Physico-Chemical Properties, Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation

Abstract

Purpose Inhalation therapy is popular to treat lower respiratory tract infections. Azithromycin is effective against some bacteria that cause respiratory tract infections; but it has poor water solubility that may limit its efficacy when administrated as inhalation therapy. In this study, dry powder inhaler formulations were developed by co-spray drying azithromycin with L-leucine with a purpose to improve dissolution. Methods The produced powder formulations were characterized regarding particle size, morphology, surface composition and in-vitro aerosolization performance. Effects of L-leucine on the solubility and in-vitro dissolution of azithromycin were also evaluated. Results The spray dried azithromycin alone formulation exhibited a satisfactory aerosol performance with a fine particle fraction (FPF) of 62.5 ± 4.1%. Addition of L-leucine in the formulation resulted in no significant change in particle morphology and FPF, which can be attributed to enrichment of azithromycin on the surfaces of composite particles. Importantly, compared with the spray-dried amorphous azithromycin alone powder, the co-spray dried powder formulations of azithromycin and L-leucine demonstrated a substantially enhanced in-vitro dissolution rate. Such enhanced dissolution of azithromycin could be attributed to the formation of composite system and the acidic microenvironment around azithromycin molecules created by the dissolution of acidic L-leucine in the co-spray dried powder. Fourier transform infrared spectroscopic data showed intermolecular interactions between azithromycin and L-leucine in the co-spray dried formulations. Conclusions We developed the dry powder formulations with satisfactory aerosol performance and enhanced dissolution for a poorly water soluble weak base, azithromycin, by co-spray drying with an amino acid, L-leucine.

Understanding the Impacts of Surface Compositions on the In-Vitro Dissolution and Aerosolization of Co-Spray-Dried Composite Powder Formulations for Inhalation

“…Equilibrium azithromycin solubility of the raw azithromycin, the spray-dried azithromycin, physical mixtures (at the same molar composition as spray-dried formulations in Table 1) of azithromycin and colistin as well as the spray-dried composite formulations was determined (33). Briefly, an excess of azithromycin (i.e., 5 mg/mL equivalent of azithromycin of each formulation) was added to 5 mL of phosphate buffer saline (PBS, pH 7.4) maintained at room temperature (22 ± 2 °C) and 37 ±1 °C.…”

“…The dissolution kinetics of selected powder formulations were investigated using two different methods: beaker methods and Franz diffusion cell using the protocol described previously with minor modifications (33, 40). The dissolution of powder was carried out using aerosolized particles with aerodynamic diameter smaller than 5 µm (41).…”

“…Our early study has shown that spray drying azithromycin with L-leucine improved the solubility and dissolution of azithromycin DPI formulations due to the molecular interactions and low pH microenvironment (33). Recently, the combination of two or more active components (typically referred as co-amorphous drug delivery systems) have been shown to effectively improve the solubility and dissolution of poorly water-soluble drugs (34).…”

Simultaneous Particle Size Reduction and Homogeneous Mixing to Produce Combinational Powder Formulations for Inhalation by the Single-Step Co-Jet Milling

“…In general, it is challenging to obtain homogeneous mixtures of 2 very cohesive particles because the cohesive particles stick to each other strongly. 28,29 The formulations produced via co-jet milling demonstrated an acceptable content homogeneity, with drug contents in 90%-110% and acceptance value 15% (Table 1).…”

Formulation and Manufacturing of Solid Dosage Forms

“…Requirement of high-dose medications makes development of DPIs very challenging because use of excipients is limited to avoid high powder load. Mangal et al developed a composite particle formulation of azithromycin using the spray drying technique (16). Incorporation of Lleucine in the composite particle significantly improved dissolution behavior of poorly water soluble azithromycin, which has great potential to improve treatment efficacy because azithromycin has to be dissolved to be active.…”