PHARMACEUTICAL COMBINATION FORMULATION

Abstract

The present invention relates to a tablet comprising candesartan or candesartan cilexetil and amlodipine or its pharmaceutically acceptable salt as active ingredients, the tablet using a particular solubilizer in order to significantly improve the stability and dissolution properties of the active ingredients. In addition, the present invention relates to a method of preparing the tablet.

Claims

1. A tablet comprising candesartan or candesartan cilexetil as the first active ingredient and amlodipine or its pharmaceutically acceptable salt as the second active ingredient, characterized in that it comprises macrogol-15-hydroxystearate as a solubilizer.

2. The tablet of claim 1, wherein the first active ingredient is candesartan cilexetil.

3. The tablet of claim 1, wherein it does not comprise any sugar alcohol.

4. The tablet of claim 1, wherein the weight ratio of candesartan or candesartan cilexetil to macrogol-15-hydroxystearate is 1:0.03?1:2.

5. The tablet of claim 1, wherein it is single-layer tablet, multi-layer tablet or nucleated tablet.

6. The tablet of claim 5, wherein the multi-layer tablet is double-layer tablet.

7. The tablet of claim 6, wherein the double-layer tablet is composed of the first layer and the second layer, the first layer comprising candesartan or candesartan cilexetil and macrogol-15-hydroxystearate, and the second layer comprising amlodipine or its pharmaceutically acceptable salt.

8. The tablet of claim 1, wherein its storage period is 6 weeks to 3 years.

Description

MODE FOR INVENTION

[0055] The features of the invention will be explained below in more detail by reference to Examples, but the scope of the invention should not be construed as being limited to the following embodiments. In addition, it will be apparent to one skilled in the art that various changes and modifications can be made to the invention without departing from the spirit thereof.

EXAMPLE 1

Preparation of Double-Layer Tablet

[0056] Hydroxypropylcellulose 6 g and macrogol-15-hydroxystearate 3 g were dissolved in purified water and ethanol to prepare a binding solution (1). Candesartan cilexetil 16 g, microcrystalline cellulose 65 g and pregelatinized starch 10 g were uniformly mixed in a high speed mixer to prepare a mixture (1). The binding solution (1) was added onto the mixture (1), granulated, and then dried. Screened granules (1) were obtained by sieving with a 20-mesh sieve in semi-dried state, and sieving with a 30-mesh sieve in dried state.

[0057] Silicified microcrystalline cellulose 79 g was added to the screened granules (1), and mixed in a double-cone mixer. Then, magnesium stearate 1 g was added to obtain a lubricated mixture (1).

[0058] Hydroxypropylcellulose 5 g was dissolved in purified water and ethanol to prepare a binding solution (2). Amlodipine besylate 13.87 g, microcrystalline cellulose 71.13 g and pregelatinized starch 10 g were pre-mixed and mixed in a double-cone mixer to prepare a mixture (2). The binding solution (2) was added onto the mixture (2), granulated, and then dried. Screened granules (2) were obtained by sieving with a 20-mesh sieve in semi-dried state, and sieving with a 30-mesh sieve in dried state.

[0059] Microcrystalline cellulose 64 g and pregelatinized starch 15 g were added to the screened granules (2), and mixed in a double-cone mixer. Then, magnesium stearate 1 g was added to obtain a lubricated mixture (2).

[0060] The lubricated mixture (1) and the lubricated mixture (2) were compressed into a double-layer tablet by a tableting machine (Autotab-200TR, Ichihashi seiki) using a 9.4 mm-diameter punch (the first layer weight: 180 g, the second layer weight: 180 g).

[0061] The obtained double-layer tablet was coated with Opadry (10.0 g/T) by a coating machine (Hi-coater, Freund).

EXAMPLE 2

Preparation of Double-Layer Tablet

[0062] Hydroxypropylcellulose 6 g and macrogol-15-hydroxystearate 3 g were dissolved in purified water and ethanol to prepare a binding solution (1). Candesartan cilexetil 16 g, microcrystalline cellulose 65 g and pregelatinized starch 10 g were uniformly mixed in a high speed mixer to prepare a mixture (1). The binding solution (1) was added onto the mixture (1), granulated, and then dried. Screened granules (1) were obtained by sieving with a 20-mesh sieve in semi-dried state, and sieving with a 30-mesh sieve in dried state.

[0063] Silicified microcrystalline cellulose 79 g was added to the screened granules (1), and mixed in a double-cone mixer. Then, magnesium stearate 1 g was added to obtain a lubricated mixture (1).

[0064] Hydroxypropylcellulose 2.5 g was dissolved in purified water and ethanol to prepare a binding solution (2). Amlodipine besylate 6.935 g, microcrystalline cellulose 35.565 g and pregelatinized starch 5 g were pre-mixed and mixed in a double-cone mixer to prepare a mixture (2). The binding solution (2) was added onto the mixture (2), granulated, and then dried. Screened granules (2) were obtained by sieving with a 20-mesh sieve in semi-dried state, and sieving with a 30-mesh sieve in dried state.

[0065] Microcrystalline cellulose 32 g and pregelatinized starch 7.5 g were added to the screened granules (2), and mixed in a double-cone mixer. Then, magnesium stearate 0.5 g was added to obtain a lubricated mixture (2).

[0066] The lubricated mixture (1) and the lubricated mixture (2) were compressed into a double-layer tablet by a tableting machine (Autotab-200TR, Ichihashi seiki) using an 8.5 mm-diameter punch (the first layer weight: 180 g, the second layer weight: 90 g).

[0067] The obtained double-layer tablet was coated with Opadry (7.5 g/T) by a coating machine (Hi-coater, Freund).

EXAMPLE 3

Preparation of Double-Layer Tablet

[0068] Hydroxypropylcellulose 3 g and macrogol-15-hydroxystearate 1.5 g were dissolved in purified water and ethanol to prepare a binding solution (1). Candesartan cilexetil 8 g, microcrystalline cellulose 32.5 g and pregelatinized starch 5 g were uniformly mixed in a high speed mixer to prepare a mixture (1). The binding solution (1) was added onto the mixture (1), granulated, and then dried. Screened granules (1) were obtained by sieving with a 20-mesh sieve in semi-dried state, and sieving with a 30-mesh sieve in dried state.

[0069] Silicified microcrystalline cellulose 39.5 g was added to the screened granules (1), and mixed in a double-cone mixer. Then, magnesium stearate 0.5 g was added to obtain a lubricated mixture (1).

[0070] Hydroxypropylcellulose 2.5 g was dissolved in purified water and ethanol to prepare a binding solution (2). Amlodipine besylate 6.935 g, microcrystalline cellulose 35.565 g and pregelatinized starch 5 g were pre-mixed and mixed in a double-cone mixer to prepare a mixture (2). The binding solution (2) was added onto the mixture (2), granulated, and then dried. Screened granules (2) were obtained by sieving with a 20-mesh sieve in semi-dried state, and sieving with a 30-mesh sieve in dried state.

[0071] Microcrystalline cellulose 32 g and pregelatinized starch 7.5 g were added to the screened granules (2), and mixed in a double-cone mixer. Then, magnesium stearate 0.5 g was added to obtain a lubricated mixture (2).

[0072] The lubricated mixture (1) and the lubricated mixture (2) were compressed into a double-layer tablet by a tableting machine (Autotab-200TR, Ichihashi seiki) using a 7.5 mm-diameter punch (the first layer weight: 90 g, the second layer weight: 90 g).

[0073] The obtained double-layer tablet was coated with Opadry (5.0 g/T) by a coating machine (Hi-coater, Freund).

EXAMPLE 4

Preparation of Double-Layer Tablet

[0074] Hydroxypropylcellulose 3 g and macrogol-15-hydroxystearate 1.5 g were dissolved in purified water and ethanol to prepare a binding solution (1). Candesartan cilexetil 8 g, microcrystalline cellulose 32.5 g and pregelatinized starch 5 g were uniformly mixed in a high speed mixer to prepare a mixture (1). The binding solution (1) was added onto the mixture (1), granulated, and then dried. Screened granules (1) were obtained by sieving with a 20-mesh sieve in semi-dried state, and sieving with a 30-mesh sieve in dried state.

[0075] Silicified microcrystalline cellulose 39.5 g was added to the screened granules (1), and mixed in a double-cone mixer. Then, magnesium stearate 0.5 g was added to obtain a lubricated mixture (1).

[0076] Hydroxypropylcellulose 2.5 g was dissolved in purified water and ethanol to prepare a binding solution (2). Amlodipine besylate 3.468 g, microcrystalline cellulose 39.032 g and pregelatinized starch 5 g were pre-mixed and mixed in a double-cone mixer to prepare a mixture (2). The binding solution (2) was added onto the mixture (2), granulated, and then dried. Screened granules (2) were obtained by sieving with a 20-mesh sieve in semi-dried state, and sieving with a 30-mesh sieve in dried state.

[0077] Microcrystalline cellulose 32 g and pregelatinized starch 7.5 g were added to the screened granules (2), and mixed in a double-cone mixer. Then, magnesium stearate 0.5 g was added to obtain a lubricated mixture (2).

[0078] The lubricated mixture (1) and the lubricated mixture (2) were compressed into a double-layer tablet by a tableting machine (Autotab-200TR, Ichihashi seiki) using a 7.5 mm-diameter punch (the first layer weight: 90 g, the second layer weight: 90 g).

[0079] The obtained double-layer tablet was coated with Opadry (5.0 g/T) by a coating machine (Hi-coater, Freund).

EXAMPLE 5

Preparation of Single-Layer Tablet

[0080] Hydroxypropylcellulose 6 g and macrogol-15-hydroxystearate 3 g were dissolved in purified water and ethanol to prepare a binding solution (1). Candesartan cilexetil 16 g, microcrystalline cellulose 65 g and pregelatinized starch 10 g were uniformly mixed in a high speed mixer to prepare a mixture (1). The binding solution (1) was added onto the mixture (1), granulated, and then dried. Screened granules (1) were obtained by sieving with a 20-mesh sieve in semi-dried state, and sieving with a 30-mesh sieve in dried state.

[0081] Hydroxypropylcellulose 5 g was dissolved in purified water and ethanol to prepare a binding solution (2). Amlodipine besylate 13.87 g, microcrystalline cellulose 71.13 g and pregelatinized starch 10 g were pre-mixed and mixed in a double-cone mixer to prepare a mixture (2). The binding solution (2) was added onto the mixture (2), granulated, and then dried. Screened granules (2) were obtained by sieving with a 20-mesh sieve in semi-dried state, and sieving with a 30-mesh sieve in dried state.

[0082] Silicified microcrystalline cellulose 79 g, microcrystalline cellulose 64 g and pregelatinized starch 15 g were added to the screened granules (1) and the screened granules (2), and mixed in a double-cone mixer. Then, magnesium stearate 2 g was added to obtain a lubricated mixture.

[0083] The lubricated mixture was compressed into a single-layer tablet by a tableting machine (Autotab-200TR, Ichihashi seiki) using a 9.4 mm-diameter punch (tablet weight: 360 g/T).

[0084] The obtained single-layer tablet was coated with Opadry (10.0 g/T) by a coating machine (Hi-coater, Freund).

EXAMPLE 6

Preparation of Double-Layer Tablet

[0085] Hydroxypropylcellulose 6 g and macrogol-15-hydroxystearate 3 g were dissolved in purified water and ethanol to prepare a binding solution (1). Candesartan cilexetil 16 g, microcrystalline cellulose 65 g, pregelatinized starch 10 g and silicified microcrystalline cellulose 79 g were uniformly mixed in a high speed mixer to prepare a mixture (1). The binding solution (1) was added onto the mixture (1), granulated, and then dried. Screened granules (1) were obtained by sieving with a 20-mesh sieve in semi-dried state, and sieving with a 30-mesh sieve in dried state.

[0086] Magnesium stearate 1 g was added to the screened granules (1) to obtain a lubricated mixture (1).

[0087] Hydroxypropylcellulose 5 g was dissolved in purified water and ethanol to prepare a binding solution (2). Amlodipine besylate 13.87 g, microcrystalline cellulose 135.13 g and pregelatinized starch 25 g were pre-mixed and mixed in a double-cone mixer to prepare a mixture (2). The binding solution (2) was added onto the mixture (2), granulated, and then dried. Screened granules (2) were obtained by sieving with a 20-mesh sieve in semi-dried state, and sieving with a 30-mesh sieve in dried state.

[0088] Magnesium stearate 1 g was added to the screened granules (2) to obtain a lubricated mixture (2).

[0089] The lubricated mixture (1) and the lubricated mixture (2) were compressed into a double-layer tablet by a tableting machine (Autotab-200TR, Ichihashi seiki) using a 9.4 mm-diameter punch (the first layer weight: 180 g, the second layer weight: 180 g).

[0090] The obtained double-layer tablet was coated with Opadry (10.0 g/T) by a coating machine (Hi-coater, Freund).

[0091] Table 1 below shows the composition and weight of tablets prepared in Examples 1 to 6. In Table 1, Ex. stands for Example. The product prepared in Ex. 1, 2, 3, 4 and 6 respectively is a double-layer tablet, whereas the product prepared in Ex. 5 is a single-layer tablet. In Table 1, the extragranular mixing-part indicates the part formed on the outside of granule by mixing additional materials following granulation.

TABLE-US-00001 TABLE 1 Weight (g) Composition Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 The granule-part in the first layer of double-layer tablet candesartan cilexetil 16.00 16.00 8.00 8.00 16.00 microcrystalline cellulose 65.00 65.00 32.50 32.50 65.00 pregelatinized starch 10.00 10.00 5.00 5.00 10.00 hydroxypropylcellulose 6.00 6.00 3.00 3.00 6.00 macrogol-15-hydroxystearate 3.00 3.00 1.50 1.50 3.00 silicified microcrystalline 79.00 cellulose The extragranular mixing-part in the first layer of double-layer tablet silicified microcrystalline 79.00 79.00 39.50 39.50 cellulose magnesium stearate 1.00 1.00 0.50 0.50 1.00 The granule-part in the second layer of double-layer tablet amlodipine besylate 13.87 6.935 6.935 3.468 13.87 microcrystalline cellulose 71.13 35.565 35.565 39.032 135.13 pregelatinized starch 10.00 5.00 5.00 5.00 25.00 hydroxypropylcellulose 5.00 2.50 2.50 2.50 5.00 The extragranular mixing-part in the second layer of double-layer tablet microcrystalline cellulose 64.00 32.00 32.00 32.00 pregelatinized starch 15.00 7.50 7.50 7.50 magnesium stearate 1.00 0.50 0.50 0.50 1.00 sugar alcohol (ex. mannitol) The first-granule-part in the single-layer tablet candesartan cilexetil 16.00 microcrystalline cellulose 65.00 pregelatinized starch 10.00 hydroxypropylcellulose 6.00 macrogol-15-hydroxystearate 3.00 The second-granule-part in the single-layer tablet amlodipine besylate 13.87 microcrystalline cellulose 71.13 pregelatinized starch 10.00 hydroxypropylcellulose 5.00 The extragranular mixing-part in the single-layer tablet microcrystalline cellulose 64.00 silicified microcrystalline 79.00 cellulose pregelatinized starch 15.00 magnesium stearate 2.00 The coating-part OPADRY 10.00 7.50 5.00 5.00 10.00 10.00 Total weight 370.0 277.5 185.0 185.0 370.0 370.0

COMPARATIVE EXAMPLE 1

[0092] A double-layer tablet was prepared by the same method as in Example 1, except that polyethylene glycol-6000 3 g was used instead of macrogol-15-hydroxystearate 3 g as a solubilizer.

COMPARATIVE EXAMPLE 2

[0093] A double-layer tablet was prepared by the same method as in Example 1, except that beta-cyclodextrin 3 g was used instead of macrogol-15-hydroxystearate 3 g as a solubilizer.

COMPARATIVE EXAMPLE 3

[0094] A double-layer tablet was prepared by the same method as in Example 1, except that d-a-tocopheryl polyethylene glycol-1000 succinate 3 g was used instead of macrogol-15-hydroxystearate 3 g as a solubilizer.

COMPARATIVE EXAMPLE 4

[0095] A double-layer tablet was prepared by the same method as in Example 1, except that sodium lauryl sulfate 3 g was used instead of macrogol-15-hydroxystearate 3 g as a solubilizer.

COMPARATIVE EXAMPLE 5

[0096] A double-layer tablet was prepared by the same method as in Example 1, except that microcrystalline cellulose 3 g was further added instead of using a solubilizer.

[0097] Table 2 below shows the composition and weight of tablets prepared in Example 1 and Comparative Examples 1 to 5. In Table 2, Ex. stands for Example, and Comp. Ex. stands for Comparative Example. The product prepared in Ex. 1 and Comp. Ex. 1 to 5 respectively is a double-layer tablet. In Table 2, the extragranular mixing-part indicates the part formed on the outside of granule by mixing additional materials following granulation.

TABLE-US-00002 TABLE 2 Weight (g) Comp. Comp. Comp. Comp. Comp. Composition Ex. 1 Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 The granule-part in the first layer of double-layer tablet candesartan cilexetil 16.00 16.00 16.00 16.00 16.00 16.00 microcrystalline cellulose 65.00 65.00 65.00 65.00 65.00 68.00 pregelatinized starch 10.00 10.00 10.00 10.00 10.00 10.00 hydroxypropylcellulose 6.00 6.00 6.00 6.00 6.00 6.00 macrogol-15-hydroxystearate 3.00 polyethylene glycol-6000 3.00 beta-cyclodextrin 3.00 d-?-tocopheryl polyethylene 3.00 glycol-1000 succinate sodium lauryl sulfate 3.00 The extragranular mixing-part in the first layer of double-layer tablet silicified microcrystalline 79.00 79.00 79.00 79.00 79.00 79.00 cellulose magnesium stearate 1.00 1.00 1.00 1.00 1.00 1.00 The granule-part in the second layer of double-layer tablet amlodipine besylate 13.87 13.87 13.87 13.87 13.87 13.87 microcrystalline cellulose 71.13 71.13 71.13 71.13 71.13 71.13 pregelatinized starch 10.00 10.00 10.00 10.00 10.00 10.00 hydroxypropylcellulose 5.00 5.00 5.00 5.00 5.00 5.00 The extragranular mixing-part in the second layer of double-layer tablet microcrystalline cellulose 64.00 64.00 64.00 64.00 64.00 64.00 pregelatinized starch 15.00 15.00 15.00 15.00 15.00 15.00 magnesium stearate 1.00 1.00 1.00 1.00 1.00 1.00 The coating-part OPADRY 10.00 10.00 10.00 10.00 10.00 10.00 Total weight 370.0 370.0 370.0 370.0 370.0 370.0

EXPERIMENTAL EXAMPLE 1

Stability Test

[0098] When the active ingredient candesartan is stored after prepared in the form of tablet together with other active ingredients or additives, it is often observed that it is decomposed as time passes. The typical impurity resulted from the decomposition of active ingredient candesartan includes desethyl candesartan, and any unknown impurities are also detected.

[0099] Similarly, amlodipine or its pharmaceutically acceptable salt, which is another active ingredient comprised in the tablet according to the present invention, results in degradation products by other active ingredients or additives present in the combination formulation. The typical impurity includes amlodipine impurity A (USP), and any unknown impurities are also detected. The chemical name of amlodipine impurity A (USP) is 3-ethyl 5-methyl 2- [(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methylpyridine-3,5-dicarboxylate fumarate.

[0100] It is general that a combination formulation such as the tablet according to the present invention shows the increased amount of impurities when it is stored in the long term. Thus, stability of tablets can be evaluated by determining the amount of impurities.

[0101] At first, the coated tablets prepared in Examples 1 to 6 and Comparative Examples 1 to 5 were separately put in a HDPE body/LDPE cap bottle. They were stored under the condition of 50? C./75% RH (relative humidity) for 6 weeks.

[0102] After that, twenty coated tablets were added into a 200 mL flask, filled up with water 20 mL, and mixed by shaking to completely disintegrate the tablets. Diluent A 95 mL was then added to the resultant, extracted by sonication while occasionally shaking, mixed with water 75 mL, and cooled at room temperature. And then, Diluent B was added to the resultant to make 200 mL of total solution volume. The obtained solution was filtered through a membrane filter to prepare a test solution.

[0103] 20 ?L of test solution and standard solution were subjected to the operating condition below, and the Liquid Chromatography of the General Test Methods in the Korean Pharmacopoeia was performed to calculate the peak areas A.sub.T and A.sub.S of the test solution and standard solution. Solvent peak and additives, benzenesulfonate derived peaks were excluded from the calculation. The additives derived peaks were excluded from the calculation by determining peaks of the placebo test solution prepared without main ingredients.

[0104] The impurities derived from candesartan cilexetil were measured at a wavelength of 215 nm, and the impurities derived from amlodipine besylate were measured at a wavelength of 238 nm. Any unknown impurities were measured at wavelengths 215 nm and 238 nm, respectively.

[0105] Operating Condition [0106] Detector: Ultraviolet (UV)-absorption photometer (measurement wavelength: 215 nm and 238 nm) [0107] Column: Waters Symmetry C8 (4.6?250 mm, 5 ?m) [0108] Column temperature: 30? C. [0109] Mobile phase A: triethylamine 4 mL added to water 1000 mL, then adjusted to a pH of 3.0 by phosphoric acid [0110] Mobile phase B: a mixed solution of methanol and acetonitrile (10:90) [0111] Diluent A: a mixed solution of methanol and acetonitrile (5:45) [0112] Diluent B: a mixed solution of methanol, acetonitrile and water (5:45:50) [0113] Flow rate: 1.0 mL/min

[0114] Table 3 below shows the gradient of mobile phase A and mobile phase B over time. The measurement of peak areas was performed at 36 min.

TABLE-US-00003 TABLE 3 Time (min) Mobile phase A (%, v/v) Mobile phase B (%, v/v) 0-3 65 35 3-18 65 .fwdarw. 20 35 .fwdarw. 80 18-23 20 80 23-28 20 .fwdarw. 5 80 .fwdarw. 95 28-36 5 95 36-37 5 .fwdarw. 65 95 .fwdarw. 35 37-47 65 35

[0115] Table 4 below shows the amount of known and/or unknown impurities derived from candesartan as a relative weight ratio based on 100% of candesartan content. Only the desethyl candesartan is representatively shown as the known impurity derived from candesartan.

TABLE-US-00004 TABLE 4 The representative known Total impurities derived impurity derived from from candesartan candesartan: desethyl (including both known and candesartan unknown impurities) Acceptance criterion: Acceptance criterion: Condition not more than 2.0% not more than 4.7% Ex. 1 At the start of the test 0.20 0.55 After stored at 50? C./ 0.58 1.76 75% RH for 6 weeks Ex. 2 At the start of the test 0.19 0.57 After stored at 50? C./ 0.60 1.71 75% RH for 6 weeks Ex. 3 At the start of the test 0.18 0.56 After stored at 50? C./ 0.55 1.70 75% RH for 6 weeks Ex. 4 At the start of the test 0.18 0.58 After stored at 50? C./ 0.57 1.72 75% RH for 6 weeks Ex. 5 At the start of the test 0.20 0.54 After stored at 50? C./ 0.75 2.22 75% RH for 6 weeks Ex. 6 At the start of the test 0.21 0.56 After stored at 50? C./ 0.80 2.31 75% RH for 6 weeks Comp. Ex. 1 At the start of the test 0.21 0.60 After stored at 50? C./ 1.24 3.41 75% RH for 6 weeks Comp. Ex. 2 At the start of the test 0.21 0.61 After stored at 50? C./ 3.15 4.56 75% RH for 6 weeks Comp. Ex. 3 At the start of the test 0.21 0.66 After stored at 50? C./ 2.12 3.78 75% RH for 6 weeks Comp. Ex. 4 At the start of the test 0.22 0.58 After stored at 50? C./ 2.27 4.97 75% RH for 6 weeks Comp. Ex. 5 At the start of the test 0.24 0.67 After stored at 50? C./ 3.38 5.23 75% RH for 6 weeks

[0116] As shown in Table 4, when the tablets of Comparative Examples 2, 3, 4 and 5 were stored under the condition of 50? C./75% RH for 6 weeks, the amount of known and/or unknown impurities derived from candesartan exceeded the acceptance criteria. In the tablet of Comparative Example 1, it was observed that the amount of known and/or unknown impurities derived from candesartan met the acceptance criteria, but was relatively higher than those in the tablet of Examples 1 to 6.

[0117] On the contrary, the amount of known and/or unknown impurities derived from candesartan in all the tablets of Examples 1 to 6 met the acceptance criteria. Particularly, in the double-layer tablet of Examples 1 to 4 which were prepared with extragranular mixing, the amount of impurities derived from candesartan active ingredient was remarkably low.

[0118] It means that candesartan or candesartan cilexetil among the active ingredients comprised in the combination formulation of tablet according to the present invention has the stability significantly improved by a particular type of solubilizer. Accordingly, although the tablet according to the present invention is stored for 6 weeks, it can be used in maintaining its efficacy intactly since the candesartan or candesartan cilexetil is almost not decomposed over time.

[0119] Table 5 below shows the total amount of unknown impurities derived from the combination formulation comprising candesartan and amlodipine as a relative weight ratio based on the content of combination formulation.

TABLE-US-00005 TABLE 5 The unknown impurities derived from the combination formulation of candesartan and amlodipine Acceptance criterion: Condition not more than 0.2% Ex. 1 At the start of the test 0.03 After stored at 50? C./ 0.10 75% RH for 6 weeks Ex. 2 At the start of the test 0.03 After stored at 50? C./ 0.11 75% RH for 6 weeks Ex. 3 At the start of the test 0.03 After stored at 50? C./ 0.10 75% RH for 6 weeks Ex. 4 At the start of the test 0.03 After stored at 50? C./ 0.10 75% RH for 6 weeks Ex. 5 At the start of the test 0.03 After stored at 50? C./ 0.19 75% RH for 6 weeks Ex. 6 At the start of the test 0.03 After stored at 50? C./ 0.18 75% RH for 6 weeks Comp. Ex. 1 At the start of the test 0.03 After stored at 50? C./ 0.20 75% RH for 6 weeks Comp. Ex. 2 At the start of the test 0.02 After stored at 50? C./ 0.23 75% RH for 6 weeks Comp. Ex. 3 At the start of the test 0.12 After stored at 50? C./ 0.50 75% RH for 6 weeks Comp. Ex. 4 At the start of the test 0.02 After stored at 50? C./ 0.25 75% RH for 6 weeks Comp. Ex. 5 At the start of the test 0.02 After stored at 50? C./ 0.24 75% RH for 6 weeks

[0120] As shown in Table 5, when the tablets of Comparative Examples 1 to 5 are stored under the condition of 50? C./75% RH for 6 weeks, it was observed that the total amount of unknown impurities derived from the combination formulation comprising candesartan and amlodipine exceeds the acceptance criterion.

[0121] On the contrary, all the tablets of Examples 1 to 6 met the acceptance criterion. Particularly, in the double-layer tablet of Examples 1 to 4 which were prepared with extragranular mixing, the total amount of unknown impurities is remarkably low.

[0122] It means that when macrogol-15-hydroxystearate is used as a particular type of solubilizer, the stability of two active ingredients comprised in the combination formulation of tablet according to the present invention is significantly improved. Accordingly, although the tablet according to the present invention is stored for 6 weeks, it can be used in maintaining its efficacy intactly since all of two active ingredients are almost not decomposed over time.

EXPERIMENTAL EXAMPLE 2

Long-Term Stability Test

[0123] The coated tablets prepared in Example 1 were put in a HDPE body/LDPE cap bottle, and were stored under the first condition of 25? C./60% RH for 12 months. In parallel with this, they were independently stored under the second condition of 40? C./70% RH for 6 months. After that, the amount of impurities was measured by the same method as in Experimental Example 1. The results thereof are shown in Tables 6 to 8 below.

TABLE-US-00006 TABLE 6 The representative known Total impurities derived impurity derived from from candesartan candesartan: desethyl (including both known and candesartan unknown impurities) Acceptance criterion: Acceptance criterion: Condition not more than 2.0% not more than 4.7% Ex. 1 At the start of 0.20 0.55 the test After stored at 0.38 0.80 25? C./60% RH for 12 months After stored at 0.70 1.69 40? C./70% RH for 6 months

TABLE-US-00007 TABLE 7 The representative known Total impurities derived impurity derived from from amlodipine amlodipine: amlodipine (including both known and impurity A (USP) unknown impurities) Acceptance criterion: Acceptance criterion: Condition not more than 0.5% not more than 0.7% Ex. 1 At the start of 0.09 0.15 the test After stored at 0.08 0.24 25? C./60% RH for 12 months After stored at 0.21 0.40 40? C./70% RH for 6 months

TABLE-US-00008 TABLE 8 The unknown impurities derived from the combination formulation of candesartan and amlodipine Acceptance criterion: Condition not more than 0.2% Ex. 1 At the start of 0.03 the test After stored at 0.05 25? C./60% RH for 12 months After stored at 0.10 40? C./70% RH for 6 months

[0124] As shown in Tables 6 to 8, the tablet according to the present invention shows much less amount of impurities than the acceptance criteria when stored at 25? C./60% RH for 12 months, and also when stored at 40? C./70% RH for 6 months.

[0125] Therefore, the particular solubilizer used in the tablet of the present invention, macrogol-15-hydroxystearate inhibits the decomposition of two active ingredients comprised in the combination formulation, minimizes the formation of impurities, and significantly improves the storage stability even though the tablet is stored for a long term.

EXPERIMENTAL EXAMPLE 3

Dissolution Test

[0126] The coated tablets prepared in Examples 1 to 6 and Comparative Examples 1 to 5 were evaluated by a dissolution test according to the paddle method in the Korean Pharmacopoeia at 37.0?0.5? C. and 75 rpm using 0.35% Polysorbate 20-containing phosphate buffer (pH 6.5) 900 mL.

[0127] 10 mL of dissolution medium was taken, and then filtered through a membrane filter to prepare a test solution. Six tablets of Examples and Comparative Examples were tested respectively, and Table 9 below shows the average value, minimum value and maximum value of dissolution rate (%).

[0128] Operating Condition [0129] Detector: Ultraviolet (UV)-absorption photometer (measurement wavelength: 238 nm) [0130] Column: Waters Symmetry C18 (3.9?150 mm, 5 ?m) [0131] Column temperature: 30? C. [0132] Phosphate buffer (pH 6.5): 17.3 mL of 0.5 mol/L sodium hydrogen phosphate solution and water were added to 24 mL of 1 mol/L sodium dihydrogen phosphate solution to make 1000 mL of total volume. It was adjusted to a pH of 6.45?6.55 by adding sodium hydroxide or phosphoric acid. [0133] Mobile phase: Disodium hydrogen phosphate anhydrous 1.42 g was dissolved in water 1000 mL, and then adjusted to a pH of 6.0 by adding diluted phosphoric acid. After that, sodium 1-octanesulfonate 4.32 g was added. 500 mL of a mixed solution of acetonitrile and methanol (900:100) was added to 500 mL of the solution obtained, and then filtered. [0134] Diluent: a mixed solution of methanol, acetonitrile and water (5:55:40) [0135] Flow rate: 1.0 mL/min [0136] Measurement time of peak areas: 10 min

TABLE-US-00009 TABLE 9 Dissolution rate of candesartan after 15 minutes (%) Average Min. Max. Ex. 1 78.4 76.2 80.8 Ex. 2 80.1 76.5 83.1 Ex. 3 81.0 77.1 82.1 Ex. 4 80.8 78.2 82.9 Ex. 5 75.0 72.7 78.6 Ex. 6 79.1 75.4 81.2 Comp. Ex. 1 68.4 67.1 69.2 Comp. Ex. 2 58.0 55.2 59.8 Comp. Ex. 3 60.8 55.6 65.0 Comp. Ex. 4 56.0 49.1 66.2 Comp. Ex. 5 35.2 30.7 37.7

[0137] As shown in Table 9, the dissolution rate of candesartan active ingredient remarkably increased when macrogol-15-hydroxystearate was used as a solubilizer in comparison with when different types of solubilizers were used at the same amount or when any solubilizer was not used.

[0138] It means that although the water-solubility and bioavailability of the active ingredient candesartan is low, its property dissolved from the tablet in the GI tract is improved in the tablet according to the present invention. Accordingly, the tablet makes the level of drug in the blood to be maintained at the constant level, and the treatment effect of hypertension to be achieved at the desired level.

EXPERIMENTAL EXAMPLE 4

[0139] The impact of sugar alcohol(s) in a tablet was evaluated by assessing the dissolution rate, hardness, tabletability, and productivity of tablet.

[0140] The tablets of Comparative Example 6 to 11 were prepared by the same method as Examples 1 to 6, except that mannitol is comprised as sugar alcohol. In order to minimize an experimental error by making equal both total weights of Comparative Examples 6 to 11 and of the corresponding Examples 1 to 6, the amount of microcrystalline cellulose or microcrystalline cellulose+silicified microcrystalline cellulose was reduced by the amount of mannitol further added in Comparative Example 6 to 11.

[0141] Table 10 below shows the composition and weight of tablets prepared in Comparative Examples 6 to 11. In Table 10, Comp. Ex. stands for Comparative Example. The product prepared in the Comp. Ex. 6, 7, 8, 9 and 11 respectively is a double-layer tablet, whereas the product prepared in the Comp. Ex. 10 is a single-layer tablet. In Table 10, the extragranular mixing-part indicates the part formed on the outside of granule by mixing additional materials following granulation.

TABLE-US-00010 TABLE 10 Weight (g) Comp. Comp. Comp. Comp. Comp. Comp. Composition Ex. 6 Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11 The granule-part in the first layer of double-layer tablet candesartan cilexetil 16.00 16.00 8.00 8.00 16.00 microcrystalline cellulose 13.00 13.00 6.50 6.50 13.00 pregelatinized starch 10.00 10.00 5.00 5.00 10.00 hydroxypropylcellulose 6.00 6.00 3.00 3.00 6.00 macrogol-15-hydroxystearate 3.00 3.00 1.50 1.50 3.00 silicified microcrystalline 16.00 cellulose mannitol 52.00 52.00 26.00 26.00 115.00 The extragranular mixing-part in the first layer of double-layer tablet silicified microcrystalline 16.00 16.00 8.00 8.00 cellulose magnesium stearate 1.00 1.00 0.50 0.50 1.00 mannitol 63.00 63.00 31.50 31.50 The granule-part in the second layer of double-layer tablet amlodipine besylate 13.87 6.935 6.935 3.468 13.87 microcrystalline cellulose 14.00 7.00 7.00 8.00 27.00 pregelatinized starch 10.00 5.00 5.00 5.00 25.00 hydroxypropylcellulose 5.00 2.50 2.50 2.50 5.00 mannitol 57.13 28.565 28.565 31.032 108.13 The extragranular mixing-part in the second layer of double-layer tablet microcrystalline cellulose 13.00 6.50 6.50 6.50 pregelatinized starch 15.00 7.50 7.50 7.50 magnesium stearate 1.00 0.50 0.50 0.50 1.00 mannitol 51.00 25.50 25.50 25.50 The first-granule-part in the single-layer tablet candesartan cilexetil 16.00 microcrystalline cellulose 13.00 pregelatinized starch 10.00 hydroxypropylcellulose 6.00 macrogol-15-hydroxystearate 3.00 mannitol 52.00 The second-granule-part in the single-layer tablet amlodipine besylate 13.87 microcrystalline cellulose 14.00 pregelatinized starch 10.00 hydroxypropylcellulose 5.00 mannitol 57.13 The extragranular mixing-part in the single-layer tablet microcrystalline cellulose 13.00 silicified microcrystalline 16.00 cellulose pregelatinized starch 15.00 magnesium stearate 2.00 mannitol 114.00 The coating-part OPADRY 10.00 7.50 5.00 5.00 10.00 10.00 Total weight 370.0 277.5 185.0 185.0 370.0 370.0

[0142] The dissolution rates of candesartan active ingredient were determined as in Experimental Example 3 on the coated tablets prepared in Examples 1 to 6 and Comparative Examples 6 to 11. Six tablets of Examples and Comparative Examples were tested respectively, and Table 11 below shows the average value, minimum value and maximum value of dissolution rate (%).

TABLE-US-00011 TABLE 11 Dissolution rate of candesartan after 15 minutes (%) Average Min. Max. Average Min. Max. Ex. 1 78.4 76.2 80.8 Comp. Ex. 6 59.7 55.0 63.9 Ex. 2 80.1 76.5 83.1 Comp. Ex. 7 52.6 48.7 54.6 Ex. 3 81.0 77.1 82.1 Comp. Ex. 8 60.8 55.8 65.4 Ex. 4 80.8 78.2 82.9 Comp. Ex. 9 51.0 47.7 53.3 Ex. 5 75.0 72.7 78.6 Comp. Ex. 10 50.7 48.6 53.0 Ex. 6 79.1 75.4 81.2 Comp. Ex. 11 50.6 47.9 53.1

[0143] As shown in Table 11, the dissolution rate of candesartan active ingredient in the tablet comprising sugar alcohol such as mannitol (Comparative Examples 6 to 11) was about 20?30% lower than that in the tablet not comprising any sugar alcohol (Examples 1 to 6).

[0144] Next, the hardness was measured on the coated tablets prepared in Examples 1 to 6 and Comparative Examples 6 to 11 respectively, and the results are shown in Table 12.

TABLE-US-00012 TABLE 12 Hardness Ex. 1 18~19 kp Ex. 2 16~17 kp Ex. 3 15~16 kp Ex. 4 16~17 kp Ex. 5 15~16 kp Ex. 6 16~17 kp Comp. Ex. 6 12~13 kp Comp. Ex. 7 9~10 kp Comp. Ex. 8 10~11 kp Comp. Ex. 9 9~10 kp Comp. Ex. 10 12~13 kp Comp. Ex. 11 12~13 kp

[0145] As shown in Table 12, the hardness of tablets comprising sugar alcohol such as mannitol (Comparative Examples 6 to 11) was about 20?40% lower than that of tablets not comprising any sugar alcohol (Examples 1 to 6). If it does not have a sufficient hardness, thefriability and the possibility of coating defect increase in the manufacturing process thereof, particularly in the coating process thereof. It means that the uniform quality of tablets cannot be assured, and the productivity is not good.

[0146] Therefore, if a sugar alcohol is comprised in the tablet of the present invention using macrogol-15-hydroxystearate as a solubilizer, there is a decrease in the dissolution rate of active ingredient candesartan or candesartan cilexetil and the hardness of tablet, and thereby it is disadvantageous in terms of tabletability and productivity. Accordingly, it is preferable that any sugar alcohol is not comprised in the tablet of the present invention.

EXPERIMENTAL EXAMPLE 5

Safety Study

[0147] A study was conducted to evaluate the safety in human for the combination formulation of the present invention.

[0148] A combination formulation of the present invention was prepared comprising candesartan cilexetil 16 mg and amlodipine 10 mg and comprising macrogol-15-hydroxystearate as a solubilizer. A single dose of tablet obtained was orally administered to 46 healthy adult males at the age of 19?45.

[0149] As a result, it was observed that adverse events such as dizziness occurred in some subjects, but there was no serious adverse drug reaction which was clinically significant. It means that the combination formulation according to the present invention is safe for human beings.