Insulin chemically modified

A synthesis of chemically modified insulin 364 containing LA covalently bonded to the -amino group of Lys of insulin has been described <2006PPL135>. Its potency regarding glucose-lowering activity was similar to that of native insulin, but the compound loses efficacy more slowly. 

Figure 9.20 The solubility dependence of (a) insulin and (b) trilysyl insulin, a chemically modified insulin with an isoelectric point of 7.4 compared with the isoelectric point of unmodified insulin of 5.3.

Intemasal delivery of peptide and protein drugs is severely restricted by pre-systemic elimination due to enz5miatic degradation or mucociliary clearance and by the limited extent of mucosal membrane permeability. a-CyD has been shown to remove some fatty acids from nasal mucosa and to enhance the nasal absorption of leuprolide acetate in rats and dogs. The utility of chemically modified CyDs as absorption enhancers for peptide drugs in rats has been demonstrated. For example, DM-P-CyD was shown to be a potent enhancer of insulin absorption in rats, and a minimal effective concentration of DM-(3-CyD for absorption enhancement exerted only a mild effect on the in vitro ciliary movement.The scope of interaction of insulin with CyDs is limited, because CyDs can only partially include the hydrophobic amino acid residues in peptides with small stability constants. Under in vivo conditions, these complexes will readily dissociate into separate components, and hence the displacement by membrane lipids may further destabilize the complexes. The direct interaction of peptides with CyDs is therefore of minor importance in the enhancement of nasal absorption. Of the hydrophilic CyDs tested, DM- 3-CyD had the most prominent inhibitory effect on the enzymatic degradation of both BLA and insulin in rat nasal tissue homogenates. Because of the limited interaction between peptides and CyDs,... 

Asada, H., Douen, T., WaM, M., Adachi, S., Fujita, T., Yamamoto, A., and Muranishi, S., 1995, Absorption characteristics of chemically modified-insulin derivatives with various fatty acids in the small and large intestine, J. Pharm. Sci. 84 682-687. 

An apparently more effective method for prolonging the half-life of insulin in the blood is to add substituents at the end of the A- or B-chain (or both) that alter the chemical properties of the molecule and delay its breakdown in the body. A product known as HOE 901 (insulin glargine) has two glycine residues added to one end of the B-chain and the A21 asparagine residue replaced with another glycine residue. These changes modify the acidity of the insulin molecule, reducing the rate at which it is absorbed and metabolized in the body. 

An important consideration to the pharmacologist is the useful lifetime of a drug in the body. Protein hormones have been modified chemically to lower their rate of removal from the bloodstream, prolong the effect of the injected hormone, and thus reduce the required frequency of administration. The modification of animal insulin by coupling to protamine-zinc is probably the best-known example. Others are the studies by Marshall on the possibility of lengthening the lifetime in the bloodstream of injected proteins by supplying them as dextran conjugates... 

Ethyl acetate has also been shown to increase the solubility of chlortalidone and to modify the polymorphic crystal forms obtained for piroxicam pivalate and mefenamic acid, and has been used in the formulation of microspheres.Its use as a chemical enhancer for the transdermal iontophoresis of insulin has been investigated. 

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