Studies On Curcumin Loaded Gelatin Microspheres For Lung Targeting

Objective: In order to explore a new method and new technique for lung targeted drug deliver y system (LTDDS). Lung cancer was one of the most serious malignant tumors threatening people's health and lives. Curcumin extracted from curcuma L was a natural active ingredient, and it had a wide effect of precaution and therapy on tumors, moreover, low side-effect made it posses a spacious application perspective. However, the low solubility and low oral administration bioavailability limited its application in clinic. In this study, lung targeted gelatin microspheres of curcumin (C-GMS) was prepared in which the biodegradable gelatin was used as carrier, and curcumin was selected as model drug. Furthermore, Physicochemical properties in vitro were characteristized, and pharmacokinetics and tissue distribution in rabbits were investigated to evaluate its lung targeting.Methods: The method of emulsification-linkage was used to prepare C-GMS. According to the results of single factor tests, the formulation and preparation technology was screened and optimized by orthogonal design experiment. The morphology of microspheres was observed through scanning electron microscope and light microscope, then the powder mass properties such as bulk density, angle of repose, particle diameter and size distribution were also investigated. The entrapment efficiency and drug loading capacity for microspheres were determined using the method of UV spectrophotometry. The release property and mechanism of microspheres in vitro were studied by dialysising. The stability test was subsequently carried out. Finally pharmacokinetics, tissue distribution and lung targeting were performed in rabbits with curcumin injection as control.Results: The major factors affecting particle diameter, entrapment efficiency and drug loading capacity were the volume ratio of oil phase to aqueous phase, the weight ratio of drug to gelatin, the concentrations of emulsifier and gelatin. The optimal formulation and technology was obtained with the volume ratio of oil to aqueous at 1:5, the weight ratio of drug to gelatin at 1:10, the concentrations of emulsifier and gelatin at 1% and 10%, respectively, and the stirring rate at 1100r/min. Microspheres obtained according to the optimal technology were pallide-flavens powder, and presented spherical under scanning electron microscope and light microscope. The mean particle diameter was 18.9μm and particle size of 86.6% of microspheres was in the range of 5～30μm. The repose angle of obtained microsphere was 41.2°, and bulk density was 0.583g/ml. The entrapment efficiency and the average drug loading capacity were 6.15% and 75.5%, respectively.The release in vitro of microspheres was following the first-order kinetics equation, ln(100- Q)=-0.0298t+4.5454 , R²=0.9984, t_1/2=21.25h. The t_1/2 of crude drug of curcumin was 0.51h assayed by the same method. There was significant difference between the above two t_1/2. Thus a conclusion could be obtained that C-GMS had a significant effect of sustained release.During stored at 3-5℃in refrigerator, room temperature (15-25℃) and 37℃for 3 months, surface morphology and drug loading capacity of microspheres were not almost changed. The results indicated that C-GMS had an excellent stability.The concentration-time curve of C-GMS suspension injected through ear vein followed a single compartment model, and t_1/2 was 18.435h. However, the concentration-time curves of intravenous curcumin injection were consistent with two-compartment model, and t_1/2α and t_1/2β were 0.063h and 0.655h, respectively. The microspheres could mainly deliver curcumin to lung tissue after iv administration (Ce=36.19) and the curcumin concentration in lung was significantly higher than those in other tissues and blood.Conclusion: C-GMS prepared had a superior property of sustained release, and the results of pharmacokinetics and tissue distribution in rabbits showed that C-GMS could produce a significant lung targeting effect.