Design of Insulin Variants for Improved Treatment of Diabetes - Peptide and Protein Design for Biopharmaceutical Applications - page 265

Various insulin derivatives, such as glycosylated insulins [131,132],
have been investigated in search of fast-acting insulin, but none appear to
have reached clinical trials.
Apart from their use as bolus insulins, the fast-acting insulins are also
recommended for use in insulin pumps (continuous subcutaneous insulin
infusion, CSII) [133]. An insulin pump can slowly and steadily supply
insulin in a programmed basal pattern, accompanied by manual entering
of bolus doses into the pump computer, as needed to cover meals and
snacks. Modern insulin pumps are roughly the size of a mobile phone.
The insulin is delivered to the body via a tube and a catheter inserted on
the stomach or hip. The catheter must be replaced every three days or
inflammation becomes a problem. A common annoyance with insulin
pump therapy is precipitation of insulin in the tubing, which can lead to
failed delivery. Insulin aspart (NovoRapid) is the most soluble of the
commercially available fast-acting insulins, because of the extra negative
charge from the Asp residue. Insulin aspart has therefore been recom-
mended as the pump insulin of choice [134].

7.7 GLUCOSE-SENSITIVE INSULIN PREPARATIONS

Blood glucose concentration is influenced by many factors, and diabetes
patients often experience unexpected and unpredictable fluctuations in
blood glucose. This problem makes it difficult to always predict the right
dosing and timing of insulin administrations. Against this background,
scientists have devised glucose-dependent insulin release systems in pursuit
of autonomous regulation of insulin in synchronization with blood glucose.
Various polymers with glucose-binding motifs have been prepared, which
can bind or entrap insulin or insulin derivatives in the subcutaneous tissue
and release the drug in a glucose-dependent fashion [135-141]. The glucose-
binding motifs in these polymers have been large proteins like concanavalin
A, or small-molecule carbohydrate binders such as aryl boronic acids.
Although the research area of glucose-controlled insulin release has
been active since the late 1970s, none of the systems have apparently
matured to reach clinical trials. Problems with the polymer approaches
include, among other things:

1. Larger volume of drug when an external polymer is needed. A large
volume can lead to unmanageable vials and pens and to unaccep-
table pain at the injection site.