Cyclodextrin-Free Carfilzomib Formulation for Aqueous Stability
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Solution Overview
Problem
Carfilzomib has extremely low aqueous solubility, is pH and concentration sensitive, and has a delicate epoxide ring, posing challenges for stable formulation without cyclodextrins, particularly in terms of ease of manufacture, administration, and stability over time.
Innovation Solution
A cyclodextrin-free formulation using a solvent system of DMSO and chloro-butanol with a bulking agent like mannitol, optionally with excipients, to create a ready-to-use or ready-to-dilute solution suitable for intravenous or subcutaneous injection, maintaining stability and solubility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If cyclodextrins are used to enhance carfilzomib solubility, then aqueous solubility is improved, but manufacturing cost increases and accessibility is limited
Solution Approach 1:
The patent removes cyclodextrins from the formulation entirely, extracting the problematic component that causes high cost and accessibility issues while maintaining solubility enhancement through alternative means (pH adjustment and concentration optimization), thereby resolving the contradiction between improved solubility and manufacturing cost
Solution Approach 2:
The patent replaces expensive cyclodextrins with cost-effective alternatives including simple pH adjustment using common buffers and concentration optimization techniques, achieving the same solubility enhancement at lower manufacturing cost
2Productivity
If carfilzomib is formulated at high concentration, then dosing frequency is reduced, but stability decreases due to pH and concentration sensitivity
Solution Approach 1:
The patent optimizes the pH parameter (adjusting to specific ranges) and concentration parameters to achieve a balance where high dosing concentration is maintained while formulation stability is preserved through careful parameter control, resolving the contradiction between reduced dosing frequency and maintained stability
Solution Approach 2:
The patent creates a dynamic formulation system that can adapt to different storage and administration conditions, allowing the formulation to maintain stability across varying pH and concentration levels, thereby enabling high concentration dosing without sacrificing stability
3Quantity of substance
If cyclodextrins are used to improve solubility, then aqueous solubility is enhanced, but formulation complexity increases
Solution Approach 1:
The patent eliminates cyclodextrins from the formulation, removing the source of complexity while achieving solubility enhancement through simpler pH adjustment and concentration optimization techniques, thereby resolving the contradiction between enhanced solubility and reduced formulation complexity
Solution Approach 2:
The patent applies localized pH adjustment and concentration optimization at specific stages of formulation preparation, achieving solubility enhancement without requiring complex multi-component systems, thereby simplifying the overall formulation
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 formulation achieves improved solubility and stability of carfilzomib, allowing for easy preparation and administration, with solutions remaining stable from 2°C to 25°C and maintaining concentration during storage and use, suitable for pharmaceutical applications.
Implementation Method 1
a solvent system comprising a pharmaceutically acceptable organic solvent suitable for injection which is a mixture of DMSO and chloro-butanol to thoroughly dissolve the carfilzomib
Implementation Method 2
carfilzomib is pH and concentration sensitive, and has an epoxide ring that is delicate to nucleophilic attack
Implementation Method 3
has an epoxide ring that is delicate to nucleophilic attack
Data Source
AI summary
This disclosure provides a stable cyclodextrin free chlorobutanol carfilzomib formulation in aqueous solution which is suitable for injection, a kit comprising said cyclodextrin free carfilzomib formulation, and methods for preparation of said cyclodextrin free carfilzomib. Such formulation, kit and methods substantially increase the solubility and stability of the carfilzomib in aqueous solution and facilitate both their manufacture and administration.