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Title:  Compositions for preventing hormone induced adverse effects
United States Patent: 
7,144,586
Issued: 
December 5, 2006

Inventors: 
Levy; Joseph (Omer, IL), Sharoni; Yoav (Omer, IL)
Assignee: 
Lycored Natural Products Industries Ltd. (Beer Sheva, IL)
Appl. No.: 
09/799,251
Filed: 
March 5, 2001


 

Outsourcing Guide


Abstract

A unit dosage form suitable for once daily administration to a human comprising a physiologically effective amount of at least one hormone selected from the group consisting of steroidal estrogen, estradiol, estrone, medroxyprogesterone, norethindrone, norethisterone, progestin, norgestrel, and progesterone, and at least one carotenoid wherein the carotenoid is in an amount effective to prevent the adverse effects which may result from the administration of the hormone.

OBJECTS AND SUMMARY OF THE INVENTION

The presently claimed compositions are useful for preventing the adverse effects associated with the administration of hormones. The compositions of the instant invention are in unit dosage form suitable for once daily administration to a human.

An object of the instant invention is to provide compositions for preventing adverse effects associated with the administration of phytoestrogens.

A further object of the present invention is to provide compositions for preventing adverse effects associated with the administration of steroidal hormones or progestins.

Yet another object of the instant invention is to provide compositions that are useful for preventing adverse effects associated with the administration of phytoestrogens, steroidal hormones or progestins, and that do not inhibit the beneficial activity of such hormones.

DETAILED DESCRIPTION OF THE INVENTION

As used throughout this specification, "hormone" refers to steroidal estrogens, progestins, and nonsteroid estrogens (phytoestrogens) derived from higher plants, as well as chemically modified derivatives, synthetic equivalents, and mixtures thereof.

As used throughout this specification, "steroidal estrogen" or "estrogen" refers to estradiol, estrone, estriol, synthetic equivalents, chemically modified derivatives, and mixtures thereof.

As used throughout this specification, "progestin" refers to agents that cause progesterone effects, such as, for example, progesterone, medroxyprogesterone, norethindrone, norethisterone, norgestrel, synthetic equivalents, chemically modified derivatives, and mixtures thereof.

As used throughout this specification, "phytoestrogen" refers to soy protein isoflavones, flavones, as well as the glucoside, malonylglucoside and acetylglucoside derivatives, synthetic equivalents, chemically modified derivatives, and mixtures thereof. Illustrative phytoestrogens include, for example, daidzein, genistein, and glycitein.

As used throughout this specification, "administration" or "administering" refers to the introduction to a subject by one or more of various routes, including oral ingestion, dermal, vaginal, intrauterine, intramuscular or intravenous injection.

Carotenoids useful for the instant invention comprise, but are not limited to, lycopene, alpha-carotene, beta-carotene, zeta-carotene, phytoene, phytofluene, lutein, zeaxanthin, cryptoxanthin astaxantine, and mixtures thereof. The carotenoids can be obtained from natural or synthetic sources or from genetically modified organisms.

The present invention provides compositions useful for preventing adverse effects associated with the administration of hormones. Such adverse effects include, for example, an increased risk for the development of cancer. The compositions of the instant invention are in a unit dosage form suitable for once daily administration to a human. The compositions comprise a physiologically effective amount of at least one hormone and at least one carotenoid in an amount effective to prevent such adverse effects. The instantly claimed compositions can prevent the adverse effects associated with the administration of hormones without inhibiting the beneficial activity of such hormones.

A single carotenoid as well as combinations and mixtures thereof can be used in the compositions of the present invention. It has surprisingly been found that various combinations of lycopene, phytoene and phytofluene demonstrate a beneficially synergistic effect in preventing the adverse effects associated with the administration of hormones. Accordingly, carotenoid mixtures of lycopene and phytoene; lycopene and phytofluene; and lycopene, phytoene, and phytofluene can be used in the presently claimed compositions. When administering such a mixture, a mixture of lycopene and phytoene is preferred.

Upon consuming phytoestrogen-containing products, the physiological concentration of these phytoestrogens in the subject's blood serum can reach levels of 0.4 to 4 M. FIG. 1 panel A demonstrates that incubation of ECC-1 endometrial cancer cells in the presence of the phytoestrogens genistein or daidzein, or a mixture of the two as occurs in soy extract, at such a concentration range, induces a significant increase in cell proliferation rate (indicated by cpm, counts per minute). Hence, subjects who reach these phytoestrogen concentrations increase their risk of certain types of cancer, inter alia, endometrial and mammary cancer.

FIG. 2 (see Original Patent) panel A demonstrates this effect by comparing the cell proliferation rate of cancer cells incubated in the presence of increasing concentrations of the phytoestrogen genistein both in the presence and absence of lycopene. It is clearly shown that the increased rate of cell proliferation induced by genistein is substantially inhibited by the presence of lycopene. The same effect is seen in both endometrial cancer cells (FIG. 2, upper graphs) and mammary cancer cells (FIG. 2, lower graphs) This inhibiting effect is further demonstrated in FIG. 4 (see Original Patent) where it can be clearly seen that not only lycopene, but also carotenoids such as astaxanthin, phytoene and beta-carotene are effective inhibitors of the cell proliferation induced by the phytoestrogen genistein.

Physiological concentrations of phytoestrogens to levels greater than about 10 MM can occur immediately following consumption of foodstuffs or dietary supplements comprising phytoestrogens. Such levels are greater than 0.4 to 4 M, which is the steady state physiological concentration range of phytoestrogens in humans who have consumed phytoestrogens. FIG. 1 (see Original Patent), panel B demonstrates that such transiently high concentrations of phytoestrogens can induce cell proliferation and thus increase the risk for cancer. FIG. 1, panel B demonstrates that incubation of ECC-1 endometrial cancer cells with 40 MM daidzein or genistein, or a mixture of the two as occurs in soy extract, significantly increases cell proliferation within the first day in culture. The inhibitory effect of the phytoestrogens was significant only from the second day of incubation. The compositions of the present invention operate to prevent the adverse effects of such elevated phytoestrogen levels which can occur immediately subsequent to consumption of phytoestrogen-containing products or compositions.

Co-administering at least one carotenoid to a phytoestrogen-consuming subject in an amount of about 2 mg per day attenuates the risk for cancer which is associated with the consumption of phytoestrogens. The present invention encompasses a unit dosage form suitable for once daily administration to a human comprising a physiologically effective amount of at least one phytoestrogen and at least one carotenoid, preferably in an amount of about 2 mg. Preferably, the carotenoid is in an amount sufficient to cause effective serum concentrations of said carotenoid of up to about 1.5 .mu.M.

Where the composition of the present invention comprises at least one phytoestrogen, the carotenoid is preferably one which does not exhibit substantial provitamin A activity. Carotenoids which do not exhibit substantial provitamin A activity include, for example, lycopene, zeta-carotene, phytoene, phytofluene, lutein, zeaxanthin, and astaxantine. Where the carotenoid comprises a mixture of carotenoids, such mixture preferably comprises lycopene and phytofluene; more preferably lycopene, phytofluene, and phytoene; most preferably lycopene and phytoene. A further embodiment of the instant invention is a unit dosage form suitable for once daily administration to a human comprising a physiologically effective amount of at least one hormone selected from the group consisting of steroidal estrogen, estradiol, estrone, medroxyprogesterone, norethindrone, norethisterone, progestin, norgestrel, and progesterone, and at least one carotenoid present in an amount effective to prevent the adverse effects which may result from the administration of such hormone. This unit dosage form can prevent the adverse effects associated with the administration of such hormones without inhibiting the beneficial activity of such hormones. Preferably, the carotenoid is in an amount from about 2 to about 10 mg, more preferably from about 2 to about 6 mg, most preferably about 2 mg. Preferably, the carotenoid is an amount sufficient to cause effective serum concentrations of said carotenoid of up to about 1.5 .mu.M. Where the carotenoid comprises a mixture of carotenoids, such mixture preferably comprises lycopene and phytofluene; more preferably lycopene, phytofluene, and phytoene; most preferably lycopene and phytoene.

The instantly claimed compositions that comprise at least one steroidal estrogen or progestin are particularly helpful for hormone replacement therapies used to treat menopause in women. Conventional hormone replacement therapies used to treat menopause can increase the risk for developing certain cancers. The compositions of the present invention can be used in hormone replacement therapies, while also preventing adverse effects such as the risk for developing cancer which can be associated with the administration of steroidal estrogens or progestins. The presently claimed compositions can prevent such adverse effects without inhibiting the beneficial activity of the hormones.

The compositions of the present invention can be used to prevent the additive adverse effects on cell proliferation incurred by elevated levels of the growth factor IGF-1 hormone intake in the presence of phytoestrogens. IGF-1 occurs naturally in the serum of normal individuals, but its occurrence at elevated levels significantly increases the risk for developing cancers of the breast, prostate, colon, or rectum. FIG. 3 (see Original Patent) panel A demonstrates that incubation of hormone dependent MCF-7 mammary cancer cells with both genistein (in the range from about 0.4 to 4 M) and IGF-1 (30 nM) significantly increases the cell proliferation rate, as compared to control cultures stimulated only with genistein. Addition of lycopene in the range of 3 to 5 MM inhibits the cell proliferation stimulated by the combined presence of IGF-1 and genistein. Accordingly, a composition of the instant invention comprising at least one phytoestrogen and at least one carotenoid, can be administered to a subject with elevated IGF-1 levels in order to prevent the additive adverse affects caused by such elevated IGF-1 levels.
 

Claim 1 of 10 Claims

1. A unit dosage form composition suitable for once daily administration to a human comprising active components which consist essentially of (1) a physiologically effective amount of at least one hormone selected from the group consisting of steroidal estrogen, estradiol, estrone, medroxyprogesterone, norethindrone, norethisterone, progestin, norgestrel, and progesterone, and (2) at least one carotenoid wherein said carotenoid is in an amount effective to prevent the adverse effects which may result from the administration of said hormone, said composition being substantially free of any other active components.

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