Spray-Freeze Drying: a Suitable Method for Aerosol Delivery of Antibodies in the Presence of Trehalose and Cyclodextrins
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Abstract
We aimed to prepare spray-freeze-dried powder of IgG considering physicochemical stability and aerodynamic aspects. Spray-freeze drying (SFD) exposes proteins to various stresses which should be compensated by suitable stabilizers. The competence of cyclodextrins (CDs), namely beta-cyclodextrin (βCD) and hydroxypropyl βCD (HPβCD), at very low concentrations, was investigated in the presence of separate mannitol- and trehalose-based formulations. Spray-freeze-dried preparations were quantified in terms of monomer recovery and conformation by size exclusion chromatography (SEC-HPLC) and Fourier transform infrared (FTIR) spectroscopy, respectively. Differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) were employed to identify the thermal characteristics of powders. Particle morphology was visualized by scanning electron microscopy (SEM). Aerodynamic behavior of powders was checked through an Anderson cascade impactor (ACI). Although all formulations protected antibody from aggregation during the SFD process (aggregation < 1%), mannitol-containing ones failed upon the storage (19.54% in the worst case). Trehalose-HPβCD incomparably preserved the formulation with fine particle fraction (FPF) of 51.29%. Crystallization of mannitol resulted in IgG destabilization upon storage. Although employed concentration of CDs is too low (less than 50:1 molar ratio to protein), they successfully served as stabilizing agents in SFD with perfect improvement in aerosol functionality.
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KEY WORDS
IgG spray-freeze drying cyclodextrins trehalose stability aerodynamic propertyAbbreviations
- IgG
Immunoglobulin G
- SFD
Spray-freeze drying
- CDs
Cyclodextrines
- βCD
Beta-cyclodextrin
- HPβCD
Hydroxypropyl beta-cyclodextrin
- SEC-HPLC
Size exclusion high-performance liquid chromatography
- FTIR
Fourier transform infrared
- DSC
Differential scanning calorimetry
- XRD
X-ray diffraction
- SEM
Scanning electron microscopy
- ACI
Anderson cascade impactor
- FD
Freeze drying
- SD
Spray drying
- w/v
Weight/volume
- Tg
Glass transition temperature
- rhDNAse
Recombinant human deoxyribonuclease
- HPMC
Hydroxypropyl methylcellulose
- IVIG
Intravenous immunoglobulin
- i.t.
Intratracheally
- FPF
Fine particle fraction
- LDH
Lactate dehydrogenase
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