Stable pharmaceutical formulation comprising a HMG-CoA reductase inhibitor

Abstract

Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, and derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus, and some are obtained by treating the fermentation products using the methods of chemical synthesis or they are the products of total chemical synthesis. The aforementioned active substances may be destabilised by the environmental factors, their degradation may also be accelerated by interactions with other pharmaceutical ingredients, such as fillers, binders, lubricants, glidants and disintegrating agents, therefore the pharmaceutical ingredients and the process for preparation of the pharmaceutical formulation should be meticulously chosen to avoid the aforementioned undesired interactions and reactions. The present invention relates to a stable solid pharmaceutical formulation for the treatment of hypercholesterolemia and hyperlipidemia. More precisely, the present invention relates to the new stable solid pharmaceutical formulation containing as an active ingredient a HMG-CoA reductase inhibitor, such as atorvastatin, pravastatin, fluvastatin and cerivastatin or pharmaceutically acceptable salts thereof.

1 . A stable solid pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor,  
       characterized in that 
 an active substance is contained which is capable of providing a pH in the range from 7 to 11.  
 
     
     
         2 . A stable solid pharmaceutical formulation as defined in  claim 1 ,  
       characterized in that 
 an active substance is contained which is capable of providing a pH in the range from 8 to 10.  
 
     
     
         3 . A stable solid pharmaceutical formulation as defined in  claim 1  or  2 , wherein the active substance is a HMG-CoA reductase inhibitor in the form of a salt.  
     
     
         4 . A stable solid pharmaceutical formulation as defined in any one of  claims 1  to  3 , wherein the active substance, which had been incorporated into the formulation, contained a buffering agent.  
     
     
         5 . A stable solid pharmaceutical formulation as defined in  claim 4 , wherein the active substance, which had been incorporated into the formulation, contained the buffering agent in an amount of less than 1%.  
     
     
         6 . A stable solid pharmaceutical formulation as defined in any one of  claims 1  to  5 , wherein the active substance is selected from the group consisting of pravastatin, atorvastatin, fluvastatin, cerivastatin and a pharmaceutically acceptable salt thereof.  
     
     
         7 . A stable solid pharmaceutical formulation as defined in  claim 6 , wherein the active substance is a sodium salt of pravastatin (pravastatin Na) or a calcium salt of atorvastatin (atorvastatin Ca).  
     
     
         8 . A stable solid pharmaceutical formulation as defined in  claim 1 , which further comprises at least one constituent selected from the group consisting of a filler, a binder, a disintegrating agent, a glidant, a buffering agent; optionally further comprising at least one constituent selected among colouring agents, lakes, aromas, adsorbents, film formers and plasticizers.  
     
     
         9 . A stable solid pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor,  
       characterized in that 
 the pharmaceutical formulation is capable of providing a pH below 9.  
 
     
     
         10 . A stable solid pharmaceutical formulation according to  claim 9 ,  
       characterized in that 
 the pharmaceutical formulation is capable of providing a pH in the range from 6 to 9.  
 
     
     
         11 . A stable solid pharmaceutical formulation according to  claim 9 ,  
       characterized in that 
 the pharmaceutical formulation is capable of providing a pH in the range from 7 to 8.5.  
 
     
     
         12 . A stable solid pharmaceutical formulation according to  claim 9 ,  
       characterized in that 
 an active substance being capable of providing a pH in the range from 7 to 11 is incorporated into said solid pharmaceutical formulation.  
 
     
     
         13 . A stable solid pharmaceutical formulation according to  claim 9 ,  
       characterized in that 
 an active substance being capable of providing a pH in the range from 8 to 10 is incorporated into said solid pharmaceutical formulation.  
 
     
     
         14 . A stable solid pharmaceutical formulation as defined in  claim 12  or  13 , wherein the active substance is a HMG-CoA reductase inhibitor in the form of a salt.  
     
     
         15 . A stable solid pharmaceutical formulation according to any one of  claims 12  to  14 , wherein the incorporated active substance contains a buffering agent.  
     
     
         16 . A stable solid pharmaceutical formulation according to  claim 15 , wherein the buffering agent is contained in an amount of less than 1%.  
     
     
         17 . A stable solid pharmaceutical formulation according to  claim 15 , wherein additional amounts of a buffering agent are incorporated into said formulation.  
     
     
         18 . A stable solid pharmaceutical formulation according to any one of  claims 9  to  17 , wherein the active substance is selected from the group consisting of pravastatin, atorvastatin, fluvastatin, cerivastatin and a pharmaceutically acceptable salt thereof.  
     
     
         19 . A stable solid pharmaceutical formulation as defined in  claim 18 , wherein the active substance is a sodium salt of pravastatin (pravastatin Na) or a calcium salt of atorvastatin (atorvastatin Ca).  
     
     
         20 . A stable solid pharmaceutical formulation as defined in  claim 9 , which further comprises at least one constituent selected from the group consisting of a filler, a binder, a disintegrating agent, a glidant, a buffering agent; optionally further comprising at least one constituent selected among colouring agents, lakes, aromas, adsorbents, film formers and plasticizers.  
     
     
         21 . A process for the preparation of a stable solid pharmaceutical formulation according to any of the aforementioned claims, wherein the mixture of the active substance, filler, binder, buffering agent, disintegrating agent and optionally surfactant and other commonly used ingredients for solid pharmaceutical formulations are homogenised in suitable mixers, glidants and/or lubricants are added, the mixture is then re-homogenised and the resulting mixture is compressed into tablets or filled into capsules; optionally the tablets may be film-coated.  
     
     
         22 . A process for the preparation of a stable solid pharmaceutical formulation according to any of the  claims 1  to  20 , wherein the mixture of the active substance, filler, binder, buffering agent, disintegrating agent and optionally surfactant and other commonly used ingredients for solid pharmaceutical formulations are homogenised in suitable mixers, granulated with a suitable solvent; the resulting granulation is dried in suitable dryers; to the dried granulations, glidants and/or lubricants are added and optionally other ingredients for solid pharmaceutical formulations and the resulting mixture is re-homogenised and compressed into tablets or filled into capsules; optionally the tablets may be film-coated.  
     
     
         23 . A stabilized pharmaceutically active substance consisting only of a mixture of a HMG-CoA reductase inhibitor and a buffering agent.  
     
     
         24 . A stabilized pharmaceutically active substance according to  claim 23 , wherein the buffering agent is present in the mixture in an amount of less than 1 wt.—% based on the total weight of the pharmaceutically active substance.  
     
     
         25 . A stabilized pharmaceutically active substance according to  claim 23  or  24 , wherein the HMG-CoA reductase inhibitor is in the form of a salt.  
     
     
         26 . A stabilized pharmaceutically active substance according to  claim 23  or  24 , wherein the buffering agent imparts a pH in the range from 7 to 11 to the pharmaceutically active substance.  
     
     
         27 . A stabilized pharmaceutically active substance according to any one of  claims 23  to  26 , wherein the HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, atorvastatin, fluvastatin, cerivastatin and a pharmaceutically acceptable salt thereof.  
     
     
         28 . A stabilized pharmaceutically active substance according to  claim 27 , wherein the HMG-CoA reductase inhibitor is a sodium salt of pravastatin (pravastatin Na) or a calcium salt of atorvastatin (atorvastatin Ca).  
     
     
         29 . A method for the stabilization of a HMG-CoA reductase inhibitor as an active substance in a solid pharmaceutical formulation, wherein an active substance being capable of providing a pH in the range from 7 to 11 is incorporated into a pharmaceutical formulation which is capable of providing a pH below 9.  
     
     
         30 . The method according to  claim 29 , wherein the pharmaceutical formulation is capable of providing a pH in the range from 6 to 9.  
     
     
         31 . The method according to  claim 29 , wherein the pharmaceutical formulation is capable of providing a pH in the range from 7 to 8.5.  
     
     
         32 . The method according to  claim 29 , wherein the active substance is a HMG-CoA reductase inhibitor in the form of a salt.  
     
     
         33 . The method according to  claim 29 , wherein the incorporated active substance contains a buffering agent in order to provide a pH for said active substance in the range from 7 to 11.  
     
     
         34 . The method according to  claim 33 , wherein the incorporated active substance contains less than 1% of a buffering agent.  
     
     
         35 . The method according to  claim 33  or  34 , wherein additional amounts of a buffering agent are incorporated into the pharmaceutical formulation in order to provide a pH for said pharmaceutical formulation of below 9.  
     
     
         36 . The method according to any one of  claims 29  to  35 , wherein the active substance is selected from the group consisting of pravastatin, atorvastatin, fluvastatin, cerivastatin and a pharmaceutically acceptable salt thereof.  
     
     
         37 . The method according to  claim 36 , wherein the active substance is a sodium salt of pravastatin (pravastatin Na) or a calcium salt of atorvastatin (atorvastatin Ca).  
     
     
         38 . The method according to  claim 29 , wherein said stable solid pharmaceutical formulation further comprises at least one constituent selected from the group consisting of a filler, a binder, a disintegrating agent, a glidant, a buffering agent; optionally further comprising at least one constituent selected among colouring agents, lakes, aromas, adsorbents, film formers and plasticizers.