Controlled release of donepezil intercalated in smectite clays
Introduction
Drug delivery systems have been of great interest for the past few decades to realize the effective and targeted drug delivery and minimize the side effects in the field of pharmaceutics (Chandrasekar et al., 2007, Allen and Cullis, 2004, Sinha and Trehan, 2003). Nowadays, various synthetic polymers have been intensively studied as a delivery carrier due to their well-known therapeutic benefits, such as biocompatibility, biodegradability, and long-term safety of drugs. However, the polymers, such as polylactide (PLA) and polylactide-co-glycolide (PLGA), are known to have some drawbacks resulting from their hydrophobic nature. For example, due to the accumulation of hydrophilic drugs near the surface of polymer based carriers, a high burst effect was often observed (Sinha and Trehan, 2003). Moreover, because of their hydrolysis to lactic and glycolic acid monomers, the acidic environment was formed at the inside of the polymer-based carriers, which could cause undesirable drug degradation (Sinha and Trehan, 2003, Soppimath et al., 2001). Thus, new effective delivery systems for hydrophilic drug have been needed to resolve the problems stated above.
The smectite clay, a kind of layered aluminosilicates, is composed with tetrahedral sheets of SiO4 unit and octahedral sheets of Al3+ ions. The isomorphous substitution of Al3+ with Mg2+ or Fe2+ on octahedral sheets or that of Si4+ with Al3+ on tetrahedral ones can generate negative surface charge (Swartzen Allen and Martijevic, 1974, Thomas et al., 1999). The former two are considered as montmorillonite (MMT) and laponite (LA), respectively and the latter as saponite (SA) (Chattopadhyay and Traina, 1999, Liu and Kerry Thomas, 1991). In order to compensate the excessive negative layer charges, the interlayer cations, which are in general solvated, are stabilized between the layers. As a result, the smectite clay possesses hydrophilicity, high dispersibility in water, and most importantly, cation exchange capacity (CEC) (Lin et al., 2002). With CEC and swelling property along the (0 0 l) axis of these layered minerals, smectite clays can encapsulate various protonated and hydrophilic organic molecules into the interlayer space of the (0 0 l) plane, which can be released in controlled manners by replacement with other kinds of cations in the release media (Dong and Feng, 2005, Yang and Hu, 2006). Therefore, the smectite clays are suggested to be good delivery carriers of hydrophilic drugs.
The smectite clay and donepezil were employed as inorganic matrices and organic guest molecules, respectively. The donepezil, chemically (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one, is a well-known drug for Alzheimer's disease. This disease is related to the cognitive dysfunction and progressive deterioration of memory due to the cholinergic deficit. The donepezil, an acetylcholine-blocking agent, is known to prevent the rapid hydrolysis of acetylcholine in synapses of central and peripheral nervous system, and hence a potent drug for Alzheimer’ disease. However, the adverse effects have been still reported due to the increase in gastric acid secretion caused by enhanced cholinergic activity through the gastrointestine (Contreras et al., 2001, da Silva et al., 2006).
In this study, donepezil-nanoclay hybrids were successfully synthesized employing three different clay materials, which were MMT, LA, and SA. They could be expected to enhance the encapsulation efficiency of drugs and reduce the adverse effect of donepezil because the clay used in this study is able to reduce the acidity by absorbing proton and control the drug release behavior (Chattopadhyay and Traina, 1999, Liu and Kerry Thomas, 1991). The donepezil-nanoclay hybrids were characterized via powder XRD, FT-IR, thermogravimetry (TG), zetasizer, and scanning electron microscopy (SEM). The release profiles of donepezil were also studied with UV–vis spectrometry and HPLC.
Section snippets
Materials
The donepezil and clay materials were used without any purification. Na+-MMT (Kunipia-F, Kunimine Corp.), Na+-SA (Sumecton SA, Kunimine Industries), and Na+-LA (Laponite XLG, Rockwood Additives Ltd.) were used as the host materials. The chemical formulas of MMT, SA, and LA are Na0.7K0.02Ca0.04(Si7.78Al0.22)(Al3.20Mg0.64Fe0.16)O20(OH)4, Na0.35Mg0.14(Si7.20Al0.80)(Al0.03Mg5.97)O20(OH)4, and Na0.70Si8.00(Mg3.50Li0.30)O20(OH)4, and the CECs were 100, 71, and 63 mequiv./100 g, respectively (Kakegawa
Powder X-ray diffraction analysis
Fig. 1 shows the XRD patterns of donepezil only and donepezil-nanoclay hybrids. All characteristic crystalline peaks (18° < 2θ < 40°) of the pristine clays (Fig. 1(b)–(d)) were seen in the XRD patterns for all the hybrids (Fig. 1(e)–(g)) prepared in the present study. For the hybrids, the shift of (0 0 l) peaks to a lower 2θ angle was clearly observed, which indicated that drug molecules were successfully intercalated into the interlayer space of clay. Notably, no XRD peaks, corresponding to
Conclusion
In this study, donepezil molecules were successfully intercalated by cation exchange reaction without any deterioration of their functional groups. The thermal stability of drug molecules was also improved after the hybridization. We found that the CEC of the clay could determine the absorption amount and molecular arrangement of the drug molecules in the interlayers, as well as the release patterns of donepezil. The release rate could be easily enhanced utilizing a bulky cationic polymer,
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) and also partly supported by the Ministry of Commerce, Industry and Energy (MOCIE) through the project of NGNT (No. 10024135-2005-11) and “Seoul Research and Business Development Program (10816)”.
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