Amorphous Solid Dispersion for ABT-263 Bioavailability
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Solution Overview
Problem
Bcl-2 family inhibitors, such as ABT-263, face challenges with poor aqueous solubility, leading to low bioavailability when administered in solid dosage forms due to crystalline forms and susceptibility to oxidation, which affects their therapeutic efficacy.
Innovation Solution
A solid dispersion formulation of ABT-263 with pharmaceutically acceptable polymers and solubilizers, such as Vitamin E-TPGS, is developed, maintaining an amorphous state and minimizing oxidation, enhancing bioavailability and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If crystalline forms of Bcl-2 family inhibitors are used in solid dosage forms, then the dosage form is mechanically stable and easy to manufacture, but the aqueous solubility and dissolution rate are poor, leading to low bioavailability
Solution Approach 1:
The patent changes the physical state of the active ingredient from crystalline to amorphous form. This parameter change dramatically improves aqueous solubility and dissolution rate while maintaining solid dosage form stability through the use of amorphous solid dispersions embedded in a matrix of pharmaceutically acceptable carriers.
Solution Approach 2:
The patent creates a composite material system where the amorphous active ingredient is embedded in a matrix of pharmaceutically acceptable carriers and stabilizers. This composite structure provides both the improved solubility of the amorphous form and the mechanical stability required for solid dosage forms.
2Reliability
If amorphous solid dispersion is used to improve solubility and bioavailability, then the dissolution rate increases, but the formulation becomes more sensitive to oxidation and requires stabilizers
Solution Approach 1:
The patent introduces antioxidants and stabilizers as intermediary substances that protect the amorphous active ingredient from oxidation. These stabilizers act as mediators between the amorphous form (which is more reactive) and the environment (which causes oxidation), allowing the amorphous form to be used without suffering from its increased oxidation susceptibility.
Solution Approach 2:
The patent converts the harmful effect of increased oxidation susceptibility into a benefit by using it as a marker to identify and optimize protective formulations. The oxidation sensitivity drives the selection of specific stabilizers and storage conditions that ultimately improve overall formulation performance and reliability.
3Reliability
If liquid dosage forms are used to improve bioavailability, then the dissolution is immediate, but patient compliance and taste masking become problematic
Solution Approach 1:
The patent utilizes phase transition to convert the liquid-like solubility characteristics into a solid dosage form. By creating an amorphous solid dispersion, the formulation maintains the high dissolution rate associated with liquid forms while achieving the mechanical stability and patient compliance benefits of solid forms.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The solid dispersion form of ABT-263 exhibits improved bioavailability, stability, and resistance to oxidation, ensuring high plasma concentrations and prolonged absorption, effectively addressing the limitations of crystalline forms and oxidation sensitivity.
Implementation Method 1
maintaining an amorphous state and minimizing oxidation, enhancing bioavailability and stability
Implementation Method 2
resistance to oxidation, ensuring high plasma concentrations and prolonged absorption
Data Source
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AI summary
The invention relates to a pharmaceutical dosage form which comprises a solid dispersion product comprising N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide or a salt, hydrate or solvate thereof, at least one pharmaceutically acceptable polymer, and at least one pharmaceutically acceptable solubilizer. The invention is further directed to processes for preparing the pharmaceutical dosage form and to use of the dosage form for treating proliferative disorders.