Biomedical Engineering Reference
In-Depth Information
Importantly, the advent of recombinant access to insulin also made
possible relatively easy production of insulin mutants, which, along with
chemical modification and formulation, is the toolset for pharmaceutical
insulin engineering.
7.4
PROLONGED-ACTING INSULIN SOLIDS
In the early days, basal supply of insulin over 24 hours was attempted via
multiple daily injections, but this approach was inefficient and annoying,
especially during sleep. Ironically, the early supplies of insulin from animal
sources were quite impure, and high-molecular-weight protein impurities
helped retain insulin at the site of injection. This helped achieve prolonged
insulin action, but the impurities also gave other problems such as allergies
and immunogenic reactions. Today, commercial insulin preparations are
highly pure [62,63], and several novel mechanisms for prolongation of the
action to basal coverage have been engineered.
In the 1930s to 1940s, Nordisk Gentofte introduced prolonged-acting
insulin via insulin co-crystallization with protamine [64,65]. The product
name is NPH (Neutral Protamine Hagedorn) or isophane. Protamine is a
basic (cationic) protein isolated from fish sperm. Insulin is an anionic
peptide with overall net charge of
4 at physiological pH. Insulin-
protamine co-crystals dissolve slowly upon injection in human subcutis,
and thereby provide basal insulin supply for approximately 12 hours.
NPH crystals can be mixed with regular insulin, and such mixtures can
provide both basal and bolus coverage in one injection. Injection of a
mixture of NPH and regular insulin before breakfast and dinner is a
widespread insulin regiment still used today. Several NPH:insulin mix
ratios are commercially available, with 30:70 as the most common mix.
The described morning-plus-evening regimen is easy to adhere to, provid-
ing good patient compliance, but it lacks proper coverage for lunch and
snacks. NPH-mix insulins were recently upgraded to include engineered
fast-acting insulins as the bolus component, thus allowing injection of the
mix with the meal, not half an hour before the meal [66].
NPH insulin is still widely used today, but it suffers from several
problems. Since NPH is crystalline, it is supplied as a suspension, which
must be carefully resuspended before each injection. Even with the most
careful resuspension (gentle turning and rolling of the vial), the hetero-
geneity of the preparation can result in large differences in insulin dosings
between each injection. NPH dosing can be compared to serving ice cubes
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