SELECTION OF THE COMPOSITION OF A LIPOSOMAL DOSAGE FORM OF A RUSSIAN SOMATOSTATIN ANALOGUE WITH ANTITUMOR ACTIVITY

Objective: Was to create the composition of the liposomal pharmaceutical form for injections of somatostatin analogue cyphetrylin using soybean phosphatidylcholine (SPC). Methods: The cyphetrylin, active pharmaceutical ingredient (API), developed in the Chemical Synthesis Laboratory, the N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation; SPC and polyethylene glycol-2000-distearoylphosphatidylethanolamine (PEG-DSPE, Lipoid, Germany); cholesterol ≥99% (Sigma-Aldrich, Japan). The lipid film hydration method with subsequent liposomal dispersion filtration/extrusion through nylon membrane filters was used for the phospholipid vesicle production. Based on API and lipid components in different molar ratios, we studied over 15 model liposomal compositions and assessed each lipid's impact in use on quality attributes of resulting dispersions. Derived model samples of liposomal dispersion were estimated in terms of quality and efficiency of cyphetrylin encapsulation into vesicles, their average size and the surface charge (zeta potential), polydispersity index (PDI) and dispersion viscosity. We used spectral photometry, dispersion laser spectroscopy, electrophoretic particle mobility assay, and viscometry to assess these features. Results: Pharmaceutical form components' desirable molar ratios determined: cyphetrylin/SPC at 1:60.0 and SPC/cholesterol/PEG-DSPE at 1:0.2:0.004, were determined. This composition allows cyphetrylin liposomal dispersion production with relatively stable vesicles of uniform size, 176 nm in diameter, and a 100% maximum rate of API encapsulation into the bilayer. Conclusion: Technological and chemical/pharmaceutical studies resulted in selecting a preferable composition of an injectable liposomal pharmaceutical form model of somatostatin analog-based on the SPC.

Assessing the Impact of Technological Factors on the Stability of Liposomes the Photosensitizer Phthalocyanine Series

Introduction.Liposomal technologies are widely used in medicine and cosmetology as a delivery system for diagnostic and medicinal products and biologically active substances. The undoubted practical importance at the stage of development of a liposomal preparation is represented by the characteristic and assessment of the sustainability of the obtained product, and special attention is paid to the study of the latter. Essentially, the methods for their preparation affect the stability of liposomes; therefore, the study of the influence of technological factors on the properties of the product at various stages of the preparation of liposomes is very important. This article is devoted to the study of the dependence of the quality of liposomes loaded with a phthalocyanine photosensitizer – thiosens, on the conditions of their production.Aim.Detection of the influence of various technological factors on the stability indicators of the liposomal form of the thiosens photosensitizer.Materials and methods.For this purpose, an analysis of the average size, polydispersity and zeta (ζ) potential of the liposomes of thiosens obtained at the stage of hydration of the lipid film, filtration of the liposomal dispersion, its extrusion, homogenization, ultrasonic treatment, and lyophilization was carried out.Results and discussion.During the preparation of a liposomal preparation, various changes in conditions can be made within the framework of the technological process. At each stage of obtaining a liposomal form, there are many critical points and parameters that must be strictly monitored and controlled. In the course of the work, the influence of technological factors on the stability of liposomal intermediate and finished products was assessed. The conditions of the most effective hydration with the formation of a stable dispersion of multilayer liposomes of thiosens and the optimal method of their grinding have been determined. It was also shown that liposomes formed after rehydration of the lyophilisate are more uniform in size and have the highest ζ-potential value in comparison with non-lyophilized liposomal dispersion.Conclusion.Using the example of a thiosens phthalocyanine photosensitizer liposomes, the influence of various technological factors on the stability of this nanostructure is shown, therefore, the characteristic and assessment of the sustainability of the resulting product according to 3 main indicators – vesicle size, polydispersity index, and ζ-potential are of undoubted practical importance.

Subcellular biosynthesis and transport of gangliosides formed from exogenous lactosylceramide in rat liver

In order to clarify the mechanisms of ganglioside biosynthesis and transport we intravenously administered a liposomal dispersion of radiolabelled lactosylceramide (LacCer) to rats and then followed the time course of the individual gangliosides which became radioactive in the Golgi-apparatus and plasma-membrane fractions prepared from the liver. After administration of radiolabelled LacCer the liver retained a substantial amount of radioactivity, which was distributed among an organic phase (mainly residual LacCer), a fraction containing low-Mr substances (mainly 3H2O) and a ganglioside fraction. The hepatocytes were found to provide the bulk of gangliosides biosynthesized from exogenous LacCer. After subcellular fractionation, the total radioactive gangliosides increased in the Golgi apparatus up to 8 h, to then decrease and practically disappear at 24 h; in the plasma membranes they were progressively concentrated, accounting for high absolute values. Ganglioside patterns were greatly modified with time in both the Golgi apparatus and plasma membrane, but without significant differences between them. Biosynthesis in the Golgi apparatus and accumulation in the plasma membrane of each individual ganglioside followed a precursor-product relationship. The obtained results indicated that once a ganglioside is biosynthesized in the Golgi apparatus, it is in part made available for translocation to the plasma membrane, which rapidly occurs, and is in part retained in the Golgi apparatus, where it acts as a precursor for the biosynthesis of more glycosylated gangliosides.