Protamine insulin preparations

Vincent GM, Janowski M, Menlove R. Protamine allergy reactions during cardiac catheterization and cardiac surgery risk in patients taking protamine-insulin preparations. Cathet Cardiovasc Diagn 1991 23(3) 164-8. 

This crystalline salmiridine-insulin can be removed if desired, as by filtration but it is not necessary to do that, as the suspension of crystalline salmiridine-insulin may be preserved as thus prepared, and dispensed and used (in the same manner as known preparations of protamine insulin and protamine-zinc-insulin are used) in the original suspending medium in which it is formed. 

Insulin is ordered by die generic name (insulin zinc suspension, extended) or the trade (brand) name (Humulin U) (see the Summary Drug Table Insulin Preparations). The nurse must never substitute one brand of insulin for anodier unless the substitution is approved by the health care provider because some patients may be sensitive to changes in brands of insulin. In addition, it is important never to substitute one type of insulin for anodier. For example, do not use insulin zinc suspension instead of die prescribed protamine zinc insulin. 

Insulin suspensions. When the hormone is injected as a suspension of insulin-containing particles, its dissolution and release in subcutaneous tissue are retarded (rapid, intermediate, and slow insulins). Suitable particles can be obtained by precipitation of apolar, poorly water-soluble complexes consisting of anionic insulin and cationic partners, e.g the polycationic protein protamine or the compound aminoqui-nuride (Surfen). In the presence of zinc and acetate ions, insulin crystallizes crystal size determines the rate of dissolution. Intermediate insulin preparations (NPH or isophane, lente or zinc insulin) act for 18 to 26 h, slow preparations (protamine zinc insulin, ultralente or extended zinc insulin) for up to 36 h. 

Isophane insulin preparations containing equimolar quantities of insulin and protamine in order to prolong its duration of action... 

Protamine zinc and extended insulin zinc suspension (Ultralente) are often referred to as long-acting insulin preparations. These insulins have more protamine and zinc in the mixture than is found in isophane insuhn suspension. Insuhn zinc suspension, extended Ultralente Insulin), is quite similar to the protamine zinc insulin suspension except that it does not contain protamine. Both of these long-acting insuhns have an approximate duration of action of 36 hours. 

These are made by precipitating insulin with protamine or zinc to form amorphous, relatively insoluble crystals which are injected as a suspension from which the insulin is slowly absorbed. Since all intermediate- and long-acting insulin preparations are suspensions, not solutions, they cannot be given intravenously as this would result in drug microembolization. 

Yoshino K, Takeda N, Muramatsu M, Morita H, Mune T, Ishizuka T, Yasuda K. [A case of generalized allergy to both human insulin and protamine in insulin preparation]. J Jpn Diabetes Soc 1999 42 927-30. 

Bruni S, Barolo P, Gamba S, Grassi G, Blatto A. Case of generalized allergy due to zinc and protamine in insulin preparation. Diabetes Care 1986 9(5) 552. 

Insulin preparations that are commercially available differ in their relative onset of action, maximal activity, and duration of action. Conjugation of the insulin molecule with either zinc or protamine, or both, will convert the normally rapidly absorbed parenterally administered insulin to a preparation with a more prolonged duration of action. The various formulations of insulin are usually classified as short acting (0.5 to 14 h), intermediate acting (1 to 28 h), and long acting (4 to 36 h). The duration of action can vary, however, depending on injection volume, injection site, and blood flow at the site of administration. 

The importance of zinc ions for stabilizing insulin preparations has been known since the first reported crystallization of insulin in the presenoe of zino ions in 1934 (36). Suspensions of zinc insulin were used at that time. Presently, all pharmaceutical preparations are either solutions of zino insulin or suspensions of insoluble forms of zino insulin. A longer-acting and more stable form of insulin is protamine zinc insulin, which is prepared by precipitating insulin in the presence of zinc ions and protamine, a basic protein. This precipitate is known to contain two zinc ions per insulin hexamer. A somewhat shorter-acting and more useful preparation is neutral protamine Hagedorn (NPH) insulin, which includes m-cresol... 

Whereas extensive purification has resulted in a very pure and homogeneous insulin product, the protamine used for retardation in NPH type preparations (see Section 2.2.1) is highly inhomogeneous as it contains four major components, which are present in approximately equal amounts. AU four components show close structural homology with one another, and consequently they generate nearly identical protamine-insulin complexes (Hoffinaneta/., 1990). 

It has been shown that, if zinc is present, the hypoglycemic action of protamine-insulin or spermine-insulin compounds (which are more effective than pure insulin) is greatly prolonged. Insulin preparations contain zinc as a micro-constituent. 

J. D. Broussard and M. E. Patterson, Comparison of two ultralente insulin preparations with protamine zinc insulin in clinically normal cats. Am. J. Vet. Res., 1994, 55, 127-131. 

NPH Isophane Human Insulin Suspension. NPH isophane insulin, also called Humulin N, Insulatard NPH Human, or Novolin N is an intermediate-acting form of human insulin produced by recombinant DNA techniques. Mixtures Humulin 70/30 and Novolin 70/30 contain 70% NPH isophane and 30% regular, whereas Humulin 50/50 contains 50% NPH isophane and 50% regular. It is adrninistered subcutaneously and should not be given intravenously. Absorption is delayed because the insulin is conjugated with protamine in a complex of reduced isoelectric solubiUty. Therapeutically, this preparation is probably comparable to purified porcine NPH insulin. However, human NPH insulin may have a slightly shorter duration of action than comparable purified porcine products. 

Neutral Protamine Hagedorn, better known as NPH insulin, is prepared by a process in which protamine is conjugated with... 

Semilente insulin is a suspension of amorphous insulin zinc. The onset is 1-3 hours after subcutaneous administration, reaches maximum effect in 5-10 hours and the effect lasts 10-16 hours. Isophane insulin (NPH Neutral solution. Protamine, Hagedorn s laboratoiy insulin) is an intermediate-acting preparation prepared with protamine. The maximum effect is reached in 4-12 hours and lasts 8-26 hours. Patients using these preparations who present for cardiac surgery are at increased risk for anaphylactic reactions to protamine. Ultralente insulin is a long-acting preparation formed with zinc rather than protamine. Zinc retards the release of insulin and these preparations have a duration of up to 36 hours. Protamine zinc insulin, which contains both protamine and zinc, has a duration of 28-36 hours. 

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