1. In vitro formulation optimization of intranasal galantamine leading to enhanced bioavailability and reduced emetic response in vivo.
- Author
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Leonard AK, Sileno AP, Brandt GC, Foerder CA, Quay SC, and Costantino HR
- Subjects
- Administration, Intranasal, Administration, Oral, Analysis of Variance, Animals, Biological Availability, Cell Membrane Permeability drug effects, Cells, Cultured, Chemistry, Pharmaceutical, Cholinesterase Inhibitors adverse effects, Cholinesterase Inhibitors chemistry, Dose-Response Relationship, Drug, Drug Compounding, Edetic Acid pharmacology, Electric Impedance, Epithelial Cells drug effects, Epithelial Cells metabolism, Excipients chemistry, Factor Analysis, Statistical, Ferrets, Galantamine adverse effects, Galantamine chemistry, Humans, Phosphatidylcholines pharmacology, Rats, Rats, Sprague-Dawley, Respiratory Mucosa cytology, Respiratory Mucosa drug effects, Respiratory Mucosa metabolism, Tight Junctions drug effects, Tight Junctions metabolism, beta-Cyclodextrins pharmacology, Cholinesterase Inhibitors administration & dosage, Cholinesterase Inhibitors pharmacokinetics, Excipients pharmacology, Galantamine administration & dosage, Galantamine pharmacokinetics, Vomiting chemically induced
- 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.
- Published
- 2007
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