Therapeutic hormones - Pharmaceutical Biotechnology: Concepts and Aapplications - page 302

Table 11.4 Some pharmacokinetic characteristics of short, intermediate and long-acting insulin
preparations

Onset (hours after
administration)

Peak activity (hours
after administration) Category Duration (h)

Short-acting 0.5-1 2-5 6-8

Intermediate-action 2 4-12 up to 24

Long-acting 4 10-20 up to 36

much more slowly from the depot (injection) site. This is characterized by a slower onset of action,
but one of longer duration (Table 11.4).
In healthy individuals, insulin is typically secreted continuously into the bloodstream at low basal
levels, with rapid increases evident in response to elevated blood sugar levels. Insulin secretion usually
peaks approximately 1 h after a meal, falling off to base levels once again within the following 2 h.
The blood insulin level is continuously up- or down-regulated as appropriate for the blood glu-
cose levels at any given instant. Conventional insulin therapy does not accurately reproduce such
precise endogenous control. Therapy consists of injections of slow- and fast-acting insulins, as
appropriate, or a mixture of both. No slow-acting insulin preparation, however, accurately repro-
duces normal serum insulin baseline levels. An injection of fast-acting insulin will not produce
a plasma hormone peak for 1.5-2 h post injection, and levels then remain elevated for up to 5 h.
Hence, if fast-acting insulin is administered at mealtime, diabetics will still experience hyper-
glycaemia for the fi rst hour, and hypoglycaemia after 4-5 h. Such traditional animal or human
insulin preparations must thus be administered 30 min or so before eating, and the patient must
not subsequently alter their planned mealtime.
Insulin, at typical normal plasma concentrations (approximately 1 10 9 mol l 1 ) exists in true
solution as a monomer. Any insulin injected directly into the bloodstream exhibits a half-life of
only a few minutes.
The concentration of insulin present in soluble insulin preparations (i.e. fast-acting insulins), is
much higher (approximately 1 10 3 mol l 1 ). At this concentration, the soluble insulin exists as
a mixture of monomer, dimer, tetramer and zinc-insulin hexamer. These insulin complexes have
to dissociate in order to be absorbed from the injection site into the blood, which slows down the
onset of hormone action.
In order to prolong the duration of insulin action, soluble insulin may be formulated to generate
insulin suspensions. This is generally achieved in one of two ways:

1. Addition of zinc in order to promote Zn-insulin crystal growth (which take longer to disas-
sociate and, hence, longer to leak into the bloodstream from the injection depot site).

2. Addition of a protein to which the insulin will complex, and from which the insulin will only
be slowly released. The proteins normally used are protamines, which are basic polypep-
tides naturally found in association with nucleic acid in the sperm of several species of fi sh.
Depending on the relative molar ratios of insulin:protamine used, the resulting long-acting
insulins generated are termed protamine-Zn-insulin or isophane insulin. Biphasic insulins
include mixtures of short- and long-acting insulins, which attempt to mimic normal insulin
rhythms in the body.