Oral Solid-Dispersion Formulations for Androgen Receptor Degraders
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Solution Overview
Problem
There is a need for improved pharmaceutical formulations of bifunctional compounds that target the Androgen Receptor (AR) for the treatment of prostate cancer, particularly for metastatic and castrate-resistant forms, to enhance their efficacy and delivery.
Innovation Solution
Development of a pharmaceutical formulation comprising Compound A, a PROTAC protein degrader, in oral dosage forms such as tablets, sachets, and capsules, utilizing a solid dispersion with specific excipients like release modifiers, fillers, disintegrants, glidants, and lubricants in intra- and extra-granular portions to optimize drug delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Compound A is formulated in conventional oral dosage forms, then the basic delivery requirement is met, but the bioavailability and therapeutic efficacy are insufficient
Solution Approach 1:
The formulation is divided into intra-granular and extra-granular portions, with the intra-granular portion containing the solid dispersion of Compound A and release modifier, while the extra-granular portion contains disintegrant, glidant, and lubricant. This segmentation allows optimized delivery of the PROTAC compound while maintaining manufacturability through a systematic granulation process.
Solution Approach 2:
The patent employs a solid dispersion formulation where Compound A is dispersed in a specific ratio (about 60.000% w/w to about 70.000% w/w) with a release modifier within the intra-granular portion. This parameter optimization enhances bioavailability and therapeutic efficacy by controlling the release characteristics of the PROTAC compound.
2Productivity
If the formulation uses solid dispersion with release modifier, then the bioavailability is improved, but the manufacturing process becomes more complex
Solution Approach 1:
The release modifier in the solid dispersion serves multiple functions: it controls the release rate of Compound A, enhances bioavailability, and maintains stability within the granule. This multi-functionality justifies the added formulation complexity by delivering multiple therapeutic benefits through a single component.
Solution Approach 2:
The formulation uses a composite structure combining solid dispersion (Compound A + release modifier) with traditional excipients (disintegrant, glidant, lubricant) in the extra-granular portion. This composite approach optimizes both the therapeutic performance and the manufacturability of the oral dosage form.
3Reliability
If Compound A is targeted for AR degradation, then the therapeutic effect is enhanced, but the risk of off-target effects increases
Solution Approach 1:
The formulation acts as an intermediary system that delivers Compound A in a controlled manner to the target site. The solid dispersion with release modifier and the granulation structure serve as intermediaries that regulate the release and distribution of the PROTAC compound, thereby enhancing targeted AR degradation while minimizing off-target effects through controlled bioavailability.
Data Source
AI summary
The present disclosure relates to formulations of Compound A:or a pharmaceutically acceptable salt thereof. The present disclosure also relates to methods of manufacturing such formulations and uses of those formulations in treating prostate cancer.