Original Research Article
Application and evaluation of layered silicate–chitosan composites for site specific delivery of diclofenac

https://doi.org/10.1016/j.bbe.2014.08.004Get rights and content

Abstract

The present study focuses on the in situ intercalation of anionic drug (diclofenac sodium, DS) and cationic polymer, Chitosan (CS) in montmorillonite (MMT) for drug release applications. The prepared DS/CS-MMT composites were further compounded with alginate (AL) to form beads to modify release response in gastric juice. The DS/CS-MMT composites were characterized by UV spectroscopy, XRD, FT-IR, TGA and DSC. Antibacterial assay of drug loaded composites was investigated and in vitro cell viability assay results point out the drug encapsulated in clay plates are less toxic to the cell than pristine drug. The in vitro release experiments revealed that the DS was released from DS/CS-MMT/AL in a controlled and pH dependent manner.

Introduction

Nowadays, the interdisciplinary nature of the biopolymer composite materials and its application in the medical science arena brings together scientists, technologies and medical specialists from fundamental science, applied chemistry, biology, physics, materials and biomedical engineering. Biopolymer–clay composites have potential to develop critical formulation that can be extended for biomedical applications, varying from diagnostic tools and medical devices, tissue engineering and controlled drug delivery matrixes to numerous biomedical technologies inspired by fundamental biology and applied biomedical applications [1].

Recently, preparation and application of biopolymer/layered silicate material composites as controlled drug delivery vehicles and biomedical engineering have been attracting much attention owing to their unique structure and functional properties. Layered silicate materials, e.g. Smectite clays (laponite, saponite and montmorillonite) have been used for preparing for this class of composites. The synergistic effect of biopolymer and layered silicate material as well as the strong interfacial interactions between them by electrostatic interaction and hydrogen bonding could improve the mechanical properties, swelling behavior, drug loading efficiency and controlled release behavior of the pristine biopolymer matrices. In summation, these properties could be further tailored by changing the character and capacity of layered silicate materials. The chitosan/montmorillonite composites were demonstrated to exhibit excellent anti-fatigue behavior and better pulsatile drug release compared with neat chitosan [2]. Wang et al., studied pH-sensitive chitosan-g-poly(acrylic acid)/vermiculite/sodium alginate (CTS-g-PAA/VMT/SA) hydrogel beads. The authors reported that the release rate of drug from the composite hydrogel beads was remarkably slowed down due to presence of vermiculite [2], [3]. The construction of hybrid poly(lactic-co-glycolic acid)/montmorillonite could significantly cut the initial burst release of paclitaxel [4], [5].

Montmorillonite (MMT) is an ideal material for the formulation of drug delivery vehicle because of its excellent properties, such as the ability to adsorb dietary toxins, bacterial toxins associated with gastrointestinal disturbances, hydrogen ions in acidosis and metabolic toxins such as steroid metabolites associated with pregnancy [4]. Nevertheless, the release of drugs from MMT has been tested to be initially very fast, owing to the weak interaction between the drugs and the MMT particles [6], [7]. The compounding of polymer and MMT seems to be a viable means to sustain the release of drugs and to make polymer/MMT composites applications as long-term controlled drug release carriers [8], [9], [10]. Diclofenac sodium (DS), [2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid] is a non-steroidal anti-inflammatory drug and one of the best commonly used NSAIDS and its short half-life of 1–2 h demands preparation of a controlled release formulation. In order to prolong the circulation time of DS and increase its efficacy, numerous researchers have attempted to modify its delivery by use of polymer conjugates or by incorporation of the DS into particulate carriers [11], [12], [13]. The ultimate aim of these strategies is to reduce DS associated side effects and thereby improve its therapeutic index.

Herein we focused on the layered aluminosilicate clay, montmorillonite (MMT)/chitosan (CS) composites modified with alginate (AL) as delivery systems of diclofenac sodium. CS-MMT and DS/CS-MMT composite hydrogels were prepared under optimal reaction conditions by ion-exchange and gelation techniques and characterized. The drug loaded composites were evaluated for in vitro release characteristics in simulated gastric juice and phosphate buffer. In present study, experiments were designed to assess the effect of DS/CS-MMT on viability of A549 (human lung adenocarcinoma epithelial cell line) along with antibacterial activities.

Section snippets

Materials

Diclofenac sodium salt, alginic acid sodium salt (Viscosity: 20.0–40.0 cP in 1% water, Molecular weight: 7334 Da, according to manufacturer), chitosan, medium molecular weight (Viscosity: 200 cPs in 1% glacial acetic acid, deacetylation degree (DD) 80%, Avg. Molecular weight: 8401 Da, according to manufacturer) and cellulose acetate dialysis tube (Cutoff molecular weight at 7000 Da) were acquired from Sigma–Aldrich, USA. RPMI-1640 (Roswell Park Memorial Institute 1640), Trypan blue, MTT

Intercalation chemistry of DS and CS in interlayer gallery of MMT

The successful intercalation of DS and CS in MMT was carried out under optimized reaction conditions, e.g. biopolymer to clay ratio, pH of the reaction and the initial concentration of drug. The cationic nature of CS and the anionic nature of the DS makes these molecules exceptional candidates for intercalation in MMT by means of ion exchange and chemical interactions between DS/CS and MMT. Depending on the CS concentration added to the MMT suspension, CS chains arrange in monolayer or bilayer

Conclusions

We have successfully intercalated CS into MMT galleries which was further entrapped in AL matrix to form composites hydrogel beads for oral drug delivery system by ion exchange and gelation methods. The molecular arrangement of the drug molecules in the basal spacing of CS-MMT composites were confirmed by XRD, FT-IR, TGA and DSC.

The antibacterial activity of MMT, CS-MMT and DS/CS-MMT was evaluated by well-diffusion on agar. The results showed that DS/CS-MMT composites had stronger antibacterial

Acknowledgments

Authors are thankful to Directors, CSIR-CSMCRI, Bhavnagar and Institute of Science, Nirma University, Ahmedabad for providing necessary infrastructure facilities and the Council of Scientific and Industrial Research (CSIR), Government of India, New Delhi, India, for financial support under the project “Speciality Materials based on Engineered Clays” (SPEC, CSC-0135) and Senior Research Fellowship to Dr. B.D. Kevadiya, Special thanks to Dr. P. Bhatt (XRD), Mr. V. Agarwal (FTIR), Mrs. Sheetal

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