Alternative Routes of Insulin Delivery

Owens DR, Zinman B, Bolli G. Alternative routes of insulin delivery. Diabetic Med 2003 20 886-98. 

Laube, B.L., Benedict, G.W., and Dobs, A.S. (1998). The lung as an alternative route of delivery for insulin in controlling postprandial glucose levels in patients with diabetes. Chest, 114, 1734-1739. 

Heinemann L, Pfutzner A, Heise T. Alternative routes of administration as an approach to improve insulin therapy update on dermal, oral, nasal and pulmonary insulin delivery. Curr Pharm Des 2001 7(14) 1327-51. 

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... 

Alternative routes for administering insulin are also being considered.51 In particular, a form of insulin (Exubera) has been developed that can be administered by inhalation or nasal spray, thus precluding the need for subcutaneous injection.88,104 Other modifications of the insulin molecule or use of chemical enhancers can increase the permeability of this hormone so that insulin can be administered through the skin (transcu-taneously) or even via oral or buccal routes.2,35 Technologic and practical advancements in insulin delivery continue to be explored, and methods for administering insulin may be safer and more convenient in the future. 

The pulmonary and transdermal routes are the least investigated of the alternative, nonparenteral delivery routes for insulin, and perhaps therefore they still hold some promise. The potential of pulmonary delivery for bolus therapy has been demonstrated as this route is feasible from a bioavailability standpoint, even without the addition of enhancers. However, long-term safety remains to be established. Inhalation of insulin may offer fairly reproducible absorption kinetics, but it is a major challenge from a device point of view to ensure reproducibility of the administered dose. 

Virtually all therapeutic proteins must enter the blood in order to promote a therapeutic effect. Such products must usually be administered parenterally. However, research continues on the development of non-parenteral routes which may prove more convenient, less costly and obtain improved patient compliance. Alternative potential delivery routes include transdermal, nasal, oral and bucal approaches, although most progress to date has been recorded with pulmonary-based delivery systems (Chapter 4). An inhaled insulin product ( Exubera , Chapters 4 and 11) was approved in 2006 for the treatment of type I and II diabetes. 

Parenteral administration is not perceived as a problem in the context of drugs which are administered infrequently, or as a once-off dose to a patient. However, in the case of products administered frequently/daily (e.g. insulin to diabetics), non-parenteral delivery routes would be preferred. Such routes would be more convenient, less invasive, less painful and generally would achieve better patient compliance. Alternative potential delivery routes include oral, nasal, transmucosal, transdermal or pulmonary routes. Although such routes have proven possible in the context of many drugs, routine administration of biopharmaceuticals by such means has proven to be technically challenging. Obstacles encountered include their high molecular mass, their susceptibility to enzymatic inactivation and their potential to aggregate. 

Pulmonary delivery currently represents the most promising alternative to parenteral delivery systems for biopharmaceuticals. Delivery via the pulmonary route moved from concept to reality in 2006 with the approval of Exubera, an inhalable insulin product (Chapter 11). Although the lung is not particularly permeable to solutes of low molecular mass (e.g. sucrose or urea), macromolecules can be absorbed into the blood via the lungs surprisingly well. In fact, pulmonary... 

With the advent of new biotechnological techniques endogenous compounds like insulin, buserelin or octreotide have become available at affordable prices. All of these substances still have to undergo needle application. Until today the development of alternative delivery systems for the nasal, buccal, peroral, rectal and pulmonary routes for the administration of those class III drugs according to the biopharmaceutics classification system (BCS) (Amidon et al. 1995) could not keep pace with this development of endogenous compounds or is not economic enough for the health care payers (e.g. insulin application via the pulmonary route). 

Particle design applied to pharmaceutical processing has the potential to improve the efficacy of current medications as well as to open the way to the use of alternative delivery routes. An example is the administration of drugs, such as insulin, that are subject to extensive gastrointestinal breakdown and thus cannot be administered orally. The alternative is parenteral administration, which has major side effects, especially in long-term or chronic conditions. 

Insulin is a hydrophobic peptide drug for diabetes. Diabetes mellitus is a serious pathologic condition responsible for major health care problems all around the world costing billions of dollars annually. In the United States, it represents the fourth leading cause of death. Diabetes also leads to severe complications such as kidney disease, retinopathy, neuropathy, leg or foot amputations and heart disease [2G. As a consequence of poor oral bioavailabiUty and current lack of alternative delivery routes, insulin is presently administered parentally. The subcutaneous route, requiring single or multiple daily injections, is the main stay of conventional insulin therapy [27]. 

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