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2008, Vol. 22, No. 4 (pp. 223-237) ISSN: 1173-8804

Drug Delivery
Improved Oral Delivery of Insulin Nanoparticles

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DRUG DELIVERY

Biodrugs 2008; 22 (4): 223-237 1173-8804/08/0004-0223/$48.00/0 © 2008 Adis Data Information BV. All rights reserved.

Strategies Toward the Improved Oral Delivery of Insulin Nanoparticles via Gastrointestinal Uptake and Translocation
Camile B. Woitiski,1 Rui A. Carvalho,2 Ant´ nio J. Ribeiro,1 Ronald J. Neufeld3 and Francisco Veiga1 o
1 2 3 Laboratory of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal Department of Biochemistry and Center of Neurosciences and Cellular Biology, University of Coimbra, Coimbra, Portugal Department of Chemical Engineering, Queen’s University, Kingston, Ontario, Canada

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 1. Barriers to Oral Insulin Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 2. Strategies for Effective Oral Insulin Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 3. Nanoparticle Delivery Systems for Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 4. Mechanisms of Particle Uptake and Translocation through the Gastrointestinal Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 4.1 Paracellular Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 4.2 Transcytosis or Transcellular Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 4.3 Lymphatic Pathway via the M Cells of the Peyer’s Patches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 5. Parameters for Effective Nanoparticle Absorption through the Gastrointestinal Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 5.1 Influence of Particle Size on Uptake and Translocation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 5.2 Surface Properties for Optimal Particle Uptake and Translocation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 6. Measuring Particle Absorption and Effectiveness of Insulin Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

Abstract

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited.

The design of strategies that improve the absorption of insulin through the gastrointestinal tract is a considerable challenge in the pharmaceutical sciences and would significantly enhance the treatment of diabetes mellitus. Several strategies have been devised to overcome physiologic and morphologic barriers to insulin absorption, including the inhibition of acidic and enzymatic degradation, enhancement of membrane permeability or widening of tight junctions, chemical modification of insulin, and the formulation of carrier systems. In particular, the concept of nanoparticulate carriers for oral insulin delivery has evolved through remarkable advances in nanotechnology. Investigations focused on uptake and translocation via Peyer’s patches have demonstrated high levels of nanoparticle absorption based on significant alterations in the glycemic response to various glucogenic sources. This paper reviews the mechanisms for insulin and particle uptake and translocation through the gastrointestinal tract, and the potential barriers to this, outlines the design of nanoparticulate carriers for the oral delivery of insulin, and presents prospects for its clinical application.

Peptide- and protein-based drugs are often unstable and display limited absorption through the gastrointestinal tract. These limitations are serious, as peptides and proteins are increasingly becom-

ing a preferred approach to drug development because of their high selectivity and ability to provide effective and potent physiologic action.[1] The intestinal absorption of peptide- and protein-

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based drugs has been described by a combination of mechanisms, and several strategies have been designed to improve uptake and translocation and, consequently, the physiologic responses. Exogenous insulin is used in diabetes mellitus treatment, and oral delivery is of interest as it reproduces the physiologic profile of insulin undergoing first hepatic bypass.[2,3] Endogenous insulin secreted by the pancreas passes into the portal circulation and inhibits hepatic glucose production, resulting in a hypoglycemic effect.[4] The oral delivery of insulin would improve glucose homeostasis and also reduce the incidence of peripheral hyperinsulinemic effects.[5] However, 200 nm commonly exhibit a more rapid clearance rate from the blood than particles