Formulation of insulin products

Insulin, whatever its source, may be formulated in a number of ways, generally in order to alter its pharmacokinetic profile. Fast (short)-acting insulins are those preparations that yield an elevated blood insulin concentration relatively quickly after their administration (which is usually by s.c. or, less commonly, by i.m. injection). Slow-acting insulins, on the other hand, enter the circulation

Table 11.3 Native and engineered human insulin preparations that have gained approval for general medical use. Reproduced in updated form with permission from: Walsh, G. 2005. Therapeutic insulins and their large-scale manufacture. Applied Microbiology and Biotechnology, 67, 151-159

Product

Description

Structure

Company

Approved

Recombinant products of native human insulin sequence Humulin

Novolin

Insuman

Actrapid/Velosulin/ Monotard/ Insulatard/ Protaphane/ Mixtard/ Actraphane/ Ultratard Exubera

Engineered insulins Humalog (Insulin lispro)

Liprolog (Insulin lispro)

NovoRapid (Insulin Aspart)

Novolog (Insulin Aspart)

Levemir (Insulin detemir)

Apidra (Insulin Glulisine)

Lantus (Insulin glargine; optisulin)

Recombinant human insulin produced in E. coli Recombinant human insulin produced in S. cerevisiae Recombinant human insulin produced in E. coli All contain recombinant human insulin produced in S. cerevisiae formulated as short/ intermediate/long acting product)

Recombinant human insulin produced in E. coli but administered via the pulmonary route

Recombinant short-acting human insulin analogue produced in E. coli Recombinant short-acting human insulin analogue produced in E. coli Recombinant short-acting human insulin analogue produced in S. cerevisiae Recombinant short-acting human insulin analogue produced in S. cerevisiae Recombinant long-acting human insulin analogue produced in S. cerevisiae Recombinant rapid-acting insulin analogue produced in E. coli

Recombinant long-acting human insulin analogue produced in E. coli

Identical to native human insulin Identical to native human insulin

Identical to native human insulin Identical to native human insulin

Eli Lilly Novo Nordisk

Hoechst AG Novo Nordisk

Identical to native human insulin

Engineered: inversion of native B28-B29 proline-lysine sequence Engineered: inversion of native B28-B29 proline-lysine sequence Engineered: B28 proline replaced by aspartic acid

Engineered: B28 proline replaced by aspartic acid

Engineered: devoid of B30 threonine and a C14 fatty acid is covalently attached to B29 lysine

Engineered: B3 asparagine is replaced by a lysine and B29 lysine is replaced by glutamic acid.

Engineered: A 21 asparagine replaced by glycine and B chain elongated by two arginines

Pfizer

Eli Lilly

Eli Lilly

Novo Nordisk

Novo Nordisk

Novo Nordisk

Aventis pharmaceuticals

Aventis pharmaceuticals

2006 (USA)

1996 (USA and EU)

2001 (USA)

2004 (USA)

2000 (USA and EU)

Intermediate Acting Insulin Peak
Figure 11.3 A likely purification scheme for human insulin prb. A final RP-HPLC polishing step yields a highly pure product. Refer to text for details
Novasep Insuline Processhttp://www.novasep.com"/>
Figure 11.4 Process-scale HPLC column. Photograph courtesy of NovaSep Ltd, http://www.novasep.com
Table 11.4 Some pharmacokinetic characteristics of short, intermediate and long-acting insulin preparations

Category

Onset (hours after administration)

Peak activity (hours after administration)

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 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 mealtime, diabetics will still experience hyper-glycaemia for the first 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 X 10~9 mol T1) 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 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 disassociate 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 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. Biphasic insulins include mixtures of short- and long-acting insulins, which attempt to mimic normal insulin rhythms in the body.

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