Insulin absorption modification

The disposition of insulin was shown to be susceptible to non-absorptive losses to metabolism and mucociliary clearance. Modification of the deposition profile of insulin in the lung showed that higher absorption rates were obtained for more peripheral deposition and co-administration of a metabolic inhibitor reduced losses to exopeptidase metabolism [101], It is acknowledged by the investigators that the IPL technique and the dosing technique of Byron and coworkers are not widely accessible and have therefore not been widely adopted [119], Active absorption has also been studied in this system as described in Sect. 6.2.43. 

M. Hashizume, T. Douen, M. Murakami, A. Yamamoto, K. Takada, S. Muranishi, Improvement of Large Intestinal Absorption of Insulin by Chemical Modification with Palmitic Acid in Rats , J. Pharm. Pharmacol. 1992, 44, 555-559. 

Rapid-acting insulin analogues (lispro, insulin aspart [Humalog, Novo log]) have been engineered to contain amino acid modifications that promote rapid entry into the circulation from subcutaneous tissue. They begin to exert their effects as early as 5 to 10 minutes after administration. Lispro insulin, the first insulin analogue to be approved in Europe and the United States, is produced by switching the positions of lysine-proline amino acid residues 28 and 29 of the carboxy terminus of the p-chain. Lispro insulin displays very similar actions to insulin and has a similar affinity for the insulin receptor, but it cannot form stable hexamers or dimers in subcutaneous tissue, which promotes its rapid uptake and absorption. 

Hashizume, M., Douen, T., Murakami, M., et al. Improvement of large intestinal absorption of insulin by chemical modification with palmitic acid in rats. J. Pharm. Pharmacol. 44 555-559, 1992. 

Recent development of insulin analogues has altered the rates of absorption. Insulin with aspartate and glutamate substituted at positions B9 and B27 respectively crystallizes poorly and has been termed "monomeric insulin (Vora et al., 1988). This insulin is absorbed more rapidly from subcutaneous depots and thus may be useful in meeting postprandial demands. In contrast, other insulin analogues tend to crystallize at the site of injection and are absorbed more slowly (Markussen et al., 1988). Insulins with enhanced biological potency have been produced by substitution of aspartate for histidine at position BIO and by modification of the C-terminal residues of the B-chain (Schwartz et al., 1989). 

In this chapter, we summarize the general approaches that have been used to successfully achieve the formulation goals for oral delivery minimize enzymatic degradation enhance intestinal absorption maximize blood level reproducibility deliver drug through the gut wall and produce a palatable and acceptable dosage form. Then insulin will be used as an example to show how oral bioavailability has been achieved through chemical modification. 

Regular crystalline insulin naturally self-associates into a hexam-eric (six insulin molecules) stmcture when injected subcutaneously. Before absorption through a blood capillary can occur, the hexamer must dissociate first to dimers, and then to monomers. This principle is the premise for additives such as protamine and zinc described below, and modification of amino acids for insulin analogs. Lispro, aspart, and glulisine insulins dissociate rapidly to monomers, thus absorption... 

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