Inhaled dry powder liposomal azithromycin for treatment of chronic lower respiratory tract infection.

A dry powder inhaled liposomal azithromycin formulation was developed for the treatment of chronic respiratory diseases such as cystic fibrosis and bronchiectasis. Key properties including liposome size, charge and encapsulation efficiency powder size, shape, glass transition temperature (Tg), water content and in vitro respiratory deposition were determined. Antimicrobial activity against cystic fibrosis (CF) respiratory pathogens was determined by MIC, MBC and biofilm assays. Cytotoxicity and cellular uptake studies were performed using A549 cells. The average liposome size was 105 nm, charge was 55 mV and encapsulation efficiency was 75 %. The mean powder particle size d[v,50] of 4.54 µm and Mass Median Aerodynamic Diameter (MMAD) was 5.23 µm with a mean Tg of 76˚C and water content of 2.1 %. These excellent physicochemical characteristics were maintained over one year. Liposomal loaded azithromycin demonstrated enhanced activity against P. aeruginosa clinical isolates grown in biofilm. The formulation was rapidly delivered into bacterial cells with > 75 % uptake in 1 h. Rapid uptake into A549 cells via a cholesterol-dependent endocytosis pathway with no cytotoxic effects apparent. These data demonstrate that this formulation could offer benefits over current treatment regimens for people with chronic respiratory infection.

In-Vitro In-Vivo Correlation (IVIVC) of Inhaled Products Using Twin Stage Impinger.

In vitro dissolution testing as a form of quality control has become a necessity in the pharmaceutical industry. As such, the need to establish a method that investigates the in vitro dissolution profile of inhaled products should be taken into account. The prime focus in this study was to examine the in-vitro in-vivo correlation utilising a modified version of the Twin Stage Impinger and to promote an in vitro dissolution model by enhancing the Fine Particle Dose (FPD) collection method for dry powder inhalers. The Twin Impinger was modified by inserting a stainless steel membrane holder disk in the base of the lower chamber. The design, with optimum drug deposition, was adopted for the dissolution study of budesonide and salbutamol. Afterwards, the membrane holder system was placed in the bottom of the dissolution vessel. Phosphate buffer saline (PBS), simulated lung fluid (SLF, Gamble solution) and Phosphate buffer (PB) were used in the study. The paddle dissolution apparatus, containing 300 mL of the medium, was operated at 75 rpm paddle speed. Samples were collected at defined time intervals and analysed using a validated HPLC method. The largest proportion of the budesonide dose was dissolved in PBS compared to PB and SLF. This was due to the presence of surfactant (0.2% w/v polysorbate), which enhances the wettability and the solubility of the poorly soluble drug (budesonide). The similarity factors for PBS and PB were 47.6 and 69.7, respectively, using SLF as a reference, whereas the similarity factor for salbutamol dissolution between PB and SLF was 81.3, suggesting PB is a suitable substitute. Comparison using both the predicted and actual in vivo pharmacokinetics (PK) values of the two drugs, as well as the pattern of their Concentration-Time (c-t) profiles, showed good similarity, which gave an indication of the validity of this in vitro dissolution method.

Development and evaluation of nanoemulsion and microsuspension formulations of curcuminoids for lung delivery with a novel approach to understanding the aerosol performance of nanoparticles.

Extensive research has demonstrated the potential effectiveness of curcumin against various diseases, including asthma and cancers. However, few studies have used liquid-based vehicles in the preparation of curcumin formulations. Therefore, the current study proposed the use of nanoemulsion and microsuspension formulations to prepare nebulised curcuminoid for lung delivery. Furthermore, this work expressed a new approach to understanding the aerosol performance of nanoparticles compared to microsuspension formulations. The genotoxicity of the formulations was also assessed. Curcuminoid nanoemulsion formulations were prepared in three concentrations (100, 250 and 500 µg/ml) using limonene and oleic acid as oil phases, while microsuspension solutions were prepared by suspending curcuminoid particles in isotonic solution (saline solution) of 0.02% Tween 80. The average fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of the nebulised microsuspension formulations ranged from 26% and 7.1 µm to 40% and 5.7 µm, for 1000 µg/ml and 100 µg/ml respectively. In a comparison of the low and high drug concentrations of the nebulised nanoemulsion, the average FPF and MMAD of the nebulised nanoemulsion formulations prepared with limonene oil ranged from 50% and 4.6 µm to 45% and 5.6 µm, respectively; whereas the FPF and MMAD of the nebulised nanoemulsion prepared with oleic acid oil ranged from 46% and 4.9 µm to 44% and 5.6 µm, respectively. The aerosol performance of the microsuspension formulations were concentration dependent, while the nanoemulsion formulations did not appear to be dependent on the curcuminoids concentration. The performance and genotoxicity results of the formulations suggest the suitability of these preparations for further inhalation studies in animals.