Adagrasib Tablet Composition for Bioavailability and GI Tolerability
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Solution Overview
Problem
Existing adagrasib formulations suffer from adverse events such as nausea, vomiting, and diarrhea, and lack suitable bioavailability and shelf-life stability, with no KRas inhibitor achieving regulatory approval due to safety and efficacy issues.
Innovation Solution
A solid pharmaceutical composition of adagrasib, formulated as tablets with specific excipients like microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, and magnesium stearate, providing targeted pharmacokinetic values and reducing gastrointestinal adverse events.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adagrasib is formulated as a capsule, then it provides adequate bioavailability, but it causes gastrointestinal adverse events and suffers from shelf-life stability issues
Solution Approach 1:
The patent changes the physical form parameter from capsule to tablet and modifies the formulation composition by incorporating specific excipients like microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, and magnesium stearate. These parameter changes resolve the contradiction by maintaining adequate bioavailability while reducing gastrointestinal adverse events and improving shelf-life stability through optimized formulation chemistry and physical structure.
2Ease of manufacture
If adagrasib is formulated as a capsule, then it is easy to manufacture, but it lacks shelf-life stability and suffers from liquid capsule leakage
Solution Approach 1:
The patent changes the physical state parameter from liquid capsule to solid tablet form, which inherently improves shelf-life stability and eliminates leakage issues. The manufacturing process is maintained as straightforward by using conventional tablet compression technology with pre-mixed excipients, thus resolving the contradiction between ease of manufacture and stability.
Solution Approach 2:
The patent creates a composite tablet formulation by combining adagrasib with multiple excipients (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, magnesium stearate) in specific proportions. This composite material approach enhances shelf-life stability while maintaining manufacturability through standard pharmaceutical processing techniques.
3Reliability
If KRas inhibitors are developed to treat cancer, then they target oncogenic mutations, but they fail to achieve regulatory approval due to safety and efficacy issues
Solution Approach 1:
The patent optimizes the pharmacokinetic parameters of adagrasib through formulation modifications, achieving controlled release and reduced peak plasma concentrations. This resolves the safety- efficacy contradiction by maintaining adequate drug exposure for efficacy while reducing gastrointestinal adverse events through modified release kinetics and improved formulation stability.
Data Source
AI summary
Pharmaceutical compositions in solid form comprising adagrasib, suitable for oral dosage to treat subjects having cancer; as well as methods of manufacturing the compositions, and methods of treating cancer.