PHARMACEUTICAL COMPOSITION OF SINGLE DOSAGE FORM FOR TREATING OR PREVENTING HYPERTENSION AND HYPERLIPIDEMIA

Abstract

A single dosage form of pharmaceutical composition for treatment of hypertension and hyperlipidemia is provided. Stability and uniform dissolution rates of drugs may be ensured by mixing compositions containing desired drugs and formulating the mixture into a single compartment form, whereby a manufacturing process becomes simple while reducing processing costs. Further, a formulation having biological equivalence to conventional single formulations may be obtained.

Claims

1. A pharmaceutical composition in a single dosage form, comprising: a composition comprising olmesartan medoxomil; a composition comprising amlodipine or a salt thereof; and a composition comprising rosuvastatin or a salt thereof, wherein the above compositions are mixed together and formulated into the single dosage form of pharmaceutical composition, and wherein one or more of the compositions is comprised in the form of granulates or pellets.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has a dosage form selected from: a single layer tablet; a capsule comprising one or more selected from the group consisting of granulates, pellets and powder; or a granulate formulation.

3. The pharmaceutical composition according to claim 1, wherein the composition comprising olmesartan medoxomil in the pharmaceutical composition is comprised in the form of granulates.

4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has a dosage form selected from: a single layer tablet in which granulates comprising olmesartan medoxomil and amlodipine or a salt thereof and granulates comprising rosuvastatin or a salt thereof are mixed together; a single layer tablet in which granulates comprising olmesartan medoxomil and amlodipine or a salt thereof and a composition comprising rosuvastatin or a salt thereof are mixed together; a single layer tablet in which olmesartan medoxomil granulates, a composition comprising amlodipine or a salt thereof and a composition comprising rosuvastatin or a salt thereof are mixed together; a single layer tablet in which olmesartan medoxomil granulates, a composition comprising amlodipine or a salt thereof and granulates comprising rosuvastatin or a salt thereof are mixed together; or a single layer tablet in which olmesartan medoxomil granulates and granulates comprising amlodipine or a salt thereof and rosuvastatin or a salt thereof are mixed together.

5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has a dosage form selected from: a capsule in which pellets comprising olmesartan medoxomil and amlodipine or a salt thereof, and pellets or powder comprising rosuvastatin or a salt thereof are comprised; a capsule in which granulates comprising olmesartan medoxomil and amlodipine or a salt thereof, and pellets or powder comprising rosuvastatin or a salt thereof are comprised; a capsule in which pellets comprising olmesartan medoxomil and amlodipine or a salt thereof, and granulates comprising rosuvastatin or a salt thereof are comprised; a capsule in which granulates comprising olmesartan medoxomil and amlodipine or a salt thereof, and granulates comprising rosuvastatin or a salt thereof are comprised; or a capsule in which olmesartan medoxomil granulates, and granulates comprising amlodipine or a salt thereof and rosuvastatin or a salt thereof are comprised.

6. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has a dosage form selected from: a granulate formulation in which granulates comprising omesartan medoxomil and amlodipine or a salt thereof and granulates comprising rosuvastatin or a salt thereof are comprised; or a granulate formulation in which olmesartan medoxomil granulates and granulates comprising amlodipine or a salt thereof and rosuvastatin or a salt thereof are comprised.

7. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises two or more disintegrants selected from the group consisting of pre-gelatinized starch, sodium croscarmellose, crospovidone, low-substituted hydroxylpropyl cellulose, calcium carboxymethyl cellulose, sodium starch glycolate, copovidone and combined silicate.

8. The pharmaceutical composition according to claim 7, wherein the disintegrant is comprised in an amount of 10 to 60 parts by weight (“wt. parts”) to total 100 wt. parts of the pharmaceutical composition.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition comprises, with regard to total 100 wt. parts of the pharmaceutical composition, 4 to 40 wt. parts of one or more disintegrants selected from pre-gelatinized starch and sodium starch glycolate, as well as 2 to 30 wt. parts of one or more disintegrants selected from the group consisting of sodium croscarmellose, crospovidone, copovidone, low-substituted hydroxylpropyl cellulose and calcium carboxymethyl cellulose.

10. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises dibasic calcium phosphate hydrate, anhydrous calcium phosphate, calcium carbonate or a mixture thereof.

11. The pharmaceutical composition according to claim 10, wherein dibasic calcium phosphate hydrate, anhydrous calcium phosphate, calcium carbonate or a mixture thereof is comprised in an amount of 3 to 20 wt. parts to total 100 wt. parts of the pharmaceutical composition.

12. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a single layer tablet coated with a coating agent.

13. The pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is a single layer tablet coated with polyvinylalcohol, polyvinylalcohol copolymer or hydroxypropyl methylcellulose (HPMC).

14. The pharmaceutical composition according to claim 1, wherein the salt of amlodipine is amlodipine besylate.

15. The pharmaceutical composition according to claim 1, wherein the salt of rosuvastatin is rosuvastatin calcium.

16. The pharmaceutical composition according to claim 1, wherein olmesartan medoxomil has D(90) of 5 to 45 μm.

17. The pharmaceutical composition according to claim 1, wherein amlodipine or a salt thereof has D(90) of 5 to 100 μm.

18. The pharmaceutical composition according to claim 1, wherein rosuvastatin or a salt thereof has D(90) of 5 to 50 μm.

19. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used for treating or preventing hypertension and hyperlipidemia.

20. The pharmaceutical composition according to claim 1, wherein an dissolution rate of amlodipine or a salt thereof is equivalent to that of amlodipine or a salt thereof in Sebica™ tablet.

21. The pharmaceutical composition according to claim 1, wherein an dissolution rate of rosuvastatine or a salt thereof is equivalent to that of rosuvastatin or a salt thereof in Crestor™ tablet.

22. The pharmaceutical composition according to claim 1, wherein olmesartan medoxomil and amlodipine or a salt thereof in the pharmaceutical composition exhibit an area under curve (AUC) of blood concentration-time and the maximum serum concentration (C.sub.max) at bioequivalent levels as compared to Sebica™ tablet having the same active ingredient dose.

23. The pharmaceutical composition according to claim 1, wherein the rosuvastatin calcium salt in the pharmaceutical composition exhibits an area under curve (AUC) of blood concentration-time and the maximum serum concentration (C.sub.max) at bioequivalent levels as compared to Crestor™ tablet having the same active ingredient dose.

24. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used for administration to a patient who requires a combination therapy of amlodipine and olmesartan medoxomil and, at the same time, should be administered with rosuvastatin.

25. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises olmesartan medoxomil, amlodipine and rosuvastatin in the following doses, on the basis of a unit dosage form: 40 mg of olmesartan medoxomil, 10 mg of amlodipine or a salt thereof, and 20 mg of rosuvastatin or a salt thereof; 40 mg of olmesartan medoxomil, 10 mg of amlodipine or a salt thereof, and 10 mg of rosuvastatin or a salt thereof; 40 mg of olmesartan medoxomil, 5 mg of amlodipine or a salt thereof, and 10 mg of rosuvastatin or a salt thereof; 40 mg of olmesartan medoxomil, 5 mg of amlodipine or a salt thereof, and 5 mg of rosuvastatin or a salt thereof; 20 mg of olmesartan medoxomil, 5 mg of amlodipine or a salt thereof, and 10 mg of rosuvastatin or a salt thereof; 20 mg of olmesartan medoxomil, 5 mg of amlodipine or a salt thereof, and 5 mg of rosuvastatin or a salt thereof; 20 mg of olmesartan medoxomil, 5 mg of amlodipine or a salt thereof, and 2.5 mg of rosuvastatin or a salt thereof; 40 mg of olmesartan medoxomil, 2.5 mg of amlodipine or a salt thereof, and 20 mg of rosuvastatin or a salt thereof; 40 mg of olmesartan medoxomil, 2.5 mg of amlodipine or a salt thereof, and 10 mg of rosuvastatin or a salt thereof; 20 mg of olmesartan medoxomil, 2.5 mg of amlodipine or a salt thereof, and 10 mg of rosuvastatin or a salt thereof; 20 mg of olmesartan medoxomil, 2.5 mg of amlodipine or a salt thereof, and 5 mg of rosuvastatin or a salt thereof; or 20 mg of olmesartan medoxomil, 2.5 mg of amlodipine or a salt thereof, and 2.5 mg of rosuvastatin or a salt thereof.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

[0073] The foregoing summary, as well as the following detailed description of the preferred invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the preferred invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown. In the drawings:

[0074] FIG. 1 illustrates the results of dissolution tests of formulations in Preparative Examples 1 to 8 compared to a control drug with regard to olmesartan medoxomil.

[0075] FIG. 2 illustrates the results of dissolution tests of formulations in Preparative Examples 1 to 8 compared to a control drug with regard to amlodipine besylate.

[0076] FIG. 3 illustrates the results of dissolution rates of formulations in Preparative Examples 1 to 8 compared to a control drug with regard to rosuvastatin calcium salt.

DETAILED DESCRIPTION OF THE INVENTION

Best Mode

Example

[0077] Hereinafter, the present invention will be described in more detail in the following examples. However, the following examples illustrate only the content of the present invention and are not intended to limit or restrict the scope of the present invention resent invention. What is easily inferred by those skilled in the art from the detailed description and examples of the present invention is construed as belonging to the scope of the present invention.

PREPARATION EXAMPLE

Preparative Example 1 to 6: Preparation of Single Layer Tablet Comprising Olmesartan/Amlodipine Composition and Rosuvastatin Composition

[0078] A formulation of each of the preparative examples was prepared with change in terms of types of additives such as disintegrants, excipients, etc. and content thereof.

TABLE-US-00001 TABLE 1 Prep. Prep. Prep. Prep. Prep. Prep. Example Example Example Example Example Example Ingredient 1 2 3 4 5 6 Composition 1 Olmesartan medoxomil 40 40 40 40 40 40 Amlodipine besylate 13.89 13.89 13.89 13.89 13.89 13.89 Microcrystalline — — — 66.11 — 38.11 cellulose Silicified 76.11 90.11 91.11 — 69.11 — microcrystalline cellulose Lactose hydrate — — — — — 20 Hydroxypropyl — — — — — 5 cellulose Povidone — — — — 7 — Hydroxypropyl — — 5 — — — cellulose methyl cellulose Pre-gelatinized starch 35 — 15 35 35 Sodium starch glycolate 21 — — — 35 Sodium croscarmellose 15 15 5 5 — — Crospovidone — — 10 — — — Copovidione — — — — 15 — Calcium carboxymethyl — — — 20 — — cellulose Low-substituted — — — — — 28 hydroxypropyl cellulose Composition 2 Rosuvastatin calcium 10.4 10.4 10.4 10.4 10.4 10.4 Lactose hydrate 79.8 42.6 65.6 74.8 41.8 74.8 Microcrystalline — 30 — — 25.8 — cellulose Silicified 41.8 — 40 15.8 — 45 microcrystalline cellulose Dibasic calcium 18 — — 36 54 — phosphate hydrate Anhydrous calcium — — 36 — — — phosphate Calcium carbonate — 54 — — — 21.8 Sodium starch glycolate — — — 5 5 — Crospovidone 15 10 — — — 15 Sodium croscarmellose 7 5 — — — 5 Low-substituted — 20 — 20 35 — hydroxypropyl cellulose Combined silicate — — 20 — — — Post-mixing Colloidal silicon 4 4 4 4 4 4 dioxide Magnesium stearate 4 4 4 4 4 4 Sum Total mass per tablet 360 360 360 360 360 360

[0079] In Preparative Examples 1 to 6, after forming granulates comprising olmesartan medoxomil and amlodipine besylate as well as rosuvastatin calcium granulates, these granulates were mixed with lubricants (post-mixing), followed by compressing the same to prepare single layer tablets.

TABLE-US-00002 TABLE 2 Prep. Prep. Exam- Exam- Ingredient ple 7 ple 8 Composition 1 Olmesartan medoxomil 40 40 Silicified microcrystalline cellulose 76.11 45.11 Dibasic calcium phosphate hydrate — 36 Pre-gelatinized starch 35 35 Sodium croscarmellose 10 — Crospovidone 5 10 Post-mixing 1 Amlodipine besylate 13.89 13.89 Rosuvastatin calcium 10.4 10.4 Lactose hydrate 76.8 63.93 Silicified microcrystalline cellulose 38 41.67 Dibasic calcium phosphate hydrate 21.8 — Calcium carbonate — 36 Sodium starch glycolate 25 — Crospovidone — 10 Sodium croscarmellose — 10 Post-mixing 2 Colloidal silicon dioxide 4 4 Magnesium stearate 4 4 Sum Total mass per tablet 360 360

[0080] In Preparative Examples 7 and 8, after forming granulates comprising olmesartan medoxomil, the formed granulates were mixed with a composition comprising amlodipine and rosuvastatin calcium (post-mixing 1) and lubricants (post-mixing 2), followed by compressing the same to prepare single layer tablets.

EXPERIMENTAL EXAMPLE

Experimental Example 1: Dissolution Test

[0081] Comparative dissolution tests were performed on the formulations prepared in the preparative examples of the present invention under the following dissolution test conditions.

[0082] As a control drug used in the comparative dissolution tests, 10/40 mg of Sebica™ tablets (amlodipine besylate/olmesartan medoxomil) and 20 mg of Crestor™ tablets (rosuvastatin calcium) were used.

[0083] Sebica™ and Crestor™ tablets have each film-coated single tablet form. Sebica™ tablet comprises silicified microcrystalline cellulose, pre-gelatinized starch, sodium croscarmellose and magnesium stearate as excipients, and further comprises polyvinylalcohol, macrogol/polyethyleneglycol 3350, titanium dioxide, talc and iron oxide as film coating agents.

[0084] On the other hand, Crestor™ tablet comprises microcrystalline cellulose, lactose hydrate, tribasic calcium phosphate, crospovidone and magnesium as excipients, and comprises hypromellose, triacetin, titanium dioxide and iron oxide as film coating agents.

[Dissolution Test Conditions]

[0085] Dissolution solution: solution 1 or solution 2 in Korean Pharmacopoeia Disintegration Test Method, or water
Omesartan medoxomil: Water
Amlodipine besylate: solution 1, pH 1.2
Rosuvastatin calcium: solution 2, pH 6.8

Temperature: 37±0.5° C.

[0086] Test method: Korean Pharmacopoeia dissolution test method No. 2 (paddle method)
Paddle rotation speed: 50 rpm
Analysis method: UPLC method
(*) UPLC operating conditions [0087] Column: ACQUITY UPLC BEH C18 (2.1×50 mm 1.7 μm) [0088] Detector: Ultraviolet absorbance photometer (239 nm) [0089] Flow rate: 0.1 mL/min [0090] Analysis time: 30 minutes [0091] Mobile phase: Phosphoric acid buffer/acetonitrile=80/20

[0092] The dissolution test results of the above formulations are shown in the table below.

TABLE-US-00003 TABLE 3 Olmesartan medoxomil dissolution rate Dissolution time 0 min 5 min 10 min 15 min 30 min 45 min 60 min Prep. Example 1 0 18.18 44.36 54.91 71.05 78.42 82.22 Prep. Example 2 0 29.82 49.87 60.65 76.75 83.80 87.84 Prep. Example 3 0 24.87 44.31 55.82 72.13 79.65 83.42 Prep. Example 4 0 26.46 45.55 56.53 72.72 80.58 84.59 Prep. Example 5 0 27.12 46.27 57.20 73.04 80.24 83.33 Prep. Example 6 0 26.62 43.94 54.59 70.09 78.10 81.89 Prep. Example 7 0 25.98 49.96 59.26 69.48 83.96 85.30 Prep. Example 8 0 38.80 59.46 68.63 79.86 84.72 87.37 Sebica + Crestor 0 18.17 25.43 28.61 31.79 34.83 37.08

TABLE-US-00004 TABLE 4 Amlodipine besylate dissolution rate Dissolution 0 10 15 30 45 60 time min 5 min min min min min min Prep. Example 1 0 94.25 95.83  96.35 95.79 95.02 95.03 Prep. Example 2 0 61.86 90.33  94.85 96.22 95.19 96.02 Prep. Example 3 0 97.98 99.65  98.71 98.30 98.54 98.91 Prep. Example 4 0 83.40 90.63  91.57 91.84 92.04 93.44 Prep. Example 5 0 90.34 90.03  91.22 92.30 92.13 92.87 Prep. Example 6 0 96.83 95.11  98.30 98.44 99.79 99.25 Prep. Example 7 0 85.64 91.80  93.35 96.14 96.52 99.38 Prep. Example 8 0 84.10 87.36  89.11 90.62 91.75 93.24 Sebica + Crestor 0 99.67 99.77 100.37 98.57 98.48 98.53

TABLE-US-00005 TABLE 5 Rosuvastatin calcium dissolution rate Dissolution 0 5 10 15 30 45 60 time min min min min min min min Prep. 0  80.67  92.55  93.91  94.69  95.48  95.82 Example 1 Prep. 0  90.45  95.87  96.43  96.66  97.29  97.16 Example 2 Prep. 0  89.75  94.86  95.89  97.36  97.90  98.05 Example 3 Prep. 0  84.60  91.66  93.61  97.26  99.54 101.71 Example 4 Prep. 0  86.82  93.26  94.79  96.71  97.67  98.43 Example 5 Prep. 0  87.55  91.74  93.37  93.84  94.15  94.56 Example 6 Prep. 0  91.52  96.12  96.65  98.51  99.82 100.41 Example 7 Prep. 0 100.51 101.74 101.91 101.8 101.81 101.78 Example 8 Sebica + Crestor 0  87.92  89.97  90.37  91.80  92.50  94.66

[0093] All of the formulations in Preparation Examples 1 to 6 had higher dissolution rates for olmesartan compared to the control drug at all times, while the dissolution rates for amlodipine and rosuvastatin, respectively, were not significantly different from each other, that is, amlodipine and rosuvastatin showed similar dissolution rates compared to the control drug. In fact, although the constitutional composition of olmesartan/amlodipine slightly affected initial dissolution rate of rosuvastatin, it was confirmed that there is no significant influence on overall dissolution profile of rosuvastatin.

[0094] In general, for determination of similarity in the comparative dissolution test, the Ministry of Food and Drug Safety Notice No. 2017-28, Chapter 3, Article 21 was referred.

[0095] In the case of olmesartan, since the average dissolution rate of the control drug is less than 50% within the defined test time, the dissolution rate deviation must be within ±8% or the similarity factor value (f2) should be 55 or more, so as to be determined to have equivalence. In the formulations of Preparation Examples 1 to 8, it could be seen that the dissolution rate of olmesartan is not equivalent to that of the control drug, and has high deviation of 30% or more relative to the control drug. In the case of amlodipine and rosuvastatin, the average dissolution rate of the control drug is 85% or more within 15 minutes so that, if the dissolution rate deviation is within ±15%, it may be determined as equivalent.

Preparative Example 1A: Preparation of Coating Tablets

[0096] The naked tablet prepared in Preparative Example 1 was coated with the coating agent according to the following constitutional compositions, thereby forming a coating tablet of Preparative Example 1A.

TABLE-US-00006 TABLE 6 Constitutional composition of single layer coating tablet comprising olmesartan/amlodipine composition and rosuvastatin composition Prep. Ingredient Example 1A Composition 1 Olmesartan medoxomil 40 Amlodipine besylate 13.89 Silicified microcrystalline cellulose 76.11 Pre-gelatinized starch 35 Sodium croscarmellose 15 Composition 2 Rosuvastatin calcium 10.4 Lactose hydrate 79.8 Silicified microcrystalline cellulose 38 Dibasic calcium phosphate hydrate 21.8 Crospovidone 15 Sodium croscarmellose 7 Post-mixing Colloidal silicon dioxide 4 Magnesium stearate 4 Sum Total mass per tablet 360 Coating Opadry ™ 12.00 Total mass per tablet (coating tablet) 372.00

[0097] The dissolution test results of the formulation in Preparative Example 1A were similar to that of the formulation in Preparative Example 1.

Preparative Example 9: Preparation of Coating Tablets

[0098] Coating tablets in Preparative Examples 9 to 13 were prepared according to the following constitutional compositions.

TABLE-US-00007 TABLE 7 Constitutional composition of single layer coating tablets comprising olmesartan/amlodipine/rosuvastatin compositions Prep. Prep. Prep. Prep. Prep. Ingredient Example 9 Example 10 Example 11 Example 12 Example 13 Composition Olmesartan medoxomil 40 40 40 40 40 Amlodipine besylate 13.89 13.89 13.89 13.89 13.89 Rosuvastatin calcium 10.4 10.4 10.4 10.4 10.4 Lactose hydrate 46.71 79.8 35.71 82.71 48.71 Microcrystalline cellulose 102 — 58 102 70 Silicified microcrystalline cellulose 50 117.91 — 50 — Pre-gelatinized starch 35 35 150 35 35 Crospovidone — 15 — — — Sodium croscarmellose 26 22 26 — 26 Dibasic calcium phosphate hydrate — 18 18 18 Calcium carbonate — — — — 108 Colloidal silicon dioxide 4 4 4 4 4 Magnesium stearate 4 4 4 4 4 Coating Opadry.sup. ™ 12.00 12.00 12.00 12.00 12.00 Total mass per tablet (coating tablet) 372.00 372.00 372.00 372.00 372.00

[0099] In Preparative Examples 9 to 13, the compositions were mixed/compressed to produce single layer tablets, followed by coating the same without pre-preparation of granulates or pellets. The results of the dissolution rate tests for the formulations in Preparative Examples 9 to 13 were different from the results of the same tests for the formulations in Preparative Example 1 to 8. Although the initial dissolution rate of olmesartan medoxomil within 15 minutes was substantially equivalent to that of the control drug, thereafter, it was confirmed that the dissolution rate was increased to a non-equivalent level. In preparative Examples 9 to 13, amlodipine besylate and rosuvastatin calcium showed each initial dissolution rate lower than that of the control drug, thereby demonstrating non-equivalence.

TABLE-US-00008 TABLE 8 Olmesartan medoxomil dissolution rate 0 10 15 30 45 60 Dissolution time min 5 min min min min min min Prep. Example 9 0 18.37 26.63 33.65 41.02 50.42 58.44 Prep. Example 10 0 18.37 30.63 37.65 47.02 51.42 54.43 Prep. Example 11 0 17.71 37.42 43.21 55.77 60.18 65.02 Prep. Example 12 0 13.21 25.33 40.16 49.93 57.03 63.89 Prep. Example 13 0 13.08 24.17 39.21 50.33 55.02 58.96 Sebica + Crestor 0 18.17 25.43 28.61 31.79 34.83 37.08

TABLE-US-00009 TABLE 9 Amlodipine besylate dissolution rate 0 10 15 30 45 60 Dissolution time min 5 min min min min min min Prep. Example 9 0 64.57 72.33  85.51 88.97 90.28 92.31 Prep. Example 10 0 84.34 95.05  96.34 97.89 98.91 99.57 Prep. Example 11 0 56.73 87.37  90.01 92.17 93.39 94.41 Prep. Example 12 0 55.59 73.89  84.19 90.06 91.76 93.59 Prep. Example 13 0 43.84 89.08  90.33 91.97 92.94 94.09 Sebica + Crestor 0 99.67 99.77 100.37 98.57 98.48 98.53

TABLE-US-00010 TABLE 10 Rosuvastatin calcium dissolution rate 0 10 15 30 45 60 Dissolution time min 5 min min min min min min Prep. Example 9 0 75.63 87.74 92.81 93.79 94.84 95.29 Prep. Example 10 0 88.91 90.03 93.89 94.44 95.81 96.63 Prep. Example 11 0 57.24 68.91 82.37 89.01 91.14 92.24 Prep. Example 12 0 82.67 90.45 93.33 94.02 94.89 95.71 Prep. Example 13 0 63.37 80.46 88.21 92.48 93.39 95.52 Sebica + Crestor 0 87.92 89.97 90.37 91.80 92.50 94.66

Experimental Example 2: Stability Test

[0100] With regard to the formulations of Preparative Examples 1 to 10, each formulation was coated with Opadry™, packed in a bottle (including silica gel) and stored under stress testing conditions until a chemical stability test between major ingredients and excipients was conducted. More particularly, a HDPE bottle in which tablets are placed was stored under stress testing conditions (60° C., 80% relative humidity) for 4 weeks, followed by confirming total content of related substance (%) through UPLC. [0101] UPLC operating conditions [0102] Column: ACQUITY UPLC BEH C18 (2.1×50 mm 1.7 μm) [0103] Detector: Ultraviolet absorbance photometer (239 nm) [0104] Flow rate: 0.1 mL/min [0105] Analysis time: 30 minutes [0106] Mobile phase: Phosphoric acid buffer/acetonitrile=80/20

TABLE-US-00011 TABLE 11 Stability test result at 2 at 4 week week under under stress stress Item Initial testing testing Prep. Olmesartan-derived related 0.63 0.74 0.78 Example 1 substance Amlodipine-derived related 0.09 0.09 0.09 substance Rosuvastatin-derived related 0.29 0.41 0.85 substance Prep. Olmesartan-derived related 0.51 0.63 0.72 Example 2 substance Amlodipine-derived related 0.00 0.00 0.00 substance Rosuvastatin-derived related 0.25 0.45 0.68 substance Prep. Olmesartan-derived related 0.64 0.76 0.81 Example 3 substance Amlodipine-derived related 0.00 0.00 0.00 substance Rosuvastatin-derived related 0.11 0.34 0.77 substance Prep. Olmesartan-derived related 0.48 0.53 0.61 Example 4 substance Amlodipine-derived related 0.00 0.00 0.00 substance Rosuvastatin-derived related 0.34 0.52 0.78 substance Prep. Olmesartan-derived related 0.55 0.64 0.77 Example 5 substance Amlodipine-derived related 0.00 0.00 0.00 substance Rosuvastatin-derived related 0.21 0.43 0.65 substance Prep. Olmesartan-derived related 0.41 0.55 0.62 Example 6 substance Amlodipine-derived related 0.00 0.00 0.00 substance Rosuvastatin-derived related 0.18 0.36 0.54 substance Prep. Olmesartan-derived related 0.55 0.72 0.88 Example 7 substance Amlodipine-derived related 0.00 0.00 0.00 substance Rosuvastatin-derived related 0.66 0.83 0.98 substance Prep. Olmesartan-derived related 0.81 0.96 1.11 Example 8 substance Amlodipine-derived related 0.10 0.13 0.17 substance Rosuvastatin-derived related 0.55 0.66 0.78 substance Prep. Olmesartan-derived related 0.42 0.96 1.11 Example 9 substance Amlodipine-derived related 0.18 0.36 0.56 substance Rosubastatin-derived related 0.75 1.66 2.78 substance Prep. Olmesartan-derived related 0.61 0.75 0.97 Example 10 substance Amlodipine-derived related 0.00 0.01 0.01 substance Rosuvastatin-derived related 0.23 0.93 1.91 substance

[0107] All of the formulations in Preparative Examples 1 to 8 did not have a significant difference in terms of contents of related substances, thereby confirming effectively maintained stability. On the other hand, in the case of Preparative Example 9 in which dibasic calcium phosphate hydrate or calcium carbonate is not included and separate drugs are simply mixed to prepare the formulation, it was confirmed that the related substance is remarkably increased after 4 weeks under stress testing conditions to show deteriorated stability. Based on the results of Preparative Examples 3, 4 and 6 to 9, it was confirmed that dibasic calcium phosphate hydrate, anhydrous calcium phosphate and calcium carbonate are excipients having similar influence on stability of each component.

Experimental Example 3: Bioequivalence Test

[0108] The formulation of Preparation Example 1 was subjected to a pharmacokinetic test (PK test) to evaluate its bioequivalence with the control drug.

[0109] That is, 36 beagle dogs were divided into 2 groups of 16 each, wherein a first group was orally administered with the tablets of Preparation Example 1 while a second group received oral administration of 10/40 mg of Sebica tablets (amlodipine besylate/olmesartan medoxomil) and 10 mg of Crestor tablets in combination. Blood was collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 24, 48 and 72 hours after administration, and UPLC-MS/MS (Waters ACQUITY UPLC™ system) was used to quantify the blood concentrations of olmesartan, amlodipine and rosuvastatin, respectively. After quantification, AUC and C.sub.max of each of olmesartan, amlodipine and rosuvastatin at the time of administration of the control drug (combined administration) and the test drug were statistically processed to evaluate bioequivalence between the formulations.

[0110] The bioequivalence evaluation was conducted in accordance with the standard guidelines for bioequivalence of the KFDA. That is, after log transformation of the AUC and C.sub.max values of olmesartan, amlodipine and rosuvastatin, the geometric mean was estimated, followed by calculating projected 90% confidence intervals for geometric mean ratio. If the 90% confidence interval ranges from 0.8 to 1.25, two formulations under comparison are considered to be biologically equivalent.

[0111] Results of the bioequivalence evaluation conducted as described above are shown in Table 12 below. In Table 12, T/R ratio was obtained by dividing the geometric mean of the evaluation items for test formulations by the geometric mean of the evaluation items for a control formulation [i.e., T/R ratio=geometric mean of evaluation items (test formulation)/geometric mean of evaluation items (control)]. If the T/R ratio is higher than 1, it means that the test drug is averagely absorbed more than the control drug, or that the maximum serum concentration of the test drug is averagely higher than the control drug. On the contrary, if T/R ratio is less than 1, it means that the test drug is averagely less absorbed than the control group, or that the blood concentration of the test drug is averagely lower than that of the control drug. In other words, as the T/R ratio is getting farther from 1, it is determined with high probability to be biologically unequal.

TABLE-US-00012 TABLE 12 PK of single layer tablets of Preparative Example 1 Ingredient PK parameter 90% confidence interval (T/R ratio) Olmesartan AUC 0.9669-1.1171 (1.039) Cmax 0.8598-1.0699 (0.959) Amlodipine AUC 0.9144-1.0028 (0.957) Cmax 0.9243-0.9895 (0.956) Rosuvastatin AUC 0.8842-1.1975 (1.028) Cmax 0.8622-1.2224 (1.067)

Preparative Examples 14 to 19: Preparation of Low Dose Single Layer Tablets

[0112] Single layer tablets of Preparative Examples 14 to 16 were prepared with the following constitutional compositions on the basis of the constitutional compositions of the single layer tablets of Preparative Example 1.

TABLE-US-00013 TABLE 13 Constitutional composition of single layer tablets comprising olmesartan/amlodipine composition and rosuvastatin composition Prep. Prep. Prep. Prep. Prep. Prep. Ingredient Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Composition 1 Olmesartan medoxomil 40 40 40 20 20 20 Amlodipine besylate 13.89 6.945 6.945 6.945 6.945 6.945 Silicified microcrystalline 76.11 83.055 83.055 38.055 38.055 38.055 cellulose Pre-gelatinized starch 35 35 35 17.5 17.5 17.5 Sodium croscarmellose 15 15 15 7.5 7.5 7.5 Composition 2 Rosuvastatin calcium 5.2 10.4 5.2 10.4 5.2 2.6 Lactose hydrate 85 79.8 85 34.7 39.9 42.5 Silicified microcrystalline 38 38 38 19 19 19 cellulose Dibasic calcium phosphate 21.8 21.8 21.8 10.9 10.9 10.9 hydrate Crospovidone 15 15 15 7.5 7.5 7.5 Sodium croscarmellose 7 7 7 3.5 3.5 3.5 Post-mixing Colloidal silicon dioxide 4 4 4 2 2 2 Magnesium stearate 4 4 4 2 2 2 Sum Total mass per tablet 360 360 360 180 180 180

[0113] In Preparative Examples 14 to 19, granulates comprising olmesartan medoxomil and amlodipine besylate and rosuvastatin calcium granulates were prepared, respectively, and these granulates were mixed with lubtricants (post-mixing), followed by compressing the mixture to form single layer tablets.

Dissolution test results of the formulations in Preparative Examples 14 to 19 are shown in Tables 14 to 16 below.

TABLE-US-00014 TABLE 14 Olmesartan medoxomil (pH 6.8) 0 10 15 30 45 60 Dissolution time min 5 min min min min min min Prep. Example 14 0 46.04 60.52 67.08 75.31 78.66 79.76 Prep. Example 15 0 34.16 51.61 58.93 67.64 71.68 74.06 Prep. Example 16 0 31.30 51.54 59.26 69.22 73.45 76.35 Prep. Example 17 0 43.99 60.79 66.89 73.78 75.62 77.23 Prep. Example 18 0 45.20 59.93 65.98 73.93 76.87 79.39 Prep. Example 19 0 44.15 57.36 62.74 71.80 75.32 77.13

TABLE-US-00015 TABLE 15 Amlodipine besylate (pH 1.2) 0 10 15 30 45 60 Dissolution time min 5 min min min min min min Prep. Example 14 0 90.11 92.37 92.34 92.60 94.02 93.37 Prep. Example 15 0 88.77 96.06 89.16 92.28 92.31 96.84 Prep. Example 16 0 96.83 95.11 98.30 98.44 99.79 99.25 Prep. Example 17 0 98.47 97.68 97.87 97.49 97.99 99.40 Prep. Example 18 0 97.19 96.05 94.79 95.40 95.07 97.68 Prep. Example 19 0 95.28 96.91 97.23 97.89 98.31 98.76

TABLE-US-00016 TABLE 16 Rosuvastatin (pH 6.8) 0 10 15 30 45 60 Dissolution time min 5 min min min min min min Prep. Example 14 0 89.34 93.12 94.68 95.86 96.73 97.45 Prep. Example 15 0 90.96 93.50 94.28 94.90 95.05 95.13 Prep. Example 16 0 89.65 92.22 93.06 94.12 94.49 94.98 Prep. Example 17 0 92.95 93.78 95.24 96.88 97.91 98.71 Prep. Example 18 0 89.76 94.75 95.44 96.43 97.96 97.71 Prep. Example 19 0 88.48 92.77 94.14 95.98 97.29 97.94

[0114] The formulations of Preparative Examples 14 to 19 are products obtained by adjusting raw drug substances and contents thereof in the formulation of Preparative Example 1. It could be determined that the dissolution rates of olmesartan, amlodipine and rosuvastatin components are substantially equal in specific eluates corresponding to separate ingredients despite changes in raw drug substances and contents there.

[0115] It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims.