IN VITRO FORMULATION OPTIMIZATION OF INTRANASAL GALANTAMINE LEADING TO ENHANCED BIOAVAILABILITY AND REDUCED EMETIC RESPONSE IN VIVO.

This study by researchers at Nastech Pharmaceuticals demonstrated that MatTek’s EpiAirway in vitro human tracheal/bronchial tissue equivalent can be used to accurately assess the drug permeability, tight junction modulation, and cellular toxicity of new intranasal drug formulations. The purpose of the current investigation was to optimize an intranasal (IN) galantamine (an acetylcholinesterase inhibitor used for treatment of Alz-heimer’s disease) formulation using an in vitro tissue model (EpiAirway), 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 (EpiAirway) 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, intranasal galantamine resulted in a dramatically lowered incidence of GI-related side effects, e.g., retching and emesis. These findings illustrate that intranasal 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 intranasal galantamine compared to oral dosing.

AIR-100, Acetylcholinesterase inhibitor, Alzheimer’s disease, Drug permeability, EpiAirway, Excipients, Intranasal, Intranasal (IN) delivery, Lactate dehydrogenase (LDH), MTT, MTT assay, Permeation enhancers, Transepithelial electric resistance

Disodium edetate (EDTA), Galantamine, Galantamine lactate, L-á-phosphatidylcholine didecanoyl (DDPC), â-cyclodextrin (Me-â-CD)