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 hour. 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.
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Materials
Azithromycin was purchased from Dexa-Medica (Palembang, Indonesia). Clarithromycin lactobionate powder for infusion (PhEur grade) was purchased from AAH (Bowmed Ibisqus, UK). SPC (Lipoid SPC, 100%) was purchased from Lipoid (Steinhausen, Switzerland). Ammonium Chloride, D (+) – lactose monohydrate (PhEur grade), L-leucine (PhEur grade), TPGS, dimethyl dioctadecyl ammonium bromide (DDAB), glycine, potassium phosphate monobasic (Reagent PlusTM, ≥99%), potassium acid phthalate, methanol (HPLC grade, ≥99.9%), acetonitrile (HPLC grade, ≥99.9%), sodium chloride (PhEur grade), and the 0.20 μm membrane filter (Whatman®) were purchased from Sigma–Aldrich. Citric acid monohydrate (PhEur grade) and sodium hydroxide pellets were obtained from Merck. Chloroform (99.2%), tris (hydroxylmethyl) methylamine Aanlar (99%), sodium hydrogen carbonate (Ph. Eur grade), sodium acetate trihydrate AnalaR NORMAPUR® (Ph. Eur. grade), Sodium carbonate anhydrous (ACS grade), calcium chloride dihydrate (Ph. Eur grade), disodium hydrogen phosphate and phosophoric acid (85%) were purchased from VWR (Lutterworth, UK). α,α-Trehalose ( Hayashibara) dehydrate (high purity, low endotoxin, FERRO Pfanstiehl Mayfield Heights, USA). Dialysis membrane (Spectra/Por 7: 10 kDa, 1 mL MWCO 10,000 regenerated cellulose Spectrum Laboratories, California, USA). Aluminium standard lids and aluminium hermetic pans/lids TA instruments – Waters LLC, New Castle, USA).
Yahya H. Dallal Bashi, Ahlam Ali, Yuosef Al Ayoub, Khaled H. Assi, Rachel Mairs, Helen O. McCarthy, Michael M. Tunney, Vicky L. Kett, Inhaleddry powder liposomal azithromycin for treatment of chronic lower respiratory tract infection, International Journal of Pharmaceutics, 2024, 123841, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.123841.
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