Insulin iontophoresis

Lastly, we address insulin delivery to which much effort has been dedicated. While the insulin spikes required postprandially may be difficult to achieve with iontophoresis, the method may have the potential to mimic the physiological, nearly constant, basal secretion (1 lU/h) of the hormone, which is observed in the non-diabetic adult (i.e., a requirement that is not provided by intermittent subcutaneous injections). A recent, excellent review ° of the work performed (almost exclusively in animal models) concludes that while insulin iontophoresis can be sufficient to treat a small diabetic animal, the best deliveries achieved are still 1-2 orders of magnitude below that necessary to meet the basal secretion level in humans. It seems unlikely, therefore, that we will see an insulin iontophoretic delivery system on the market in the foreseeable future. 

Sage, B.H., Jr. Insulin iontophoresis. In Protein Delivery— Physical Systems, Sanders, L.M., Hendren, R.W., Eds. Plenum Publishing Corp. New York, 1997 319-341. 

By this analysis, iontophoresis is an attractive concept. It is basically a needleless miniature infusion pump, having many of the attractive features of the infusion pump without the needles and tubes. The remainder of this chapter will look in detail at iontophoretic delivery of insulin. The next section will describe briefly how iontophoresis works and will summarize the evidence which suggests utility for insulin. In section 4, insulin iontophoresis will be considered both from the theoretical point of view and in terms of the state of the art as reflected in the published Hterature. Section 5 will examine the insulin molecule itself from the point of view of deliverability by iontophoresis and discuss how the molecule might be changed to improve iontophoretic delivery. The final section will discuss prospects for fUture commercialization of an iontophoretic dosage form for treating diabetics. 

Based on the above paragraphs, there is considerable evidence to suggest a strong fit between the characteristics of iontophoresis and the needs for insulin delivery. In the next section, the state of the art, in terms of theoretical predictions and laboratory results of insulin iontophoresis, will be presented. 

The first report of insulin iontophoresis was not related to diabetes management. It was an attempt to see if insulin could affect the saline content of sweat in cystic fibrosis patients (Shapiro et al, 1975). A decrease in sweat chloride was observed after insulin iontophoresis however, the role of the insulin, and whether insulin reached the circulatory system for systemic effect, was not clear. 

The authors then tried cathodal iontophoresis of a monomeric form of insulin, sulfated insulin, in pigs in the belief that the smaller molecular size of the monomeric insulin (MW 5800) versus hexameric regular insulin (MW 35,000) would iontophorese better. In one of the animals studied, a large rise in serum insulin which correlated with a large fall in serum glucose was observed. However, in each of the other animals studied, no similar result was obtained. The authors concluded that insulin iontophoresis is possible and that a smaller monomeric insulin is important. The reasons for failure in all the animals but one remain unknown. 

An insulin delivery system, in order to be approved for sale, must be shown to be both safe and efficacious. Since an insulin iontophoresis product would be worn on the skin, it must not damage the skin in any way, and, since it would be worn all day, every day, it must also be comfortable. And, of course, it must be able to deliver the required insulin dose. The safety issue is not amenable to theory at this time the limitations, however, can be estimated from recent studies. The delivery question is more amenable to theory it does establish constraints on what may be consider-edpossible. 

The graph in Fig. 2 can be used to address the most fundamental question regarding insulin iontophoresis—is it theoretically possible, under the most favorable conditions, to deliver the required dose Based on the discussion in Section 2.1, the needs are a basal delivery rate of 1-2 units per hour coupled with a bolus of up to 20 units over about a half-hour. Figure 2 indicates that a delivery rate of 40 units per hour could be achieved with a 1 mM solution of insulin, which is equivalent to about 4mg/ml or 100 units/ml. Regular (currently marketed human, pork, or beef) insulin has a water solubility that exceeds this value. Thus, it is theoretically possible to iontophorese insulin at the required rate. However, an idealized model has been used to reach this conclusion. Specifically, it was assumed that insulin exists as an ideal solution (with a MW of 5800), that the mobility of insulin is independent of pH and has a value close to its maximum value, and that the molecule is not degraded on its way through the skin. For regular insulins, these assumptions are not true. In the next section, the physicochemical properties of insulin that impact its deliverability by iontophoresis are described. 

Safety is an important factor when determining the quality of any iontophoresis electrode. During transdermal iontophoretic delivery using metal electrodes, an applied DC current will induce pH changes on the electrode/skin interface [178], pH measurement is used to eliminate the possibility of unsafe pH changes (chemical bums). It has been reported that the pH shift caused by platinum electrodes has a significant influence on the permeation and stability of insulin [175],... 

O. Pillai, N. Kumar, C.S. Dey, S. Borkute, S. Nagalingam, and R. Panchagnula, Transdermal iontophoresis of insulin. Part 1 A study on the issues associated with the use of platinum electrodes on rat skin. J. Pharmacy Pharmacol. 55, 1505-1513 (2003). 

Pillai O, Nair V, Panchagnula R. Transdermal iontophoresis of insulin IV. Influence of chemical enhancers. Int J Pharm 2004 269 109-120. 

Rastogi, S. K., and Singh, J. (2005), Effect of chemical penetration enhancer and iontophoresis on the in vitro percutaneous absorption enhancement of insulin through porcine epidermis, Pharm. Dev. Technol., 10(1), 97-104. 

Kari, B. Control of blood glucose levels in alloxan-diabetic rabbits by iontophoresis of insulin. Diabetes 55 217, 1986. 

Langkjaer, L. Brange, J. Grodsky, G.M. Guy, R.H. Iontophoresis of monomeric insulin analogues in vitro effects of insulin charge and skin pretreatment. J. Control Release... 

Ethyl acetate has also been shown to increase the solubility of chlortalidone and to modify the polymorphic crystal forms obtained for piroxicam pivalate and mefenamic acid, and has been used in the formulation of microspheres.Its use as a chemical enhancer for the transdermal iontophoresis of insulin has been investigated. 

---