Pharmaceutical formulations for preventing drug tolerance

Abstract

Isosorbide mononitrate formulations and methods of treatment are disclosed. The formulations and treatments provide for subtherapeutic levels of the mononitrate in a washout period to prevent nitrate tolerance.

What is claimed:  
     
         1 . A controlled absorption ISMN containing pellet formulation for oral administration, said pellet comprising: 
 i) a core of 
 (a) a powder mixture containing an ISMN or a pharmaceutically acceptable salt thereof and optionally one or more excipients selected from an organic acid or base and a pharmaceutically acceptable diluent, and  
 (b) a polymeric material containing a major proportion of a pharmaceutically acceptable water soluble polymer and optionally a minor proportion of a pharmaceutically acceptable water insoluble polymer,  
   said core comprising layers of said powder mixture and said polymeric material superimposed one upon the other and said polymeric material being present in an amount effective to ensure that all of said powder mixture is coated into said core; and 
 ii) a multi-layer membrane surrounding said core and containing a major proportion of a pharmaceutically acceptable film-forming, water-insoluble polymer and optionally a minor proportion of a pharmaceutically acceptable film-forming, water soluble polymer,  
 the number of layers in said membrane and the ratio of said water-soluble polymers to said water-insoluble polymers being effective to permit release of said ISMN from said pellet at a rate allowing controlled absorption thereof over a 24 hour period following oral  
   administration, said rate being measured in vivo and having a Tmax between 2 and 10 hours and achieving minimum effective blood levels from 12 to 20 hours over a 24 hour period.    
     
     
         2 . A pellet formulation according to  claim 1 , wherein the ISMN is isosorbide-5-mononitrate.  
     
     
         3 . A pellet formulation according to  claim 1 , wherein the ISMN or pharmaceutically acceptable salt thereof and organic acid or base and/or pharmaceutically acceptable diluent are present in a ratio of from 1:4 to 50:1.  
     
     
         4 . A pellet formulation according to  claim 1 , wherein the polymeric material of the core includes a major proportion of a polymer which is freely permeable to ISMN and water and aminor proportion of a polymer which is slightly permeable to ISMN and water.  
     
     
         5 . A pellet formulation according to  claim 1 , wherein the multi-layer membrane is composed of a major proportion of a polymer which is slightly permeable to ISMN and water and optionally a minor proportion of a polymer which is freely permeable to ISMN and water.  
     
     
         6 . A pellet formulation according to  claim 1 , wherein the multi-layer membrane is composed of a major proportion of a non-porous polymer and optionally a minor proportion of a porous polymer.  
     
     
         7 . A controlled absorption ISMN formulation for oral administration comprising a blend of pellets as defined in  claim 1  in admixture with a rapidly releasing form of ISMN or a pharmaceutically acceptable salt thereof to ensure a rapid attainment of effective therapeutic blood levels of ISMN within 3 hours following administration.  
     
     
         8 . A controlled absorption ISMN formulation for oral administration comprising a blend of pellets as defined in  claim 1  in admixture with a rapidly releasing form of ISMN or a pharmaceutically acceptable salt thereof to ensure a rapid attainment of effective therapeutic blood levels of ISMN within 3 hours following administration, wherein the rapidly releasing form of ISMN comprises pellets as defined in  claim 1  without said multi-layer membrane.  
     
     
         9 . A capsule or tablet comprising a formulation of pellets according to  claim 1 .  
     
     
         10 . A capsule or tablet comprising a formulation of pellets according to  claim 7 .  
     
     
         11 . A preparation for the once-daily, percutaneous administration of ISMN or a pharmaceutically acceptable salt thereof which comprises ISMN or a pharmaceutically acceptable salt thereof uniformly distributed in a solid, semi-solid or mucilaginous medium which can be placed in intimate contact with the skin, the release of said ISMN or pharmaceutically acceptable salt thereof from said preparation being at a rate allowing controlled absorption thereof over a 24 hour period following topical application of said preparation, said rate being measure in vivo and having a Tmax between 2 and 16 hours and achieving minimum effective blood levels from 12 to 20 hours over a 24 hour period.  
     
     
         12 . A preparation according to  claim 11 , wherein the solidifying or gel-forming agent is a gum selected from the group consisting of guar gum, acacia gum, ghatti gum, karaya gum, tragacanth gum and xanthan gum or a mixture thereof.  
     
     
         13 . A preparation according to  claim 11 , wherein the solidifying or gel-forming agent is a synthetic or natural polysaccharide selected from the group consisting of alkylcelluloses, hydroxyalkylcelluloses, cellulose ethers, cellulose esters, nitrocelluloses, dextrin, agar, carrageenan, pectin, furcellaran and starch or starch derivatives and mixtures thereof.  
     
     
         14 . A preparation according to  claim 11  which contains a penetration enhancer.  
     
     
         15 . A method for administering a drug once-daily to inhibit the development of drug tolerance in humans being treated with said drug, which comprises administering to said humans on a once-daily basis a formulation adapted to achieve therapeutically effective levels of said drug in the blood over a period of not more than 20 hours of the day and further adapted to cause said blood levels to fall significantly below said therapeutic levels throughout the remainder of the 24 hour period.  
     
     
         16 . A method for administering a drug once-daily to inhibit the development of drug tolerance in humans being treated with said drug, which comprises administering to said humans on a once-daily basis a formulation adapted to achieve therapeutically effective levels of said drug in the blood over a period of not more than 20 hours of the day and further adapted to cause said blood levels to fall significantly below said therapeutic levels throughout the remainder of the 24 hour period, wherein the drug is a controlled absorption ISMN formulation according to  claim 1 .  
     
     
         17 . A method for administering a drug once-daily to inhibit the development of drug tolerance in humans being treated with said drug, which comprises administering to said humans on a once-daily basis a formulation adapted to achieve therapeutically effective levels of said drug in the blood over a period of not more than 20 hours of the day and further adapted to cause said blood levels to fall significantly below said therapeutic levels throughout the remainder of the 24 hour period, wherein the drug is a preparation of ISMN according to  claim 1.