A statistical approach to the development of a transdermal delivery system for ondansetron

Abstract

Transdermal delivery of drugs has gained attention as an alternative to intravenous and oral methods of delivery. However, the skin permeation of drugs is generally poor. To overcome this problem, many permeation enhancers have been developed. In this study, ondansetron hydrogels were prepared, and their skin permeation and pharmacological effects were evaluated in mice. To prepare the hydrogels, a Box–Behnken design was introduced. Fifteen formulations of ondansetron hydrogels composed of hydroxyethylcellulose and hydroxypropylcellulose as gel bases, l-menthol as a penetration enhancer and isopropanol (IPA), N-methyl-2-pyrrolidone (NMP) and water as a solvent were prepared. The quantities of IPA (X₁), l-menthol (X₂) and NMP (X₃) were selected as causal factors. We performed an in vitro skin permeation study and an in vivo skin irritation study with the test hydrogels. The flux and the total irritation score were selected as response variables. The optimal formulation, one that has an appropriate penetration and an acceptable skin irritation score, was estimated using a nonlinear response surface method incorporating thin-plate spline interpolation. The optimal formulation also delivered the desired pharmacological activity. These results indicated the feasibility of delivering ondansetron transdermally.

Introduction

Transdermal drug delivery has many advantages: it is convenient, it bypasses first-pass metabolism, and it provides a steady-state plasma concentration of the drug and long-term therapy in a single dose. These advantages lead to improved patient compliance. However, the skin permeation of clinically useful drugs is generally poor with some exception (it has small molecular weight (<300 Da) and lipophilic nature) because the stratum corneum functions as a barrier against foreign substances (Ranade, 1991). To overcome this problem, many penetration enhancers that temporarily increase the permeability of the skin have been examined (Barry, 1987, Sinha and Pal Kaur, 2000). Transdermal delivery does have shortcomings, too. One potential shortcoming, the long lag time before absorption begins, has been overcome in the case of the turobuterol delivery system. Another shortcoming, low absorption levels, could be advantageous in some cases by preventing a sudden increase in the plasma concentration of drugs immediately after administration. Especially in case of drugs that act on the brain, slow and sustained absorption of drugs via the skin and the maintenance of low plasma concentrations might be desirable.

To develop a new delivery system, we selected a drug that is often used clinically but that has no available option for transdermal delivery. Ondansetron, a serotonin (5-hydroxytryptamine) subtype 3 (5-HT₃) receptor antagonist, is used to treat nausea and vomiting associated with cancer chemotherapy, radiotherapy, anesthesia and surgery (Gregory and Ettinger, 1998). However, intravenous and oral administration are not appropriate for children and patients with various side effects. Moreover, ondansetron undergoes extensive hepatic metabolism by the cytochrome P450 enzyme system, and the elimination half-life of ondansetron is short (3–3.5 h) (Gwak et al., 2004). Therefore, the development of a transdermal delivery system for ondansetron has been desired and expected by clinicians.

In this study, the possibility of developing transdermal hydrogels containing ondansetron was evaluated. In developing transdermal preparations, it is important to design an optimized pharmaceutical formulation that has appropriate penetration with concomitant acceptable skin irritation levels. For this purpose, it is considered important to discover the optimized formulation of ondansetron hydrogels by employing a nonlinear response surface method incorporating thin-plate spline interpolation (RSM-S). Using RSM-S, we can easily understand nonlinear relationships between causal factors and response variables and obtain a stable and reproducible simultaneous optimal solution (Takayama et al., 2004). A bootstrap (BS) resampling method was used to evaluate the reliability of the optimal solution estimated by RSM-S. The BS method is a simulation technique based on the empirical distribution of the observed sample (Arai et al., 2007, Onuki et al., 2008). Those established statistical approaches are helpful in fabricating an appropriate transdermal delivery system for ondansetron. Moreover, a Kohonen self-organizing map (SOM) analysis was applied to gain a mechanistic understanding of the relationships between causal factors and response variables.