Encapsulation of ciprofloxacin within modified xanthan gum- chitosan based hydrogel for drug delivery
Graphical abstract
Introduction
In recent years, much more attention has been drawn towards developing novel controlled release drug delivery systems to overcome the reported deficiencies of conventional pharmaceutical active ingredients aiming to achieve the desired patient compliance and optimum clinical efficacy. Polysaccharides based natural polymers gained the attention of the researchers towards the development of natural polymer based hydrogels that are used as base materials in pharmaceutical applications [1].
Polyelectrolyte complexes (PECs) hydrogel is a three dimensional networks forming by interaction of opposite charged polymer chains so, they are biocompatible and suitable for biomedical and pharmaceutical applications [2]. The interaction usually involves a polymeric acid or its salt with a polymeric base or its salt in solution, results in their spontaneous self-assembly due to the promotion of strong, but reversible, electrostatic linkages between them [3]. The formation and properties of PECs depend on molecular weight, density of charge, and degree of neutralization of the polymers employed [4]. Their essential properties have been reviewed by Berger et al. [5]. In addition, these PEC exhibit a pH-dependent swelling behavior which represent an interesting property allowing the controlled-release of different entrapped substance such as, medicinal agents, enzymes or bacteria until it reaches the colon [6].
Chitosan and its derivatives hydrogels have been proven to be a potential carrier for delivery of different drug molecules with respect to size and type [7], [8], [9]. Chitosan is a hetero biopolymer of glucosamine and N-acetyl glucosamine residues, and is obtained by deacetylation of chitin. It possessed favorable biological properties, low toxicity and high susceptibility to biodegradation, mucoadhesive properties and an important capacity to enhance drug permeability, so it can be used as a potential carrier for delivery of different drug molecules [10], [11]. However, one of the inherent limitations of using chitosan in hydrogels, its insolubility at pH of >6.5, which makes limits its biomedical applications, particularly in cases that require drug delivery inside the body, especially at physiological pH [12], [13]. To overcome this limitation, chemically modified chitosan was used in such drug delivery systems. Among chitosan derivatives, N-trimethyl chitosan (TMC), a partially quaternized derivative of chitosan, exhibits a good water solubility over a wide pH range compared to chitosan [14]. It has excellent capacity to transfer hydrophilic macromolecules across mucosal epithelia even at neutral and basic pH values [15], [16], therefore, it was used in several biotechnological [17] and pharmaceutical applications [18], [19], [20], [21], [22]. In addition, TMC has antimicrobial activity better than chitosan [23]. Moreover, TMC is an attractive alternative over chitosan for the design of protein loaded particles by ionic cross-linking [24]
Polyelectrolyte complex of N-trimethylchitosan and heparin (TMC-HP) was prepared and characterized [25]. Martins et al. [26], [27] have recently reported PEC from TMC and sodium alginate PEC for controlled release of curcumin in different environments and to incorporate gold nanoparticles.
On the other hand, Xanthan gum (XG) is another example of water-soluble anionic natural polysaccharide gums that has been used widely in various applications such as; food, oil-recovery, cosmetics, water-based paints, petroleum, tissue engineering, biomedical and drug delivery [28], [29], [30]. Recently, various modification methods have been done on XG to solve its limitations such as; microbial contamination, reduce its thermal stability throughout processing and storage XG [30]. Carboxymethylation is a well-known etherification process for polysaccharides, in which hydroxyl group are etherified with carboxymethyl groups. Carboxymethyl xanthan gum (CMXG) can be used for controlled drug delivery of bovine serum albumin (BSA) [31], for prolonged release of diltiazem [32], [33], and protein delivery [34].
Ciprofloxacin (CFX), (Fig. 1) is a synthetic chemotherapeutic, a potent broad-spectrum antibiotic belonging to fluoroquinolones, has an in vitro antibacterial activity superior to other antibiotics [35], [36]. Also, Ciprofloxacin is used in the treatment of infections caused by gram-negative and sometimes gram-positive bacteria [37]. A local delivery system containing CFX is of great interest for this purpose and several previous studies have been carried out to characterize CFX delivery from different carriers [38], [39], [40], [41]. The formulations of CFX such as capsules, injections and tablets have been vastly used [42]. However, these usual administration methods exhibit that the highest bioavailability of the drug is approximately 52%. In addition, half-life of the CFX drug is too short to achieve prolonged drug release. Also, most of CFX drug will be degraded by lysosome before killing bacteria. This phenomenon usually leads to the low intracellular drug concentration.
Based on the above considerations, the aim of this study was to prepare a hydrogel based on polysaccharides, namely N-trimethyl chitosan (TMC) and carboxymethyl xanthan gum (CMXG) to load and release ciprofloxacin (CFX) drug. The physicochemical properties of the hydrogel and loaded CFX hydrogel were examined by FTIR, TGA, DSC and SEM. The drug loaded hydrogel was further characterized on the basis of drug entrapment efficiency, drug in vitro release behavior, and antimicrobial activity against Streptococcus mutans and Escherichia coli (gram-positive bacteria), Klebsiella pneumoniae and Pseudomonas aeruginosa (gram negative bacteria) and Candida albicans and Asperagillus Niga (fungi).
Section snippets
Materials
Xanthan gum (XG) was purchased from Alpha-Chemika, India. Chitosan with degree of deacetylation 95% was purchased from Aldrich. Monochloroacetic acid, dimethyl sulfate, sodium hydroxide, hydrochloric acid, sodium chloride, ethanol and other solvents used were obtained from Sigma-Aldrich (Germany). Ciprofloxacin (CFX) was purchased from Titan Biotech Ltd. (India).
Synthesis of N-trimethyl chitosan (TMC)
TMC was prepared by the methylation reaction of chitosan and dimethyl sulfate (DMS) according to the method described previously [43].
Synthesis and characterization
The 1H NMR spectrum of TMC is shown in Fig. 2a. The small peak at 2.1 ppm was assigned to the acetyl group of chitosan. The peaks at 2.97 ppm and 3.16 ppm correspond to the protons in the monomethyl and dimethyl groups respectively. The peaks at 3.42–3.53 ppm are related to the occurrence of quaternization, corresponding to the hydrogen of methyl groups bonded to quaternary nitrogen quaternized amino group. Similar 1H NMR spectrum of TMC was reported in literature [54]. From the ratio of the
Conclusions
In this study, TMC/CMCX hydrogel was prepared and characterized by FTIR, TGA and DSC analyses. Ciprofloxacin (CFX) was successfully incorporated and released from the prepared gel without the loss of structural integrity or change in functionality. The entrapment efficiency of the prepared hydrogel was found to be increased with increasing the concentration of drug reaching about 93.8 ± 2.1% with 250 µg/mL of CFX and it was shown that the drug entrapped within the gel without significant
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