RESUMO
Objective: In order to improve the bioavailability of the insoluble drug silybin, silybin supersaturated self- nanoemulsifying drug delivery systems (SLB-S-SNEDDS) containing functional oil were prepared, its characterization and in vitro evaluation were also performed. Methods: Functional oils were screened by performing potassium ferrohydride reduction and 1,1- diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging experiments. The pseudo-ternary phase diagram was drawn to investigate the emulsifying ability of emulsifier. The proportion of mixed oil phase and drug loading capacity were explored by analyzing particle size, polydispersity index (PDI), zeta potential, etc. The type and concentration of supersaturated substance in SLB-S-SNEDDS were obtained by conducting the compatibility and dissolution experiments. SLB-S-SNEDDS was characterized with appearance, particle size distribution, self-emulsification efficiency, and morphology, and its in vitro dissolution, antioxidant capacity, and cytotoxicity were also evaluated. Results: The prescriptions of SLB-S-SNEDDS were as follows: (1) wheatgerm oil/Capryol 90- Cremophor ELP-Transcutol HP; (2) seabuckthorn seed oil/Capryol 90-Cremophor ELP-Transcutol HP. One g S-SNEDDS matrix contained 0.043 g of wheatgerm oil or sea-buckthorn seed oil, 0.387 g of Capryol 90, 0.380 g of Cremophor ELP, and 0.190 g of Transcutol HP. The adding amount of silybin in S-SNEDDS prescription was 20% of the sum of the equilibrium solubility of silybin in each component, and the adding amount of Soluplus was 0.1% of the total mass described above. The two obtained SLB-S-SNEDDS were transparent homogeneous liquid with light yellow (wheat germ oil) and bright yellow (seabuckthorn seed oil) color, respectively. After being dispersed, SLB-S-SNEDDS turned into subspherical white flat emulsion droplets with the particle size of about 50 nm, and the emulsification time was 65 s. Compared with raw materials and SLB-SNEDDS, the cumulative dissolution of silybin in SLB-S-SNEDDS was maintained between 85% and 110% within 8 h, indicating that the two systems can significantly improve the dissolution of silybin. The absorbance of SLB-S-SNEDDS after reaction with potassium ferricyanide (0.452-0.782, 0.488-0.765) and the DPPH free radical clearance of SLB-S-SNEDDS (39.09%-96.02%, 30.54%-89.20%) were all higher than those of raw silybin (0.411-0.760, 22.89%-63.21%), which suggested that the two systems can enhance the antioxidant capacity of silybin. Cytotoxicity test results showed that the cell survival rate in silybin raw material group, combination of silybin and S-SNEDDS group, and blank S-SNEDDS group were greater than 90% at 5 µmol/L and 10 µmol/L drug concentration, indicating that SLB-S-SNEDDS and its auxiliary materials were safe and less toxic to human cloned colorectal adenocarcinoma cell line (Caco-2). Conclusion: The SLB-S-SNEDDS containing functional oil prepared in this paper can not only increase the cumulative dissolution of silybin, but also enhance its antioxidant capacity, which provides a useful reference for supersaturated self-nanoemulsifying drug delivery systems (S-SNEDDS) to improve the water-solubility and bioactivity of insoluble drugs.
RESUMO
OBJECTIVE: A multicenter survey is conducted to study the application,the long-term effect and safety of hydroxychloroquine(HCQ)in the treatment of rheumatic diseases in Suzhou. METHODS: Retrospectively collect the data of outpatients and inpatients from Rheumatology Department of four general hospitals in Suzhou(the First Affiliated Hospital of Suzhou University, and Suzhou Hospital of Traditional Chinese Medicine, the First People's Hospital of Kunshan, the First People's Hospital of Changshu)from June 2017 to July 2018. A special questionnaire was used to collect data on general information, diagnosis, methods and courses in the use of hydroxychloro-quine, duration, efficacy and compliance, combined medication, adverse reactions of ophthalmology and other systems, and the use of hydroxychloroquine(HCQ)during pregnancy.Result Totally there were 856 cases, including 68 males(7.9%)and 788 females(92.1%).Classification of diseases: 147 cases of RA(including secondary SS of RA), 425 cases of SLE,12 cases of APS, 167 cases of PSS,104 cases of others, and 1 case of overlap syndrome(RA with SLE)The treatment course of HCQ: minimum 0.5 years, maximum 22.75 years, with an average of 3.59(SD=3.08)years.Dosage: 0.2 g/day in 604 cases, 0.4 g/day in 424 cases, 193 cases of using 0.4 and 0.2 successively, and 21 in other cases;721 cases used continuously. There were adverse reactions in 183 cases(7 males and 176 females), which were distributed in 30 cases of RA, 105 cases of SLE, 2 cases of APS, 31 cases of SS and 15 other cases. Ophthalmological adverse reactions occurred in 70 cases, with positive correlation in 4 cases. Ophthalmological examination: 121 cases(14.1%)every year;68 cases(7.9%)every two years. There were 92 cases of adverse skin reactions, with 8 cases of positive correlation. Other systems had few adverse reactions and there was no positive correlation. Continuous medication, combination of anti-rheumatic drugs and adverse reactions were associated, and continuous medication or combination of anti-rheumatic drugs were significantly associated with adverse reactions in ophthalmology and skin, respectively. The adverse reactions of ophthalmology were related to the course of treatment, and the adverse reactions of fundus increased after taking medicine for more than 7 years.There were 37 pregnancies and HCQ was used in 17 cases throughout pregnancy, and only 1 case had non-drug-related neonatal defects. CONCLUSION: HCQ is mainly used in the treatment of SLE, SS, RA and APS in Rheumatology Department in Suzhou. HCQ medication is standardized, but ophthalmic follow-up monitoring is not. Adverse reactions are mainly in skin and ophthalmology. Continuous medication and combination of antirheumatic drugs are associated factors of adverse reactions.Long-term treatment with HCQ is safe and well-toleratrd.