Improved nasal bioavailability of elcatonin by insoluble powder formulation

Abstract

The bioavailability of elcatonin (ECT) via the nasal route was investigated with a powder dosage form utilizing water-insoluble calcium carbonate (CaCO₃) in comparison with the liquid dosage form. Total radioactivity and the radioactivity of intact [³H]ECT were measured to evaluate the nasal absorption in vivo and the nasal mucosal transport in vitro. The systemic bioavailability of both total radioactivity and intact [³H]ECT following intranasal administration of the powder formulation in rats was significantly greater than in the case of the liquid formulation. In contrast, similar permeability of ECT across excised rabbit nasal mucosa was seen for both formulations, and was close to that of [¹⁴C]inulin, suggesting that the ECT transport is predominantly paracellular in each case. However, the powder formulation significantly prolonged the residence time of [³H]ECT in the rat nasal cavity, compared with the liquid formulation. We conclude that the powder formulation utilizing CaCO₃ improves the nasal bioavailability by increasing the residence time of ECT in the nasal cavity and is likely to be effective in increasing systemic drug delivery.

Introduction

Nasal systemic drug delivery is a potentially valuable alternative to parenteral administration of polar molecules that are poorly absorbed from the digestive tract, such as polypeptides and water-soluble drugs, since the nasal route is non-invasive and makes self-medication practical, thus improving patient compliance (Pontiroli et al., 1989). However, low bioavailability following intranasal administration of polypeptides such as insulin and calcitonin as simple liquid formulations has been observed (Moses et al., 1983, Lee et al., 1994), due to their restricted permeability in the nasal mucosal membrane and to rapid efflux from the nasal cavity by the efficient physiological elimination mechanism, nasal mucociliary clearance, limiting the duration available for absorption. Consequently, several potential additives, both absorption promoters and mucoadhesive agents, have been evaluated in order to overcome these problems with nasal formulations (Dondeti et al., 1996, Behl et al., 1998). On the other hand, many reports have appeared, describing powder dosage forms, eg, microspheres or colyophilized powder using bile salts, cyclodextrins, starch, cellulose and their derivatives, and so on, for nasal delivery (Nagai et al., 1984, Illum et al., 1988, Lee et al., 1991, Edman et al., 1992, Schipper et al., 1993, Suzuki and Makino, 1999). Most of these excipients, however, can be characterized as permeation enhancers and/or mucoadhesives. In contrast, although the dry powder formulation using water-soluble lactose as a drug carrier is available for the pulmonary dry powder inhalation (Malcolmson and Embleton, 1998), this apparently does not increase the absorption of polar molecules via the nasal route (Nagai et al., 1984, Ugwoke et al., 2000). We wondered whether a powder formulation utilizing a water-insoluble compound might be effective as a drug carrier to improve nasal bioavailability.

In the present study, we chose elcatonin (ECT) and calcium carbonate (CaCO₃) as models of a polar polypeptide and a water-insoluble carrier, respectively, and examined whether CaCO₃ could increase the systemic bioavailability of ECT via the nasal route. CaCO₃ is extremely insoluble and has been used as an ingredient of foods, cosmetics and pharmaceuticals. ECT [(Asu^1,7)-eel calcitonin], a synthetic derivative that is more stable biologically than native eel calcitonin and induces strong hypocalcemia, has been administered by intravenous or intramuscular injection for the treatment of Paget's disease of bone, hypercalcemia and osteoporosis found particularly among postmenopausal women. The present experiments were designed to see whether intranasal administration of ECT could be an efficient route for systemic delivery.