title: Biologic comparison of inhaled insulin formulations: Exubera™ and novel spray-dried engineered particles of dextran-10.
abstract: Inhaled peptides and proteins have promise for respiratory and systemic disease treatment. Engineered spray-dried powder formulations have been shown to stabilize peptides and proteins and optimize aerosol properties for pulmonary delivery. The current study was undertaken to investigate the in vitro and in vivo inhalation performance of a model spray-dried powder of insulin and dextran 10 in comparison to Exubera™. Dextrans are a class of glucans that are generally recognized as safe with optimum glass transition temperatures well suited for spray drying. A 70% insulin particle loading was prepared by formulating with 30% (w/v) dextran 10. Physical characterization revealed a "raisin like" particle. Both formulations were generated to produce a similar bimodal particle size distribution of less than 3.5 μm MMAD. Four female Beagle dogs were exposed to each powder in a crossover design. Similar presented and inhaled doses were achieved with each powder. Euglycemia was achieved in each dog prior and subsequent to dosing and blood samples were drawn out to 245 min post-exposure. Pharmacokinetic analyses of post-dose insulin levels were similar for both powders. Respective dextran 10-insulin and Exubera exposures were similar producing near identical area under the curve (AUC), 7,728 ± 1,516 and 6,237 ± 2,621; concentration maximums (C max), 126 and 121 (μU/mL), and concentration-time maximums, 20 and 14 min, respectively. These results suggest that dextran-10 and other dextrans may provide a novel path for formulating peptides and proteins for pulmonary delivery.
authors.affiliation: Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, New Mexico, 87108, USA, pkuehl@lrri.org.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kuehl
authors.forename: Alan
authors.initials: A
authors.lastname: Cherrington
authors.forename: Dan E
authors.initials: DE
authors.lastname: Dobry
authors.forename: Dale
authors.initials: D
authors.lastname: Edgerton
authors.forename: Dwayne T
authors.initials: DT
authors.lastname: Friesen
authors.forename: Charles
authors.initials: C
authors.lastname: Hobbs
authors.forename: Chet L
authors.initials: CL
authors.lastname: Leach
authors.forename: Brice
authors.initials: B
authors.lastname: Murri
authors.forename: Doss
authors.initials: D
authors.lastname: Neal
authors.forename: David K
authors.initials: DK
authors.lastname: Lyon
authors.forename: David T
authors.initials: DT
authors.lastname: Vodak
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Reed
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D003911:Dextrans / Q000737:chemistry*; D004285:Dogs; D004337:Drug Carriers; D005260:Female; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D008657:Metabolic Clearance Rate; D010316:Particle Size; D011208:Powders; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D000336:Aerosols; D001786:Blood Glucose; D003911:Dextrans; D004337:Drug Carriers; C473734:Exubera; D007004:Hypoglycemic Agents; D007328:Insulin; D011208:Powders
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