Short-acting insulin has a rapid onset and a short duration of action. It may be given subcutaneously, intravenously or intramuscularly, although from a practical standpoint, the subcutaneous administration is most often used for long-term diabetic control. There are three lands of short-acting insulin preparations; namely, regular insulin, semilente insulin, and monomeric insulin analogs. (US FDA, 2002) The early short-acting insulin formulations were prepared at acidic pH and were chemically unstable. As we know now, insulin rapidly undergoes deamidation at AsnA21 in acidic solutions and results in loss of potency during prolonged storage.

The efforts to improve the chemical stability of these soluble insulin formulations led to the development of neutral, zinc complexed insulin solutions. (Brange et al. , 1992) Regular Insulin Regular insulin is a crystalline zinc insulin which is widely used to supplement intermediate- and long-acting insulin preparations. It is also the insulin used in infusion pumps because it is freely soluble in water and less likely to crystallize in the tubing during the slow infusion. In Canada, regular insulin is commonly referred to as Toronto insulin and in the United Kingdom it is referred to as soluble insulin list four ways to block normal muscle function.

Regular insulin is available in four different preparations from three different species: human, porcine, bovine or a mixture of bovine and porcine insulin. (Davis et al. , 1991) Porcine insulin and human insulin are believed to have similar potency in controlling blood glucose level. However, human insulin is less antigenic than porcine or bovine insulin. It appears that immunogenicity is one of the significant variables influencing insulin kinetics; it delays the onset of action and also reduces the bioavailability of insulin (Davis et al., 1991).

When antibody reactions do not occur, overall bioavailability of these two types of insulin are the same. All regular insulin given subcutaneously, regardless the species origin, has- an onset of action within 0. 3 and 1 hour, peaks within 2-4 hours, and has a duration of action of 5-8 hours. Regular insulin should be injected 30-45 minutes before meals. A tendency for a more rapid initial absorption in human regular insulin than porcine regular insulin has been noted in most studies. Peak concentrations of regular human insulin are 50% higher than porcine insulin.

This difference may relate to the more hydrophilic nature of human insulin than porcine insulin. The differences in pharmacokinetics may also relate to variations in the interaction between human or porcine insulin, and zinc crystals (Davis and Granner, 1996). Semilente Insulin Semilente insulin has almost the same kinetic profile as regular insulin. However, it has a much longer duration of action. It was originally used in place of regular insulin when the latter was available only in a phosphate buffer, which could not be mixed with lente or ultralente insulin.

Semilente insulin has become obsolete and is rarely used in the treatment of diabetes today (Skyler, 1988). The new short-acting insulin formulations contain zinc-insulin crystals dissolved in a clear fluid, containing phenolic preservative and an isotonocity agent. Deamidation of insulin takes place at AsnB3 in neutral formulations, at a much lower rate than that in acid solutions (Brange et al. , 1992). Addition of zinc (~0. 4%) leads to formation of insulin hexamers that stabilize insulin.

Furthermore, phenolic preservatives, such as m-cresol, were found to bind to some specific sites on the Zn-insulin hexamers, causing a conformational change that protects insulin molecules from deamidation as well as from insulin inter-molecules cross-linking reactions (Brange et al. , 1992). Derewenda et al. (1989) identified 6 phenol-binding sites on the insulin hexamer using X-ray crystallography. The phenolic ligands sitting between the monomers in each dimer form hydrogen bonds with the carbonyl oxygen of CysA6 and the amide proton of CysA11. At the same time, numerous van der waals contacts take place as well.

These interactions cause a conformational change at the N-terminus of the B-chain in each insulin monomer. The conformational equilibrium of residues B1-B8 is shifted from an extended structure to an ? -helical structure. This subsequently drives a conformational transition (referred to as T6-R6) of the insulin hexamer, from a loose structure to a compact one. The onset, peak and duration of action of the short-acting insulin formulations are listed in Table 1. A delay of action is observed even though the insulin is in the soluble state. This is due to the time required for the hexamers to dissociate into the dimers and/or monomers.

The hexamer molecules are too big to be absorbed through the biological membrane. The preservative molecules and insulin need to diffuse from the site of injection, thus dilute the protein to a certain extent so that the dissociation will be favored in the equilibrium (Brange et al. , 1992). Intermediate-acting insulins Two types of intermediate-acting native insulin formulations are widely used: NPH insulin and Lente insulin. Both types are used as basal insulin for diabetic patients. The need for longer-acting insulin to control fasting glucose production has been recognized since the introduction of insulin therapy.

The pharmacological basis for prolonging the biological action of insulin was to decrease the rate of insulin absorption. This was done by complexing insulin with various proteins or by changing the physical form of insulin by altering the zinc content in the buffer. Hagedorn and co-workers in 1936 introduced the first insulin preparation to have a prolonged action. This prolonged-acting insulin was called protamine insulin. They used protamine, obtained from fish sperm, complexed with insulin. Unfortunately, protamine insulin was not a stable preparation, so that it was never used widely (Skyler, 1988).

NPH insulin differs from any other insulin preparations by having a modifying protein, protamine, in the formulation. It is a neutral suspension of insulin crystals that are co-crystallized with zinc and protamine. Protamine is a mixture of small peptides, with 65-70% of the amino acids being arginine (Binder and Brange, 2003), primarily isolated from fish sperm. The NPH insulin crystals are essentially insoluble; however, minimal amounts of insulin and protamine are present in the solution of the formulation. NPH insulin can be mixed with regular (short-acting) insulin.

The mixture can either be prepared immediately before administration or be obtained as a pre-mixed preparation by the manufacturer. The time-action of either insulin in the mixture will remain unchanged. Formulations such as 70/30 or 50/50 NPH/regular insulin are available for improved dose accuracy. One of the issues with NPH insulin is the immunogenicity of protamine since it is from another species. A small percentage of patients who used NPH insulin have shown sensitivity to protamine. These patients are often switched to Lente insulin as the basal insulin. (Skyler, 1988) Lente insulin is a neutral suspension of zinc-insulin particles.

It is a mixture of two forms of insulin that are both insoluble, 70% rhombohedral zinc-insulin crystals and 30% amorphous insulin particles. Insulin can be precipitated into crystalline or amorphous form, depending on the precipitation conditions, such as pH and zinc concentration. Lente insulin has excessive zinc in solution, which is believed to bind to weak metal sites on the insulin hexamer, further slowing the dissolution of the insulin (Davis et al. , 1991). Lente insulin could also be mixed with regular insulin, but the mixture must be prepared right before administration.

The regular insulin might be precipitated over time after mixing, thus the course of effect of the regular insulin is changed. This is because the surplus zinc present in Lente will bind to the weak metal sites on the soluble insulin hexamers and cause precipitation. (Davis et al. , 1991) Bovine, porcine and biosynthetic and semisynthetic human insulin have been marketed as intermediate-acting insulin formulations. As with shorter acting insulins, the pharmacokinetic properties of intermediate-acting insulins are slightly different between different species.

For example, human insulin has a faster onset of action and a shorter duration of action than porcine insulin. This difference may relate to the more hydrophilic nature of human insulin than porcine insulin, or to the delaying effects of insulin antibodies. Differences in pharmacokinetics may also relate to the variation of interaction between human or porcine insulin, with protamine and zinc (Davis and Granner, 1996). Because human insulin has a shorter time course of action, if it is given immediately before dinner, the treated diabetic patients may experience early next morning insulin deficiency and morning hyperglycemia.

When lente insulin is mixed with regular insulin, after several hours some of the regular insulin will form a complex with protamine orZn2-. This slows the absorption of the shorter acting insulin component. Such an interaction does not occur when short-acting insulin is mixed with NPH insulin. This advantage has made NPH the most widely used intermediate-acting insulin in the world (Davis et al. , 1991). Long-acting insulins Protamine zinc insulin was the first stable insulin with prolonged action. It was developed by Scott and Fisher in 1936. The other long-acting insulin is ultralente insulin.

Both insulins have a very long delay in onset of action, a prolonged duration and a relatively peakless activity profile. These insulins are administered subcutaneously to provide a low basal concentration of insulin around the clock. Long-acting insulin lowers blood glucose over a period of 28-36 hours. Onset of action occurs within 4-6 hours with a peak action in 8-24 hours. Since the half-lives of these two insulins are very long, it is difficult to determine the optimal dosage. Several days of treatment is required to achieve a steady-state concentration of circulating insulin.

It may be given once or twice daily and adjusted according to the blood glucose concentration (Skyler, 1988). When long-acting insulins are given with rapid-acting insulins, regular insulin should be given by separate injection. If regular insulin is mixed with ultralente or PZI, the activity of the rapid-acting insulin may be diminished by the formation of a complex between regular insulin and Zn2+ and/or protamine. This condition is minimized when the mixture of insulin is injected immediately after the mixing (Binder and Brange, 2003).

Ultralente insulin shows a species-related feature. Ultralente human insulin clearly produces an insulin peak within IS hours after injection compared to beef/pork ultralente which is virtually peakless. Moreover, the peak concentration (120-180 ? U/ml) is almost three times higher than that of other insulin species (60 ? U /ml) or 12-36 times higher than that of non-diabetic basal insulin levels. This high human insulin level persists for almost 30 hours. The explanation for these effects is the same as that mentioned for other human insulin formulations (Davis and Granner, 1996).

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