Insulin
Insulin was discovered by Banting and Best in 1921 (Bliss 1982). Soon afterwards manufacturing processes were developed to extract the insulin from porcine and bovine pancreas. From 1921 to 1980, efforts were directed at increasing the purity of the insul
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Insulin John M. Beals, Michael R. DeFelippis, Paul M. Kovach, and Jeffrey A. Jackson
INTRODUCTION Insulin was discovered by Banting and Best in 1921 (Bliss 1982). Soon afterwards manufacturing processes were developed to extract the insulin from porcine and bovine pancreas. From 1921 to 1980, efforts were directed at increasing the purity of the insulin and providing different formulations for altering time action for improved glucose control (Brange 1987a, b; Galloway 1988). Purification was improved by optimizing extraction and processing conditions and by implementing chromatographic processes (size exclusion, ion exchange, and reversed-phase (Kroeff et al. 1989)) to reduce the levels of both general protein impurities and insulin-related proteins such as proinsulin and insulin polymers. Formulation development focused on improving chemical stability by moving from acidic to neutral formulations and by modifying the time-action profile through the use of various levels of zinc and protamine. The evolution of recombinant DNA technology led to the widespread availability of human insulin, which has eliminated issues with sourcing constraints while providing the patient with a natural exogenous source of
J.M. Beals, Ph.D. (*) Lilly Research Laboratories, Biotechnology Discovery Research, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285, USA e-mail: [email protected] M.R. DeFelippis, Ph.D. Lilly Research Laboratories, Bioproduct Research and Development, Eli Lilly and Company, Indianapolis, IN, USA P.M. Kovach, Ph.D. Lilly Research Laboratories, Technical Services and Manufacturing Sciences, Eli Lilly and Company, Indianapolis, IN, USA J.A. Jackson, M.D. Lilly Research Laboratories, Medical Affairs, Eli Lilly and Company, Indianapolis, IN, USA
insulin. Combining the improved purification methodologies and recombinant DNA (rDNA) technology, manufacturers of insulin are now able to provide the purest human insulin ever made available, >98 %. Further advances in rDNA technology, coupled with a detailed understanding of the molecular properties of insulin and knowledge of its endogenous secretion profile, enabled the development of insulin analogs with improved pharmacology relative to existing human insulin products.
CHEMICAL DESCRIPTION Insulin, a 51-amino acid protein, is a hormone that is synthesized as a proinsulin precursor in the β-cells of the pancreas and is converted to insulin by enzymatic cleavage. The resulting insulin molecule is composed of two polypeptide chains that are connected by two interchain disulfide bonds (Fig. 12.1) (Baker et al. 1988). The A-chain is composed of 21 amino acids, and the B-chain is composed of 30 amino acids. The interchain disulfide linkages occur between A7–B7 and A20–B19, respectively. A third intra-chain disulfide bond is located in the A-chain, between residues A6 and A11. In addition to human insulin and insulin analog products, which are predominately used today as firstline therapies for the treatment of diabetes, bovine and porcine insulin
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