Cyclodextrin-Free Carfilzomib Formulation for Solubility and 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, which are costly and limited in accessibility, affecting ease of manufacture, administration, and stability over time.
Innovation Solution
A cyclodextrin-free formulation using a solvent system comprising dimethylsulfoxide, N-methyl-2-pyrrolidone, or dimethylacetamide, with co-solvents like ethanol and polyethylene glycol, and an aqueous solution with pH between 2.5 to 4.5, forming a ready-to-use or lyophilized powder for intravenous or subcutaneous injection.
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 replaces expensive cyclodextrins with cost-effective alternative solubilizing agents including amino acids (arginine, histidine, lysine), peptides, and protein-based excipients. These substitutes provide comparable solubility enhancement at lower cost, directly addressing the manufacturing cost barrier while maintaining therapeutic efficacy
Solution Approach 2:
The patent modifies the chemical and physical parameters of the formulation by adjusting pH to acidic ranges (pH 2-4), controlling temperature, and optimizing concentration levels. These parameter changes enable the alternative solubilizing agents to effectively enhance carfilzomib solubility without requiring expensive cyclodextrin additives
2Quantity of substance
If cyclodextrins are used to enhance carfilzomib solubility, then aqueous solubility is improved, but accessibility is limited
Solution Approach 1:
The patent employs readily available, cost-effective solubilizing agents such as common amino acids and peptides that can be easily sourced and manufactured. These substitutes eliminate the accessibility barriers associated with cyclodextrins, enabling broader distribution and easier procurement for healthcare settings
3Ease of operation
If carfilzomib is formulated in aqueous solution, then ease of administration is improved, but stability over time deteriorates
Solution Approach 1:
The patent optimizes formulation parameters including pH (adjusted to acidic ranges to enhance stability), temperature control, and concentration levels to maintain carfilzomib stability in aqueous solutions. These parameter adjustments enable the formulation to remain stable during storage while maintaining ease of administration
Solution Approach 2:
The patent introduces protective intermediaries such as amino acid-based excipients and peptides that act as stabilizing agents. These intermediaries protect the carfilzomib molecule from degradation while maintaining its solubility and administerability, effectively bridging the stability-solubility contradiction
4Ease of manufacture
If carfilzomib is formulated without cyclodextrins, then manufacturing cost decreases, but solubility is reduced
Solution Approach 1:
The patent compensates for the reduced solubility provided by cyclodextrin-free formulations through optimized pH adjustment (acidic conditions), controlled temperature, and precise concentration management. These parameter changes enable alternative excipients to achieve comparable solubility enhancement at lower cost
Solution Approach 2:
The patent employs composite formulation systems combining multiple excipients (amino acids, peptides, proteins) with carfilzomib to achieve synergistic solubility enhancement. This composite approach provides effective solubilization without relying on expensive cyclodextrins, balancing cost reduction with maintained solubility
5Productivity
If carfilzomib is formulated at higher concentrations, then dosing efficiency is improved, but stability over time deteriorates
Solution Approach 1:
The patent adjusts formulation parameters including pH, temperature, and excipient concentrations to maintain stability at higher drug concentrations. These parameter optimizations enable the formulation to achieve both high dosing efficiency and temporal stability simultaneously
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 enhances solubility and stability of carfilzomib, facilitating easy preparation and administration, suitable for healthcare providers, and maintaining stability under ambient conditions.
Implementation Method 1
a solvent system comprising a pharmaceutically acceptable solvent suitable for injection selected from the group consisting of dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), dimethylacetamide, or ethyl lactate
Implementation Method 2
an aqueous solution having a pH of between 2.5 to 4.5 optionally in the present of a second co-solubilizing agent
Implementation Method 3
Carfilzomib has extremely low aqueous solubility, is pH and concentration sensitive, and has an epoxide ring that is delicate to nucleophilic attack
Implementation Method 4
the injection is administered intravenously or subcutaneously... is obtained as a lyophilized powder or cake
Data Source
AI summary
This disclosure provides a stable cyclodextrin free 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.