Stadnichenko O. Scientific backgrounding and development of liposomal antineoplastic drugs on the basis of irinotecan and oxaliplatin

The thesis is devoted to the scientific and experimental substantiation of the composition and technology of the production of two lyophilized liposomal forms of irinotecan hydrochloride and oxaliplatin intended for the treatment of cancer. The review of scientific world literature on the problem of development and creation of cytostatic forms of medicine was conducted. A scientifically-substantiated model of conducting pharmaceutical development of LLFI and LLFO is proposed. A scientifically-substantiated model of conducting pharmaceutical development of LLFI and LLFO is proposed. A general methodology for determining the degree of encapsulation for water-soluble LLFI and LLFO by the HPLC method in its gel filtration variant is proposed. Analytical techniques have been developed, validated and tested. The methods are used both in the control of LRP, and in the intermediate technological control of production. An experiment was conducted to determine the composition of the lipid membrane and to select an optimal cryoprotectant. Methods of obtaining monolamilary liposomes with the size of 80-120 nm by methods of ultrasonic sounding and extrusion at high pressure have been investigated. The kinetics of irinotecan hydrochloride encapsulation in liposomes was investigated. Developed by MCA for LLFI and LLFO. A technological scheme for obtaining drugs is proposed and tested. The scale of the developed technologies is carried out. Recommendations on methods of cleaning the equipment in the manufacture of drugs at one site are given. For the first time, using preclinical in vitro and in vivo tests, it has been shown that in comparison with non-liposomal solutions for irinotecan and oxaliplatin injections, their liposomal form has lower toxicity rates with the same antitumor activity. Permission for clinical trials has been obtained.