Abstract:
An oral formulation comprising a biguanide and an organic acid has less unpleasant tastes such as bitterness and saltiness.

Description:
This application is the national phase under 35 U.S.C. §371 of PCT International Application No. PCT/JP99/02192 which has an International filing date of Apr. 26, 1999, which designated the United States of America. 
    
    
     TECHNICAL FIELD 
     The present invention relates to an oral fomulation comprising a biguanide and an organic acid. 
     BACKGROUND OF THE INVENTION 
     Biguanides such as metformin have unpleasant tastes such as bitterness and saltiness. The dosages of metformin are about 250 mg per dose in Japan and about 850 mg per dose in United States of America. In spite of such big dosages, only tablets are on sale at present. 
     There are several known methods for masking bitterness of bitter drugs, for instance, for solid formulations, sugar coated tablets, film coated tablets, capsules and the like are useful. Powders, fine granules and granules are formulated with sweetening agents or flavors; microcapsules, non-enteric coated formulation, spray-dried formulation with low melting point wax, formulation with lecithin (JP 62-265234-A) and the like may also be used. For solutions, there are formulations with water-insoluble high molecular weight compound such as ethylcellulose and hydroxypropylmethylcellulose phthalate (JP 52-41214-A); formulations with acidic phospholipids or lyso-phospholipids (JP 7-67552-A); and formulations with a large amount of citric acid (JP 4-58452-B). 
     DISCLOSURE OF THE INVENTION 
     The inventors of the present invention have intensively carried out research, and found that an oral formulation comprising a biguanide and an organic acid has less unpleasant tastes such as bitterness and saltiness. Thus, the present invention has been accomplished. 
     The present inventions includes: 
     [1] An oral formulation comprising a biguanide and an organic acid. 
     [2] An oral formulation comprising a biguanide, an organic acid and a sweetening agent. 
     [3] An oral formulation according to [1] or [2] wherein the biguanide is metformin or a pharmaceutical salt thereof. 
     [4] An oral formulation according to any one of [1] to [3] wherein the organic acid is malic acid, citric acid, tartaric acid or mixture thereof. 
     [5] An oral formulation according to any one of [1] to [4] wherein the sweetening agent is aspartame™, saccharine, saccharine sodium, stevioside or mixture thereof. 
     [6] An oral formulation according to any one of [1] to [5] wherein the ratio (w/w) of the biguanide to the organic acid is 1:0.1 to 1:50. 
     [7] An oral formulation according to any one of [2] to [6] wherein the ratio (w/w) of the biguanide to the sweetening agent is 1:0.001 to 1:10 
     [8] An oral formulation according to any one of [1] to [7] wherein the formulation is solution, jelly, gum drops, dry syrup, powders, fine granules or granules. 
     [9] An oral formulation according to any one of [1] to [8] wherein the pH of the solution is 3.5 to 6 in case that the formulation is solution, and the pH of the solution which is formed by dissolving or dispersing the formulation to 10 times more (w/w) volume of water, is 3.5 to 6 in case that the formulation is not solution. 
     DETAILED DESCRIPTION OF THE INVENTION 
     “Biguanide” includes compounds having a biguanide structure such as metformin, buformin, phenformin and pharmaceutically acceptable salts thereof. 
     “Organic acid” includes malic acid, citric acid, tartaric acid, ascorbic acid, succinic acid, fumaric acid, maleic acid, gluconic acid, glucuronic acid and mixtures thereof. Preferable organic acids are organic acids having 2 or 3 carboxyl groups such as malic acid, citric acid and tartaric acid, more preferably malic acid. The ratio (w/w) of the biguanide to the organic acid is, for example, 1:0.01 to 1:50, preferably 1:0.02 to 1:10, more preferably 1:0.05 to 1:1. In the case of malic acid, the preferable ratio (w/w) of the biguanide to malic acid is 1:0.05 to 1:0.5. 
     “Sweetening agent” includes aspartame™, saccharin, saccharin sodium, stevioside, thaumatin, erythritol, sorbitol, xylitol, glycerin and mixtures thereof. Preferable sweetening agents are aspartame™, saccharin, saccharin sodium and stevioside. The ratio (w/w) of the biguanide to the sweetening agent is, for example, 1:0.001 to 1:10, preferably 1:0.02 to 1:1. 
     When the formulation is a solution, preferably the pH of the solution is 3.5 to 6, more preferably 4 to 6, to decrease the unpleasant tastes and to keep the biguanide stable. If the formulation is not a solution, the preferable pH of the solution or dispersion which is formed by dispersing the formulation in water (1 part of the formulation to 10 parts of water, by weight), is 3.5 to 6, more preferably 4 to 6; This is in order to decrease the unpleasant tastes and to keep the biguanide stable. 
     “Oral formulation” includes solution, jelly, gum drops, dry syrup, powders, fine granules and granules. Preferably the formulation is not in the form of tablets. 
     The formulation of the present invention may include at pharmaceutically acceptable non-toxic and inactive additives. Additives include excipients such as corn starch, potato starch, white sugar, mannitol, xylitol, sorbitol, talc, kaolin, calcium monohydrogen phosphate, calcium sulfate, calcium carbonate, crystalline cellulose; lubricants such as magnesium stearate and potassium stearate; disintegrators such as carboxymethylcellulose calcium and low substituted hydroxymethylcellulose; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinypyrrolidone, gelatin, methylcellulose, Arabia gum and polyvinylalcohol; coloring agents; correctives; adsorbents; preservatives; stabilizers; moistening agents; de-charging agents; pH adjusters; and the like. 
     The formulation may include flavors such as lemon, orange, grapefruit, pine, banana, chocolate and yogurt to decrease the unpleasant tastes more. 
     The formulation of the present invention can be prepared by well known methods. In the case of solid formulations, the formulation can be prepared, for example, by extruding granulation methods, crushing granulation methods, dry granulation methods, fluidized bed granulation methods, tumbling granulation methods, high shear mixing granulation methods, wet compression methods, direct compression methods and the like. 
     The formulation of the present invention will contain the conventional amounts of active ingredient (biguanide) and will be used in conventional manner to administer doses in accordance with normal practice by routes and according to dosage regimes which are familiar to pharmacologists and medical practitioners. 
    
    
     The present invention will be described in detail below, referring to Examples and Experiments, which are not limitative of the present invention. 
     EXAMPLE 1 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Solution of metformin hydrochloride 
               
             
          
           
               
                   
                 Ingredient 
                 weight % 
               
               
                   
                   
               
               
                   
                 Metformin hydrochloride 
                   5% 
               
               
                   
                 Malic acid 
                  0.8% 
               
               
                   
                 Aspartame ™ 
                  0.3% 
               
               
                   
                 Lemon flavor 
                  0.1% 
               
               
                   
                 Purified water 
                 93.8% 
               
               
                   
                   
               
             
          
         
       
     
     5% Solution of metformin hydrochloride is prepared by dissolving metformin hydrochloride, malic acid, aspartame™ and lemon flavor into purified water. 
     EXAMPLE 2 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Solution of metformin hydrochloride 
               
             
          
           
               
                   
                 Ingredient 
                 weight % 
               
               
                   
                   
               
               
                   
                 Metformin hydrochloride 
                   5% 
               
               
                   
                 Malic acid 
                  0.8% 
               
               
                   
                 Saccharin sodium 
                   1% 
               
               
                   
                 Lemon flavor 
                  0.1% 
               
               
                   
                 Purified water 
                 93.1% 
               
               
                   
                   
               
             
          
         
       
     
     5% Solution of metformin hydrochloride is prepared by dissolving metformin hydrochloride, malic acid, saccharine sodium and lemon flavor into purified water. 
     EXAMPLE 3 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Solution of metformin hydrochloride 
               
             
          
           
               
                   
                 Ingredient 
                 weight % 
               
               
                   
                   
               
               
                   
                 Metformin hydrochloride 
                   5% 
               
               
                   
                 Citric acid 
                   2% 
               
               
                   
                 Aspartame ™ 
                  0.3% 
               
               
                   
                 Lemon flavor 
                  0.1% 
               
               
                   
                 Purified water 
                 92.6% 
               
               
                   
                   
               
             
          
         
       
     
     5% Solution of metformin hydrochloride is prepared by dissolving metformin hydrochloride, citric acid, aspartame™ and lemon flavor into purified water. 
     EXAMPLE 4 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Solution of metformin hydrochloride 
               
             
          
           
               
                   
                 Ingredient 
                 weight % 
               
               
                   
                   
               
               
                   
                 Metformin hydrochloride 
                    5% 
               
               
                   
                 Malic acid 
                  1.5% 
               
               
                   
                 Saccharin sodium 
                  0.25% 
               
               
                   
                 Erythritol 
                   10% 
               
               
                   
                 Lemon flavor 
                  0.1% 
               
               
                   
                 Purified water 
                 83.15% 
               
               
                   
                   
               
             
          
         
       
     
     5% Solution of metformin hydrochloride is prepared by dissolving metformin hydrochloride, malic acid, saccharin sodium, erythritol land lemon flavor into purified water. 
     EXAMPLE 5 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Solution of metformin hydrochloride 
               
             
          
           
               
                   
                 Ingredient 
                 weight % 
               
               
                   
                   
               
               
                   
                 Metformin hydrochloride 
                   5% 
               
               
                   
                 Malic acid 
                  1.5% 
               
               
                   
                 Aspartame ™ 
                  0.2% 
               
               
                   
                 Sorbitol 
                   6% 
               
               
                   
                 Grapefruit flavor 
                  0.1% 
               
               
                   
                 Purified water 
                 87.2% 
               
               
                   
                   
               
             
          
         
       
     
     5% Solution of metformin hydrochloride is prepared by dissolving metformin hydrochloride, malic acid, aspartame™, sorbitol and grapefruit flavor into purified water. 
     EXAMPLE 6 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Solution of metformin hydrochloride 
               
             
          
           
               
                   
                 Ingredient 
                 weight % 
               
               
                   
                   
               
               
                   
                 Metformin hydrochloride 
                    5% 
               
               
                   
                 Malic acid 
                  1.5% 
               
               
                   
                 Saccharin 
                  0.03% 
               
               
                   
                 Glycerin 
                   10% 
               
               
                   
                 Lemon flavor 
                  0.1% 
               
               
                   
                 Purified water 
                 83.37% 
               
               
                   
                   
               
             
          
         
       
     
     5% Solution of metformin hydrochloride is prepared by dissolving metformin hydrochloride, malic acid, saccharin, glycerin and lemon flavor into purified water. 
     EXAMPLE 7 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Solution of metformin hydrochloride 
               
             
          
           
               
                   
                 Ingredient 
                 weight % 
               
               
                   
                   
               
               
                   
                 Metformin hydrochloride 
                    5% 
               
               
                   
                 Malic acid 
                  1.5% 
               
               
                   
                 Saccharin sodium 
                  0.25% 
               
               
                   
                 Saccharin 
                  0.03% 
               
               
                   
                 Lemon flavor 
                  0.1% 
               
               
                   
                 Purified water 
                 93.12% 
               
               
                   
                   
               
             
          
         
       
     
     5% Solution of metformin hydrochloride is prepared by dissolving metformin hydrochloride, malic acid, saccharin sodium, saccharin and lemon flavor into purified water. 
     EXAMPLE 8 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Dry syrup of metformin hydrochloride 
               
             
          
           
               
                   
                 Ingredient 
                 Amount 
               
               
                   
                   
               
               
                   
                 Metformin hydrochloride 
                  500 g 
               
               
                   
                 Malic acid 
                  80 g 
               
               
                   
                 Saccharin sodium 
                  25 g 
               
               
                   
                 Erythritol 
                  865 g 
               
               
                   
                 Polyvinylpyrrolidone K30 
                  30 g 
               
               
                   
                 Total 
                 1500 g 
               
               
                   
                   
               
             
          
         
       
     
     Metformin hydrochloride, malic acid, saccharin sodium, erythritol and polyvinylpyrrolidone K30 are mixed with 200 g of mixture of purified water and ethanol (1:1 (w/w)) to give wet solid. 33% Dry syrup of metformin hydrochloride is prepared by milling the wet solid with a granulation mill to adjust the size of the granules, followed by drying. 
     EXAMPLE 9 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Jelly of metformin hydrochloride 
               
             
          
           
               
                   
                 Ingredient 
                 weight % 
               
               
                   
                   
               
               
                   
                 Metformin hydrochloride 
                   5% 
               
               
                   
                 Gelatin 
                  0.5% 
               
               
                   
                 Malic acid 
                  0.8% 
               
               
                   
                 Aspartame ™ 
                  0.3% 
               
               
                   
                 Lemon flavor 
                  0.1% 
               
               
                   
                 Purified water 
                 93.3% 
               
               
                   
                   
               
             
          
         
       
     
     Jelly of metformin hydrochloride is prepared by dissolving or dispersing metformin hydrochloride, malic acid, aspartame™ and lemon flavor into gelatin solution which is made by dissolving gelatin to purified water over 80° C., followed by cooling. 
     EXAMPLE 10 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Fine granules of buformin hydrochloride 
               
             
          
           
               
                   
                 Ingredient 
                 Amount 
               
               
                   
                   
               
               
                   
                 Buformin hydrochloride 
                  100 g 
               
               
                   
                 Mannitol 
                  300 g 
               
               
                   
                 Lactose 
                  300 g 
               
               
                   
                 Corn starch 
                  150 g 
               
               
                   
                 Malic acid 
                  90 g 
               
               
                   
                 Aspartame ™ 
                  30 g 
               
               
                   
                 Methyl cellulose 
                  30 g 
               
               
                   
                 Total 
                 1000 g 
               
               
                   
                   
               
             
          
         
       
     
     Buformin hydrochloride, mannitol, lactose, corn starch, malic acid, aspartame™ and methylcellulose are mixed with 200 g of purified water to give wet solid. 10% Fine granules of buformin hydrochloride are prepared by granulating the wet solid with a basket granulation mill, followed by drying. 
     EXAMPLE 11 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Gum drops of buformin hydrochloride 
               
             
          
           
               
                   
                 Ingredient 
                 Amount 
               
               
                   
                   
               
               
                   
                 Buformin hydrochloride 
                  100 mg 
               
               
                   
                 Gelatin 
                  600 mg 
               
               
                   
                 Citic acid 
                  100 mg 
               
               
                   
                 Saccharin sodium 
                  25 mg 
               
               
                   
                 Sorbitol 
                 1550 mg 
               
               
                   
                 Lemon flavor 
                  25 mg 
               
               
                   
                 Purified water 
                  600 mg 
               
               
                   
                 Total 
                 3000 mg 
               
               
                   
                   
               
             
          
         
       
     
     Gum drops of buformin hydrochloride are prepared by dissolving or dispersing buformin hydrochloride, citric acid, saccharin sodium, sorbitol and lemon flavor into gelatin solution which is made by dissolving gelatin to purified water over 80° C., followed by molding the mixture and cooling. 
     EXAMPLE 12 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Powders of buformin hydrochloride 
               
             
          
           
               
                   
                 Ingredient 
                 Amount 
               
               
                   
                   
               
               
                   
                 Buformin hydrochloride 
                  100 mg 
               
               
                   
                 Mannitol 
                  560 mg 
               
               
                   
                 Corn starch 
                  200 mg 
               
               
                   
                 Citric acid 
                  100 mg 
               
               
                   
                 Aspartame ™ 
                  30 mg 
               
               
                   
                 Magnesium stearate 
                  10 mg 
               
               
                   
                 Total 
                 1000 mg 
               
               
                   
                   
               
             
          
         
       
     
     10% powders of buformin hydrochloride are prepared by mixing buformin hydrochloride, mannitol, corn starch, citric acid, aspartame™ and magnesium stearate. 
     EXAMPLE 13 
     Solutions of Metformin Hydrochloride at Various pH 
     Using the same amount of each ingredient of Example 1, 5% solutions of metformin hydrochloridc at various pH are prepared by dissolving or dispersing metformin hydrochloride, malic acid, aspartame™ and lemon flavor into about 80% of purified water, followed by adjusting pH of the solution to pH 2, 3, 3.5, 4, 5 or 6 using dilute hydrochloric acid or dilute sodium hydroxide solution and adding more purified water. 
     REFERENCE EXAMPLE 1 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Solution of metformin hydrochloride 
               
             
          
           
               
                   
                 Ingredient 
                 weight % 
               
               
                   
                   
               
               
                   
                 Metformin hydrochloride 
                  5% 
               
               
                   
                 Purified water 
                 95% 
               
               
                   
                   
               
             
          
         
       
     
     5% Solution of metformin hydrochloride is prepared by dissolving metformin hydrochloride into purified water. 
     Experiment 1 
     Tasting Experiment 
     Tasting experiments on the solutions of Examples 1 to 3 and Reference example 1 were carried out with 20 panelists. The numbers of panelists who felt the solution “not bitter”, “a little bitter” and “very bitter” are shown in Table 1. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Solution 
                 “not bitter” 
                 “a little bitter” 
                 “very bitter” 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Example 1 
                 11 
                 8 
                 1 
               
               
                 Example 2 
                 10 
                 9 
                 1 
               
               
                 Example 3 
                 11 
                 8 
                 1 
               
               
                 Reference example 1 
                 0 
                 2 
                 18 
               
               
                   
               
             
          
         
       
     
     Tasting experiments on the solutions of Examples 4 to 7 were also carried out, with satisfactory results. 
     Experiment 2 
     Tasting and Stability Experiments 
     Tasting and stability experiments on the solutions at various pH of Example 13 were carried out, in the same manner as Experiment 1. A stability experiment was carried out by measuring the remaining amount of metformin in the solutions with HPLC after heating the solutions in vials at 60 C. for 2 weeks. The results are shown in Table 2. 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 pH 
                 taste 
                 remaining amount (%) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 2 
                 very sour 
                 78 
               
               
                 3 
                 sour 
                 86 
               
               
                 3.5 
                 good 
                 94 
               
               
                 4 
                 good 
                 96 
               
               
                 5 
                 good 
                 98 
               
               
                 6 
                 good 
                 100 
               
               
                 7 
                 very bitter 
                 98 
               
               
                   
               
             
          
         
       
     
     Metformin hydrochloride is not stable below pH 3.5, and the solution tastes sour. The solution over pH 7 has bitterness. 
     Normally we feel bitterness most in solution formulation. Therefore these experiments on the solutions indicate that other formulations such as jelly, gum drops, dry syrup, powders, fine granules and granules have less unpleasant tastes as well. 
     The present invention provides an oral formulation of biguanide with less unpleasant tastes. With this invention, people in every age group, for example, elderly people and little children can easily have sufficient amount of biguanide.