Drug Master File Essay

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. 2008, Vol. 22, No. 4 (pp. 223-237) ISSN: 1173-8804 Drug Delivery Improved Oral Delivery of Insulin Nanoparticles Terms and Conditions for Use of PDF The provision of PDFs for authors’ personal use is subject to the following Terms ; Conditions: The PDF provided is protected by copyright. All rights not specifically granted in these Terms ; Conditions are expressly reserved. Printing and storage is for scholarly research and educational and personal use.

Any copyright or other notices or disclaimers must not be removed, obscured or modified. The PDF may not be posted on an open-access website (including personal and university sites). The PDF may be used as follows: • to make copies of the article for your own personal use, including for your own classroom teaching use (this includes posting on a closed website for exclusive use by course students); • to make copies and distribute copies (including through e-mail) of the article to research colleagues, for the personal use by such colleagues (but not commercially or systematically, e. g. ia an e-mail list or list serve); • to present the article at a meeting or conference and to distribute copies of such paper or article to the delegates attending the meeting; • to include the article in full or in part in a thesis or dissertation (provided that this is not to be published commercially). 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? io 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

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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- 224 Woitiski et al. 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