Preparation containing benzimidazole derivative

Abstract

The present invention relates to a novel formulation comprising a benzimidazole derivative. The formulation for oral administration comprising a compound of Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof; and at least one disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glycolate and low-substituted hydroxypropylcellulose, exhibits an excellent storage stability and has an effect on preventing a phenomenon of decline in dissolution rate, thus being usefully used as a formulation for oral administration.

Claims

1. A formulation for oral administration comprising a compound of (S)-4((5,7-difluorochroman-4-yl)oxy)-N,N-2-trimethyl-1H-benzo[d]imidazole-6-carboxamide of Formula 1 or a pharmaceutically acceptable salt thereof; and at least one disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glycolate and low-substituted hydroxypropylcellulose, wherein the formulation is a tablet; and wherein a dissolution rate of the tablet increases or decreases by less than 6% from an initial value when stored under a stress condition of 60° C. and 80% relative humidity for 7 days: ##STR00002##

2. The formulation for oral administration according to claim 1, wherein a content of the disintegrant is 1 to 20 wt % of the total weight of the formulation.

3. The formulation for oral administration according to claim 1, wherein the disintegrant is low-substituted hydroxypropylcellulose having a substitution degree of a hydroxypropoxy group that amounts to 5 to 16 mass %.

4. The formulation for oral administration according to claim 1, wherein the formulation further comprises at least one ingredient selected from the group consisting of a binder, a filler and a lubricant.

5. The formulation for oral administration according to claim 4, wherein the binder is at least one selected from the group consisting of starch, microcrystalline cellulose, colloidal silicon dioxide, mannitol, lactose, polyethylene glycol, polyvinyl pyrrolidone co-polymer, hydroxypropyl cellulose, gelatin and a mixture thereof.

6. The formulation for oral administration according to claim 4, wherein the filler is at least one selected from the group consisting of lactose, microcrystalline cellulose, mannitol and colloidal silicon dioxide.

7. The formulation for oral administration according to claim 4, wherein the lubricant is at least one selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium benzoate, sodium stearyl fumarate, glyceryl monooleate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, zinc stearate and a paraffin group.

Description

DESCRIPTION OF DRAWINGS

(1) FIG. 1 illustrates a graph of comparing dissolution rates of a tablet according to Example 1 with each other, respectively under initial and stress conditions, wherein the Example 1 comprises croscarmellose sodium.

(2) FIG. 2 illustrates a graph of comparing dissolution rates of a tablet according to Example 12 with each other, respectively under initial and stress conditions, wherein the Example 12 comprises low-substituted hydroxypropylcellulose.

(3) FIG. 3 illustrates a graph of comparing dissolution rates of a tablet according to Comparative Example 1 with each other, respectively under initial and stress conditions, wherein the Comparative Example 1 comprises crospovidone.

(4) FIG. 4 illustrates a graph of comparing dissolution rates of a tablet according to Comparative Example 2 with each other, respectively under initial and stress conditions, wherein the Comparative Example 2 comprises Starch 1500.

MODE FOR INVENTION

(5) Hereinafter, configuration and effects of the present invention will be described in more detail through preparation examples, examples and experimental examples. However, the following preparation examples, examples and experimental examples are provided only for the purpose of illustrating the present invention, and thus the present invention is not limited thereto.

Preparation Example 1: Preparing of a Tablet Containing Croscarmellose Sodium

(6) A method for preparing a tablet of Example 1 is as follows.

(7) A main active ingredient (S)-4((5,7-difluorochroman-4-yl)oxy)-N,N-2-trimethyl-1H-benzo[d]imidazole-6-carboxamide was mixed with mannitol, microcrystalline cellulose and croscarmellose sodium. Then, a binder solution comprising hydroxypropylcellulose and distilled water was added to a mixture resulting from the above mixing process, then a kneading and drying process, and then an sizing was carried out. After that, a substance resulting from the above sizing process was mixed with colloidal silicon dioxide and magnesium stearate, after which a resulting mixture was compressed into and prepared as a tablet. Contents of components comprised in the tablet of the above Example 1 are such as those shown in the following Table 1.

(8) Tablets of Examples 2 and 3 were prepared by respectively using lactose and starch instead of mannitol, in comparison with the tablet of Example 1, but, except for that, they were prepared by means of the same method for preparing a tablet as described in the above Example 1. Contents of components comprised in the tablets of the above Examples 2 and 3 are such as those shown in the following Table 1.

(9) Tablets of Examples 4 and 5 were prepared by respectively using polyvinylpyrrolidone and copovidone instead of hydroxypropylcellulose, in comparison with the tablet of Example 1, but, except for that, they were prepared by means of the same method for preparing a tablet as described in the above Example 1. Contents of components comprised in the tablets of the above Examples 4 and 5 are such as those shown in the following Table 1.

(10) Tablets of Examples 6 to 9 were prepared by varying an amount of croscarmellose sodium, in comparison with the tablet of Example 1, but, except for that, they were prepared by means of the same method for preparing a tablet as described in the above Example 1. Contents of components comprised in the tablets of the above Examples 6 to 9 are such as those shown in the following Table 1.

(11) A tablet of Example 10 was prepared by doubling an amount of a main active ingredient, in comparison with the tablet of Example 1, but, except for that, they were prepared by means of the same method for preparing a tablet as described in the above Example 1. Contents of components contained in the tablet of the above Example 10 are such as those shown in the following Table 1.

(12) TABLE-US-00001 TABLE 1 Example (Amount Used, mg) Classification Component 1 2 3 4 5 6 7 8 9 10 Main active (S)-4((5,7- 50 50 50 50 50 50 50 50 50 100 ingredient difluorochroman-4-yl)oxy)- N,N-2-trimethyl-1H- benzo[d]imidazole-6- carboxamide Excipient Mannitol 50 — — 50 50 54 44 40 30 100 Lactose — 62 — — — — — — — — Starch — — 62 — — — — — — — Microcrystalline cellulose 80 68 68 80 80 80 80 80 80 160 Colloidal silicon dioxide 2  2 2  2 2 2 2 2 2 4 Disintegrant Croscarmellose sodium 10 10 10 10 10 6 16 20 30 20 Binder Hydroxypropylcellulose 6  6 6 — — 6 6 6 6 12 Polyvinylpyrrolidone — — —  6 — — — — — — Copovidone — — — — 6 — — — — — Lubricant Magnesium stearate 2  2 2  2 2 2 2 2 2 4 Total Weight 200 200  200 200  200 200 200 200 200 400

Preparation Example 2: Preparing of a Tablet Containing Sodium Starch Glycolate

(13) Tablets of Examples 11 and 12 were prepared by using sodium starch glycolate instead of croscarmellose sodium as a disintegrant in comparison with the tablet of Example 1, but, except for that, they were prepared by means of the same method for preparing a tablet as described in the above Example 1. Contents of components comprised in the tablets of the above Examples 11 and 12 are such as those shown in the following Table 2.

(14) TABLE-US-00002 TABLE 2 Example (Amount Used, mg) Classification Component 11 12 Main active (S)-4((5,7-difluorochroman-4- 50 50 ingredient yl)oxy)-N,N-2-trimethyl-1H- benzo[d]imidazole-6-carboxamide Excipient Mannitol 50 62 Microcrystalline cellulose 80 58 Colloidal silicon dioxide 2 2 Disintegrant Sodium starch glycolate 10 20 Binder Hydroxypropylcellulose 6 6 Lubricant Magnesium stearate 2 2 Total Weight 200 200

Preparation Example 3: Preparing of a Tablet Containing Low-Substituted Hydroxypropylcellulose

(15) A tablet of Example 13 was prepared by using low-substituted hydroxypropylcellulose instead of croscarmellose sodium as a disintegrant in comparison with the tablet of Example 1, but, except for that, they were prepared by means of the same method for preparing a tablet as described in the above Example 1. Contents of components comprised in the tablet of the above Example 13 are such as those shown in the following Table 3.

(16) TABLE-US-00003 TABLE 3 Example 13 Classi- (Amount fication Component Used, mg) Main active (S)-4((5,7-difluorochroman-4-yl)oxy)-N,N-2- 50 ingredient trimethyl-1H-benzo[d]imidazole-6- carboxamide Excipient Mannitol 50 Microcrystalline cellulose 80 Colloidal silicon dioxide 2 Disintegrant Low-substituted hydroxypropylcellulose 10 Binder Hydroxypropylcellulose 6 Lubricant Magnesium stearate 2 Total Weight 200

Preparation Example 4: Preparing of a Simple Mix Tablet Containing Sodium Starch Glycolate

(17) An excipient and a disintegrant, including a main active ingredient, were simply mixed and sized, after which a lubricant was further mixed therewith and a resulting mixture was pressed into a tablet, such that the tablet for oral administration of Example 14 was prepared. Contents of components comprised in the tablet of the above Example 14 are such as those shown in the following Table 4.

(18) TABLE-US-00004 TABLE 4 Example 14 Classi- (Amount fication Component Used, mg) Main active (S)-4((5,7-difluorochroman-4-yl)oxy)-N,N-2- 50 ingredient trimethyl-1H-benzo[d]imidazole-6- carboxamide Excipient Lactose 84 Silicified microcrystalline cellulose 56 Colloidal silicon dioxide 2 Disintegrant Sodium starch glycolate 6 Lubricant Magnesium stearate 2 Total Weight 200

Preparation Example 5: Preparing of a Tablet Containing Crospovidone

(19) A tablet for oral administration of Comparative Example 1, which used crospovidone as a disintegrant, was prepared by means of the same method for preparing a tablet as described in Example 1, with contents of components shown in the following Table 5.

(20) TABLE-US-00005 TABLE 5 Comparative Example 1 Classi- (Amount fication Component Used, mg) Main active (S)-4((5,7-difluorochroman-4-yl)oxy)-N,N-2- 50 ingredient trimethyl-1H-benzo[d]imidazole-6- carboxamide Excipient Mannitol 62 Microcrystalline cellulose 68 Colloidal silicon dioxide 2 Binder Hydroxypropylcellulose 6 Disintegrant Crospovidone 10 Lubricant Magnesium stearate 2 Total Weight 200

Preparation Example 6: Preparing of a Tablet Containing Starch 1500

(21) A tablet for oral administration of Comparative Example 2, which used Starch 1500 as a disintegrant, was prepared by means of the same method for preparing a tablet as described in Example 1, with contents of components shown in the following Table 6.

(22) TABLE-US-00006 TABLE 6 Comparative Example 1 Classi- (Amount fication Component Used, mg) Main active (S)-4((5,7-difluorochroman-4-yl)oxy)-N,N-2- 50 ingredient trimethyl-1H-benzo[d]imidazole-6- carboxamide Excipient Mannitol 50 Microcrystalline cellulose 80 Colloidal silicon dioxide 2 Binder Hydroxypropylcellulose 6 Disintegrant Starch 1500 10 Lubricant Magnesium stearate 2 Total Weight 200

Experimental Example 1: Storage Stability Test

(23) Tablets of Examples 1 to 14, prepared according to the above Preparation Examples 1 to 4, were inserted into each of high-density polyethylene (HDPE) bottles, after which resulting bottles were stored under a stress condition (60° C., 80% RH) for 7 days, such that properties of the tablets were identified and a purity test thereof was carried out as well.

(24) (1) Impurity Test Evaluation on Tablet Comprising Croscarmellose Sodium

(25) Particularly, as a result of carrying out an evaluation on the occurrence or increase of impurities after the storage of the tablets of Examples 1 to 10, as prepared by using croscarmellose sodium as a disintegrant, no pattern of occurrence or increase of impurities was identified in all the tablets of Examples 1 to 10 (Table 7).

(26) TABLE-US-00007 TABLE 7 Example Component (%) 1 2 3 4 5 9 10 Initial Content (API) 99.94 99.94 99.81 99.94 99.79 99.93 100.00 Condition Total impurities 0.06 0.06 0.19 0.06 0.21 0.07 0.00 Stress Condition Content (API) 99.94 99.94 99.80 99.94 99.81 99.93 99.98 Storage for Total impurities 0.06 0.06 0.2 0.06 0.19 0.07 0.02 7 Days

(27) Accordingly, the formulation comprising the compound of Formula 1, which used croscarmellose sodium as a disintegrant, produced almost no impurities, thus identifying that the formulation was excellent in storage stability.

(28) (2) Purity Test Evaluation on Tablet Comprising Sodium Starch Glycolate or Low-Substituted Hydroxypropylcellulose

(29) Particularly, as a result of carrying out an evaluation on a production or increase of impurities after the storage of the tablets of Examples 11 to 12, as prepared by using sodium starch glycolate as a disintegrant, as well as the tablet of Example 13, as prepared by using low-substituted hydroxypropylcellulose as a disintegrant, it was identified that no pattern of occurrence or increase of impurities was identified in all the tablets of the Examples 11 to 13 (Table 8).

(30) TABLE-US-00008 TABLE 8 Example Component (%) 11 13 Initial Condition Content (API) 99.84 99.94 Total impurities 0.16 0.06 Stress Condition Content (API) 99.83 99.93 Storage for 7 Days Total impurities 0.17 0.07

(31) Accordingly, a formulation comprising the compound of Formula 1, which used sodium starch glycolate or low-substituted hydroxypropylcellulose as a disintegrant, produced almost no impurities, thus identifying that the formulation was excellent in storage stability.

Experimental Example 2: Dissolution Stability Test

(32) Tablets of Examples 1 to 14, prepared according to the above Preparation Examples 1 to 4, were inserted into each of high-density polyethylene (HDPE) bottles, after which resulting bottles were stored under a stress condition (60° C., 80% RH) for 7 days, such that an in vitro dissolution test and an HPLC analysis were carried out.

(33) (1) Evaluation on Dissolution Rate of Tablet Comprising Croscarmellose Sodium

(34) Particularly, a dissolution experiment was carried out on tablets of Examples 1 to 10, as prepared by using croscarmellose sodium as a disintegrant, wherein conditions for the dissolution experiment were such as those described below:

(35) 1) Basis of dissolution test: Dissolution test method in general test methods in the 11.sup.th Revision of the Korean Pharmacopoeia

(36) 2) Dissolution test method: Dissolution test method II, paddle method

(37) 3) Dissolution test solution: 900 ml of pH 4.0 acetate buffer solution

(38) 4) Temperature condition: Maintained at 37.2° C.±0.5° C.

(39) 5) Analysis method: HPLC method Detector: Ultraviolet absorptiometer (measurement wavelength: 262 nm) Column: C18 5 um/4.6×150 mm column Mobile phase: Acetonitrile: Distilled water [gradient]

(40) As a result of comparing dissolution rates with each other at a time of 15 minutes after onset of dissolution, it was found that the dissolution rates fall within the specified criteria, and it was identified that there occurred no phenomenon of decline in dissolution rate in all the tablets of the Examples 1 to 10 (Table 9 and FIG. 1).

(41) TABLE-US-00009 TABLE 9 Time Example (15 Minutes) 1 2 3 4 5 6 7 8 9 10 Dissolution Rate 85.0 80.6 80.7 86.5 81.5 85.0 88.8 86.0 81.9 77.1 (%) under Initial Condition Dissolution Rate 85.7 78.1 75.5 84.0 85.1 81.3 89.4 84.2 82.0 76.6 (%) under Stress Condition (7 days in storage)

(42) (2) Evaluation on Dissolution Rate of Tablet Comprising Sodium Starch Glycolate or Low-Substituted Hydroxypropylcellulose

(43) Particularly, a dissolution experiment was carried out on tablets of Examples 11, 12 and 14, as prepared by using sodium starch glycolate as a disintegrant, as well as a tablet of Example 13, as prepared by using low-substituted hydroxypropylcellulose as a disintegrant, wherein conditions for the dissolution experiment were such as those described below:

(44) 1) Basis of dissolution test: Dissolution test method in general test methods in the 11.sup.th Revision of the Korean Pharmacopoeia

(45) 2) Dissolution test method: Dissolution test method II, paddle method

(46) 3) Dissolution test solution: 900 ml of pH 4.0 acetate buffer solution

(47) 4) Temperature condition: Maintained at 37.2° C.±0.5° C.

(48) 5) Analysis method: HPLC method Detector: Ultraviolet absorptiometer (measurement wavelength: 262 nm) Column: C18 5 um/4.6×150 mm column Mobile phase: Acetonitrile: Distilled water [gradient]

(49) As a result of comparing dissolution rates with each other at a time of 15 minutes after onset of dissolution, it was found that the dissolution rates fall within the specified criteria, it was identified that there occurred no phenomenon of decline in dissolution rate in all the tablets of the Examples 11 to 14 (Table 10 and FIG. 2).

(50) TABLE-US-00010 TABLE 10 Example Time (15 Minutes) 11 12 13 14 Dissolution Rate (%) under Initial 85.5 84.8 76.8 81.1 Condition Dissolution Rate (%) under Stress 82.3 84.7 75.3 79.6 Condition (7 days in storage)

(51) (3) Evaluation on Dissolution Rate of Tablet Comprising Crospovidone or Starch 1500

(52) Particularly, a dissolution experiment was carried out on tablets of Comparative Examples 1 and 2, as prepared by using crospovidone or Starch 1500 as a disintegrant, wherein conditions for the dissolution experiment were such as those described below:

(53) 1) Basis of dissolution test: Dissolution test method out of general test methods in the 11.sup.th Revision of the Korean Pharmacopoeia

(54) 2) Dissolution test method: Dissolution test method II, paddle method

(55) 3) Dissolution test solution: 900 ml of pH 4.0 acetate buffer solution

(56) 4) Temperature condition: Maintained at 37.2° C.±0.5° C.

(57) 5) Analysis method: HPLC method Detector: Ultraviolet absorptiometer (measurement wavelength: 262 nm) Column: C18 5 um/4.6×150 mm column Mobile phase: Acetonitrile: Distilled water [gradient]

(58) As a result of comparing dissolution rates with each other at a time of 15 minutes after onset of dissolution, it was identified that there occurred a phenomenon of decline in dissolution rate after storage in the stress condition in comparison with the initial condition (Table 11 and FIGS. 3 and 4).

(59) TABLE-US-00011 TABLE 11 Comparative Example Time (15 Minutes) 1 2 Dissolution Rate (%) under Initial 85.2 61.7 Condition Dissolution Rate (%) under Stress 68.6 40.3 Condition (7 days in storage)

(60) According to the Experimental Example 2 above, it was identified that the formulation, as prepared by using croscarmellose sodium, sodium starch glycolate or low-substituted hydroxypropylcellulose as a disintegrant, showed almost no phenomenon of decline in dissolution rate at pH 4.0, which is a biological environment in stomach and intestines, when compared to the formulation, as prepared by using crospovidone or Starch 1500 as a disintegrant.

(61) While certain portions of the present invention have been described in detail above, such specific descriptions are set forth only to illustrate preferred exemplary embodiments, so it is obvious to those skilled in the art that the scope of the present invention is not limited thereto.

(62) Therefore, the actual scope of the present invention will be defined by the accompanying claims and equivalents thereto.