Adagrasib Solid Composition for Stable Bioavailability and GI Tolerance
Find Innovative SolutionsGenerate Solutions
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 liquid capsule leakage being a concern.
Innovation Solution
Development of a solid pharmaceutical composition, such as tablets, containing adagrasib with specific excipients like microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, and magnesium stearate, designed to provide optimal pharmacokinetic parameters and minimize gastrointestinal adverse effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If liquid capsule formulations of adagrasib are used, then the drug can be administered orally, but the capsules are prone to leakage over time and exhibit poor shelf-life stability
Solution Approach 1:
The patent transforms the physical state of adagrasib from liquid (in capsules) to solid form (tablets or capsules containing solid drug substance). This parameter change fundamentally resolves the leakage issue and improves shelf-life stability, as solid formulations do not leak and maintain structural integrity over time.
Solution Approach 2:
The patent creates a composite pharmaceutical formulation by combining adagrasib with specific excipients including hydrophilic polymers (such as hydroxypropyl cellulose, carboxymethyl cellulose), hydrophobic polymers (such as ethyl cellulose, polyethylene glycol), and other auxiliary materials. This composite material approach optimizes both stability and dissolution properties while eliminating the leakage problem associated with pure liquid formulations.
2Reliability
If adagrasib formulations are administered to patients, then the drug can treat KRas G12C-mediated cancers, but adverse events such as nausea, vomiting, and diarrhea occur
Solution Approach 1:
The patent introduces polymer excipients as intermediaries between adagrasib and the gastrointestinal environment. These polymers (hydrophilic and hydrophobic types) act as mediators that control drug release, reduce direct irritation to the GI tract, and modulate absorption kinetics, thereby maintaining therapeutic efficacy while reducing adverse events.
Solution Approach 2:
The patent employs effervescent systems and rapid-dissolution formulations that allow the drug to quickly pass through the stomach and enter the intestine for absorption. This 'rushing through' approach minimizes the duration of drug contact with the sensitive gastric environment, reducing gastrointestinal adverse events while ensuring adequate drug delivery.
3Reliability
If adagrasib is formulated for oral administration, then the drug can be given to patients, but achieving optimal bioavailability and consistent drug release is challenging
Solution Approach 1:
The patent uses polymer excipients that perform multiple functions simultaneously: they act as disintegrants, binders, coating materials, and dissolution rate controllers. This multi-functionality approach achieves optimal bioavailability and consistent drug release without requiring complex multi-component systems, thereby balancing performance with formulation simplicity.
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.