| Diclazuril, a drug in triazine benzacetonitril family, is a new, highly effective and lowly toxic coccidiostats, the safety and bioavailability of which, unfortunately, is affected by its drawbacks such as low content in drugs and poor solubility in water. In addition, the short time active role and instability of Diclazuril, requiring continuous medication, bring inconvenience for clinical use. The enteric microcapsules, prepared by enteric polymer materials are good for improving the stability in the stomach and targeting. In order to prepare sustained-release and stable Diclazuril drug delivery system and cure intestinal disease caused by coccidiosis, the Diclazuril enteric targeting microcapsules were studied and developed in this study. The Diclazuril enteric microcapsules were manufactured by the methods of intra-liquid desiccation using Eudragit L as coating material. The related properties and pharmacokinetic in rabbits of Diclazuril enteric microcapsules were studied.The content detection method was established by ultraviolet spectrophotometry for determining the encapsulation efficiency and drug loading. The regression equation of concentration and absorbance of Diclazuril was:A=0.034903C-0.003619 (r=0.9999, n=5). The linear range was 5-25μg/mL. The intro-day and inter-day precision was 0.31-0.86%and0.53-1.49%, respectively. The recovery rate was 98.72-100.34%. The results accord with the drug content determination requirements.The formulation and technology was studied with the orthogonal design and the single factor design. The optimal preparation techniques were as follows:the amount of Eudragit L, Span-80 and Magnesium Stearate was 1.5g,2.5g and 1.25g respectively, the speed of stir was 300r/min. The results indicated that the Diclazuril enteric microcapsule had a spherical shape, smooth surface, in-adhesive and the microcapsule particle mean size was 270μm. The mean encapsulation and mean loading rate was 87.42%and 26.57%respectively. In vitro release experiment, the dissolution behavior of the active compound and enteric microcapsule in artificial gastrointestinal was determined. The release of Diclazuril from the enteric microcapsules in vitro substantiated role of sustained release, compared with the active compound, meanwhile, the dissolution behavior of Diclazuril enteric microcapsule in vitro also proved that it is a enteric-target preparation. The stability experiment show that after microencapsulation the ability of Diclazuril resist light, heat and moisture was improved.The Diclazuril enteric microcapsule and Diclazuril were administrated on health rabbits by lavage. Using drug concentration in plasma as an indicator, their pharmacokinetic differences were compared. Plasma drug concentration was determined by HPLC, limit of detection of plasma concentration was 0.16μg/mL. Pharmacokinetic parameters were analyzed by DAS2.0 pharmacokinetic program. The data was analyzed by SPSS (17.0). The results showed that data of A(Diclazuril), B(enteric microcapsule) group was in line with a two-compartment model (weight= 1/CC), The main pharmacokinetic parameters and the fitting equation as follows:A group:T1/2Ka was(3.451±0.089)h; T1/2a was (15.813±0.098)h; T1/2βwas (26.088±0.177)h; Tmax was (6±0.000)h; Cmax was (58.541±0.021)mg/L; AUC(0-∞) was (4129.138±13.546) mg/L*h; MRT(0-∞) was (64.011±0.44)h; the fitting equation: C=147.794e-0.037t+18.418e-0.005t-166.212e-0.216t. B Group:T1/2Ka was (11.957±0.375)h; T1/2αwas (17.938±0.343)h; T1/2βwas (29.523±0.219)h; Tmax was (24±0.000)h; Cmax was (76.738±0.073)mg/L; AUC(0-∞) was (6017.061±16.872) mg/L*h; MRT(0-∞) was (75.904±0.623)h; the fitting equation: C=258.328e-0.043t+22.058e-0.023t-280.386e-0.058t. It is concluded that Diclazuril give a slow absorption and elimination, long half-life and high bioavailability after it was made into microcapsule.The Diclazuril enteric microcapsule was successfully prepared in this experiment. The method was handy and simple, and the quality was adjustable. The quality evaluation, release test in vitro and pharmacokinetic experiment indicated that Diclazuril enteric microcapsule obtained targeting, sustained-release, and better stability. It is potential to be used as a good carrier in drug delivery system. |
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