Insulins preparations

J. Brange, Gaknics of Insulin The Physico-Chemical and Pharmaceutical Mspects of Insulin and Insulin Preparations, Springer-Vedag, Berlin, 1987. 

Diabetes Mellitus. Table 1 Pharmakokinetic characteristics of the most commonly used insulin preparations and analogs... 

An individual can also become insulin resistant because of the development of antibodies gainst insulin. These patients have impaired receptor function and become so unresponsive to insulin that the daily dose requirement may be in excess of500 units per day (U/ d), rather than the usual 40 to 60 U/d. High-potency insulin in a concentrated form (U500 see the Summary Drug Table Insulin Preparations) is used for patients requiring more than 200 U/d. 

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. 

Care must be taken when giving insulin to use the correct insulin. Names and packaging are similar and can easily be confused. The nurse carefully reads all drug labels before preparing any insulin preparation. For example, Humalog (insulin lispro) and Humulin R (regular human insulin) are easily confused because of die similar names. 

Insulin must be administered via the parenteral route, usually the subcutaneous (SC) route Insulin cannot be administered orally because it is a protein and readily destroyed in the gastrointestinal tract. Regular insulin is the only insulin preparation given intravenously (IV). Regular insulin is given 30 to 60 minutes before a meal to achieve optimal results. 

Insulin aggregation and precipitation was an impediment to the development of implantable devices for insulin delivery as noted by several investigators working with conventional insulin infusion devices [51-54]. The potential causes of the observed aggregation and precipitation are thermal effects, mechanical stress, the nature of the materials in contact with the insulin solution, formulation factors, and the purity of the insulin preparation. 

Reverse-phase HPLC (RP-HPLC) separates proteins on the basis of differences in their surface hydophobicity. The stationary phase in the HPLC column normally consists of silica or a polymeric support to which hydrophobic arms (usually alkyl chains, such as butyl, octyl or octadecyl groups) have been attached. Reverse-phase systems have proven themselves to be a particularly powerful analytical technique, capable of separating very similar molecules displaying only minor differences in hydrophobicity. In some instances a single amino acid substitution or the removal of a single amino acid from the end of a polypeptide chain can be detected by RP-HPLC. In most instances, modifications such as deamidation will also cause peak shifts. Such systems, therefore, may be used to detect impurities, be they related or unrelated to the protein product. RP-HPLC finds extensive application in, for example, the analysis of insulin preparations. Modified forms, or insulin polymers, are easily distinguishable from native insulin on reverse-phase columns. 

Although a high degree of homology is evident between insulins from various species, the same is not true for proinsulins, as the C peptide sequence can vary considerably. This has therapeutic implications, as the presence of proinsulin in animal-derived insulin preparations can potentially elicit an immune response in humans. 

Traditionally, commercial insulin preparations were produced by direct extraction from pancreatic tissue of slaughterhouse pigs and cattle, followed by multistep chromatographic purification. However, the use of animal-derived product had a number of potential disadvantages, including ... 

The RP-HPLC polishing step not only removes E. coli-derived impurities, but also effectively separates modified insulin derivatives from the native insulin product. The resultant extremely low levels of impurities remaining in these insulin preparations fail to elicit any significant immunological response in diabetic recipients. 

Table 11.3 Native and engineered human insulin preparations that have gained approval for general medical use. Reproduced in updated form with permission from Walsh, G. 2005. Therapeutic insulins and their large-scale manufacture. Applied Microbiology and Biotechnology, 67, 151-159...

Table 11.4 Some pharmacokinetic characteristics of short, intermediate and long-acting insulin preparations...

The concentration of insulin present in soluble insulin preparations (i.e. fast-acting insulins), is much higher (approximately 1 x KT2 3 mol I ). At this concentration, the soluble insulin exists as a mixture of monomer, dimer, tetramer and zinc-insulin hexamer. These insulin complexes have to dissociate in order to be absorbed from the injection site into the blood, which slows down the onset of hormone action. 

Insulin, a hormone produced by the pancreas, is essential for the metabolism of glucose, proteins, and fats. Insulins are classified on the basis of the duration of action as rapid-, intermediate-, or long-acting and on the basis of source or species, such as human or animal (beef, pork, and mixtures of beef and pork). Table 10.1 summarizes insulin preparations currendy available in the United States. 

Venugopalan P, Sapre A, Venkatesan N, and Vyas SP (2001) Pelleted bioadhesive polymeric nanoparticles for buccal delivery of insulin Preparation and characterization. Pharmazie 56 217-219. 

TVpes of preparations (B). As a peptide, insulin is unsuitable for oral administration (destruction by gastrointestinal proteases) and thus needs to be given parenterally. Usually, insulin preparations are injected subcutaneously. The duration of action depends on the rate of absorption from the injection site. 

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. 

Many successful protein products, including antibodies, have been marketed over the years for the treatment of a number of diseases. One of the oldest examples of a protein product is insulin, still one of the most successful drugs after 70-80 years of its discovery. Early insulin preparations, derived from natural sources, are being replaced by recombinant human insulin preparations and new formulations are being marketed that provide a more gradual and continuous release profile and maximise glucose control in diabetic patients. " ... 

Insulin preparations Half-life Onset Peak Duration Compatible... 

Mixing of insuiins-The effects of mixing insulin aspart or lispro with insulins of animal source or insulin preparations produced by other manufacturers have not been studied (see Warnings). 

Insulin aspart If insulin aspart is mixed with NPH human insulin, draw insulin aspart into the syringe first. Do not mix insulin aspart with crystalline zinc insulin preparations. When used in external subcutaneous infusion pumps for insulin, do not mix with any other insulins or diluent. 

Hypogiycemic reactions Hypoglycemia when using this concentrated insulin can be prolonged and severe. As with other human insulin preparations, hypoglycemia reactions may be associated with the administration of concentrated insulin. However, deep secondary hypoglycemic reactions may develop 18 to 24 hours after the original injection of concentrated insulin. 

IDDM is caused by T cell-mediated autoimmune destruction of the insulin-producing P-pancreatic islet cells in genetically predisposed individuals. This is probably due to the expression of a super antigen on the surface of the jS cells in such individuals, although the molecular detail of what extent factors trigger onset of the jS cell destruction remain to be elucidated. IDDM may, however, be controlled by parenteral administration of exogenous insulin preparations, usually by regular s.c. injection. 

Insulin preparations used initially were little more than crude pancreatic extracts. The therapeutic value of such products was marginal, as severe adverse reactions were commonplace (due to the presence of impurities). This was made worse by the frequency of injections required. The introduction of an acid-alcohol precipitation step yielded insulin preparations of moderate purity, thus partially overcoming the range and severity of side effects noted. 

Additional impurities, such as glucagon, somatostatin, pancreatic polypeptide and vasoactive intestinal polypeptide, are present in most conventional insulin preparations at lower levels. The presence of such contaminants can impact upon product safety and efficacy in a number of ways. 

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

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