Gedatolisib Aqueous Formulation Using Cyclodextrin for Clear IV Dosing
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Solution Overview
Problem
Existing formulations of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, known as gedatolisib, are not sufficiently water soluble for intravenous or parenteral administration at therapeutic dosage levels, and existing aqueous solutions are prone to particulate formation, which can cause vascular occlusion.
Innovation Solution
A pharmaceutical aqueous formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, or its pharmaceutically acceptable organic or inorganic acid salt, is stabilized with pharmaceutically acceptable beta- or gamma-cyclodextrin and an organic or inorganic acid, excluding sulphonic acid, to achieve a clear solution concentration of at least 6mg/ml, preventing particulate formation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If gedatolisib is formulated as an aqueous solution for intravenous administration, then the drug can be administered effectively, but the free base form is insufficiently water soluble to achieve therapeutic dosage levels
Solution Approach 1:
The patent changes the chemical form of gedatolisib from free base to acid salt (using pharmaceutically acceptable acids such as hydrochloric acid, phosphoric acid, sulfuric acid, etc.), which fundamentally alters the solubility parameters and enables high-concentration aqueous formulations
Solution Approach 2:
The patent introduces cyclodextrins as intermediary substances that form inclusion complexes with gedatolisib, enhancing its aqueous solubility and enabling stable high-concentration formulations without requiring extreme pH conditions
2Reliability
If existing aqueous formulations are used, then some solubility is achieved, but particulate formation occurs which can cause vascular occlusion
Solution Approach 1:
Cyclodextrins act as intermediary substances that solubilize gedatolisib through inclusion complex formation, preventing precipitation and particulate formation in aqueous solutions, thereby ensuring solution clarity and patient safety
Solution Approach 2:
The patent optimizes pH parameters within specific ranges (pH 2-6 preferably pH 3-5) and controls ionic strength through the selection of appropriate acids and their concentrations, maintaining the drug in a fully solubilized state that prevents particulate formation
3Reliability
If acid salts of gedatolisib are formulated to improve solubility, then water solubility increases, but formulation stability and clarity may be compromised
Solution Approach 1:
Cyclodextrins serve as protective intermediaries that stabilize the solubilized gedatolisib molecules through inclusion complex formation, preventing degradation and maintaining formulation clarity and stability over time
Solution Approach 2:
The patent carefully controls multiple parameters including pH (optimized range pH 2-6), ionic strength, and cyclodextrin-to-drug ratio to achieve the optimal balance between solubility enhancement and formulation stability, preventing both precipitation and degradation
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 allows for safe and effective intravenous or parenteral administration by maintaining a stable, particle-free, clear solution suitable for therapeutic doses without occluding blood vessels.
Implementation Method 1
pharmaceutically acceptable beta- or gamma-cyclodextrin... to achieve a clear solution concentration of at least 6mg/ml, preventing particulate formation
Data Source
Figure 1
AI summary
The present invention relates to a pharmaceutical aqueous formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, or a pharmaceutically acceptable organic or inorganic acid salt thereof, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, that is a clear solution, with the proviso that the organic or inorganic acid (including a salt thereof) is not a sulphonic acid. Such a formulation is particularly suitable for intravenous or parenteral administration to a patient.