Abstract:
A formulation and a method for manufacturing pergolide mesylate is disclosed whereby substantially stable pergolide mesylate can be manufactured without having to introduce stabilizing additives.

Description:
The instant application claims priority to the U.S. Provisional Application No. 60/223,774, filed Aug. 8, 2000 by the same inventors. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to the field of pharmaceuticals and, more particularly, to a formulation and a process of manufacturing stable pergolide mesylate. 
     BACKGROUND OF THE INVENTION 
     Pergolide Mesylate is an ergot derivative dopamine receptor agonist at both D 1  and D 2  receptor sites. Pergolide mesylate is chemically designated as 8(beta)-[(Methylthio)methyl]-6-propylergoline monomethanesulfonate, and has the following structural formula:                           
     The formula weight of the base is 314.5; 1 mg of base corresponds to 3.18 μmol. 
     Pergolide Mesylate is sold under the trade name PERMAX® and is provided for oral administration in tablets containing 0.05 mg (0.159 μmol), 0.25 mg (0.795 μmol), or 1 mg (3.18 μmol) pergolide as the base. The tablets also contain croscarmellose sodium, iron oxide, lactose, magnesium stearate, and povidone. The 0.05-mg tablet also contains methionine, and the 0.25-mg tablet also contains F D &amp; C Blue No. 2. 
     Pharmaceutically, pergolide mesylate is a potent dopamine receptor agonist. Pergolide is 10 to 1,000 times more potent than bromocriptine on a milligram per milligram basis in various in vitro and in vivo test systems. Pergolide mesylate inhibits the secretion of prolactin in humans; it causes a transient rise in serum concentrations of growth hormone and a decrease in serum concentrations of luteinizing hormone. In Parkinson&#39;s disease, pergolide mesylate is believed to exert its therapeutic effect by directly stimulating post-synaptic dopamine receptors in the nigrostriatal system. 
     Information on oral systemic bioavailability of pergolide mesylate is unavailable because of the lack of a sufficiently sensitive assay to detect the drug after the administration of a single dose. However, following oral administration of  14 C radio-labeled pergolide mesylate, approximately 55% of the administered radioactivity can be recovered from the urine and 5% from expired CO 2 , suggesting that a significant fraction is absorbed. Data on post absorption distribution of pergolide are unavailable. 
     Pergolide is approximately 90% bound to plasma proteins. This extent of protein binding may be important to consider when pergolide mesylate is co-administered with other drugs known to affect protein binding. 
     U.S. Pat. No. 4,797,405 which is incorporated herein by reference discloses that pergolide decomposes upon exposure to light to sulfoxide species. As a result, it is necessary to handle the compound and store the ultimate dosage form in a light-controlled environment so as to avoid a demonstrable drop in potency of the therapeutic agent. In order to retard this drop in potency, certain stabilizing agents have been incorporated into pharmaceutical compositions containing pergolide to reduce decomposition when exposed to light. Each of U.S. Pat. Nos. 4,797,405 and 5,114,948 disclose various stabilizing agents that purportedly retard decomposition to sulfoxide. However, beyond addition of stabilizing additives, the references fail to remedy the decomposition problem. 
     SUMMARY OF THE INVENTION 
     The present invention provides for stable pergolide mesylate in dry dosage form and in therapeutically effective amount without the addition of stabilizing compound. A process for manufacturing stable pergolide mesylate is also provided for both dry and wet granulates. The pergolide mesylate compound produced according to the invention is found to be substantially stable even without the presence of stabilizing compounds. 
     DETAILED DESCRIPTION 
     The embodiments of the present invention are described according to the following examples. The advantages of the invention are illustrated by way of comparative data in tables that follow. 
    
    
     EXAMPLE 1 
     Wet Granulation 
     
       
         
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
             
             
               
                 A. 0.05 mg Tablets 
               
             
          
           
               
                 Pergolide Mesylate 
                 0.065 
                 mg* 
               
               
                 Lactose Monohydrate NF 
                 157.565 
                 mg 
               
               
                 Microcrystalline Cellulose NF 
                 80.0 
                 mg 
               
               
                 Pregelatinized Starch NF 
                 30.0 
                 mg 
               
               
                 Sodium Starch Glycolate NF 
                 30.0 
                 mg 
               
               
                 Magnesium Stearate NF 
                 2.25 
                 mg 
               
               
                 Color Ferric Oxide NF 
                 0.12 
                 mg 
               
               
                 Purified Water USP (processing solvent only) 
               
               
                 Alcohol USP 95% (processing solvent only) 
                   
               
               
                 TOTAL 
                 300.0 
                 mg 
               
               
                   
               
             
          
           
               
                 B. 0.25 mg Tablets 
               
             
          
           
               
                 Pergolide Mesylate 
                 0.325 
                 mg** 
               
               
                 Lactose Monohydrate NF 
                 156.575 
                 mg 
               
               
                 Microcrystalline Cellulose NF 
                 80.0 
                 mg 
               
               
                 Pregelatinized Starch NF 
                 30.0 
                 mg 
               
               
                 Sodium Starch glycolate NF 
                 30.0 
                 mg 
               
               
                 Magnesium stearate NF 
                 2.25 
                 mg 
               
               
                 Color ferric Oxide NF 
                 0.65 
                 mg 
               
               
                 Color FDC Blue No. 2 
                 0.2 
                 mg 
               
               
                 Purified Water USP (processing solvent only) 
               
               
                 Alcohol USP 95% USP (processing solvent only) 
                   
               
               
                 TOTAL 
                 300.0 
                 mg 
               
               
                   
               
             
          
           
               
                 C. 1.0 mg Tablets 
               
             
          
           
               
                 Pergolide Mesylate 
                 1.3 
                 mg*** 
               
               
                 Lactose Monohydrate NF 
                 155.95 
                 mg 
               
               
                 Microcrystalline Cellulose NF 
                 80.0 
                 mg 
               
               
                 Pregelatinized Starch NF 
                 30.0 
                 mg 
               
               
                 Sodium Starch Glycolate NF 
                 30.0 
                 mg 
               
               
                 Magnesium Stearate NF 
                 2.25 
                 mg 
               
               
                 Color Ferric Oxide NF 
                 0.5 
                 mg 
               
               
                 Purified Water USP (processing solvent only) 
               
               
                 Alcohol USP 95% (processing solvent only) 
                   
               
               
                 TOTAL 
                 300 
                 mg 
               
               
                   
               
               
                 *Equivalent to 0.05 mg Pergolide base.  
               
               
                 **Equivalent to 0.25 mg Pergolide Base.  
               
               
                 ***Equivalent to 1 mg Pergolide Base.  
               
             
          
         
       
     
     Lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate and the colors were mixed in a high speed mixer. Pergolide mesylate was dissolved in a mixture of purified water and alcohol USP (1:3). The granulation was performed by adding pergolide mesylate solution to the powder mixture. The wet granulation was dried in a fluid bed drier at 50° C., using an air flow of 200-500 m 3 /h/kg for 30-60 minutes (LOD: 0.5-2.5%). Once dry, the granulates were milled. Thereafter, magnesium stearate was added to the milled granulate and mixed. The final blend was compressed into oval shaped tablets on a rotary tableting machine (batch size ca. 7 Kg tablets). 
     Stability studies were initiated at accelerated conditions (40° C. and 75% relative humidity) for three months and compared with Permax® (Atena) tablets. The following stability results were obtained: 
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Stability study of 0.05 mg pergolide tablets prepared according to the 
               
               
                 principles of the invention. 
               
             
          
           
               
                   
                   
                   
                 Degradation 
               
               
                   
                   
                   
                 Products (%) Total 
               
               
                   
                   
                 Degradation 
                 (excluding 
               
               
                   
                   
                 Products (%) 
                 pergolide 
               
               
                 Interval 
                 Assay (%) 
                 Pergolide Sulfoxide 
                 Sulfoxide) 
               
               
                   
               
               
                 0 Mo. 
                 99.4 
                 1.1 
                 &lt;0.05 
               
               
                 3 Mo. 
                 94.2 
                 4.8 
                 1.3 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Permax ® (0.05 mg) 
               
             
          
           
               
                   
                   
                   
                 Degradation 
               
               
                   
                   
                   
                 Products (%) Total 
               
               
                   
                   
                 Degradation 
                 (excluding 
               
               
                   
                   
                 Products (%) 
                 pergolide 
               
               
                 Interval 
                 Assay (%) 
                 Pergolide Sulfoxide 
                 Sulfoxide) 
               
               
                   
               
               
                 0 Mo. 
                 100.0 
                 1.7 
                 0.3 
               
               
                 3 Mo. 
                  95.9 
                 3.6 
                 0.4 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Stability study of 0.25 mg pergolide tablets prepared according to the 
               
               
                 principles of the invention. 
               
             
          
           
               
                   
                   
                   
                 Degradation 
               
               
                   
                   
                   
                 Products (%) Total 
               
               
                   
                   
                 Degradation 
                 (excluding 
               
               
                   
                   
                 Products (%) 
                 pergolide 
               
               
                 Interval 
                 Assay (%) 
                 Pergolide Sulfoxide 
                 Sulfoxide) 
               
               
                   
               
               
                 0 Mo. 
                 103.1 
                 0.3 
                 &lt;0.5 
               
               
                 3 Mo. 
                  99.3 
                 1.3 
                  0.5 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Permax ® (0.25 mg) 
               
             
          
           
               
                   
                   
                   
                 Degradation 
               
               
                   
                   
                   
                 Products (%) Total 
               
               
                   
                   
                 Degradation 
                 (excluding 
               
               
                   
                   
                 Products (%) 
                 pergolide 
               
               
                 Interval 
                 Assay (%) 
                 Pergolide Sulfoxide 
                 Sulfoxide) 
               
               
                   
               
               
                 0 Mo. 
                 104.6 
                 2.0 
                  0.1 
               
               
                 3 Mo. 
                 100.6 
                 3.6 
                 &lt;0.1 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Stability study of 1.0 mg pergolide tablets manufactured according to the 
               
               
                 principles of the invention. 
               
             
          
           
               
                   
                   
                   
                 Degradation 
               
               
                   
                   
                   
                 Products (%) Total 
               
               
                   
                   
                 Degradation 
                 (excluding 
               
               
                   
                   
                 Products (%) 
                 pergolide 
               
               
                 Interval 
                 Assay (%) 
                 Pergolide Sulfoxide 
                 Sulfoxide) 
               
               
                   
               
             
          
           
               
                 0 Mo. 
                 103.3 
                 0.1 
                  0.4 
               
               
                 3 Mo. 
                 99 
                 &lt;0.05 
                 &lt;0.1 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 Permax ® (1.0 mg) 
               
             
          
           
               
                   
                   
                   
                 Degradation 
               
               
                   
                   
                   
                 Products (%) Total 
               
               
                   
                   
                 Degradation 
                 (excluding 
               
               
                   
                   
                 Products (%) 
                 pergolide 
               
               
                 Interval 
                 Assay (%) 
                 Pergolide Sulfoxide 
                 Sulfoxide) 
               
               
                   
               
               
                 0 Mo. 
                 103.8 
                 0.9 
                 0.1 
               
               
                 3 Mo. 
                  98.1 
                 1.9 
                 0.1 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 2 
     Dry Granulation 
     
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 Each 0.05 mg pergolide tablet contains: 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Pergolide Mesylate 
                 0.065 
                 mg* 
               
               
                   
                 Lactose Monohydrate NF 
                 117.835 
                 mg 
               
               
                   
                 Microcrystalline Cellulose NF 
                 60.0 
                 mg 
               
               
                   
                 Pregelatinized Starch NF 
                 30.0 
                 mg 
               
               
                   
                 Sodium Starch Glycolate NF 
                 30.0 
                 mg 
               
               
                   
                 Magnesium Stearate NF 
                 2.0 
                 mg 
               
               
                   
                 Color Ferric Oxide NF 
                 0.1 
                 mg 
               
               
                   
                 TOTAL 
                 240.0 
                 mg 
               
               
                   
                   
               
               
                   
                 *Equivalent to 0.05 mg Pergolide base.  
               
             
          
         
       
     
     Pergolide mesylate was mixed in a suitable container with lactose monohydrate microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, color ferric oxide and ⅓ of the magnesium stearate quantity. The powder mixture was compressed in a slug tableting machine. The slug tablets were milled and mixed with the rest of the magnesium stearate. The powder mixture was compressed into oval shaped tablets on a rotary tableting machine (batch size 140,000 tabs.) Analytical results were as follows: 
     Uniformity of content: 97.6%; RSD 3.5% 
     Uniformity of blend: 97.5%; RSD 1.0% 
     Stability studies were initiated at accelerated conditions (40° C. at 75% relative humidity for three months). The results are tabulated in Table 7, 8 and 9. 
     
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 Stability of 0.05 mg pergolide dry tablets. 
               
             
          
           
               
                   
                   
                   
                 Degradation 
                 Degradation 
               
               
                   
                   
                   
                 products (%) 
                 products (%), total 
               
               
                   
                   
                   
                 (Pergolide 
                 (excluding 
               
               
                   
                 Interval 
                 Assay (%) 
                 sulfoxide) 
                 pergolide sulfoxide) 
               
               
                   
                   
               
               
                   
                 0 Mo. 
                 98.8 
                 0.5 
                 &lt;0.1 
               
               
                   
                 3 Mo. 
                 91.4 
                 2.4 
                 &lt;0.1 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 Stability of 0.25 mg Pergolide dry tablets. 
               
             
          
           
               
                   
                   
                   
                 Degradation 
               
               
                   
                   
                 Degradation 
                 Products (%), total 
               
               
                   
                   
                 Products (%) 
                 excluding pergolide 
               
               
                 Interval 
                 Assay (%) 
                 (Pergolide Sulfide) 
                 sulfide. 
               
               
                   
               
               
                 0 Mo. 
                 96.2 
                 0.1 
                 &lt;0.1 
               
               
                 3 Mo. 
                 95.0 
                 0.8 
                 &lt;0.1 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                 Stability of 1 mg pergolide dry tablets. 
               
             
          
           
               
                   
                   
                   
                 Degradation 
               
               
                   
                   
                 Pergolide Products 
                 Products (%), total 
               
               
                   
                   
                 (% pergolide 
                 excluding pergolide 
               
               
                 Interval 
                 Assay (%) 
                 sulfoxide) 
                 sulfoxide 
               
               
                   
               
             
          
           
               
                 0 Mo. 
                 97.0 
                 &lt;0.1 
                 &lt;0.1 
               
               
                 3 Mo. 
                 96.2 
                 0.2 
                 &lt;0.1