Abstract
Background: Previously we showed that the release properties of a liposomal ciprofloxacin (CFI) formulation could be attenuated by incorporation of drug nanocrystals within the vesicles. Rather than forming these drug nanocrystals during drug loading, they were created post manufacture simply by freezing and thawing the formulation. The addition of surfactant to CFI, either polysorbate 20 or Brij 30, provided an additional means to modify the release profile or incorporate an immediate-release or ‘burst’ component as well. The goal of this study was to develop a CFI formulation that retained its nanocrystalline morphology and attenuated release profile after delivery as an inhaled aerosol.Methods: Preparations of 12.5 mg/mL CFI containing 90 mg/mL sucrose and 0.1% polysorbate 20 were formulated between pH 4.6 to 5.9, stored frozen, and thawed prior to use. These thawed formulations, before and after mesh nebulization, and after subsequent refrigerated storage for up to 6 weeks, were characterized in terms of liposome structure by cryogenic transmission electron microscopy (cryo-TEM) imaging, vesicle size by dynamic light scattering, pH, drug encapsulation by centrifugation-filtration, and in vitro release (IVR) performance.Results: Within the narrower pH range of 4.9 to 5.3, these 12.5 mg/mL liposomal ciprofloxacin formulations containing 90 mg/mL sucrose and 0.1% polysorbate 20 retained their physicochemical stability for an additional 3 months refrigerated storage post freeze-thaw, were robust to mesh nebulization maintaining their vesicular form containing nanocrystalline drug and an associated slower release profile, and formed respirable aerosols with a mass median aerodynamic diameter (MMAD) of ∼3.9 μm and a geometric standard deviation (GSD) of ∼1.5.Conclusions: This study demonstrates that an attenuated release liposomal ciprofloxacin formulation can be created through incorporation of drug nanocrystals in response to freeze-thaw, and the formulation retains its physicochemical properties after aerosolization by mesh nebulizer.
Highlights
Treatment of many lung diseases involved systemic delivery of the drug; this modality was generally replaced by inhalation that is more effective due to targeting drug to the site of disease and safer due to reduced systemic side-effects.[1,2,3,4] Inhalation delivery provides effective therapy for a number of lung diseases where the drug operates at the site of disease [e.g., cystic fibrosis, asthma, and chronic obstructive pulmonary disease (COPD)].For many classes of inhaled drug products, there are a variety of inhalation delivery technologies, including metered dose inhalers (MDIs), dry powder inhalers (DPIs), and soft-mist inhalers and nebulizers that provide preference options to the end user, the patient.[5]
Previously we showed that the release properties of a liposomal ciprofloxacin (CFI) formulation could be attenuated by incorporation of drug nanocrystals within the vesicles
This study demonstrates that an attenuated release liposomal ciprofloxacin formulation can be created through incorporation of drug nanocrystals in response to freeze-thaw, and the formulation retains its physicochemical properties after aerosolization by mesh nebulizer
Summary
Treatment of many lung diseases involved systemic delivery of the drug; this modality was generally replaced by inhalation that is more effective due to targeting drug to the site of disease and safer due to reduced systemic side-effects.[1,2,3,4] Inhalation delivery provides effective therapy for a number of lung diseases where the drug operates at the site of disease [e.g., cystic fibrosis, asthma, and chronic obstructive pulmonary disease (COPD)].For many classes of inhaled drug products, there are a variety of inhalation delivery technologies, including metered dose inhalers (MDIs), dry powder inhalers (DPIs), and soft-mist inhalers and nebulizers that provide preference options to the end user, the patient.[5]. The encapsulation and drug release properties of a liposomal ciprofloxacin formulation were modified to provide either faster release, through the addition of surfactant under hyperosmotic conditions,(20) or slower release, by transformation of the drug into nanocrystalline form in response to freeze-thaw [Cipolla, unpublished data]. This transformation introduces a rate-limiting dissolution step prior to diffusion of drug across the vesicle bilayer. Conclusions: This study demonstrates that an attenuated release liposomal ciprofloxacin formulation can be created through incorporation of drug nanocrystals in response to freeze-thaw, and the formulation retains its physicochemical properties after aerosolization by mesh nebulizer
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