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Pharmacokinetic Considerations of New Insulin Formulations and Routes of Administration

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Summary

There is a continuing search for improved insulin formulations in order to imitate as closely as possible the physiological pattern of insulin secretion, and thereby to minimise the complications of diabetes mellitus. The major advances achieved to date are in the area of human insulin analogue synthesis resulting from the introduction of recombinant DNA techniques, and in improved delivery systems that utilise noninvasive or minimally invasive modes of administration.

To accommodate postprandial hyperglycaemia, monomeric insulin formulations have been developed, of which insulin lispro (the Lys-Pro analogue) is already approved for clinical use. These formulations have a rapid rate of absorption and, therefore, have to be administered at meal time (unlike the previous short-acting formulations). Their residence time is also about 2-fold shorter than regular human insulin; this minimises the risk of the excessive hypoglycaemic effect that characterises regular human insulin formulations. Certain proinsulin formulations with hepatoselective activity have been developed but were found to be poorly tolerated. The newer proinsulin molecules do not show hepatoselective properties.

In order to generate basal insulin levels, peakless long-acting formulations have been developed, including: a soluble formulation (which upon subcutaneous administration, produces a ‘depot-like’ sustained release mechanism), albumin-bound insulin and cobalt-insulin hexamer formulations. To improve patient compliance the ‘pen’ device was developed for subcutaneous injections. Programmable infusion pumps were developed to avoid repetitive subcutaneous injections.

Great efforts have been made in searching for noninvasive modes of insulin administration that will avoid the need for parenteral administration. These include: oral, colonic, rectal, nasal, ocular, buccal, pulmonary, uterine and transdermal routes of administration. Various enhancers have been tested to increase the bioavailability of each route. At present these alternative routes do not provide clinically relevant substitutes for the subcutaneous mode of administration.

In conclusion, although the newer formulations provide certain advantages, there is still much to be done to further facilitate and improve insulin therapy.

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  1. Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, P.O.Box 12065, Jerusalem, 91120, Israel

    Amnon Hoffman

  2. Diabetes Unit, Division of Medicine, Hadassah University Hospital, Jerusalem, Israel

    Ehud Ziv

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  1. Amnon Hoffman
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Hoffman, A., Ziv, E. Pharmacokinetic Considerations of New Insulin Formulations and Routes of Administration. Clin. Pharmacokinet. 33, 285–301 (1997). https://doi.org/10.2165/00003088-199733040-00004

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