Insulin alternative administration routes

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. 

The subcutaneous route for administration of insulin has many serious drawbacks, and alternative routes continue to attract considerable research interest. Nearly all available orifices of the human body seem to have gained attention as presenting possible noninvasive sites for insulin absorption. However, even by using modem enhancer techniques, only a small or minor fraction of the hormone becomes bioavailable when provided by most of these routes, except perhaps the pulmonary route. Key barriers to insulin absorption via the alternative routes are the resistance of those membranes to insulin penetration, the tendency of insulin to exist in associated form, and insulin proteolysis. Protection from proteolysis through some sort of encapsulation, the use of complex emulsion systems, and/or the use of protease inhibitors—association of the hormone with polymeric particles, and addition of permeation enhancers have been utilized to overcome those barriers. The absorption and enzymatic barriers to nonparenterally administered protein dmgs and the use of enhancers to modify absorption have been discussed in recent reviews (Lee, 1986 Lee e/a/., 1991a Zhou, 1994). The present review of alternative administration of insulin mainly covers investigations published since 1970. 

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. 

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. 

Since the first introduction of insulin to treat diabetic patients in 1923, much effort has been made to seek alternative convenient and painless routes for insulin administration instead of daily injections. In this respect the pulmonary route has received the most attention, and substantial evidence has shown inhaled insulin to be an effective, well-tolerated, noninvasive alternative route [53-56]. Insulin therapy is required for patients with type 1 diabetes. Although some patients with type 2 diabetes can control their disease with oral antidiabetics, many will eventually also require insulin. Thus, inhaled insulin shows promise for type 2 diabetic patients [54, 56]. There are two principal inhalation systems for insulin, namely aqueous solution and dry powder. The dry powder form (Exubera ) has been approved by FDA and the European Medicines Agency (EMEA) in January 2006. 

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). 

In the treatment of diabetes mellitus, insulin is generally administered by injection. However, the injections may cause local side effects and allergic reactions, and may also result in the patients physical and mental pain. Thus, alternative routes of administration such as nasal [2], buccal [3], pulmonary [4], rectal [5], and ocular [7] have... 

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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