Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-16
2004-01-13
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S358000, C514S824000
Reexamination Certificate
active
06677361
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to topical formulations for transdermal delivery of niacin and esters and alcoholic fatty-acid esters as described herein derivatives thereof and the transdermal treatment of hyperlipidemia and hypercholesterolemia with these agents. Therapeutic uses of the system are also described. The topical formulations are useful for, e.g., treating hyperlipidemia in a mammal.
Hyperlipidemia and hypercholesterolemia are conditions that have a well established correlation with increased risk of other conditions, such as heart attacks, atherosclerosis, and other deleterious ailments. There are numerous agents available for lowering cholesterol and lipid levels, including gemfibrizol, probucol, and, more recently, the “statins” e.g, lovastatin.
Niacin (nicotinic acid), a water soluble B-complex vitamin, is used orally for the treatment of hyperlipidemia and has been shown to be effective in reducing total plasma cholesterol (C), low density lipoproteins LDL-C and very low density lipoprotein triglycerides (VLDL-triglycerides), all of which are associated with health risks, while raising serum levels of high density lipoproteins (HDL-C) which are considered a “healthy” lipoprotein, in patients with type II, III, IV, and V hyperlipoproteinemia.
Although the mechanism by which niacin alters lipid profiles has not been well defined, its mechanisms of action have been shown to include inhibition of free fatty acid release from adipose tissue (see Carlson, L. A., Froberg, S. O. and Nye, E. R., Nicotinic acid in the rat. 11. Acute effects of nicotinic acid on plasma, liver, heart, and muscle lipids,
Acta Med Scand
180: 571-579, 1966), and increased lipoprotein lipase activity (see Priego, J. G., Pina, M., Armijo, M., Sunkel, C. and Maroto, M. L., Action of etofibrate, clofibrate and nicotinic acid on the metabolism of lipids in normolipemic rats. Short term effects and method of action,
Arch Farmacol Toxicol
5: 29-42, 1979). More than 14 million Americans have elevated blood LDL-C levels. HMG-CoA reductase inhibitors (statins) are the most widely used class of drugs for treating patients with elevated levels of LDL-C. Niacin, however, is the only drug recommended by the American Heart Association for HDL improvement in primary prevention of cardiovascular diseases in addition to lowering LDL-C. Niacin therapy is not only very cost-effective as a monotherapy but it also is beneficial as a combination therapy because it complements the effects of other classes of lipid-lowering drugs. Niacin is a second or third choice for isolated, hypercholesterolemia because of a high incidence of side effects associated with oral niacin therapy. However, it has a therapeutic advantage as a monotherapy when reduction of both LDL-C and triglycerides are desired such as for patients with severe combined hyperlipidemia. Niacin can also be used in combination with other cholesterol-lowering agents such as the “statins” to maximize lipid-lowering activity. One study shows that a niacin/lovastatin combination is highly effective in lowering LDL-C, triglycerides and lipoprotein a[Lp(a)] while retaining niacin's potency in raising HDL-C (Kashyap, M. L., Evans R., Simmons, P. D., Kohler, R. M. and McGoven, M. E., New combination niacin/statin formulation shows pronounced effects on major lipoproteins and well tolerated,
J Am Coll Card Suppl.
A 35: 326, 2000).
Niacin has been widely used for reducing serum cholesterol levels because it is considered a cost-effective therapy. In oral doses of 2 to 3 g daily, it reduces levels of total and LDL-C by an average of 20% to 30%, reduces triglyceride levels 35% to 55%, increases HDL-C 20% to 35%, and reduces Lp(a) in humans. Niacin also reduces total mortality as well as mortality from coronary artery disease (see The Coronary Drug Project Research Group,
JAMA
231: 360-381, 1975; and Canner, P. L., Berge, K. G., Wenger, N. K., Stamler, J., Friedman, L., Prineas, R. J. and Friedewald, W., Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin,
J Am Coll Cardiol
8: 1245-1255, 1986.) and it helps to slow or reverse the progression of atherosclerosis (see Blankenhorn, D. H., Nessim, S. A., Johnson, R. L., Samnarco, M. E., Azen, S. P. and Cashin-Hemphill, L., Beneficial effects of combined colestipol-niacin therapy on coronary atheroscloerosis and coronary venous bypass grafts,
JAMA
257: 3233—3240, 1987.; and Cashin-Hemphill L.; Mack, W. J., Pogoda, J. M., Samnarco, M. E., Azen, S. P. and Blankenhorn, D. H., Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up,
JAMA
264: 3013-3017, 1990).
Oral niacin therapy has side effects that limit its utility. Although niacin is a vitamin, it must be used in therapeutic doses to lower cholesterol. At these doses, both immediate-release and sustained-release niacin can have several side effects. The most common side effect of niacin is flushing, a warm feeling in the skin usually associated with redness and sometimes itching. Flushing is not dangerous but most patients find it very uncomfortable, which seriously limits patient compliance with therapy. Niacin-induced flushing can be substantially attenuated by pretreatment with cyclooxygenase inhibitors, suggesting that the vasodilation is caused by a prostaglandin-mediated mechanism (see Carlson, L. A., Nicotinic acid and inhibition of fat mobilizing lipolysis. Present status, of effects on lipid metabolism,
Adv Exp Med Biol
109: 225-23 8, 1978).
Liver function tests are always monitored in patients taking niacin since elevation of serum transaminase levels has been associated with niacin treatment, and sustained-release niacin formulations have been associated with more serious liver problems (see McKenney, J. M., Proctor, J. D., Harris, S., and Chinchili, V. M., A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients,
JAMA
271: 672-777, 1994; and Stafford, R. S., Blumenthal, D. and Pasternak, R. C., Variations in cholesterol management practices of U.S. physicians,
J Am Coll Cardiol
29: 139-146, 1997). Other possible side effects of oral niacin therapy include activation of peptic ulcers, gout, and worsening of diabetes control. Given the potential for side effects, oral niacin therapy requires careful clinical monitoring.
The pharmacokinetic profile of niacin taken orally is complex due to rapid and extensive first-pass metabolism, resulting in a nonlinear relationship between niacin dose, thus there is no correlation between the lipid parameters and plasma niacin levels. For example, data show that Niaspan® doses of 1,000 mg results in an improvement in lipid profiles with barely detectable increases in plasma niacin (see Physicians Desk Reference, 53rd edition, p 1505-1506, 1999). Niaspan® is an extended release niacin formulation approved by the FDA for the treatment of hypercholesterolemia and hypertriglyceridemia (Capuzzi, D. M., Guyton, J. R., Morgan, J. M., Goldberg, A. C., Kriesberg, R. A., Brusco, O. A. and Brody, J., Efficacy and safety of an extended-release niacin (Niaspan): A long term study,
Am J Cardiol
82: 74u-8 I u, 1998; and Morgan, J. M., Capuzzi, D. M., and Guyton, J. R., A new extended-release niacin (Niaspan): Efficacy, tolerability, and safety in hypercholesterolemic patients,
Am J Cardiol
82: 29u-34u, 1998). Thus, significant improvement in the serum lipid profile can be achieved without a dramatic increase in nicotinic acid plasma levels after the oral administration of niacin (see Knopp, R. H., Alagona, P., Davidson, M., Goldberg, A. C., Kafonek, S. D., Kashyap, M., Sprecher, D., Superko, H. R., Jenkins, S., Marcovina, S., Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia,
Metabolism
47: 1097-104, 1998). This demonstrates that sustained elevation of blood levels of niacin is not required to achieve a therapeutic effect. Indeed, the data support the argument that tis
Jacobson Elaine L.
Jacobson Myron K.
Kim Hyuntae
Kim Moonsun
Qasem Jaber G.
Fulbright & Jaworski LLP
Jagoe Donna
Krass Frederick
University of Kentucky Research Foundation
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