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-11975001-B2
Publication Date
2024-05-07
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 comprising a solid dispersion of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one (Compound 1), which is a PARP inhibitor, together with at least one selected polymer. The formulation constrains the weight ratio of Compound 1 to the polymer to a range of 1:1 to 1:9, and constrains the total concentration of Compound 1 in the solid dispersion to 10% by weight to 50% by weight.
The solid dispersion is described as aiming to stabilize an amorphous form and enable increased bioavailability and drug loading to support fewer daily units. The described problem is that conventional immediate-release tablets for Compound 1 provide poor exposure, which is addressed by using a solid-dispersion approach.
A key part of the invention is the selection of matrix polymers characterized as having low hygroscopicity and high softening temperature, with copovidone described as particularly suitable. Matrix-polymer definition is supported by metrics such as low DVS water content at defined relative humidity and softening temperature criteria, and the patent describes polymer-drug molecular interaction effects and solid-state homogeneity using spectroscopic and solid-state analytical approaches.
Claims Coverage
The provided independent claim set contains 1 independent claim. The inventive features are centered on a constrained immediate-release solid-dispersion composition of Compound 1 with specifically selected polymers and defined quantitative composition ranges.
Immediate-release solid dispersion with constrained Compound 1 and polymer ranges
An immediate-release pharmaceutical composition comprising a solid dispersion comprising 100 mg to 200 mg of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one (Compound 1) and at least one polymer chosen from copovidone, povidone, hypromellose phthalate, hypromellose acetate succinate, 2-hydroxypropyl-β-cyclodextrin, hypromellose, polymethacrylates, hydroxypropyl cellulose, and cellulose acetate phthalate, wherein the weight ratio of Compound 1 to the at least one polymer is from 1:1 to 1:9 and wherein the total concentration of Compound 1 in the solid dispersion is from 10% by weight to 50% by weight.
Overall, the claims provided cover an immediate-release solid-dispersion formulation of Compound 1 with selected polymer classes and specific composition constraints on Compound 1 amount, polymer selection, weight ratio, and total drug concentration.
Stated Advantages
Increased bioavailability compared with an immediate-release tablet and with Gelucire at a fixed dose, as reported for dogs.
Allows higher drug loading via a solid dispersion approach, aiming to enable fewer daily units.
Improved stability performance is described for copovidone solid dispersions and film-coated tablets.
Documented Applications
Cancer treatment, including BRCA1/BRCA2 homologous recombination deficient tumors.
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