Methods for the formulation and manufacture of artesunic acid for injection
Inventors
Ellis, William Y. • Lim, Peter • Maniar, Manaj
Assignees
United States Department of the Army • US Army Medical Research and Development Command
Publication Number
US-7956086-B2
Publication Date
2011-06-07
Expiration Date
2027-06-12
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Abstract
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.
Core Innovation
The invention provides a method for the manufacture of a sterile intravenous or intramuscular formulation of artesunic acid. The method involves first sterilizing artesunic acid powder with ethylene oxide and placing it into a sterile container. This sterilized powder is then dissolved in sterile sodium phosphate buffered solution to produce an injectable formulation suitable for intravenous or intramuscular administration.
The sodium phosphate buffered solution dissolves and dilutes the artesunic acid powder without caking or frothing, resulting in an improved drug product. The invention also relates to the formulation itself and to a method of treating patients with either uncomplicated or severe and complicated malaria using the formulated artesunic acid.
The problem being solved is that prior formulations of artesunic acid for injection, such as the commercially available product manufactured in China, produce fizzing and incomplete dissolution when dissolved in carbonate-containing buffers like sodium bicarbonate. This results in frothing, caking, and carbon dioxide evolution, which hinders rapid and complete dissolution, complicates preparation, and reduces dosage reliability. Furthermore, existing products do not conveniently allow immediate use upon dissolution, involve multi-step dilution, and are not manufactured under the U.S. FDA's Current Good Manufacturing Practice (cGMP) standards.
The invention addresses these problems by using ethylene oxide sterilization of artesunic acid powder to maintain stability and purity, employing a physiologically compatible sodium phosphate buffer that avoids CO2 evolution, provides rapid and thorough dissolution without frothing or caking, and by manufacturing the formulation under cGMP to deliver a sterile, non-pyrogenic, stable product with a shelf life of two years. This enables reliable preparation and administration of artesunic acid for the treatment of severe and complicated malaria.
Claims Coverage
The patent contains three independent claims focusing on the method of producing a sterile artesunic acid product, the kit for making the formulation, and the method of treating malaria using the formulation. The main inventive features center on sterilization without decomposition, dissolution in a sodium phosphate buffer that avoids CO2 production, and pharmaceutical dosing methods.
Method for producing artesunic acid product with extended shelf life and no CO2 upon dissolution
The method comprises sterilizing artesunic acid powder and dissolving it in a physiologically acceptable buffered solution to produce an injectable formulation that does not produce CO2 and has a shelf life of two years.
Composition of physiologically acceptable sodium phosphate buffered solution for dissolution
The buffered solution used is sodium phosphate with an average concentration of about 0.30±0.05 M and a pH of about 8.0±0.3, which dissolves the artesunic acid without caking or frothing.
Kit comprising ethylene oxide sterilized artesunic acid powder and sodium phosphate solution
A kit with a first vial containing ethylene oxide sterilized artesunic acid powder purged with nitrogen and a second vial containing sodium phosphate solution at the defined molarity and pH, which forms a sterile artesunic acid solution without clumping or CO2 production when mixed.
Method of treating malaria patients using sterile artesunic acid formulation
The method involves preparing the sterile artesunic acid injectable formulation by the described sterilization and dissolution method and administering it by intravenous or intramuscular injection according to specified dosing regimens.
The claims cover novel aspects of artesunic acid formulation including sterilization by ethylene oxide without decomposition, dissolution in a sodium phosphate buffer that prevents CO2 evolution and caking, the ready-to-use injectable formulation, a kit for preparing this formulation, and methods of malaria treatment employing this formulation.
Stated Advantages
The sterile sodium phosphate buffered solution dissolves artesunic acid rapidly within 2-3 minutes with only gentle swirling, which is several times faster than existing commercial formulations.
The dissolution process in phosphate buffer does not produce CO2 gas, preventing frothing and caking, thereby allowing clear determination of complete dissolution.
The formulation is immediately usable upon dissolution with no need for additional dilution steps required by other products.
The solution has a physiologically acceptable pH (around 7.2) and osmolality (around 320), which are favorable for parenteral administration compared to other buffers with higher pH and osmolality.
The phosphate buffer allows achieving higher concentrations of artesunic acid suitable for effective intramuscular treatment.
The artesunic acid powder is sterilized under cGMP conditions using ethylene oxide without decomposition, meeting sterility and endotoxin USP requirements, thereby ensuring a non-pyrogenic and stable product with a two-year shelf life.
Documented Applications
Intravenous treatment of patients with uncomplicated, severe, and complicated malaria using sterile artesunic acid injectable formulation.
Intramuscular injection of artesunic acid for malaria treatment at specific dosing regimens.
Use in clinical trials including Phase Ia, Ib, and II trials involving intravenous artesunic acid to evaluate safety, tolerance, pharmacokinetics, and pharmacodynamics.
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