In vitro and ex vivo assessment of microporous Faujasite zeolite (NaX-FAU) as a carrier for the oral delivery of danazol

Abstract

Microporous zeolite NaX-FAU has been systemically evaluated for the oral delivery of the poorly water-soluble compound danazol. For this purpose, danazol-loaded zeolitic particles were prepared by the incipient wetness method and were characterized by means of N₂ physisorption, X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and high-resolution transmission electron microscopy (HRTEM). The zeolitic formulation shows a high drug payload and drug stability over a period of six months under accelerated storage conditions. The dissolution profile of danazol-loaded zeolitic particles was assessed in simulated gastric fluid (SGF) pH 1.2; fasted state simulated intestinal fluids (FaSSIF) and fed state simulated intestinal fluid (FeSSIF) showing a gradual and increasing drug dissolution in the different media. Ex vivo studies using the everted gut sac model show an increased drug transport across rat intestinal epithelium when loaded in the zeolitic particles. Our results suggest that microporous Faujasite zeolite (NaX-FAU) could be used as a drug delivery system to facilitate the oral delivery of poorly water soluble compounds.

Introduction

Oral drug absorption encounters multiple restraints commonly originating from the physicochemical properties of the active compounds. Since the majority of active compounds suffer from poor aqueous solubility, dissolution throughout the gastrointestinal tract is insufficient, resulting in poor drug permeability and low bioavailability after oral administration [1].

The use of porous inorganic materials has emerged as a formulation strategy to increase the solubility of sparingly soluble compounds [2,3]. Drug encapsulation into the porous matrices facilitates conversion of the crystalline form of the drug into its amorphous state of higher free energy, which in turn can increase its solubility [[4], [5], [6]].

Several inorganic materials have being explored as drug carriers opening new possibilities for biomedical applications [7]. Zeolites are among those materials that have enticed considerable attention in drug delivery, due to their innate unique properties [[8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]]. Furthermore, it is possible that zeolites provide protection for drugs that are easily decomposed due to humidity, such as degradation [26]. Zeolites are microporous aluminosilicate materials based on an infinitely extending three-dimensional framework of SiO₄ and AlO₄ tetrahedra linked to each other by sharing oxygens that results in a uniform network of channels and pores (pore size < 2 nm) [27]. On the contrary, ordered mesoporous materials are amorphous silicate materials with highly ordered hexagonal arrangements of pores (channels or cages) with narrow size distributions in the mesoscale range (2–50 nm) [28].

Τhe biological properties (non-toxicity and good biocompatibility) and stability in biological environments have rendered zeolites appropriate for medical use, mainly as drug delivery systems [29]. So far, zeolites have been successfully used as detoxicants and decontaminants, when added in animal nutrition, as well as antibacterial and antidiarrheal agents. Although zeolites have been used in veterinary medicine and zootechnology, in vivo studies using zeolitic particles are relatively scarce [30]. In a study, the supplementation of the normal diet with two clinoptilolite dietary supplements (Megamin and Lycopenomin) in immunocompromised patients was accompanied with absence of any side effects and significant reduction of lymphocytes CD56 ⁺ and significant increase of CD4⁺, CD19 ⁺ and CD3⁺ lymphocytes [31]. Potgieter and co-researchers investigated the effect of Absorbatox™ 2.4 D clinoptilolite as a gastroprotective agent in patients with endoscopically negative gastroesophageal reflux disease (ENGORD) and nonsteroidal anti-inflammatory drug induced gastritis [32]. A significant reduction in heartburn, discomfort and pain was reported in the patients receiving the clinoptilolite treatment [32].

In view of the promise of zeolites as carriers for oral drug administration, we loaded NaX-FAU zeolite with danazol, a BCS class II non-ionizable compound with low aqueous solubility (0.4–0.6 μg/mL) [33,34] and limited bioavailability after oral administration, and further characterized the formulation by means of various physicochemical techniques. Faujasite is a mineral group in the zeolite family of silicate minerals. Its structure consists of truncated octahedra interconnected through double six-membered rings. The pores are defined by a 12-membered oxygen ring with an aperture of 7.4 Å and their interconnection leads to the formation of the main cavities of the zeolite. The silica to alumina ratio is the determinant factor of the zeolite type (X or Y), with high aluminum contents resulting in high exchange capacities that constitute zeolites useful in ion-exchange and adsorption applications, as well as molecular sieves in drug delivery applications, enabling control over drug loading and release kinetics based on the zeolite framework [27]. In vitro release studies of the loaded particles were performed in simulated gastric and intestinal fluids, whereas their ex vivo performance was assessed using the everted sac-model. Finally, these studies were complemented by stability tests of the formulation under accelerated storage conditions.