Development of pilot technology for liposomal irinotecan production
Keywords:irinotecan, liposomes, lipid bilayer, pilot-industrial technology, pharmaceutic process
Purpose of the study. Based on the experiment to propose technology for obtaining the liposomal form of irinotecan. To analyze the resulting intermediates, suggest control points.
Materials and methods. Lipids manufactured by Lipoid, Germany were used to make liposomes. Cholesterol, citric acid monohydrate, solvents were used by Sigma-Aldrich, USA. The lipid film was produced on a rotary evaporator Buchi 210 with a vacuum controller at a residual pressure of 0.02 atm. The pH was monitored on a pH meter of Seven Compact (Mettler Toledo, USA). For homogenization, a high-pressure extrusion method was used, which was carried out on a Microfluidiser M-110P (Microfluidics, USA). The size of the liposomes was determined at 20 °C on a Zetasizer Nano ZS (Malvern Instruments, UK). The technology of the “chemical gradient” was carried out using the ultrafiltration method at the pilot plant ASF-018 (Vladiart, Russia). The level of encapsulation of irinotecan in liposomes, irinotecan concentration, and impurity content were monitored by high performance liquid chromatography (HPLC) using Shimadzu LC-20 chromatographs (Japan). The lyophilization process was performed on Quarco equipment (PRC).
Results. Technologies of nano-structured drugs obtaining require an integrated approach to development. The article discusses the order of the liposomal form of irinotecan production, the experience gained in the pharmaceutical development and the introduction of the drug into pilot production is structured. The key stages of production, the necessary points for "in process" control, and quality control of the finished medicinal product are analyzed. The differences between the laboratory scale technology and the technology implemented in pilot scale are considered.
The implementation of the presented technology was laid down at the stage of pharmaceutical development and scientifically-practically confirmed by a number of conducted experiments. As a result, product series with stable quality indicators were obtained with reproducible and controlled process parameters.
Conclusions. The original experimental-industrial technology of obtaining liposomal form of irinotecan is proposed. The stages of the technology are analyzed from the point of view of industrial implementation, control points are proposed.
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