Abstract:
Disclosed is a pharmaceutical composition containing losartan carboxylic acid and a preparing method thereof. The pharmaceutical composition has the improved dissolution speed and dissolution rate, and the reduced variation in dissolution depending on the pH of a medium.

Description:
BACKGROUND 
       [0001]    1. Field 
         [0002]    The present invention relates to a pharmaceutical composition containing losartan carboxylic acid (2-butyl-4-chloro-1-[(2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl)methyl]-1H-imidazole-5-carboxylic acid) having improved dissolution rate and dissolution variation, and a preparing method thereof. 
         [0003]    2. Description of Related Art 
         [0004]    Losartan carboxylic acid (2-butyl-4-chloro-1-[(2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl)methyl]-1H-imidazole-5-carboxylic acid) represented by the following chemical formula 1 has effects of angiotensin II receptor antagonist and thus can be used for treatment of high blood pressure: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0005]    It is known that losartan carboxylic acid has effects of angiotensin II receptor antagonist that are about 10 to 14 times stronger and a half life longer than losartan, and thus can be useful as a medicine for high blood pressure (See J Hypertens, 1993 February 1(2):155-62 and J Chromatogr, 1992 January 17(2):295-301). When losartan is absorbed and then metabolized into losartan carboxylic acid, the effects of angiotensin II receptor antagonist increase. In this instance, interindividual differences in metabolic capability may result in interindividual variations in the efficacy. However, losartan carboxylic acid can fundamentally reduce the metabolic variation. Also, losartan carboxylic acid does not need metabolism and consequently has a relatively fast efficacy. 
         [0006]    As described above, the usefulness of losartan carboxylic acid is well known, but so far studies have not been actively made on the pharmaceutical characteristics of losartan carboxylic acid. 
       SUMMARY 
     Technical Problem 
       [0007]    Accordingly, it is an object of the present invention to provide a pharmaceutical composition containing losartan carboxylic acid having a variety of advantages and a preparing method thereof. 
       Technical Solution 
       [0008]    To achieve the object, the present invention provides a pharmaceutical composition containing a solid dispersion having losartan carboxylic acid represented by the following chemical formula 1 and water-soluble polymer uniformly dispersed therein: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0009]    The inventors discovered through various evaluations that losartan carboxylic acid has a low dissolution speed and a low dissolution rate in a medium having a low pH, and when losartan carboxylic acid contacts water, losartan carboxylic acid agglomerates, resulting in reduced dissolution rate and a variation in dissolution. To overcome these drawbacks, the inventors suggested a solid dispersion of losartan carboxylic acid and water-soluble polymer. That is to say, the present invention is based on that a solid dispersion of losartan carboxylic acid and water-soluble polymer can solve the problems involving a low dissolution speed and a low dissolution rate of losartan carboxylic acid at a low pH. It is expected that improvement in the dissolution rate at a low pH can reduce a variation in absorption depending on the change of pH following the consumption of food and reduce the interindividual variations in absorption. 
         [0010]    In the solid dispersion of losartan carboxylic acid and water-soluble polymer, the water-soluble polymer may include any one of polyethylene glycol, polyoxyethylene-polyoxypropylene copolymer, polyvinyl alcohol-polyethylene glycol copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinyl alcohol, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, polyvinyl acetate, polyalkene oxide, polyalkene glycol, diethylaminoacetate, aminoalkyl methacrylate copolymer, sodium alginate, and gelatin, or mixtures thereof. 
         [0011]    Preferably, the water-soluble polymer includes at least one selected from the group consisting of polyethylene glycol, polyoxyethylene-polyoxypropylene copolymer, and polyvinyl alcohol-polyethylene glycol copolymer. Among these water-soluble polymers, polyethylene glycol (PEG), polyethylene oxide (PEO) or polyoxyethylene (POE) can dramatically improve the dissolution rate and the initial dissolution speed in comparison with the others. 
         [0012]    In this instance, polyethylene glycol having an average molecular weight of 6000, 4000, or 1500 may be used singularly or in combination, however the present invention is not limited in this regard. Taking the phase stability, easiness of preparation of the pharmaceutical composition and the like into account, polyethylene glycol having an average molecular weight of 6000 is the most preferred. 
         [0013]    More preferably, the water-soluble polymer is a mixture of at least one polyethyleneglycol-based polymer selected from the group consisting of polyethylene glycol, polyoxyethylene-polyoxypropylene copolymer and polyvinyl alcohol-polyethylene glycol copolymer, and polymer other than polyethyleneglycol-based polymer. The mixture of polyethyleneglycol-based polymer and other polymer may contribute to the optimum dissolution speed and dissolution rate. Preferably, the other polymer is povidone, hydroxypropylmethylcellulose, or hydroxypropylcellulose, more preferably, povidon or hydroxypropylmethylcellulose. 
         [0014]    More preferably, the solid dispersion or the pharmaceutical composition includes silica, crospovidone, or mixtures thereof. Silica or crospovidone serves as an agent of suppressing the agglomeration of losartan carboxylic acid, thereby improving the dissolution speed and the dissolution rate, and reduces a variation in dissolution. This agglomeration suppressing agent favors the phase stability of the pharmaceutical composition containing losartan carboxylic acid. 
         [0015]    The agglomeration suppressing agent may be included in the solid dispersion, or may be mixed with the solid dispersion after the solid dispersion is formed. To maximize the agglomeration suppressing effect, the agglomeration suppressing agent is preferably included in the solid dispersion of losartan carboxylic acid and the water-soluble solid. 
         [0016]    In addition to the above components, the solid dispersion and/or the pharmaceutical composition according to the present invention may further include an additive, for example, an excipient, a flavoring agent, a coloring agent, a lubricant, or a filling agent, typically used to prepare a formulation for oral administration in a tablet, granule, capsule or pellet form. 
         [0017]    The solid dispersion of the present invention may be prepared by dissolving the components together such as losartan carboxylic acid, water-soluble polymer, and the like, followed by drying, or by melting the components together, followed by cooling. Alternatively, the dissolving and melting steps may be simultaneously carried out to prepare the solid dispersion of the present invention. 
         [0018]    More specifically, the present invention also provides a method for preparing a pharmaceutical composition containing losartan carboxylic acid having improved dissolution speed and dissolution rate, the method including (S1) preparing a solution of losartan carboxylic acid and water-soluble polymer, and (S2) drying the solution to yield a solid dispersion. 
         [0019]    A solvent for the solution may include, but is not limited to, at least one of water, ethanol, methanol, isopropyl alcohol, dichloromethane, chloroform, and acetone. 
         [0020]    The drying may be performed by a general drying process using hot air. To maintain the mixing uniformity during the drying, agitation or shaking is preferably performed together with the drying. For mass production, a spray drying process is preferred. To perform the spray drying process, a fluidized bed granulator, a spray dryer, or a C/F instantizer may be used. 
       Effects of the Invention 
       [0021]    The present invention provides a pharmaceutical composition containing losartan carboxylic acid having improved dissolution speed and dissolution rate and reduced variation in dissolution depending on the pH, and a preparing method thereof. 
     
    
     
       DESCRIPTION OF THE DRAWINGS 
         [0022]      FIG. 1  is a graph illustrating the bio-absorption evaluation results of a composition containing losartan carboxylic acid having improved dissolution speed and dissolution rate. 
       
    
    
     DETAILED DESCRIPTION 
       [0023]    Hereinafter, the present invention will be described in detail. Prior to the description, it should be understood that the terms used in the specification and appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present invention on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. 
         [0024]    &lt;Preparation of Comparative Example 1 and Examples 1-4&gt; 
         [0025]    Comparative example 1 and Examples 1-4 were prepared by simply mixing losartan carboxylic acid and other components listed in Table 1 based on the contents of Table 1, and filling capsules with the mixtures. 
         [0000]    
       
         
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                   
                 Comparative 
                 Exam- 
                 Exam- 
                 Exam- 
                 Exam- 
               
               
                 (Unit: mg) 
                 example 1 
                 ple 1 
                 ple 2 
                 ple 3 
                 ple 4 
               
               
                   
               
             
             
               
                 Losartan 
                 10.0 
                 10.0 
                 10.0 
                 10.0 
                 10.0 
               
               
                 carboxylic acid 
               
               
                 Lactose 
                 87.0 
                 77.0 
                 77.0 
                 77.0 
                 77.0 
               
               
                 Microcrystalline 
                 87.0 
                 77.0 
                 77.0 
                 77.0 
                 77.0 
               
               
                 cellulose 
               
               
                 Polyethylene 
                 — 
                 — 
                 — 
                 — 
                 10.0 
               
               
                 glycol 6000 
               
               
                 Povidone 
                 — 
                 10.0 
                 — 
                 — 
                 — 
               
               
                 HPMC 
                 — 
                 — 
                 10.0 
                 — 
                 — 
               
               
                 HPC 
                 — 
                 — 
                 — 
                 10.0 
                 — 
               
               
                 Aerosil ® 
                 — 
                 10.0 
                 — 
                 10.0 
                 10.0 
               
               
                 KOLLIDON 
                 — 
                 — 
                 10.0 
                 — 
                 — 
               
               
                 CL-SF ® 
               
               
                 Sodium 
                 14.0 
                 14.0 
                 14.0 
                 14.0 
                 14.0 
               
               
                 carboxymethyl 
               
               
                 starch 
               
               
                 Magnesium 
                  2.0 
                  2.0 
                  2.0 
                  2.0 
                  2.0 
               
               
                 stearate 
               
               
                   
               
             
          
         
       
     
         [0026]    In Table 1, HPMC is hydroxypropyl methyl cellulose, HPC is hydroxypropyl cellulose, Aerosil® is the trade name of fumed silica, and KOLLIDON CL-SF® is the trade name of super-fine crospovidone. 
         [0027]    &lt;Evaluation of Dissolution of Comparative Example 1&gt; 
         [0028]    By using the prepared Comparative example 1, dissolution experiments was made in a buffer having a pH of 1.2 (prepared by mixing 2.0 g of sodium chloride with 7.0 ml of hydrochloric acid and adding purified water until it totals 1 liter), a buffer having a pH of 4.0 (prepared by mixing 0.05 mol/L acetic acid solution with 0.05 mol/L sodium acetate solution (41:9) and adjusting a pH to 4.0), a buffer having a pH of 6.8 (prepared by mixing 250 ml of 0.2 mol/L potassium dihydrogen phosphate test solution with 118 ml of 0.2 mol/L sodium hydroxide test solution and adding water until it totals 1 liter), and purified water. In this instance, a paddle method was used, an amount of a dissolution medium was 900 ml, and a paddle rotation rate was 50 rpm. The dissolution rate (%) over time (min) is shown in Table 2 below. 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 2 
               
             
             
               
                   
                   
               
               
                   
                 Dissolution rate for dissolution medium (%) 
                   
               
             
          
           
               
                 Time (min) 
                 pH 1.2 
                 pH 4.0 
                 pH 6.8 
                 Purified water 
               
               
                   
               
             
          
           
               
                 0 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
               
               
                 5 
                 15.5 
                 19.1 
                 25.3 
                 25.1 
               
               
                 10 
                 26.6 
                 29.9 
                 39.2 
                 40.2 
               
               
                 15 
                 31.6 
                 34.9 
                 47.5 
                 48.4 
               
               
                 30 
                 39.5 
                 48.7 
                 59.7 
                 60.3 
               
               
                 45 
                 44.1 
                 60.4 
                 67.8 
                 68.1 
               
               
                 60 
                 46.9 
                 69.1 
                 71.1 
                 72.0 
               
               
                 90 
                 50.6 
                 73.5 
                 74.9 
                 77.3 
               
               
                 120 
                 52.6 
                 76.6 
                 77.6 
                 80.8 
               
               
                   
               
             
          
         
       
     
         [0029]    As shown in Table 2, it was seen that losartan carboxylic acid exhibited relatively low dissolution speed and dissolution rate in a buffer having a pH of 1.2. This means that absorption of losartan carboxylic acid in the stomach may vary with the pH change of the stomach following the consumption of food or depending on the interindividual variations in the stomach pH, and accordingly, the dissolution speed and dissolution rate of losartan carboxylic acid in a buffer having a pH of 1.2 needs to be adjusted. In subsequent experiments, a buffer having a pH of 1.2 was mainly used as a dissolution medium. 
         [0030]    It was observed that losartan carboxylic acid slightly agglomerated during the dissolution experiment of Comparative example 1. When losartan carboxylic acid contacted purified water or a buffer, losartan carboxylic acid gelled. The gelling causes a variation in dissolution and reduces the dissolution speed and the dissolution rate, and thus needs to be controlled. 
         [0031]    &lt;Evaluation of Dissolution of Examples 1-4&gt; 
         [0032]    Like Comparative example 1, the dissolution of Examples 1-4 in a buffer having a pH of 1.2 was evaluated. The results are shown in Table 3. 
         [0000]    
       
         
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 3 
               
             
             
               
                   
                   
               
               
                   
                 Dissolution rate (%) 
               
             
          
           
               
                 Time (min) 
                 Example 1 
                 Example 2 
                 Example 3 
                 Example 4 
               
               
                   
               
             
          
           
               
                 0 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
               
               
                 5 
                 25.1 
                 24.3 
                 24.8 
                 40.1 
               
               
                 10 
                 37.5 
                 39.6 
                 37.8 
                 57.3 
               
               
                 15 
                 43.4 
                 45.5 
                 43.7 
                 63.1 
               
               
                 30 
                 52.4 
                 55.6 
                 53.4 
                 70.1 
               
               
                 45 
                 57.2 
                 61.3 
                 58.4 
                 72.8 
               
               
                 60 
                 61.2 
                 65.5 
                 61.9 
                 75.6 
               
               
                 90 
                 65.9 
                 69.4 
                 67.0 
                 77.7 
               
               
                 120 
                 69.2 
                 72.7 
                 69.6 
                 78.8 
               
               
                   
               
             
          
         
       
     
         [0033]    As shown in Table 3, the dissolution speed and the dissolution rate in a buffer having a pH of 1.2 was improved to some extent by simply mixing with hydrophilic polymer, and when polyethylene glycol was used as hydrophilic polymer, the improvement effects of dissolution speed and dissolution rate marked the top. 
         [0034]    Also, agglomeration of losartan carboxylic acid in a dissolution medium was suppressed by adding fumed silica, Aerosil®, or super-fine crosprovidone, KOLLIDON CL-SF®, as an agglomeration suppressing agent, and it is expected that the suppression of agglomeration may improve the dissolution speed and the dissolution rate of losartan carboxylic acid. 
         [0035]    &lt;Preparation of Examples 5-10&gt; 
         [0036]    A solid dispersion including losartan carboxylic acid and water-soluble polymer was prepared according to the ingredients and the contents given in Table 4. 
         [0037]    The water-soluble polymer (polyethylene glycol, povidone, HPMC, and HPC) was dissolved in an amount of purified water equivalent to 1 part by weight per the total amount of the water-soluble polymer, and ethanol was added thereto in an amount equivalent to 1 part by weight per the total amount of the purified water. Next, after losartan carboxylic acid was completely dissolved in the resulting solution, lactose, microcrystalline cellulose, and Aerosil® or KOLLIDON CL-SF® were added thereto, followed by uniform mixing and drying at about 40° C. Subsequently, sodium carboxymethyl starch and magnesium stearate were added thereto, and filled into a capsule. 
         [0000]    
       
         
               
               
               
               
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 Example 
               
               
                 (Unit: mg) 
                 Example 5 
                 Example 6 
                 Example 7 
                 Example 8 
                 Example 9 
                 10 
               
               
                   
               
             
             
               
                 Losartan 
                 10.0 
                 10.0 
                 10.0 
                 10.0 
                 10.0 
                 10.0 
               
               
                 metabolome 
               
               
                 Lactose 
                 77.0 
                 77.0 
                 77.0 
                 77.0 
                 72.0 
                 72.0 
               
               
                 Microcrystalline 
                 77.0 
                 77.0 
                 77.0 
                 77.0 
                 72.0 
                 72.0 
               
               
                 cellulose 
               
               
                 Polyethylene 
                 — 
                 — 
                 — 
                 10.0 
                 10.0 
                 10.0 
               
               
                 glycol 
               
               
                 Povidone 
                 10.0 
                 — 
                 — 
                 — 
                 10.0 
                 — 
               
               
                 HPMC 
                 — 
                 10.0 
                 — 
                 — 
                 — 
                 10.0 
               
               
                 HPC 
                 — 
                 — 
                 10.0 
                 — 
                 — 
                 — 
               
               
                 Aerosil ® 
                 10.0 
                 — 
                 10.0 
                 10.0 
                 10.0 
                 — 
               
               
                 KOLLIDON 
                 — 
                 10.0 
                 — 
                 — 
                 — 
                 10.0 
               
               
                 CL-SF ® 
               
               
                 Sodium 
                 14.0 
                 14.0 
                 14.0 
                 14.0 
                 14.0 
                 14.0 
               
               
                 carboxymethyl 
               
               
                 starch 
               
               
                 Magnesium 
                  2.0 
                  2.0 
                  2.0 
                  2.0 
                  2.0 
                  2.0 
               
               
                 stearate 
               
               
                   
               
             
          
         
       
     
         [0038]    &lt;Evaluation of Dissolution of Examples 5-10&gt; 
         [0039]    Like Example 1, the dissolution of Examples 5-10 in a buffer having a pH of 1.2 was evaluated. The results are shown in Table 5. 
         [0000]    
       
         
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
                 TABLE 5 
               
             
             
               
                   
                   
               
               
                   
                 Dissolution rate (%) 
               
             
          
           
               
                 Time 
                 Exam- 
                 Exam- 
                   
                   
                   
                 Example 
               
               
                 (min) 
                 ple 5 
                 ple 6 
                 Example 7 
                 Example 8 
                 Example 9 
                 10 
               
               
                   
               
             
          
           
               
                 0 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
               
               
                 5 
                 36.1 
                 31.0 
                 22.3 
                 44.0 
                 29.4 
                 26.8 
               
               
                 10 
                 56.7 
                 43.0 
                 35.3 
                 60.2 
                 53.0 
                 48.4 
               
               
                 15 
                 63.7 
                 54.3 
                 44.4 
                 67.3 
                 70.1 
                 62.8 
               
               
                 30 
                 74.3 
                 67.9 
                 61.0 
                 77.1 
                 87.7 
                 81.3 
               
               
                 45 
                 83.0 
                 74.9 
                 74.7 
                 81.6 
                 93.8 
                 88.1 
               
               
                 60 
                 87.7 
                 83.8 
                 78.2 
                 84.7 
                 95.7 
                 91.5 
               
               
                 90 
                 90.7 
                 90.5 
                 83.1 
                 88.9 
                 99.0 
                 97.3 
               
               
                 120 
                 92.2 
                 91.8 
                 87.5 
                 92.6 
                 101.4 
                 99.8 
               
               
                   
               
             
          
         
       
     
         [0040]    As shown in Table 5, it was found that the preparation of a solid dispersion improved the dissolution rate on the whole. In particular, Example 9 showed that about 90% of losartan carboxylic acid was discharged in about 30 minutes after the start of dissolution, and thus exhibited the improved dissolution speed in comparison with the other examples. From the above dissolution results, it was estimated that polyethylene glycol improved the initial dissolution speed and the total dissolution rate, and the water-soluble polymer used with polyethylene glycol improved the dissolution rate at the end of dissolution, however the present invention is not limited in this regard. 
         [0041]    &lt;Evaluation of Dissolution for Dissolution Medium in Example 9&gt; 
         [0042]    Like Comparative example 1, the dissolution of Example 9 in different dissolution media was evaluated. The results are shown in Table 6. 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 6 
               
             
             
               
                   
                   
               
               
                   
                 Dissolution rate for dissolution medium (%) 
                   
               
             
          
           
               
                 Time (min) 
                 pH 1.2 
                 pH 4.0 
                 pH 6.8 
                 Purified water 
               
               
                   
               
             
          
           
               
                 0 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
               
               
                 5 
                 43.3 
                 69.8 
                 71.8 
                 68.2 
               
               
                 10 
                 59.9 
                 91.2 
                 98.0 
                 96.9 
               
               
                 15 
                 75.1 
                 97.4 
                 100.1 
                 98.4 
               
               
                 30 
                 88.7 
                 101.0 
                 101.3 
                 100.1 
               
               
                 45 
                 91.7 
                 99.8 
                 101.8 
                 100.8 
               
               
                 60 
                 94.7 
                 100.2 
                 102.6 
                 100.3 
               
               
                 90 
                 95.9 
                 100.6 
                 102.7 
                 100.6 
               
               
                 120 
                 98.3 
                 100.8 
                 102.5 
                 101.2 
               
               
                   
               
             
          
         
       
     
         [0043]    As shown in Table 6, it was found that Example 9 completed dissolution in all the dissolution media in a short time, and had the improved dissolution rate in comparison with Comparative example 1. It is expected that this improvement can speed up the absorption of losartan carboxylic acid after administration, leading to a more efficient drug delivery. Also, it is expected to reduce the variations in dissolution speed and dissolution rate depending on the pH, thereby considerably reducing the variations in absorption within an individual and between individuals that may occur under the influence of food and the like. 
         [0044]    &lt;Evaluation of Bio-Absorption of Example 9&gt; 
         [0045]    In the same way of Example 9, an experiment for absorption evaluation was made using a tablet containing 20 mg of losartan carboxylic acid for each tablet. The number of subjects was six, and a tablet containing losartan carboxylic acid was taken on an empty stomach together with 240 mL of water. The concentration in blood of losartan carboxylic acid was measured using LC/MS/MS. The results are shown in Table 1. 
         [0046]    As shown in Table 1, the composition containing losartan carboxylic acid according to the present invention showed good absorption. The composition of Example 9 had a mean Cmax of 374.2 ng/ml, a mean Tmax of 1.8 hr, and an AUC (last) of about 2209.4.