Immediate release pharmaceutical formulation of 4-[3-(4- cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H- phthalazin-1-one
Inventors
Bechtold, Michael Karl • Cahill, Julie Kay • Fastnacht, Katja Maren • Lennon, Kieran James • Liepold, Bernd Harald • Packhaeuser, Claudia Bettina • Steitz, Benedikt
Assignees
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Publication Number
US-11633396-B2
Publication Date
2023-04-25
Expiration Date
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.
Core Innovation
The invention relates to an immediate-release pharmaceutical composition for cancer. The composition includes a core composition with a solid dispersion comprising 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (Compound 1), wherein at least one matrix polymer is present and one of the matrix polymers is copovidone. The total concentration of Compound 1 in the core composition is from 10% by weight to 40% by weight, and the weight ratio of Compound 1 to copovidone is from 1:1 to 1:4.
The disclosed approach addresses limited exposure from conventional immediate-release tablets for Compound 1 and limitations associated with other solid-form dispersion excipients. Compound 1 is described as near poor solubility in terms of BCS, and the formulation context addresses solubility, permeability, and efflux factors. The selection of a matrix polymer with low hygroscopicity and high softening temperature properties, especially copovidone, is presented as responsive to these limitations.
The solid dispersion is characterized as providing a stable amorphous solid form of Compound 1 within the dispersion, as supported by XRPD and DSC and additional solid-state characterization including PDF, SSNMR, and AFM/nano-thermal. The description contrasts instability at higher drug loadings with hygroscopic povidone, PEG, and poloxamers, and reports stability when copovidone is used up to the target loadings. Solvent evaporation and melt extrusion/hot-melt extrusion are described as formulation approaches for producing the core composition as a solid dispersion.
Documented examples include immediate-release tablet and capsule compositions containing the Compound 1/copovidone solid dispersion core, with optional excipients such as fillers, binders, disintegrants, lubricants, and surfactants/plasticizers. Comparative dog pharmacokinetic results are presented to support improved exposure, including AUC and Cmax, for copovidone solid dispersions versus immediate-release and Gelucire formulations.
Claims Coverage
The partial content includes three independent claims: an immediate-release pharmaceutical composition with Compound 1 in a copovidone-containing solid dispersion (independent claims clm-00001 and clm-00019) and an immediate-release pharmaceutical composition with a specifically fixed Compound 1:copovidone ratio and loading (independent claim clm-00024). Across these independent claims, the core inventive features are the specific Compound 1, the immediate-release solid-dispersion structure using copovidone as the matrix polymer, and defined Compound 1 loading and Compound 1-to-copovidone weight-ratio ranges (or fixed values in clm-00024).
Immediate-release solid dispersion with copovidone matrix polymer
An immediate-release pharmaceutical composition comprising a core composition comprising a solid dispersion comprising Compound 1 (4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one) and at least one matrix polymer wherein one matrix polymer is copovidone.
Compound 1 loading and Compound 1-to-copovidone weight ratio range
The core composition has a total concentration of Compound 1 from 10% by weight to 40% by weight, and a weight ratio of Compound 1 to copovidone from 1:1 to 1:4.
Immediate-release active agent selection including Compound 1 and pharmaceutically acceptable forms
An immediate-release pharmaceutical composition wherein the solid dispersion includes at least one active agent chosen from Compound 1, pharmaceutically acceptable salts thereof, and solvates thereof, and wherein one matrix polymer is copovidone.
Compound 1 loading and expanded Compound 1-to-copovidone weight ratio range
The core composition has a total concentration of Compound 1 from 10% by weight to 40% by weight, and a weight ratio of Compound 1 to copovidone from 1:1 to 1:9.
Fixed composition with specified Compound 1 loading and Compound 1:copovidone ratio
An immediate-release pharmaceutical composition comprising a core composition comprising a solid dispersion comprising Compound 1 and copovidone, wherein the total concentration of Compound 1 in the core composition is 25% by weight and the weight ratio of Compound 1 to copovidone in the core composition is 1:2.3.
The independent claims collectively cover immediate-release pharmaceutical compositions where Compound 1 is formulated as a solid dispersion with copovidone as the matrix polymer, together with specified Compound 1 loading and Compound 1-to-copovidone weight-ratio constraints, including broader ratio ranges (1:1 to 1:4, and 1:1 to 1:9) and a fixed loading/ratio embodiment (25% by weight; 1:2.3) in the fixed composition claim.
Stated Advantages
Improved exposure (AUC and Cmax) compared with immediate-release and Gelucire formulations in the documented dog pharmacokinetic comparison.
Documented Applications
Immediate-release tablet and capsule compositions for cancer using Compound 1 as a PARP inhibitor (including solid dispersion cores and optional excipients described in the document).
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