Artesunic Acid Formulation Dissolution and Sterility
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Solution Overview
Problem
Current artesunic acid formulations for parenteral injection are unstable, prone to decomposition, and have poor dissolution characteristics, leading to incomplete solution formation and uncertainty in drug concentration, with existing products not meeting Good Manufacturing Practice (cGMP) standards and requiring additional dilution steps.
Innovation Solution
The formulation uses ethylene oxide-sterilized artesunic acid dissolved in a 0.30 M, pH 8.0 sodium phosphate buffered solution, which prevents gas evolution and ensures rapid, complete dissolution without caking or frothing, allowing for immediate use and compliance with cGMP standards.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If artesunic acid is dissolved in 5% sodium bicarbonate solution, then the drug can be prepared for injection, but the solution fizzes and cakes resulting in incomplete dissolution and uncertain concentration
Solution Approach 1:
The patent changes the dissolution medium from 5% sodium bicarbonate to sterile water for injection, fundamentally altering the dissolution parameters to eliminate CO2 evolution and caking while ensuring complete dissolution and accurate concentration
Solution Approach 2:
The patent converts the harmful effect of CO2 evolution (fizzing and caking) into a benefit by selecting a dissolution medium (sterile water) that prevents this reaction entirely, thereby eliminating the harmful phenomenon rather than working around it
2Reliability
If artesunic acid is sterilized and stored in a vial, then the product can be manufactured under cGMP standards, but the powder may decompose when exposed to moisture or aqueous solutions
Solution Approach 1:
The patent uses nitrogen gas to purge the vial headspace and create an inert atmosphere, preventing moisture-related decomposition of artesunic acid while maintaining sterility and chemical stability during storage
Solution Approach 2:
The patent introduces nitrogen gas as an intermediary between the artesunic acid powder and the external environment, acting as a protective barrier that prevents moisture ingress and decomposition while allowing the drug to remain stable in solid form
3Productivity
If the dissolution process is allowed to proceed with gas evolution, then the drug dissolves, but the gas bubbles trap undissolved particles and lengthen dissolution time
Solution Approach 1:
The patent changes the dissolution medium to sterile water, which eliminates gas evolution during dissolution, thereby preventing bubble formation that would trap undissolved particles and significantly reducing dissolution time
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 provides a sterile, non-pyrogenic, rapidly dissolving artesunic acid formulation suitable for intravenous or intramuscular administration, with improved stability and usability, meeting cGMP requirements and extending shelf life, and has shown successful results in clinical trials for treating severe malaria.
Implementation Method 1
the artesunic acid powder is dissolved in sterile sodium phosphate buffered solution to produce a solution suitable for intravenous or intramuscular administration
Implementation Method 2
the artesunic acid powder is sterilized with ethylene oxide
Data Source
AI summary
A method for the manufacture of a sterile intravenous or intramuscular formulation of artesunic acid and the formulation are the subject of this invention. First the artesunic acid powder is sterilized with ethylene oxide and placed into a sterile container. The contained sterilized powder is then dissolved in sterile sodium phosphate buffered solution to produce an injectable intravenous or intramuscular formulation. The sodium phosphate dissolves and dilutes the artesunic acid powder without caking or frothing resulting in an improved drug product. The invention also relates to the formulation and a method of treating a patient with either uncomplicated or severe and complicated malaria.