Elsevier

Applied Clay Science

Volume 186, 1 March 2020, 105418
Applied Clay Science

Research paper
Theoretical and experimental investigation on the intercalation of metformin into layered clay minerals

https://doi.org/10.1016/j.clay.2019.105418Get rights and content

Highlights

  • Metformin is intercalated as a monolayer in the interlayer space of montmorillonite and Laponite®.

  • Theoretical calculations confirm the experimental parameters of MF-clay intercalation.

  • Theoretical studies confirm a more favorable adsorption energy of MF in Laponite®.

  • Encapsulation of metformin-clay hybrids in pectin affords controlled release of the drug.

Abstract

This work introduces a comparative study on the use of two layered clays, a natural Wyoming montmorillonite (commercialized as Cloisite®Na; Mt) and a synthetic hectorite (commercialized as Laponite® XLG; Lap), to encapsulate metformin (MF), which is the most widely used oral drug for the treatment of type II diabetes. The aim was the evaluation of the suitability of the synthetic Lap clay as substrate for the controlled release of MF in comparison to the montmorillonite clay previously studied, in view to dispose of a convenient and well-regulated clay-based component for pharmaceutical formulation production. The combination of molecular modeling and experimental characterization techniques, such as FTIR, XRD, CHN chemical analysis and EDX, allowed us to study the adsorption process and the final molecular arrangement of MF in the interlayer space of the two silicates. The intercalation of MF in both clays follows an ion-exchange mechanism that leads to a basal spacing increase of 0.36 nm and 0.40 nm for the Lap-MF and Mt-MF systems, respectively, and the intercalated amount of MF matches the cation exchange capacity of each clay. Calculations at molecular level showed thermodynamically favorable systems produced by cation exchange reaction, where the MF species form a monolayer in the interlayer of both clays. In view to the application of these materials as delivery systems of MF, the release of the drug from Lap-MF and Mt-MF intercalation compounds was evaluated in pH conditions that simulate those of the gastrointestinal tract. Interestingly, Lap-MF allows a complete release of the loaded drug, guaranteeing the possibility of reaching an efficient drug delivery system. However, the large MF release in acid medium in both systems makes necessary a further encapsulation of the intercalation compound in a protective polymer matrix to increase the delivery in the intestine. Promising results were obtained using pectin as encapsulating matrix, leading to a gradual release of MF in the simulated gastrointestinal tract conditions.

Introduction

Metformin (MF) is a biguanide-type drug widely indicated for the treatment of type II diabetes (Turner, 1998). This is a widespread chronic metabolic disease, characterized by elevated glucose level in blood (hyperglycemia) (King et al., 2001; Krentz and Bailey, 2005; Levetan, 2007). This type of diabetes is primarily caused by a state of action of insulin resistance associated with a relative deficiency of its secretion by metabolism (King et al., 2001; Lenhard and Gottschalk, 2002; Chatterjee et al., 2017). According to the World Health Organization (WHO) the number of deaths from diabetes reached 1.6 million in 2016, which made this disease the seventh cause of death in the world (WHO, 2019a). Currently, metformin hydrochloride is the reference drug used for the treatment of type II diabetes, being able to decrease blood glucose concentration by mechanisms other than insulin or sulphonylurea (Sirtori, 1994; Rojas and Gomes, 2013; Pala and Rotella, 2014; Sterrett et al., 2016; Chatterjee et al., 2017). This drug also decreases plasma insulin concentrations, contributing to increase peripheral glucose uptake and decreasing hepatic glucose production (Laliberte and Neumiller, 2010; Sterrett et al., 2016). For this reason, the World Health Organization has listed metformin as an essential medicine (WHO, 2019b), being the most used oral medication for diabetes. Moreover, this drug is gaining great prominence in recent years, showing high efficacy as antitumor agent mainly in the treatment of prostate, colon and breast cancers (Gupta et al., 2013, Gupta et al., 2018; Aldea et al., 2014). However, this drug has several disadvantages caused by the low absolute bioavailability of 50–60% and a biological half-life of 6.2 h, which implies the administration of high doses for an optimal therapeutic effect that can produce serious gastrointestinal problems (Pala and Rotella, 2014). In this context, the design of drug delivery systems (DDS) is required to offer a controlled release and, consequently, to diminish these side effects. Although the most commonly used carrier materials for the release of MF to date are biopolymers (Ghazaie et al., 2017; Martínez-Gómez et al., 2017; Verma and Ahuja, 2017), some mesoporous materials (Li et al., 2017; Shariatinia and Zahraee, 2017), porous silicon (García-Briones et al., 2019) and clay minerals are now frequently employed as supports of a wide variety of drugs in DDS (Carretero, 2002; Aguzzi et al., 2007; Viseras et al., 2010; Hun Kim et al., 2016; Yang et al., 2016; Alcântara and Darder, 2018; Massaro et al., 2018; Ruiz-Hitzky et al., 2019) and so they could also serve as substrates for MF, as we have recently reported by preparing montmorillonite-MF systems (Rebitski et al., 2018b). Though less explored than montmorillonite, synthetic hectorites, such as Laponite®, whose composition and purity can be better controlled than in natural clays (Christidis et al., 2018), are gaining interest in recent years for the intercalation of drugs (Tomás et al., 2018).

The synthetic hectorite used in this work is the Laponite® XLG commercial product especially applied for pharmaceutical preparations with the Na0.7[(Si8Mg5.5 Li0.3)O20(OH)4] general formula, cation exchange capacity (CEC) of 63 mEq per 100 g and disk-shaped crystals of approximately 25 nm in diameter and 0.92 nm in height (BYK Additives and Instruments, 2014; Tomás et al., 2018). On the other hand, the Cloisite®Na used in this work is a Wyoming Na-montmorillonite (Mt) of Na0.33[(AlMg)2(Si4O10)(OH)2]·nH2O formula with a CEC of 93 mEq per 100 g and particle size of 600 nm ± 92 nm. Taking into account the different characteristics of these two layered silicates, this study was set with the aim of exploring and analyzing in a comparative way their behavior as substrates for adsorption and release of metformin.

Computational modeling tools at the molecular level are here applied for a better understanding of the interactions between the drug and clays. By means of computational modeling, it can be known the geometrical structure of metformin, the structural dimensions of the unit cell, the distribution of the drug along the interlayer space, the interpretation of the clays interlayer spacing shift, atomic organization etc., including interaction energy associated with the adsorption process.

Several works based on computational modeling have achieved results of great relevance in the understanding of the interactions between molecules (drugs, herbicides, surfactants, etc.) and minerals (sepiolite, palygorskite, halloysite, montmorillonite, Laponite, etc.,) as for example; adsorption of sulfonamides on phyllosilicate (Francisco-Márquez et al., 2017), pilocarpine on Laponite® (Cunha et al., 2017), surfactants on montmorillonite (Borrego-Sánchez et al., 2018a), neomycin on montmorillonite and sepiolite (Rebitski et al., 2018a), or to study the interaction of ethambutol with palygorskite (Meirelles et al., 2019). The final objective of the present study is also to evaluate and compare the release of MF intercalated in the Lap and Mt substrates incorporated in a biopolymer matrix of pectin, forming bionanocomposite materials. Bionanocomposites based on polymers are known as good carriers of different types of drugs (Darder et al., 2007) like ibuprofen (Alcântara et al., 2010; Ribeiro et al., 2014), diclofenac (Lisuzzo et al., 2019), or amoxicillin (Rebitski et al., 2019) among others. Pectin is a natural complex heteropolysaccharide extracted from apple and citrus fruits, which is composed of (1,4)-linked α-D-galacturonic acid residues and variety of neutral sugars such as rhamnose, galactose and arabinose (Cheikh et al., 2019). Pectin presents properties of biocompatibility, biodegradability, and has very interesting mucoadhesive properties for biomedical applications (Chourasia and Jain, 2003; Rajpurohit et al., 2010; Liu et al., 2012; George et al., 2019). Thus, pectin was selected in the current study as encapsulation matrix to afford additional control in the release of metformin from the Laponite® and montmorillonite supports.

Section snippets

Starting materials and reagents

Metformin (MF) was purchased from Sigma–Aldrich as 1,1-dimethylbiguanide hydrochloride (C4H12ClN5), with MW of 165.62 g mol−1 and purity 97%. Laponite® XLG (Lap) was kindly provided by BYK Additives & Instruments, and Cloisite®Na by Southern Clay Products. Deionized water (resistivity of 18.2 MΩ cm) was obtained with an Elga Maxima Ultrapure Water equipment. Pectin (PEC) from citrus fruit was purchased from Sigma-Aldrich. Aqueous solutions were prepared from chemicals of analytical reagent

Experimental formation of MF-clay intercalation compounds

In a preliminary study on the intercalation of MF in the Mt clay mineral, an adsorption isotherm was obtained to determine the maximum amount of MF adsorbed by this silicate (Rebitski et al., 2018b). For that purpose, a given amount of Mt was mixed with a set of MF solutions with concentration ranging from 1 to 30 times the CEC of the clay to stablish the corresponding adsorption isotherm at 25 °C. Here we have prepared a sample using 15 times the CEC, which warranties the maximum adsorption of

Conclusion

The present work reports a comparative study on the suitability of two lamellar clays, a synthetic hectorite (Lap) and natural montmorillonite, as supports for the controlled release of metformin, the drug most commonly used for the treatment of type II diabetes. Metformin was intercalated in both clay minerals following an ion-exchange mechanism, leading to intercalated amounts that match the CEC of each clay. Computational methods confirmed the experimental results, yielding similar basal d

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by the MINECO (Spain) and FEDER (EU) funds (projects MAT2015-71117-R, and FIS2016-77692-C2-2-P), Andalusian RNM1897 grant and the CNPq (Brazil) predoctoral fellowship 204360/2014-5. Ediana Paula Rebitski also acknowledges the reception of the Martin Vivaldi award granted by the Spanish Clay Society.

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    Manuscript recognized with the 2019 Martin Vivaldi Award, sponsored by the European Clay Groups Association and supported by the Spanish Clay Society, at the International Conference on Clay Science and Technology (EUROCLAY), Paris - Francia 2019.

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