Abstract:
The present invention relates to stable aqueous oral formulation of bisphosphonic acid or its pharmaceutically acceptable salts. More particularly, the present invention relates to stable aqueous oral formulation of alendronate sodium. The present invention also relates to a process for the preparation of stable aqueous oral formulation of alendronate sodium.

Description:
CROSS REFERENCE TO THE RELATED APPLICATION 
       [0001]    This application claims the priority of an Indian Patent application No. 799/CHE/2007 filed on Apr. 16, 2007. 
       FIELD OF THE INVENTION 
       [0002]    The present invention relates to stable aqueous oral formulation of bisphosphonic acid or its pharmaceutically acceptable salts. More particularly, the present invention relates to stable aqueous oral formulation of alendronate sodium. 
         [0003]    The present invention also relates to a process for the preparation of stable aqueous formulation of alendronate sodium. 
       BACKGROUND OF THE INVENTION 
       [0004]    Alendronate sodium is chemically known as (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt. Alendronate as disclosed in U.S. Pat. No. 4,621,077, is a specific inhibitor of osteoclast-mediated bone resorption and is indicated for the treatment of urolithiasis and inhibiting bone reabsorption. 
         [0005]    Alendronate is commercially available as alendronate sodium trihydrate in the form of tablets and oral solution under the trade name Fosamax® (Merck). Tablets have certain disadvantage for patients who are unable to swallow tablets readily. To overcome the problem of difficulty in swallowing, alendronate in solution formulation have been developed with an increased patient compliance. Commercially available alendronate oral solution contain 91.35 mg of alendronate monosodium salt trihydrate, which is molar equivalent to 70 mg of free acid alendronate as active ingredient and excipients such as sodium citrate dihydrate and citric acid anhydrous as buffering agents, sodium propylparaben 0.0225% and sodium butylparaben 0.0075% as preservatives, sodium saccharin, artificial raspberry flavor and purified water. 
         [0006]    Given below are the patents/patent publications, which disclose aqueous oral formulations of alendronate. 
         [0007]    U.S. Pat. No. 4,814,326 discloses aqueous solution of diphosphonic acid with amino carboxylic acid as stabilizer with pH 4.5-5.65. 
         [0008]    U.S. Pat. No. 5,462,932 discloses composition comprising a pharmaceutically effective amount of alendronate, in a pharmaceutically acceptable carrier and a sufficient amount of a buffer to maintain a pH of the composition in the range of 2 to 8 and complexing agent to prevent the precipitation of alendronate sodium in aqueous solution. 
         [0009]    U.S. Pat. No. 5,994,329 discloses liquid composition comprising alendronate monosodium trihydrate, sodium propylparaben, sodium butylparaben, sodium citrate dihydrate, citric acid anhydrous, sodium saccharin, sodium hydroxide and water. 
         [0010]    US 2003/0139378 discloses an oral liquid composition comprising: a) a therapeutically effective amount of at least one bisphosphonate or a pharmaceutically acceptable salt thereof, b) a pharmaceutically acceptable carrier, and c) a pharmaceutically acceptable buffer, wherein a dose of said oral liquid pharmaceutical composition has a buffering capacity sufficient to buffer at least 50 mL of 0.1 N HCl to a pH of greater than or equal to 3.5. 
         [0011]    US 2004/087550 discloses a composition for prevention of metabolic diseases of bones comprising: at least one bisphosphonate including alendronate sodium, viscosity agents comprising carboxymethylcellulose and xanthan gum; at least one flavoring agent and purified water. 
         [0012]    WO 98/14196 discloses an aqueous liquid formulation comprising: alendronic acid; a sufficient amount of a buffer such that the pH of the formulation is between approximately 3.5 and approximately 7.5 and 15 ml of the formulation is able to raise the pH of 50 ml 0.1N HCl to a pH of at least 3 and optionally, one or more additional agents selected from the group consisting of preservatives, flavoring agents, colorants, and sweeteners. 
         [0013]    WO 08/028,547 discloses liquid composition for prevention of bone metabolic diseases, comprising alendronic acid or its acceptable pharmaceutical salts, or mixtures thereof, a viscosity agent selected from the group consisting of alginate, propylglycolalginate, arabic gum (acacia), xanthan gum, guar gum, locust bean, carrageenan gum, karaya gum, tragacanth gum, chitosan, sodium carboxymethyl cellulose and carbomer or mixtures thereof, at least one flavoring agent and purified water. 
         [0014]    The above prior art references discloses various liquid formulations of alendronate sodium using amino carboxylic acid, buffer, viscosity agents and complexing agent to stabilize alendronate in aqueous formulations. 
         [0015]    However, still there is a need to develop stable aqueous formulation comprising alendronate wherein said formulation is free of buffers and stabilizers. The inventors of the present invention surprisingly found that stable alendronate solution can be prepared by maintaining pH less than 5.0 using inorganic acid without using any buffers and stabilizers. 
       OBJECTIVE OF THE INVENTION 
       [0016]    Accordingly, the main objective of the present invention is to provide stable aqueous formulation comprising alendronate sodium. 
         [0017]    Yet another objective of the present invention is to provide stable aqueous formulation comprising alendronate sodium in such a way that it will comply with the reference product. 
         [0018]    Yet another objective of the present invention is to provide simple process for the preparation of stable aqueous formulation of alendronate sodium. 
       SUMMARY OF THE INVENTION 
       [0019]    Accordingly, the main embodiment of the present invention is to provide stable aqueous oral formulation comprising alendronate sodium and inorganic acid, wherein the said formulation has pH in the range of about 2 to 5 and is essentially free of buffers and stabilizers. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0020]    Yet in another embodiment of the present invention, the stable aqueous formulation further comprises one or more excipients selected from preservatives, sweetening agents and flavoring agents. 
         [0021]    The inorganic acid according to the present invention includes dilute hydrochloric acid, dilute sulfuric acid, dilute phosphoric acid and the like. The inorganic acid used in the formulation inhibits the microbial growth and makes the solution stable for a prolonged period of time. 
         [0022]    Suitable preservatives used according to the present invention are selected from sodium benzoate, potassium sorbate, benzyl alcohol, parabens (p-hydroxybenzoic acids esters) such as methylparaben, ethylparaben, propylparaben, butylparaben and the like or mixtures thereof. The amount of preservatives used may be in the range of about 0.02 to about 2% by weight of the composition. 
         [0023]    Suitable sweetening agents include saccharin sodium, sodium cyclamate, sorbitol, xylitol, sucrose, glycerol, aspartame and the like. The amount of sweetening agent used may be in the range of about 0.1 to about 2% by weight of the composition. 
         [0024]    Suitable flavoring agents include peppermint flavor, spearmint flavor, lime flavor, apple flavor, pear flavor, peach flavor, raspberry flavor, plum flavor, pineapple flavor and the like. The amount of flavorants used may be in the range of about 0.05 to about 5% by weight of the composition. 
         [0025]    In another embodiment, the amount of alendronate sodium used according to the present invention is in the range of about 1% to about 30% by weight of the composition. 
         [0026]    In a preferred embodiment, the stable aqueous oral formulation comprises about 1% to about 30% by weight of alendronate sodium, an inorganic acid such as dilute hydrochloric acid, dilute sulfuric acid and dilute phosphoric acid; about 0.02 to about 2% by weight of preservatives such as methylparaben, ethylparaben, propylparaben and butylparaben; about 0.1 to about 2% by weight of sweetening agents such as saccharin sodium, sodium cyclamate, sorbitol, xylitol; about 0.05 to about 5% by weight of flavoring agents such as peppermint flavor, spearmint flavor and artificial raspberry flavor, wherein the said formulation has pH in the range of about 2 to 5 and is essentially free of buffers and stabilizers. 
         [0027]    In a preferred embodiment, the stable aqueous oral formulation comprises 
         [0000]    alendronate sodium—50 to 100 mg
 
inorganic acid—0.0001 to 0.001 mg
 
preservatives—30 to 80 mg
 
sweetening agents—20 to 200 mg
 
flavoring agents—20 to 100 mg
 
purified water—QS to 75 ml,
 
wherein the said formulation has pH in the range of about 2 to 5 and is essentially free of buffers and stabilizers.
 
         [0028]    In another embodiment of the present invention, there is provided a process for the preparation of stable aqueous formulation comprising alendronate sodium and inorganic acid, wherein the said formulation has pH in the range of about 2 to 5 and is essentially free of buffers and stabilizers, comprises the steps of: 
         [0000]    i) dissolving the preservatives in water,
 
ii) adding sweetening agent to the solution of step (i),
 
iii) adding alendronate sodium to the solution of step (ii) and stirring it to get clear solution,
 
iv) adding inorganic acid to the solution of step (iii),
 
v) adjusting the pH of solution using 0.85% v/v hydrochloric acid,
 
vi) adding flavoring agent to the solution of step (v) and
 
vii) finally making up the volume with water to obtain a clear solution.
 
         [0029]    The stable aqueous formulation of alendronate sodium of the present invention are useful in the therapeutic or prophylactic treatment of disorders in calcium and phosphate metabolism and associated diseases such as osteoporosis which includes post-menopausal osteoporosis, steroid-induced osteoporosis, male osteoporosis, disease-induced osteoporosis, idiopathic osteoporosis, Paget&#39;s disorder, abnormally increased bone turnover, periodontal disease, localized bone loss associated with periprosthetic osteolysis and bone fractures. 
         [0030]    The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry. 
       EXAMPLE 1 
       [0031]      
         [0000]                                                          Ingredients   Mg/75 ml                                        Alendronate sodium   91.363           Saccharin sodium   75.000           Propylparaben sodium   16.875           Butylparaben sodium   5.625           Artificial raspberry flavor   50.000           Hydrochloric acid   0.000765           Hydrochloric acid   QS for pH adjustment           Purified water   QS to 75.000 ml                        
The processing steps involved in manufacturing a stable aqueous solution given in example 1 are given below:
 
1. propylparaben sodium and butylparaben sodium were dissolved in water under continuous stirring,
 
2. to the solution of step (1) saccharin sodium was added and stirred to obtain clear solution,
 
3. to the solution of step (2) alendronate sodium was added and again stirred to obtain clear solution,
 
4. hydrochloric acid was added to the solution of step (3),
 
5. pH of the solution was adjusted using 0.85% v/v hydrochloric acid,
 
6. artificial raspberry flavor was added to the solution obtained in step (5) and
 
7. finally the volume was adjusted with water.
 
The formulations given in examples 2 and 3 were prepared using similar procedure described in example 1.
 
       EXAMPLE 2 
       [0032]      
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 Ingredients 
                 Mg/75 ml 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Alendronate sodium 
                 91.363 
               
               
                   
                 Saccharin sodium 
                 75.000 
               
               
                   
                 Propylparaben sodium 
                 16.875 
               
               
                   
                 Artificial raspberry flavor 
                 50.000 
               
               
                   
                 Hydrochloric acid 
                 0.000765 
               
               
                   
                 Hydrochloric acid 
                 QS for pH adjustment 
               
               
                   
                 Purified water 
                 QS to 75.000 ml 
               
               
                   
                   
               
             
          
         
       
     
       EXAMPLE 3 
       [0033]      
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 Ingredients 
                 Mg/75 ml 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Alendronate sodium 
                 91.363 
               
               
                   
                 Saccharin sodium 
                 75.000 
               
               
                   
                 Propylparaben sodium 
                 16.875 
               
               
                   
                 Methylparaben sodium 
                 33.750 
               
               
                   
                 Artificial raspberry flavor 
                 50.000 
               
               
                   
                 Hydrochloric acid 
                 0.000765 
               
               
                   
                 Hydrochloric acid 
                 QS for pH adjustment 
               
               
                   
                 Purified water 
                 QS to 75.000 ml 
               
               
                   
                   
               
             
          
         
       
     
       Stability Data 
       [0034]    Aqueous alendronate sodium solutions prepared according the present invention were found to be stable. The amount of alendronate sodium was analyzed for 1 month at 40° C. and 75% relative humidity. The stability data is given in table 1. 
         [0000]    
       
         
               
               
               
             
               
               
               
             
               
               
               
             
           
               
                   
                 TABLE 1 
               
             
             
               
                   
                   
               
               
                   
                 % of Alendronate sodium 
                   
               
             
          
           
               
                 Example No. 
                 Initial 
                 1M 
               
               
                   
               
             
          
           
               
                 1 
                 101.6 
                 101 
               
               
                 2 
                 102.1 
                 103.1 
               
               
                 3 
                 99.3 
                 99.9