Research ArticlesNanoparticulate biopolymers deliver insulin orally eliciting pharmacological response
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
References (42)
- et al.
Hypoglycemic effect of novel oral microspheres of insulin with protease inhibitor in normal and diabetic rats
Int J Pharm
(1992) - et al.
Enhanced oral absorption of insulin from desolvated fatty‐acid sodium glycocholate emulsions
Int J Pharm
(1994) - et al.
Absorption characteristics of chemically modified‐insulin derivatives with various fatty acids in the small and large intestine
J Pharm Sci
(1995) - et al.
A novel approach using functional peptides for efficient intestinal absorption of insulin
J Control Release
(2007) - et al.
A novel vitamin B12‐nanosphere conjugate carrier system for peroral delivery of insulin
J Control Release
(2007) - et al.
Cyclodextrin‐insulin complex encapsulated polymethacrylic acid based nanoparticles for oral insulin delivery
Int J Pharm
(2006) - et al.
Poly(alkylcyanoacrylate) nanospheres for oral administration of insulin
J Pharm Sci
(1997) - et al.
Novel oral insulin delivery systems based on complexation polymer hydrogels: Single and multiple administration studies in type 1 and 2 diabetic rats
J Control Release
(2006) - et al.
Investigation of lectin‐modified insulin liposomes as carriers for oral administration
Int J Pharm
(2005) - et al.
Insulin and the gastrointestinal tract
J Control Release
(1997)