Ixabepilone Formulation with Multiblock Copolymer
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Solution Overview
Problem
Ixabepilone, used in treating metastatic or locally advanced breast cancer, is difficult to formulate due to low solubility, degradation in aqueous media, sensitivity to pH and light, and poor wetting properties, leading to infusion-related side effects associated with CREMOPHOR EL, necessitating alternative compositions that do not require CREMOPHOR EL reconstitution.
Innovation Solution
A composition comprising ixabepilone with a multiblock poly(amino acid) copolymer and glycine, formulated to improve solubility and stability, and administered in a unit dose form that does not rely on CREMOPHOR EL, enhancing safety and efficacy by reducing side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If CREMOPHOR EL is used as a formulation vehicle for ixabepilone, then solubility is improved, but infusion-related side effects increase
Solution Approach 1:
The patent extracts ixabepilone from the problematic CREMOPHOR EL formulation vehicle and formulates it with alternative excipients (sulfobutyl ether beta cyclodextrin, polyethylene glycol, and water), thereby maintaining solubility while eliminating the harmful side effects associated with CREMOPHOR EL
Solution Approach 2:
The patent uses a composite formulation system combining sulfobutyl ether beta cyclodextrin (for solubilization), polyethylene glycol (for stability and solubility enhancement), and water, creating an alternative formulation that achieves the solubility needed without the toxic effects of CREMOPHOR EL
2Ease of operation
If CREMOPHOR EL is used in formulation, then drug delivery is achieved, but pre-medication and prolonged infusion times are required
Solution Approach 1:
The patent removes CREMOPHOR EL from the formulation, eliminating the need for pre-medication with antihistamines and prolonged infusion times, while maintaining effective drug delivery through alternative solubilization strategies using sulfobutyl ether beta cyclodextrin and polyethylene glycol
3Ease of operation
If CREMOPHOR EL is used for formulation, then ixabepilone can be administered, but plasticizer extraction from tubing occurs
Solution Approach 1:
The patent extracts ixabepilone from the CREMOPHOR EL vehicle that causes plasticizer extraction, formulating instead with water-compatible excipients (sulfobutyl ether beta cyclodextrin and polyethylene glycol) that do not interact with polyvinyl chloride tubing, thereby enabling standard IV administration without harmful plasticizer leaching
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 new composition provides effective treatment of metastatic or locally advanced breast cancer with reduced infusion-related side effects and improved pharmacokinetic profiles, as demonstrated by plasma concentration graphs and growth studies in mice and rats.
Implementation Method 1
ixabepilone, or a pharmaceutically acceptable salt thereof, and a copolymer... improve solubility
Implementation Method 2
copolymer represented by formula I... multiblock poly(amino acid) copolymer
Implementation Method 3
propensity to degrade in aqueous media... improve solubility and stability
Data Source
AI summary
Provided herein are compositions comprising ixabepilone, or a pharmaceutically acceptable salt thereof, and a copolymer represented by formula I:Also provided are methods of treating cancer using the compositions described herein, and methods of preparing the compositions.