Hepatoselective pharmaceutical actives

Details Hepatoselective pharmaceutical actives Hepatoselective pharmaceutical actives

1996-02-13

1998-12-29

Weddington, Kevin K.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514539, A61K 3828, A61K 3124

Patent

active

058542086

DESCRIPTION:

BRIEF SUMMARY
This Application is a 371 of PCT/GB94/1784 filed Aug. 15, 1994.
The present invention relates to novel hepatoselective pharmaceutical actives. In particular it relates to novel hepatoselective insulin analogues suitable for use in an improved treatment of diabetes mellitus.
When drugs and other pharmaceutical actives are administered to the human or animal body it may be required that the active is needed to be present primarily in the liver or to act primarily on the tissues of the liver. That is, the active is required to be hepatoselective. Achieving hepatoselectivity can be difficult, in particular where the active is administered by injection into the skin. One case in which achievement of hepatoselectivity would be especially desirable is the administration of insulin.
The hormone insulin, secreted by the pancreas, has various important roles to play in glucose metabolism. In the liver, after binding to cell surface receptors, insulin promotes the conversion of glucose to glycogen (glycogenesis), promotes protein synthesis and inhibits fat breakdown. Insulin deficiency results in breakdown of glycogen (glycogenolysis), protein and conversion of products of fat and protein breakdown to glucose (gluconeogenesis) leading to a raised plasma glucose level (hyperglycaemia). In subjects who produce adequate amounts of insulin the blood glucose level remains within a certain range. Any excess of glucose is stored in the liver and muscles as glycogen.
Insulin also acts on cell membrane receptors in other tissues to enhance the entry of glucose into cells, thereby diminishing the plasma glucose concentration.
Thus insulin acts to reduce the plasma glucose level by reducing the production of glucose by the liver and by increasing uptake and metabolism of glucose by the liver and by increasing uptake and metabolism of glucose by peripheral tissues.
Deficiency of insulin due to disease of the islets of Langerhans and/or deficiency of insulin action results in diabetes mellitus, a condition in which the blood glucose concentration is high.
In subjects who are not diabetic insulin is produced in the pancreas and transported directly to the hepatic circulation and hence is transported to the liver before any other organs or regions of the body. Thus the liver experiences a very high exposure to the insulin produced. Usually at least 50% of the insulin produced is bound to receptors in the liver, and hence acts in the liver. Insulin bound to receptors in the liver is removed from the circulation and degraded by the liver cells. The insulin which is not bound in the liver and hence passes to the peripheral circulation is therefore at a much lower concentration. Thus the peripheral tissues (eg fat and muscle) which are also targets of the insulin experience a smaller exposure to the insulin secreted.
In diabetic subjects treatment is often carried out by insulin-replacement therapy. In general an insulin preparation is injected subcutaneously. The most common subcutaneous insulin regimen involves twice-daily injection of mixtures of short- and intermediate-acting insulin preparations. Insulin is absorbed from the subcutis into the peripheral circulation and thence to the entire body, including the liver. With such a system the liver and the peripheral tissues tend to experience approximately equal exposure to insulin.
There are various disadvantages and negative side-effects with the use of this system.
First, if sufficient insulin is injected to enable a high enough concentration to be present in the hepatic circulation then too high a concentration will be present in the peripheral circulation. Similarly if a suitable concentration is present in the peripheral circulation the concentration of insulin in the hepatic circulation will be inadequate.
There is believed to be a danger associated with high concentrations of insulin in the peripheral circulation (hyperinsulinaemia) of cardiovascular disease.
Second, there is a serious risk of hypoglycaemia in diabetic subjects receiving insulin replacement therapy by subcuta

REFERENCES:
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Windhoz et al. The Merck Index, 10th, p. 723 abstract No. 4866.
Chemical Abstracts (99:116795m) Kaliman et al. (1983).
J. Brange et al., Diabetes Care, vol. 13, No. 9 "Monomeric Insulins and Their Experimental and Clinical Implications" 9, Sep. 1990, pp. 923-925.
Ronald S. Spangler, "Selective insulinization of liver in conscious diabetic dogs", Am. J. Physiol. 249 (Endocrinal. Metab. 12) pp. E152-159 (1985).
J. Markussen et al, Soluble, fatty acid acylated insulins bind to albumin and show protracted action in pigs, No. 262, pp. 002-009.
Journal of Controlled Release, (1992), pp. 179-188, Trials of Lipid modification of peptide hormones for intestinal delivery.
Pharmaceutical Research, vol. 6, No. 2, (1989), Synthesis of Palmitoyl Derivatives of Insulin and Their Biological Activities.
Proceedings of the Second International Insulin Symposium Aachen, Germany, Sep. 4-7, 1979, Insulin Chemistry, Structure and Function of Insulin and Related Hormones.
F. Shojaee-Moradi, et al, "Convalent Insulin Dimers Are Hepatoselective", Abstract, Medical and Scientific Section, Apr. 13-15, 1989.

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