drug 5 min 10 min 15 min 20 min 30 min 45 min Pitavastatin Ca 81% 98% 102% 102% 102% 102% Ezetimibe 69% 96% 102% 103% 104% 104%

Stability of Pitavastatin Calcium

[0088] Pitavastatin calcium was found not stable. Thus, in the present disclosure, an alkaline agent (herein, magnesium oxide) was added into the formulation to stabilize pitavastatin calcium. Herein, the tablets having similar components described in Example 1 were used as the test samples.

[0089] The test samples packed in Alu-alu blisters were store under 55° C./75% RH. The results are shown in the following Table 8.

TABLE-US-00008 TABLE 8 Assay of pitavastatin Sample Time calcium (%) Without MgO Initial 94.3 One week 91.3 Two weeks 88.2 With MgO Initial 96.3 One week 94.7 Two weeks 95.9 Note: Assay of pitavastatin calcium (%) = (Content of pitavastatin calcium of the test sample after storage/Content of pitavastatin calcium of the initial test sample) × 100%

Stability of Ezetimibe

[0090] The stability of ezetimibe pellets with acidic agent (herein, citric acid) was measured herein. Herein, the capsules shown in Example 5 were used as the test samples. The capsules comprising ezetimibe pellets were stored under 40° C./75% RH and 55° C./75% RH, and detected by Waters Alliance HPLC system with UV 245 nm. The amounts of the impurities were measured by liquid chromatography (Hypersil Gold C18). The formulations and the results are shown in the following Table 9.

TABLE-US-00009 TABLE 9 Formulation of Content of the Major Total the pellets citric acid in im- im- and contents of each the Storage purity purity components formulation condition (%) (%) Sugar sphere, 0 mg/unit Initial 0.05 0.1 100.0 mg/unit 5 Days/55° C. 0.62 0.8 Ezetimibe, 10.0 mg/unit 1 Month/40° C. 0.07 0.2 Mannitol, 32.9 mg/unit 0.10 mg/unit Initial 0.04 0.1 Povidone, 11.0 mg/unit 5 Days/55° C. 0.18 0.2 Sodium Lauryl Sulfate, 1 Month/40° C. 0.07 0.1 2.0 mg/unit Talc, 4.1 mg/unit Sugar sphere, 100.0 0.05 mg/unit Initial 0.06 0.2 mg/unit 5 Days/55° C. 0.20 0.4 Ezetimibe, 10.0 mg/unit 1 Month/40° C. 0.05 0.1 Mannitol, 32.2 mg/unit* 0.10 mg/unit Initial 0.05 0.2 Povidone, 10.7 mg/unit 5 Days/55° C. 0.18 0.4 Tween 80, 2.0 mg/unit 1 Month/40° C. 0.06 0.2 Talc, 5.0 mg/unit 0.20 mg/unit Initial 0.06 0.2 5 Days/55° C. 0.22 0.4 1 Month/40° C. 0.05 0.2 0.35 mg/unit Initial 0.06 0.1 5 Days/55° C. 0.37 0.4 1 Month/40° C. 0.12 0.2 0.70 mg/unit Initial 0.06 0.1 5 Days/55° C. 0.40 0.5 1 Month/40° C. 0.09 0.1 Note: Product impurity profile: Largest impurity - NMT0.2% and Total impurity - NMT1.0% *The amount of mannitol in the formulation was decreased as the amount of the citric acid was increased to maintain the total weight of each unit.

Stability of Composition of Pitavastatin Calcium and Ezetimibe

[0091] The composition of pitavastatin calcium and ezetimibe prepared in Example 5 of the present disclosure were packed in Alu-alu blisters and stored under long term stability (25° C./60% RH). The assay of pitavastatin calcium and ezetimibe as well as the impurities were measured. The results are shown in the following Table 10 and Table 11.

TABLE-US-00010 TABLE 10 Assay (%) Drug Initial 3 Months 6 Months 9 Months 12 Months Pitavastatin Ca 98.2 96.4 97 95 96.5 Ezetimibe 100 99.5 101 102.9 99.7

TABLE-US-00011 TABLE 11 Impurities (%) 3 6 9 12 Drug Impurities Initial Months Months Months Months Pitavastatin Ca Major 0.02 0.03 0.09 0.08 0.05 Total 0.02 0.03 0.09 0.13 0.05 Ezetimibe Major 0.06 0.06 0.06 0.06 0.06 Total 0.06 0.06 0.06 0.06 0.06

[0092] The above results indicate that the solid oral pharmaceutical composition provided by the present disclosure has excellent stability by adding suitable stabilizing agents.

[0093] Although the present disclosure has been explained in relation to its embodiment, it is to be understood that many other possible modifications and variations can be made without departing from the spirit and scope of the disclosure as hereinafter claimed.