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 destabilized 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 - 38 . (canceled) 
   
   
       39 . A process for the preparation of a stable solid pharmaceutical formulation containing as an active ingredient a HMG-CoA reductase inhibitor, the process comprising the steps of:
 a) homogenizing a mixture of an active composition consisting of said active ingredient and a buffering agent, wherein the active composition has a pH in the range from 7 to 11, with at least one constituent selected from the group consisting of a filler binder, buffering agent, disintegrating agent and optionally surfactant and other commonly used ingredients for solid pharmaceutical formulations in suitable mixers,   b) adding glidants and/or lubricants,   c) re-homogenizing the mixture and   d) compressing the resulting mixture into tablets, or filling the resulting mixture into capsules;   e) optionally film-coating the tablets,   
     wherein said HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin and atorvastatin and a pharmaceutically acceptable salt thereof, and wherein the pharmaceutical formulation has a pH in the range from 6 to 9. 
   
   
       40 . The process according to  claim 39  wherein a second buffering agent is mixed in the homogenizing step. 
   
   
       41 . A process for the preparation of a stable solid pharmaceutical formulation the process comprising the steps of:
 a) homogenizing a mixture of an active composition consisting of an active ingredient and a buffering agent, wherein said active ingredient is a HMG-CoA reductase inhibitor selected from the group consisting of pravastatin and atorvastatin and a pharmaceutically acceptable salt thereof, and wherein the active composition has a pH in the range from 7 to 11 with at least one constituent selected from the group consisting of a filler, binder, buffering agent, disintegrating agent and optionally surfactant and other commonly used ingredients for solid pharmaceutical formulations in suitable mixes,   b) granulating the mixture with a suitable solvent,   c) drying the resulting granulation in suitable dryers,   d) adding the dried granulations glidants and/or lubricants and optionally other ingredients for solid pharmaceutical formulations,   e) re-homogenizing the mixture, and   f) compressing the resulting mixture into tablets, or filling the resulting mixture into capsules;   g) optionally film-coating the tablets,   
     wherein the pharmaceutical formulation has a pH in the range from 6 to 9. 
   
   
       42 . The process according to  claim 41 , wherein a second buffering agent is mixed in the homogenizing step. 
   
   
       43 . A method for stabilizing an active substance in a solid pharmaceutical formulation, the method comprising;
 preparing a mixture of said active substance and a buffering agent imparting a pH in the local environment around the active substance in the range from 7 to 11 wherein said active substance is a HMG-CoA reductase inhibitor selected from the group consisting of pravastatin and atorvastatin and a pharmaceutically acceptable salt there and said buffering agent is present in an amount less than 1% based on the total weight of the pharmaceutically active substance, an   incorporating said mixture as an active substance into a pharmaceutical formulation, thus having a pH in the range from 6 to 9.   
   
   
       44 . The method according to  claim 43 , wherein the pharmaceutical formulation has a pH in the range from 7 to 8.5. 
   
   
       45 . The method according to  claim 43 , wherein the active substance is a HMG-CoA reductase inhibitor in the form of a salt. 
   
   
       46 . The method according to  claim 43 , wherein the active substance contains a buffering agent in order to provide a pH for said active substance in the range from 7 to 11 and additional amounts of a buffering agent are incorporated into the pharmaceutical formulation in order to provide a pH for said pharmaceutical formulation below 9 and a lower pH limit of 6. 
   
   
       47 . The method according to  claim 43 , wherein the active substance is a sodium salt of pravastatin or a calcium salt of atorvastatin. 
   
   
       48 . The method according to  claim 43 , wherein said stable solid pharmaceutical formulation further comprises at least on constituent selected from the group consisting of a filler, a binder, a disintegrated agent, a glidant; optionally further comprising at least one constituent selected among coloring agents, lakes, aromas, adsorbents, film formers and plasticizers. 
   
   
       49 . A process for the preparation of a stable solid pharmaceutical formulation the process comprising the steps of:
 a) homogenizing a mixture of an active composition consisting of an active ingredient and a buffering agent, wherein said active ingredient is a HMG-CoA reductase inhibitor selected from the group consisting of pravastatin and atorvastatin and a pharmaceutically acceptable salt thereof, and   
     wherein the active composition has a pH in the range from 7 to 11, and said buffering agent is present in an amount less than 1% based on the total weight of the pharmaceutically active substance, with at least on constituent selected from the group consisting of a filler, binder, buffering agent, disintegrating agent and optionally surfactant and other commonly used ingredients for solid pharmaceutical formulations in suitable mixers,
 b) adding glidants and/or lubricants, 
 c) re-homogenizing the mixture and 
 d) compressing the resulting mixture into tablets or filling the resulting mixture into capsules; 
 e) optionally film-coating the tablets, 
 
     wherein the pharmaceutical formulation has a pH below 9 and a lower pH limit of 6. 
   
   
       50 . A process for the preparation of a stable solid pharmaceutical formulation containing as an active ingredient a HMG-CoA reductase inhibitor, the process comprising the steps of:
 a) mixing a combination of said active ingredient and a buffering agent, wherein the active composition has a pH in the range from 7 to 11, with at least one constituent selected from the group consisting of a filler binder, buffering agent, disintegrating agent and optionally surfactant and other commonly used ingredients for solid pharmaceutical formulations in suitable mixers to form a mixture;   b) adding glidants and/or lubricants,   c) combining said mixture from (a) and said ingredients added in (b), and   d) compressing the resulting mixture into tablets, or filling the resulting mixture into capsules;   e) optionally film-coating the tablets,   
     wherein said HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin and atorvastatin and a pharmaceutically acceptable salt thereof, and wherein the pharmaceutical formulation has a pH in the range from 6 to 9.