Apixaban Oral Liquid Formulation Solubility
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Solution Overview
Problem
The development of oral liquid dosage forms of apixaban is hindered by its low aqueous solubility, leading to high dose volumes and discomfort for patients, particularly geriatric and pediatric populations, who struggle with swallowing large volumes.
Innovation Solution
The creation of non-aqueous and aqueous oral solutions of apixaban that contain higher concentrations of the drug in a minimum amount of solvent, without excessive propylene glycol or glycerin, and without surfactants or certain solubilizers, to achieve stable and patient-compliant formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If apixaban is formulated as an aqueous solution with multiple solubilizers, then solubility is improved, but the number of excipients increases and the formulation complexity increases
Solution Approach 1:
The patent removes water and multiple solubilizers from the formulation, extracting only the essential component (propylene glycol) needed to achieve adequate solubility. This simplifies the formulation from multiple excipients to a minimal set, directly resolving the contradiction between solubility enhancement and formulation complexity.
Solution Approach 2:
The patent changes the formulation parameters by limiting propylene glycol to less than 35% w/v, which is sufficient to achieve the desired solubility without requiring multiple additional solubilizers. This parameter optimization allows adequate drug dissolution while maintaining formulation simplicity.
2Volume of moving object
If apixaban is formulated with high concentration, then dose volume is reduced, but solubility requirements increase
Solution Approach 1:
The patent optimizes the propylene glycol concentration parameter to less than 35% w/v, which provides sufficient solubility capacity to dissolve apixaban at high concentrations (0.25-10 mg/mL) without requiring excessive solvent volume, thus achieving both high concentration and reduced dose volume.
Solution Approach 2:
The patent creates a composite formulation system where propylene glycol serves as both the solvent and solubilizer, combining multiple functions into a single excipient. This composite approach enables high drug concentration dissolution while maintaining formulation simplicity and avoiding the need for multiple separate solubilizing agents.
3Quantity of substance
If propylene glycol content is increased to dissolve apixaban, then solubility is improved, but patient compliance may deteriorate due to taste and safety concerns
Solution Approach 1:
The patent optimizes the propylene glycol concentration to be less than 35% w/v, which is the minimum threshold required to achieve adequate apixaban solubility. By setting this upper limit, the formulation maintains sufficient solubility while minimizing the amount of propylene glycol, thereby reducing taste issues and safety concerns that would affect patient compliance.
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 proposed solutions enable the formulation of apixaban in smaller dose volumes, improving patient compliance and comfort, while maintaining bioavailability and pharmacokinetic properties similar to existing tablet formulations.
Implementation Method 1
Liquid formulations disclosed and taught by the WO'678 publication comprises apixaban and a vehicle that comprises non-ionic surfactant, ionic surfactant, hydrophilic polymer, polyhydric alcohol, polyethylene glycol, and carbohydrate. These excipients are identified as solubilizers
Data Source
AI summary
The present invention discloses liquid dosage forms of apixaban in the form of aqueous & non-aqueous solutions for oral administration. The formulations of the present invention can include higher amount of apixaban with lower amount of solvent and/or vehicles.