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DEVELOPMENT OF A NOVEL HIGH-CONCENTRATION GALANTAMINE FORMULATION SUITABLE FOR INTRANASAL DELIVERY.
Leonard, A.K., Sileno, A.P., MacEvilly, C., Foerder, C.A., Quay, S.C., and Costantino, H.R.
Nastech Pharmaceutical Company Inc., 3450 Monte Villa Parkway, Bothell, WA 98021.
Journal of Pharmaceutical Sciences, 94, 1736-1746, (2005).
Keywords: Acetylcholinesterase inhibitor, Bioavailability, Bromoide ion, Cellular toxicity, Drug permeability, Drug solubility, EpiAirway, Epithelial, Formulation, Galantamine, Gastrointestinal (GI), Hydrobromide (HBr), In vitro / in vivo correlation, In vitro tissue model, Intranasal, Intranasal (IN), Lacatate dehydrogenase (LDH), MTT, Nasal drug delivery, Pharmacokinetics (PK), Salt exchange, Solubility, Toxicity, Transepithelial electrical resistance (TER)
Endpoints: Cytoxicity assay, MTT assay, Permeation rate, Transepithelial electrical resistance (TER)
Materials Tested: Galantamine formulations
Summary:
The goal of this Nastech Pharmaceutical Co. study was to develop an intranasal formulation of the acetylcholinesterase inhibitor galantamine, an important therapeutic for treating Alzheimer’s disease.
To allow for delivering a therapeutically relevant dose, it was necessary to greatly enhance drug solubility. Various approaches were examined to this end, including adding co-solvents, cyclodextrins, and counterion exchange. Of these, the latter, e.g., replacement of bromide ion with lactate or gluconate, resulted in a dramatic drug solubility increase, more than 12-fold. NMR confirmed the molecular structure of new drug salt forms.
EpiAirway, an in vitro epithelial tissue model, was used to assess drug permeability and cellular toxicity. In vitro, galantamine lactate formulations performed as well or better than their hydrobromide counterparts with respect to drug permeation across the epithelial membrane with minimal toxicity.
In vivo studies in rats compared pharmacokinetic (PK) profiles of different formulations. The in vivo studies confirmed that IN galantamine achieves systemic blood levels comparable to those of conventional oral administration.
Both the in vitro and in vivo data support the feasibility of intranasal administration of this important drug.
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