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 . An extrudate for use in an immediate release pharmaceutical formulation, the extrudate formed during melt extrusion and comprising an 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 is copovidone, wherein the ratio by weight of the active agent and matrix polymer is in the range from about 1:2 to about 1:4. 
     
     
         2 . The extrudate as claimed in  claim 1 , wherein the active agent is in stable amorphous form. 
     
     
         3 . The extrudate as claimed in  claim 2 , wherein at least 90% by weight of the active agent is in amorphous form. 
     
     
         4 . The extrudate as claimed in  claim 1 , wherein the copovidone is a co-polymer of 1-vinyl-2-pyrollidone and vinyl acetate in a ratio of 6:4 by mass. 
     
     
         5 . The extrudate as claimed in  claim 1 , wherein the solid dispersion includes a surface-active agent and/or plasticiser. 
     
     
         6 . The extrudate as claimed in  claim 5 , 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 polysorbates 20, 40, 60 and 80; polyoxyethylene castor oil derivatives Cremophor RH40™; polyoxyethylene stearates and poloxamers. 
     
     
         7 . A method of producing an extrudate according to  claim 1 , 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 copovidone wherein the ratio by weight of the active agent to copovidone is in the range of 1:2 to 1:4;   (ii) increasing the temperature of the mixture to produce a melt; and   (iii) extruding the melt to produce a solid product.   
     
     
         8 . The method as claimed in  claim 7 , wherein in step (iii) the melt is extruded as rods or into one or more moulds. 
     
     
         9 . The extrudate as claimed in  claim 5 , wherein the plasticizer is selected from acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, glycerine, glycerine monostearate, mannitol, mineral oil, lanolin alcohols, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine and triethyl citrate. 
     
     
         10 . The extrudate as claimed in  claim 1 , wherein the solid dispersion further comprises a glidant. 
     
     
         11 . The extrudate as claimed in  claim 10 , wherein the glidant is colloidal silicon dioxide. 
     
     
         12 . The extrudate as claimed in  claim 1 , wherein the extrudate is in the form of rods or moulds. 
     
     
         13 . A method of producing an immediate-release pharmaceutical formulation comprising:
 (i) mixing 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one or a pharmaceutically acceptable salt or solvate thereof with copovidone, wherein the ratio by weight of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one to copovidone is in the range of from 1:2 to 1:4;   (ii) increasing the temperature of the mixture to produce a melt;   (iii) extruding the melt to produce an extrudate according to  claim 1 ;   (iv) grinding the extrudate;   (v) optionally mixing the ground extrudate with one or more additional excipients or ingredients; and   (vi) tabletting into a suitable dosage form wherein the total concentration of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one in the composition is in the range of from 20% by weight to 30% by weight and wherein the total amount of amount of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one in the composition is in the range from 25 mg to 400 mg.   
     
     
         14 . The method according to  claim 13 , wherein the mixture formed in step (i) further comprises a glidant.