Physicochemical characterization and aerosol dispersion performance of organic solution advanced spray-dried microparticulate/nanoparticulate antibiotic dry powders of tobramycin and azithromycin for pulmonary inhalation aerosol delivery
Graphical abstract
Introduction
Pulmonary delivery of therapeutics locally to the lung has many advantages over other administration routes (Hickey and Mansour, 2009). Pulmonary drug delivery systems comprise four main categories: nebulizers, pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), and soft-mist inhalers (SMIs). Within each class further differentiation is determined by metering, means of dispersion, or design. DPIs have some advantages over other devices, including relatively high dose delivery and greater chemical stability of the solid-state compare to the liquid state.
There are several methods available to make respirable particles, including micronization, precipitation, freeze drying, and spray drying (Hickey and Mansour, 2008, Hickey and Mansour, 2009, Mansour et al., 2009). Spray drying is a one-step high through-put process with the ability to engineer and produce particles in a more controlled manner (such as directing particle size and size distribution, particle and surface morphology) which are important particle features (Wu et al., 2010) for pulmonary dry powder drug delivery by inhalation. The chronic lung infections occurring in cystic fibrosis (CF) reside predominantly in the lower respiratory tract and small peripheral airways (Taylor et al., 1992) where disease progression starts (Tiddens, 2002, Worlitzsch et al., 2002). Microparticulate and nanoparticulate aerosols in the aerodynamic diameter range of ∼0.5–2 μm in diameter (Murray and Nadel, 1988, Stahlhofen et al., 1980, Usmani et al., 2005) which can target and deposit in those lung regions exhibit sedimentation and diffusion (Raabe, 1982) particle deposition mechanisms, respectively.
As two model first-line CF antibiotic drugs in this comprehensive and systematic study, tobramycin (TOB) and azithromycin (AZI) are aminoglycoside and macrolide antibiotics, respectively. TOB and AZI represent different antibiotic drug classes with different physicochemical properties such as hydrophobicity. At present, nebulized liquid inhalation antibiotic aerosols of TOB and aztreonam are approved by the United States Food and Drug Administration (U.S. FDA) for administration by nebulized liquid aerosol inhalation (Park et al., 2011, Paterson, 2006). TOBI® Podhaler® (TOB DPI) has recently gained approval in Europe and in the United States. AZI, a new generation macrolide antibiotic, has been approved by the FDA for treatment of community acquired pneumonia and exacerbations of chronic obstructive pulmonary disease (Prescott and Johnson, 2005) and possesses favorable anti-inflammatory pulmonary effects that have been reported in a long-term study with oral aizthromycin in lung transplant recipients with bronchiolitis obliterans syndrome (BOS) (Shitrit et al., 2005). The clinical success in the treatment of pulmonary infections in a targeted manner providing high therapeutic concentrations locally in the lung, minimizing systemic exposure, and hence decreasing the factors that give rise to the major medical problem of bacterial antibiotic resistance has been reported recently (Garcia-Contreras and Hickey, 2002, Hayes et al., 2009, Park et al., 2011, Song, 2008).
The performance of DPI formulations is influenced by particle properties (such as size and size distribution) and particle surface properties (such as surface morphology and interparticulate forces including van der Waals, electrostatic, and capillary forces), as described in detail by the authors (Hickey and Mansour, 2008, Hickey and Mansour, 2009, Hickey et al., 2007a, Hickey et al., 2007b, Suarez and Hickey, 2000, Wu et al., 2010, Xu et al., 2010, Xu et al., 2011). The advantages of particle engineering by spray drying for the design of DPI formulations are related to the optimization of important particle properties such as surface morphology, particle morphology, particle size, and size distribution by controlling and tailoring spray drying parameters such as feeding solution conditions (i.e. solvent type, concentration, and feeding rate) and drying gas condition (i.e. gas type, inlet and outlet temperatures, and flow rate) (Hickey and Mansour, 2008, Mansour et al., 2009, Mizoe et al., 2007). In this study, organic solution closed-mode spray drying technique is employed utilizing organic solvent (i.e. an alcohol) for minimization of residual water content and smaller particle size due to its non-aqueous nature and lower surface tension. No water is present in the solvent feed systems, as they are pure alcohol solutions. Compared to the high surface tension of water at ∼72 mN/m, alcohols such as methanol (which are also regarded as “green chemicals”) have a much lower surface tension in the range of 22–25 mN/m.
One of the novel aspects of this reported study is that we demonstrate for the first time that inhalable microparticulate/nanoparticulate dry powders of these two antibacterial drugs (representing two different major antibiotic drug classes) can be produced and optimized using organic solution advanced spray-drying conditions in closed-mode (no water but only alcohol) which we have previously reported for the first time for pulmonary delivery applications as DPIs (Li and Mansour, 2011, Meenach et al., 2013, Wu et al., 2013a, Wu et al., 2013b). In addition, this comprehensive and systematic study aims to design, optimize, and develop novel microparticulate/nanoparticulate antibiotic (TOB and AZI) dry powder aerosols using advanced organic solution spray drying, comprehensively examine the effect of spray-drying conditions on the solid-state physicochemical properties and aerosol dispersion performance of particles for each antibiotic drug, and systematically compare the influence of different physicochemical properties on aerosol dispersion performance as novel DPIs. Moreover, this study probes and correlates the fundamental interplay between various spray-drying conditions, particle physicochemical properties, and aerosol dispersion performance as DPIs.
Section snippets
Materials
Tobramycin (TOB) (U.S.P. grade) (C18H37N5O9; M.W.: 467.515 g/mol) was obtained from Spectrum (New Brunswick, New Jersey). Azithromycin (AZI) (U.S.P. grade) (C38H72N2O12; M.W.: 748.984 g/mol) was purchased from APAC pharmaceutical LLC (Columbia, MD) with a purity of 98%. Methanol (HPLC grade, ACS-certified grade, purity 99.9%) and chloroform (HPLC grade, ACS-certified grade, purity 99.9%) were obtained by Fisher Scientific (Pittsburgh, PA, USA). HYDRANAL@-Coulomat AD was from Sigma–Aldrich (St.
Scanning Electron Microscopy (SEM)
SD TOB and AZI particles were successfully produced by using low (10%), medium (50%), and high (100%) pump rates from organic solution advanced spray drying in closed-mode (no water) using dilute drug organic solution (no water). The detailed spray-drying conditions were detailed in Section 2.2 and Table 1. The particle morphology and surface morphology of all powders were visualized via SEM in Fig. 1. The particle size of raw material for each sample was far beyond the maximum respiratory size
Discussion
The present work clearly demonstrates that microparticulate/nanoparticulate antibiotic DPIs consisting of first-line antibiotics used in CF treatments can be successfully designed and optimized by organic solution advanced spray drying in closed-mode from dilute drug solution (no water). In addition, linear correlation between spray drying pump rates and FPF were discovered, as also between thermal analysis parameters and FPF (an aerosol parameter), which will be discussed.
By using this novel
Conclusions
This study has demonstrated for the first time that the microparticulate/nanoparticulate aerosols of first-line CF antibiotic drugs, tobramycin and azithromycin, were successfully designed and optimized for DPIs using three rationally chosen pump rates (i.e. low, medium, and high) by organic solution advanced spray drying in closed-mode (no water). These inhalation particles possessed the essential particle and surface properties that minimize interparticulate interactions, therefore
Acknowledgements
The authors gratefully acknowledge fellowship support from the UK Center of Membrane Sciences, the Graduate School Academic Year Fellowship and the Daniel R. Reedy Quality Achievement Fellowship awarded to Xiaojian Li. The authors thank Dr. Dicky Sick Ki Yu for SEM access, Dr. Tonglei Li for XRPD and HSM access, and Dr. Hilt for ATR-FTIR access at the University of Kentucky.
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