Aerosol Performance and Stability of Liposomes Containing Ciprofloxacin Nanocrystals.

Journal of aerosol medicine and pulmonary drug delivery (2015-10-16)
David Cipolla, Huiying Wu, Igor Gonda, Hak-Kim Chan
RESUMO

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. 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. 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. 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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Sigma-Aldrich
Methanol, anhydrous, 99.8%
Sigma-Aldrich
Triethylamine, ≥99.5%
Sigma-Aldrich
HEPES, ≥99.5% (titration)
Sigma-Aldrich
Sucrose, for molecular biology, ≥99.5% (GC)
Sigma-Aldrich
Sodium chloride, BioXtra, ≥99.5% (AT)
Sigma-Aldrich
Methanol, ACS reagent, ≥99.8%
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HEPES, BioPerformance Certified, ≥99.5% (titration), suitable for cell culture
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Triethylamine, ≥99%
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Sodium chloride, for molecular biology, DNase, RNase, and protease, none detected, ≥99% (titration)
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Sucrose, ≥99.5% (GC)
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Sucrose, BioXtra, ≥99.5% (GC)
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Sodium chloride, BioReagent, suitable for cell culture, suitable for insect cell culture, suitable for plant cell culture, ≥99%
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Sodium chloride solution, 0.9% in water, BioXtra, suitable for cell culture
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Sodium chloride solution, 5 M in H2O, BioReagent, for molecular biology, suitable for cell culture
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Sucrose, BioUltra, for molecular biology, ≥99.5% (HPLC)
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Triethylamine, puriss. p.a., ≥99.5% (GC)
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Methanol, puriss. p.a., ACS reagent, reag. ISO, reag. Ph. Eur., ≥99.8% (GC)
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Sucrose, ≥99.5%
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HEPES buffer solution, 1 M in H2O
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Sodium chloride solution, 5 M
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Sucrose, puriss., meets analytical specification of Ph. Eur., BP, NF
SAFC
Sodium chloride solution, 5 M
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Triethylamine, BioUltra, ≥99.5% (GC)
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Sucrose, ACS reagent
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Sucrose, BioReagent, suitable for cell culture, suitable for insect cell culture, ≥99.5% (GC)
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Sodium chloride, meets analytical specification of Ph. Eur., BP, USP, 99.0-100.5%
SAFC
HEPES
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Methanol, Laboratory Reagent, ≥99.6%
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HEPES, BioUltra, for molecular biology, ≥99.5% (T)
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Sodium chloride, BioUltra, for molecular biology, ≥99.5% (AT)