International Journal of Biological Macromolecules
Al3+ ion cross-linked interpenetrating polymeric network microbeads from tailored natural polysaccharides
Highlights
► Acid resistant chemical modification of locust bean gum was done. ► IPN microbeads were developed in a complete aqueous environment. ► pH sensitive release decreases the gastric side-effects of diclofenac sodium. ► Enhanced drug encapsulation efficiency. ► Avoid the use of toxic and hazardous chemicals and solvents during preparation.
Introduction
Various synthetic polymers have been used in the past while trying to develop multi-unit microparticulate dosage forms using solvent evaporation techniques. These techniques, although popular, are based on organic solvents. Possible toxicity in chronic dosing due to the presence of even traces of organic solvents in the dosage forms, the flammability, the environment associated with the use of large volume of organic solvents coupled with stringent governmental regulation that restricts their use, have put in question their long-term viability [1].
Natural gums are promising biodegradable materials and these can be chemically modified to have tailor-made materials for drug delivery systems. In addition, they are non-toxic, freely available, and less expensive compared to their synthetic counterparts [2]. Additionally, they do not require organic solvents for their processing [3]. Therefore, in the years to come, there is going to be continued interest in the natural polysaccharides and their modifications, with the aim to have a microparticulate carrier system for controlled oral drug delivery. Among the natural polysaccharides, sodium alginate has been studied extensively for the preparation of drug-loaded calcium alginate beads for controlled oral delivery [4], [5], [6], [7]. Although alginate beads do not swell appreciably in acidic fluid, the beads swell and erode/disintegrate rapidly in simulated intestinal fluids, leading to quick release of the loaded drugs [8], [9], [10] and hence, calcium alginate beads alone do not seem suitable as an oral controlled release system. Further, coating of alginate beads with polyelectrolytes such as poly-l-lysine [11], polyethyleneimine [12], and chitosan [13], has been investigated for the controlled delivery of drugs. However, these had a limited degree of success. Chitosan beads have been fabricated by ionic cross-linking with sodium tripolyphosphate [14], [15], however, higher porosity of the beads led to rapid release of drug in acidic dissolution medium [16]. Phosphorylated chitosan beads of ibuprofen were developed by ionotropic gelation with counter poly-anion [17], tripolyphosphate at pH 4.0. The drug release in alkaline dissolution medium (pH 7.4) was noticeably higher than the release in acidic medium (pH 1.4) due to the ionization of phosphate groups and high solubility of drug in alkaline medium. Furthermore, water-soluble derivatives of chitosan including N-carboxymethyl chitosan [18] and thiol-containing chitosan [19] were synthesized for the development of indomethacin-loaded gelled beads. However, they reported similar findings to that observed with phosphorylated chitosan beads. Even the use of pectin beads has some drawbacks due to their rapid in vitro drug release [20], [21].
Native guar gum and xanthan gum could not form gelled beads in the presence of divalent or trivalent metal ions. However, chemical modification of these gums via carboxymethylation led to the formation of drug-loaded gelled beads. It was reported that barium chloride cross-linked carboxymethyl guar gum beads had a maximum bovine serum albumin (BSA) loading efficiency of 53% depending upon the concentration of barium (Ba2+) ions and released only 5% of the encapsulated BSA in pH 1.2 NaCl–HCl buffer in 6 h; however, the beads released almost 81% of their content within 4 h in pH 7.4 Tris–HCl buffer [22]. It has been reported that diltiazem–resin complex-loaded carboxymethyl xanthan beads released ∼75–82% drug in simulated gastric fluid within 2 h and 75–98% drug in simulated intestinal fluid within 5 h [23]. It appears that each and every polymeric bead system has its merits and demerits; and none of these is a suitable carrier system for oral controlled drug delivery. Hence, there is a need to screen other natural polysaccharides for the development of polymeric bead systems which could overcome the problems associated with such existing systems.
Locust bean gum is a high molecular weight branched polysaccharide and is extracted from the seeds of carob tree Ceratonia siliqua. It consists of a (1, 4)-linked β-d-mannopyranose backbone with branch points from their 6-positions linked to α-d-galactose (1, 6-linked α-d-galactopyranose) [24]. This galactomannan occurs as a white to yellow-white powder, odorless and tasteless, but acquires a leguminous taste when boiled in water. It is less soluble in water and needs heating to dissolve. Being non-ionic, it is not affected by pH or ionic strength. It is dispersible in either hot or cold water to form a solution, having a pH within 5.4–7.0, that may be converted to a gel by the addition of small amount of sodium borate. Its film forming property is used in the textile industry, making it ideal as a sizing and finishing agent, as well as in the pharmaceutical and cosmetics industries for the production of lotions and creams [25]. It also finds its application as excipients for tablets [26]. Moreover, this ingredient is approved for food uses by the US Food and Drug Administration (FDA). In the present investigation, locust bean gum was chemically modified to alter its physicochemical properties, e.g. primary structures, hydrophilicity, polyelectrolytic nature, solution rheology, and gel forming behavior, such that specific functional properties can be improved [27]. Carboxymethylation is a well established chemical treatment of polysaccharides to convert the hydroxyl groups into carboxymethylate.
Earlier, we have developed the SCMC based IPN system for oral controlled release application [28]. So as a part of our ongoing research work on the application of hydrophilic biopolymers, the present work describes the development and evaluation of IPN hydrogel microspheres composed of SCMLBG and SCMC to encapsulate diclofenac sodium (DS), a model drug with a shorter biological half-life of 1–2 h. The microspheres prepared have been characterized by different techniques to understand their various physicochemical behaviors and in vitro drug release characteristics.
Section snippets
Materials
DS was obtained from Yarrow Chemicals Products, Mumbai, India. Locust bean gum was purchased from Hi-Media Laboratories Pvt. Ltd., Mumbai, India. Before use, the gum was washed thoroughly with methanol for 24 h and dried. Monochloroacetic acid was purchased from Loba Chemie Pvt. Ltd., Mumbai, India. Sodium carboxymethyl cellulose (SCMC; high viscosity of 2%, 3000–5000 mPa at 20 °C) and AlCl3·6H2O were purchased from Hi-Media Laboratories Pvt. Ltd., Mumbai, India. Tween 80 was supplied by S.D. Fine
Determination of degree of substitution
In the present investigation, a natural polysaccharide, locust bean gum (LBG) was chemically modified to sodium carboxymethyl locust bean gum (SCMLBG) and characterized with respect to its degree of O-carboxymethyl substitution, toxicity, aqueous solubility, solution rheology, and gel-forming behaviors in the presence of divalent or trivalent metal ions. Finally, its gel-forming ability with trivalent aluminum ions (Al3+) was utilized for the development of a novel IPN polymeric bead system for
Conclusion
Tailored natural polysaccharide IPN beads composed of SCMLBG and SCMC were prepared by single water-in-water (w/w) emulsion gelation method from an aqueous environment containing SCMC as an emulsion stabilizer and Al3+ ions as a cross-linking agent for SCMXG. This carbohydrate blend microbead was characterized by SEM, particle size analysis, FTIR, DSC and XRD technique. SEM micrographs exhibited a spherical morphology of the prepared beads. XRD results confirmed the amorphous distribution of
Acknowledgments
Some of the authors are grateful to Prof. R.M. Dubey, Vice Chancellor of IFTM University, for providing necessary facilities for this research work and Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India, for their kind cooperation and facilities provided to carry out the present research work.
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