Thiol functionalized polymethacrylic acid-based hydrogel microparticles for oral insulin delivery
Introduction
Nano/microparticles composed of bioadhesive polymers are promising systems for oral drug delivery applications [1]. They can extend the residence time of dosage forms in the gastrointestinal tract (GIT), and hence improve the bioavailability of orally administered drugs. Hydrogels composed of hydrophilic polyacrylates such as poly(acrylic acid) (PAA) and poly(methacrylic acid) (PMAA) exhibit mucoadhesive properties [2], [3]. PAA/PMAA-based hydrogels are also capable of chelating divalent ions (e.g. calcium and zinc), which in turn affects the thermodynamic stability and the biological activity of calcium-dependent proteolytic enzymes like trypsin and chymotrypsin [4]. A reduction in extracellular divalent ion concentration can also result in the opening of epithelial tight junctions, allowing paracellular drug transport across the intestinal epithelium [5].
Surface modification was suggested as an interesting approach in further improving the efficacy of mucoadhesive delivery systems [6], [7]. Attachment of specific functional entities (such as lectins, thiols, etc.) to the polymer surface has proved effective in enhancing their mucoadhesion behaviour [8], [9]. In general, bioadhesive polymers display non-specific interactions with mucus layers. In contrast, lectins/thiol groups mediate mucoadhesion through specific interactions to promote adherence with the mucosal layer. Lectins have the ability to bind glycoproteins of the mucus in a specific manner, thereby improving interaction with mucosal surfaces [10], [11]. On the other hand, addition of thiol groups to polymers, often referred as ‘thiomers’, can significantly enhance polymer–mucus interaction by the formation of disulphide linkages [12].
Interestingly, the introduction of thiol functional groups has also improved the permeation enhancing capability of mucoadhesive polymers [13]. Surface thiolation of hydrogel systems seems to be an interesting approach in this respect, assuming that thiol groups may help in anchoring the delivery system to the mucus layer surface, whereas the hydrogel character of the system may help its diffusion across the mucus layer to reach absorption sites on the epithelium. PCP hydrogel particles developed by the ionic gelation method are attractive in developing oral insulin delivery systems [14]. An attempt has been made to improve the efficacy of PCP hydrogel carriers by the attachment of surface thiol groups [7]. Mucoadhesion experiments were conducted and the ability of these systems to improve the paracellular permeability of hydrophilic macromolecules was studied with the help of Caco-2 cells and excised intestinal tissue. Thiol groups at varying concentrations were attached to the PCP particles and, based on the results obtained, an optimized system was selected for this investigation.
In the present study in vitro and in vivo studies were performed to evaluate the efficacy of thiolated PCP microparticles for oral insulin delivery. Detailed in vitro experiments were carried out to evaluate the efficacy of modified particles in terms of swelling, insulin loading/release, protease inhibition and insulin transport properties. Finally, an in vivo experiment was conducted in a diabetic animal model to evaluate the potential of this oral insulin delivery system.
Section snippets
Materials
Methacrylic acid (MAA), 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (EDC), ethylene glycol dimethacrylate (EDMA), 5,5′-dithiobis (nitrobenzoic acid) (Ellman’s reagent), l-cysteine, 2-[N-morpholino]ethanesulfonic acid (MES), polyethylene glycol (PEG) molecular weight 20 kDa, potassium persulphate, streptozotocin (STZ), trypsin from bovine pancreas (11,100 U mg−1), N-α-benzoyl-l-arginine p-nitroanilide (BAPNA), α-chymotrypsin from bovine pancreas (55 U mg−1), N-benzoyl-l-tyrosine
Synthesis and evaluation of the microparticles
PCP microparticles were obtained by an ionic gelation method and thiol groups were attached by a surface modification strategy. Table 1 gives the average particle size and thiol content (including total sulphur content) of the hydrogel particles. The average size of the PCP particles was ∼1 μm, whereas the surface thiolated particles had an average size of ∼2 μm. Optical microscopic images of the dried hydrogel particles are shown in Fig. 1. Thiolated particles had an aggregate structure,
Discussion
PCP hydrogel microparticles were prepared by an ionic gelation method and a surface modification approach was undertaken to introduce thiol functionalities. Polymeric nano/microparticles with attached thiol groups were utilized to develop advanced drug delivery systems [23], [24], [25]. In these studies thiolation was mainly on the polymer backbone. Nanoparticles were generated from these modified polymers. In the present study thiolation was on carboxylic groups exposed on the surface of the
Conclusion
Surface thiolation has been proposed as a possible strategy to enhance the efficacy of hydrogel-based oral insulin delivery systems. Thiolation reduced the swelling capacity of PCP hydrogel microparticles. Thiolation also affected the efficacy of insulin incorporation and the release properties of PCP microparticles. Although the protease inhibition capacity of PCP particles was slightly reduced on thiol modification, this strategy of microparticle modification provided an improvement in
Acknowledgements
Financial support from the Department of Science and Technology, New Delhi, under the FADDS programme is kindly acknowledged. S.S. thanks the French Embassy in India for the award of a Sandwich Ph.D. fellowship. The authors thank Dr. Véronique Marsaud (UMR-CNRS 8612) and Dr. Rekha M.R. (SCTIMST) for their help in cell culture studies and in vivo experiments, respectively.
References (31)
- et al.
Specific and non-specific bioadhesive particulate systems for oral delivery to the gastrointestinal tract
Adv Drug Deliv Rev
(1998) - et al.
Engineering design and molecular dynamics of mucoadhesive drug delivery systems as targeting agents
Eur J Pharm Biopharm
(2009) - et al.
Hydrogels as mucoadhesive and bioadhesive materials: a review
Biomaterials
(1996) - et al.
The effect of complexation hydrogels on insulin transport in intestinal epithelial cell models
Acta Biomater
(2010) - et al.
Mucoadhesion mechanism of chitosan and thiolated chitosan–poly(isobutyl cyanoacrylate) core–shell nanoparticles
Biomaterials
(2007) - et al.
Surface functionalized polymethacrylic acid based hydrogel microparticles for oral drug delivery
Eur J Pharm Biopharm
(2010) - et al.
Lectin-mediated drug targeting: history and applications
Adv Drug Deliv Rev
(2004) - et al.
Permeation enhancing polymers in oral delivery of hydrophilic macromolecules: thiomer/GSH systems
J Control Release
(2003) - et al.
Elaboration and characterization of thiolated chitosan-coated acrylic nanoparticles
Int J Pharm
(2006) - et al.
Cyclodextrin–insulin complex encapsulated polymethacrylic acid based nanoparticles for oral insulin delivery
Int J Pharm
(2006)
Optimization of an in vitro procedure for the determination of the enzymatic inhibition potency of multifunctional polymers
J Control Release
Synthesis and evaluation of lauryl succinyl chitosan particles towards oral insulin delivery and absorption
J Control Release
Synthesis and structural analysis of copper(II) cysteine complexes
Inorg Chim Acta
Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery
Biomaterials
Specific permeability modulation of intestinal paracellular pathway by chitosan–poly (isobutyl cyanoacrylate) core–shell nanoparticles
Eur J Pharm Biopharm
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2018, International Journal of PharmaceuticsCitation Excerpt :Despite fast release in SIF, in vitro experiments reveal that the microcarrier could protect insulin against enzymatic degradation, and promote insulin absorption across duodenal membranes. Among hydrogel-based delivery systems, PMAA offers favourable properties for oral insulin delivery, including pH-sensitive swelling behaviour, prolonged GI residence time, proteolytic inhibition by its calcium chelating property, and the ability to promote reversible paracellular absorption (Sajeesh et al., 2010a, 2010b). In the radiation process, there are no harmful radical initiators, solvents, crosslinking agents, and separation agents involved for preparation of PMAA, therefore the method is economic, simple and environmentally friendly.