Insulin prodrugs

Kurtzhals, P., Kiehr, B., and Sorensen, A. R., 1995a, The cobalt(III)-insulin hexamer is a prolonged-acting insulin prodrug, / Pharm. Sci. 84 1164-1168. 

In an effort to develop a peroral application system for insulin, Saffran was the first to use azopolymers as protective colon delivery coating, by use of the aforementioned strategy of azo-linked prodrugs [58, 59], Originally, he used azo-linked copolymers of styrene and hydroxyethylmethacrylate to coat and protect the insulin. However, this approach is not restricted to hydroxyethylmethacrylate and can indeed be accomplished in the same way by an almost unlimited number of similar polymer types. 

Prodrugs occur in nature. One example is proinsulin, which is synthesized in the pancreas and releases its active moiety, insulin, and an inactive peptide. Codeine is another example it can be regarded as a prodrug of morphine, which is responsible for its analgesic effect. 

Erbe DV, Klaman LD, Wilson DP et al (2009) Prodrug delivery of novel PTPIB inhibitors to enhance insulin signalling. Diabetes Obes Metab 11 579-588... 

Prodrugs also occur in the organism. As an example of an endogenous prodrug, proinsulin is synthesized in the pancreas to be released as its active moiety insulin and an inactive propeptide. To some extent, the bioactivation of neurotransmitters could also be termed prodrug design by nature and there are many other examples in the realm of mammalian... 

Yamamoto et al. [4] showed that 0.01% aprotinin (a serine protease inhibitor) reduced the metabolism of insulin and proinsuHn in homogenates of albino rabbit buccal mucosa, which otherwise would have occurred at 70-80% within 2.5 hours. Moreover, Lehr et al. suggest that polycar-bophil, a bioadhesive polymer, may protect some peptides from proteolysis, though the mechanism of this is unknown [5]. Others [6] have developed a series of pro-dmgs for peptides, with the aim of overcoming the metabohc barrier imposed by different peptidases. Stable prodrugs proved to be N-hydroxymethylated derivatives of the assessed dipeptides Gly-L-Leu and Gly-L-Ala [6]. 

For this purpose, mammalian cells were incubated with the self-silenced peptide analog (13) introduced in Section 3.2.2 as well as the prodrug (15) introduced in Section 3.2.3, and subsequently treated either with or without insulin. 

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