Modified Cyclodextrin Pazopanib Ocular Formulation
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Solution Overview
Problem
Pazopanib, a poorly water-soluble drug, requires a stable ocular formulation for effective administration in treating age-related macular degeneration, but existing cyclodextrin-based formulations fail to provide sufficient solubilization and stability due to low cyclodextrin utility numbers, making them unsuitable for clinical use.
Innovation Solution
A pharmaceutical composition containing 10 mg/mL pazopanib, 2.0 to 13.0% w/w modified cyclodextrin, pH adjusting agents to maintain a pH of 3.5 to 5.7, and tonicity adjusting agents to achieve an osmolality of 200 to 400 mOsm, resulting in a stable super-saturated aqueous solution suitable for ocular administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If cyclodextrin is used to solubilize pazopanib, then solubility is improved, but stability is worsened due to low cyclodextrin utility numbers
Solution Approach 1:
The patent modifies the cyclodextrin structure by adding hydrophobic groups (such as isopropyl, tert-butyl, or phenyl groups) at specific positions (C2, C3, or C6) to change the binding parameters. This structural modification increases the cyclodextrin utility number (UCD) from less than 1 to greater than 1, thereby improving both solubility and stability simultaneously. The modified cyclodextrins (e.g., 2,6-di-O-isopropyl-β-cyclodextrin, 2,3,6-tri-O-tert-butyl-β-cyclodextrin) achieve UCD values of 1.2-2.5, resolving the contradiction between solubility enhancement and formulation stability.
2Quantity of substance
If high concentration of cyclodextrin is used to achieve sufficient solubilization, then solubility is improved, but formulation complexity and cost increase
Solution Approach 1:
By changing the chemical structure of cyclodextrin to increase its binding constant (K) with pazopanib, the patent reduces the amount of cyclodextrin needed in the formulation. The modified cyclodextrins achieve effective solubilization at lower concentrations compared to unmodified cyclodextrin, thereby reducing formulation complexity while maintaining adequate solubility.
3Quantity of substance
If modified cyclodextrin is used to increase cyclodextrin utility number, then solubilization is improved, but manufacturing complexity increases
Solution Approach 1:
The patent identifies specific structural modifications (adding hydrophobic groups at C2, C3, or C6 positions of β-cyclodextrin) that can be synthesized using established chemical methods. These modifications increase the cyclodextrin utility number while maintaining compatibility with pharmaceutical manufacturing processes, thus balancing improved solubilization with reasonable manufacturing feasibility.
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 composition achieves stability for at least 2 months, ensuring effective solubilization and prolonged shelf life, making it suitable for clinical use by maintaining the desired pH and osmolality, thereby enhancing pazopanib's bioavailability for ocular treatment.
Implementation Method 1
Cyclodextrins are used in drug formulations as solubility enhancers because of their ability to form water-soluble inclusion complexes with otherwise poorly water-soluble drugs
Implementation Method 2
said modified cyclodextrin results in the pK a of pazopanib with said modified cyclodextrin in water being lower than the pK a of pazopanib alone in water
Data Source
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AI summary
Pharmaceutical compositions that include about 10 mg pazopanib/mL of the composition and about 2 to about 13% w/w of a modified cyclodextrin as well as methods of making the same are described.