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-12178816-B2
Publication Date
2024-12-31
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 patent relates to an immediate-release solid oral pharmaceutical composition in the form of a tablet comprising a solid dispersion matrix polymer system containing 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one (Compound 1). The formulation addresses solubility and permeability limitations and the constraints associated with Biopharmaceutics Classification System (BCS) behavior for PARP inhibitor Compound 1 in conventional immediate-release approaches. The disclosed approach targets improved dissolution and performance relative to prior immediate-release tablets and prior lipidic Gelucire formulations at higher drug loads.
A key aspect of the invention is the use of matrix polymers with low hygroscopicity and high softening temperature to promote and maintain a stable amorphous solid form of Compound 1 within the solid dispersion. The patent describes polymer property criteria including low equilibrium water content under humidity and glass transition and melting temperature thresholds (Tg/Tm >100°C). Copovidone is highlighted as a candidate matrix polymer, and the polymer selection is positioned as supporting stable amorphous behavior and limiting crystallinity under stress conditions.
The patent also discloses formulation and analytical concepts for solid dispersion characterization and stability, including assessment of the amorphous fraction by XRPD and crystallinity detection by DSC/XRPD/hot-stage microscopy concepts. It further reports comparative bioavailability results in dogs showing higher exposure for copovidone solid dispersions versus an immediate-release tablet and versus Gelucire across multiple loadings and dosage forms. Example immediate-release tablet compositions are described that include copovidone with excipient categories such as fillers, disintegrants, and lubricants, with optional excipient classes where applicable.
Claims Coverage
The independent claim set covers an immediate-release tablet formulation and constrains the composition by four inventive features: defined Compound 1 content, defined polymer selection and Compound 1-to-polymer weight ratio in an extrudate, inclusion of a glidant, and defined total Compound 1 concentration in the tablet. Dependent claims refine these features with specific glidant, narrowed polymer selection, narrower ratio range, and excipient classes.
Immediate-release tablet extrudate with Compound 1 and matrix polymer
An immediate-release pharmaceutical composition in the form of a tablet comprising an extrudate comprising 100 mg to 200 mg of Compound 1; 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; and at least one glidant.
Compound 1-to-polymer weight ratio constraint
The weight ratio of Compound 1 to the at least one polymer in the extrudate is in the range of from 1:1 to 1:9.
Total Compound 1 concentration constraint in the tablet
The total concentration of Compound 1 in the tablet is in the range of from 10% by weight to 35% by weight.
Specific glidant as colloidal silicon dioxide
The at least one glidant is colloidal silicon dioxide.
Polymer selection narrowed to copovidone and povidone
The at least one polymer is chosen from copovidone and povidone.
Narrowed Compound 1-to-polymer ratio range
The weight ratio of Compound 1 to the at least one polymer in the extrudate is 1:1 to 1:4.
Excipient selection from soluble filler and lubricant
The at least one excipient is chosen from at least one soluble filler and at least one lubricant.
Overall, the claims define an immediate-release tablet whose extrudate comprises Compound 1 with named matrix polymers and glidant(s), while constraining Compound 1-to-polymer weight ratio and total Compound 1 concentration in the tablet. Dependent refinements narrow the glidant to colloidal silicon dioxide, restrict polymer selection to copovidone and/or povidone, tighten the ratio range to 1:1 to 1:4, and specify excipient categories including soluble filler(s) and lubricant(s).
Stated Advantages
Higher bioavailability and higher exposure (AUC and Cmax) for copovidone solid dispersions versus an immediate-release tablet and versus Gelucire across multiple loadings and dosage forms.
Documented Applications
Immediate-release pharmaceutical tablet formulation of a PARP inhibitor (Compound 1) based on solid dispersion with matrix polymers for improving in vivo exposure in a dog comparative bioavailability context [documented comparative bioavailability results].
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