Thundiparambil Azeez Sonia

In vitro evaluation of quaternized polydimethylaminoethylmethacrylate sub-microparticles for oral insulin delivery

This investigation describes the synthesis and in vitro evaluation of cationic hydrogel sub-microparticles based on polydimethylaminoethylmethacrylate for oral insulin delivery. Polymerization of dimethylaminoethylmethacrylate was carried out in aqueous medium with potassium persulfate as the initiator. Quaternization of the resulting hydrogel was carried out to introduce cationic surface groups and the derivatization was confirmed by zeta potential measurements, nuclear magnetic resonance and infrared spectroscopies. Swelling behavior of these particles was evaluated for dependence of pH. Insulin-loaded particles were subjected to in vitro release experiments at gastric and intestinal pH. Moreover, cytotoxicity evaluation showed that both polydimethylaminoethylmethacrylate and its quaternized derivative were non-toxic to Caco-2 and L929 cell lines. The presence of quaternary ammonium groups improved the cationic charge and enhanced the mucoadhesive properties of the hydrogel. Confocal microscopic observations showed that these sub-microparticles were capable of opening tight junctions between the Caco-2 cells and thus increased the paracellular permeability. The above studies suggest that cationic hydrogel sub-microparticles can act as a good candidate for oral insulin delivery.

N-hydroxypropyltrimethylammonium polydimethylaminoethylmethacrylate sub-microparticles for oral delivery of insulin--an in vitro evaluation.

The present study describes the synthesis and in vitro evaluation of quaternised polydimethylaminoethylmethacrylate for oral delivery of insulin. Quaternisation of the polymer was carried out by conjugating N-hyroxypropyltrimethylammonium chloride to aminoterminated polydimethylaminoethylmethacrylate. Quaternised particles were characterised by particle size, zeta potential measurements, nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), differential scanning calorimetry (DSC) and atomic force microscopy (AFM). In addition, in vitro insulin release experiments, cytotoxic evaluation on L929 & Caco-2 cells, mucoadhesion, enzymatic degradation and tight junction visualisation studies were also performed to evaluate the potential of this matrix for oral delivery of insulin. Results suggest that the quaternised particles exhibited positive zeta potential with a particle size of 513.6±17 nm. Dose-dependent cytotoxic evaluation of quaternised particles on L929 & Caco-2 cells confirmed the nontoxic nature of the matrix. Quaternised particles were more mucoadhesive compared to parent polymer. Adhesive behaviour of mucin with quaternised particles were confirmed by DSC. Moreover these particles exhibited calcium chelating ability and displayed significant inhibitory effect towards trypsin and chymotrypsin. These particles also helped in the opening of tight junctions by disruption of actin filaments and binding to Zona Occludens (ZO-1) proteins. Preliminary studies suggest that the quaternised particles can act as suitable candidates for oral delivery of insulin.

Experimental techniques involved in the development of oral insulin carriers

With the advent of biotechnology, synthetic organic chemistry, polymer science and nanotechnology, development of an effective formulation for oral insulin delivery has always been the critical endeavour. Barriers associated with oral insulin delivery, such as stability, enzymatic degradation and ineffective absorption, could be overcome by using carrier-mediated drug delivery approaches like liposomes, inorganic and polymeric nanoparticles, as they could circumvent these limitations and enhance effective oral delivery. Of these, carrier systems based on polymeric nanocarriers have been extensively studied for oral insulin delivery at preclinical level due to their favourable properties, for example biocompatibility. This chapter discusses some of the experimental techniques involved in the development of an effective oral insulin carrier, mainly based on polymeric nanocarriers, reported in literature.

Diabetes mellitus – an overview

The prevalence of diabetes mellitus, a chronic metabolic disorder, has increased dramatically over the years, and the trend is continuing at an alarming rate. The development of acute and chronic complications adds greatly to the morbidity and mortality associated with this silent disease, making it a major health concern. This chapter presents an overview of diabetes mellitus, its symptoms and complications. Furthermore, conventional treatment options, such as the use of oral hypoglycaemic agents and insulin therapy, and innovative approaches like incretin therapy, gene therapy and stem cell therapy are also briefly discussed.

Routes of administration of insulin

The most ubiquitous treatment strategy for DM focuses on the control of postprandial blood glucose, i.e. glucose level after food intake. The goal of an exogenous insulin regimen in diabetics is to mimic the physiological profile observed in a healthy person (non-diabetic). In the past few years, there has been a great deal of interest and research worldwide in the development of non-invasive routes for delivery of insulin. Various routes of administration have been explored to avoid regular dependence on multiple subcutaneous injections and to improve the metabolic effects of insulin. The objective of this chapter is to provide an update on the various approaches that have been explored so far to achieve therapeutic insulin levels using non-invasive drug delivery routes.

Oral insulin delivery – challenges and strategies

The conventional and current mode of administration of insulin frequently relies on subcutaneous injection. Though the oral route is the most preferred mode of delivery, insulin cannot be administered orally due to enzymatic and chemical barriers in the stomach, degradation by proteolytic enzymes in the intestine, and poor permeability across the intestinal epithelium. Researchers have developed a number of innovative strategies, such as the use of mucoadhesives, niosomes, etc., to develop a successful oral delivery system for insulin. This chapter reviews some of the most promising techniques currently developed for oral delivery of insulin for the treatment of diabetes that requires frequent injections of insulin.

Lipids and inorganic nanoparticles in oral insulin delivery

Lipid-based nanoparticles such as liposomes and SLNs and inorganic nanoparticles like gold, silver, zirconium phosphate, etc. are nowadays extensively explored as carriers for oral delivery of insulin. Lipid nanoparticles enhance drug absorption in the GI tract, improve mucosal adhesion due to their small particle size, increase the GIT residence time, protect the loaded insulin from chemical and enzymatic degradation, and gradually release insulin from the lipid matrix into blood, resulting in improved therapeutic action. Compared with polymeric carriers, lipid nanoparticles, due to their physiological and biodegradable properties, decrease adverse side effects and chronic toxicity of the drug delivery systems. This chapter highlights the importance of lipid and inorganic nanoparticles to modify the release profile and the pharmacokinetic parameters of oral delivery of insulin.

Polymers in oral insulin delivery

Abstract One of the greater challenges faced by oral delivery of insulin is the reduced bioavailability. Among the different types of carrier-based delivery systems currently being pursued for oral insulin delivery, biodegradable polymeric nanoparticles have received considerable attention due to their versatility and wide range of properties. With the advancement in nanotechnology and synthetic organic chemistry, researchers are exploring the potential use of polymeric nanoparticles as carriers. A wide variety of polymers, both natural and synthetic, have been used as carriers for oral delivery of insulin. This chapter reviews both synthetic and natural polymers used as carriers for oral delivery of insulin.