Oxidized Phospholipid Capsule Formulation Stability
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Solution Overview
Problem
Oxidized phospholipids, such as VB-201, are challenging to formulate into traditional dosage forms due to their sticky and hygroscopic nature, leading to instability and inhomogeneity in liquid-fill capsules, which results in leakage and cracking.
Innovation Solution
The development of pharmaceutical compositions comprising oxidized phospholipids with a thermosoftening carrier and an anti-adherent agent, where the oxidized phospholipid is mixed with the anti-adherent agent before contacting the thermosoftening carrier, creating a stable solid or semi-solid matrix that prevents leakage and enhances homogeneity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If oxidized phospholipids are formulated into liquid-fill capsules, then oral administration is achieved, but the sticky and hygroscopic nature causes inhomogeneity and instability
Solution Approach 1:
The patent changes the physical state parameter of the carrier from solid to liquid by heating above its melting point, enabling capsule filling. The carrier then solidifies upon cooling to provide stability. This parameter change resolves the contradiction by allowing oral administration in capsule form while maintaining formulation stability through temperature-controlled phase transitions.
Solution Approach 2:
The patent creates a composite fill composition combining oxidized phospholipids (active ingredient) with a thermosoftening carrier (e.g., poloxamer or polyethylene glycol). This composite material leverages the carrier's solvating power to dissolve the sticky phospholipids while providing a stable matrix that prevents inhomogeneity and instability upon cooling.
2Quantity of substance
If oxidized phospholipids are dissolved in solvent mixture for soft capsules, then solubilization is achieved, but the solvent volume required is too large for economically acceptable capsule sizes
Solution Approach 1:
The patent changes the temperature parameter to above the carrier's melting point, transforming it from a solid to a liquid state. This enables the carrier to dissolve the oxidized phospholipids efficiently, achieving adequate solubilization in a smaller volume that results in economically acceptable capsule sizes while maintaining manufacturing feasibility.
3Ease of manufacture
If the fill composition is made liquid for easy filling, then filling process is simplified, but leakage and cracking occur due to instability
Solution Approach 1:
The patent employs a dynamic system where the carrier's physical state changes with temperature. During filling, the carrier is heated to become liquid for easy pouring into capsules. After filling, the carrier solidifies upon cooling to provide structural integrity, preventing leakage and cracking. This dynamic phase transition resolves the contradiction between ease of filling and capsule reliability.
Solution Approach 2:
The patent utilizes the phase transition of the thermosoftening carrier from solid to liquid at elevated temperatures and back to solid upon cooling. This phase transition enables liquid-fill processing during manufacturing while ensuring solid-state stability in the final product, thereby preventing leakage and cracking while simplifying the filling process.
4Device complexity
If oxidized phospholipids are mixed directly with thermosoftening carrier, then formulation is simplified, but inhomogeneity occurs due to adherent properties
Solution Approach 1:
The patent applies preliminary action by pre-mixing the oxidized phospholipids with an anti-adherent agent before contacting with the thermosoftening carrier. This preliminary step prevents the sticky phospholipids from adhering to equipment surfaces and ensures uniform distribution, achieving homogeneity without significantly complicating the overall formulation process.
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 solution stabilizes the oxidized phospholipid formulation, preventing leakage and cracking, and significantly improves the homogeneity of the final product, ensuring consistent dosing and extended stability.
Implementation Method 1
the carrier has a melting point in a range from about 40 °C to about 100 °C, and the mixing is performed above the melting point
Implementation Method 2
contacting the oxidized phospholipid with the thermosoftening carrier, to thereby obtain the liquid-fill composition
Data Source
Figure 1A
Figure 1B
Figure 2
AI summary
The current disclosure provides pharmaceutical compositions containing an oxidized phospholipid, such as l-hexadecyl-2-(4'-carboxybutyl)-glycero-3-phosphocholine (VB-201) and a thermosoftening carrier, e.g., a poloxamer. The pharmaceutical compositions may further comprise an anti-adherent agent, such as talc and/or a thixotropic agent. The current disclosure further provides processes for preparing the pharmaceutical compositions. The disclosure further provides capsules containing the pharmaceutical compositions. Uses of such pharmaceutical compositions and capsules in treating inflammatory disorders are also disclosed.