Abstract:
The present invention relates to a solid pharmaceutical composition for oral administration, containing the following components (A) and (B): (A) 
     2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (compound a) or an acid addition salt thereof, and (B) organic acid selected from the group consisting of tartaric acid, malic acid, ascorbic acid and benzoic acid. An improvement is achieved in the dissolubility of the compound a, which is useful as a therapeutic agent for hypercholesterolemia, arteriosclerosis, and the like.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention relates to a solid pharmaceutical composition for oral administration having enhanced dissolubility. 
       BACKGROUND OF THE INVENTION 
       [0002]    2-[4-[2-(Benzimidazol-2-ylthio) ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (hereinafter, referred to as compound a) or an acid addition salt thereof is known to have an excellent acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitory action, and an excellent intracellular cholesterol transport inhibitory action, and to be useful as a therapeutic agent for hypercholesterolemia, arteriosclerosis and acute myocardial infarction (Patent Documents 1 and 2). 
       PRIOR ART DOCUMENTS 
     Patent Document 
       [0003]    Patent Document 1: WO 1998/054153 
         [0004]    Patent Document 2: WO 2005/020996 
       SUMMARY OF THE INVENTION 
     Problem to be Solved by the Invention 
       [0005]    Most of the patients of hypercholesterolemia, arteriosclerosis and the like are elderly people, and the treatment of these diseases requires long times periods. Therefore, as the therapeutic agents for these diseases, pharmaceutical compositions for oral administration that can be stably administered for a long time period are desirable. When conventional pharmaceutical compositions for oral administration are orally administered, active medicinal ingredients rapidly dissolve out from the compositions in the upper digestive tract such as the stomach, and are first absorbed, and the effect of a drug occurs. 
         [0006]    However, compound a has low solubility in weakly acidic environments to alkaline environments (for example, the solubility in water is 0.05% (W/V)). Therefore, in the case of patients of achlorhydria, which is considered to develop more frequently in elderly people, there has been a concern that the dissolubility of the compound a from the pharmaceutical composition in the stomach may be insufficient, and there may be variations in the efficacy of the drug. 
         [0007]    Accordingly, an object of the present invention is to provide a solid pharmaceutical composition for oral administration containing the compound a, which has improved dissolubility in the digestive tract. 
       Solution to Problem 
       [0008]    Thus, the inventors of the present invention conducted extensive investigations on the improvement of the dissolubility of a solid composition containing a compound a, and as a result, the inventors found that among various additives, acidic substances improve the dissolubility of the compound a. Thus, the inventors further conducted an investigation, and as a result, they found that among various acidic substances, tartaric acid, malic acid, ascorbic acid or benzoic acid has an especially excellent effect of improving the dissolubility of the compound a. Thus, the present invention was completed. 
         [0009]    That is, the present invention is to provide a solid pharmaceutical composition for oral administration containing the following components (A) and (B): 
         [0000]    2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (compound a) or an acid addition salt thereof, and (B) organic acid selected from the group consisting of tartaric acid, malic acid, ascorbic acid, and benzoic acid. 
         [0010]    Furthermore, the present invention is to provide a composition as described above, in which the mass ratio of the compound a in the component (A) to the component (B), (A/B) is 10/3 to 1/20. 
         [0011]    Moreover, the present invention is to provide a method for treating hypercholesterolemia or arteriosclerosis, the method including orally administering a solid pharmaceutical composition containing (A) compound a or an acid addition salt thereof, and (B) organic acid selected from the group consisting of tartaric acid, malic acid, ascorbic acid, and benzoic acid. 
       Effects of Invention 
       [0012]    Since the solid pharmaceutical composition of the present invention has satisfactory dissolubility of the compound a in the digestive tract, the solid pharmaceutical composition provides a rapid and stabilized therapeutic effect for hypercholesterolemia, arteriosclerosis and the like by oral administration. 
     
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         [0013]      FIG. 1  shows the results of a dissolution test in Test Example 1. 
       
    
    
     DESCRIPTION OF EMBODIMENTS 
       [0014]    The compound a (component (A)), which is an active ingredient of the pharmaceutical composition of the present invention, is known to have an excellent ACAT inhibitory action and an excellent intracellular cholesterol transport inhibitory action, as described in the Patent Document 1, and to be useful as a therapeutic agent for hypercholesterolemia, arteriosclerosis and the like. Examples of the acid addition salt of the compound a include addition salts of inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid; and addition salts of organic acids such as acetic acid, lactic acid and succinic acid, and among these, a hydrochloride is preferred. Furthermore, the compound a may also be in the form of a hydrate. Further, the compound a can be prepared by the preparation method described in the Patent Document 1. 
         [0015]    The content of the compound a in the pharmaceutical composition of the present invention is preferably 10 mg to 300 mg, and more preferably 25 mg to 200 mg, from the viewpoint of therapeutic effects. There are no particular limitations on the particle size of the compound a to be used; however, from the viewpoints of dissolubility, absorbability and the like, an average particle size of 0.1 μm to 200 μm is preferred, and 1 μm to 150 μm is more preferred. 
         [0016]    The pharmaceutical composition of the present invention contains (A) compound a and (B) organic acid selected from the group consisting of tartaric acid, malic acid, ascorbic acid and benzoic acid (hereinafter, also referred to as (B) organic acid). These organic acids (B) have a function to markedly improve the dissolubility of compound a from a pharmaceutical composition. Examples of tartaric acid include DL(±)-tartaric acid, L(+)-tartaric acid, and D(−)-tartaric acid, and preferably L(+)-tartaric acid. Examples of malic acid include dl-malic acid, d-malic acid, and l-malic acid, and preferably dl-malic acid. Examples of ascorbic acid include preferably L(+)-ascorbic acid. As commercially available products of these organic acids (B), for example, L(+)-tartaric acid (manufactured by Wako Pure Chemical Industries, Ltd.), tartaric acid of the Japanese Pharmacopoeia (manufactured by Taihei Chemical Industrial Co., Ltd.), DL-malic acid, L(−)-malic acid (manufactured by Wako Pure Chemical Industries, Ltd.), L(+)-ascorbic acid (manufactured by KANTO CHEMICAL CO., INC.), benzoic acid (manufactured by Wako Pure Chemical Industries, Ltd.), benzoic acid of the Japanese Pharmacopoeia (manufactured by FUSHIMI Pharmaceutical Co., Ltd.) and the like are available. Among these organic acids (B), from the viewpoint of dissolubility, taste and the like, tartaric acid and malic acid are particularly preferable. Further, these organic acids (B) may be used alone or in combination of two or more. Furthermore, from the viewpoint of the effect of improving the dissolubility of the compound a, the average particle size of these organic acids (B) is preferably 1000 μm or less, particularly preferred is 500 μm or less. 
         [0017]    The content of (B) organic acid is preferably an amount of more than 0.2 parts by mass, and more preferably 0.3 parts by mass or greater, relative to 1 part by mass of the compound a, from the viewpoint of the dissolubility of the compound a. Furthermore, there are no particular limitations on the upper limit of the content of (B) organic acid, but in view of the preparation of solid compositions, it is preferable to set the upper limit to 20 parts by mass or less, and more preferably 5 parts by mass or less, relative to 1 part by mass of the compound a. Therefore, the mass ratio of the compound a in the component (A) to each of organic acid (B), (A/B) in the pharmaceutical composition is preferably set in the range of 5/1 to 1/20, more preferably in the range of 10/3 to 1/20, and even more preferably in the range of 2/1 to 1/5. 
         [0018]    When the pharmaceutical composition of the present invention further contains (C) a disintegrant in addition to the compound a in component (A) and (B) organic acid, the dissolubility of the compound a is further markedly improved. Examples of such a disintegrant include crospovidone, croscarmellose sodium, pregelatinized starch, partly pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose sodium, carmellose calcium, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch. 
         [0019]    Among these, crospovidone, croscarmellose sodium, pregelatinized starch, partly pregelatinized starch, and sodium carboxymethyl starch are particularly preferred. 
         [0020]    Crospovidone is a crosslinked polymer of N-vinyl-2-pyrrolidone. As for crospovidone, it is preferable to use a product having an average particle size of 5 μm to 100 μm. Croscarmellose sodium is a crosslinked polymer of carmellose sodium. Pregelatinized starch is a product obtained by pregelatinizing starch and water by heating, and rapidly drying the pregelatinized product. Partly pregelatinized starch is a product obtained by heating corn starch together with water under normal pressure or under pressure to partly pregelatinize starch grains, and drying the pregelatinized product. Sodium carboxymethyl starch(also called as sodium starch glycolate) is a sodium salt of carboxymethyl ether of starch. 
         [0021]    Among these disintegrants (C), it is particularly preferable to use crospovidone or pregelatinized starch from the viewpoint of the effect of improving the dissolubility of the compound a. As commercially available products of crospovidone, for example, POLYPLASDONE XL, POLYPLASDONE XL-10, POLYPLASDONE INF-10 (manufactured by ISP Japan, Ltd.), KOLLIDON CL, KOLLIDON CL-F, KOLLIDON CL-SF, and KOLLIDON CL-M (manufactured by BASF Japan, Ltd.) are available. Furthermore, as commercially available products of pregelatinized starch, for example, SWELSTAR PD-1 (manufactured by Asahi Kasei Chemicals Corp.), LYCATAB PGS (manufactured by Roquette Japan K.K.), and AMICOL (manufactured by Nippon Starch Chemical Co., Ltd.), and the like are available. 
         [0022]    The content of the (C) disintegrant is preferably 0.1 to 1 part by mass, and more preferably 0.2 to 0.8 parts by mass, relative to 1 part by mass of the component a. 
         [0023]    The pharmaceutical composition of the present invention is a solid composition for oral administration, and specific examples thereof include tablets, granules, fine granules, capsules, powders, and pills. However, among these, tablets, granules and capsules are preferred, and tablets are particularly preferred in view of ingestability. 
         [0024]    The solid composition of the present invention may have an excipient, a binder, a lubricant and the like added thereto, in addition to the compound a, (B) organic acid and (C) a disintegrant, and may be formulated into the respective forms. Examples of the excipient include lactose, corn starch, crystalline cellulose, sucrose, glucose, mannitol, sorbitol, and calcium carbonate. Examples of the binder include hydroxypropyl cellulose, hypromellose, hydroxyethylethyl cellulose, hydroxyethylmethyl cellulose, polyvinylpyrrolidone, and polyvinyl alcohol. Examples of the lubricating agent include magnesium stearate, stearic acid, palmitic acid, calcium stearate, and talc. 
         [0025]    When the dissolubility of the compound a is considered, the contents of the excipient, binding agent and lubricating agent in the pharmaceutical composition of the present invention are preferably set to 0.2 to 4 parts by mass for the excipient, 0.05 to 1 part by mass for the binding agent, and 0.01 to 0.08 parts by mass for the lubricating agent, relative to 1 part by mass of the compound a. 
         [0026]    There are no particular limitations on the method for preparing the solid pharmaceutical composition of the present invention, but for example, in the case of tablets, the tablets can be produced by uniformly mixing the various components described above, and producing the tablets by a general-purpose wet granulation compression method, a direct powder compression method, or the like. Furthermore, the tablets thus obtained may be further subjected to film coating, sugar coating, sustained release coating, or the like. In this case, examples of the coating agent include hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, titanium oxide, talc, polyethylene glycol, triethyl citrate, stearic acid, hydrated silicon dioxide, and light silicic anhydride. Examples of the sugar coating include gum arabic, purified gelatin, gelatin, purified sucrose, sucrose, precipitated calcium carbonate, talc, and calcium dihydrogen phosphate hydrate. Examples of the sustained release coating agent include methacrylic acid copolymer LD, ethyl cellulose, aminoalkyl methacrylate copolymer RS, and hypromellose. 
         [0027]    Despite the fact that the compound a has low solubility in water, the pharmaceutical composition of the present invention has markedly improved dissolubility of the compound a from the composition, as a result of the addition of (B) organic acid. The reason for this is not clearly known, but it can be speculated that when the compound a is brought into contact with water, the incorporation of (B) organic acid causes a decrease in the pH in the vicinity of the compound a in the microscopic scale. However, as it is obvious from the comparisons made between Examples and Comparative Examples below, if the reason is merely a decrease in the pH, the dissolubility of the compound a will also be improved by adding salicylic acid or phthalic anhydride. However, since a satisfactory effect of improving dissolubility cannot be obtained with these organic acids, it can be contemplated that certain factors other than pH are involved. That is, the effect of the present invention can be considered to be unique to the combination of the compound a and specific (B) organic acid used in the present invention. 
       EXAMPLES 
       [0028]    Next, the present invention will be described in detail by way of Examples, but the present invention is not intended to be limited to these. 
         [0029]    The following Examples were carried out using monohydrochloride of the compound a (hereinafter, referred to as compound a hydrochloride). Furthermore, the compound a hydrochloride was synthesized by using the method described in Patent Document 1 and known methods. 
       Example 1 
       [0030]    53.65 mg of compound a hydrochloride (50 mg in terms of compound a) and 50 mg of L(+)-tartaric acid were pulverized and mixed in a mortar, and thus a sample 2 (103.65 mg) was obtained. 
       Example 2 
       [0031]    53.65 mg of compound a hydrochloride and 50 mg of dl-malic acid were pulverized and mixed in a mortar, and thus a sample 4 (103.65 mg) was obtained. 
       Example 3 
       [0032]    53.65 mg of compound a hydrochloride and 50 mg of benzoic acid were pulverized and mixed in a mortar, and thus a sample 1 (103.65 mg) was obtained. 
       Example 4 
       [0033]    53.65 mg of compound a hydrochloride and 50 mg of L(+)-ascorbic acid were pulverized and mixed in a mortar, and thus a sample 3 (103.65 mg) was obtained. 
       Comparative Example 1 
       [0034]    53.65 mg of compound a hydrochloride was pulverized and mixed in a mortar, and thus a sample 5 (53.65 mg) was obtained. 
       Comparative Example 2 
       [0035]    53.65 mg of compound a hydrochloride and 50 mg of salicylic acid were pulverized and mixed in a mortar, and thus a sample 6 (103.65 mg) was obtained. 
       Comparative Example 3 
       [0036]    53.65 mg of compound a hydrochloride and 50 mg of sorbic acid were pulverized and mixed in a mortar, and thus a sample 7 (103.65 mg) was obtained. 
       Comparative Example 4 
       [0037]    53.65 mg of compound a hydrochloride and 50 mg of phthalic anhydride were pulverized and mixed in a mortar, and thus a sample 8 (103.65 mg) was obtained. 
       Comparative Example 5 
       [0038]    53.65 mg of compound a hydrochloride and 50 mg of boric acid were pulverized and mixed in a mortar, and thus a sample 9 (103.65 mg) was obtained. 
       Test Example 1 Dissolution Test 
       [0039]    The dissolubility of the samples 1 to 9 was examined according to the second method (paddle method) of the dissolution test method according to the general test methods of the Japanese Pharmacopoeia. 
         [0040]    103.65 mg of each of the samples 1 to 9 (53.65 mg for sample 5 only) was introduced into 900 mL of the second fluid for dissolution test according to the Japanese Pharmacopoeia, and the test was carried out under the conditions of a temperature of 37±0.5° C. and a speed of paddle rotation of 50 rpm. Thus, the concentrations of the compound a after 5, 10, 15, 30, 45 and 60 minutes were measured. The sample solution collected at each time point was filtered through a membrane filter made of PTFE (DISMIC-25HP manufactured by Toyo Roshi Kaisha, Ltd.) having a pore size of 0.45 μm, and was analyzed by a high performance liquid chromatographic method using a reversed phase column (manufactured by Nomura Chemical Co., Ltd.; Develosil ODS-HG-5). Thus, the dissolution rates were calculated. The results are presented in Table 1 and  FIG. 1 . 
       Test Example 2 Measurement of pH Value 
       [0041]    103.65 mg of each of the samples 1 to 9 (53.65 mg for sample 5 only) was introduced into a beaker, and 50 mL of purified water was added thereto. While the mixture was stirred with a magnetic stirrer, the pH of the solution was measured with a glass electrode type hydrogen ion concentration meter (manufactured by Toa Electronics, Inc.; HM-50V). 50 mL of purified water was further added thereto, and then the measurement of pH was carried out in the same manner. The results are presented in Table 1. 
         [0000]    
       
         
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 Comparative 
                 Comparative 
                 Comparative 
                 Comparative 
                 Comparative 
               
               
                 Time (min) 
                 Example 1 
                 Example 2 
                 Example 3 
                 Example 4 
                 Example 1 
                 Example 2 
                 Example 3 
                 Example 4 
                 Example 5 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                  0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                  5 
                 51.9 
                 39.5 
                 26.0 
                 25.3 
                 0 
                 9.1 
                 2.2 
                 10.0 
                 21.4 
               
               
                 10 
                 56.1 
                 48.1 
                 37.3 
                 32.3 
                 5.7 
                 16.8 
                 4.5 
                 14.3 
                 13.9 
               
               
                 15 
                 59.9 
                 51.6 
                 42.0 
                 36.6 
                 3.1 
                 23.3 
                 8.1 
                 17.5 
                 14.0 
               
               
                 30 
                 63.4 
                 56.1 
                 47.1 
                 42.3 
                 5.2 
                 29.2 
                 14.3 
                 24.0 
                 16.6 
               
               
                 45 
                 66.1 
                 59.0 
                 48.7 
                 45.8 
                 7.1 
                 33.8 
                 20.0 
                 27.5 
                 16.7 
               
               
                 60 
                 67.3 
                 60.5 
                 48.9 
                 47.0 
                 10.2 
                 37.2 
                 23.5 
                 28.3 
                 16.9 
               
               
                 pH (50 mL) 
                 2.97 
                 3.08 
                 3.40 
                 3.47 
                 5.02 
                 2.88 
                 3.72 
                 3.12 
                 5.02 
               
               
                 pH (100 mL) 
                 3.06 
                 3.17 
                 3.46 
                 3.59 
                 5.07 
                 2.98 
                 3.75 
                 3.22 
                 5.07 
               
               
                   
               
             
          
         
       
     
         [0042]    As can be seen from the above results, when compound a was used alone, the compound a hardly dissolved, and in the mixture with each organic acid or boric acid, only the mixture with L(+)-tartaric acid, dl-malic acid, benzoic acid or L(+)-ascorbic acid exhibited a dissolution rate value of greater than 40% after 30 minutes, which is the criterion of determination. Among them, it was seen the significant effect of improving the dissolution rate by mixing with L(+)-tartaric acid or dl-malic acid.