R van der Geest1, M Danhof, H E Boddé. 1. Division of Pharmaceutical Technology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
Abstract
PURPOSE: To investigate the feasibility of transdermal iontophoretic delivery of apomorphine in patients with Parkinson's disease, transdermal transport rates were optimized and validated across human stratum corneum and freshly dermatomed human skin in vitro. METHODS: In all experiments R-apomorphine hydrochloride was applied in the anodal compartment. The effect on the flux of the following parameters was studied, using a flow through transport cell current density, pH, concentration, ionic strength, osmolarity, buffer strength, temperature and skin type. RESULTS: Transdermal transport of apomorphine was directly controlled by the presence or absence of current. Passive delivery was minimal and no depot effect was observed. A linear relationship was found between current density and steady-state flux. At room temperature the lag time was 30 to 40 minutes. A maximal steady-state flux was obtained when the donor concentration approached maximum solubility. By increasing the temperature of the acceptor chamber to 37 degrees C the steady-state flux was increased by a factor of 2.3 and the lag time decreased to +/- 3 minutes. No effect of osmolarity and buffer strength and only a small effect of ionic strength and pH on the transport rate were observed. The flux through dermatomed human skin was decreased compared to stratum corneum. This effect was shown not to be caused by skin metabolism. CONCLUSIONS: The results obtained in vitro indicate that the iontophoretic delivery of apomorphine can be controlled and manipulated accurately by the applied current. The in vitro flux furthermore depends on the donor composition, temperature and skin type. Under optimized conditions, transport rates resulting in therapeutically effective plasma concentrations are feasible, assuming a one to one in vitro/in vivo correlation.
PURPOSE: To investigate the feasibility of transdermal iontophoretic delivery of apomorphine in patients with Parkinson's disease, transdermal transport rates were optimized and validated across human stratum corneum and freshly dermatomed human skin in vitro. METHODS: In all experiments R-apomorphine hydrochloride was applied in the anodal compartment. The effect on the flux of the following parameters was studied, using a flow through transport cell current density, pH, concentration, ionic strength, osmolarity, buffer strength, temperature and skin type. RESULTS: Transdermal transport of apomorphine was directly controlled by the presence or absence of current. Passive delivery was minimal and no depot effect was observed. A linear relationship was found between current density and steady-state flux. At room temperature the lag time was 30 to 40 minutes. A maximal steady-state flux was obtained when the donor concentration approached maximum solubility. By increasing the temperature of the acceptor chamber to 37 degrees C the steady-state flux was increased by a factor of 2.3 and the lag time decreased to +/- 3 minutes. No effect of osmolarity and buffer strength and only a small effect of ionic strength and pH on the transport rate were observed. The flux through dermatomed human skin was decreased compared to stratum corneum. This effect was shown not to be caused by skin metabolism. CONCLUSIONS: The results obtained in vitro indicate that the iontophoretic delivery of apomorphine can be controlled and manipulated accurately by the applied current. The in vitro flux furthermore depends on the donor composition, temperature and skin type. Under optimized conditions, transport rates resulting in therapeutically effective plasma concentrations are feasible, assuming a one to one in vitro/in vivo correlation.
Authors: R van der Geest; T van Laar; P P Kruger; J M Gubbens-Stibbe; H E Boddé; R A Roos; M Danhof Journal: Clin Neuropharmacol Date: 1998 May-Jun Impact factor: 1.592