Stable insulin preparation for implanted insulin pumps. Laboratory and animal trials

The stability and longevity of the polyethylene-polypropylene glycol-stabilized insulin have been tested in vitro and in vivo in an implanted insulin-infusion device, the programmable implantable medication system (PIMS). In vitro tests demonstrated long-term compatibility with refill cycles of up to 3 mo, with a preparation of 400 U/ml. Total test period in vitro was 3.2 device-yr (combined time of device use). Insulin retained 88-93% native structure. A major modification, which was biologically active and nonimmunogenic, was identified and partially characterized. Examination of one device by scanning electron microscopy and X-ray microanalysis after 1 yr of insulin infusion revealed surfaces clean of insulin precipitate or other material along the entire insulin-delivery pathway. Surface analysis of the silicone-lined polyethylene catheters after 6 mo of infusion also showed no evidence of major insulin precipitate. In vivo stability trials were accomplished with PIMS implanted in diabetic dogs with an intraperitoneal delivery site. There has been no insulin blockage of the catheter of active pumps after 5.1 dog-yr (combined time of trials) of trials (up to 5 mo between refills in a single dog). Structural stability of insulin was analyzed by high-performance liquid chromatography. On average, 90.8% of the insulin sampled from the reservoir in vivo was native insulin, with an average of 96.2% retention of active forms.