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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 IGF-1
Glucagon
GH
Transcription factors C-Myc
C-Fos
egr-1
By the mid-1930s, commercial insulin was being prepared by crystallization from crude porcine or bovine extracts. The crystallized preparation was generally subjected to a recrystallization step in order to further increase the product’s purity. Such preparations are termed ‘conventional insulins’ (Box 8.2).
Chromatographic or electrophoretic analysis of conventional insulins generally yields three major fractions or bands (a, b and c). Fraction a contains high molecular mass material which can be removed from the product by additional recrystallization steps. The major components of fraction b are proinsulin and insulin dimers, while insulin, as well as slightly modified forms of insulin (e.g. arginine-insulin and desamido-insulin), are found in fraction c.
Additional impurities, such as glucagon, somatostatin, pancreatic polypeptide and vasoactive intestinal polypeptide, are present in most conventional insulin preparations at lower levels. The presence of such contaminants can impact upon product safety and efficacy in a number of ways.
Many of the contaminants are immunogenic in man. This is particularly significant in the case of insulin as, unlike most other biopharmaceuticals, it usually must be administered daily for life. The frequency of administration will ultimately trigger a strong immunological response, even against weak immunogens. Porcine insulin, differing from human insulin by only a single amino acid (residue 30 of the B-chain; threonine in humans, alanine in pigs), is essentially non-immunogenic in man. However, many of the porcine insulin contaminants (including porcine proinsulin) are immunogenic.
Bovine insulin, differing from the human form by three amino acids, does elicit an immunological response in humans. This can trigger long-term complications, including insulin resistance (as anti-insulin antibodies neutralize some of the administered product). The presence of these antibodies can also affect the pharmacokinetic profile of the drug, as antibody-bound insulin molecules are largely resistant to the normal insulin degradative process. (Pharmacokinetics is the study of how a drug interacts with the body in terms of its absorption, distribution, metabolism and excretion; Chapter 2.)
310 BIOPHARMACEUTICALS
Box 8.2. Insulin products: a glossary of terms
Conventional insulins: bovine or porcine insulin purified only by crystallization
Single peak insulins: bovine or porcine insulin that have undergone a further gel filtration
purification step
Highly purified insulins: insulin purified by gel filtration and ion-exchange chromato-
graphy
Human insulin (emp): insulin of human sequence manufactured by enzymatic modifica-
tion of porcine insulin
Human insulin (crb): recombinant human insulin in which A- and B-chains are
expressed separately in bacteria
Human insulin (prb): recombinant human insulin in which proinsulin is expressed in
bacteria
Human insulin (pyr): recombinant human insulin produced in yeast
Insulin B.P./Eur.P./USP: insulin of bovine or porcine origin
Human insulin B.P./Eur.P.: insulin of human sequence produced either by enzymatic
modification of porcine insulin or by recombinant DNA technology
Insulin human USP: insulin of human sequence produced either by enzymatic
modification of porcine insulin or by recombinant DNA technology
Soluble insulin = regular insulin = unmodified insulin: any insulin solution from any source
which is not formulated/changed in any way in order to prolong its duration of action
Protamine zinc insulin: insulin complexed to excess protamine in order to prolong its
duration of action
Isophane insulin: preparations containing equimolar quantities of insulin and protamine
in order to prolong its duration of action
Insulin-zinc suspension: suspension of insulin, generated by crystallization with zinc,
formulated in this way in order to prolong its duration of action
Biphasic insulin: mixture of insulin preparations that provide for immediate and
prolonged action
The higher molecular mass contaminants in conventional insulin preparations include various proteases. Such preparations are generally maintained in solution at acidic pH values (often as low as pH 2.5-3.5). This minimizes the risk of proteolytic degradation of the insulin molecules, as contaminant proteases are inactive at such pH values.
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