Immediate release pharmaceutical formulation of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2h-phthalazin-1-one

Abstract

The present invention relates to a pharmaceutical formulation comprising the drug 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one in a solid dispersion with a matrix polymer that exhibits low hygroscopicity and high softening temperature, such as copovidone. The invention also relates to a daily pharmaceutical dose of the drug provided by such a formulation. In addition, the invention relates to the use of a matrix polymer that exhibits low hygroscopicity and high softening temperature in solid dispersion with 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one for increasing the bioavailability of the drug.

1 . A pharmaceutical formulation comprising and active agent in solid dispersion with a matrix polymer, wherein the active agent is 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one or a salt or solvate thereof, and the matrix polymer exhibits low hygroscopicity and high softening temperature. 
     
     
         2 . The formulation as claimed in  claim 1 , wherein the active agent is in stable amorphous form. 
     
     
         3 . The formulation as claimed in  claim 2 , wherein at least 90% of the active agent is in amorphous form. 
     
     
         4 . The formulation as claimed in any one of  claims 1  to  3 , wherein the matrix polymer is selected from: copovidone, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), 2-hydroxypropyl-β-cyclodextrin (HPBCD), hydroxypropyl methylcellulose (Hypromellose, HPMC), polymethacrylates, hydroxypropyl cellulose (HPC), and cellulose acetate phthalate (CAP). 
     
     
         5 . The formulation as claimed in any one of  claims 1  to  3 , wherein the matrix polymer is copovidone. 
     
     
         6 . The formulation as claimed in  claim 5 , wherein the copovidone is a co-polymer of 1-vinyl-2-pyrollidone and vinyl acetate in a ratio of 6:4 by mass. 
     
     
         7 . The formulation as claimed in  claim 6 , wherein the ratio of active agent:matrix polymer by weight is from 1:0.25 to 1:10. 
     
     
         8 . The formulation as claimed in  claim 7 , wherein the ratio of active agent:matrix polymer by weight is 1:≧2 to 1:10. 
     
     
         9 . The formulation as claimed in  claim 8  wherein the amount of active agent per unit dose is at least 20%. 
     
     
         10 . The formulation as claimed in  claim 9 , wherein the solid dispersion includes a surface-active agent and/or plasticiser. 
     
     
         11 . The formulation as claimed in  claim 10 , wherein the surface-active agent is selected from: sodium dodecyl sulphate (sodium lauryl sulphate); docusate sodium; cetrimide; benzethonium chloride; cetylpyridinium chloride; lauric acid; polyoxyethylene alkyl ethers; polyoxyethylene sorbitan fatty acid esters, e.g. polysorbates 20, 40, 60 and 80; polyoxyethylene castor oil derivatives, e.g. Cremophor RH40™; polyoxyethylene stearates and poloxamers. 
     
     
         12 . The formulation as claimed in  claim 1 , which is for mucosal administration. 
     
     
         13 . The formulation as claimed in  claim 1 , wherein the solid dispersion is made by solvent evaporation or melt extrusion. 
     
     
         14 . The formulation as claimed in  claim 13 , wherein the solid dispersion is made by melt extrusion. 
     
     
         15 . A method for increasing the bioavailability of the drug 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one in a patient in need of said drug, comprising administering to said patient a formulation comprising 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one in a solid dispersion with a matrix polymer that exhibits low hygroscopicity and high softening temperature as claimed in  claim 1 . 
     
     
         16 . A method as claimed in  claim 15 , wherein the formulation comprises 10 to 1500 mg of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         17 . A daily pharmaceutical dose of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4 fluoro-benzyl]-2H-phthalazin-1-one for treating cancer in the patient, wherein the dose comprises 10 to 1000 mg of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one in a solid dispersion with a matrix polymer that exhibits low hygroscopicity and high softening temperature. 
     
     
         18 . The pharmaceutical dose according to  claim 17 , wherein the matrix polymer is copovidone. 
     
     
         19 . A method of producing a solid amorphous dispersion of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one comprising:
 (i) mixing a suitable amount of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one or a pharmaceutically acceptable salt or solvate thereof with a desired amount of at least one matrix polymer, wherein the matrix polymer exhibits low hygroscopicity and high softening temperature;   (ii) increasing the temperature of the mixture to produce a melt; and   (iii) extruding the melt to produce a solid product.   
     
     
         20 . The method as claimed in  claim 19 , wherein in step (iii) the melt is extruded into one or more moulds.