Research Articles
Nanoparticulate biopolymers deliver insulin orally eliciting pharmacological response

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Abstract

The aim of this study was to characterize and evaluate a novel oral insulin nanoparticulate system based on alginate‐dextran sulfate core, complexed with a chitosan‐polyethylene glycol‐albumin shell. Insulin‐loaded nanospheres (25, 50, 100 IU/kg) administered orally to diabetic rats reduced glycemia in a dose dependent manner. This effect lasted over 24 h with a maximal effect after 14 h. Nanospheres increased insulin plasma level and improved glycemic response to an oral glucose overload. After 4 days oral administration (50 IU/kg/day), the metabolic status of diabetic rats improved with a reduction in water intake, urine excretion and proteinuria. FITC‐insulin‐loaded nanospheres administered to an isolated intestinal loop were taken up by the intestinal mucosa. They strongly adhered to villus apical enterocytes and markedly labeled Peyer's patches. It is concluded that nanospheres preserve insulin and exert an antidiabetic effect after oral administration. This is explained by a protective effect against proteolytic enzymes by the albumin coating, by the mucoadhesive properties of chitosan‐polyethylene glycol, and by the possibility of chitosan reversibly altering tight junctions leading to an improved absorption of insulin. This formulation demonstrates beneficial effects on diabetic symptoms and will be of interest in the treatment of diabetes with oral insulin. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5290–5305, 2008

Section snippets

INTRODUCTION

Diabetes mellitus is a metabolic illness requiring strict glycemic control to reduce its progression and complications. Insulin replacement therapy provides the most effective means for glycemic control. Replicating physiological insulin secretion as a means of restoring normal metabolism, minimizes complications, and has thus becomes the essential goal of diabetes treatment.1

Amongst alternative routes for insulin administration, the oral route is potentially the most convenient and

Materials

Low viscosity sodium alginate (viscosity of 2% solution at 25°C, 250 cps) was purchased from Sigma (St. Louis, MO). Chitosan (50 kDa), albumin, pepsin and streptozotocin were purchased from Sigma–Aldrich Chimie (L'Isle d'Abeau Chesnes, France). Setacarb calcium carbonate was obtained from Omya (Orgon, France). Paraffin oil was supplied by Vaz Pereira (Lisbon, Portugal). The emulsifier, Span 80, dextran sulfate (5 kDa) and PEG 4000 were purchased from Fluka, Chemie GmbH (Buchs, Switzerland).

Characterization of Insulin‐Loaded Nanospheres

Insulin‐loaded nanospheres showed a unimodal size distribution with 90% of the particles having a diameter less than 1842 nm, and 50% less than 812 nm as seen in Figure 1. Small agglomerates were observed under SEM as seen in Figure 2 however agglomerates readily dispersed after manual mixing. SEM images showed that individual particles were mainly less than 1000 nm. The charge of uncoated nanospheres was negative (−16 ± 2 mV) as shown in Table 1 but addition of polycationic chitosan coating

DISCUSSION

The oral route of free insulin delivery takes advantage of the portal‐hepatic route of absorption. However, insulin is degraded by proteolytic enzymes in the GIT and, being a small peptide, is less absorbed by the intestinal mucosa. Alginate‐dextran sulfate nanospheres coated with chitosan‐PEG‐albumin preserve the biological activity of entrapped insulin, and strongly elicit an hypoglycaemic response when administered subcutaneously or orally. Albumin‐coating and PEG stabilizing effect seem to

CONCLUSIONS

Alginate‐dextran sulfate core, chitosan‐polyethylene glycol‐albumin coated nanospheres protect insulin during nanosphere formulation and from proteolytic degradation during gastrointestinal transit. Insulin‐loaded nanospheres with small size (50% less than 812 nm) and encapsulation efficiency of 85% were produced by emulsion dispersion/triggered gelation, followed by polyelectrolyte coating. Blood glucose reduction following oral administration was higher than 70% of the basal value while empty

Acknowledgements

The authors are grateful for financial support from the Fundação para a Ciência e Tecnologia, Portugal (SFRH/BD/13673/2003) and the Natural Sciences and Engineering Research Council of Canada, and the gift of insulin from Hospitais da Universidade de Coimbra. The authors also would like to thank Nathalie Ubrich, from Faculty of Pharmacy of Nancy, for her kind technological support in labelling insulin. We also thank Burak Erdinc from the Chemical Engineering Department of Queen's University for

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