The engineering of the timed release into the bloodstream of a drug goes by the name “drug delivery” these days. The first insulin with an engineered profile activity was developed in the mid 1930’s by Hans Christian Hagedorn. It was initially called protamine insulin, later neutral protamine Hagedorn insulin, abbreviated as NPH insulin. It still goes by this name.
Hans Christian Hagedorn was a Danish physician. He was one of the first to introduce insulin into Denmark, and eventually obtained a license from the University of Toronto to produce insulin. This production supplied Scandinavia with insulin from a facility they called the Nordisk Insulin Laboratory.
In the 1930’s Hagedorn became interested in modifying the activity profile of insulin, or slowing the absorption of insulin into the bloodstream. He knew that when certain proteins contaminate insulin preparations, they lengthened the activity profile of insulin, but also caused irritation in recipients. He searched for a protein that would lengthen the activity profile, but not cause the irritation and came upon protamine, a protein found in sperm.
Protamine has a structural function within the cell. It helps DNA pack itself into a compact structures inside of a sperm cell. Hagedorn isolated protamine from fish cells and mixed it with insulin. The insulin protamine mixture forms a milky appearing solution.
The protamine organizes insulin into microscopic clumps. These clumps, when injected into the body, take longer to come apart then insulin alone. This clumping causes the NPH insulin to be more slowly released into the blood stream. NPH insulin was first sold by Nordisk in 1950.
Once Hagedorn showed that insulin can be manipulated to retain its biological activity, but change its pharmacodynamics characteristics (activity profiles), others engineered other forms of insulin with beneficial properties. The next step was the development of zinc protamine insulin by someone at the University of Toronto. Zinc protamine insulin had an even longer activity curve than NPH insulin.
An initial impetus of Hagedorn was to enable diabetic patients to survive on one insulin shot per day. If one tried to provide all the insulin a patient needed with a single shot in the morning, hypoglycemia would occur during the night, because too much insulin remained in the body after digestion of the days meals. What was needed was a preparation of insulin that, once injected under the skin, would slowly be released into the bloodstream.
The importance of Hagedorn’s discovery is not just the existence of NPH insulin, but it includes the basic realization that the delivery of insulin from subcutaneous injection into the bloodstream could be modified or engineered. A second engineered insulin was soon developed by D A Scott at the University of Toronto: zinc protamine.
With these engineered insulins, the promise of a one shot per day regimen was apparently realized. The one shot would consists of a combination of NPH and regular insulin. The NPH insulin provided the basal dose, enough insulin to carry the patient through 24 hours, but not so much that will cause hypoglycemia during the night. [zinc protamine insulin, Lawrence and Archer].