SELECTION OF THE COMPOSITION OF A LIPOSOMAL DOSAGE FORM OF A RUSSIAN SOMATOSTATIN ANALOGUE WITH ANTITUMOR ACTIVITY
Keywords:Somatostatin analogue, Liposomes, Soybean phosphatidylcholine, Pharmaceutical dosage form, Composition, The molar ratio
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.
Bulbake U, Doppalapudi S, Kommineni N, Khan W. Liposomal formulations in clinical use: an updated review. Pharmaceutics 2017;2:12.
Bangham AD. Liposomes: the babraham connection. Chem Phys Lipids 1993;1−3:275−85.
Svistelnik AV, Khanin AL. Liposomal drugs: opportunities and prospects. Med Kuzbass 2014;2:7−16.
Lee MK. Liposomes for enhanced bioavailability of water-insoluble drugs: in vivo evidence and recent approaches. Pharmaceutics 2020;3:264.
Lee Y, Thompson DH. Stimuli-responsive liposomes for drug delivery. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2017;5:10.
Khan YY, Suvarna V. Liposomes containing phytochemicals for cancer treatment−an update. Int J Curr Pharm Res 2017;1:20−4.
Gala UH, Miller DA, Williams RO. Harnessing the therapeutic potential of anticancer drugs through amorphous solid dispersions. Biochim Biophys Acta Rev Cancer 2020;1:188319.
Smirnova AP, Sushinina LP, Ustinkina SV, Shprakh ZS, Budko AP, Smirnova LI, et al. Synthesis and antitumor activity cifetrilin when administered orally. Russ J Biother 2009;2:18.
Shprakh ZS, Yartseva IV, Ignateva EV, Smirnova AP, Sushinina LP, Ustinkina SV, et al. Synthesis and chemico-pharmaceutical characteristics of somatostatin analog with antitumor activity. Pharm Chem J 2014;3:159−62.
Kubasova IYu, Borisova LM, Kiseleva MP, Smirnova LI, Smirnova AP, Ustinkina SV, et al. Search of potential antitumour compounds among of somatostatin hypothalamic hormone analogues. Russ J Biother 2006;3:128–33.
Shprakh Z. Somatostatin analogues for the treatment of neuroendocrine tumours. Dosage forms and routes of administration (review). Int J Appl Pharm 2020;12:6−11.
Mikhaevich EI, Yavorskaya NP, Golubeva IS, Polozkova AP, Partolina SA, Oborotova NA. Studying the possibility of oral delivery of cifetrilin. Russ J Biother 2012;1:3–8.
Shprakh Z, Orlova O, Ignatieva E, Oborotova N, Bunyatyan N. Formulation and evaluation of somatostatin analogue tablets. Int J Appl Pharm 2019;4:220−3.
Shprakh Z, Borisova LM, Kiseleva MP, Smirnova ZS. Preclinical study of cyphetrylin antitumor efficiency on experimental animal tumors. Exp Clin Pharmacol 2019;8:27−31.
Singha Roy A, Das S, Samanta A. Design, formulation and evaluation of liposome containing Isoniazid. Int J Appl Pharm 2018;10:52−6.
Sanarova EV, Zhang Xi, Dmitrieva MV, Lantsova AV, Orlova OL, Polozkova AP, et al. Features of the technology of liposomal formulation of a analog hypothalamic hormone somatostatin. Russ J Biother 2016;4:78–84.
Mehanna M, Elmaradny H, Samaha M. Mucoadhesive liposomes as ocular delivery system: physical, microbiological, and in vivo assessment. Drug Dev Ind Pharm 2010;36:108−18.
Zhou T, Tang X, Zhang W, Feng J, Wu W. Preparation and in vitro and in vivo evaluations of 10-hydroxycamptothecin liposomes modified with stearyl glycyrrhizinate. Drug Delivery 2019;1:673−9.
Budai L, Kaszas N, Grof P, Lenti K, Maghami K, Antal I, et al. Liposomes for topical use: a Physico-chemical comparison of vesicles prepared from egg or soy lecithin. Sci Pharm 2013;4:1151−66.
Van Hoogevest P, Wendel A. The use of natural and synthetic phospholipids as pharmaceutical excipients. Eur J Lipid Sci Technol 2014;9:1088−107.
Zweers ML, Grijpma DW, Engbers GH, Feijen J. The preparation of monodisperse biodegradable polyester nanoparticles with a controlled size. J Biomed Mater Res B Appl Biomater 2003;66:559–66.