HDAC Inhibitor Formulations Using Cyclodextrin Complexes
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Solution Overview
Problem
Current HDAC inhibitors, such as PXD-101, face challenges with low solubility in aqueous solutions, physical and chemical instability, and formulation issues that affect their efficacy and stability.
Innovation Solution
The development of pharmaceutical compositions combining HDAC inhibitors with cyclodextrin, arginine, and meglumine, which enhance solubility, stability, and concentration, allowing for improved formulation as ready-to-use solutions or lyophilisates, and intravenous administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If HDAC inhibitors are formulated in aqueous solutions, then they can be administered intravenously, but their solubility is low and stability is poor
Solution Approach 1:
The patent uses cyclodextrins as intermediary molecules that form inclusion complexes with HDAC inhibitors. The cyclodextrin's hydrophobic cavity accommodates the hydrophobic drug molecule, while the hydrophilic exterior ensures water solubility. This mediator resolves the contradiction by enabling intravenous administration through aqueous solutions while protecting the drug from degradation, thus improving both ease of operation and reliability.
Solution Approach 2:
The patent creates composite formulations combining HDAC inhibitors with cyclodextrins, arginine, and meglumine. These composite materials leverage the complementary properties of each component: cyclodextrins provide solubility enhancement and stability, arginine and meglumine act as salt formers to improve solubility. The composite formulation simultaneously achieves intravenous administrability and enhanced chemical stability.
2Quantity of substance
If HDAC inhibitors are formulated with higher concentration, then treatment efficacy is improved, but solubility limitations are reached
Solution Approach 1:
Cyclodextrins act as mediators that increase the apparent solubility of HDAC inhibitors by forming inclusion complexes. This allows the formulation to achieve higher drug concentrations in aqueous solutions without precipitation, directly resolving the contradiction between concentration and solubility.
Solution Approach 2:
The patent changes the physical-chemical parameters of the formulation by introducing cyclodextrins and pH-adjusting agents (arginine, meglumine). These parameter changes modify the solubility characteristics of the system, enabling higher drug concentrations to be maintained in solution. The pH adjustment also optimizes the ionization state of the drug, further enhancing solubility at higher concentrations.
3Ease of manufacture
If HDAC inhibitors are stored in aqueous solutions, then they remain ready for use, but physical and chemical instability occurs
Solution Approach 1:
Cyclodextrins serve as protective intermediaries that shield the HDAC inhibitor molecules from aqueous environment-induced degradation. The inclusion complex protects the drug from hydrolysis and oxidation, enabling stable storage in ready-to-use aqueous formulations. This resolves the contradiction by allowing the formulation to be both ready-for-use and stable during storage.
Solution Approach 2:
The patent employs preliminary stabilization measures by incorporating cyclodextrins and pH buffers into the formulation before storage. This preliminary action of complex formation and pH optimization prevents degradation during storage, allowing the product to remain stable in ready-to-use aqueous form without requiring complex storage conditions.
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
These compositions provide increased stability and concentration of HDAC inhibitors, enabling effective administration and treatment of conditions mediated by HDAC, including cancer and psoriasis, with improved stability and solubility.
Implementation Method 1
cyclodextrin, arginine, and meglumine, which enhance solubility
Implementation Method 2
combining HDAC inhibitors with cyclodextrin, arginine, and meglumine
Data Source
AI summary
This invention pertains to pharmaceutical compositions comprising certain carbamic acid compounds (e.g., which inhibit HDAC (histone deacetylase) activity) (e.g., PXD-101, N hydroxyl-3-(3-phenylsulfamoyl-phenyl)-acrylamide)) and one or more additional ingredients selected from cyclodextrin, arginine, and meglumine. The present invention also pertains to the use of such compositions, for example, in the inhibition of HDAC, and in the treatment of conditions mediated by HDAC, cancer, proliferative conditions, psoriasis, etc.