title: Design of spray dried insulin microparticles to bypass deposition in the extrathoracic region and maximize total lung dose.
abstract: Inhaled drugs all too often deliver only a fraction of the emitted dose to the target lung site due to deposition in the extrathoracic region (i.e., mouth and throat), which can lead to increased variation in lung exposure, and in some instances increases in local and systemic side effects. For aerosol medications, improved targeting to the lungs may be achieved by tailoring the micromeritic properties of the particles (e.g., size, density, rugosity) to minimize deposition in the mouth-throat and maximize the total lung dose. This study evaluated a co-solvent spray drying approach to modulate particle morphology and dose delivery characteristics of engineered powder formulations of insulin microparticles. The binary co-solvent system studied included water as the primary solvent mixed with an organic co-solvent, e.g., ethanol. Factors such as the relative rate of evaporation of each component of a binary co-solvent mixture, and insulin solubility in each component were considered in selecting feedstock compositions. A water-ethanol co-solvent mixture with a composition range considered suitable for modulating particle shell formation during drying was selected for experimental investigation. An Alberta Idealized Throat model was used to evaluate the in vitro total lung dose of a series of spray dried insulin formulations engineered with different bulk powder properties and delivered with two prototype inhalers that fluidize and disperse powder using different principles. The in vitro total lung dose of insulin microparticles was improved and favored for powders with low bulk density and small primary particle size, with reduction of deposition in the extrathoracic region. The results demonstrated that a total lung dose >95% of the delivered dose can be achieved with engineered particles, indicating a high degree of lung targeting, almost completely bypassing deposition in the mouth-throat.
authors.affiliation: Faculty of Pharmacy, the University of Sydney, NSW 2006, Australia; Novartis Pharmaceuticals Corp., San Carlos, CA, United States. Electronic address: keith.ung@novartis.com.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Ung
authors.affiliation: Novartis Pharmaceuticals Corp., San Carlos, CA, United States.
authors.forename: Nagaraja
authors.initials: N
authors.lastname: Rao
authors.affiliation: Novartis Pharmaceuticals Corp., San Carlos, CA, United States.
authors.forename: Jeffry G
authors.initials: JG
authors.lastname: Weers
authors.affiliation: Novartis Pharmaceuticals Corp., San Carlos, CA, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Huang
authors.affiliation: Faculty of Pharmacy, the University of Sydney, NSW 2006, Australia.
authors.forename: Hak-Kim
authors.initials: HK
authors.lastname: Chan
mesh_terms: D000280:Administration, Inhalation; D001682:Biological Availability; D015195:Drug Design; D058995:Dry Powder Inhalers / Q000379:methods*; D006801:Humans; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry* / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008863:Microspheres; D010316:Particle Size; D011208:Powders; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism
chemical_list: D007328:Insulin; D011208:Powders; D011994:Recombinant Proteins
keywords: Alberta idealized throat; Dry powder inhaler; Engineered particles; In vitro total lung dose; Microparticles; Spray drying