Abstract
Previously, we showed that the encapsulation and release properties of a liposomal ciprofloxacin formulation could be modified post manufacture, by addition of surfactant in concert with osmotic swelling of the liposomes. This strategy may provide more flexibility and convenience than the alternative of manufacturing multiple batches of liposomes differing in composition to cover a wide range of release profiles. The goal of this study was to develop a surfactant-associated liposomal ciprofloxacin (CFI) formulation possessing good long-term stability which could be delivered as an inhaled aerosol. Preparations of 12.5 mg/ml CFI containing 0.4% polysorbate 20 were formulated between pH 4.7 and 5.5. These formulations, before and after mesh nebulization, and after refrigerated storage for up to 2 years, 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. Within the narrower pH range of 4.9 to 5.2, these formulations retained their physicochemical stability after 2-year refrigerated storage, were robust to mesh nebulization, and formed respirable aerosols with a volume mean diameter (VMD) of 3.7 μm and a geometric standard deviation (GSD) of 1.7. This study demonstrates that it may be possible to provide a range of release profiles by simple addition of surfactant to a liposomal formulation post manufacture, and that these formulations may retain their physicochemical properties after long-term refrigerated storage and following aerosolization by mesh nebulizer.
Highlights
Liposomes represent a versatile formulation and delivery technology that can be used to modulate a drug’s pharmacokinetic profile with the potential to improve both the safety and efficacy of treatment [1,2]
Polysorbate 20 when added to CFI in a hypotonic environment at a concentration between 0.4 and 1.6%, caused ~30 to 40% of the encapsulated ciprofloxacin to be released from the liposomes, versus only ~6 to 8% release when the surfactant was added to CFI under isotonic conditions (Fig. 1)
The 12.5 mg/mL CFI formulation containing 0.4% polysorbate 20 when prepared in a hypotonic environment possessed a faster release rate in the in vitro release (IVR) assay, whereas lower concentrations of polysorbate 20 did not significantly alter the release rate (Fig. 2a)
Summary
Liposomes represent a versatile formulation and delivery technology that can be used to modulate a drug’s pharmacokinetic profile with the potential to improve both the safety and efficacy of treatment [1,2]. Once a liposome formulation has been manufactured, its drug release properties are not typically modifiable. In order to provide personalized therapy to individuals, who may optimally respond to distinct drug release profiles, multiple batches of liposomes would have to be manufactured possessing different release kinetics. Because of the complexity and expense of this approach, from both a manufacturing and regulatory perspective, none of the currently marketed liposomal products come in multiple formats each with its own unique release behavior. A simple and flexible approach which allows modification of the drug release rate of a single liposomal formulation post manufacture, could address this issue
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