WO2001003687A2 - Procede et compositions d'inhibition de la biosynthese ou de la bioactivite d'hormones sexuelles steroidiennes endogenes chez des sujets humains - Google Patents

Procede et compositions d'inhibition de la biosynthese ou de la bioactivite d'hormones sexuelles steroidiennes endogenes chez des sujets humains Download PDF

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WO2001003687A2
WO2001003687A2 PCT/US2000/018909 US0018909W WO0103687A2 WO 2001003687 A2 WO2001003687 A2 WO 2001003687A2 US 0018909 W US0018909 W US 0018909W WO 0103687 A2 WO0103687 A2 WO 0103687A2
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compound
phytoestrogen
derivative
conjugate
phytosterol
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WO2001003687A3 (fr
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Claude L. Hughes, Jr.
Denis A. Magoffin
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Cedars Sinai Medical Center
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Cedars Sinai Medical Center
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives

Definitions

  • This invention relates to the medical arts.
  • the present invention relates to the field of hormone therapy and, more particularly, to the inhibition of steroidogemc biosynthesis and/or the bioactivity of steroid sex hormones.
  • Sex hormones include the female hormones (estrogens), m the form of female sex steroids, such as estradiol or estrone, and the male hormones (androgens), such as androstenedione and testosterone. These hormones are essential to the development of primary and secondary sexual characteristics. Estrogen provides women other physiological benefits. Women experiencing estrogen deficiency resulting from natural menopause, surgical removal of the ovaries, or ovarian failure resulting from chemotherapy, are known to be at higher than normal risk for atherosclerotic cardiovascular disease and osteoporosis. In addition, many postmenopausal women report reduced libido and sexual functioning.
  • Estrogen replacement therapy has long been used to prevent cardiovascular disease and osteoporosis in postmenopausal women and thus extend their life expectancy Androgens, such as testosterone, are also produced by a woman ' s healthy ovary, albeit the serum levels of androgen in women are normally much lower than those found m men. In women, androgens also play a role m promoting cardiovascular health. (P.M. Sarrel, Cardiovascular Aspects of Androgens in Women, Sem. Reprod. Endocrinol.
  • Androgens are essential for continued spermatogenesis, and in maintaining libido, positive mood, cognitive function, and skeletal and lean muscular mass and strength. Androgen replacement therapy is prescribed for hypogonadal men, who typically receive testosterone or a derivative (C Wang and R S Swerdloff, Androgen Replacement Therapy, Ann. Med. 29(4).365-70 [1997]) Androgen replacement therapy also leads to increased body weight and improved quality of life for men and women suffering from AIDS wasting. (K. Miller et al , Transdermal Testosterone Administration in Women with Acquired Immunodeficiency Syndrome Wasting. A Pilot Study, J. Clin. Endocrinol. Metab. 85(8).2717-25 [1998]; A.S. Dobs etal , Endocrine disorders in men infected with human immunodeficiency virus, Am. J Med. 84:61-15 [1988])
  • steroid sex hormones are associated with increased disease ⁇ sks.
  • estrogen produced endogenously or provided by ERT, is associated with an increased risk for cancers of the breast and endomet ⁇ um, endomet ⁇ osis, thromboembolic disease, gall bladder disease, and, in some cases, idiosyncratic increases in blood pressure, hypercalcemia, hypercoagulabihty, and hypert ⁇ glyce ⁇ demia.
  • Testosterone and androstenedione are also associated with increased breast cancer risk in women (A. Zelemuch-Jacotte et al , Relation of Serum Levels of Testosterone and Dehydroepiandrosterone Sulfate to Risk of Breast Cancer in Postmenopausal Women, Am J Epidemiol. 145(11).1030-38 [1997], F Berrmo et al , Serum Sex Hormone Levels After Menopause and Subsequent Breast Cancer, J Natl. Cancer Inst. 88(5):291-96 [1996]; J.F.
  • aromatizable androgens such as testosterone
  • can be converted to steroidal estrogens by aromatase activity D.F. Dimick et al , A comparative study of the metabolic fate of testosterone, 17a-methyl-testosterone, 19-nor-testosterone, 17a-methyl- 19-nor- testosterone and 17a-methyl ⁇ estr-5(10)-ene-17-b-OL-3-one ion normal males, Clin. Chim Acta 6:63-67 [1961]
  • the aromatase cytochrome P450 complex (E.C. 1.14.13; P450 ARQM , the product of the CYP19 gene, also known as estrogen synthetase) is a microsomal enzyme that catalyzes the synthesis of estrogens from aromatizable androgens. Specifically, aromatase catalyses three consecutive hydroxylation reactions that convert C-19 androgens to aromatic C-18 estrogemc steroids, for example, androstenedione to esrrone and testosterone to estradiol (Reviewed in S . Chen, Aromatase and Breast Cancer, Frontiers in Bioscience 3 :d922-d933 [ 1998]).
  • Aromatase is expressed m a tissue-specific manner. In premenopausal women aromatase is mainly expressed in the ovaries, but significant expression also occurs in breast tissue In postmenopausal women and in men, aromatase activity is much lower and concentrated m adipose tissue and skin cells. Aromatase is also expressed m the prostates of men with prostate cancer and BPH, as well as 5 ⁇ -reductase, the enzyme that catalyzes the conversion of testosterone to the androgenically more potent dihydrotestosterone (M Tsugaya et al.. Aromatase mRNA levels in benign prostatic hyperplasia and prostate cancer, Int. J. Urol.
  • Aromatase is expressed at higher levels m human breast cancer tissue than m normal breast tissue, and estrogens produced via aromatization in situ in breast tissue play a more important role in the development of breast cancer than circulating estrogen. In breast cancer cells, aromatase activity resulting m estrogen biosynthesis stimulates tumor growth in both an autocrme and a parac ⁇ ne manner.
  • aromatase inhibiting drugs have been used for prevention and treatment of breast cancer in cases where anti-estrogen therapy has been ineffective.
  • aromatase inhibitors include lmidazole derivatives, Letrozole, Vorozole, Anastrozole, substituted androstenedione derivatives, such as 4-hydroxyandrostened ⁇ one (LENTERON), and ammoglutethimide.
  • LENTERON 4-hydroxyandrostened ⁇ one
  • ammoglutethimide S. Chen [1998];K.S. Hirsch et al., Method of inhibiting aromatase, U.S. Patent No. 4,766,140; F. Lab ⁇ e et al., Aromatase inhibitors, U.S. Patent No. 5,227,375; K.
  • Nnmura et al. Method of inhibiting aromatase, U.S. Patent No. 5,547,973; A.J. Ka ⁇ alainen et al., Selective aromatase inhibiting compounds, U.S. Patent No. 5,703,109; F. Faustmi et al., Steroidic aromatase inhibitors, U.S. Patent No.4,771 ,043).
  • Ammoglutethimide is a non-specific aromatase inhibitor that also inhibits enzymatic activity by cytochrome P450 cholesterol side chain cleavage complex (P450 scc ; desmolase). (S. Chen [1998]).
  • This enzyme located on the inner mitochond ⁇ al membrane, catalyzes the first step of steroidogenesis leading to the biosynthesis of the steroid sex hormones, i.e., the conversion of cholesterol to pregnenolone and isocapraldehyde by sequential oxidations of the cholesterol side chain.
  • Phytoestrogens include lignan, isoflavone, flavone, and coumestan compounds, and their metabolites, such as equol.
  • the lignans, isoflavones, flavones, and coumestans have structures that are conformationally similar to the structure of 17- ⁇ -estrad ⁇ ol, thus they act as estrogen analogues with respect to estrogen receptor binding sites (C.L Hughes et al , Dietary soy phytoestrogens and the health of menopausal women overview and evidence of cardioprotectwn from studies in no- human primates, In: Progress in the Management of the Menopause, B.G Wren [ed.], The Parthenon Publishing Group, pp 30-39 [1997])
  • Some dietary phytoestrogens were also reported to reduce serum cholesterol and hypercholesterolemic atherosclerosis m mammals (K. Prasad, Reduction of serum cholesterol and hypercholesterolemic atherosclerosis in rabbits by secois
  • the lignans have core structural elements related to both the coumestans and the isoflavones, but their affinity for estrogen receptor binding sites is less than either of these or the flavones.
  • Naturally occurring lignans are obtained from numerous sources including, oilseed plants, such as sesame or lmseed, seaweeds, flax seed flour or defatted flax seed meal, whole legumes, legume hulls, cereal brans, whole gram cereals, vegetables, fruits, including nuts and berries. (L.U. Thompson et al , Mammalian lignan production from various foods, Nutr. Cancer 16(l):43-52 [1991]).
  • Sources ⁇ ch in coumestans include grapes and currants, wine, or apples.
  • Legumes and grains are ⁇ ch m dietary phytoestrogens, with soy content of the isoflavones genistein, daidzem, and their conjugates on the order of 3 mg/gram of soy protein.
  • Fermentation of isoflavone containing foods such as fermentation of soy to tempeh, decreases the total isoflavone content but increases the bioavailabihty of isoflavones.
  • A.M. Hutchms et al Urinary isoflavonoid phytoestrogen and lignan excretion after consumption of fermented and unfermented soy products, ] Am Diet. Assoc.
  • Kelly et al taught a method for treating or reducing the predisposition to benign breast disease, prostate cancer, or elevated serum cholesterol, by administering a composition comprising at least two phytoestrogens or phytoestrogen- de ⁇ ved isoflavones (Kelly et al , Health supplements containing phyto-oestrogens, analogues or metabolites thereof, U.S. Patent 5,830,887). Hughes et al described a pharmaceutical preparation for oral delivery of a combination of mammalian estrogen and soy-de ⁇ ved phytoestrogen to reduce the ⁇ sk of coronary heart disease and osteoporosis m women. (Hughes et al.
  • Plant sterols are another common dietary component that may have hormonal effects m humans A few plants contain modest levels of estrogemc (C, 8 ), androgemc (C 19 ), or progestagemc (C 21 ) steroids, but sterols with longer side chains (C 26 -C 30 ) are quite common, many having a structure similar to that of cholesterol, including campesterol, ⁇ -sitosterol, fucosterol, stigmasterol, stigmastanol, and stigmastadienone (Reviewed in C L Hughes, Plant Sterols are they mammalian reproductive hormones 7 , Sex Steroids 3(1) 285-91 [1992]) Dietary phytosterols are absorbed, transported and metabolized like cholesterol, they suppress circulating levels of free cholesterol in humans and other mammals, and thus may have a general positive effect on cardiovascular health (C B Kallen et al , Steroidogenic acute regulatory protein (StAR) is a sterol transfer protein, ] Biol
  • Thakkar et al taught a pharmaceutical preparation comprising a dispersible powder for oral administration consisting essentially of sitosterol (a form of phytosterol) and an excipient (Thakkar et al , Pharmaceutical dispersible powder of sitosterols and a method for the preparation thereof, U S Patent No 3,881,005)
  • Jandacek taught plant sterols with enhanced cholesterol-lowering properties in disclosing a food composition comp ⁇ smg at least one edible oil in admixture with a plant sterol (Jandacek, Edible oils having hypocholesterolemic properties, U S Patent No 5,865,939)
  • Weigand taught a method for reducing serum cholesterol and other hpids by administering a combination of sitosterol and a steroid compound (Weigand, Reducing cholesterol levels with sitosterols and cholamc acid, U S Patent No 3,852,440)
  • ⁇ -Sitosterol and other phytosterols are thought to act either as substrates or inhibitors of P450 scc and thus may affect the kinetics of cholesterol biosynthesis m a yet unknown manner; they are, therefore, thought to be likely modulators of steroidal hormone production. (C.L. Hughes [1992]). However, the effect of phytosterols has been thought to be p ⁇ ma ⁇ ly estrogemc.
  • the sterol content of vegetable oils ranges from 0.5% to 1%, and typical human consumption in Western countries is 150-250 mg of phytosterols per day, consequently, dietary phytosterols may be converted to a substantial amount of estradiol by endogenous steroidogenic metabolism or by intestinal bacte ⁇ a before abso ⁇ tion into the blood stream, posmg an increased ⁇ sk of breast and endometrial cancers.
  • ⁇ -Sitosterol was reported to bind to cytosohc estrogen receptor binding sites in rat liver and ute ⁇ ne cells in vitro and to have weak estrogemc effects at low dose upon rats m vivo. (E.R.
  • the present invention is directed to a method of inhibiting biosynthesis or bioactivity of endogenous steroid sex hormones in both men and women.
  • the method involves a combined administration of phytosterol(s) and phytoestrogen(s).
  • the invention is particularly beneficial in the prevention of breast and endometrial cancers in women, for which the estrogemc steroid, estradiol, is a known ⁇ sk factor
  • the method is applicable to adult premenopausal and postmenopausal women, including postmenopausal women receiving estrogen replacement therapy. Using the method, these women can continue to enjoy the benefits of improved cardiovascular and skeletal health, provided by ERT, with lower breast and endometrial cancer risks
  • the method is also beneficial to virtually all men over 50 years old in preventing or reducing benign prostatic hype ⁇ lasia
  • BPH prostatic cancer
  • the method provides cardiovascular benefits to both men and women from the activity of phytosterols and phytoestrogens m lowering serum cholesterol and in ameliorating dyshpidemia, shifting hpid profiles toward relatively higher HDL and lower LDL values.
  • the present invention is also related to pharmaceutical compositions useful for inhibiting the biosynthesis or bioactivity of endogenous steroid sex hormones m humans.
  • the pharmaceutical composition is formulated m a delivery system to deliver a dose of 50 to 250 mg of phytosterol compound(s) and 20 to 150 mg of phytoestrogen compound(s), at which beneficial levels there is essentially no toxic risk.
  • the present invention is directed to the combined use of phytosterol and phytoestrogen compounds in a method of inhibiting biosynthesis or bioactivity of an endogenous steroid sex hormone in a human subject.
  • the method involves administering to a human subject a combination of a dose of at least one phytosterol compound together with a dose of at least one phytoestrogen compound in an amount sufficient to inhibit the biosynthesis or bioactivity of an endogenous steroid sex hormone, such as an estrogen, for example, estradiol or estrone, or an aromatizable or non- aromatizable androgen, such as, androstenedione, dehydroepiandrosterone, testosterone, or dihydrotestosterone.
  • an endogenous steroid sex hormone such as an estrogen, for example, estradiol or estrone
  • an aromatizable or non- aromatizable androgen such as, androstenedione, dehydroepiandrosterone, testosterone, or dihydrotestosterone.
  • progestins for example, progesterone and 17-hydroxyprogesterone, that are precursors to estrogen and androgen biosynthesis.
  • the phytosterol(s) and phytoestrogen compound(s) are administered substantially simultaneously, such that effective amounts of phytosterol and phytoestrogen compounds, or their de ⁇ vatives, are present together in the human subject's serum for at least a pe ⁇ od of 1 to 8 hours daily, and most preferably 24 hours daily
  • the method involves admmiste ⁇ ng to a human subject a pharmaceutically acceptable composition of the present invention, containing a combination of at least one phytosterol compound and at least one phytoestrogen compound.
  • Useful phytosterol and phytoestrogen compounds are primarily derived from natural or transgenic plant sources. But some can also be derived from fungal sources, e.g., the isoflavones zearalenone and ⁇ -zearalenol, metabolites de ⁇ ved from the fungus Fusarium. Other useful steroidogenic biosynthesis-inhibiting or steroid bioactivity-mhibitmg phytosterol or phytoestrogen compounds are bacterial metabolites of plant- or fungus-derived phytosterol or phytoestrogen compounds.
  • bacte ⁇ al action m the mammalian gastrointestinal tract leads to conversion of various lignan species to enterodiol and enterolactone, which are the major lignan species found in human serum and excreted in human and other mammalian urine after ingestion of a va ⁇ ety of dietary lignans, e.g., matairesmol or secoisola ⁇ ciresinol diglycoside.
  • enterodiol and enterolactone are the major lignan species found in human serum and excreted in human and other mammalian urine after ingestion of a va ⁇ ety of dietary lignans, e.g., matairesmol or secoisola ⁇ ciresinol diglycoside.
  • phytoestrogen species obtained as bacte ⁇ al metabolites include aglycones of flavone and coumestan glucoside precursors.
  • aglycones of flavone and coumestan glucoside precursors include aglycones of flavone and coumestan glucoside precursors.
  • D.H. Kim et al Intestinal bacterial metabolism offlavonoids and its relation to some biological activities, Arch. Pharm. Res. 21 ( 1 ): 17-23 [ 1998] ; H. Schneider et al , Anaerobic transformation of quercetm-3-glycos ⁇ de by bacteria from the human intestinal tract, Arch Microbiol.
  • phytosterol compound or phytoestrogen compound is metabolized m any way or deconjugated m a human gastrointestinal tract before its entry into the blood stream does not limit the embodiments of phytosterol or phytoestrogen compounds that can be used m accordance with the present invention.
  • the present invention is not committed to any particular mechanism by which a particular compound operates to inhibit biosynthesis (steroidogenesis) or bioactivity of one or more steroid sex hormones.
  • the phytosterol compound(s) and phytoestrogen compound(s) are obtained commercially Alternatively, they are pu ⁇ fied from naturally occur ⁇ ng sources by known biochemical means. Synthetic or semi-synthetic versions or de ⁇ vatives of phytosterol or phytoestrogen compounds are also useful in the present pharmaceutical composition and methods of synthesis or de ⁇ vatization are known (E g., J.L. Belletire et al , The role of anwn coupling in the synthesis of d ⁇ enzylbutane lignans, J. Nat. Prod. 55(2).184-93 [1992]).
  • Useful phytosterol compounds include campesterol, sitosterol, fucosterol, stigmasterol, stigmastanol, or stigmastadienone.
  • a most preferred phytosterol compound is sitosterol .
  • ⁇ -sitosterol is preferred, but ⁇ - or ⁇ -sitosterol are also useful forms of sitosterol.
  • Other preferred phytosterol compounds include phytosterol de ⁇ vatives or conjugates, for example, the conjugate ⁇ -sitosterol- ⁇ - D-glucopyranoside. In the present pharmaceutical composition a mixture of phytosterol compounds can also be employed.
  • Useful phytoestrogen compounds include lignan compounds, isoflavone compounds, flavone compounds, or coumestan compounds, or derivatives, conjugates of any of these Phytoestrogens include free (unconjugated) or conjugated forms, for example, sulfated, or sulfonated phytoestrogen conjugates, or glucoside, glucuronide, or sulfoglucuronide phytoestrogen conjugates A mixture of phytoestrogen compounds can also be employed
  • Suitable lignan compounds include sesamm, justiciresinol, la ⁇ ciresinol, lsola ⁇ ciresmol. secoisolariciresinol, 0-demethylseco ⁇ sola ⁇ c ⁇ resmol, didemethylsecoisola ⁇ ciresinol, demethoxysecoisola ⁇ ciresinol, matairesmol, syrmgaresinol, episy ⁇ ngaresmol, diasy ⁇ ngaresinol, massoniresinol, h ⁇ oresinol, entrodiol, enterolactone, gomism A, gomisin C, gomism D, nordihydroguaiaretic acid, 3'-0-methyl nordihydroguaiaretic acid, arctigenin, or 3'-0- demethylarctigenm, or de ⁇ vatives or conjugates of any of these.
  • lignan conjugates examples include synngaresmol- ⁇ -D-glucoside, massoniresinol 4"-0- ⁇ -D-glucopyranos ⁇ de, secoisolariciresinol diglycoside, andramontoside, abutyrolactone lignan disaccha ⁇ de.
  • G. Brunner et al Enzymatic synthesis and chromatographic purification of lignan glucuronides, Biomed Chromatogr l(2).89-92 [1986]).
  • a most preferred phytoestrogen is an isoflavone compound.
  • Preferred are genistein, daidzem, biochanm A, glycitem, zearalenone, beta-zearalenol, formononetm, O-desmethylangolensm, lp ⁇ flavone, apigen , phloretm, baicalem, alpmumisoflavone, hydroxyalpmumisoflavone, or a de ⁇ vative or conjugate of any of these
  • An example of a useful phytoestrogen de ⁇ vative is equol, which is a metabolite de ⁇ ved primarily from daidzem.
  • Other useful de ⁇ vatives include dihydrodaidzem, tetrahydrodaidzem, dihydrogemstem, 2-dehydro-O-demethylangolens ⁇ n
  • the phytoestrogen is a flavone compound.
  • Useful examples include kaempferol, galangm, fisetm, mo ⁇ n, chrysin, tectochrysm (5-hydroxy-7-methoxyfiavone), lsoprunetm, wighteone, laburnetm, diosmetm, genistm, gemsteone, ephedroidm, baicahn, puera ⁇ n, poncmn, hespe ⁇ din, na ⁇ ngin, lsorhamnetin, norwogenm, 2,5-d ⁇ hydroxy-6,7-d ⁇ methoxyflavonone, and their derivatives and conjugates.
  • xanthohumol isoxanthohumol, desmethoxyxanthohumol, narmgenm, 6- and 8-prenylna ⁇ ngen ⁇ ns, 6-geranylna ⁇ ngenm, which are de ⁇ ved from hops and beer.
  • Useful flavone conjugates include flavone glucosides, for example, 7-methoxy-flavone-5-0- glucosides (E.g., A. Zahir et al , Five new flavone 5-O-glycos ⁇ des from Lethedon tannaensis lethesides and lethediosides, J. Nat. Prod.
  • flavone conjugate examples include kaempferol-3-O-beta-D-glucopyranos ⁇ de, ⁇ sorhamnet ⁇ n-4'-0- ⁇ -glucos ⁇ de, and flavonone sulfonates, for example, galangm-8-sulfonate, galangm-3-0-beta-D-glucos ⁇ de-8- sulfonate, and kaempferol-8-sulfonate.
  • the phytoestrogen compound is a coumestan compound(s).
  • Examples include coumestrol, quercetm, resveratrol, rutm, myricetin, luteolin, or derivatives or conjugates of any of these.
  • Examples of useful coumestan derivatives include 3-O-methylquercet ⁇ n and 3',4'-d ⁇ -0- benzyl-3 -O-methylquercetm.
  • useful coumestan conjugates include, for example, quercetm-3 -O- ⁇ -D-glucopyranoside, quercetm-4'-0- ⁇ -D-glucopyranos ⁇ de, quercetm-3,4-d ⁇ O- ⁇ -D-glucos ⁇ de, quercet ⁇ n-7-O- ⁇ -D-glucopyranos ⁇ de, 4-(G)- ⁇ -glucopyranosylrut ⁇ n (G-rutm)
  • any suitable method is used to determine that biosynthesis or bioactivity of endogenous steroid sex hormones has been inhibited.
  • "direct" measurements can be made of serum or other tissue-specific levels of steroid sex hormones, such as estradiol, estrone, estrone sulfate; testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate
  • "indirect” measurements can be made of hormone dependent markers in the blood plasma such as sex hormone binding globulin (bound or unbound) or prostate-specific antigen.
  • target tissue or “disease” measurements can be made of disease responses, for example, ultrasonic measurements showing the sh ⁇ nkage of ute ⁇ ne leiomyomata (fibroids) or diminished prostate size as determined by ultrasonic or digital exam, m response to treatment in accordance with the present method.
  • biopsy samples can be assayed for expression or activity of enzymes of the steroidogenic biosynthetic pathway, such as aromatase, P450 scc , 17-hydroxystero ⁇ d dehydrogenase, 17 ⁇ -hydroxylase/C 17 . 20 lyase, or 5 ⁇ -reductase, in specific tissues such as breast, uterus, prostate, or any other tissue of interest.
  • An effective dose for inhibiting biosynthesis or bioactivity of an endogenous steroid sex hormone in a human subject is an amount sufficient to inhibit the level of one or more steroid sex hormone(s) m serum or in a localized tissue, or to inhibit bioactivity (e.g., by specific receptor- mediated or non-receptor-mediated mechanisms ofbioactivity) of a steroid sex hormone, compared to the level or bioactivity m the subject before combined administration to the subject of phytosterol and phytoestrogen compound(s) in accordance with the present method.
  • a dose effective to inhibit biosynthesis (steroidogenesis) in a human subj ect is an amount sufficient to reduce expression or activity of aromatase, P450 scc , 17-hydroxystero ⁇ d dehydrogenase, 17 ⁇ -hydroxylase/C 17 . 2Q lyase, 5 ⁇ - reductase, or other enzyme of the steroidogenic pathway, m a tissue of the subject, for example, breast or prostate tissue.
  • the effective dose for each human subject will depend upon the size and physiologic reactions of the subject to whom or to which the pharmaceutical preparations of the present invention are administered, and these reactions to the administered dose can be monitored by the presc ⁇ bmg physician
  • a phytosterol compound is delivered in an effective dose of 1 to 5 milligrams per kilogram of body weight per day
  • the phytoestrogen compound is delivered in a dose of 0.5 to 2 milligrams per kilogram of body weight per day
  • the phytosterol and phytoestrogen compounds are administered by any suitable method. Representative methods include giving, providing, feeding or force-feeding, dispensing, inserting, prescribing, furnishing, treating with, taking, swallowing, eating or applying a pharmaceutical composition of the present invention.
  • a preferred embodiment of the present method involves a systemic delivery route, i.e., a route whereby delivery of a phytosterol compound and a phytoestrogen compound are delivered to body tissues p ⁇ ma ⁇ ly via the blood stream. Entry of phytosterol and phytoestrogen compounds into the blood stream of a human can occur by any route, system, device, method or mechanism
  • a systemic delivery route can also include delivery through the skin, mucosa or epithelium of the mouth including the subhngual epithelium, the rectum, or the vaginal epithelium.
  • Systemic delivery systems include, but are not limited to, ingestion, injection, or intravenous drip, most conventionally.
  • a preferred ingestive delivery system is a pharmaceutically acceptable food additive or food supplement for humans, formulated as a powder, tablet, capsule or caplet.
  • Other useful systemic delivery systems are known and include, but are not limited to, implant; adhesive transdermal patches; topical creams, gels or ointments for transdermal delivery; transmucosal delivery mat ⁇ ces or supposito ⁇ es or gels. It is contemplated that the compositions of the present invention are formulated to deliver an effective dose of a phytosterol compound and a phytoestrogen compound by these or any other pharmaceutically acceptable systemic delivery system.
  • the present invention also relates to a pharmaceutical composition comp ⁇ smg a combination of at least one phytosterol compound and at least one phytoestrogen compound.
  • the pharmaceutical composition of the present invention can optionally contain pharmaceutically acceptable solvent(s), adjuvant(s) or non- medicinal car ⁇ er(s), bmder(s), th ⁇ ckener(s), or filler substance(s) that are known to the skilled artisan Common fillers include, but are not limited to, sucrose or lactose, or polyme ⁇ c substances like starch
  • additional medicinal or nutritive additives in combination with a phytosterol and phytoestrogen compound as may be desired to suit the more particular needs of the practitioner.
  • the present pharmaceutical composition can be formulated and manufactured at more than one concentration, such that modular incremental amounts of phytosterol compound(s) and phytoestrogen compound(s) are easily administered.
  • the composition is formulated in a delivery system to deliver a dose of 50 to 250 mg of phytosterol compound(s) and 20 to 150 mg of phytoestrogen compound(s).
  • the composition is formulated in a delivery system to deliver a dose of 175 to 225 milligrams of the phytosterol compound(s) and 75 to 125 milligrams of the phytoestrogen compound(s) These preferred dose ranges provide beneficial effect with essentially no toxic risk
  • a preferred embodiment of the present pharmaceutical composition is formulated for a systemic delivery system such as, but not limited to, mgestive, injection, or intravenous d ⁇ p systems.
  • a preferred mgestive dehvery system is a pharmaceutically acceptable food additive or food supplement for humans, formulated as a powder, tablet, capsule or caplet.
  • Another preferred embodiment of the present pharmaceutical composition is a topical cream, ointment or gel to be applied to the skin.
  • a composition of the present invention comp ⁇ ses a phytosterol compound and a phytoestrogen compound in a pharmaceutically acceptable delivery system comp ⁇ smg a permeation or penetration enhancer, such as polyethylene glycol monolaurate, dimethyl sulfoxide, N-vmyl-2-pyrrol ⁇ done, N-(2-hydroxyethyl)-pyrrol ⁇ done, or 3- hydroxy-N-methyl-2 -pyrrolidone.
  • a va ⁇ ety of conventional thickeners often used in creams, ointments and gels, such as, but not limited to, algmate, xanthan gum, or petrolatum, may also be employed in this embodiment of a composition of the present invention.
  • composition of the present invention is a formulation for systemic transmucosal delivery of a phytosterol compound and a phytoestrogen compound.
  • a va ⁇ ety of pharmaceutically acceptable systems for transmucosal delivery of therapeutic agents are known in the art and are compatible with the practice of the present invention. (Heiber et al , Transmucosal delivery of macromolecular drugs, U.S. Pat. Nos. 5,346,701 and 5,516,523; Longenecker et al. , Transmembrane formulations for drug administration, U.S. Pat. No.4,994,439).
  • Transmucosal delivery devices may be in free form, such as a cream, gel, or ointment, or may comp ⁇ se a determinate form such as a tablet, patch, or troche.
  • delivery of a phytosterol compound and a phytoestrogen compound may be via a transmucosal delivery system comp ⁇ smg a laminated composite of, for example, an adhesive layer, a backing layer, a permeable membrane defining a reservoir containing a phytosterol compound and a phytoestrogen compound, a peel seal disc underlying the membrane, one or more heat seals, and a removable release lmer.
  • a transmucosal delivery system comp ⁇ smg a laminated composite of, for example, an adhesive layer, a backing layer, a permeable membrane defining a reservoir containing a phytosterol compound and a phytoestrogen compound, a peel seal disc underlying the membrane, one or more heat seals, and a removable release lmer.
  • a tablet or patch for delivery through the oral mucosa can comp ⁇ se an inner layer containing the therapeutic agent of choice, a permeation enhancer, such as a bile salt or fusidate, and a hydrophi c polymer, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, dextran, pectin, polyvmyl pyrrolidone, starch, gelatin, or any of a number of other polymers known to be useful for this pu ⁇ ose.
  • a permeation enhancer such as a bile salt or fusidate
  • a hydrophi c polymer such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, dextran, pectin, polyvmyl pyrrolidone, starch, gelatin, or any of a number of other polymers known to be useful for this pu ⁇ ose.
  • This inner layer can have one surface adapted to contact and adhere to the moist mucosal tissue of the oral cavity and may have an opposing surface adhering to an overlying non-adhesive inert layer.
  • a transmucosal delivery system can be in the form of a bilayer tablet, in which the inner layer also contains additional binding agents, flavoring agents, or fillers.
  • Some useful systems employ a non-ionic detergent along with a permeation enhancer.
  • composition of the present invention is a gel for systemic delivery of a phytosterol compound and a phytoestrogen compound via the rectal or vaginal mucosa, similar to gels commonly used for the delivery of va ⁇ ous other therapeutic agents.
  • Hydrogel mat ⁇ ces are known for this pu ⁇ ose. (Feijen, Biodegradable hydrogel matrices for the controlled release of pharmacologically active agents , U.S. Pat. No.4,925,677).
  • Such biodegradable gel mat ⁇ ces can be formed, for example, by cross-linking a protemaceous component and a polysaccha ⁇ de or mucopolysaccha ⁇ de component, then loading with a phytosterol compound and a phytoestrogen compound to be delivered.
  • Another preferred embodiment of the composition of the present invention is the systemic delivery of a phytosterol compound and a phytoestrogen compound via a biodegradable matrix implanted within the body or under the skin of a human or non-human vertebrate.
  • the implant mat ⁇ x may be a hydrogel similar to those desc ⁇ bed above Alternatively, it may be formed from a poly- alpha-ammo acid component.
  • Transdermal delivery systems can be of any number of va ⁇ eties known in the art.
  • delivery of a phytosterol compound and a phytoestrogen compound can be via a transdermal delivery system comp ⁇ smg a laminated composite of an adhesive layer, a backing layer, a permeable membrane defining a reservoir containing a phytosterol compound and a phytoestrogen compound, a peel seal disc underlying the membrane, one or more heat seals, and a removable release liner.
  • a transdermal delivery system comp ⁇ smg a laminated composite of an adhesive layer, a backing layer, a permeable membrane defining a reservoir containing a phytosterol compound and a phytoestrogen compound, a peel seal disc underlying the membrane, one or more heat seals, and a removable release liner.
  • a transdermal delivery device can be a matrix type transdermal patch.
  • a matrix type transdermal patch can be Transdermal estrogen/progestin dosage unit, system and process, U.S. Pat. Nos 4,906, 169 and 5,023,084, Cleary etal., Diffusion matrix for transdermal drug administration and transdermal drug delivery devices including same, U.S. Pat. No. 4,911,916; Mollaud et al, EVA-based transdermal matrix system for the administration of an estrogen and/or a progestogen, U.S. Pat. No. 5.605,702, Venkateshwaran et al, Transdermal drug delivery matrix for coadministering estradiol and another steroid, U S. Pat.
  • the matrix of the patch can comprise a basal support layer, such as an acrylic or ethylene/vmyl acetate copolymer or a polyurethane foam or cellulosic material, and an adhesive, such as, but not limited to, polysiloxane
  • the polymer matrix also contains a phytosterol compound and a phytoestrogen compound, as desc ⁇ bed above, and optionally, a penetration- enhancing vehicle or earner, such as N-vmyl-2-pyrrohdone, N-(2-hydroxyethyl)-pyrrohdone, or 3- hydroxy-N-methyl-2-pyrrol ⁇ done.
  • the adhesive patch may be pressure-sensitive, to release the phytosterol compound and a phytoestrogen compound across the skm of the patient when the patch matrix has been applied to the skm.
  • the patch may optionally comprise an inert backing layer m addition to a matrix layer, or can comp ⁇ se multiple dosage units or layers.
  • the present pharmaceutical compositions in accordance with the present method of inhibiting biosynthesis or bioactivity of an endogenous steroid sex hormone in a human subject, the process of steroidogenic biosynthesis of sex steroids is inhibited and/or the bioactivity of one or more endogenous steroid sex hormone(s) is inhibited (or reduced).
  • the present invention provides the benefits of lowered ⁇ sk with respect to cancers of the breast, endomet ⁇ um, and prostate, and of BPH, while simultaneously preserving the benefits to cardiovascular and skeletal health, libido and energy, and cognitive function that are associated with aromatizable androgens and estrogens.

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Abstract

L'invention se rapporte à un procédé et à des compositions d'inhibition de la biosynthèse ou de la bioactivité d'hormones sexuelles stéroïdes endogènes chez des sujets humains mâles et femelles. Ledit procédé consiste à administrer une combinaison d'un ou de plusieurs phytostérols et d'un ou de plusieurs phytoestrogènes dans le but d'inhiber l'activité enzymatique dans la voie biosynthétique stéroïdogène qui assure la transformation des progestatifs stéroïdes et des androgènes en hormones stéroïdiennes plus puissantes, telles que l'oestradiol et la dihydrotestostérone. L'invention se rapporte également à une composition pharmaceutique destinée à inhiber la biosynthèse ou la bioactivité d'hormones sexuelles stéroïdes endogènes chez des sujets humains. La composition pharmaceutique est formulée dans un système d'administration délivrant une dose de 50 à 250 mg d'un ou de plusieurs phytostérols, du type campestérol, sitostérol, fucostérol, stigmastérol, stigmastanol ou stigmastadiénone, ou d'un dérivé ou conjugué d'un de ces composés, et de 20 à 150 mg d'un ou de plusieurs phytoestrogènes du type composé(s) de lignane, isoflavone, flavone ou coumestane.
PCT/US2000/018909 1999-07-13 2000-07-12 Procede et compositions d'inhibition de la biosynthese ou de la bioactivite d'hormones sexuelles steroidiennes endogenes chez des sujets humains Ceased WO2001003687A2 (fr)

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EP1190630A1 (fr) * 2000-09-22 2002-03-27 Unilever N.V. Utilisation de prényle de flavones
WO2002074315A1 (fr) * 2001-03-21 2002-09-26 Schering Aktiengesellschaft Preparations pharmaceutiques combinees renfermant des inhibiteurs de l'aromatase et des substances a activite oestrogenique et leur utilisation dans la production d'un medicament pour l'oestrogenotherapie de substitution
WO2002076241A1 (fr) * 2001-03-23 2002-10-03 N.V. Nutricia Preparation destinee a la prevention et/ou au traitement de metabolisme osseux modifie
US6589982B2 (en) 2000-09-22 2003-07-08 Lipton, Division Of Conopco, Inc. Use of prenylated flavones
EP1360959A1 (fr) * 2002-05-10 2003-11-12 Schering Aktiengesellschaft Utilisation des 8-prénylflavanones pour la thérapie anti-angiogénèse et la thérapie fibrinolitique
WO2004000304A1 (fr) * 2002-06-19 2003-12-31 Hormos Medical Corporation Formulation de lignane
WO2003100092A3 (fr) * 2002-05-28 2004-10-14 Evotec Neurosciences Gmbh Utilisation diagnostique et therapeutique de cyp11a1 pour des maladies de neurodegenerescence
EP1618875A4 (fr) * 2003-04-08 2006-05-24 Kirin Brewery Composition destinee a l'inhibition ou a la prevention de la baisse de la densite osseuse et boisson correspondante
DE102007029042A1 (de) * 2007-06-21 2008-12-24 Analyticon Discovery Gmbh Pharmazeutische Zusammensetzung mit einem Trihydroxychromenone-Derivate
EP2025335A1 (fr) * 2007-08-16 2009-02-18 InterMed Discovery GmbH Extraits contenant des modulateurs du récepteur X hépatique, composés et leur utilisation dans le contrôle du poids et traitement des troubles du métabolisme lipidique
WO2009003838A3 (fr) * 2007-07-05 2009-03-19 Unilever Nv Composition comprenant des polyphénols
WO2009003832A3 (fr) * 2007-07-05 2009-03-19 Unilever Nv Composition comprenant des polyphénols
US7723053B2 (en) 2001-11-20 2010-05-25 Allergan, Inc. High-throughput screen for identifying selective persistent sodium channels channel blockers
US7736677B2 (en) * 2001-06-20 2010-06-15 Metaproteomics, Llc Xanthohumol and tetrahydro-isoalpha acid based protein kinase modulation cancer treatment
FR2940123A1 (fr) * 2008-12-22 2010-06-25 Granions Lab Des Association de composes pour le traitement ou la prevention des bouffees de chaleur et des sueurs engendrees par la menopause
JP2012092138A (ja) * 2011-12-27 2012-05-17 Maruzen Pharmaceut Co Ltd 皮膚化粧料及び頭髪化粧料
JP2012121913A (ja) * 2012-03-05 2012-06-28 Maruzen Pharmaceut Co Ltd 皮膚化粧料及び頭髪化粧料
US20140023618A1 (en) * 2012-07-23 2014-01-23 Applied Biology Systems and methods for treatment of androgenetic skin conditions by microbial organisms
CN106404955A (zh) * 2016-09-10 2017-02-15 长治市食品药品检验所 一种测定高粱红色素中槲皮素‑7‑葡萄糖苷含量的方法
CN106822091A (zh) * 2017-02-14 2017-06-13 天津中医药大学 山奈酚在制备用于预防和/或治疗由睾酮水平过高引起的疾病的药物中的用途
IT201700027628A1 (it) * 2017-03-13 2018-09-13 Neilos S R L Composizione per uso nella riduzione della crescita dei peli
KR20190103617A (ko) * 2018-02-28 2019-09-05 전북대학교산학협력단 플라보노이드 유도체 및 이리도이드 유도체로 구성된 화합물 조합을 유효성분으로 함유하는 남성 호르몬장애 또는 갱년기 예방 및 치료용 조성물
CN114984126A (zh) * 2022-07-15 2022-09-02 深圳德荫堂生物科技有限公司 一种适用女性补充荷尔蒙的生物药剂及生产方法

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US5523087A (en) * 1995-02-15 1996-06-04 Bio-Virus Research Incorporated Pharmaceutical compositions for the treatment of diabetic male sexual dysfunction
WO1998021946A1 (fr) * 1996-11-18 1998-05-28 Internutria, Inc. Composition et traitement des symptomes de transition reproductive persistante

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US6589982B2 (en) 2000-09-22 2003-07-08 Lipton, Division Of Conopco, Inc. Use of prenylated flavones
EP1190630A1 (fr) * 2000-09-22 2002-03-27 Unilever N.V. Utilisation de prényle de flavones
US7179837B1 (en) 2000-09-22 2007-02-20 Lipton, Division Of Conopco, Inc. Use of prenylated flavones
WO2002074315A1 (fr) * 2001-03-21 2002-09-26 Schering Aktiengesellschaft Preparations pharmaceutiques combinees renfermant des inhibiteurs de l'aromatase et des substances a activite oestrogenique et leur utilisation dans la production d'un medicament pour l'oestrogenotherapie de substitution
WO2002076241A1 (fr) * 2001-03-23 2002-10-03 N.V. Nutricia Preparation destinee a la prevention et/ou au traitement de metabolisme osseux modifie
US7736677B2 (en) * 2001-06-20 2010-06-15 Metaproteomics, Llc Xanthohumol and tetrahydro-isoalpha acid based protein kinase modulation cancer treatment
US7723053B2 (en) 2001-11-20 2010-05-25 Allergan, Inc. High-throughput screen for identifying selective persistent sodium channels channel blockers
EP1360959A1 (fr) * 2002-05-10 2003-11-12 Schering Aktiengesellschaft Utilisation des 8-prénylflavanones pour la thérapie anti-angiogénèse et la thérapie fibrinolitique
WO2003094910A1 (fr) * 2002-05-10 2003-11-20 Schering Aktiengesellschaft Utilisation de 8-prenylflavanones pour des therapies anti-angiogenese et fibrinolytique
WO2003100092A3 (fr) * 2002-05-28 2004-10-14 Evotec Neurosciences Gmbh Utilisation diagnostique et therapeutique de cyp11a1 pour des maladies de neurodegenerescence
US7582677B2 (en) 2002-06-19 2009-09-01 Hormos Medical Corp. Lignan formulations
WO2004000304A1 (fr) * 2002-06-19 2003-12-31 Hormos Medical Corporation Formulation de lignane
EP1618875A4 (fr) * 2003-04-08 2006-05-24 Kirin Brewery Composition destinee a l'inhibition ou a la prevention de la baisse de la densite osseuse et boisson correspondante
DE102007029042A1 (de) * 2007-06-21 2008-12-24 Analyticon Discovery Gmbh Pharmazeutische Zusammensetzung mit einem Trihydroxychromenone-Derivate
WO2009003838A3 (fr) * 2007-07-05 2009-03-19 Unilever Nv Composition comprenant des polyphénols
WO2009003832A3 (fr) * 2007-07-05 2009-03-19 Unilever Nv Composition comprenant des polyphénols
WO2009021622A1 (fr) * 2007-08-16 2009-02-19 Intermed Discovery Gmbh Extraits contenant des modulateurs des récepteurs hépatiques x, composés et leur utilisation, notamment dans la maîtrise du poids
EP2025335A1 (fr) * 2007-08-16 2009-02-18 InterMed Discovery GmbH Extraits contenant des modulateurs du récepteur X hépatique, composés et leur utilisation dans le contrôle du poids et traitement des troubles du métabolisme lipidique
JP2010536720A (ja) * 2007-08-16 2010-12-02 インターメッド・ディスカバリー・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 肝臓ｘ受容体モジュレーターと組み合わせた抽出物、化合物および特に体重管理におけるそれらの使用
FR2940123A1 (fr) * 2008-12-22 2010-06-25 Granions Lab Des Association de composes pour le traitement ou la prevention des bouffees de chaleur et des sueurs engendrees par la menopause
JP2012092138A (ja) * 2011-12-27 2012-05-17 Maruzen Pharmaceut Co Ltd 皮膚化粧料及び頭髪化粧料
JP2012121913A (ja) * 2012-03-05 2012-06-28 Maruzen Pharmaceut Co Ltd 皮膚化粧料及び頭髪化粧料
US20140023618A1 (en) * 2012-07-23 2014-01-23 Applied Biology Systems and methods for treatment of androgenetic skin conditions by microbial organisms
WO2014018549A3 (fr) * 2012-07-23 2014-04-10 Applied Biology, Inc. Systèmes et procédés de traitement d'états de peau androgénétique par des organismes microbiens
CN106404955A (zh) * 2016-09-10 2017-02-15 长治市食品药品检验所 一种测定高粱红色素中槲皮素‑7‑葡萄糖苷含量的方法
CN106404955B (zh) * 2016-09-10 2019-12-17 长治医学院 一种测定高粱红色素中槲皮素-7-葡萄糖苷含量的方法
CN106822091A (zh) * 2017-02-14 2017-06-13 天津中医药大学 山奈酚在制备用于预防和/或治疗由睾酮水平过高引起的疾病的药物中的用途
IT201700027628A1 (it) * 2017-03-13 2018-09-13 Neilos S R L Composizione per uso nella riduzione della crescita dei peli
WO2018167657A1 (fr) * 2017-03-13 2018-09-20 Neilos S.r.l. Composition destinée à être utilisée dans la réduction de la pousse des poils
KR20190103617A (ko) * 2018-02-28 2019-09-05 전북대학교산학협력단 플라보노이드 유도체 및 이리도이드 유도체로 구성된 화합물 조합을 유효성분으로 함유하는 남성 호르몬장애 또는 갱년기 예방 및 치료용 조성물
WO2019168324A1 (fr) * 2018-02-28 2019-09-06 전북대학교산학협력단 Composition pour la prévention et le traitement de troubles hormonaux ou d'andropause chez les hommes, contenant, en tant que principe actif, une combinaison de composés comprenant des dérivés flavonoïdes et des dérivés iridoïdes, et leur utilisation
CN114984126A (zh) * 2022-07-15 2022-09-02 深圳德荫堂生物科技有限公司 一种适用女性补充荷尔蒙的生物药剂及生产方法

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