Pharmaceutical Nanotechnology
Laponite-based nanohybrid for enhanced solubility and controlled release of itraconazole

https://doi.org/10.1016/j.ijpharm.2007.08.008Get rights and content

Abstract

Laponite, a form of layered aluminosilicates, and itraconazole, a water insoluble drug, were hybridized through an interfacial reaction at the boundary between water and a water-immiscible liquid. The reaction was carried out under a controlled pH to maintain both physical and chemical stability of the drug. The X-ray diffraction patterns and spectroscopic analyses indicated that itraconazole was intercalated into the interlayer space of clay with a lateral monolayer structure. No significant chemical structural change of itraconazole was seen through the formation of the hybrid. The hybrid system exhibited enhanced solubility and controlled release of itraconazole. The released amount of itraconazole could be controlled in the range from 18 to 75%, depending on the kinds of cations in the release media.

Introduction

Recently, various nanohybrid materials have attracted considerable research interest due to their useful physicochemical properties, which cannot be achieved by the individual components in and of themselves (Choy et al., 1998, Choy et al., 2002, Paek et al., 2005, Kwak et al., 2002). In particular, there has been rapid development of bioinorganic hybrid systems for effective drug delivery (Choy et al., 2004a, Choy et al., 2000, Choy et al., 1999). Bioinorganic hybrid systems can allow controlled delivery of various therapeutic agents into the target tissues/organs with high efficiency. Among a variety of inorganic materials, smectite clays are associated with great potential (Choy et al., 2004b, Lin et al., 2002). The interlayer space of smectite clays could be an effective reservoir for various biomolecules due to their high retention capacity. The molecules, stabilized by electrostatic forces between the inorganic layers, can be protected chemically and biologically from the body's environments and also released the compound of interest in a controlled manner. Most of all, the water solubility of the drug, when intercalated into the clay, can be greatly enhanced because the drug molecules are distributed in ionic form. Therefore, such hybrid system is known to be advantageous especially for the controlled release of the drugs with low solubility.

Itraconazole (ITA) (4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methyl-propyl)-3H-1,2,4-triazol-3-one) is a synthetic anti-fungal drug, which is composed of a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs). Three chiral centers are present in each diasteromer which possess a molecular formula of C35H38Cl2N8O4 and molecular weight of 705.64 g/mol (Jain and Sehgal, 2001, Grant and Clissol, 1987). ITA is poorly soluble in aqueous media (less than 1 μg/ml in aqueous solutions at pHs of 1–12.7) with a partition coefficient greater than 5 in octanol/water at pH 6. Thus, in spite of the high antifungal activity, the bioavailability of unformulated crystalline ITA is extremely low (Jung et al., 1999, Verreck et al., 2003). In order to enhance its solubility and dissolution rate, various formulations have been developed, including solid dispersions (Leuner and Dressman, 2000, Verreck et al., 2003), solid solution (Kapsi and Ayres, 2001), and complexes (Peerers et al., 2002, Miyake et al., 1999). However, these routes may not prevent the drugs from recrystallization or may not provide for controlled delivery (Choy et al., 2000, Choy et al., 1999, Choy et al., 2004b). In addition, such routes often required complicated procedures.

In this study, we attempted a new approach, the hybridization of ITA with laponite clay, in order to enhance water solubility and facilitate controlled release. Laponite, a plate like synthetic hectorite-type clay, was used as the host clay, which possesses high purity required for the systematic study. To explore the potential of smectite group as an ITA delivery vehicle, this study focused on the characterization of ITA-laponite hybrid along with the release behavior of ITA.

Section snippets

Materials

Laponite (XLG, Laporte Industries Ltd.), synthetic swelling clay with tri-octahedral 2:1 layered structure, has the chemical composition of SiO2, 59.5%; MgO, 27.5%; LiO2, 0.8% and Na2O, 2.8%. Because some of octahedral magnesium ions in the octahedral sheets are substituted by lithium ions, negative layer charges are developed which are compensated by exchangeable sodium ions located in the interlayer space. Its monoclinic crystals (C2/m) with a dimension of ca. 1 nm × 25 nm have a negative charge

Powder X-ray diffraction analysis

Fig. 1 shows the powder XRD patterns of the pure laponite, ITA-laponite hybrid, and ITA itself. The unmanipulated laponite exhibited a broad XRD pattern indicating low crystallinity and small particle size (Park et al., 2004). Upon intercalation, the basal spacing significantly expanded from approximately 14 to 16.08 Å, suggesting the replacement of interlayer cation by ITA. Subtracting the silicate layer thickness (9.2 Å) from the basal spacing (16.08 Å) of the ITA-laponite hybrid, the gallery

Conclusion

ITA, an antifungal drug molecule, could be intercalated into interlayer space of laponite and deintercalated in the ionized form. Based on the ease of intercalation and deintercalation, clay could be a good candidate as a drug delivery carrier for pharmaceutical applications. Clay could play a role as solubility controller, since the intercalation of drug molecules into interlayer space would enhance the dissolution rate of the drug like ITA secondary to surface area, wettability or solubility

Acknowledgements

This work was financially supported by the SRC/ERC program of MOST/KOSEF through the Center for Intelligent Nano-Bio Materials at Ewha Womans University (Grant: R11-2005-008-00000-0).

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