The Development of Intratumoral in Situ Implant With Berberine Bisulphate

Abstract

Berberine (BB) is an isoquinoline alkaloid, which is obtained from Berberis (Barberry), more often Berberis vulgaris, of the Berberidaceae family. The interest of the scientific community in this molecule was caused by its vast number of pharmacological effects: antitumor, hypolipidemic, anti-inflammatory, antiarrhythmic, antidiabetic, etc. The antitumor effect of BB consists in the inhibition of the cell cycle in the G1 phase, the induction of apoptosis in tumor cells, the effect on mitogen-activated kinases, and the suppression of metastasis. The main reason for the infrequent use of this molecule is its poor solubility and low bioavailability. Thus, the best solution to overcome these problems is intratumoral implantation. During the analysis of scientific publications, it was found that in the process of developing intratumoral implants when creating matrices with various active substances, it is most often preferred to use poloxamers, since the temperature stimulus is the most characteristic and reliable in therapy. Thus, the aim of the study is to develop the composition and technology of an intratumoral thermosensitive implant of berberine bisulfate (BBB). The study used 101.6% BBB substance (Vifitech, Russia). Kolliphor® P188, Kolliphor® P338, Kollisolv® P124 and Soluplus®, polysorbate-80, PEG-1500 (BASF, Germany) were used as solubilizers. N-methylpyrrolidone was also considered as a candidate for dissolution media. Solubilization of BBB was carried out by adding surfactants and their combinations, by the method of solid dispersions, liquid-liquid extraction. BBB showed very low solubility in N-methylpyrrolidone. The final composition contained Kolliphor® P 407 (15.0%), Kolliphor® P 188 (2.0%), Kollisolv® P124 (2.0%), BBB (1.3%) with a phase transition rate of 2 minutes and phase transition temperature 37-38℃. For the obtained optimal composition, the “Dissolution” test was carried out using a dialysis bag, in a phosphate buffer solution pH 6.8, at a constant temperature of 37℃. Sampling was carried out after 1 hour, 2 hours, 3 hours, 5 hours, 24 hours and 96 hours. The concentration of the substance was determined using spectrophotometry. As a result of the studies carried out, the most suitable composition for an intratumoral implant was created, and the necessary tests were carried out. It can also be concluded that the use of poloxamers is effective in improving the dissolution of BBB. Further research is required.