In vitro formulation optimization of intranasal galantamine leading to enhanced bioavailability and reduced emetic response in vivo.

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.

Therapeutic utility of a novel tight junction modulating peptide for enhancing intranasal drug delivery.

Previously, a novel tight junction modulating (TJM) peptide was described affording a transient, reversible lowering of transepithelial electrical resistance (TER) in an in vitro model of nasal epithelial tissue. In the current report, this peptide has been further evaluated for utility as an excipient in transepithelial drug formulations. Chemical stability was optimal at neutral to acidic pH when stored at or below room temperature, conditions relevant to therapeutic formulations. The TJM peptide was tested in the in vitro tissue model for potential to enhance permeation of a low-molecular-weight (LMW) drug, namely the acetylcholinesterase inhibitor galantamine, as well as three peptides, salmon calcitonin, parathyroid hormone 1-34 (PTH(1-34)), and peptide YY 3-36 (PYY(3-36)). In all cases, the TJM peptide afforded a dramatic improvement in drug permeation across epithelial tissue. In addition, a formulation containing PYY(3-36) and TJM peptide was dosed intranasally in rabbits, resulting in a dramatic increase in bioavailability. The TJM peptide was as or more effective in enhancing PYY(3-36) permeation in vivo at a 1000-fold lower molar concentration compared to using LMW enhancers. Based on these in vitro and in vivo data, the novel TJM peptide represents a promising advancement in intranasal formulation development.

Development of a novel high-concentration galantamine formulation suitable for intranasal delivery.

The goal of the current study was to develop an intranasal (IN) 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, for example, 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. An in vitro epithelial tissue model was used to assess drug permeability and cellular toxicity. In vitro, galantamine lactate formulations performed as well as or better than their hydrobromide (HBr) 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 IN administration of this important drug.