title: In vitro formulation optimization of intranasal galantamine leading to enhanced bioavailability and reduced emetic response in vivo.
abstract: The purpose of the current investigation was to optimize an intranasal (IN) galantamine (an acetylcholinesterase inhibitor used for treatment of Alzheimer's disease) formulation using an in vitro tissue model, to correlate those results to in vivo bioavailability, and to compare emetic response to oral dosing. A design-of-experiments (DOE) based formulation screening employing an in vitro tissue model of human nasal epithelium was used to assess drug permeability, tight junction modulation, and cellular toxicity. In vivo studies in rats compared pharmacokinetic (PK) profiles of different formulations dosed intranasally. Finally, studies in ferrets evaluated PK and gastrointestinal (GI) related side effects of oral compared to nasal dosage forms. Galantamine permeation was enhanced without increasing cytotoxicity. Pharmacokinetic testing in rats confirmed the improved drug bioavailability and demonstrated an in vitro-in vivo correlation. Compared to oral dosing, IN galantamine resulted in a dramatically lowered incidence of GI-related side effects, e.g., retching and emesis. These findings illustrate that IN delivery represents an attractive alternative to oral dosing for this important Alzheimer's disease therapeutic. To our knowledge, the data herein represent the first direct confirmation of reducing GI-related side effects for IN galantamine compared to oral dosing.
authors.affiliation: Nastech Pharmaceutical Company Inc., 3450 Monte Villa Parkway, Bothell, WA 98021, USA.
authors.forename: Alexis Kays
authors.initials: AK
authors.lastname: Leonard
authors.affiliation: Nastech Pharmaceutical Company Inc., 3450 Monte Villa Parkway, Bothell, WA 98021, USA.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Sileno
authors.affiliation: Nastech Pharmaceutical Company Inc., 3450 Monte Villa Parkway, Bothell, WA 98021, USA.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Brandt
authors.affiliation: Nastech Pharmaceutical Company Inc., 3450 Monte Villa Parkway, Bothell, WA 98021, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Foerder
authors.affiliation: Nastech Pharmaceutical Company Inc., 3450 Monte Villa Parkway, Bothell, WA 98021, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Quay
authors.affiliation: Nastech Pharmaceutical Company Inc., 3450 Monte Villa Parkway, Bothell, WA 98021, USA. Electronic address: rcostantino@nastech.com.
authors.forename: Henry R
authors.initials: HR
authors.lastname: Costantino
mesh_terms: D000281:Administration, Intranasal; D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D001682:Biological Availability; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D004492:Edetic Acid / Q000494:pharmacology; D017097:Electric Impedance; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005079:Excipients / Q000737:chemistry / Q000494:pharmacology*; D005163:Factor Analysis, Statistical; D005289:Ferrets; D005702:Galantamine / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D010713:Phosphatidylcholines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D014839:Vomiting / Q000139:chemically induced*; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D005079:Excipients; D010713:Phosphatidylcholines; D047392:beta-Cyclodextrins; C480658:didecanoylphosphatidylcholine; C108732:methyl-beta-cyclodextrin; D005702:Galantamine; D004492:Edetic Acid