Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-09-15
2001-09-11
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C514S184000, C514S866000
Reexamination Certificate
active
06287586
ABSTRACT:
BACKGROUND OF THE INVENTION
Non-insulin-dependent diabetes mellitus (NIDDM) is a metabolic disease that affects about 5% to 7% of the population in western countries (and 10% of individuals over age 70). It is characterized by hyperglycemia and often accompanied by a number of other conditions, including hypertension, obesity and lipid disturbances. The underlying pathology is impaired beta-cell function of uncertain cause. Insulin resistance, which both precedes and predicts impaired glucose tolerance, may be the cause of beta-cell failure, or it may simply reveal the presence of a primary beta-cell defect.
Diet and exercise therapy alone are generally not successful in controlling hyperglycemia in NIDDM. In contrast to IDDM, in which insulin deficiency is the problem and insulin replacement the treatment, in NIDDM the pharmacological approach to hyperglycemia is more varied and more rapidly evolving. The data suggest that any improvement in the degree of blood glucose control will postpone development and slow the progression of microvascular complications. Treatment goals for people with diabetes that emphasize glycemic control are therefore recommended.
There are four classes of currently approved antidiabetic drugs in the United States, each of which have different effects on one or more of the pathogenetic abnormalities of NIDDM. The sulfonylurea agents all appear to act primarily by potentiating insulin secretion. In contrast, the biguanides have no direct effect on insulin secretion. Their mechanism or mechanisms of action are not completely understood but include a reduction in hepatic glucose production and perhaps an increase in peripheral insulin sensitivity and reduction in intestinal glucose absorption. A third class of drugs is the &agr;-glucosidase inhibitors, which inhibit specific enzymes that break down starches in the small intestine, thereby delaying carbohydrate absorption and attenuating postprandial hyperglycemia. A fourth class of therapeutic drugs is the insulin preparations that supplement endogenous insulin.
Biguanides lower blood glucose primarily by reducing intestinal glucose absorption and hepatic glucose production. Metformin, (1,1-dimethylbiguanide) is rapidly absorbed and cleared through the kidneys. The drug has been shown to reduce fasting and postprandial blood glucose by an average of 2 to 3 mmol/L. It may also enhance insulin sensitivity at postreceptor levels and stimulate insulin-mediated glucose disposal, but it does not stimulate insulin secretion.
The number of patients who respond to biguanide therapy diminishes over the years because of a number of factors, e.g. drug noncompliance because of side effects, dietary noncompliance, weight gain, declining beta-cell function, and the increasing use of diabetogenic drugs such as glucocorticoids, thiazides, and beta-blockers. Metformin is contraindicated in patients with renal dysfunction or conditions that compromise renal function. The drug is also contraindicated in acute or chronic metabolic acidosis.
Compositions that are effective in treating non-insulin dependent diabetes, such as improved biguanide compositions, are of great interest. The invention described herein provides for such improved compositions and methods for their use.
Relevant Literature
Complexes formed between vanadium and biguanides have been described by Chakraborty and Das (1989)
Analytica Chimica Acta
218:341-344; Syamal (1983)
Ind. J. Pure
&
Applied Phys.
21:130-132; Calatayud et al. (1981)
Afinidad
XXXVIII:537-540; Babykutty et al. (1974)
Thermochimica Acta
8:271-282. A complex of vanadium and 1,1-dimethylbiguanide is disclosed by Ray (1961)
Chem. Rev.
61:313-359.
The insulin-like effect of the vanadate ion (VO
4
3−
) in vitro has been known since 1980, see Nature 284:556-558 (1980), when it was shown that the insulin-like stimulation of glucose oxidation in rat adipocytes was due to the vanadyl ion. In 1985, McNeill et al. (1985) Science 227: 1474-1477, reported that vanadate, when administered in drinking water, decreased the elevated blood glucose and prevented the depression of cardiac performance in rats made diabetic with streptozotocin (STZ). Subsequently, there has been interest in the insulin-mimetic effects of both vanadate and vanadyl, since Sakurai et al. (1980) Biochem. Biophys. Res. Comm. 96: 293-298, showed that vanadate is reduced in vivo to vanadyl.
Work by McNeill et al. (see Am. J. Physiol 257: H904-H911 (1989), Metabolism 38: 1022-1028 (1985), Diabetes 38: 1390-1395 (1989) and Can. J. Physiol & Pharmacol. 68: 486-491 (1990); U.S. Pat. Nos. 5,527,790; 5,300,496; has shown that vanadyl administered orally as vanadyl sulfate, or as vanadyl maltol complexes lowers blood glucose and blood lipids in STZ diabetic rats and prevents secondary complications of diabetes such as cataracts and cardiac dysfunction.
SUMMARY OF THE INVENTION
Pharmaceutical compositions of vanadium biguanide complexes, and methods of use, are provided for the treatment of hyperglycemia and related disorders, e.g. hypertension, obesity, and lipid disturbances. The pharmaceutical compositions also find use in the treatment of hyperproliferative disorders. The pharmaceutically active complexes of the invention comprise a biguanide chelant, preferably a 1-substituted biguanide chelant, capable of chelating vanadium to form a six-membered unsaturated vanadium-containing ring. The vanadium of the complex is coordinated with oxygen, sulphur or nitrogen, particularly oxygen coordinated. The complexes are formulated with a physiologically acceptable carrier. In a preferred embodiment, the complexes are formulated for oral administration.
REFERENCES:
patent: 5188833 (1993-02-01), Kamijo et al.
patent: 5300496 (1994-04-01), McNeill et al.
patent: 5527790 (1996-06-01), McNeill et al.
patent: 5620967 (1997-04-01), McNeill et al.
patent: 93/06811 (1993-04-01), None
Babykutty et al. (1974), “Thermal Decomposition of the Biguanide Complexes of the 3d-Transition Metals,”Thermochimica Acta, vol. 8:271-282.
Chakraborty et al. (1989), “Indirect Determination of Vanadium by Atomic Absorption Spectrometry,”Analytica Chimica Acta, vol. 218:341-344.
McNeill et al. (1985), “Effect of Vanadate on Elevated Blood Glucose and Depressed Cardiac Performance of Diabetic Rats,”Science, vol. 227:1474-1477.
Pederson et al. (Nov. 1989), “Long-Term Effects of Vanadyl Treatment on Streptozocin-Induced Diabetes in Rats,”Diabetes, vol. 38:1390-1395.
Ramanadham et al. (1989), “Oral Vanadyl Sulfate in Treatment of Diabetes Mellitus in Rats,”Am. J. Physiol., vol. 257:H904-H911.
Ramanadham et al. (Oct. 1989), “Sustained Prevention of Myocardial and Metabolic Abnormalities in Diabetic Rats Following Withdrawal from Oral Vanadyl Treatment,”Metabolism, vol. 38(10):1022-1028.
Ramanadham et al. (1990), “Enhanced in Vivo Sensitivity of Vanadyl-Treated Diabetic Rats to Insulin,”Can J. Physiol. and Pharmacol., vol. 68:486-491.
Ray (1961), “Complex Compounds of Biguanides and Guanylureas with Metallic Elements,”Chem Rev., vol. 61:313-359.
Sakurai et al. (Sep. 1980), “Detection of Oxovanadium (IV) and Characterization of its Ligand Environment in Subcellular Fractions of the Liver of Rats Treated with Pentavalent Vanadium (V),”Biochem. and Biophys. Res. Comm., vol. 96(1):293-298.
Shechter et al. (Apr. 1980), “Insulin-Like Stimulation of Glucose Oxidation in Rat Adipocytes by Vanadyl (IV) Ions,”Nature, vol. 284:556-558.
Syamal (1983),Ind. J. Pure and Applied Phys., vol. 21:130-132.
Babykutty, P.V., et al., “Electronic and Infrared Spectra of Biguanide Complexes of the 3d-Transition Metals,”Journal of Inorganic&Nuclear Chemistry(1974) vol. 36(12):3685-3688.
Elpern, Bill, “Chemistry of the Biguanides,”Annals of the New York Academy of Sciences(Mar. 26, 1968) vol. 148(3):577-586.
McNeill, “Bis(maltolato)oxovanadium(IV) is a Potent Insulin Mimic,”Journal of Medicinal Chemistry, US, American Chemical Society, Washington (Apr. 17, 1992) vol. 35(8):1489-1491.
Ramasarma, T., “Vanadium Complexes With Insulin Mimic Actions-A Second Line of Protection Against Diabete
McNeill John H.
Orvig Chris
Bozicevic Field & Francis LLP
Nguyen Helen
Sherwood Pamela J.
The University of British Columbia
Webman Edward J.
LandOfFree
Pharmaceutical compositions of vanadium biguanide complexes... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical compositions of vanadium biguanide complexes..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical compositions of vanadium biguanide complexes... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2448336