Abstract:
A pharmaceutical formulation suitable for multi-dose administration comprising endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methyl-1H-indazole-3-carboxanide hydrochloride, a preservative selected from the group consisting of alkyl paraben and phenol, and a buffer selected from the group consisting of acetate and phosphate buffers is disclosed.

Description:
[0001]     This invention relates to improved formulations of endo-N-9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride. The formulations of this invention are useful as anti-emetics, particularly in the treatment of cytotoxic agent-induced ernesis.  
       BACKGROUND OF THE INVENTION  
       [0002]     Endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methyl-1H-indazole-3-carboxanide hydrochloride, its use as an anti-emetic, particularly in the treatment of cytotoxic agent induced emesis, and methods for its synthesis are disclosed in U.S. Pat. No. 4,886,808. Endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride is commercially available and is also known by the generic name granisetron hydrochloride.  
         [0003]     An injectable dosage form of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methyl-1-indazole-3-carboxamide hydrochloride was first commercialized as a 1 mL single use vial containing an aqueous solution comprising 1.12 mg of granisetron hydrochloride equivalent to granisetron 1 mg. The recommended dosage for granisetron hydrochloride is 10 mcg/kg infused intravenously over 5 minutes, beginning within 30 minutes before initiation of chemotherapy.  
         [0004]     The 1 mg/mL single dose vial has proved undesirable in a number of ways. The recommended dose is 10 mcg/kg of body weight. Thus, the 1 mL vial is not optimal for patients weighing greater than 100 kg, and a portion of a second vial will have to be utilized and the remaining medication discarded. Similarly, product wastage will occur when administering to lighter patients who do not require the full 1 mL dose. Numerous advantages are realized from a suitable multidose vial of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride. The advantages of a multidose vial of endo-N-9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride include: making weight-based dosing more efficient thereby minimizing wasted product, conserving resources, containing costs, making better use of storage space and more cost-effective to produce and transport.  
         [0005]     U.S. Pat. No. 6,294,548 discloses a multi-dose aqueous formulation of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methyl-1H-indazole-3-carboxanide hydrochloride and a host of possible preservatives, including meta-cresol, benzyl alcohol, methylparaben, propylparaben and a combination of methylparaben and propylparaben. According to the patent, the parabens are effective as preservatives, but unstable in autoclaving. Autoclaving is preferred by most regulatory agencies for ensuring sterility of pharmaceutical formulations.  
         [0006]     It has now been found that certain combinations of preservatives and buffer systems yield formulations that are suitably stable during autoclaving. More particularly, it has been found that a pharmaceutical formulation comprising endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methyl-1H-indazole-3-carboxanide hydrochloride, one or more preservatives selected from the group consisting of alkyl paraben and phenol, and a buffer selected from the group consisting of acetate and phosphate buffers can be autoclaved to yield a sterile multidose formulation. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0007]     The parabens of the present invention are preferably C 1-4 alkyl parabens and salts thereof, which may be used alone or in combination with each other. Particularly preferred is methylparaben, in an amount of about 0.45 to 2.5 mg/mL and propylparaben, in an amount of about 0.05 to 0.45 mg/mL. The most preferred paraben preservative system is the combination of methylparaben and propylparaben, wherein the methylparaben is present in an amount of about 1.8 mg/mL and the propylparaben is present in an amount of about 0.2 mg/mL.  
         [0008]     Where the preservative is phenol, it may be present in the formulation in an amount of 0.5 to 10 mg/mL, preferably about 5 mg/mL.  
         [0009]     The buffer used in the pharmaceutical formulation of the present invention is an acetate or phosphate buffer. Preferred is an acetate buffer, which can be prepared from acetic acid and an acetate such as sodium, ammonium or potassium acetate. The amount of buffer employed in the formulation will be dictated by desired pH, with typical pHs ranging from 3.0 to 8.0, preferably 3.0 to 6.0.  
         [0010]     The pharmaceutical formulation of the present invention can be sterilized by techniques known in the art, such as aseptic filtration (aseptic fill) or terminal heat sterilization (autoclaving). Terminal beat sterilization, such as by steam or cascading heated water, is, as previously noted, preferred to aseptic fill by most regulatory agencies. Sterilization can be measured by F o , Sterilization Process Equivalent Time, which represents the equivalent number of minutes at 121.1° C. delivered to a container in a sterilization process. According to the present invention, sterilization is preferably carried out by autoclaving at a temperature from 115 to 125° C. for a period of 15 to 30 minutes, preferably at 121° C. ±1° C. for a period of 19-24 minutes.  
         [0011]     Buffer Selection Study  
                                               TABLE 1                           Phosphate Buffer Formula                Concentration   Formulation       Ingredient   (mg/mL)   Attribute                    Granisetron HCl   1.12   mg/mL*   Active agent       Sodium Chloride, USP   9       Tonicity agent       Sodium Phosphate Monobasic,   2.74       Buffering agent       Monohydrate, USP       Sodium Phosphate Dibasic,   0.02       Buffering agent       Anhydrous, USP       Purified Water, qs Ad   qs to 1   mL   Vehicle                 *equivalent to 1 mg of Granisetron base             
 
         [0012]    
       
         
               
             
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                   
               
               
                 Acetate Buffer Formula 
               
             
          
           
               
                   
                 Concentration 
                 Formulation 
               
               
                 Ingredient 
                 (mg/mL) 
                 Attribute 
               
               
                   
               
             
          
           
               
                 Granisetron HCl 
                 1.12 
                 mg/mL* 
                 Active agent 
               
               
                 Sodium Chloride, USP 
                 9 
                   
                 Tonicity agent 
               
               
                 Glacial Acetic Acid, USP 
                 0.60 
                   
                 Buffering agent 
               
               
                 Sodium Acetate, Anhydrous, USP 
                 0.82 
                   
                 Buffering agent 
               
               
                 Purified Water, qs Ad 
                 qs to 1 
                 mL 
                 Vehicle 
               
               
                   
               
               
                   *equivalent to 1 mg of Granisetron base    
               
             
          
         
       
     
         [0013]     Procedure  
         [0014]     In a suitable compounding vessel, add Purified Water equal to approximately 80% of batch size at room temperature. Then weigh and add Sodium Chloride, USP into the compounding vessel and mix until all is dissolved. Verify complete dissolution by visual inspection. Weigh and add he entire quantity of buffering agents as provided in Tables 1-2 for each formulation and mix until all is dissolved. Verify complete dissolution by visual inspection. Weigh and add the entire quantity of Granisetron HCl to the compounding vessel and mix until Granisetron HCl is dissolved. Measure pH. Qs the solution to final weight with purified water. Mix the bulk for not less than 5 minutes. Filter the solution through a sterilized 0.22 μm membrane filter. Fill the filtered solution into glass vials at 4 mL fill/vial and seal the is vials with rubber stopper. Terminally sterilize the filled vials using a water cascade autoclave to a target F o  of 30.  
         [0015]     Results  
         [0016]     The data reveals that all test results are satisfactory. A comparison of the assay and related compound results between the un-autoclaved and autoclaved samples from both the acetate and phosphate buffer formulae does not indicate any instability in either formulation.  
         [0017]     Preservative Selection Study  
                                               TABLE 3                           Parabens Formula                Concentration   Formulation       Ingredient   (mg/mL)   Attribute                    Granisetron HCl   1.12   mg/mL*   Active agent       Sodium Chloride, USP   9       Tonicity agent       Glacial Acetic Acid,   0.21       Buffering agent       USP       Sodium Acetate, Anhydrous,   0.85       Buffering agent       USP       Methylparaben, NF   1.8       Preservative agent       Propylparaben, NF   0.2       Preservative agent       Purified Water, qs Ad   qs to 1   mL   Vehicle                 *equivalent to 1 mg of Granisetron base             
 
         [0018]    
       
         
               
             
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                   
               
               
                 Phenol Formula 
               
             
          
           
               
                   
                 Concentration 
                 Formulation 
               
               
                 Ingredient 
                 (mg/mL) 
                 Attribute 
               
               
                   
               
             
          
           
               
                 Granisetron HCl 
                 1.12 
                 mg/mL* 
                 Active 
               
               
                 Sodium Chloride, USP 
                 9 
                   
                 Tonicity Agent 
               
               
                 Glacial Acetic Acid, USP 
                 0.52 
                   
                 Buffering agent 
               
               
                 Sodium Acetate, Anhydrous, 
                 0.82 
                   
                 Buffering agent 
               
               
                 USP 
               
               
                 Phenol, USP 
                 5.0 
                   
                 Preservative agent 
               
               
                 Purified Water, qs Ad 
                 qs to 1 
                 mL 
                 Vehicle 
               
               
                   
               
               
                   *equivalent to 1 mg of Granisetron base    
               
             
          
         
       
     
         [0019]     Procedure  
         [0020]     Compound a batch of Granisetron Hydrochloride Injection, 1.12 mg/mL, 4 mL fill/vial using the acetate buffer system. Add the selected preservative as s listed above. Qs to final volume with purified water. Filter the solution using a 0.22 μm membrane filter. Fill the solution into glass vials and stopper using rubber stoppers (overlay vials containing phenol with nitrogen). Autoclave the filled vials at 121° C. to a F o  of 15.  
         [0021]     Results  
         [0022]     The stability data reported below reveals that all test results are satisfactory. The stability evaluation is performed at accelerated stability conditions 40° C.±2° C./75%±5% RH for up to 3 months.  
         [0023]     Granisetron assay data indicates no significant stability trends over a 3-month period at 40° C. No significant increase in degration products is observed. Methylparaben and propylparaben and phenol assays remain stable throughout the study. Antimicrobial preservative effectiveness testing is performed at the initial time point and all test results meet the USP &lt;51&gt; specification for an injectable product.  
                                           TABLE 5                           Stability of Granisetron/Parabens Formulation                Autoclaved                        40° C./75% RH       Test   Unautoclaved   Initial   3 Months               Granisetron HCl   99.6   100.4    101.3        Degradation Product   Total: &lt;0.05   Total: 0.05   Total = 0.05%       Methyl Paraben   99.5   99.5   99.0       Propyl parabens   98.9   98.8   98.1                 Formulation: Each mL contains Granisetron HCl 1.12 mg/mL, Sodium Chloride, USP 9 mg/mL, Glacial Acetic Acid, USP 0.52 mg/mL, Sodium Acetate Anhydrous, USP 0.82 mg/mL, Methylparaben, NF 1.8 mg/mL, Propylparaben, NF 0.2 mg/mL and Water for Injection qs to 1 mL.             
 
         [0024]    
       
         
               
             
               
               
             
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                   
               
               
                 Stability of Granisetron/Phenol Formulation 
               
             
          
           
               
                   
                 Autoclaved 
               
             
          
           
               
                   
                   
                   
                 40° C./75% RH 
               
               
                 Test 
                 Unautoclaved 
                 Initial 
                 3 Months 
               
               
                   
               
               
                 Granisetron HCl 
                 100.3 
                 100.3 
                 101.4 
               
               
                 Degradation Product 
                 Total: &lt;0.05 
                 Total: 0.05 
                 Total = 0.36% 
               
               
                 Phenol 
                  99.3 
                 100.5 
                 102.4 
               
               
                   
               
               
                   Formulation: Each mL contains Granisetron HCl 1.12 mg/mL, Sodium Chloride, USP 9 mg/mL, Glacial Acetic Acid, USP 0.62 mg/mL, Sodium Acetate Anhydrous, USP 0.82 mg/mL, Phenol, USP 0.5 mg/mL and Water for injection qs to 1 mL