The aim of the current study was to encapsulate celecoxib (Cxb) in the Nanostructured Lipid Carrier (Cxb-NLC) nanoparticles and evaluate the lung disposition of nanoparticles following nebulization in Balb/c mice. Cxb-NLC nanoparticles were prepared with Cxb, Compritol, Miglyol and sodium taurocholate using high-pressure homogenization. Cxb-NLC nanoparticles were characterized for physical and aerosol properties. In-vitro cytotoxicity studies were performed with A549 cells. The lung deposition and pharmacokinetic parameters of Cxb-NLC and Cxb solution (Cxb-Soln) formulations were determined using Inexpose™ system and Pari LC star jet nebulizer. The particle size and entrapment efficiency of Cxb-NLC formulation were 217 ± 20 nm and > 90%, respectively. The Cxb-NLC released the drug in controlled fashion, and in vitro aersolization of Cxb-NLC formulation showed FPF of 75.6 ± 4.6 %, MMAD of 1.6 ±0.13 μm and GSD of 1.2 ± 0.21. Cxb-NLC showed dose and time dependent cytotoxicity against A549 cells. Nebulization of Cxb-NLC demonstrated 4 fold higher AUC t/ D in lung tissues compared to Cxb-Soln. The systemic clearance of Cxb-NLC was slower (0.93 L/h) compared to Cxb-Soln (20.03 L/h). Cxb encapsulated NLC were found to be stable and aerodynamic properties were within the respirable limits. Aerosolization of Cxb-NLC improved the Cxb pulmonary bioavailability compared to solution formulation which will potentially lead to better patient compliance with minimal dosing intervals.
Simultaneous quantification of cyclosporin A (CsA) and its major metabolite (AM1) in blood has been achieved using time-of-flight secondary-ion mass spectrometry (TOF-SIMS) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDIJTOF-MS). Previous investigations indicated that spectral interferences exist in the analysis of CsA blood samples by the above methods. In TOF-SIMS, interference is caused by overlap of the Ag-cationized internal standard, cyclosporin D (CsD), with the Ag-cationized metabolite, AM1. To resolve this interference and obtain quantitative information, cross-correlation analysis was applied to the TOF-SIMS data. Application of damped non-linear least squares curve-fitting was carried out to resolve an interference in the MALDIJTOF-MS data due to multiple cationization products (i.e. Na and K). Measurement of standard samples indicates that the minimum accuracy (95% confidence level) of the TOF-SIMS method was better than 9% for CsA and 13% for AM1 using only one standard curve.' Similarly, the minimum accuracy of the MALDIROF-MS method was determined to be 14% for CsA and better than 25% for AM1. Blood samples obtained from transplant patients receiving CsA were analyzed by polyclonal fluorescence polarization immunoassay, highperformance liquid chromatography (HPLC), and by both TOF-MS methods. Both TOF-MS results for CsA and mono-hydroxylated CsA are in good agreement with the HPLC results.
1. Cyclosporin A (cyclosporine, CSA) is an immunosuppressive drug with a narrow therapeutic index. In the present study the metabolism of CSA was investigated in the liver and small intestinal microsomes obtained from rat, hamster, rabbit, dog, baboon and man by measuring the disappearance of CSA and the formation of the principal metabolites of CSA, namely hydroxylated and N-demethylated CSA. 2. CSA was metabolized at a very slow rate (2-8% metabolism in 30 min) in rat liver microsomes whereas microsomes from dog livers were very efficient (70-100% metabolism in 30 min) in metabolizing CSA. Hydroxylation and N-demethylation accounted for most of the CSA metabolized in all the species tested. 3. Microsomes from the small intestine produced qualitatively a similar metabolic profile as compared with the microsomes from the liver, but at a slower rate in all the species tested. The relative importance of the different metabolic pathways, however, differed between species. 4. This study points to the importance of recognizing the similarities and the differences in the metabolism of CSA in different species when data from animal studies are extrapolated to man.
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