A Study On Pharmacokinetics And Pulmonary Distribution And Clearance Of Beclomethasone Dipropionate Nano-capsules

Background: Inhaled corticosteroids is the most effective anti-inflammation drugs in asthma therapy by now. Nevertheless, most drugs are rapidly cleared from the lungs and passed into the systemic circulation. This explains the relatively short therapeutic effect of inhaled drugs, the necessity for frequent dosages, and the occurrence of unwanted systemic side effects. PLGA nanoparticles are a carrier system for drug delivery currently under wide investigation. They seem to be particularly appropriate for drug carriers, as they are biodegradable and histocompatible. The sustained release of drugs from nanoparticles prolongs its effect and offers several advantages over the conventional dosage forms.Objective: To study pharmacokinetics and pulmonary distribution as well as clearance of beclomethasone dipropionate nano-capsules. To explore its lung deposition and slow-releasing effects. Methods: (1) BDP nano-capsules were prepared using PLGA as matrix and the water-in-oil-in-water (w/o/w) and solvent evaporation techniques. The morphology and diameter of nano-capsules were observed by scanning electron microscope. (2) 96 mice were randomly divided into two groups (3H-BDP group, 3H-BDP-PLGA nano-capsules group). Blood, lung, heart, liver, spleen and kidney tissues were harvested at different time-point after drug administration intratracheal to assay radioactivity through liquid scintillation counter. (3) Concentration-time data were calculated by 3P87 software to get the best model and pharmacokinetics parameters. (4) BDP-PLGA nano-capsules co-loaded with BDP andfluorescein sodium were nebulised to guinea pigs, tissue section of lung were prepared to observe pulmonary distribution with fluorescence microscope.Results: (1) The features of BDP-PLGA nano-capsules were described as a sphere with smooth surface whose average diameter is 220.4 nm. Fluorescence granules have been observed in distal end of lower respiratory tract and alveoli of guinea pig for several days after inhaled nebulized nano-capsules encapsulated fluorescein sodium. (2) The plasma concentration-time course of BDP shows a two-compartment model after a single dose in mice with some parameters: (BDP group: Tl/2(Ka) 0.38min , Tl/2(a) 9.27min, Tl/2(3) 386.27 min, T(peak) 1.94min, Cmax 55. 62ug/ml; BDP-PLGA nano-capsules group: Tl/2(Ka) 13.68min, Tl/2(a) 142. 60min, Tl/2(3) 1240. 22 min, T(peak) 74. 27min, Cmax 13. 52ug/ml). (3) There is no significant difference between the drug remaining in lungs of BDP and BDP-PLGA nano-capsules at 1 and 15 minutes, and with time goes by the drug remains of BDP-PLGA nano-capsules is higher than BDP. (4) Drug concentration in main tissue of BDP-PLGA nano-capsules group was far below than BDP group. Concentration in liver and kidney is higher than other tissues, especially in liver.Conclusion: (1) Inhaled BDP-PLGA nano-capsules have a widely deposition in peripheral lung tissue for its micronized diameter. (2) The pharmacokinetic of BDP could be fit for two-compartment model in mice after a single dose intratracheal. The absorption process is quick. Main metabolism and elimination are in liver and kidney. (3) Compared with BDP, BDP-PLGA nano-capsules have good sustained release character in mice, encapsulated drug was slow releasing with nano-capsules...