Tablet and method of preparing the same
10420728 ยท 2019-09-24
Assignee
Inventors
Cpc classification
A61K9/2866
HUMAN NECESSITIES
A61K9/2018
HUMAN NECESSITIES
A61K31/513
HUMAN NECESSITIES
A61K9/284
HUMAN NECESSITIES
A61K31/506
HUMAN NECESSITIES
International classification
A61J3/00
HUMAN NECESSITIES
A61K31/513
HUMAN NECESSITIES
A61K9/28
HUMAN NECESSITIES
Abstract
Disclosed is a method for preparing a tablet. The method can improve the compressibility of the active ingredients and produce tablets of uniform quality, bringing about the advantage of increasing tablet hardness with an increase in compression pressure, easily controlling disintegration time, and decreasing tablet friability by using the active ingredient fimasartan, a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof having a specific particle size distribution.
Claims
1. A method for preparing a tablet, comprising: milling at least 50% (v/v) of an active ingredient based on the total amount of the active ingredient into particles which have a diameter of 10 m or less, the active ingredient being fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof; mixing the particles of the milled active ingredient with a pharmaceutically acceptable additive to give a mixture; and forming the tablet from the mixture.
2. The method of claim 1, wherein the milling is carried out in such a way that 90% (v/v) of the active ingredient based on the total amount of the active ingredient contained in the tablet is milled into the particles having a diameter of 25 m or less.
3. The method of claim 1, wherein the milling is carried out in such a way that 90% (v/v) of the active ingredient based on the total amount of the active ingredient contained in the tablet is milled into the particles having a diameter of 15 m or less and 50% (v/v) of the active ingredient based on the total amount of the active ingredient contained in the tablet is milled into the particles having a diameter of 6 m or less.
4. The method of claim 1, wherein the milling is carried out in such a way that the active ingredient contained in the tablet is milled into particles having a diameter of 0.5 m or more.
5. The method of claim 1, wherein the milling is carried out in such a way that the active ingredient contained in the tablet is milled into particles having a diameter of 2 m or more.
6. The method of claim 1, wherein the milling is carried out in such a way that the active ingredient contained in the tablet is milled into particles with a diameter of 3 m or more.
7. The method of claim 1, wherein the forming the tablet comprises: preparing granules from the mixture; adding an additional pharmaceutically acceptable additive to the granule to give a granule-containing mixture; and compressing the granule-containing mixture into the tablet.
8. The method of claim 7, wherein the forming the tablet further comprises adding a binder to the mixture before the preparation of granules.
9. The method of claim 1, wherein forming the tablet comprises compressing the mixture into the tablet.
10. The method of claim 1, wherein the active ingredient is a hydrate of fimasartan potassium.
11. The method of claim 1, wherein the active ingredient is fimasartan potassium trihydrate.
12. The method of claim 1, wherein the pharmaceutically acceptable additive is selected from the group consisting of lactose or a hydrate thereof, microcrystalline cellulose, croscarmellose sodium, magnesium stearate and mixture thereof.
13. A tablet, comprising fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, and a pharmaceutically acceptable additive, wherein 50% (v/v) of the active ingredient based on the total amount of the active ingredient is a particle having a diameter of 10 m or less.
14. The tablet of claim 13, wherein 90% (v/v) of the active ingredient based on total amount of the active ingredient is the particles having a diameter of 25 m or less.
15. The tablet of claim 13, wherein 90% (v/v) of the active ingredient based on total amount of the active ingredient contained in the tablet is the particles having a diameter of 15 m or less and 50% (v/v) of the active ingredient based on the total amount of the active ingredient is the particles having a diameter of 6 m or less.
16. The tablet of claim 13, wherein the active ingredient comprises the particles having a diameter of 0.5 m or more.
17. The tablet of claim 13, wherein the active ingredient comprises the particles having a diameter of 2 m or more.
18. The tablet of claim 13, wherein the active ingredient comprises the particles having a diameter of 3 m or more.
19. The tablet of claim 13, wherein the tablet is a coated tablet.
20. The tablet of claim 13, wherein the active ingredient is fimasartan potassium trihydrate.
Description
BRIEF DESCRIPTION OF DRAWINGS
(1)
MODE FOR THE INVENTION
(2) A better understanding of the present invention may be obtained through the following examples which are set forth to illustrate, but are not to be construed as limiting the present invention. Unless stated otherwise, the reagents and materials used in Examples were purchased from Sigma-Aldrich Korea.
Preparation Example 1
(3) Using a jet mill (JE-12, JE Powder), fimasartan potassium trihydrate (Boryung Pharmaceuticals) was milled to give particles having a size distribution of D50=1.7 m and D90=5.0 m (Refer
Preparation Example 2
(4) Using a jet mill (JE-12, JE Powder), fimasartan potassium trihydrate (Boryung Pharmaceuticals) was milled to give particles having a size distribution of D50=2.9 m and D90=11.2 m (Refer
Preparation Example 3
(5) Using a jet mill (JE-12, JE Powder), fimasartan potassium trihydrate (Boryung Pharmaceuticals) was milled to give particles having a size distribution of D50=3.7 m and D90=11.4 m (Refer
Preparation Example 4
(6) Using a jet mill (JE-12, JE Powder), fimasartan potassium trihydrate (Boryung Pharmaceuticals) was milled to give particles having a size distribution of D50=5.3 m and D90=13.6 m (Refer
Preparation Example 5
(7) Using a jet mill (JE-12, JE Powder), fimasartan potassium trihydrate (Boryung Pharmaceuticals) was milled to give particles having a size distribution of D50=7.3 m and D90=22.6 m (Refer
Preparation Example 6
(8) Using a jet mill (JE-12, JE Powder), fimasartan potassium trihydrate (Boryung Pharmaceuticals) was milled to give particles having a size distribution of D50=12.1 m and D90=37.3 m (Refer
Preparation Example 7
(9) Using a jet mill (JE-12, JE Powder), fimasartan potassium trihydrate (Boryung Pharmaceuticals) was milled to give particles having a size distribution of D50=15.2 m and D90=69.0 m (Refer
Preparation Example 8
(10) Using a jet mill (JE-12, JE Powder), fimasartan potassium trihydrate (Boryung Pharmaceuticals) was slightly milled to give particles. Then, the particles were allowed to pass through a standard 170 mesh sieve (sieve size 90 m, KS No. 170) in order that the selected particles had a size distribution of D50=37.8 m and D90=134.96 m (Refer
(11) The distributions of the particle size are table 1 below:
(12) TABLE-US-00001 TABLE 1 Particle size distribution of Preparation Examples 1 to 8 PREPARATION EXAMPLEs 1 2 3 4 5 6 7 8 D50 1.7 2.9 3.7 5.3 7.3 12.1 15.2 37.8 D90 5.0 11.2 11.4 13.6 22.6 37.3 69.0 134.9 (unit: m)
Example 1
(13) In a fluidized bed granulator (GPCG-1, Glatt, Germany), 43 mg of fimasartan potassium trihydrate of Preparation Example 1, 29 mg of lactose monohydrate, 7 mg of microcrystalline cellulose, and 15 mg of croscamellose sodium were mixed, with compressed air of 55 C. fed at a rate of 3 m.sup.3/min to the granulator to form a mixture.
(14) Separately, a liquid binder was prepared by dissolving 2 mg of hydroxypropyl cellulose in 25 mg of pure water. The liquid binder was sprayed at a rate of 26 g/min over the mixture, followed by manufacturing granules. The granules were dried in the fluidized bed granulator while a compressed air of 85 C. was fed at a rate of 3 m.sup.3/min to the granulator.
(15) The resulting granules were mixed with 1.5 mg of magnesium stearate, and compressed at a compression pressure of 300 kgf to prepare an uncoated tablet. The uncoated tablet was then coated with Opadry to afford a coated tablet.
Example 2
(16) With the exception that the compression was carried out at a compression pressure of 500 kgf, a coated tablet was prepared as the same procedure as in Example 1.
Example 3
(17) With the exception that the compression was carried out at a compression pressure of 800 kgf, a coated tablet was prepared as the same procedure as in Example 1.
Example 4
(18) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 2 were used, a coated tablet was prepared in the same procedure as in Example 1.
Example 5
(19) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 2 were used and that the compression was carried out at a compression pressure of 500 kgf.
Example 6
(20) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 2 were used and that the compression was carried out at a compression pressure of 800 kgf.
Example 7
(21) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 3 were used, a coated tablet was prepared in the same procedure as in Example 1.
Example 8
(22) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 3 were used and that the compression was carried out at a compression pressure of 500 kgf.
Example 9
(23) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 3 were used and that the compression was carried out at a compression pressure of 800 kgf.
Example 10
(24) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 4 were used, a coated tablet was prepared in the same procedure as in Example 1.
Example 11
(25) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 4 were used and that the compression was carried out at a compression pressure of 500 kgf.
Example 12
(26) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 4 were used and that the compression was carried out at a compression pressure of 800 kgf.
Example 13
(27) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 5 were used, a coated tablet was prepared in the same procedure as in Example 1.
Example 14
(28) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 5 were used and that the compression was carried out at a compression pressure of 500 kgf.
Example 15
(29) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 5 were used and that the compression was carried out at a compression pressure of 800 kgf.
Comparative Example 1
(30) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 6 were used, a coated tablet was prepared in the same procedure as in Example 1.
Comparative Example 2
(31) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 6 was used and that the compression was carried out at a compression pressure of 500 kgf.
Comparative Example 3
(32) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 6 were used and that the compression was carried out at a compression pressure of 800 kgf.
Comparative Example 4
(33) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 7 were used, a coated tablet was prepared in the same procedure as in Example 1.
Comparative Example 5
(34) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 7 were used and that the compression was carried out at a compression pressure of 500 kgf.
Comparative Example 6
(35) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 7 were used and that the compression was carried out at a compression pressure of 800 kgf.
Comparative Example 7
(36) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 8 were used, a coated tablet was prepared in the same procedure as in Example 1.
Comparative Example 8
(37) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 8 were used and that the compression was carried out at a compression pressure of 500 kgf.
Comparative Example 9
(38) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 8 were used and that the compression was carried out at a compression pressure of 800 kgf.
Comparative Example 10
(39) A tablet was prepared in the same procedure as in Example 1, with the exception that fimasartan potassium trihydrate was not used and 72 mg of lactose monohydrate was used.
Test Example 1
(40) Tablets prepared in the Examples 1 to 15 and the Comparative Examples 1 to 9 were assayed for hardness, disintegration time, and friability. Hardness was measured according to Chapter 1217 (Tablet Breaking Force) of the United States Pharmacopeia (USP). For the analysis procedure of disintegration time, reference was made to Chapter 701 (Disintegration), USP. Friability was calculated according to the following equation after a friability test was performed according to Chapter 1216 (Tablet Friability), USP.
Friability (%)={(Weight (mg) of 20 initial tablets Weight (mg) of 20 tablets post friability test)/Weight (mg) of 20 initial tablets}100(%)
(41) Results are summarized in Table 2 below.
(42) TABLE-US-00002 TABLE 2 Assay for Hardness, Disintegration Time and Friability of Tablets of Examples 1 to 15 and Comparative Examples 1 to 9 Compression Hard- Disinte- Fria- Preparation Pressure ness gration bility Examples Example (kgf) (kp) Time (min) (%) Example 1 Preparation 300 8.1 3.75 1.6 Example 2 Example 1 500 13.5 5.33 0.3 Example 3 800 16.1 8.67 0.1 Example 4 Preparation 300 7.3 3.25 1.7 Example 5 Example 2 500 12.1 4.92 0.2 Example 6 800 14.6 9.17 0.2 Example 7 Preparation 300 6.5 2.50 1.7 Example 8 Example 3 500 10.9 4.83 0.4 Example 9 800 14.2 8.75 0.3 Example 10 Preparation 300 6.4 2.50 1.7 Example 11 Example 4 500 10.8 4.83 0.4 Example 12 800 13.8 8.50 0.4 Example 13 Preparation 300 5.8 2.33 2.2 Example 14 Example 5 500 9.2 4.50 0.5 Example 15 800 11.8 7.75 0.4 Comparative Preparation 300 3.2 1.25 2.4 Example 1 Example 6 Comparative 500 9.2 4.50 0.5 Example 2 Comparative 800 11.8 7.75 0.4 Example 3 Comparative Preparation 300 2.8 0.83 3.7 Example 4 Example 7 Comparative 500 6.3 2.17 1.9 Example 5 Comparative 800 6.7 2.42 1.8 Example 6 Comparative Preparation 300 2.2 0.58 4.2 Example 7 Example 8 Comparative 500 5.0 1.67 2.3 Example 8 Comparative 800 5.1 1.92 2.2 Example 9
(43) As is clearly understood from data of Table 2, the tablets tended to increase in hardness with an increase in compression pressure when the active ingredient particles had a D50 of 10 m or less (a maximum particle diameter of 10 m or less in 50% (v/v) of the active ingredient based on the total amount of the active ingredient) and a D90 of 25 m or less (a maximum particle diameter of 25 m or less in 90% (v/v) of the active ingredient based on the total amount of the active ingredient).
(44) In contrast, the tablets of the Comparative Examples did not significantly increase in hardness although compressed at increased compression pressures. For example, even at a compression pressure of 800 kgf, the tablets of the Comparative Examples were found to have a hardness of approximately 7 kp or less, which was similar to the hardness of the tablets of Examples compressed at a compression pressure of 300 kgf.
(45) It is thus understood from the results that when the active ingredient in the tablet has the specific particle size distribution which is a D50 of 10 m or less and a D90 of 25 m or less, the fimasartan potassium trihydrate particles can be of high compressibility so that they can be more greatly compressed with an increase in compression pressure, which makes it possible to easily control the hardness and disintegration time of the tablet and to decrease the friability of the tablet to 1% or less. Hence, the method of the present invention allows tablets to be homogeneous in physical properties even in mass production.
(46) To the contrary, as shown in Comparative Examples, when the fimasartan potassium trihydrate has a particle size distribution of a D50 greater than 10 m and a D90 greater than 25 m, their compressibility is poor, making it difficult to manufacture a tablet having sufficient hardness even at a high compression pressure. With such a particle size distribution of the active ingredient particles, there is difficulty in controlling the hardness and disintegration time of the tablet, and decreasing friability to 1%. As a result, non-uniform physical properties were detected over the tablets manufactured on a mass scale, thus degrading the product quality.
Test Example 2
(47) Granules prepared in the Examples and the Comparative Examples were assayed for density and Can's index. Density was measured according to Chapter 616 in General Chapter (Bulk density and Tapped density of powders) of the United States Pharmacopeia (USP). Carr's index was calculated according to the following equation:
Carr's index=100{1(Bulk density/Tapped density)}
(48) Results are summarized in Tables 3, below.
(49) TABLE-US-00003 TABLE 3 Assay for Density and Carr's index of Granules of Examples and Comparative Examples Properties of granules Preparation Bulk Density Tapped Density Carr's Examples Example (g/mL) (g/mL) index Example 1 Preparation 0.381 0.520 26.7 Example 1 Example 4 Preparation 0.379 0.516 26.6 Example 2 Example 7 Preparation 0.381 0.515 26.0 Example 3 Example 10 Preparation 0.380 0.517 26.5 Example 4 Example 13 Preparation 0.382 0.515 25.8 Example 5 Comparative Preparation 0.401 0.503 20.3 Example 1 Example 6 Comparative Preparation 0.403 0.495 18.6 Example 4 Example 7 Comparative Preparation 0.409 0.482 15.1 Example 7 Example 8 Comparative 0.469 0.532 11.8 Example 10
(50) As is clearly understood from data of Table 3, the granules has higher Carr's index when the active ingredient particles had a D50 of 10 m or less (a maximum particle diameter of 10 m or less in 50% (v/v) of the active ingredient based on the total amount of the active ingredient) and a D90 of 25 m or less (a maximum particle diameter of 25 m or less in 90% (v/v) of the active ingredient based on the total amount of the active ingredient) compared to those of the active ingredients having the D50 value of exceeds 10 m.
(51) When the Carr's index is increased, the compressibility is increased. Thus, it is confirmed that the granules including the fimasartan potassium hydrate having a D50 of 10 m or less and a D90 of 25 m or less superior compressibility.
Example 16
(52) A tablet was prepared in the same procedure as in Example 1, with the exception that 29 mg of D mannitol was used instead of lactose monohydrate and that the compression was carried out at a compression pressure of 500 kgf.
Example 17
(53) With the exception that the compression was carried out at a compression pressure of 800 kgf, a coated tablet was prepared as the same procedure as in Example 16.
Example 18
(54) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 2 were used, a coated tablet was prepared in the same procedure as in Example 16.
Example 19
(55) A tablet was prepared in the same procedure as in Example 16, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 2 were used and that the compression was carried out at a compression pressure of 800 kgf.
Example 20
(56) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 3 were used, a coated tablet was prepared in the same procedure as in Example 16.
Example 21
(57) A tablet was prepared in the same procedure as in Example 16, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 3 were used and that the compression was carried out at a compression pressure of 800 kgf.
Example 22
(58) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 4 were used, a coated tablet was prepared in the same procedure as in Example 16.
Example 23
(59) A tablet was prepared in the same procedure as in Example 16, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 4 were used and that the compression was carried out at a compression pressure of 800 kgf.
Example 24
(60) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 5 were used, a coated tablet was prepared in the same procedure as in Example 16.
Example 25
(61) A tablet was prepared in the same procedure as in Example 16, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 5 were used and that the compression was carried out at a compression pressure of 800 kgf.
Comparative Example 11
(62) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 6 were used, a coated tablet was prepared in the same procedure as in Example 16.
Comparative Example 12
(63) A tablet was prepared in the same procedure as in Example 16, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 6 were used and that the compression was carried out at a compression pressure of 800 kgf.
Comparative Example 13
(64) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 7 were used, a coated tablet was prepared in the same procedure as in Example 16.
Comparative Example 14
(65) A tablet was prepared in the same procedure as in Example 16, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 7 were used and that the compression was carried out at a compression pressure of 800 kgf.
Comparative Example 15
(66) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 8 were used, a coated tablet was prepared in the same procedure as in Example 16.
Comparative Example 16
(67) A tablet was prepared in the same procedure as in Example 16, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 8 were used and that the compression was carried out at a compression pressure of 800 kgf.
Test Example 3
(68) Tablets prepared in the Examples 16 to 25 and the Comparative Examples 11 to 16 were assayed for hardness, disintegration time, and friability the same as those of TEST EXAMPLE 1.
(69) TABLE-US-00004 TABLE 4 Assay for Hardness, Disintegration Time and Friability of Tablets of Examples 16 to 25 and Comparative Examples 11 to 16 Compression Hard- Disinte- Fria- Preparation Pressure ness gration bility Examples Example (kgf) (kp) Time (min) (%) Example 16 Preparation 500 13.2 3.50 0.2 Example 17 Example 1 800 15.9 5.25 0.1 Example 18 Preparation 500 12.0 3.25 0.3 Example 19 Example 2 800 14.6 5.00 0.1 Example 20 Preparation 500 11.2 3.17 0.2 Example 21 Example 3 800 14.1 4.83 0.1 Example 22 Preparation 500 10.6 3.00 0.3 Example 23 Example 4 800 13.6 4.50 0.2 Example 24 Preparation 500 9.6 2.83 0.3 Example 25 Example 5 800 11.4 4.00 0.2 Comparative Preparation 500 6.3 1.67 1.6 Example 11 Example 6 Comparative 800 7.1 2.00 1.4 Example 12 Comparative Preparation 500 6.1 1.33 2.5 Example 13 Example 7 Comparative 800 6.5 1.50 2.3 Example 14 Comparative Preparation 500 5.0 1.67 3.1 Example 15 Example 8 Comparative 800 5.1 1.00 3.0 Example 16
Example 26
(70) A tablet was prepared in the same procedure as in Example 1, with the exception that 29 mg of corn starch was used instead of lactose monohydrate and that the compression was carried out at a compression pressure of 500 kgf.
Example 27
(71) With the exception that the compression was carried out at a compression pressure of 800 kgf, a coated tablet was prepared as the same procedure as in Example 26.
Example 28
(72) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 2 were used, a coated tablet was prepared in the same procedure as in Example 26.
Example 29
(73) A tablet was prepared in the same procedure as in Example 26, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 2 were used and that the compression was carried out at a compression pressure of 800 kgf.
Example 30
(74) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 3 were used, a coated tablet was prepared in the same procedure as in Example 26.
Example 31
(75) A tablet was prepared in the same procedure as in Example 26, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 3 were used and that the compression was carried out at a compression pressure of 800 kgf.
Example 32
(76) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 4 were used, a coated tablet was prepared in the same procedure as in Example 26.
Example 33
(77) A tablet was prepared in the same procedure as in Example 26, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 4 were used and that the compression was carried out at a compression pressure of 800 kgf.
Example 34
(78) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 5 were used, a coated tablet was prepared in the same procedure as in Example 26.
Example 35
(79) A tablet was prepared in the same procedure as in Example 26, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 5 were used and that the compression was carried out at a compression pressure of 800 kgf.
Comparative Example 17
(80) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 6 were used, a coated tablet was prepared in the same procedure as in Example 26.
Comparative Example 18
(81) A tablet was prepared in the same procedure as in Example 26, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 6 were used and that the compression was carried out at a compression pressure of 800 kgf.
Comparative Example 19
(82) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 7 were used, a coated tablet was prepared in the same procedure as in Example 26.
Comparative Example 20
(83) A tablet was prepared in the same procedure as in Example 26, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 7 were used and that the compression was carried out at a compression pressure of 800 kgf.
Comparative Example 21
(84) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 8 were used, a coated tablet was prepared in the same procedure as in Example 26.
Comparative Example 22
(85) A tablet was prepared in the same procedure as in Example 26, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 8 were used and that the compression was carried out at a compression pressure of 800 kgf.
Test Example 4
(86) Tablets prepared in the Examples 26 to 35 and the Comparative Examples 17 to 22 were assayed for hardness, disintegration time, and friability the same as those of TEST EXAMPLE 1.
(87) Results are summarized in Table 5 below.
(88) TABLE-US-00005 TABLE 5 Assay for Hardness, Disintegration Time and Friability of Tablets of Examples 26 to 35 and Comparative Examples 17 to 22 Compression Hard- Disinte- Fria- Preparation Pressure ness gration bility Examples Example (kgf) (kp) Time (min) (%) Example 26 Preparation 500 13.5 5.67 0.1 Example 27 Example 1 800 16.3 8.83 0.1 Example 28 Preparation 500 12.3 5.33 0.2 Example 29 Example 2 800 14.9 8.67 0.2 Example 30 Preparation 500 11.6 5.17 0.2 Example 31 Example 3 800 14.5 8.25 0.1 Example 32 Preparation 500 10.2 4.83 0.2 Example 33 Example 4 800 13.2 7.83 0.1 Example 34 Preparation 500 9.3 4.75 0.2 Example 35 Example 5 800 11.4 7.67 0.1 Comparative Preparation 500 6.8 2.83 1.5 Example 17 Example 6 Comparative 800 6.9 3.00 1.2 Example 18 Comparative Preparation 500 6.4 2.25 2.1 Example 19 Example 7 Comparative 800 6.8 2.75 2.1 Example 20 Comparative Preparation 500 5.2 1.67 2.6 Example 21 Example 8 Comparative 800 5.4 1.25 2.4 Example 22
Example 36
(89) A tablet was prepared in the same procedure as in Example 1, with the exception that 2.0 mg of hydroxypropylmethyl cellulose was used instead of hydroxypropyl cellulose and that the compression was carried out at a compression pressure of 500 kgf.
Example 37
(90) With the exception that the compression was carried out at a compression pressure of 800 kgf, a coated tablet was prepared as the same procedure as in Example 36.
Example 38
(91) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 2 were used, a coated tablet was prepared in the same procedure as in Example 36.
Example 39
(92) A tablet was prepared in the same procedure as in Example 36, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 2 were used and that the compression was carried out at a compression pressure of 800 kgf.
Example 40
(93) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 3 were used, a coated tablet was prepared in the same procedure as in Example 36.
Example 41
(94) A tablet was prepared in the same procedure as in Example 36, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 3 were used and that the compression was carried out at a compression pressure of 800 kgf.
Example 42
(95) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 4 were used, a coated tablet was prepared in the same procedure as in Example 36.
Example 43
(96) A tablet was prepared in the same procedure as in Example 36, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 4 were used and that the compression was carried out at a compression pressure of 800 kgf.
Example 44
(97) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 5 were used, a coated tablet was prepared in the same procedure as in Example 36.
Example 45
(98) A tablet was prepared in the same procedure as in Example 36, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 5 were used and that the compression was carried out at a compression pressure of 800 kgf.
Comparative Example 23
(99) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 6 were used, a coated tablet was prepared in the same procedure as in Example 36.
Comparative Example 24
(100) A tablet was prepared in the same procedure as in Example 36, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 6 were used and that the compression was carried out at a compression pressure of 800 kgf.
Comparative Example 25
(101) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 7 were used, a coated tablet was prepared in the same procedure as in Example 36.
Comparative Example 26
(102) A tablet was prepared in the same procedure as in Example 36, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 7 were used and that the compression was carried out at a compression pressure of 800 kgf.
Comparative Example 27
(103) With the exception that the fimasartan potassium trihydrate particles of Preparation Example 8 were used, a coated tablet was prepared in the same procedure as in Example 36.
Comparative Example 28
(104) A tablet was prepared in the same procedure as in Example 36, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 8 were used and that the compression was carried out at a compression pressure of 800 kgf.
Test Example 5
(105) Tablets prepared in the Examples 36 to 45 and the Comparative Examples 23 to 28 were assayed for hardness, disintegration time, and friability the same as those of TEST EXAMPLE 1.
(106) Results are summarized in Table 6 below.
(107) TABLE-US-00006 TABLE 6 Assay for Hardness, Disintegration Time and Friability of Tablets of Examples 36 to 45 and Comparative Examples 23 to 28 Compression Hard- Disinte- Fria- Preparation Pressure ness gration bility Examples Example (kgf) (kp) Time (min) (%) Example 36 Preparation 500 14.6 6.83 0.1 Example 37 Example 1 800 18.2 10.67 0.0 Example 38 Preparation 500 13.6 5.67 0.0 Example 39 Example 2 800 16.8 10.67 0.0 Example 40 Preparation 500 12.5 5.17 0.0 Example 41 Example 3 800 16.2 10.00 0.0 Example 42 Preparation 500 11.8 5.00 0.1 Example 43 Example 4 800 15.6 9.33 0.0 Example 44 Preparation 500 10.5 4.75 0.1 Example 45 Example 5 800 14.1 8.83 0.1 Comparative Preparation 500 7.2 3.25 1.1 Example 23 Example 6 Comparative 800 7.6 3.83 1.1 Example 24 Comparative Preparation 500 6.6 2.83 1.5 Example 25 Example 7 Comparative 800 6.9 2.83 1.4 Example 26 Comparative Preparation 500 5.3 2.25 2.0 Example 27 Example 8 Comparative 800 5.8 2.67 1.8 Example 28
Comparative Example 29
(108) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate was not used, 72 mg of lactose monohydrate was used and the compression was carried out at a compression pressure of 500 kgf.
Comparative Example 30
(109) A tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate was not used, 72 mg of lactose monohydrate was used and the compression was carried out at a compression pressure of 800 kgf.
Test Example 6
(110) Tablets prepared in the Comparative Examples 29 and 30 were assayed for hardness, disintegration time, and friability the same as those of TEST EXAMPLE 1.
(111) Results are summarized in Table 7 below.
(112) TABLE-US-00007 TABLE 7 Assay for Hardness, Disintegration Time and Friability of Tablets of Comparative Examples 29 to 30 Compression Pressure Hardness Disintegration Friability Examples (kgf) (kp) Time (min) (%) Comparative 500 5.8 2.75 2.4 Example 29 Comparative 800 6.1 3.83 2.1 Example 30
(113) As is clearly understood from data of Tables 4 to 6, the tablets according to Examples 16 to 45 exhibited superior hardness, disintegration time, and friability to those of comparative Examples 11 to 28 although the additives included in the tablet is changed from lactose monohydrate and hydroxypropyl cellulose into D mannitol (Examples 16 to 25), corn starch (Examples 26 to 35) and hydroxypropylmethyl cellulose (Examples 36 to 45), respectively.
(114) Additionally, as shown in Table 7, when tablet was prepared without the active ingredient of the fimasartan potassium trihydrate, hardness, disintegration time and friability are inferior to those of tablets according to Examples 1 to 45 including the active ingredient of the fimasartan potassium trihydrate.
(115) Thus, it is confirmed that the properties of the tablet are not greatly affected by the additives when the amount of the active ingredients of fimasartan potassium trihydrate is high in the tablet.