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Formulation of rifampicin–cyclodextrin complexes for lung nebulization

Abstract : Lung administration of antibiotics by nebulization is promising for improving treatment efficiency for pulmonary infections, as it increases drug concentration at sites of infection while minimizing systemic side effects. For poorly soluble molecules like rifampicin, cyclodextrins (CD) may improve lung delivery by permitting higher dosing. For this purpose, we investigated rifampicin–CD complexes in terms of rifampicin apparent solubility enhancement, effect on in vitro permeability on Calu-3 broncho-alveolar cells, effect on in vitro antibacterial activity against Acinetobacter baumannii and nebulization characteristics measured by NGI cascade impactor. Complexation efficiency between rifampicin and methylated β-cyclodextrin (RAMEB) or hydroxypropyl-β-cyclodextrin (HPβCD) was pH-dependent, involving the piperazin group. Rifampicin phase solubility diagrams constructed at pH 9 showed an AL-type curve for RAMEB and a BS-type for HPβCD. Stability constants calculated for a 1:1 molar ratio of CD/rifampicin were 73.4 ± 8.2 M− 1 for RAMEB and 68.5 ± 5.2 M− 1 for HPβCD. Complexes with RAMEB or HPβCD increased 22 times and 7.6 times respectively the apparent solubility of rifampicin and were found to be satisfactorily stable for 2 days when diluted in a solution at physiological pH. The nebulization of the complex solution created droplets in size range compatible with pulmonary deposition. Furthermore, the presence of HPβCD decreased the MMAD of the aerosolized droplets. Activity of RAMEB and HPβCD complexes measured by the total rifampicin MIC against A. baumannii was similar or lower to free rifampicin MIC respectively. Complexation did not alter the rifampicin permeability in the timescale of 1h as evaluated with a Calu-3 epithelial cell model, but acted as a reservoir for rifampicin. In conclusion, this work reports that CDs can be used as vectors for pulmonary nebulization to increase the amount of active rifampicin and optimize its lung pharmacokinetic profile.
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Frederic Tewes, Julien Brillault, William Couet, Jean-Christophe Olivier. Formulation of rifampicin–cyclodextrin complexes for lung nebulization. Journal of Controlled Release, Elsevier, 2008, 129, pp.93 - 99. ⟨10.1016/j.jconrel.2008.04.007⟩. ⟨inserm-01102812⟩



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