Ian W. Kellaway

Insulin nanoparticles: Stability and aerosolization from pressurized metered dose inhalers

Nanoparticles containing insulin have been produced by emulsification processes followed by freeze-drying. Purified nanoparticles were suspended in hydrofluoroalkane (HFA) 134a, using essential oils (cineole and citral) as suspension stabilizers to form pressurized metered dose inhaler (pMDI) formulations. The retention of insulin integrity after formulation processing was determined using high performance liquid chromatography (HPLC), size exclusion chromatography (SEC), circular dichroism (CD) and fluorescence spectroscopy. The results indicated that the native structure of insulin was retained after formulation processing. Aerosolization properties of the manufactured pMDI formulations were determined using a multi-stage liquid impinger. The results showed that the nanoparticles were suitable for peripheral lung deposition, with a fine particle fraction (FPF(<1.7 microm)) of approximately 45% (w/w). In conclusion, the pMDI formulations with nanoparticles containing insulin developed in this study have the potential to deliver protein therapeutics via inhalation for systemic action.

Novel nanoparticles for pulmonary drug administration.

A novel one-step, low energy method, which avoids harsh processing conditions including potentially toxic and chemically reactive cross-linking agents, for the production of hydrophilic drug nanoparticles suitable for dispersion in the hydrofluoroalkane propellants was investigated. Reverse-phase microemulsions were used as the template for the production of nanoparticles. Two microemulsion systems were investigated: water/sodium bis(2-ethylhexyl) sulphosuccinate (AOT)/iso-octane and water/lecithin/propan-2-ol/iso-octane. Nanoparticles were captured by snap freezing with subsequent freeze-drying. Nanoparticles were dispersed in 1,1,1,2,3,3,3-heptafluoropropane (HFA-227) and the aerosol performance of the pressurised metered dose inhaler (pMDI) assessed by cascade impaction. Spherical nanoparticles less than 300 nm in size were produced. Nanoparticles produced using AOT as the surfactant could not be dispersed in HFA-227. However lecithin based nanoparticles could be dispersed in co-solvent modified HFA-227 and produced fine aerosols (Mass Median Aerodynamic Diameter ≤1.5 μm, fine particle fraction > 58%). This data suggests that a high fraction of the nanoparticles would be deposited (targeted) within the lung with the deposition being mainly alveolar. That is the ideal deposition profile for the systemic delivery of drugs via the lungs.

The processing of nanoparticles containing protein for suspension in hydrofluoroalkane propellants

Nanoparticles delivered from pressurized metered dose inhalers (pMDIs) potentially offer a means of efficiently delivering proteins to the lung. Nanoparticles containing the model protein lysozyme have been produced using microemulsion and nanoprecipitation methods. Freeze-drying water in oil emulsions, with chloroform as the organic solvent, followed by washing of excess surfactant (lecithin) led to the production of lactose nanoparticles having approximately 300 nm mean size. Substitution of lactose with lysozyme led to a significant increase in the mean size of nanoparticles (645-750 nm). This may have been due to the surface activity of lysozyme which altered the emulsification properties. The retained biological activity of lysozyme increased with increased lactose concentration in the formulation, and approximately 99% biological activity was retained when 20% (w/w) lactose was used. Ethanol used in the formulation in place of chloroform changed the production process from emulsification to nanoprecipitation. A monodisperse system (mean size approximately 275 nm, polydispersity index approximately 0.1) of spherical nanoparticles containing 80% (w/w) bioactive lysozyme (retained activity 99%) was generated. The nanoparticles washed with ethanol containing DPPC, oleic acid or Span 85 (2%, w/v) could readily be dispersed in HFA 134a without further processing, and a stable suspension was formed. Lysozyme remained stable (retained biological activity 98%) even after the nanoparticles were suspended in HFA 134a. This indicates the potential of nanoparticles for delivery of proteins from HFA-based pressurized metered dose inhaler formulations.

Peptide washout and permeability from glyceryl monooleate buccal delivery systems

ABSTRACT Simultaneous evaluation of the permeation and washout of a peptide from the mucoadhesive liquid crystalline phases of glyceryl monooleate (GMO) has been investigated using a donor compartment flow-through diffusion cell. [d-Ala2, d-Leu5]enkephalin (DADLE) was incorporated into the cubic and lamellar liquid crystalline phases of GMO and applied to excised porcine buccal mucosa mounted in the donor compartment flow-through cell. Phosphate-buffered saline pH 7.4 (PBS) was pumped across the upper surface of the liquid crystalline phases to mimic salivary flow. The steady-state fluxes of DADLE and GMO from the cubic phase were significantly greater than that from the lamellar phase (P<0.01). There was no statistical difference between the amounts of DADLE and GMO washed out from the lamellar and cubic phases (P>0.05). The donor compartment flow-through diffusion cell was found to be a useful tool to evaluate the impact of salivary washout on mucoadhesive oral mucosal delivery systems.