Noninvasive Delivery of Insulin

One of the inherent features of iontophoresis—in fact, one that is embodied in the definition of iontophoresis—is the ability to deliver a drug through the skin without prior preparation of the skin. An iontophoretic system for dehvery of insulin would be a skin patch. Insulin passes through the skin and into the systemic circulation by action of a weak electric current. This current is barely perceptible as it passes through the skin and has been shown to not alter the barrier function of the skin (Ledger, 1992). The only apparent effect that iontophoresis has on the skin is a blushlike erythema of the skin under the patch, which resolves in a few hours. 

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Noninvasive delivery of insulin via most mucosal membranes requires the use of chemical enhancement for notable insulin absorption (see Section 3.3 and Table II). However, most permeation enhancers have, in addition to their effect on the mucosal membrane, an often pronounced influence on insulin three-dimensional structures. Thus, sodium salicylate (Touitou et al, 1987) as well as bile salts (Gordon etal, 1985) have been shown to dissociate insulin oligomers into monomers. This effect improves membrane permeability, but it may also reduce the physical stability and increase the susceptibility of insulin to enzymatic degradation. The exposure of new epitopes may also influence the immunological properties of the insulin formulation. 

One of the main drivers for the development of new pulmonary drug delivery systems has been the potential for noninvasive systemic delivery of protein and peptide compounds. The systemic delivery of macromolecules via the airways would overcome the inconvenience and cost associated with current methods of administration (injection), and appears likely given the large surface area of the airways and the thin pulmonary epithelium. Most research has concentrated on pulmonary delivery of insulin for the treatment of diabetes. Recently, one insulin product has completed phase three studies and is now undergoing review by European regulatory agencies for marketing approval. 

The objectives of the present chapter are to provide a brief overview of the complexity and diversity of insulin formulation, to give a historical review of the efforts to improve parenteral delivery of insulin, and, with an emphasis on the last 25 years efforts, to survey the numerous studies performed in a search for acceptable insulin delivery through various noninvasive routes. 

Despite the enormous success of biotechnology products to date, much effort continues to be focused on the development of more convenient and noninvasive routes of administration for those products that require frequent and prolonged dosing. Here we present an overview of the technologies, both developed and emerging, which are applicable to protein dehvery. In addition, chapters 11 through 13 detail case studies on physical methods for delivery of insulin and growth hormone. 

Insulin is the protein that has been most investigated for pulmonary administration. Insulin levels are not maintained in diabetic patients, and precise control over blood glucose levels is needed. Insulin is a small protein, 5.8 kDa, which is composed of two chains that are covalently linked by an interchain disulfide bond. Currently, insulin is administered by injection, several times a day for many diabetics. The ability to deliver insulin via a noninvasive route would free diabetics from inconvenient, invasive insulin delivery methods and possibly eliminate secondary problems associated with diabetes, such as diabetic retinopathy. 

Cefalu, W.T. Concept, strategies, and feasibility of noninvasive insulin delivery. Diabetes Care 2004, 27 (1), 239-246. 

The quest for complete restoration of physiology, possibly by finding the optimal route of administration of the hormone, has been continuously and strenuously pursued. Nonetheless, the dream of noninvasive insulin delivery by alternative routes of administration is far from realization, and the fantasy of oral insulin treatment has been one of great ambition and continuous failure (Berger, 1993). The only routes that still hold some... 

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