Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2003-01-09
2004-11-30
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S458000, C424S459000, C424S462000, C424S468000, C424S470000, C424S474000, C424S482000, C424S489000, C424S497000
Reexamination Certificate
active
06824790
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to delivery of polycyclic, aromatic, antioxidant or anti-inflammatory compounds to a biological organism. In particular, the invention relates to liposomes and formulations of drugs, nutrients and other compounds into liposomes to improve or effect delivery of such beneficial compounds to cells and tissues in an organism. Specifically, the invention provides such liposome compositions of polycyclic, aromatic, antioxidant or anti-inflammatory compounds in formulations advantageously administered orally to an animal.
2. Background of the Related Art
Cardiovascular disease (including atherosclerosis, myocardial infarction, ischemia, stroke, pulmonary embolism and other thrombotic diseases) and cancer are major causes of mortality in the U.S., being responsible for up to two-thirds of all deaths per annum. Despite advances in preventative medicine, diet, exercise, diagnostics and therapeutic approaches that have increased the average lifespan of U.S. citizens and reduced the number of premature deaths, these diseases ultimately are no less responsible for mortality than they were a generation ago.
Certain plant-derived compounds have been recognized as being beneficial both as anticancer and anticardiovascular disease agents. This class of compounds is generally recognized to include polycyclic, aromatic compounds having antioxidant or anti-inflammatory activity, and include the flavonoids (such as flavone, quercetin and chrysin) and derivatives of stilbenes, such as resveratrol. The effects of these compounds as anticancer and anticardiovascular disease agents are both anecdotal and subject to modern scientific scrutiny. One example of anecdotal evidence for the beneficial effects of these compounds is with regard to what has been termed “French paradox.” The paradox is that although the French diet is high in nutrients (such as cholesterol and saturated fats) that have been associated with a risk of arteriosclerosis and cardiovascular disease, French citizens have less cardiovascular disease than their counterparts in other Western countries. The purported reason for this result is that French citizens also consume more red wine that other Western country citizens, and red wine is high (5-50 parts per million) in one polycyclic, aromatic antioxidant compound, resveratrol (Siemann & Creasy, 1992,
Am. J. Enol. Vitic.
43: 49-52; Kopp et al., 1998,
Eur. J. Endocrinol.
138: 619-620). Resveratrol is also a component of a traditional oriental medicine, Ko-jo-kon, used to treat ailments of the heart, blood vessels and liver. Soleas et al., 1997,
Clin. Biochem.
30: 91-113.
Resveratrol is found in red wine due to its presence in grape skins and is thought to be a phytoalexin that provides protection against fungi. Celotti et al., 1996,
J. Chromatog.
730: 47-52. It is also found (at much lower concentrations) in eucalyptus, spruce, lily, mulberry and peanuts.
Resveratrol has also been the subject of several scientific studies. The Copenhagen Heart Study (1995) showed that the relative risk of mortality from coronary artery disease was reduced by 20% when red wine was consumed once a month, by 30% when red wine was consumed once or twice weekly, and by 40% when red wine was consumed 3-5 times per week. Other researchers investigated the physiologic basis for these results. Pendurthi et al. (1999) showed that resveratrol, dose-dependently, inhibited transcription and expression of tissue factor in endothelial cells.
Arterioscherosis Thrombosis and Vascular Biol.
19: 419-426. Resveratrol has been shown to have antioxidant (Chanvitayapongs et al., 1997,
Neuroreport
8: 1499-1502; Belguendouz et al., 1998,
Biochem. Pharmacol.
55: 811-816; Frankel et al., 1993,
Lancet
341: 1103-1104), platelet aggregation inhibiting (Bertelli et al., 1996,
Drugs Exp. Clin. Res.
22: 61-63; Rotondo et al., 1998,
Brit. J. Pharmacol.
123: 1691-1699) and vasodilating (Chen et al., 1996,
Gen. Pharm.
27: 363-366) properties. Resveratrol has also been shown to have cancer chemopreventative properties (Jang et al., 1997,
Science
275: 218-220), putatively by inhibiting COX-1 and COX-2 and tumor promotion thereby (Subbaramaiah et al.,
J. Biol. Chem.
273: 21875-21882; Clement et al., 1998,
Blood
92: 996-1002; Fontecave et al., 1998,
FEBS Lett.
421: 277-279).
As a consequence, the World Health Organization estimates that coronary artery disease could be reduced by up to 40% if resveratrol or resveratrol-containing foods were consumed in proper amounts.
Chrysin (5,7-dihydroxyflavone) is a naturally-occurring flavone found in passion flower (
Passiflora coerulea
) extracts. Chrysin has activity as an anxiolytic agent (Wolfman et al., 1994,
Pharmacol. Biochem. Behav.
47: 1-4; Paladini et al., 1999,
J. Pharm. Pharmacol.
51: 519-526), an anticonvulsant (Medina et al., 1990,
Biochem. Pharmacol.
40: 2227-31), an agent that reverses P-glycoprotein mediated multidrug resistance in human cancer cells (Barron et al., 2
nd
International Electronic Conference on Synthetic Organic Chemistry (ECSOC-2), Sep. 1-20, 1998, www.mdpi.org/ecsoc), and as a protein kinase inhibitor (Hagiwara et al., 1988,
Biochem. Pharmacol.
37: 2987-2992). Myocardial infarction risk in elderly men is decreased by chrysin (Hertog et al., 1993,
Lancet
342: 1007-1011). Chrysin is believed to act by inhibiting aromatase, an enzyme responsible, inter alia, for converting testosterone to estrogen.
Quercetin (3,3′, 4′, 5,7-pentahydroxyflavone) is a natural substance found in apples, onions, tea and red wine (like resveratrol, it is derived from grape skins). Quercetin has been shown to be an antioxidant. Cai et al., 1999,
Free Radical Biol. Med.
27: 822-829. Quercetin has been shown to be an efficacious agent for preventing and treating prostate cancer by workers at the Mayo Clinic. Xing et al., American Association for Cancer Research, 26
th
Annual Meeting, Mar. 26, 2001. Prostate cancer is the second leading cause of death in men, with 31,500 fatalities and 200,000 diagnoses per year. Quercetin is currently in therapeutic use for treating inflammatory diseases and disorders.
A major goal in the pharmacological arts has been the development of reagents and methods that reduce the necessity of administering therapeutic compounds, drugs and other agents invasively (i.e., such as by injection). Most preferably, it has been a consistent goal in the art to develop therapeutic compounds, drugs and agents and formulations thereof that permit oral administration (see, for example U.S. Pat. No. 4,963,526 to Ecanow issued Oct. 16, 1990), although other reduced-invasiveness formulations such as suppositories have also been developed. Among the various routes of drug administration, the oral intake of drugs is undoubtedly preferred because of its versatility, safety and patient comfort.
In addition, it has been a goal in the nutritional arts to develop preparations that increase transit of certain nutrients through the gastrointestinal tract to increase uptake and delivery of such nutrients into the bloodstream. In particular, such preparations have been developed to permit chemically-labile nutrients (such as vitamins and other sensitive compounds) to pass through the chemically-hostile environment of the stomach for absorption in the intestines (see, for example, U.S. Pat. No. 5,958,450 to Tashiro issued Sep. 28, 1999). Preparations having enhanced intestinal uptake have also been deemed desirable.
One approach known in the prior art for improving efficiency of delivery of therapeutic compounds, drugs and other agents has been to envelop such compounds in a specialized lipid structure termed a liposome (see, for example, U.S. Pat. No. 4,744,989 to Payne et al. issued May 17, 1988). Liposomes generically comprise an enclosed lipid droplet having a core, typically an aqueous core, containing the compound. In certain embodiments, the compound is chemically conjugated to a lipid component of the liposome. In other embodiments, the compound is simply con
EnzRel Inc.
Kishore Gollamudi S.
McDonnell Boehnen & Hulbert & Berghoff LLP
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