Summary
Exposure of insulin solutions to elevated temperatures for prolonged periods of time will inevitably lead to chemical modifications of the hormon. Contact with different materials in dosing devices, other design-related factors and motion appear to be chemically more detrimental than storage in glass vials at the same temperature. An in vitro test, designed to mimick the in vivo situation, consisted of delivery of insulin at 37 °C while the device was constantly moved on a shaking apparatus. Insulin quality was assessed using high performance liquid chromatography. A polyethylenepoly-propylene glycol-stabilized neutral human insulin solution (HOE 21 PH) was used. A single insulin derivative is the major modification product which, after passage of the complete infusion system, amounts to up to 10%. The biological potency of the derivative is indistinguishable from native insulin. Delivery of acidic insulin under implant conditions, leads to extensive and multiple insulin derivatization, even though the biological potency remains 95% after 4 weeks.
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Irsigler K, Kritz H, Lovett R (eds) (1983) Diabetes treatment with implantable insulin infusion systems. Urban & Schwarzenberg, Munich Vienna Baltimore
Irsigler K, Kritz H (1979) Long-term continuous intravenous insulin therapy with a portable insulin dosage-regulating apparatus. Diabetes 28: 196–203
Thurow H (1980) Studies on the denaturation of dissolved insulin. In: Brandenburg D, Wollmer A (eds) Insulin chemistry, structure and function of insulin and related hormones, de Gruyter, Berlin New York, pp 215–221
Lougheed WD, Woulfe-Flanagan H, Clement JR, Albisser AM (1980) Insulin aggregation in artificial delivery systems. Diabetologia 19: 1–9
Lougheed WD, Albisser AM, Martindale HM, Chow JC, Clement JR (1983) Physical stability of insulin formulations. Diabetes 32: 424–432
Blackshear PJ, Rohde TD (1982) Artificial devices for insulin infusion in the treatment of patients with diabetes mellitus. In: Brack SD (ed) Controlled drag delivery, Vol II. Clinical applications. CRC press, Boca Raton, pp 111–147
Grau U (1985) Insulin stability. In: Hepp KD, Renner R (eds) Continuous insulin infusion therapy. Experience from one decade. Schattauer, Stuttgart, New York, pp 33–46
Thurow H, Geisen K (1984) Stabilisation of dissolved proteins against denaturation at hydrophobic interfaces. Diabetologia 27: 212–218
Blackshear PJ, Rohde TD, Palmer JL, Wigness SD, Rupp WM, Buchwald H (1983) Glycerol prevents insulin precipitations and interruption of flow in an implantable insulin infusion pump. Diabetes Care 6: 387–392
Selam JL, Giraud P, Mirouze J, Saeidi S, Hedon B, Slingeneyer A, Lapinski H, Humeau C (1985) Continuous peritoneal insulin infusion with portable pumps: factors affecting the operating life of the chronic catheter. Diabetes Care 8: 34–38
Pongor S, Brownlee M, Cerami A (1983) Preparation of high-potency, non-aggregating insulins using a novel sulfation procedure. Diabetes 32: 1087–1091
Albisser AM, Lougheed W, Perlman K, Bahoric A (1980) Non-aggregating insulin solutions for long-term glucose control in experimental and human diabetes. Diabetes 29: 241–243
Bringer J, Heldt A, Grodsky GM (1981) Prevention of insulin aggregation by dicarboxylic amino acids during prolonged infusion. Diabetes 30: 83–85
Brange J, Havelund S (1983) Insulin pumps and insulin quality-requirements and problems. Acta Med Scand (Suppl) 671: 135–138
Sato S, Ebert CD, Kim SW (1983) Prevention of insulin self-association and surface adsorption. J Pharm Sci 72: 228–232
Obermeier R, Seipke G (1984) Enzyme-catalyzed semisyntheses with porcine insulin. Process Biochemistry 19: 29–32
Prestele K, Franetzki M, Kresse H (1980) Development of program-controlled portable insulin delivery devices. Diabetes Care 3: 362–368
Taylor G, Lebisch H, Weinmann P, Champion JR (1983) Devices and materials. Reports from representatives of industry. In: Irsigler K, Kritz H, Lovett R (eds) Diabetes treatment with implantable insulin infusion systems. Urban & Schwarzenberg, Munich Vienna Baltimore, pp 29–39
Irsigler K, Kritz H, Hagmüller G, Franetzki M, Prestele K, Thurow H, Geisen K (1981) Long-term continuous intraperitoneal insulin infusion with an implanted remote-controlled insulin infusion device. Diabetes 30: 1072–1075
Blackshear PJ, Dorman FD, Blackshear PL jr., Varco RL, Buchwald H (1972) The design and initial testing of an implantable infusion pump. Surg Gynecol Obstet 134: 540–543
Shoelson S, Haneda M, Blix P, Nanjo A, Sanke T, Inouye K, Steiner D (1983) Three mutant insulins in man. Nature 302: 540–543
Brange J, Langkjaer L, Havelund S, Sørensen E (1983) Chemical stability of insulin: neutral insulin solutions. Diabetologia 25: 143 (Abstract)
Luiken J, Van der Zee R, Welling GW (1984) Structure and activity of proteins after reversed-phase high-performance liquid chromatography. J Chrom 284: 482–486
European Pharmacopoeia (1975) Assay of insulin (method A) by subcutaneous injection into rabbits, Vol III. Maisonneuve S.A., Sainte Ruffine, p 75
Harfenist EJ, Craig LC (1952) Countercurrent distribution studies with insulin. J Am Chem Soc 74: 3883–3088
Carpenter FH, Crambach A (1962) On the amide content of insulin fractions isolated by partition column chromatography and countercurrent distribution. J Biol Chem 237: 404–410
Sundby F (1962) Separation and characterization of acid-induced insulin transformation products by paper electrophoresis in 7 M Urea. J Biol Chem 237: 3406–3412
Kurtz AB, Nabarro JDN (1980) Circulating insulinbinding antibodies. Diabetologia 19: 329–334
Kasama T, Iwata Y, Oshiro K, Uchida M, Sakaguchi S, Namic K, Sagiura M (1981) Antigenicity of desamido-insulin and mono- component insulin. Diabetologia 21: 65–69
Pingel M, Vølund A (1972) Stability of insulin preparations. Diabetes 21: 805–813
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Grau, U. Chemical stability of insulin in a delivery system environment. Diabetologia 28, 458–463 (1985). https://doi.org/10.1007/BF00280891
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DOI: https://doi.org/10.1007/BF00280891