Formulations of 2-(4-chlorophenyl)-N-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide
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Solution Overview
Problem
Current pharmaceutical formulations of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide face challenges in stability and bioavailability due to adverse reactions with excipients, requiring tailored excipients to ensure proper delivery and stability of the active drug substance.
Innovation Solution
Development of lyophilized formulations comprising the compound in combination with pharmaceutically acceptable excipients such as citrate buffer and bulking agents like Captisol®, mannitol, or β-cyclodextrin, which are stable at room temperature and upon reconstitution, suitable for intravenous administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional pharmaceutical excipients are used in formulations of the compound, then the formulation can be manufactured and administered, but the stability and bioavailability are compromised due to adverse reactions between excipients and the active ingredient
Solution Approach 1:
The patent removes problematic excipients from the formulation and replaces them with a minimal set of compatible components. Specifically, the formulation eliminates excipients that cause adverse reactions while retaining only those necessary for stability and bioavailability, such as citrate buffer and specific bulking agents like Captisol®, mannitol, or β-cyclodextrin.
Solution Approach 2:
The patent applies local quality by selecting excipients with specific properties tailored to the active ingredient's requirements. The formulation uses citrate buffer at controlled pH levels and bulking agents with specific solubility characteristics to create localized compatibility zones around the active ingredient, ensuring stable interactions only where needed.
2Reliability
If tailored excipients are selected to ensure stability and proper delivery, then the bioavailability and stability improve, but the formulation complexity and manufacturing difficulty increase
Solution Approach 1:
The patent applies universality by selecting excipients that perform multiple functions simultaneously. For example, citrate buffer serves both as a pH control agent and a stability enhancer, while bulking agents like Captisol® provide both solubility enhancement and stabilization. This multi-functionality reduces the total number of excipients needed, simplifying the formulation despite the specialized requirements.
3Duration of action of stationary object
If lyophilized formulations are developed with specific excipients, then long-term stability at room temperature is achieved, but the formulation requires additional processing steps and specialized excipients
Solution Approach 1:
The patent applies preliminary action by pre-selecting excipients that are inherently compatible with lyophilization processes and provide long-term stability. The formulation is designed from the outset with freeze-drying in mind, choosing excipients like mannitol and β-cyclodextrin that form stable amorphous matrices during lyophilization, preventing degradation during storage without requiring additional stabilization steps later.
Data Source
AI summary
Provided herein are lyophilized formulations of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide or a stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, tautomer, prodrug, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Methods of using the formulations and dosage forms for treating, managing, and/or preventing cancer are also provided herein.