Pazopanib Formulation for Sustained Intravitreal Release
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Solution Overview
Problem
Current formulations of therapeutic agents with low aqueous solubility, such as pazopanib, face challenges in stability and delivery to the eye due to low solubility and rapid precipitation, leading to inefficient treatment of ocular diseases like age-related macular degeneration and diabetic retinopathy, with repeated intravitreal injections posing risks and burdens to patients.
Innovation Solution
Development of stable pharmaceutical formulations of pazopanib as a monovalent or divalent salt, incorporating complexing agents like cyclodextrins and solubilizing agents like poly(vinyl pyrrolidone), along with buffering agents like Histidine HCl, which are lyophilized from solvents like dimethyl sulfoxide or trifluoro ethanol to enhance solubility and stability, allowing for controlled release through a porous structure in an intravitreal delivery device.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If repeated intravitreal injections are used to deliver therapeutic agents, then treatment efficacy is improved, but patient burden and risk of vision-threatening complications increase
Solution Approach 1:
The invention divides the treatment duration into multiple months by using a sustained-release intravitreal implant that releases the therapeutic agent gradually over time, eliminating the need for repeated monthly injections while maintaining treatment efficacy
Solution Approach 2:
The intravitreal implant is designed to automatically release the therapeutic agent over several months without requiring patient intervention or medical procedures, making the treatment system self-sustaining and eliminating repeated patient visits
2Adaptability or versatility
If therapeutic agents with low aqueous solubility are used, then treatment specificity is improved, but formulation stability and delivery efficiency deteriorate due to rapid precipitation
Solution Approach 1:
The invention uses cyclodextrin as an intermediary complexing agent that forms inclusion complexes with the low-solubility therapeutic agent, thereby increasing aqueous solubility and preventing precipitation while maintaining the agent's therapeutic specificity
Solution Approach 2:
The formulation combines the therapeutic agent with cyclodextrin and other excipients to create a composite formulation that maintains the agent's specificity while improving stability through the complexing action of cyclodextrin
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 formulations achieve extended stability and solubility of pazopanib, preventing precipitation and ensuring sustained release over several months, thereby improving treatment efficacy and reducing the frequency and risks associated with intravitreal injections.
Implementation Method 1
incorporating complexing agents like cyclodextrins
Implementation Method 2
solubilizing agents like poly(vinyl pyrrolidone)
Implementation Method 3
which are lyophilized from solvents like dimethyl sulfoxide or trifluoro ethanol
Data Source
AI summary
The present disclosure relates to stable formulations of receptor tyrosine kinase inhibitors (TKI), e.g., pazopanib; methods of preparation thereof; and use of the disclosed formulations in sustained delivery of the active agent to a target site. The disclosure further relates to methods of converting one polymorphic Form of a TKI to another polymorphic Form and/or an amorphous form.