Copyright © 2012 by American Scientific Publishers All rights reserved. Printed in the United States of America Reviews in Advanced Sciences and Engineering Vol. 1, pp. 1–12, 2012 (www.aspbs.com/rase) Oral Insulin Delivery: Unveiling Patented Approaches Ashok K. Tiwary, Bharti Sapra, Vikas Rana, and Gurpreet Kaur ∗ Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India ABSTRACT Oral route is the most commonly used, economical and convenient route of delivering drugs because no special skill is required for administering medications. Insulin is generally not delivered orally because of its proteinaceous nature due to which it undergoes inactivation by the acids and proteases of the gastrointestinal tract resulting in negligible oral bioavailability. Newer strategies are being explored for overcoming the problems associated with oral delivery of insulin. These include the use of permeation enhancers, protease inhibitors, enteric coatings and polymer microsphere formulations. These strategies aim at making insulin absorbable and bioavailable following oral administration. This article reviews the challenges and recently patented approaches in an endeavor to overcome the limitations associated with oral insulin delivery. KEYWORDS: Oral Delivery, Protein Delivery, Hydrogels, Nanoparticles, Microemulsions, Multiple Emusions. CONTENTS 1. Introduction ................................. 1 2. Modified Polymer Hydrogel Based Formulations ......... 2 3. Particulate Carrier Systems ....................... 5 4. Insulin Microemulsions .......................... 8 5. Two-Phase Liquid System ........................ 9 6. Targeted Enteral Delivery System ................... 10 7. Miscellaneous Systems .......................... 10 8. Future Perspective ............................. 11 References and Notes ........................... 11 1. INTRODUCTION Oral route is the best choice for the administration of most drugs, regardless of their molecular weight or struc- ture. Oral administration of insulin has been an elusive goal for many investigators since the protein’s initial dis- covery by Banting and Best in 1922. 1 Oral formulations do not have to meet specialized regulatory requirements relating to issues like sterility, pyrogenicity and particulate contamination therefore, it could be highly advantageous if insulin could be administered orally. Although, differ- ent modes of administering insulin are being intensively investigated (Fig. 1), orally administered insulin can mimic the physiological fate of insulin and may provide better glucose homeostasis while immensely enhancing patient compliance. ∗ Author to whom correspondence should be addressed. Email: kaurgpt@gmail.com Received: 14 May 2012. Revised/Accepted: 12 June 2012. However, oral insulin delivery is associated with various challenges that determine fate of insulin in the GIT. The oral availability of insulin is less than 10%. Less than 0.5% of orally administered insulin enters the systemic circula- tion. Insulin is a hydrophilic drug with moderately high molecular weight. The three main obstacles encountered in protein delivery are physical barriers, enzymatic barriers and physiochemical stability. 2 The epithelial layer lining the GI tract is a tightly bound collection of cells with min- imal leakage and forms a physical barrier to absorption. Although the presence of microvilli enhances the absorp- tive area of the intestinal tract by approximately two orders of magnitude the absorption of proteins is hindered as the microvilli contain digestive enzymes. The glycocalyx and the mucus present on the top of epithelial layer presents another physical barrier to transport of proteins. In addi- tion to the physical barrier, proteins are also susceptible to degradation by the digestive enzymes located through out the gastrointestinal tract. 3 The successful oral delivery of insulin involves great challenges like overcoming enzymatic degradation, achieving epithelial permeability, and most importantly, conserving the bioactivity of the drug during formula- tion processing. Therefore, it becomes pertinent to employ excipients of diverse potentialities (stabilizers, protease inhibitors or mucoadhesives) that would provide an ele- ment of drug targeting, maintaining the stability and increasing the bioavailability of insulin. 2 Various pharma- ceutical strategies have been proposed to maximize oral insulin bioavailability from delivery systems, to overcome barriers, and to develop safe and effective oral insulin Rev. Adv. Sci. Eng. 2012, Vol. 1, No. 4 2157-9121/2012/1/001/012 doi:10.1166/rase.2012.1020 1