Controlled Release Compositions Comprising A Combination Of Isosorbide Dinitrate And Hydralazine Hydrochloride

Abstract

The invention relates to a controlled release composition comprising a combination of isosorbide dinitrate and hydralazine, such as hydralazine hydrochloride, that in operation delivers the drug in a pulsed or multi-modal manner for the treatment of angina, ischaemic heart disease, arterial hypertension and related disease conditions. Preferably, the isosorbide dinitrate and hydralazine hydrochloride can be released from the dosage form in an erodable, diffusion and/or osmotic-controlled release profile.

What is claimed is: 
     
         1 . A controlled release pharmaceutical composition comprising a population of isosorbide dinitrate and hydralazine, or a salt or derivative thereof, containing particles, wherein at least a portion of the particles incorporate a modified-release coating or, alternatively or additionally, a modified-release matrix material, such that the composition following oral delivery to a subject delivers the isosorbide dinitrate and hydralazine, or salt or derivative thereof, in a pulsatile or zero order manner. 
     
     
         2 . The composition according to  claim 1 , wherein the population of either isosorbide dinitrate or hydralazine particles, or both, have a protective coating. 
     
     
         3 . The composition according to  claim 2 , wherein the protective coating material is selected from the group comprising hydrophilic polymers, hydrophobic polymers, natural polymers, synthetic polymers and mixtures thereof. 
     
     
         4 . The composition according to  claim 1 , wherein the population of isosorbide dinitrate and hydralazine particles comprises modified-release particles. 
     
     
         5 . The composition according to  claim 1 , wherein the population of particles is an erodable formulation. 
     
     
         6 . The composition according to  claim 4 , wherein said modified-release particles have a modified-release coating. 
     
     
         7 . The composition according to  claim 4 , wherein said modified-release particles comprise a modified-release matrix coating. 
     
     
         8 . The composition of  claim 1  wherein said modified-release coating and/or said modified-release matrix material is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, natural polymers, synthetic polymers and mixtures thereof. 
     
     
         9 . The composition of  claim 8  wherein said particles incorporating a modified-release coating and/or a modified-release matrix material are combined so that said isosorbide dinitrate and hydralazine are released by erosion to the surrounding environment. 
     
     
         10 . The composition according to  claim 8 , wherein at least one portion of the composition further comprises an enhancer. 
     
     
         11 . The composition according to  claim 8 , wherein the amount of isosorbide dinitrate and hydralazine contained therein is in an amount, each, of from about 0.1 mg to about 1 g. 
     
     
         12 . The dosage form according to  claim 11  comprising a blend of the particles contained in a hard gelatin or soft gelatin capsule. 
     
     
         13 . The dosage form according to  claim 12 , wherein the particles are in the form of mini-tablets and the capsule contains a mixture of the mini-tablets. 
     
     
         14 . The dosage form according to  claim 13 , in the form of a tablet comprising a layer of compressed isosorbide dinitrate and hydralazine-containing particles. 
     
     
         15 . The dosage form according to  claim 14 , wherein the isosorbide dinitrate and hydralazine-containing particles are provided in a rapidly dissolving dosage form. 
     
     
         16 . A method for the treatment of angina, ischaemic heart disease, arterial hypertension or related disease conditions comprising administering a therapeutically effective amount of a composition according to  claim 1 . 
     
     
         17 . A method for the treatment of angina, ischaemic heart disease, arterial hypertension or related disease conditions comprising administering a therapeutically effective amount of a composition according to  claim 2 . 
     
     
         18 . The composition according to  claim 1 , wherein the particles incorporating a modified-release coating comprise a pH-dependent polymer coating which is effective in releasing a pulse of the active ingredient following a time delay of two to twelve hours. 
     
     
         19 . The composition according to  claim 18 , wherein the polymer coating comprises methacrylate copolymers. 
     
     
         20 . The composition according to  claim 1 , wherein the modified-release coating comprises a mixture of methacrylate and ammonio methacrylate copolymers in a ratio sufficient to achieve a pulse of the active ingredient following a time delay. 
     
     
         21 . The composition according to  claim 20 , wherein the ratio of methacrylate to ammonio methacrylate copolymers is between approximately 95:5 and 50:50. 
     
     
         23 . The composition according to  claim 1 , wherein the hydralazine comprises hydralazine hydrochloride. 
     
     
         23 . The composition according to  claim 1 , wherein at least one portion of the composition further comprises an antioxidant. 
     
     
         24 . The composition according to  claim 1 , wherein at least one portion of the composition further comprises a chelating agent. 
     
     
         25 . The composition according to  claim 23  wherein the antioxidant comprises ascorbic acid or a salt or derivative thereof. 
     
     
         26 . The composition according to  claim 24 , wherein the chelating agent comprises edetic acid or a salt or derivative thereof. 
     
     
         27 . The composition according to  claim 24 , wherein the chelating agent comprises citric acid or fumaric acid or any salts or derivatives thereof. 
     
     
         28 . The composition according to  claim 1 , wherein at least one portion of the composition further comprises sugar spheres. 
     
     
         29 . The composition according to  claim 1 , wherein at least one portion of the composition further comprises microcrystalline cellulose pellets. 
     
     
         30 . The dosage form according to  claim 14 , wherein the hydralazine comprises hydralazine hydrochloride. 
     
     
         31 . The dosage form according to  claim 14 , wherein the isosorbide dinitrate comprises isosorbide dinitrate or any active metabolites thereof. 
     
     
         32 . The method according to  claim 16 , wherein the hydralazine comprises hydralazine hydrochloride. 
     
     
         33 . The method according to  claim 16 , wherein the isosorbide dinitrate comprises isosorbide dinitrate or any active metabolites thereof.