Itraconazole–Laponite: Kinetics and mechanism of drug release
Introduction
Recently, the intercalation chemistry of two-dimensional (2-D) compounds was of great interest due to their potential applications as catalysts, adsorbents, molecular sieves, secondary batteries, and photocatalysts (Choy et al., 2002, Choy et al., 2003, Park et al., 2005, Paek et al., 2006). Among such 2-D compounds, natural or synthetic clay minerals have attracted a great attention (Ogawa and Kuroda, 1995, Corma, 1997). A variety of cationic species, whether they are inorganic or organic ions or even polymeric ions, could be accommodated within the interlayer space of the clay minerals. Therefore, Laponite has been extensively studied to understand the intercalation chemistry (Choy et al., 1999, Choy et al., 2000, Choy et al., 2004b).
More recently, much effort has been made for a pharmaceutical application of clay minerals, such as smectites, palygorskite, kaolinite, and talc (Lee and Fu, 2003, Choy et al., 2004a, Park et al., 2004). They were often employed as an active ingredient or excipient in pharmaceutical formulations due to their large specific surface area and adsorption capacity, enhanced rheological property, chemical inertness, and low or null toxicity (Lee and Fu, 2003). In particular, smectites have been excellent candidates as a drug delivery carrier due to their capability to intercalate large molecules into the interlayer space of 2-dimensional aluminosilicate layers and release them by ion exchange (Park et al., 2004). The interlayer space of smectites can provide a large space to reserve neutral drug molecules via ion-dipole interaction, and cationic or bio-functional ones via ion exchange reaction.
The drug-clay nanohybrid may show two distinct features, which are the programmed drug release out of the clay mineral structure and the stabilization of the fragile drugs or biomolecules. Aqueous solubility of the drugs could also be highly enhanced when they were intercalated into a hydrophilic clay mineral. The drug-clay nanohybrid could be homogenously dispersed in the aqueous media without forming any drug crystals. Due to many advantages described above, the nanohybrid could be a good candidate as a drug delivery carrier, which would make it very useful to trace its drug release mechanism. However, to the best of our knowledge, no systematic study has yet been made on the drug release or its mechanism for the clay/drug nanohybrid.
In the present study, the Laponite clay was employed as a drug carrier, with which a poorly water soluble model drug, itraconazole (ITA), was hybridized to examine its drug release patterns. 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) was developed by Janssen Pharmaceutica as an antifungal agent with a broad spectrum of treatments and has gained widespread acceptance (De Beule and Van Gestel, 2001). ITA is also known even for the treatments of Candida sp. and Aspergillus sp., the most common fungal pathogens (Jain and Sehgal, 2001).
Generally, the water insoluble drug, such as ITA, poses the limitation due to its low release rate in the aqueous media, hence low bioavailability. In this study, we focused on enhancing the release rate of ITA in a controlled manner. The pH of the release media was maintained at 1.2 to mimic the gastric fluid because ITA is known to be absorbed mostly in the stomach. To control the release rate, various types of cations were employed not only to expedite the ion exchange reaction but also to minimize recrystallization of the drug molecules released in the media. We also investigated the release kinetics and mechanisms systemically using four well known mathematical models, which are first-order, Elovich, parabolic diffusion, and power function equations.
Section snippets
Materials
Laponite XLG in cosmetic grade, was purchased from Laporte Industries Ltd. Typical Laponite particles show platelet-like shapes with the average diameter of ∼ 25 nm and layer thickness of ∼ 9.2 nm. Eudragit® E-100, aminoalkyl methacrylate copolymers (Scheme 1) containing multiple tertiary amines, was purchased from Rohm Pharma Inc.
Preparation of the Laponite-drug hybrid
An aqueous dispersion of Laponite (1 wt.%) was prepared by dispersing it in water for one day in order to get it fully swollen. The dispersion was turbid at the
Release profiles
Intercalated cations of smectite were easily exchanged by other cations. However, bulky and hydrophobic organic cations in interlayer space were not easily replaced by metal cations like Na+, Ca2+, and etc. Deintercalation of these organic cations should be facilitated by other organic cations with similar or larger molecular size and charge (Zhang et al., 1993, Luther et al., 1998).
The release profiles of ITA from the Laponite-drug hybrid in the dissolution media with different kinds of
Conclusion
The drug release mechanisms were investigated for the ITA–Laponite. The total amount of ITA release during the first 72 h varied depending on the type of cations in the dissolution media (NaCl, CH3(CH2)3NH3Cl, CH3(CH2)15NH3Cl and Eudragit® E-100). The release profiles of ITA were also tested employing four kinetic models. The first-order equation was best fit for the release profiles of ITA in NaCl, CH3(CH2)3NH3Cl, and CH3(CH2)15NH3Cl solutions, and the Elovich equation for the one in a Eudragit
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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