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

Abstract

A pharmaceutical composition of a single dosage form for treating hypertension and hyperlipidemia is provided. Compartments containing a drug are formulated in separate forms to solve problems related to the dissolution and absorption of the drug due to drug interaction, and a biologically equivalent preparation can be obtained compared with a conventional single preparation.

Claims

1. A pharmaceutical composition of a single dosage form, comprising: a compartment comprising olmesartan medoxomil and amlodipine or a salt thereof; and a compartment comprising rosuvastatin or a salt thereof, wherein the compartments are formulated in a form of being separated from each other.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a dosage form of a bilayer tablet, a tablet-in-tablet, a mini tablet- and/or a pellet-containing capsule.

3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a dosage form of a bilayer tablet comprising a layer containing olmesartan medoxomil and amlodipine or a salt thereof and a layer containing rosuvastatin or a salt thereof.

4. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a dosage form of a tablet-in-tablet including a core containing rosuvastatin or a salt thereof and a shell containing olmesartan medoxomil and amlodipine or a salt thereof; or a dosage form of a tablet-in-tablet including a core containing olmesartan medoxomil and amlodipine or a salt thereof and a shell containing rosuvastatin or a salt thereof.

5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a dosage form of a capsule containing a mini tablet containing rosuvastatin or a salt thereof and a mini tablet containing olmesartan medoxomil and amlodipine or a salt thereof; a dosage form of a capsule containing a mini tablet containing rosuvastatin or a salt thereof and a pellet or powder containing olmesartan medoxomil and amlodipine or a salt thereof; a dosage form of a capsule containing a mini tablet containing olmesartan medoxomil and amlodipine or a salt thereof and a pellet or powder containing rosuvastatin or a salt thereof; or a dosage form of a capsule containing a pellet containing olmesartan medoxomil and amlodipine or a salt thereof and a pellet containing rosuvastatin or a salt thereof.

6. The pharmaceutical composition of claim 1, wherein the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof contains dibasic calcium phosphate dihydrate.

7. The pharmaceutical composition of claim 6, wherein the dibasic calcium phosphate dihydrate is comprised in an amount of 1 to 30 parts by weight based on total 100 parts by weight of a compartment comprising olmesartan medoxomil and amlodipine or a salt thereof.

8. The pharmaceutical composition of claim 1, wherein the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof contains two or more disintegrants selected from the group consisting of pregelatinized starch, croscarmellose sodium, crospovidone, carboxymethyl cellulose calcium, sodium starch glycolate, copovidone, and complex silicate.

9. The pharmaceutical composition of claim 8, wherein the disintegrant is comprised in an amount of 5 to 60 parts by weight based on total 100 parts by weight of the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof.

10. The pharmaceutical composition of claim 8, wherein pregelatinized starch, croscarmellose sodium, and crospovidone are comprised in an amount of 4 to 40 parts by weight, 1 to 10 parts by weight, and 1 to 20 parts by weight, respectively, based on total 100 parts by weight of the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof.

11. The pharmaceutical composition of claim 1, wherein the compartment comprising rosuvastatin or a salt thereof comprises two or more disintegrants selected from the group consisting of crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, and carboxymethyl cellulose calcium.

12. The pharmaceutical composition of claim 11, wherein the disintegrant is comprised in a range of 2 to 20 parts by weight based on total 100 parts by weight of the compartment comprising rosuvastatin or a salt thereof.

13. The pharmaceutical composition of claim 11, wherein each of crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, and carboxymethyl cellulose calcium is comprised in an amount of 1 to 10 parts by weight based on total 100 parts by weight of the compartment comprising rosuvastatin or a salt thereof.

14. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a bilayer tablet or tablet-in-tablet coated with a coating agent.

15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is a bilayer tablet or tablet-in-tablet coated with polyvinyl alcohol or a polyvinyl alcohol copolymer.

16. The pharmaceutical composition of claim 1, wherein the salt of amlodipine is amlodipine besylate.

17. The pharmaceutical composition of claim 1, wherein the salt of rosuvastatin is a rosuvastatin calcium salt.

18. The pharmaceutical composition of claim 1, wherein D(90) of olmesartan medoxomil is 5 to 45 μm.

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

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

21. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is for the treatment or prevention of essential hypertension and hyperlipidemia.

22. The pharmaceutical composition of claim 1, wherein a dissolution rate of amlodipine or a salt thereof of the pharmaceutical composition shows a level equivalent to a dissolution rate of amlodipine or a salt thereof of a Sevikar™ tablet.

23. The pharmaceutical composition of claim 1, wherein a dissolution rate of rosuvastatin or a salt thereof of the pharmaceutical composition shows a level equivalent to a dissolution rate of rosuvastatin or a salt thereof of a Crestor™ tablet.

24. The pharmaceutical composition of claim 1, wherein olmesartan medoxomil and amlodipine or a salt thereof in the pharmaceutical composition show a blood concentration-area under the time curve (AUC) and a maximum blood concentration (C.sub.max) at levels biologically equivalent to a Sevikar™ tablet having the same active ingredient dose.

25. The pharmaceutical composition of claim 1, wherein a rosuvastatin calcium salt in the pharmaceutical composition shows a blood concentration-area under the time curve (AUC) and a maximum blood concentration (C.sub.max) at levels biologically equivalent to a Crestor™ tablet having the same active ingredient dose.

26. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is for administration to a patient who requires combined therapy of amlodipine and olmesartan medoxomil and simultaneously needs to be administered rosuvastatin.

27. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises olmesartan medoxomil, amlodipine, and rosuvastatin in the following doses based on a unit preparation: 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; 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; or 20 mg of olmesartan medoxomil, 2.5 mg of amlodipine or a salt thereof, and 5 mg of rosuvastatin or a salt thereof.

Description

DESCRIPTION OF DRAWINGS

[0060] FIG. 1 illustrates the dissolution test results of the preparations of Preparation Examples 7 to 9 in comparison with a reference drug with respect to olmesartan medoxomil.

[0061] FIG. 2 illustrates the dissolution test results of the preparations of Preparation Examples 7 to 9 in comparison with a reference drug with respect to amlodipine besylate.

[0062] FIG. 3 illustrates the dissolution test results of the preparations of Preparation Examples 7 to 9 in comparison with a reference drug with respect to a rosuvastatin calcium salt.

[0063] FIGS. 4 to 6 each illustrate an olmesartan medoxomil blood concentration profile, an amlodipine besylate blood concentration profile, and a rosuvastatin blood concentration profile over time when the bilayer tablet (test drug) of Preparation Example 8 and a reference drug (Sevikar tablet and Crestor tablet) are administered.

[0064] FIGS. 7 to 9 each illustrate an olmesartan medoxomil blood concentration profile, an amlodipine besylate blood concentration profile, and a rosuvastatin blood concentration profile over time when the bilayer tablet (test drug) of Preparation Example 15 and a reference drug (Sevikar tablet and Crestor tablet) are administered.

MODES OF THE INVENTION

Examples

[0065] Hereinafter, the present invention will be described in more detail in the following Examples. However, the following Examples merely exemplify the content of the present invention, and do not limit or restrict the scope of rights of the present invention. From the detailed description and examples of the present invention, it is understood that what can be easily inferred by a person skilled in the art to which the present invention pertains belongs to the scope of rights of the present invention.

Preparation Examples

[0066] Preparation of Bilayer Tablet Including Olmesartan/Amlodipine Layer and Rosuvastatin Layer

[0067] An olmesartan medoxomil/amlodipine besylate compartment (mixture) and a rosuvastatin calcium compartment (mixture) were prepared according to the compositions of the following table and typical methods.

[0068] A composite bilayer tablet including an olmesartan medoxomil/amlodipine compartment (first layer) and a rosuvastatin calcium compartment (second layer) was prepared using a bilayer tablet machine.

Experimental Examples

Experimental Example 1: Dissolution Test

[0069] A comparative dissolution test was performed on the preparations prepared according to the preparation examples of the present invention under the following dissolution test conditions.

[0070] As the reference drug used in the comparative dissolution test, a Sevikar™ 10/40 mg tablet (amlodipine besylate/olmesartan medoxomil) and a Crestor™ 20 mg tablet (rosuvastatin calcium) were used.

[0071] A Sevikar™ tablet and a Crestor™ tablet are in the form of film-coated single tablets. The Sevikar™ tablet includes silicified microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and magnesium stearate as an excipient, and includes polyvinyl alcohol, Macrogol/Polyethylene glycol 3350, titanium dioxide, talc, and iron oxide as a film coating agent.

[0072] Meanwhile, a Crestor™ tablet includes microcrystalline cellulose, lactose hydrate, tribasic calcium phosphate, crospovidone, and magnesium stearate as an excipient, and includes hypromellose, triacetin, titanium dioxide, and iron oxide as a film coating agent.

[0073] [Dissolution Test Conditions]

[0074] Dissolution solution: Korean Pharmacopoeia Dissolution Test Method First Liquid, Second Liquid, or Water

[0075] Olmesartan medoxomil: Water

[0076] Amlodipine besylate: First liquid, pH 1.2

[0077] Rosuvastatin calcium: Second liquid, pH 6.8

[0078] Temperature: 37±0.5° C.

[0079] Test method: Korean Pharmacopoeia Dissolution Test Method 2 (Paddle method)

[0080] Paddle rotation speed: 50 rpm

[0081] Analysis method: UPLC method [0082] UPLC operating conditions [0083] Column: ACQUITY UPLC BEH C18 (2.1×50 mm 1.7 μm) [0084] Detector: An ultraviolet absorption photometer (239 nm) [0085] Flow rate: 0.1 mL/min [0086] Analysis time: 30 minutes [0087] Mobile phase: Phosphate buffer/Acetonitrile=80/20

Preparation Examples 1 to 6: Preparation of Bilayer Tablet Including Olmesartan/Amlodipine Layer and Rosuvastatin Layer

[0088]

TABLE-US-00001 TABLE 1 Preparation Preparation Preparation Preparation Preparation Preparation Ingredient name Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Olmesartan medoxomil/amlodipine besylate portion Mixture Olmesartan medoxomil 40 40 40 40 40 40 Amlodipine besylate 13.89 13.89 13.89 13.89 13.89 13.89 Microcrystalline cellulose — — 92.05 — — Silicified microcrystalline 92.05 92.05 — 92.05 92.05 — cellulose Lactose hydrate — — — — — 72.05 Pregelatinized starch 40 — 40 40 40 40 Sodium starch glycolate — 40 — — — — Croscarmellose sodium 20 20 10 10 10 15 Crospovidone — — 20 — — — Copovidone — — — 20 — — Carboxymethyl cellulose — — — — 20 — calcium Low-substituted — — — — — 40 hydroxypropylcellulose Magnesium stearate 2 2 2 2 2 2 Iron oxide red 0.06 0.06 0.06 0.06 0.06 0.06 Mass(mg) 208 208 218 218 218 223 Rosuvastatin calcium portion Mixture Rosuvastatin calcium 20.8 20.8 20.8 20.8 20.8 20.8 Lactose hydrate 126.2 126.2 116.36 116.36 116.36 116.36 Microcrystalline cellulose — 40 — — — — Silicified microcrystalline 40 — 45.34 45.34 45.34 45.34 cellulose Dibasic calcium 20 20 21.8 21.8 21.8 21.8 phosphate dihydrate Crospovidone 10 10 10.7 10.7 10.7 10.7 Croscarmellose sodium 5 5 6.4 6.4 6.4 6.4 Colloidal silicon oxide 4 4 4.3 4.3 4.3 4.3 Magnesium stearate 4 4 4.3 4.3 4.3 4.3 Mass (mg) 230 230 230 230 230 230 Total Total mass per tablet(mg) 438 438 448 448 448 453

[0089] The dissolution test results of the preparations are shown in the following table.

TABLE-US-00002 TABLE 2 Olmesartan medoxomil dissolution rate Dissolution time 0 5 10 15 30 45 60 minutes minutes minutes minutes minutes minutes minutes Preparation 0 45.98 69.96 79.26 89.48 93.96 95.30 Example 1 Preparation 0 59.12 77.07 84.37 92.96 96.31 97.79 Example 2 Preparation 0 50.90 66.68 74.06 84.07 87.70 90.25 Example 3 Preparation 0 49.56 69.97 80.29 92.31 96.98 97.74 Example 4 Preparation 0 48.84 70.94 81.10 94.01 98.37 100.99 Example 5 Preparation 0 46.36 63.90 71.52 81.06 84.02 85.52 Example 6 Sevikar + 0 26.32 34.05 37.96 44.78 48.49 51.23 Crestor

TABLE-US-00003 TABLE 3 Amlodipine besylate dissolution rate Dissolution time 0 5 10 15 30 45 60 minutes minutes minutes minutes minutes minutes minutes Preparation 0 83.28 85.47 86.48 88.41 88.38 90.20 Example 1 Preparation 0 87.20 87.42 86.19 88.02 89.86 89.82 Example 2 Preparation 0 87.85 89.73 90.21 91.84 93.65 95.07 Example 3 Preparation 0 95.39 95.11 96.88 92.41 96.42 95.60 Example 4 Preparation 0 95.15 94.29 93.82 92.72 95.10 91.76 Example 5 Preparation 0 86.30 91.45 91.77 92.21 92.48 94.08 Example 6 Sevikar + 0 88.78 90.55 92.49 92.23 93.38 93.64 Crestor

TABLE-US-00004 TABLE 4 Rosuvastatin calcium dissolution rate Dissolution time 0 5 10 15 30 45 60 minutes minutes minutes minutes minutes minutes minutes Preparation 0 88.91 95.19 97.18 99.82 100.23 100.43 Example 1 Preparation 0 84.28 87.50 89.30 95.91 92.78 94.55 Example 2 Preparation 0 84.29 88.44 89.35 92.79 94.19 94.97 Example 3 Preparation 0 84.60 91.66 93.61 97.26 99.54 101.71 Example 4 Preparation 0 90.28 92.71 93.94 94.15 97.83 99.79 Example 5 Preparation 0 87.79 90.19 91.96 91.94 94.63 95.99 Example 6 Sevikar + 0 76.55 85.39 85.30 90.50 93.79 95.02 Crestor

[0090] The preparations of Preparation Examples 1 to 6 had a high dissolution rate of olmesartan in all time slots compared to the reference drug, and the dissolution rate of amlodipine did not have a large deviation as a whole. Meanwhile, the preparations of Preparation Examples 3 to 6 had a slightly higher initial dissolution rate of rosuvastatin than the reference drug, but the deviation from the reference drug was not large as a whole. It was confirmed that the composition of olmesartan/amlodipine may have some influence on the initial dissolution rate of a rosuvastatin layer, but did not have a significant influence on the overall dissolution profile of the rosuvastatin layer.

Preparation Examples 7 to 9: Composition of Bilayer Tablet Including Olmesartan/Amlodipine Layer and Rosuvastatin Layer

[0091] The following preparations were prepared by changing the types and contents of disintegrants and excipients of the above Preparation Examples.

TABLE-US-00005 TABLE 5 Composition of bilayer tablet including olmesartan/amlodipine layer and rosuvastatin layer Preparation Preparation Preparation Ingredient name Example 7 Example 8 Example 9 Olmesartan medoxomil/amlodipine besylate portion Granule Olmesartan medoxomil 40 40 40 Amlodipine besylate 13.89 13.89 13.89 Silicified microcrystalline cellulose 92.05 69.05 69.05 Dibasic calcium phosphate dehydrate — 40 — Anhydrous calcium phosphate — — 40 Pregelatinized starch 40 40 40 Croscarmellose sodium 20 15 15 Crospovidone 10 20 20 Magnesium stearate 2 2 2 Iron oxide red 0.06 0.06 0.06 Mass (mg) 218 240 240 Rosuvastatin calcium portion Mixture Rosuvastatin calcium 20.8 20.8 20.8 Lactose hydrate 116.36 116.36 116.36 Silicified microcrystalline cellulose 45.34 45.34 45.34 Dibasic calcium phosphate dehydrate — 21.8 21.8 Calcium carbonate 21.8 — — Crospovidone 10.7 10.7 10.7 Croscarmellose sodium 6.4 6.4 6.4 Colloidal silicon oxide 4.3 4.3 4.3 Magnesium stearate 4.3 4.3 4.3 Mass (mg) 230 230 230 Total Total mass per tablet (mg) 448 470 470

[0092] The dissolution test results of the preparations are shown in the following Tables 6 to 8 and FIGS. 1 to 3.

TABLE-US-00006 TABLE 6 Olmesartan medoxomil dissolution rate Dissolution time 0 5 10 15 30 45 60 minutes minutes minutes minutes minutes minutes minutes Preparation 0 30.23 48.99 59.96 76.70 84.38 88.78 Example 7 Preparation 0 50.56 74.05 84.45 94.83 97.27 98.75 Example 8 Preparation 0 31.08 47.95 57.76 72.65 80.15 84.36 Example 9 Sevikar + 0 26.32 34.05 37.96 44.78 48.49 51.23 Crestor

TABLE-US-00007 TABLE 7 Amlodipine besylate dissolution rate Dissolution time 0 5 10 15 30 45 60 minutes minutes minutes minutes minutes minutes minutes Preparation 0 99.98 95.79 96.37 101.28 97.84 97.62 Example 7 Preparation 0 88.23 93.58 93.22 93.92 93.69 94.10 Example 8 Preparation 0 93.07 91.25 93.66 96.05 96.18 95.96 Example 9 Sevikar + 0 88.78 90.55 92.49 92.23 93.38 93.64 Crestor

TABLE-US-00008 TABLE 8 Rosuvastatin calcium dissolution rate Dissolution time 0 5 10 15 30 45 60 minutes minutes minutes minutes minutes minutes minutes Preparation 0 91.43 93.73 94.05 95.08 96.15 96.04 Example 7 Preparation 0 89.99 92.55 93.40 94.69 95.41 95.89 Example 8 Preparation 0 83.86 90.55 92.80 95.07 96.26 96.78 Example 9 Sevikar + 0 76.55 85.39 85.30 90.50 93.79 95.02 Crestor

[0093] The preparations of Preparation Examples 7 to 9 still had a high dissolution rate of olmesartan compared to the reference drug. The dissolution rate of amlodipine showed the lowest deviation from the reference drug in Preparation Example 8 compared to Preparation Examples 7 and 9. The preparations of Preparation Examples 7 to 9 had a slightly higher initial dissolution rate of rosuvastatin than the reference drug, but the deviation from the reference drug was not large as a whole. The preparation of Preparation Example 8 did not have a large deviation in the dissolution rates of amlodipine and rosuvastatin compared to the reference drug, and thus showed the most similar dissolution rate compared to the reference drug among the preparations. Considering that the dissolution rate of the preparation of Preparation Example 8 is good, it was determined that dibasic calcium phosphate dihydrate plays an important role in the dissolution rate of the preparation. Meanwhile, the preparation of Preparation Example 9 had an olmesartan dissolution rate similar to that of the preparation of Preparation Example 7, and the deviation from the reference drug was shown to be at a level of 15%. The preparation of Preparation Example 9 had a smaller deviation from the reference drug than the preparation of Preparation Example 8 having a deviation of 30% or more from the reference drug. Further, in terms of the dissolution rates of amlodipine and rosuvastatin, the preparation of Preparation Example 9 had a less deviation from the reference drug than the preparation of Preparation Example 7. Therefore, an experiment of bioequivalence was performed on the preparations of Preparation Examples 8 and 9.

[0094] In general, the Ministry of Food and Drug Safety Notification No. 2017-28, Chapter 3, Article 21 is referenced for the similarity judgment of the comparative dissolution test. In the case of olmesartan, the average dissolution rate of the reference drug is less than 50% within the specified test time, so it is determined that the dissolution rate is equivalent when the dissolution rate deviation is within ±8% or the similarity factor (f2) value is 55 or more. It can be seen that in the preparations of Preparation Examples 1 to 9, the elution rate of olmesartan is not equivalent to that of the reference drug, and a deviation of 30% or more from that of the reference drug occurs. In the case of amlodipine and rosuvastatin, the average dissolution rate of the reference drug is 85% or more within 15 minutes, so a dissolution rate deviation within ±15% can be judged to be equivalent.

Preparation Examples 8A and 8B: Preparation of Coated Tablet

[0095] Coated tablets of Preparation Examples 8A and 8B were prepared by coating the naked tablets prepared according to Preparation Example 8 with a coating material of the following composition.

TABLE-US-00009 TABLE 9 Composition of bilayer coated tablet including olmesartan/amlodipine layer and rosuvastatin layer Preparation Preparation Ingredient name Example 8A Example 8B Olmesartan medoxomil/amlodipine besylate portion Olmesartan medoxomil 40.00 40.00 Amlodipine besylate 13.89 13.89 Silicified microcrystalline cellulose 69.05 69.05 Dibasic calcium phosphate dihydrate 40.00 40.00 Pregelatinized starch 40.00 40.00 Croscarmellose sodium 15.00 15.00 Crospovidone 20.00 20.00 Magnesium stearate 2.00 2.00 Iron oxide red 0.06 0.06 Olmesartan medoxomil/ 240.00 240.00 amlodipine besylate portion mass (mg) Rosuvastatin calcium portion Rosuvastatin calcium 20.80 20.80 Lactose hydrate 116.36 116.36 Silicified microcrystalline cellulose 45.34 45.34 Dibasic calcium phosphate dihydrate 21.80 21.80 Crospovidone 10.70 10.70 Croscarmellose sodium 6.40 6.40 Colloidal silicon oxide 4.30 4.30 Magnesium stearate 4.30 4.30 Rosuvastatin calcium portion mass (mg) 230.00 230.00 Total mass per tablet (naked tablet) (mg) 470.00 470.00 Coating material PVA 15.00 — PVA copolymer (PVA/macrogol grafted 15.00 polymer) Total mass per tablet (coated tablet) (mg) 485.00 485.00

[0096] The dissolution test results of the preparations of Preparation Examples 8A and 8B were similar to the dissolution test results of the preparation of Preparation Example 8.

Experimental Example 2: Bioequivalence Test

[0097] Bioequivalence with the reference drug was evaluated by performing a pharmacokinetic test (PK test) on the preparation of Preparation Example 8.

[0098] That is, 64 healthy male volunteers were divided into two groups of 32 each, the tablet of Preparation Example 8 was orally administered to the first group, and the Sevikar 10/40 mg tablet (amlodipine besylate/olmesartan medoxomil) and the Crestor 20 mg tablet were orally administered in combination to the second group. Blood was collected at 0, 0, 5, 1, 5, 2, 2, 5, 3, 4, 5, 6, 8, 10, 12, 16, 24, 48, and 72 hours after administration, and the blood concentrations of olmesartan, amlodipine, and rosuvastatin were each quantified using UPLC-MS/MS (Waters ACQUITY UPLC™ system). After quantification, bioequivalence between the preparations was evaluated by statistically processing the AUC and Cmax of olmesartan, amlodipine, and rosuvastatin at the time of administration of the reference drug (combination administration) and the test drug.

[0099] The evaluation of bioequivalence was performed in accordance with the Bioequivalence Standards Guidelines of the Ministry of Food and Drug Safety. That is, after the AUC and Cmax values of olmesartan, amlodipine and rosuvastatin were log-transformed, a geometric mean was obtained and the projected 90% confidence intervals for the geometric mean ratio were calculated. It is acknowledged that two preparations are biologically equivalent when the 90% confidence interval is 0.8 to 1.25.

[0100] The blood concentration profiles obtained by the PK test are shown in FIGS. 4 to 6. FIGS. 4 to 6 each illustrate an olmesartan medoxomil blood concentration profile, an amlodipine besylate blood concentration profile, and a rosuvastatin blood concentration profile over time when the bilayer tablet (test drug) of Preparation Example 8 and a reference drug (Sevikar tablet and Crestor tablet) are administered.

[0101] The results of the bioequivalence evaluation performed as described above are shown in the following Table 10. In Table 10, a T/R ratio was obtained by dividing the geometric mean of the evaluation items for the test preparation by the geometric mean of the evaluation items for the control preparation [that is, T/R ratio=the geometric mean of the evaluation items (test preparation)/the geometric mean of the evaluation items (control preparation)]. A T/R ratio higher than 1 means that the test drug absorbs more than the reference drug on average, and the maximum blood concentration of the test drug is higher than the reference drug on average, and a T/R ratio less than 1 means that the test drug is absorbed less than the reference drug on average, or the blood concentration of the test drug is lower than that of the reference drug on average. That is, the farther the T/R ratio is from 1, the higher the probability it is determined to be biologically non-equivalent.

TABLE-US-00010 TABLE 10 PK of bilayer tablet of Preparation Example 8 PK 90% confidence interval Ingredient parameter (T/R ratio) Olmesartan AUC 0.9716-1.0578 (1.0138) Cmax 0.9818-1.1009 (1.0396) Amlodipine AUC 1.0243-1.0757 (1.0497) Cmax 1.0369-1.1074 (1.0716) Rosuvastatin AUC 0.9453-1.0669 (1.0043) Cmax 0.9433-1.1152 (1.0257)

[0102] In addition, bioequivalence with the reference drug was evaluated by performing a pharmacokinetic test (PK test) on the preparation of Preparation Example 9 in beagle dogs. That is, 32 beagle dogs were divided into two groups of 16 each, the tablet of Preparation Example 9 was orally administered to the first group, and of the Sevikar 10/40 mg tablet (amlodipine besylate/olmesartan medoxomil) and the Crestor 20 mg tablet were orally administered to the second group. After administration, the blood concentrations were each quantified in the same manner as in the above PK test method, and then the bioequivalence between the preparations was evaluated by statistically processing the AUC and Cmax at the time of administration of the reference drug (combination administration) and the test drug. The results of the bioequivalence evaluation performed as described above are shown in the following Table 11.

TABLE-US-00011 TABLE 11 PK of bilayer tablet of Preparation Example 9 PK 90% confidence interval Ingredient parameter (T/R ratio) Olmesartan AUC 0.8223-1.0312 (0.92) Cmax 0.7924-1.0178 (0.898) Non-equivalent Amlodipine AUC 0.9207-1.0624 (0.988) Cmax 0.8535-1.0658 (0.953) Rosuvastatin AUC 0.7891-1.0523 (0.911) Non-equivalent Cmax 0.6577-0.9303 (0.782) Non-equivalent

Experimental Example 3: Comparison of Sizes of Final Tablets

[0103] The total weight of a Sevikar 10/40 mg tablet and of a Crestor 20 mg tablet used as a reference drug was 208 mg and 309 mg, respectively. The total weight of the bilayer tablet of Preparation Example 8 according to the present invention was 470 mg, which was smaller in total weight and smaller in size than the combination of the Sevikar tablet and the Crestor tablet, so that the dosing convenience for patients was enhanced.

Preparation Examples 10 to 14: Preparation of Low-Dose Bilayer Tablets

[0104] Based on the composition of the coated tablet of Preparation Example 8, bilayer tablets of Preparation Examples 10 to 14 having the following composition were prepared.

TABLE-US-00012 TABLE 12 Composition of bilayer tablet including olmesartan/amlodipine layer and rosuvastatin layer Preparation Preparation Preparation Preparation Preparation Ingredient name Example 10 Example 11 Example 12 Example 13 Example 14 Olmesartan medoxomil/amlodipine besylate portion Granule Olmesartan medoxomil 40 40 40 20 20 Amlodipine besylate 13.89 6.945 6.945 6.945 6.945 Silicified microcrystalline 69.05 75.995 75.995 34.525 34.525 cellulose Dibasic calcium phosphate 40 40 40 20 20 dihydrate Pregelatinized starch 40 40 40 20 20 Croscarmellose sodium 15 15 15 7.5 7.5 Crospovidone 20 20 20 10 10 Magnesium stearate 2 2 2 1 1 Iron oxide red 0.06 0.06 0.06 0.03 0.03 Mass(mg) 240 240 240 120 120 Rosuvastatin calcium portion Granule Rosuvastatin calcium 10.4 10.4 5.2 10.4 5.2 Lactose hydrate 58.18 58.18 29.09 58.18 29.09 Silicified microcrystalline 22.67 22.67 11.335 22.67 11.335 cellulose Dibasic calcium phosphate 10.9 10.9 5.45 10.9 5.45 dihydrate Crospovidone 5.35 5.35 2.675 5.35 2.675 Croscarmellose sodium 3.2 3.2 1.6 3.2 1.6 Colloidal silicon oxide 2.15 2.15 1.575 2.15 1.575 Magnesium stearate 2.15 2.15 1.575 2.15 1.575 Mass (mg) 115 115 58.5 115 58.5 Total Total mass per tablet(mg) 355 355 298.5 235 178.5

[0105] The dissolution test results of the preparations of Preparation Examples 10 to 14 are shown in the following Tables 13 to 15.

TABLE-US-00013 TABLE 13 Olmesartan medoxomil (pH 6.8) Dissolution time 0 5 10 15 30 45 60 minutes minutes minutes minutes minutes minutes minutes Preparation 0 46.78 66.96 77.30 90.09 95.87 99.60 Example 8 Preparation 0 48.80 69.46 78.63 89.86 94.72 97.37 Example 10 Preparation 0 46.41 68.27 77.83 89.06 93.71 96.32 Example 11 Preparation 0 50.70 70.48 84.03 94.04 98.24 100.35 Example 12 Preparation 0 50.56 70.56 84.44 95.36 98.58 102.95 Example 13 Preparation 0 51.22 71.80 85.51 95.60 98.81 102.62 Example 14

TABLE-US-00014 TABLE 14 Amlodipine besylate (pH 1.2) Dissolution time 0 5 10 15 30 45 60 minutes minutes minutes minutes minutes minutes minutes Preparation 0 83.73 89.54 91.52 93.90 Example 8 Preparation 0 84.10 87.36 89.11 90.62 Example 10 Preparation 0 85.83 89.52 89.10 91.34 Example 11 Preparation 0 84.55 86.66 88.23 92.84 Example 12 Preparation 0 85.27 87.90 89.83 90.76 Example 13 Preparation 0 83.42 89.13 90.66 93.71 Example 14

TABLE-US-00015 TABLE 15 Rosuvastatin calcium (pH 6.8) Dissolution time 0 5 10 15 30 45 60 minutes minutes minutes minutes minutes minutes minutes Preparation 0 99.82 100.76 101.65 Example 8 Preparation 0 100.51 101.74 101.91 Example 10 Preparation 0 99.73 100.22 101.40 Example 11 Preparation 0 99.52 100.58 101.24 Example 12 Preparation 0 100.80 102.69 103.31 Example 13 Preparation 0 97.81 98.80 99.33 Example 14

[0106] The preparations of Preparation Examples 10 to 14 are preparations in which raw material drugs of the preparation of Preparation Example 8 and amounts thereof have been changed. It can be seen that the dissolution rates of the olmesartan, amlodipine, and rosuvastatin ingredients are the same in the specific eluate for each ingredient, despite the change in the raw material drugs and amounts thereof.

Preparation Examples 15 and 16: Preparation of Low-Dose Bilayer Tablets

[0107] Based on the composition of the coated tablet of Preparation Example 8, bilayer tablets of Preparation Examples 15 and 16 having the following composition were prepared.

TABLE-US-00016 TABLE 16 Composition of bilayer tablet including olmesartan/amlodipine layer and rosuvastatin layer Preparation Preparation Ingredient name Example 15 Example 16 Olmesartan medoxomil/amlodipine besylate portion Granule Olmesartan medoxomil 40 40 Amlodipine besylate 6.95 6.95 Silicified microcrystalline 55 55 cellulose Dibasic calcium phosphate 36 36 dihydrate Pregelatinized starch 40 40 Croscarmellose sodium 15 15 Crospovidone 20 20 Magnesium stearate 2 2 Iron oxide red 0.05 0.05 Mass 215 215 Rosuvastatin calcium portion Granule Rosuvastatin calcium 10.4 5.2 Lactose hydrate 73.00 36.5 Silicified microcrystalline 26.50 13.25 cellulose Dibasic calcium phosphate 21.80 10.9 dihydrate Crospovidone 7 3.5 Croscarmellose sodium 5 2.5 Colloidal silicon oxide 2.15 1.075 Magnesium stearate 2.15 1.075 Mass (mg) 148 74 Total Total mass per tablet 363 289

Experimental Example 4: Dissolution Test

[0108] Using Preparation Example 15 and a Servikar™ 5/40 mg tablet (amlodipine besylate/olmesartan medoxomil) and a Crestor™ 10 mg tablet (rosuvastatin calcium) as reference drugs, a comparative dissolution test was performed by the method of Experimental Example 1.

[0109] The comparative dissolution test results are shown in the following Tables 17 to 19.

TABLE-US-00017 TABLE 17 Olmesartan medoxomil dissolution rate (water) Dissolution time 0 5 10 15 30 45 60 minutes minutes minutes minutes minutes minutes minutes Preparation 0 58.47 77.55 85.80 94.70 97.23 98.56 Example 15 Sevikar + 0 16.86 21.64 24.53 29.35 31.34 32.55 Crestor

TABLE-US-00018 TABLE 18 Amlodipine besylate dissolution rate (pH 1.2) Dissolution time 0 5 10 15 30 45 60 minutes minutes minutes minutes minutes minutes minutes Preparation 0 89.89 92.78 92.73 93.37 93.15 92.63 Example 15 Sevikar + 0 91.02 92.78 92.73 93.37 93.15 92.63 Crestor

TABLE-US-00019 TABLE 19 Rosuvastatin calcium dissolution rate (pH 6.8) Dissolution time 0 5 10 15 30 45 60 minutes minutes minutes minutes minutes minutes minutes Preparation 0 92.17 95.53 96.56 97.61 98.46 98.85 Example 15 Sevikar + 0 83.55 87.93 88.93 91.01 92.93 93.94 Crestor

[0110] The preparation of Preparation Example 15 still had a high dissolution rate of olmesartan compared to the reference drug, and did not have a large deviation in dissolution rate of amlodipine and rosuvastatin from that of the reference drug, and showed a dissolution rate similar to that of the reference drug.

Experimental Example 5: Bioequivalence Test

[0111] Bioequivalence with the reference drug was evaluated by performing a pharmacokinetic test (PK test) on the preparation of Preparation Example 15.

[0112] That is, 64 healthy male volunteers were divided into two groups of 32 each, the tablet of Preparation Example 15 was orally administered to the first group, and a Sevikar 5/40 mg tablet (amlodipine besylate/olmesartan medoxomil) and a Crestor 20 mg tablet were orally administered in combination to the second group. Blood was collected at 0, 0.5, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 24, 48, and 72 hours after administration, and the blood concentrations of olmesartan, amlodipine, and rosuvastatin were each quantified using the UPLC-MS/MS (Waters ACQUITY UPLC™ system). After quantification, bioequivalence between the preparations was evaluated by statistically processing the AUC and Cmax of olmesartan, amlodipine, and rosuvastatin at the time of administration of the reference drug (combination administration) and the test drug.

[0113] The evaluation of bioequivalence was performed in accordance with the Bioequivalence Standards Guidelines of the Ministry of Food and Drug Safety. That is, after the AUC and Cmax values of olmesartan, amlodipine and rosuvastatin were log-transformed, a geometric mean was obtained and the projected 90% confidence intervals for the geometric mean ratio were calculated. It is acknowledged that two preparations are biologically equivalent when the 90% confidence interval is 0.8 to 1.25.

[0114] The blood concentration profiles obtained by the PK test are shown in FIGS. 7 to 9. FIGS. 7 to 9 each illustrate an olmesartan medoxomil blood concentration profile, an amlodipine besylate blood concentration profile, and a rosuvastatin blood concentration profile over time when the bilayer tablet (test drug) of Preparation Example 15 and a reference drug (Sevikar tablet and Crestor tablet) are administered.

[0115] The results of the bioequivalence evaluation performed as described above are shown in the following Table 20. In Table 20, a T/R ratio was obtained by dividing the geometric mean of the evaluation items for the test preparation by the geometric mean of the evaluation items for the control preparation [that is, T/R ratio=the geometric mean of the evaluation items (test preparation)/the geometric mean of the evaluation items (control preparation)]. A T/R ratio higher than 1 means that the test drug absorbs more than the reference drug on average, and the maximum blood concentration of the test drug is higher than the reference drug on average, and a T/R ratio less than 1 means that the test drug is absorbed less than the reference drug on average, or the blood concentration of the test drug is lower than that of the reference drug on average. That is, the farther the T/R ratio is from 1, the higher the probability it is determined to be biologically non-equivalent.

TABLE-US-00020 TABLE 20 PK of bilayer tablet of Preparation Example 15 PK 90% confidence interval Ingredient parameter (T/R ratio) Olmesartan AUC 0.9351-1.0170 (0.9752) Cmax 0.9304-1.0491 (0.9880) Amlodipine AUC 1.0054-1.0526 (1.0287) Cmax 1.0064-1.0696 (1.0375) Rosuvastatin AUC 0.9644-1.0834 (1.0222) Cmax 0.9857-1.1518 (1.0655)