Studies On β-Cyclodextrin Derivatives And Its Polymers For Solubilization Of Macrolides

In this paper, the inclusion, solubilization and dissolution behavior of the inclusion complex between β-cyclodextrin (P-CD) derivatives and its polymers with macrolides (azithromycin, roxithromycin, acetylspiramycin) were Primarily investigated. The aim is to improve the solubility and dissolution rate of macrocyclic drugs by β-CD inclusion technology.Firstly, the inclusion complexes of three kinds of macrolides with β-CD and its derivatives were prepared by aqueous saturated solution method, which were characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRD) and nuclear magnetic resonance spectroscopy (1H-NMR). The impact on the inclusion process, in which inclusion rate was an index, was discussed by molar ratio, inclusion temperature, inclusion time and stirring rate, and the most suitable technology of inclusion was optimized by orthogonal designing four factors and three levels L9(34). The best inclusion process are the molar ratio of 1:1 (β-CD:AZM), inclusion temperature 40℃, inclusion time 3h, stirring speed 400 rpm. β-cyclodextrin (β-CD) and its derivatives on the capability of inclusion, solubility and dissolution behavior with poorly water soluble macrolides were studied, and compared four kinds of β-cyclodextrins inclusion complex on solubilization and dissolution ability. The results showed that dimethyl-β-cyclodextrin had better effects of increasing the azithromycin, roxithromycin and Acetylspiramycin. The effects of β-cyclodextrin derivatives of macrolides solubilization capacity and dissolution behavior, and compared four kinds of β-cyclodextrin derivatives solubilization and dissolution ability of cyclodextrin inclusion complex, the results showed that2,6-dimethyl-β-cyclode-Xtrin azithromycin, roxithromycin and acetylspiramycin have better solubilizat-ion. After inclusion by DM-β-CD, the macrolides whose solubility increased by 29.8 times,19.43 times and 17.99 times Compared to its solubility in water, respectively.Secondly, water-soluble β-CD and its derivatives polymers (β-CDP, HP-P-CDP, RM-β-CDP) with epichlorohydrin were synthesized in 30% NaOH solution by copolymer crosslinking reactio, whose influence factors of synthesis process are discussed. Furthermore, the structural of polymers were characteri-zed by FT-IR, XRD and 1H-NMR, and the results showed that the polymer retains its parent original cavity structure.Finally, P-CD and its derivatives polymers on the ability of solubility and dissolution with macrocyclic drugs, compared with β-CD and its derivatives monomer. As a result, β-CD and its derivatives polymeric inclusion compound on solubilization affect and dissolution rate were significantly higher than the monomer. Moreover, in vitro release model fitting were carried on for the original drug, physical mixtures and inclusion complexes, by calculating and linear fitting, we known that the original drug, physical mixtures and clathrates are in consistent with weibull distribution model, the correlation coefficient r ≥0.99.