Implications of regular solution theory on the release mechanism of catanionic mixtures from gels

Abstract

The aim of this study was to apply the regular solution theory of mixed micelles to gain new insights on the drug release mechanism, when using catanionic mixtures as a method of obtaining prolonged release from gels. Synergistic effects were investigated at equilibrium and quantified in terms of regular solution theory interaction parameters. The drug release from catanionic aggregates was studied both in a polymer free environment, using dialysis membranes, and in gels, using a modified USP paddle method. The drug release kinetics was modelled theoretically by combining the regular solution theory with Fick's diffusion laws assuming a contribution to the transport only from monomeric species (stationary aggregates). The theoretical predictions were found to be in reasonably good agreement with experiments. An analysis of the calculated distribution of species between aggregated and monomeric states was shown to provide further insights into the release mechanism.

Introduction

Mixtures of two oppositely charged surfactants, or catanionic mixtures, have been studied extensively during the last decades for several kinds of surfactant [1], [2], [3], [4], [5]. Lately, a number of potential pharmaceutical applications for catanionic mixtures have been considered [6]. One of the ideas is to use catanionic mixtures, in which one of the surfactants is an amphiphilic drug, for obtaining prolonged release from gels, which has already been successfully applied in several studies [6], [7], [8], [9], [10]. Gels are popular pharmaceutical dosage forms, mainly due to their mucoadhesive [11] and rheological [12] properties, facilitating an extended contact time at the site of absorption. However, as a gel is usually constituted of about 99% water the release of water soluble drugs is rapid and, hence, a strategy for prolonging the release is a necessity to benefit from the long contact time facilitated by the gel. The idea of using catanionic mixtures as a way of prolonging the release is dependent on the drug properties: the drug has to have a net charge and show some surface activity. If these requirements are met it is possible to let it form catanionic complexes with oppositely charged surfactants, and when incorporated in and released from a gel, it has been shown that the apparent diffusion coefficient decreases 10–100 times as compared with the release of non-complexed drug compound from the gel [7], [9].

The complete mechanism behind the prolonged release is unknown. However, it has been hypothesized that the drug and the surfactant form mixed aggregates that are too large to diffuse through the gel matrix, and that only monomers and small aggregates coexisting with the large aggregates diffuse freely out of the gel [9]. This hypothesis was supported by a study by Brohede et al. [13], although it was also concluded that further studies are needed on this subject. Vesicles or very large wormlike or branched micelles are often observed in catanionic mixtures of common surfactants [9], [14], [15], [16], [17], [18], [19], [20]. In these mixtures a major factor controlling the size and shape is the cationic/anionic ratio in the aggregates, which is often very close to the overall value, due to the low concentration of monomers in these systems. This is reflected also in the phase behavior where the sequence of phases depends primarily on the cationic/anionic ratio [7], [9]. However, effects from aggregate–aggregate interactions as well as pH and ionic strength are also present [8].

Since the cationic/anionic ratio has been found to be a major factor controlling the size also of catanionic drug/surfactant aggregates [7], [8], [9], [21] this parameter should be important also for the possibilities to retain aggregates by the polymer network in a gel. However, it is expected to control the release rate from such systems also by its influence on the concentration of monomers in (local) equilibrium with the aggregates. In fairly dilute solutions both aspects are expected to depend chiefly on the cationic/anionic ratio in the aggregates. It is therefore of great importance to know how the latter is related to the overall ratio. This is particularly so when surfactant and drug are released from a gel at different rates so that the overall ratio changes during the release process. For very dilute mixtures it is unclear to what extent the cationic/anionic ratio in the mixed aggregates deviates from the overall value. In a study by Caillet et al. it was reported that the aggregates formed were very close to equimolar [22]. This is in support of a previously published study by Brasher and Kaler, but in that study it was also shown how addition of salt made the cationic/anionic ratio in the aggregates more similar to that in the bulk solution [23]. In the present paper we demonstrate how a theory describing the equilibrium distribution of the components between aggregates and water can be used to predict the release rates from formulations containing catanionic drug/surfactant mixtures when combined with Fick's diffusion laws.

Many properties of mixed surfactant systems have been accounted for quantitatively or semi-quantitatively by various molecular thermodynamic models. One such important property of catanionic mixtures is that the mixed micelles with a cation/anion ratio close to unity can form without the entropic penalty of binding counterions [24]. This explains the strong synergistic effects, i.e., why the critical micelle concentration (CMC) is reduced much more than for mixtures of two non-ionic surfactants. A drawback with many theoretical models is that they require a detailed knowledge of the molecular properties of the components, often not at hand for drugs and, furthermore, that the models are not developed for amphiphilic molecules lacking a typical head-and-tail structure. Since our purpose here is to find a functional description of the distribution of the components between micelles and water rather than a detailed understanding of the underlying interactions, we will resort to the simple regular solution theory of mixed micelles [25], requiring in return the input of experimentally determined parameters. The theory is particularly suitable for demonstrator purposes because it is transparent, thereby facilitating the interpretations of results from numerical model calculations of transport processes. The major drawback is that the theory is less accurate for charged components unless there is salt present in excess.

In the first part of the paper we will use the regular solution theory to model the interaction between sodium lauryl sulfate (SDS) and two drugs, the local anesthetic tetracaine and the antihistamine diphenhydramine (Table 1), in the presence of 0.9 wt.% NaCl. The applicability of the theory to these systems has been demonstrated elsewhere [26].

In subsequent parts the theory will be combined with Ficks's diffusion laws to model the drug release with time from gel preparations. The results from the theoretical calculations will be compared with release experiments. To test the regular solution approach in a more direct way, we will investigate also the release of monomers from a liquid catanionic solution through a dialysis membrane. As a key to better understanding the release mechanism we will, in both types of experiment, analyze the release of not only the drug compound, but also the oppositely charged surfactant.