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 beta-cyclodextrin (RAMEB) or hydroxypropyl-beta-cyclodextrin (HPbetaCD) was pH-dependent, involving the piperazin group. Rifampicin phase solubility diagrams constructed at pH 9 showed an A(L)-type curve for RAMEB and a B(S)-type for HPbetaCD. 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 HPbetaCD. Complexes with RAMEB or HPbetaCD 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 HPbetaCD decreased the MMAD of the aerosolized droplets. Activity of RAMEB and HPbetaCD 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.

The relevancy of controlled nanocrystallization on rifampicin characteristics and cytotoxicity

“…In comparison to the study of Son and McConville,10 where RIF dissolution rate was enhanced by polymorphic transformation into its dihydrated form and its release profile was 74% within the first hour, the prepared RIF NS formulations showed a promising in-vitro dissolution enhancement.…”

“…8,9 Other attempts were carried out to increase the RIF solubility involving the complexation with different cyclodextrin derivatives and altering its crystal structure and particle morphology by a mean of a polymorphic transformation into a flake-like crystal hydrate. 10,11 Over recent years, nanosuspension (NS) technology received a great interest in overcoming the obstacles of poorly soluble drugs. NSs are colloidal dispersions of the pure drug in an outer liquid phase with particle size ranging between 100 and 1,000 nm.…”

Characterization, activity, and computer modeling of a molecular inclusion complex containing rifaldazine

“…In an earlier study, the mean minimum inhibitory concentrations of a randomly methylated RAABCD complex, RAAHCD complex, and free rifaldazine were reported to be 26.3 µg/mL, 5.63 µg/mL, and 15 µg/mL for Acinetobacter baumannii CIP7010T, respectively. 8 The activity of the rifaldazine complex for bacteria clearly decreased in the order of S. aureus, E. coli, and A. baumannii. The difference between the minimum inhibitory concentrations of free rifaldazine and its molecular inclusion complex indicate a complicated relationship between the drug delivery system and type of bacteria.…”

“…3 However, taking tuberculosis treatment as an example, being an antibiotic with poor solubility and low stability, rifaldazine must be administered at a high daily dose continuously for several months, with adverse effects such as hepatitis, breathlessness, flushing, nausea, and headache. 4,5 Therefore, attempts have been made in recent decades to develop alternative delivery systems for rifaldazine, including liposomes 6 and microspheres 7 for injection, cyclodextrin complexes, 8 chitosomes, 9 and liposomes 10 for lung nebulization. Disadvantages of these rifaldazine delivery systems include inconvenient administration, a complex manufacturing process, and uncertain safety.…”

Drug-Resistant Tuberculosis: Recent Approach in Polymer Based Nanomedicine

“…Nanocarrier systems can be used to deliver drugs through the parenteral, oral, nasal and pulmonary route. Moreover, Pulmonary drug delivery (PDD) of these ATDs loaded nanocarriers helps in depositing sitespecific drugs at high concentrations within the diseased lungs, thereby reducing the overall dose of a drug to patients which in turn reduces systemic side effects [7][8][9][10][11][12]. Thus, the ATDs loaded sustained release nanocarriers together with site-specific targeting holds the potential to treat intermittent therapy of drug susceptible and resistant TB.…”