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biopharmaceuticals biochemistry and biotecnology - Walsh G.

Walsh G. biopharmaceuticals biochemistry and biotecnology - John Wiley & Sons, 2003. - 572 p.
ISBN 0-470-84327-6
Download (direct link): biochemistryandbiotechnology2003.pdf
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HORMONES OF THERAPEUTIC INTEREST 315
Table 8.3. Native and engineered human insulin preparations that have gained approval for general medical use. Refer to text for further detail. rh = recombinant human
Product
Company
Humulin (rh-insulin)
Novolin (rh-insulin)
Humalog (Insulin Lispro, an insulin analogue)
Insuman (rh-insulin)
Liprolog (Bio Lysprol, a short-acting insulin)
NovoRapid (Insulin Aspart, short-acting rh-insulin analogue)
Novomix 30 (contains Insulin Aspart, short-acting rh-insulin analogue (see NovoRapid) as one ingredient Novolog (Insulin Aspart, short acting rh-insulin; see also NovoRapid entry above)
Novolog mix 70/30 (contains Insulin Aspart, short acting rh-insulin analogue as one ingredient; see also Novomix 30 entry above) Actrapid/Velosulin/Monotard/Insulatard/Protaphane/Mixtard/Actraphane/ Ultratard (all contain rh-insulin produced in S. cerevisiae, formulated as short/intermediate/long-acting products)
Lantus (insulin glargine, long acting rh-insulin)
Optisulin (insulin glargine, long-acting rh-insulin analogue, see Lantus)
Eli Lilly Novo Nordisk Eli Lilly Hoechst AG Eli Lilly Novo Nordisk Novo Nordisk
Novo Nordisk
Novo Nordisk
Novo Nordisk
Aventis Pharmaceuticals Aventis Pharma
Figure 8.6. A likely purification scheme for human insulin prb. A final RP-HPLC polishing step yields a highly pure product. Refer to text for details
316 BIOPHARMACEUTICALS
Figure 8.7. Process-scale HPLC column. Photo courtesy of NovaSep Ltd: http://www.novasep.com
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.
HORMONES OF THERAPEUTIC INTEREST 317
Table 8.4. Some pharmacokinetic characteristics of short, intermediate and long-acting insulin preparations
Category Onset (hours after Peak activity (hours Duration
administration) after administration) (hours)
Short-acting 1/2-1 2-5 6-8
Intermediate-acting 2 4-12 Up to 24
Long-acting 4 10-20 Up to 36
The blood insulin level is continuously up- or downregulated as appropriate for the blood glucose 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 reproduces 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 meal time, diabetics will still experience hyperglycaemia for the first hour, and hypoglycaemia after 4-5 h. Such traditional animal or human insulin preparations must thus be administered 1 h before eating and the patient must not subsequently alter his/her planned mealtime.
Insulin, at typical normal plasma concentrations (approximately 1 x 10~9M) 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 x 1073 M). 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 zinc-insulin crystal growth (which take longer to disassociate and, hence, longer to leak into the blood stream 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, basic polypeptides naturally found in association with nucleic acid in the sperm of several species of fish. Depending on the relative molar ratios of insulin:protamine used, the resulting long-acting insulins generated are termed protamine-Zn-insulin or isophane insulin (Box 8.2). Biphasic insulins include mixtures of short- and long-acting insulins, which attempt to mimic normal insulin rhythms in the body.
Engineered insulins
Recombinant DNA technology facilitates not only production of human insulin in microbial systems, but also facilitates generation of insulins of modified amino acid sequences. The major aims of generating such engineered insulin analogues include:
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