Lyophilized FVIII/VWF Formulation for High-Potency Low-Volume Dosing
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Solution Overview
Problem
Current FVIII/VWF products face challenges in reducing administration volume due to low solubility and high osmolality, leading to prolonged infusion times and undesirable side effects, especially in pediatric doses.
Innovation Solution
A method involving increased albumin concentration and reduced histidine and arginine levels in the formulation, maintaining osmolality within acceptable ranges, allows for higher FVIII and VWF potency per vial, reducing administration volume by up to four times without affecting solubility or stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If the concentration of excipients (histidine and arginine) is increased to improve solubility, then solubility is improved, but osmolality becomes unacceptable
Solution Approach 1:
The patent changes the concentration parameters of excipients by decreasing histidine and arginine levels while increasing albumin concentration. This parameter optimization allows achieving acceptable solubility without causing unacceptable osmolality, resolving the contradiction between solubility improvement and osmolality control.
Solution Approach 2:
The patent introduces albumin as an intermediary substance that mediates between the conflicting requirements of solubility and osmolality control. By increasing albumin concentration, the formulation achieves better solubility while the overall osmolality remains within acceptable ranges, as albumin provides solubility enhancement without proportionally increasing osmolality.
2Quantity of substance
If the reconstitution volume is reduced to increase potency, then potency is improved, but solubility decreases causing flocculates and increased reconstitution time
Solution Approach 1:
The patent optimizes the concentration parameters of excipients (decreasing histidine and arginine, increasing albumin) to enable higher potency formulations. These parameter changes allow the formulation to maintain solubility even at reduced reconstitution volumes, preventing flocculate formation and controlling reconstitution time while achieving increased potency.
3Loss of time
If the administration volume is reduced to improve treatment efficiency, then treatment duration is reduced, but product osmolality becomes unacceptable for high doses
Solution Approach 1:
The patent optimizes the excipient composition by decreasing histidine and arginine concentrations while increasing albumin. This parameter optimization enables high-dose formulations (up to 3600 IU FVIII per vial) to maintain acceptable osmolality even at reduced administration volumes, allowing shorter treatment durations without causing unacceptable osmolality-related side effects.
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 method achieves higher FVIII and VWF potency per vial, reducing infusion volume, maintaining solubility and osmolality, and ensuring stability up to 36 months at various temperatures, suitable for treating Hemophilia A and Von Willebrand Disease.
Implementation Method 1
a new method for producing a lyophilized pharmaceutical composition comprising human plasma-derived Factor VIII/Von Willebrand Factor (FVIII/VWF) complex
Implementation Method 2
The formulation step allows solubilizing the FVIII/VWF complex, lyophilizing, and reconstituting prior to administration
Data Source
AI summary
The present invention refers to a new method for producing a lyophilized pharmaceutical composition comprising human plasma-derived Factor Vlll/Von Willebrand Factor (FVIII/VWF) complex, comprising the steps of: a) providing an initial aqueous solution comprising FVIII/VWF with at least (90) III of FVIII per mg of total proteins, with a ratio of VWF/FVIII activity of at least 0.7; b) adding arginine, histidine, and human serum albumin (HAS); c) lyophilizing the FVIII/VWF solution obtained in step b); and d) reconstituting the lyophilized FVIII/VWF in water for injection thereby obtaining a therapeutic product adequate for the treatment of Hemophilia A and Von Willebrand Disease, wherein prior to administration to a patient, arginine is at a concentration between (42) and (98) mmol/L, histidine is at a concentration between (10) and (24) mmol/L, and albumin is at a concentration between (1) and (2.5) % (w/v), FVIII potency and VWF potency are equal to or higher than 200 ILI/mL, and the obtained product has a FVIII dose up to 3600 lU/vial and a VWF dose up to 5040 lll/vial.