US 2014.0099368A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0099368 A1 Heger et al. (43) Pub. Date: Apr. 10, 2014

(54) DOSAGE FORMS OF ACTIVE INGREDIENTS (30) Foreign Application Priority Data CONTAINING HYDROXYSTILBENE FOR TREATING MENOPAUSAL COMPLAINTS Feb. 4, 2005 (DE) ...... 102005OO52681 Feb. 4, 2005 (DE) ...... 102005OO5271.1 (71) Applicants: Peter Heger, Ubstadt-Weiher (DE): Reinhard Rettenberger, Goppingen Publication Classification (DE); Carl-Friedrich Spaich, Heiningen (DE) (51) Int. Cl. A63L/05 (2006.01) (72) Inventors: Peter Heger, Ubstadt-Weiher (DE): A61E36/36 (2006.01) Reinhard Rettenberger, Goppingen A619/28 (2006.01) (DE); Carl-Friedrich Spaich, Heiningen (52) U.S. Cl. (DE) CPC ...... A61 K3I/05 (2013.01); A61 K9/2886 (2013.01); A61K 36/36 (2013.01) (21) Appl. No.: 13/949,805 USPC ...... 424/479; 424/474; 424/773: 435/375; (22) Filed: Jul. 24, 2013 514/25; 514/720; 514/733 Related U.S. Application Data (57) ABSTRACT (63) Continuation of application No. 13/445,087, filed on The invention provides novel hydroxyStilbene-containing Apr. 12, 2012, now abandoned, which is a continuation dosage forms, processes for producing these dosage forms of application No. 1 1/883,667, filed on Apr. 25, 2008, and the use thereof for the treatment of menopausal Symp now Pat. No. 8,168.220, filed as application No. PCT/ toms in women, juvenile oligomenorrhea and dysmenorrhea, EP2006/000.957 on Feb. 3, 2006. primary and secondary amenorrhea or endometritis. Patent Application Publication Apr. 10, 2014 Sheet 1 of 3 US 2014/0099368A1

Piceatanno Resveratrol FIG. 1

1 OO M ------Resveratrol -- - - Estradiol PiCeaten no 80 -a- - - Rhapontigenin -HDeoxyrhapontigenin 70 -0----- cls-Rhapontigenin -- ERr 731 extraCt 60 D 50 C SS 40 30 20 10 O cy) CN w O C CO N. CO r cy SN M v \, \, \, GP GP G G. G. G. G. G. O O O O O O O O O O O O O o o d d d d d d d d d

F G. 2 Patent Application Publication Apr. 10, 2014 Sheet 2 of 3 US 2014/0099368A1

E2 N Rhapontigenin In Deoxyrhapontigenin 250 El cis-Rhapontigenin Resveratrol Piceatanno 2OO Z Rh. Rha. extract <=*= LOOLO L S S NNNNNNNNNNNNN |RSS Ositive ZZZZZZZZZZZZZZZZZZZ C-8 E-7 ZZZZZZZZZZZZZZZZZZOE-08 %, NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN Of-5NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN OOOO ControZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZ FIG. 3

O. 14 O. 12 O 1 O

s

OOO

CN 3 24 Time after intake of ERr 7318 (h) FIG. 4 Patent Application Publication Apr. 10, 2014 Sheet 3 of 3 US 2014/0099368A1

US 2014/0099368 A1 Apr. 10, 2014

DOSAGE FORMS OF ACTIVE INGREDIENTS 0005. The estrogen receptor (ER) mediates the activity of CONTAINING HYDROXYSTILBENE FOR estrogens in regulating a number of important physiological TREATING MENOPAUSAL COMPLAINTS processes, including the development and function of the female reproductive system. Whereas stimulation of pro 0001. This application is a continuation of U.S. applica cesses in these tissues has important health advantages, the tion Ser. No. 1 1/883,667, Allowed, which is the U.S. national cancer risk may be increased by Stimulation of other tissues phase application, pursuant to 35 U.S.C. S371, of PCT inter Such as the breast and the uterus, especially in the pen- and national application Ser. No. PCT/EP2006/000957, filed Feb. postmenopause. The ER family comprises two Subtypes, 3, 2006, designating the United States and published in Ger namely ERC. and ERB. Studies with ER-selective knockout man on Aug. 10, 2006 as publication WO 2006/082073 A1, mice have shown that the typical unwanted estrogen effects which claims priority to German application Ser. Nos. DE 10 Such as endometrial hyperplasia and breast cancer are medi 2005 005 268.1, filed Feb. 4, 2005 and DE 10 2005 005 271.1, ated by ERC, or as ERB acts as a negative regulator of ERC. filed Feb. 4, 2005. The entire contents of the aforementioned and is important for protecting against hyperproliferation and patent applications are incorporated herein by this reference. carcinogenesis in tissues in which both receptors are coex 0002 The invention relates to novel hydroxy stilbene-con pressed (Hewitt et al. Breast Cancer res 2003: 2: 345-352, taining dosage forms, processes for, producing these dosage Frasor et al. Endocrinology 2003: 144: 3159-3166, Lindberg forms and the use thereof for the treatment of menopausal et al. Mol Endocrinol 2003; 17:203-208). symptoms in women, juvenile oligomenorrhea and dysmen 0006 Based on the results of clinical and experimental orrhea, primary and secondary amenorrhea or endometritis. studies, increasing numbers of women refuse to use HRT for their menopausal symptoms. In addition, HRT is not indi cated for treating women who already have an endocrine BACKGROUND OF THE INVENTION dependent tumor, or show a high cancer risk, especially breast 0003. The menopause is an impairment of ovarian func cancer and endometrial cancer. For these reasons, novel tion accompanied by high levels of follicle-stimulating hor active ingredients for treating menopausal symptoms which mone (FSH) and lower levels of estradiol (E2). The time up to are free of the potential risks associated with HRT, especially the last menstruation is also referred to as “perimenopause'. also on long-term use, are very desirable. During this period, most women notice cycle irregularities 0007. There are a number of so-called phytoestrogens which last for 1 to 5 years. In most western countries, about which have claims to be effective in relation to reducing hot 80% of peri- and postmenopausal women suffer from hot flushes and sweating episodes. For most of these herbal prod flushes, in about 30% of them the hot flushes are so severe and ucts, the results of clinical studies, where in fact available, are frequent that the quality of life is noticeably impaired thereby. contradictory or show no efficacy by comparison with pla The exact physiological cause of hot flushes is unknown cebo. In addition, some constituents of these products may (Ginsburg, Obstetrics and Gynecology Clinics of North have an estrogenic activity despite their relatively weak bind America 1994; 21 (2): 381-390). Hot flushes follow a release of gonadotropin-releasing hormone (GnRH) from the hypo ing affinity for ERC. (e.g. genistein, coumestrol, equol and thalamus and are not linked to changes in the level of estradiol Zearalenone; Müller et al. Toxicol. Sci. 2004; 80: 14-25) and and estrone. They are accompanied by the release of lutein thus represent the risks similar to HRT. It has in fact been izing hormone (LH), corticotrophin, growth hormone and observed that long-term treatment with soya phytoestrogens 3-lipotrophin from the pituitary and of dehydroepiandroster led to endometrial hyperplasia (Unferet al., Fertil Steril 2004: one and androstenedion from the adrenal. FSH levels may 82: 145-148). These observations cast doubt on the long-term vary between normal and high (>20 IU/l). safety of phytoestrogens, especially in relation to the 0004 Hormone replacement therapy (HRT) replaces the endometrium. two female sex steroids estrogen and progesterone. HRT was 0008. There is thus a great need for novel active ingredi employed for many years for the treatment of menopausal ents or active ingredient combinations for treating meno symptoms and for preventing cardiovascular disorders and pausal symptoms which do not bind to ERC, i.e. are not osteoporosis in the peri- and postmenopause. It was regarded procarcinogenic, and do not promote the development of as effective and safe. However, this is no longer true since cardiovascular disorders. large randomized controlled studies were carried out and 0009. Since 1993, a dry extract of roots of Rheum rhapon showed the contrary (Beral et al., Lancet 2002: 360:942-944, ticum has been on the market in Germany under the name Collaborative Group, Lancet 1997; 359: 1047-1059). HRT Extrakt Rheum rhaponticum (ERr 731(R) (proprietary name has no positive effect on the incidence and progression of Phytoestrol(R) N) for follicle hormone replacement therapy, coronary heart disease. There is in fact evidence that it for example for treating women with menopausal symptoms, increases the risk of cardiovascular disorders in pen- and post juvenile oligomenorrhea and dysmenorrhea, primary and menopausal women. In a randomized, placebo-controlled secondary amenorrhea, and endometritis. The constituents of double-blind study of primary prevention with estrogen plus the specific ERr 731(R) extract are rhaponticin, deoxyrhapon progestin, carried out by the Women's Health Initiative ticin, rhapontigenin and deoxyrhapontigenin (table 1). (WHI), 100% more thromboses, 41% more strokes and 29% more myocardial infarctions compared with placebo found after HRT (Writing Group for WHI Investigators JAMA TABLE 1 2002: 288: 321-333, Chlebowsky et al. JAMA 2003: 289: Composition of the extract ERT 731 (8) 3243-3253). In addition, it has been found in randomized controlled studies that HRT is linked to an increased risk of Hydroxystilbene Chemical name CAS No. the occurrence of breast cancer (Million Women Study Col Rhaponticin 3,3',5-Trihydroxy-4'-methoxystilbene 155-58-8 laborators Lancet 2003; 362: 419-427, Schairer et al. JAMA 3-O-B-D-glucopyranoside 2000: 283: 485-491, Ross et al. J Natl Cancer Inst 2000; 92: Deoxyrhaponticin 3',5-Dihydroxy-4'-methoxystilbene 3O197-14-9 328-332, Colditz et al. N. Engl J Med 1995; 332: 1589-1593, 3-O-B-D-glucopyranoside Magnusson et al. Int J Cancer 1999; 81: 339-344). US 2014/0099368 A1 Apr. 10, 2014

TABLE 1-continued of active ingredients of the present type, which are very prone to become inhomogeneous during production of the Solid Composition of the extract ERT 731 & dosage form, especially of the active ingredient-containing Hydroxystilbene Chemical name CAS No. tablet core. 0014 Since active ingredient release in the intestine is Rhapontigenin 3,3',5-Trihydroxy-4'-methoxystilbene 500-65-2 desired in Some cases for the Solid dosage forms employed for (trans Rhapontigenin) the above indication, conventional formulations are provided Deoxyrhapontigenin 3',5-Dihydroxy-4'-methoxystilbene 33626-08-3 with a gastro-resistant coating. Coatings of this type usually include a plasticizer, to prevent unwanted formation of cracks, which frequently leads to intolerances such as, for 0010 All of the constituents of ERr 731(R) belong to the example, allergies, especially on prolonged intake of the group of hydroxystilbenes. Several studies have shown that medicament. On the other hand, if cracks occur there is the the number and position of the free hydroxy and methoxy risk of causing stomachache. Crack resistant but plasticizer groups strongly influences the biological activity of the free, gastro-resistant solid formulations would therefore like hydroxy stilbenes. The pharmacological effect of the hydrox wise be desirable. yStilbenes is moreoverdependent on the presence of a glucose 00.15 Disadvantages of solid oral dosage forms currently group. on the market are on occasion also to be seen in the fact that the ingredients are unable to act immediately because the release takes place only with a certain time lag, and thus RI treatment of acute symptoms such as Suddenly occurring migraines or hot flushes is not optimal. In addition, conven tional Solid dosage forms can be administered only systemi HO S. R2 cally and not locally, this being disadvantageous in the case of locally restricted health impairments such as, for example, the occurrence of vaginal problems with no other menopausal symptoms in addition. Moreover, individual dosage of Solid dosage forms, especially gastro-resistant tablets, is possible R3 to only a limited extent because they are not divisible, which RI R2 R3 likewise may be disadvantageous. Alternative dosage forms, which can be employed as required, of the above active ingre Resveratrol OH H OH dients would therefore be desirable. Rhaponticin OCH OH O-Glc Deoxyrhaponticin OCH H O-Glc 0016. Against the provision of dosage forms which are not Rhapontigenin OCH, OH OH designed for oral administration, such as, for example, gels Deoxyrhapontigenin OCH H OH for local application, is also the fact that it has to date been Astringin OH OH O-Glc assumed that the resveratrol and piceatannol precursors such Piceatannol (astringenin) OH OH OH as rhaponticin and deoxyrhaponticin are pharmacologically inactive perse and show an effect only through metabolism to 0011. There has been only inadequate investigation of resveratrol and piceatannol after oral administration. whether, and to which metabolites, the constituents of ERr (0017 FR 2835 185 describes a complex rhubarb extract 731(R) are degraded in the body for example after oral admin obtainable from rhizomes of Rheum rhaponticum, which is istration. Thus, it is merely known from investigations on the said to be characterized in that it comprises at least 50% antithrombotic and antiallergic activity of rhaponticin-con hydroxyStilbenes, with at least 50% of these hydroxy stil taining extracts from rhizoma rhei that rhaponticin is benes consisting of rhaponticin, deoxyrhaponticin, astrangin degraded by bacteria of the human intestinal tract to rhapon and piceatannol. A preferred extract comprises 15-50% by tigenin (Parket al. Arch. Pharm. Res. 2002, 25(4), 528-533). weight rhaponticin, 10-35% by weight deoxyrhaponticin, Metabolism of rhaponticinto piceatannol or of deoxyrhapon 5-10% by weight astrangin and 0.1-3% by weight piceatan ticin to resveratrol has not been observed to date. nol. This extract is, as illustrated in the examples, prepared by 0012. The commercially available product ERr 731(R) hydroalcoholic extraction of rhizomes of Rheum rhaponti (proprietary name Phytoestrol(R) N) shows certain disadvan cum. The total content of rhaponticin and deoxyrhaponticin tages in relation to dosage form and production. In particular, which can be obtained thereby is only 76% by weight. The the absolute active ingredient content in the commercial prod content of astrangin comprises 11% by weight, the content of uct is relatively low, so that the dosage form for a dose of, for piceatannol comprises 3% by weight, and the content of example, 4 mg of active ingredient is relatively large (400 mg anthracenosides comprises 0.5% by weight. In addition tablet), which is found on occasion to be disadvantageous for thereto, this extract appears to comprise about 10% by weight oral administration. further undefined constituents. It is additionally asserted in 0013 The size of the dosage form additionally has disad FR 2835 185 that the specific extract therein has, as a result Vantageous effects on the production costs, because a dispro of alleged synergistic effects of the various ingredients of the portionately large content of formulation ancillary Substances extract, biological properties which are considerably Superior is present relative to the amount of active ingredient, in turn to the effect of the individual hydroxyStilbenes, especially unnecessarily increasing the production costs. A size reduc those effects which the ingredients described therein are said tion of the Solid dosage form is not easily achieved, since to have individually. The extract described therein is alleged when the size of the dosage form is reduced, the limit for the to have antioxidant, antitumor, antiinflammatory and estro permissible variation in active ingredient content becomes genic properties. However, in fact, FR 2835 185 does not increasingly difficult to comply with. This is true in particular provide a verifiable technical teaching for the asserted phar US 2014/0099368 A1 Apr. 10, 2014 macological usability, to say nothing of the asserted Syner Such as plasticizers. In addition, such liquid or semisolid gistic effect of the complex drug extract described therein. formulations can be produced particularly easily. The experimental section describes merely individual formu lation examples of capsules, tablets or creams. In particular, DESCRIPTION OF THE FIGURES experimental data proving the alleged usability for the treat ment of disorders connected with free radicals, such as, for 0021 FIG. 1 shows the formulation of piceatannol and example, accelerated aging, cancer, arteriosclerosis, resveratrol in vivo in male and female dogs 24 hours after wrinkles, inflammatory phenomena and the like, are com administration of 100 mg of ERr 73.1/kg of body weight. pletely lacking. The asserted suitability of a combination of 0022 FIG. 2 shows the estrogenic activity of 17f8-estra the rhubarb extract described therein with a hop extract rich in diol compared with resveratrol, cis- and trans-rhapontigenin, prenyl flavonoids for the treatment of diseases standing with deoxyrhapontigenin, piceatannol and ERr 731(R) in a recom free radicals and/or for the treatment of hormonal imbalance binant yeast Screen stably expressing ER-O. The concentra Such as amenorrhea, menopause, hot flushes etc., is not tions (X axis) are molar concentrations with the exception of proved by any data either. It is moreover entirely unclear the ERr 731(R) concentration, which is indicated in lug/ml. which of the components actually present in the extract 0023 FIG.3 shows the estrogenic activity of 178-estradiol described therein (rhaponticin, deoxyrhaponticin, astrangin, compared with resveratrol, cis- and trans-rhapontigenin, piceatannol, anthracenosides, and the unanalyzed constitu deoxyrhapontigenin, piceatannol and ERr 731(R), indicated as ents present in a content of 10%) contribute to the asserted activity of alkaline phosphatase in ishikawa cells transiently pharmacological activity or, where appropriate, are in fact with ER-C. The concentrations (X axis) are molar concentra absolutely necessary for the asserted synergism. The actual tions with the exception of ERr 7310 concentration, which is disclosure of FR 2835 185 should therefore be restricted to indicated in ug/ml. the preparation of a specific, complex rhubarb extract by 0024 FIG. 4 shows the result of a pharmacokinetic inves hydroalcoholic extraction of rhizomes of Rheum rhaponti tigation on the ingredient rhaponticin in ERr 731(R) in the cum and the preparation of specific hydroxyStilbene deriva blood of a female subject after oral administration of ERr tives, and the production of various pharmaceutical formula 731(R). Rhaponticin was detectable in the blood, but not tions. In addition, there are doubts whether the complex rhapontigenin. Likewise, the metabolite thereofpiceatannol extract disclosed in FR 2835 185 can in fact be processed was undetectable in the blood under the experimental condi satisfactorily to tablets complying with the quality standards tions. of the pharmaceutical industry. 0025 FIG. 5 shows the result of experiments on the acti 0018. There is thus a need for improved dosage forms for vation of the estrogen receptor B (ERB) by the active ingre the extract ERr 731 and other compositions with similar dient combination ERr 731(R) in the human endometrial car active ingredients for more efficient treatment of various cinoma cell line HEC-1B (FIG. 5a); the aglycones trans menopausal disorders which no longer have one or more of rhapontigenin (FIG. 5b) and deoxyrhapontigenin (FIG. 5c) the disadvantages described above. are effective only at higher concentrations (E2=estradiol; RLU-relative luciferase units); *=p-0.05; *p-0.01 SUMMARY OF THE INVENTION 0019. This object has surprisingly been achieved by pro DETAILED DESCRIPTION OF THE INVENTION viding Solid dosage forms, which can easily be produced, of ERr 731(R) and comparable active ingredients and active 1. Preferred Aspects of the Invention ingredient combinations, which may additionally have a 0026. The invention relates to a solid dosage form, com higher active ingredient content. The above object has also prising an active ingredient-containing Solid core with a phar been achieved by providing for the first time semisolid and maceutically acceptable carrier and an active ingredient con liquid dosage forms of the active ingredients and combina tent of about 1 to 20% by weight, based on the total weight of tions thereof described above. the core, where the active ingredient is a hydroxystilbene 0020. This is because the following has surprisingly been containing active ingredient or a hydroxyStilbene-containing found: active ingredient combination, selected from prodrugs of res a) Smaller solid dosage forms with a higher relative active Veratrol and piceatannol (precursors). Such as, in particular, ingredient content, which have a Surprisingly small percent rhaponticin, deoxyrhaponticin, cis- and trans-rhapontigenin, age variation in the active ingredient content, can be pro deoxyrhapontigenin and astringin; and resveratrol and piceat duced. annol; and the Stereoisomeric forms thereof, in each case in b) Smaller solid dosage forms with a higher relative active the form of their salts or in the phenol form and functional ingredient content and gastro-resistant coating are in addition derivatives, and combinations of these compounds. more crack resistant than conventional tablets and can be 0027. Resveratrol and piceatannol prodrugs in the sense of formulated without plasticizer in the coating, whereby fewer the invention are in particular substances which can be con side effects occur, such as gastric problems and allergies, Verted, partly or wholly, into resveratrol and/or piceatannol in because of the absence of plasticizers. Vivo, Such as, for example, in humans and/or another mam c) Because of the surprisingly found activity of resveratrol mal. Such as, for example, dog. Possibilities in this connection and piceatannol precursors such as rhaponticin and deox are Sugar-containing (glycosides) or Sugar-free (aglycones) yrhaponticin per se, it is possible to provide liquid or semi natural or synthetic precursors of resveratrol or piceatannol. Solid formulations which include these active ingredients and Typical examples of Sugar-containing precursors include can be administered locally, can be individually dosed better rhaponticin, astringin and deoxyrhaponticin. Typical and more accurately, make the active ingredient bioavailable examples of Sugar-free precursors include rhapontigenin and more quickly and show fewer side effects such as gastric deoxyrhapontigenin. The terms “prodrug or “precursor are, problems and allergies because of the absence of additions however, not to be understood as functional restriction in the US 2014/0099368 A1 Apr. 10, 2014 context of the invention. As proven by the experimental 0032. The skilled person is additionally aware that genera/ results described hereinafter, in particular the “precursors” of species differing in provenance and differing in age (e.g. the invention per se display advantageous pharmacological harvest at various times of the vegetation period) can be effects. employed, in turn possibly influencing the nature, amount 0028. The active ingredients are preferably substantially and composition of the active ingredients and mixtures which present in the trans form. Salts are in particular the alkali can be isolated therefrom. It is likewise possible in principle metal and alkaline earth metal phenolates of the above com to use various plant parts, such as roots, rhizomes, leaves pounds which have one or more free phenolic hydroxyl and/or stalks. groups. If a plurality of hydroxyl groups is present, these can 0033. The active ingredient or the active ingredient com be partly or completely in the salt form. bination is particularly advantageously obtainable from the 0029. The active ingredient to be employed according to roots and/or other plant parts, especially of Rheum rhapOnti the invention or the active ingredient combination is in this CIF connection chemically synthesized or, in particular, is an 0034. In a further embodiment, the active ingredient com ingredient which can be isolated from natural or recombinant bination Substantially comprises rhaponticin and deox plants or an ingredient combination which can be isolated yrhaponticin, it being possible for the active ingredient com therefrom and contains at least one of the abovementioned bination in particular Substantially to comprise rhaponticin hydroxyStilbene compounds. The resulting plant extracts or and deoxyrhaponticin in a ratio by weight of about 10:1 to individual components thereof can also be subjected to 1:10, such as, for example, in a range of about 5:1 to 1:5 or 4:1 derivatization reactions in order to obtain so-called functional to 1:4 or 3:1 to 1:3 or 2:1 to 1:2 or about 1:1. derivatives. These are in particular derivatives which can be 0035. In a specific dosage form the active ingredient com converted back in the human or animal body, after adminis bination of substantially rhaponticin and deoxyrhaponticin is tration, into the underivatized starting compound again. Men present in a ratio by weight of about 2:1 to 1:2. tion should be made in particular of ethers and ester deriva 0036. A further preferred active ingredient combination tives of the compounds used according to the invention. It is may comprise rhaponticin and deoxyrhaponticin, in particu moreover possible for individual ones or all of the etherifiable lar in the ratios of amounts indicated above, and rhapontige or esterifiable groups in a molecule (especially the phenolic nin and/or deoxyrhapontigenin. The quantitative proportion and glucosidic hydroxy groups) to be derivatized. Examples of rhapontigenin and/or deoxyrhapontigenin in the total of suitable derivatives and their preparation are described for active ingredient content may vary over a wide range and is, example in FR 2835 185, which is incorporated herein by for example, in the range of about 0.01 to 20% by weight, in reference. Thus, mention may be made of esters of saturated particular 0.1 to 5% by weight, based on the total active or unsaturated, aliphatic or aromatic carboxylic acids having ingredient content. up to 25 carbonatoms. Such as 1 to 25 carbonatoms, such as, 0037 Preference is further given to active ingredient com for example, saturated C-C fatty acids (such as, for binations which have a total hydroxyStilbene content, in par example, Saturated unbranched fatty acids selected from cap ticular a total content of deoxyrhaponticin, deoxyrhapontige roic acid, enanthic acid, caprylic acid, pelargonic acid, capric nin, rhaponticin and rhapontigenin, or a total content of acid, undecanoic acid, lauric acid, tridecanoic acid, myristic rhaponticin and deoxyrhaponticin, of more than 90% by acid, pentadecanoic acid, palmitic acid, margaric acid, Stearic weight, such as, for example, 91 to 100% by weight, or 92 to acid, nonadecanoic acid, arachidic acid, behenic acid); or 99 or 93 to 98 or 94 to 97% by weight. silyl ethers, where the silicon atom carries three identical or 0038. In a further preferred embodiment there is use of an different, straight-chain or branched, Saturated or unsaturated active ingredient combination which is substantially free of hydrocarbon radicals having up to 20 carbon atoms, such as, aglycone derivatives of rhaponticin and deoxyrhaponticin, for example, C-C alkyl or C-C alkenyl. Such as, in particular, resveratrol and piceatannol. “Substan 0030. An active ingredient combination of at least two of tially free” means an aglycone content of less than 5% by the abovementioned compounds is preferably employed, weight, in particular less than 2% by weight, Such as, for such as, for example, 2, 3, 4, 5, 6, 7 or 8 individual com example, less than 1% by weight or 0.1% by weight, such as pounds, where the group of resveratrol precursors (especially 0 to 0.05% by weight, in each case based on the total content deoxyrhaponticin and deoxyrhapontigenin) and of piceatan of rhaponticin plus deoxyrhaponticin. nol precursors (especially rhaponticin and rhapontigenin) is 0039. In a further preferred embodiment an active ingre represented in each case by one compound. dient combination used is a plant dry extract which has a high 0031. In a preferred embodiment, the active ingredient or content of glycosides, in particular glycosides of the type the active ingredient combination is obtainable from plants described above. Glycosides are in particular the above-de which are selected from natural plants and plants which have scribed glycosidic precursors of resveratrol and piceatannol. been modified by breeding or recombinant, genetically modi These are present for example in a content of from 30 to 100% fied plants, which have a content of at least one of the desired by weight, 50 to 100% by weight, but preferably in contents ingredients which is higher by comparison with the corre of more than 76% by weight, such as 76 to 99% by weight or sponding unmodified plant. These plants are in particular 80 to 98% by weight or 85 to 96% by weight, in each case selected from plant of the genus Rheum spp., Astragalus spp., based on the total weight of the dry extract. Cassia spp. or Picea spp. or active ingredient-containing 0040 Preference is further given to active ingredient com plant parts. Nonlimiting examples of Suitable species of these binations which have a content of less than 0.5% by weight, genera are Rheum undulatum, Rheum palmatum, Rheum such as, for example, 0-0.49% by weight or 0.001 to 0.3 or tataricum, Rheum officinale, Rheum wittrockii, Rheum altai 0.01 to 0.2 or 0.01 to 0.1% by weight of anthraquinone and/or cum, Rheum reticulatum, Astragalus complanatus, Cassia anthraquinoids (in each case based on the dry weight of the garrettiana and Picea sitchensis. active ingredient combination). Anthraquinoids are in this US 2014/0099368 A1 Apr. 10, 2014

connection to be understood in the widest sense as Substances 0.058 b) adding an aqueous extractant thereto, having a basic anthraquinone structure. 0059 c) after the extractant has acted, obtaining a liquid 0041. A “dry extract' in the sense of the invention is one extract phase from the mixture and, where appropriate, where the residual moisture content, i.e. the residual content repeating the extraction several times, and of water and/or organic liquid (Such as extractant), is less than 0060 d) removing the extractant from the liquid extract about 5% by weight, in particular less than 2% by weight, phases obtained in this way. such as, for example, 0 to 1.5% by weight or 0.1 to 0.5% by 0061 This preferably entails carrying out an extraction weight, in each case based on the total weight of the resulting with an aqueous extractant at a pH of the mixture in the dry extract. alkaline range. 0042. Nonlimiting examples of suitable solid dosage 0062. The extracted medicinal plant is selected in particu forms are those where the active ingredient combination con lar from plants of the genus Rheum spp., Astragalus spp. sists substantially of about Cassia spp or Picea spp. 0043. 60-66% by weight rhaponticin 0063. In a preferred variant of the preparation process, the 0044 30-35% by weight deoxyrhaponticin total amount of the active ingredient or of the active ingredi 0045 0-2% by weight rhapontigenin; 0-2% by weight ent combination is mixed in portions with the pharmaceuti deoxyrhapontigenin. cally acceptable carrier, Such as, for example, Avicel or a 0046 Preferred solid dosage forms have a total active comparable cellulose-based carrier, in particular microcrys ingredient content of about 2 to 20 mg per dose unit. talline cellulose, and the mixing process is repeated after each 0047. The invention relates in particular to solid dosage addition of carrier, but at least one or twice. In particular, a forms which have a Sugar-free, in particular mono- or disac ball mill is used in this case for mixing over a period of from charide-free. Such as, for example, lactose-free, core. 30 minutes to 3 hours, such as, for example, 1 to 2 hours. It is 0048 Suitable solid dosage forms may be in the form of a possible to use for example conventional laboratory ball mills pill, a tablet, an extrudate or granules. as described in the examples for the mixing. This results in a 0049 Solid dosage forms in the form of a coated tablet, homogeneous and stable distribution of the active ingredient where appropriate with a gastro-resistant coating, are particu in the carrier. larly preferred. Such coatings are preferably free of plasticiz 0064. In a further variant of the process, the active ingre erS Such as phthalates, such as, for example, diethyl phthalate. dient core is provided with a gastro-resistant, preferably plas Coating compositions suitable in particular for producing ticizer-free, coating. gastro-resistant, plasticizer-free coatings are selected from 0065. In a further preferred variant in this connection, the known natural and synthetic coating compositions (cf., for core is Sugar-coated. example, Voigt, Pharmazeutische Technologie, 7th edition 0066. The invention also relates to liquid dosage forms 1993, Ullstein Mosby, Berlin). Particularly suitable coating comprising an active ingredient or an active ingredient com compositions are, without being restricted thereto, shellac bination as defined above in a content of about 0.1 to 20 and cellulose derivatives such as hydroxypropylmethylcellu mg/ml, such as, for example, 0.5 to 15 or 1 to 10 or 2 to 5 lose derivatives such as, for example, hydroxypropylmethyl mg/ml, in a solvent mixture comprising water and a pharma cellulose acetate Succinate, obtainable under the proprietary ceutically acceptable alcohol Such as, in particular, ethanol. name AQOAT. The solvent mixture is preferably a water?ethanol mixture 0050 Mention should be made in particular of a solid with an ethanol content of from 10 to 50 or 20 to 40 or 25 to dosage form with a total weight in the range of about 150 35% by volume, such as, for example, 30% by volume. These mg-20 mg, a core weight of 84 mgt10 mg and an active liquid dosage forms are formulated in particular as drops for ingredient content of about 3 to 10 mg. oral administration. 0051. Further preferred solid dosage forms are those hav 0067. The invention also relates to semisolid dosage forms ing a uniformity of active ingredient content (averaged over comprising an active ingredient or an active ingredient com 10 or 20 randomly selected individual dose units) not exceed bination as defined above in a content of about 1 to 12, or 2 to ing +5% by weight, such as, for example, +0.1 to 4 or +0.5 to 6, mg of active ingredient or active ingredient combination 3 or +1 to 2% by weight, based on the total weight of the dose (per gram of the formulation) in a conventional semisolid unit (e.g. determined as specified in Ph. Eur, 5th edition 2005 carrier. Suitable gel-forming carriers are generally known and (5.0/2.09.06.00)). are selected for example from Swellable cellulose derivatives 0052. The invention further relates to a process for pro Such as hydroxypropylmethylcellulose, or polyacrylates Such ducing a solid dosage form where as, for example, carbopol, or gelatin. Dosage forms of this 0053 a) the active ingredient or the active ingredient com type can be used for example as vaginal gel or vaginal Sup bination is mixed with the pharmaceutically acceptable positories. carrier, and 0068. The invention also relates to a composition compris 0054 b) the mixture is consolidated to give the active ing a solid, semisolid or liquid dosage forms as defined above. ingredient core. Compositions in the sense of the invention are in particular 0055 For this purpose, the active ingredient or the active pharmaceutical compositions or medicaments such as, for ingredient combination is preferably dissolved or dispersed example, homeopathic remedies, and medicinal plant prepa in an inert liquid and mixed with the carrier, and the solvent is rations. removed during or after the consolidation. 0069. A further aspect of the invention relates to the use of 0056. The active ingredient used according to the inven a solid, semisolid or liquid dosage form as defined above or tion or the active ingredient combination is advantageously prepared by one of the processes described above or produc prepared by ing a composition as defined above for the treatment of meno 0057 a) providing an active ingredient-containing part of pausal symptoms in women, especially for the treatment of a medicinal plant, where appropriate in comminuted form, menopausal symptoms in the pre- or postmenopause, and US 2014/0099368 A1 Apr. 10, 2014

menopausal symptoms owing to a natural or therapeutically which serve as vehicle, carrier, adsorbent or medium for the induced menopause. Menopausal symptoms are in this con active ingredient or the active ingredient combinations. nection in particular hot flushes, Sweaty episodes, sleep dis 0077. Examples of suitable excipients include, unless orders, irritability, psychological and mental exhaustion, indicated otherwise, lactose, dextrose, Sucrose, Sorbitol, man sexual problems and urinary tract symptoms. The invention nitol, starches, gum acacia, calcium phosphate, alginates, also relates to their use for treating juvenile oligomenorrhea tragacanth, gelatin, calcium silicate, microcrystalline cellu and dysmenorrhea, primary and secondary amenorrhea or lose, polyvinylpyrrolidone, cellulose and methylcellulose. endometritis. The formulations may in addition comprise usual pharmaceu 0070. Owing to the excellent tolerability of the active tically acceptable ancillary Substances such as lubricants, for ingredients or active ingredient combinations described example tallow, magnesium Stearate and mineral oil; wetting above, the invention also relates to the use during long-term agents; emulsifying and Suspending agents; preservatives therapy, which is possible without limitation in time. The Such as methyl and propyl hydroxybenzoates; antioxidants; daily dose to be administered in this connection can be in the antiirritants; insulating agents; tablet-coating aids; emulsion range from 0.1 to 20 mg or 0.5 to 15 mg, 1 to 10 or 4 to 8 mg stabilizers; film formers; gel fomers; odor-masking agents; of active ingredient or active ingredient combination Such as, taste correctives; resins; hydrocolloids; solvents; solubiliz for example, ERr 731(R). ers; neutralizers; permeation promoters; pigments; quater 0071. A treatment in the sense of the invention includes nary ammonium compounds; refatting and Superfatting both an acute and a preventive administration of compositions agents; ointment, cream or oil bases; silicone derivatives; of the invention. spreading aids; stabilizers; sterilants; tablet excipients such as 0072 Finally, the present invention also relates to the use binders, fillers, lubricants, disintegrants or coatings; propel of the active ingredients or active ingredient combinations lants; dessicants; opacifiers; thickeners; waxes; plasticizers. described above, e.g. formulated in one of the dosage forms An arrangement concerning this is based on expert knowl described above, for selective activation of ERB, i.e. activa edge as set forth for example in Fiedler, H. P. Lexikon der tion of ERB without simultaneous substantial or detectable Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebi activation of ERC. in vivo or in vitro. ete, 4th edition, Aulendorf. ECV-Editio-Kantor-Verlag, 0073. The invention therefore relates in particular also to 1996; cf. also Hager's Handbuch der PharmaZeutischen the use of an active ingredient or of an active ingredient Praxis, Springer Verlag, Heidelberg. combination as defined above (such as in particular of ERr 0078 Solvents which are suitable according to the inven 731 or similar combinations comprising rhaponticin and/or tion for producing formulations and which should be particu deoxyrhaponticin) for treating one of the disorder defined larly mentioned are monohydric or polyhydric alcohols such above by selective activation of ERB, i.e. activation of ERB as, in particular, ethanol, glycerol and mixtures thereof with without simultaneous substantial or detectable activation of water, such as, for example 1 to 50% by volume ethanol in ERO. Water. 0079 Dosage forms or pharmaceutical compositions of 2. Further Specific Refinements of Formulations According the invention are produced by using generally known meth to the Invention ods of pharmaceutical technology as described for example in Voigt, PharmaZeutische Technologie, 7th edition 1993, Ull a) Dosage Forms stein Mosby, Berlin. 0074 The teaching of the invention is directed especially 0080. In a preferred embodiment, a pharmaceutical com at the production of Solid, semisolid or liquid dosage forms position which comprises a solid dosage form is provided. for treating a person. Thus, the active ingredients to be used This solid dosage form in turn includes an active ingredient according to the invention are usually administered in the containing Solid core with a pharmaceutically acceptable car form of pharmaceutical compositions which comprise a phar rier and an active ingredient content of about 1 to 20% by maceutically acceptable excipient with at least one active weight, based on the total weight of the core, where the active ingredient of the invention and, where appropriate, further ingredient is a hydroxyStilbene-containing active ingredient active ingredients. These compositions can be administered or a hydroxyStilbene-containing active ingredient combina in particular by the oral route. tion which includes a compound selected from resveratrol 0075 Examples of suitable pharmaceutical formulations and piceatannol prodrugs, such as rhaponticin, deoxyrhapon are in particular solid pharmaceutical forms such as granules, ticin, rhapontigenin, deoxyrhapontigenin and astringin; and tablets, pastilles, Sachets, cachets, Sugar-coated tablets and resveratrol and piceatannol; and the stereoisomeric forms capsules Such as hard and Soft gelatin capsules, pessaries, thereof, in each case in the form of their salts or in the phenol Suppositories or vaginal pharmaceutical forms, semisolid form, or combinations of these compounds. Preferred active pharmaceutical forms such as ointments, creams, hydrogels, ingredient combinations are as defined above. pastes or patches, and liquid pharmaceutical forms such as I0081. This solid dosage form has for example a total active Solutions, emulsions, especially oil-in-water emulsions, Sus ingredient content of about 1 to 20 mg. Such as, for example, pensions, for example lotions, preparations for injection and 2 to 10 mg, per dose unit and can be in the form of a pill, a infusion, eye drops and ear drops, nose drops, nasal spray and tablet, an extrudate or granules, and for example be Sugar tinctures. It is also possible to use implanted delivery devices coated. If desired, it may also have a gastro-resistant coating. for administering inhibitors of the invention. Liposomes, I0082. The solid dosage form is produced for example by microspheres or polymer matrices can also be used in addi mixing the active ingredient or the active ingredient combi tion. nation with the pharmaceutically acceptable carrier, and con 0076. In the production of the compositions, active ingre Solidating the mixture to give the active ingredient core. This dients of the invention are usually mixed with an excipient or entails dissolving or dispersing the active ingredient or the diluted. Excipients may be solid, or semisolid materials active ingredient combination in an inert liquid, mixing it US 2014/0099368 A1 Apr. 10, 2014

with the carrier and removing the solvent during or after the (0095. A further preferred embodiment of the process of consolidation. The active ingredient core can then be pro the invention provides an extract which has a high content of vided where appropriate with a gastro-resistant coating glycosides, in particular glycosides of the type described before the core is Sugar-coated in a conventional way. above, such as, for example, a content of from 30 to 100% by 0083. Liquid dosage forms of the invention are produced weight, 50 to 100% by weight, 60 to 99% by weight or 80 to for example by dissolving the active ingredient(s) such as, for 98% by weight or 85 to 96% by weight, in each case based on example, an ERr731(R) dry extract in a suitable solvent such the total weight of the resulting dry extract. A “dry extract' in as, for example, a waterfalcohol mixture, where appropriate the sense of the invention is present in particular when the together with further conventional additions. residual moisture content of water and/or organic liquid (Such 0084 Semisolid dosage forms of the invention, such as, for example, gels, are produced for example by dissolving the as extractant) is less than about 5% by weight, in particular active ingredient(s), such as, for example, an ERr 731(R) dry less than 2% by weight, such as, for example, 0 to 1.5% by extract, in a suitable solvent such as, for example, a water/ weight or 0.1 to 0.5% by weight, in each case based on the alcohol mixture, alcohol or glycerol, and incorporating the total weight of the resulting dry extract. Solution into the previously Swollengel former, where appro 0096. A further preferred embodiment provides an extract priate together with further conventional additions. which is substantially free of aglycone derivatives of rhapon 0085. The mode and duration of administration of the ticin and deoxyrhaponticin, such as, in particular, resveratrol medicaments of the invention are subject to the decision of the and piceatannol. “Substantially free” means anaglycone con treating physician. The latter can establish a suitable dose and tent of less than 5% by weight, in particular less than 2% by an appropriate dosage regimen depending on the chosen route weight such as, for example, less than 1% by weight or 0.1% of administration, on the efficacy of the specific active ingre by weight, such as 0 to 0.05% by weight, in each case based dient composition, the nature and severity of the disorder to on the total weight of rhaponticin and deoxyrhaponticin. be treated, the patient's condition and his response to the therapy. For example, a suitable single dose may comprise 0097 Active ingredient combinations which are further about 0.1 to 50 mg. Such as, for example, 2 to 12 mg. ofactive preferably prepared are those having a total hydroxy stilbene ingredient or active ingredient combination as defined above, content of more than 90% by weight such as, for example, 91 and be administered 1 to 3 times a day until the desired result to 100% by weight, or 92 to 99 or 93 to 98 or 94 to 97% by of the treatment is to be observed. weight. b) Preparation of a Drug Extract which can be Used Accord I0098. Further active ingredient combinations which are ing to the Invention preferably prepared are those having a content of less than I0086 Drug extracts which can be used according to the 0.5% by weight, such as, for example, 0-0.49% by weight or invention are preferably prepared by 0.001 to 0.3 or 0.01 to 0.2 or 0.01 to 0.1% by weight, of I0087 a) providing a hydroxystilbene-containing part of anthraquinone and/or anthraquinoids (in each case based on a medicinal plant, where appropriate in comminuted the dry weight of the active ingredient combination). form, Anthraquinoids are in this case to be understood in the widest 0088 b) adding an aqueous, organic oraqueous-organic sense as Substances having a basic anthraquinone structure. extractant thereto, 0099. In a preferred embodiment, the medicinal plant to be I0089 c) after the extractant has acted, obtaining a liquid extracted is selected from natural plants and plants modified extract phase from the mixture, and where appropriate by breeding or recombinant, genetically modified plants repeating the extraction several times, and which have a content of at least one of the desired ingredients 0090 d) removing the extractant from the liquid extract which is higher by comparison with the corresponding phases obtained in this way. unmodified plant. These plants are selected in particular from 0091. In particular, the extract obtained in this way plants of the genus Rheum spp., Astragalus spp., Cassia spp. includes at least one compound selected from rhaponticin, or Picea spp. or active ingredient-containing plant parts. Non deoxyrhaponticin, rhapontigenin, deoxyrhapontigeninas Salt limiting examples of Suitable species of these genera are or in phenolic form, in a stereoisomeric form thereof. Such as Rheum undulatum, Rheum palmatum, Rheum tataricum, cis or trans form, or as mixture of such stereoisomeric forms. Rheum officinale, Rheum wittrockii, Rheum altaicum, Rheum 0092. However, the extracted hydroxy stilbenes are prefer reticulatum, Astragalus complanatus, Cassia garrettiana and ably substantially in the transform. Salts are in particular the Picea sitchensis. It is additionally preferred to employ alkali metal and alkaline earth metal phenolates of the above medicinal plants as single varieties. compounds which have one or more free phenolic hydroxyl groups. If a plurality of hydroxyl groups is present, they may 0100. The skilled worker is additionally aware that genera/ be partly or completely in the salt form. species differing in provenance and differing in age (i.e. har 0093. The resulting plant extracts or individual compo Vest at various times of the vegetation period) can be nents thereof can, as already mentioned, also be subjected to employed, in turn possibly influencing the nature, amount derivatization reactions in order to obtain so-called functional and composition of the hydroxystilbenes and mixtures which derivatives. can be isolated therefrom. It is likewise possible in principle 0094. An active ingredient combination of at least two of to use various plant parts such as roots, rhizomes, leaves the abovementioned compounds is preferably obtained. Such and/or stalks. as, for example, 2, 3, 4, 5, 6, 7 or 8 individual compounds, 0101 The respective plant part or mixture of plant parts with the group of resveratrol precursors (especially deox can, if expedient, be mechanically treated Such as, for yrhaponticin and deoxyrhapontigenin) and of piceatannol example, ground, chopped, reeled, crushed or cut. If expedi precursors (especially rhaponticin and rhapontigenin) each ent, predrying is also possible. Such as, for example, 2 hours being represented by one compound. to 2 days at 30 to 50° C., in order to reduce the liquid content. US 2014/0099368 A1 Apr. 10, 2014

0102 The hydroxyStilbene-containing part of the medici achieve precipitation which is as quantitative as possible of nal plant used for the extraction is in particular the root of the the desired extracted ingredients. medicinal plant, such as, for example, of Rheum rhapOnti 0114. The precipitate can be washed for example with CIF purified water, and this serves in particular to remove remain 0103) The invention relates in particular to a process in ing acid. which a hydroxyStilbene-containing percolate is prepared 0115 Remaining liquid is removed from the extract by from the drug. A "percolation” means a continuous extraction drying, e.g. at 30 to 50° C. or 35 to 45°C., for example over of soluble substances from a drug by continual renewal of the a period of from 1 to 100 hours, until the residual moisture is Solvent. This results in a permanent concentration gradient, so in the range indicated above. The drying takes place in a that a large part of all the soluble Substances goes into the manner known perse, e.g. in a drying oven. Freeze drying is eXtract. likewise possible. 0104. An alternative possibility is also a continuous or 0116. The invention is now further explained by means of periodic mixing of the batch Such as, for example, by stirring the following nonlimiting examples. or shaking. 0105. The temperature during the extraction according to EXPERIMENTAL SECTION the invention is usually in the range from 10 to 50° C., such as, for example, 25 to 35°C. The pressure is usually atmospheric General Methods pressure. If a speeding up of the rate of extraction or quality of 0117 Determination of Stilbenes by High-Pressure Liq the extract can be achieved, the pressure may also be varied uid Chromatography (HPLC) in the Dry Extract from during the extraction, such as, for example, raised or lowered. Rhapontic Rhubarb Root 0106 The extraction may take, depending on the chosen conditions such as the nature of the drug, batch size, extrac a) Sample Preparation: tant and temperature used, from 1 hour to several days, Such 0118 50 mg of extract, mixed with 40 ml of a mixture of as, for example, 10 to 72 hours. acetone and water (1:1) in an amberglass vessel, treated in an 0107 The extraction process can if necessary be repeated ultrasonic bath for 15 minutes and made up to 50 ml with the several times in order to ensure that isolation in particular of solvent mixture and then diluted 1:10 with the solvent mix the desired ingredients is as complete as possible. The ratio by ture. weight of introduced drug to liquid extractant may vary over a wide range and from extraction step to extraction step. The b) Procedure for the Chromatography: ratio by weight of drug to extractant is typically in the range 0119) A high-pressure liquid chromatography (HPLC) is from 10:1 to about 1:200 or about 1:2 to 1:50, or 1:4 to 1:10. carried out on a portion of the solution obtained above, with 0108. In one variant of the process, an extraction is carried the following system parameters: out with an aqueous extractant which is Substantially free of Sample loop: 20 ul organic solvent, such as, in particular, water, preferably puri fied water, at a pH of the mixture in the alkaline range, with Column: Lichrospher 5u RP 18, 250x4 mm the pH of the mixture being in particular in the range from about 11 to 12, such as, for example, about 11.3 to 11.8. Precolumn: Lichrospher 5u RP 18, 5x4 mm 0109 The pH of the mixture is adjusted for example with I0120 Column temperature: 25°C. the aid of an inorganic base selected from alkali metal and Eluent A: Acetonitrile/dist. water/phosphoric acid 85%, alkaline earth metal hydroxides such as, for example, calcium 0121 15/85/0.05 (parts by volume) hydroxide or calcium oxide. It is possible for this purpose for Eluent B: Acetonitrile/dist. water/phosphoric acid 85%, example to prepare a concentrated quicklime solution by (0.122 80/20/0.05 (parts by volume) dissolving 3 to 8 parts of CaO in 20 parts of purified water. Flow rate: 1.5 ml/min This solution is strongly alkaline and has a pH in the range Column flushing: 15 min with eluent 50% B; equilibration from about 12 to 13, such as, for example, of about 12.4 to time 15 min 12.6. 0110. The ratio of the amounts of introduced drug to base Detection: 310 mm Such as, for example, calcium hydroxide (calculated as cal cium oxide) can be according to the invention in the range HPLC: Kontron Kroma 2000 from about 5:1 to 20:1, such as about 8:1 to 12:1 or 9:1 to 11:1. 0111. The process is preferably carried out in such a way Gradient: that the desired hydroxy stilbenes are precipitated from the resulting alkaline liquid extract phase, for example by adjust (0123 ing the pH of the extract to a value in the range from about 3 to 4, such as, for example, 3.2 to 3.8, or 3.4-3.6, and, where appropriate, Subsequently removing the precipitate, washing Time % B where appropriate and drying where appropriate. O.O O 0112 Used for the acidification is any inorganic or organic O.S O acid, such as, for example, hydrochloric acid or Sulfuric acid, 7.5 75 8.5 1OO but in particular organic acids such as formic acid or acetic 9.5 O acid. 12.5 O 0113 Before removal of the precipitate it may be expedi ent to leave the batch to stir for some hours or days in order to US 2014/0099368 A1 Apr. 10, 2014

0.124. The retention times resulting under the system con neutralized during the isolation in order to prevent the pH ditions indicated above are as follows: drifting into the acidic range and thus to inhibit premature Rhaponticin: about 5.5 min precipitation of the rhaponticin. This is achieved by using Deoxyrhaponticin: about 6.8 min calcium oxide. The latter is employed as quicklime solution Rhapontigenin: about 7.2 min with a pH of 12.4-12.6. Deoxyrhapontigenin: about 9.0 min 0.130 Homogeneous mixing of the quicklime with the 0.125 For a quantitative determination, the respective peak drug alters the pH of the mixture. It is then in the range from areas are found and compared with the corresponding peak 11.3 to 11.8, thus preventing precipitation of rhaponticin, areas of a standard extract of known composition. because the phenolic form has been converted into a pheno late form. Despite the high oxalic acid content, the pH can be Preparation Example 1 kept in the alkaline range. This is attributable to the fact that the calcium hydroxide reacts with oxalic acid and forms Preparation of the Dry Extract ERr 731 from insoluble and nontoxic calcium oxalate. Rhapontic Rhubarb Root with an Aqueous Calcium I0131 Rhaponticin is extracted from the root by the sub Hydroxide Solution sequent percolation with purified water. After completion of the percolation, a pH of 3.4 to 3.6 is adjusted by adding acetic 0126. A dry extract is prepared from rhapontic rhubarb acid. This pH shift from the alkaline to the acidic range leads root employing the following: to a precipitation of rhaponticinthrough conversion back into the phenolic form. In order to achieve precipitation of rhapon ticin which is as complete as possible, the mixture is left to Drug (radix rheum rhaponticum) 50.0 kg stand for 5 days. It is then filtered. Rhaponticin remains as Calcium oxide 5.0 kg yellowish substance on the filter. Purified water 190.0 kg 0.132. The above statements about rhaponticin apply cor Acetic acid (as necessary to adjust the required pH) respondingly to the other hydroxyStilbene active ingredients isolated according to the invention. 0127. The yield which can be achieved in this case is between 2 and 3 kg per 50 kg of drug. Preparation Example 2 0128. The preparation takes place in the following steps: a) Firstly 5 kg of calcium oxide are introduced into a plastic Preparation of a Dry Extract from Rhapontic tub and made into a slurry with 20 kg of purified water. The Rhubarb Root with Various Organic Solvents formation of calcium hydroxide (quicklime) which takes I0133. The constituents mainly detectable in the rhapontic place under these conditions leads to a large rise in tempera rhubarb root used as drug here belong to the group of hydrox ture of the solution. The calcium hydroxide can therefore be yStilbenes. Present from this group in the roots are rhaponti used further only after cooling. The temperature of the solu cin (Rh) with a content of about 6% and deoxyrhaponticin tion is then 30° C. to 35° C. (DRh) with a content of about 4%. b) 50 kg of drug are introduced into a mixer, and the above I0134. It is possible by exposure to the solvent systems mentioned quicklime is added. In order to remove the quick indicated below, in a 100-fold quantity at room temperature lime as completely as possible from the plastic tub, it is rinsed for 10 minutes with shaking or stirring, to extract the propor with 10 kg of purified water. This washing liquid is likewise tions summarized below: put in the mixer. c) The drug homogeneously mixed with quicklime is intro duced into a percolator and covered with 160 kg of purified water. The percolator remains closed for 48 hours. The per Ethanol 86% Rh 100.8% colate is then collected in a suitable vessel at a flow rate of 50 DRh 99.5% Ethanol 15% Rh 77.19% ml/min. The percolation is continued until no further perco DRh 75.5% late emerges. The drug mass is not Squeezed out after comple Acetone Rh 88.3% tion, but is discarded. DRh 96.6% d) While monitoring continuously, concentrated acetic acid is Water, alkaline Rh 75.5% added to the percolate until a pH in the range from 3.4 to 3.6 (pH 11, adjusted with CaO solution) DRh 60.5% is reached. In order to achieve precipitation of the extract which is as complete as possible, the mixture is left to stand 0.135 No useful results were achieved with heptane. for 5 days. 0.136 The respective yields of crude extracts in propor e) The dry extract is obtained by filtration through Büchner tions by mass (based on drug employed) are as follows: funnels under applied vacuum. Finally, the extract is washed with 10 to 20 kg of purified water. f) The dry extract obtained after filtration is dried in a drying Ethanol 86% 35.5% oven at 40°C. until a residual moisture tolerance not exceed Ethanol 15% 32.2% ing 1% is reached. Acetone 21.4% 0129 Rhaponticin is readily soluble in aqueous solutions Heptane O% with an alkaline pH range, whereas it is precipitated as yel Water, alkaline 4.5% lowish substance in the acidic pH range (pH 3.4-3.6). Use is made of this for its isolation. Since, besides other organic 0.137 Extraction of rhapontic rhubarb root with ethanol acids, the root in particular has a high content of oxalic acid water mixtures leads to an extract which, besides the main (2/3 in water-soluble and /3 in bound form), this must be constituents rhaponticin (about 30%) and deoxyrhaponticin US 2014/0099368 A1 Apr. 10, 2014

(about 22%), comprises a further stilbene, which has not as (e.g. type 1-25 LK. Alpine, Augsburg) for at least 120 min yet been investigated, in a proportion of about 20% in the utes. The second portion of Avicel(R) is then added, and the extract. Besides these, the aglycones rhapontigenin (about mixture is again triturated in the laboratory ball mill for at 8%) and deoxyrhapontigenin (about 2%) and a further 9 least 120 minutes. After addition of the third portion of compounds which total about 20% are obtained. Avicel(R), brief mixing is again carried out. Subsequently, 0138. The results on extraction with acetone are funda after addition of the other ancillary Substances, mixing and mentally the same. tabletting are carried out as described below. 0139 Extraction with alkaline water (cf. conditions in 0150. It is surprisingly possible with this mixing variant to preparation example 1) leads to an extract of greater purity. reduce markedly the tendency to inhomogeneity and, even 0140. The main constituents rhaponticin and deox with Small dose units, to adjust an extremely uniform active yrhaponticin are present in a proportion of about 97% in the ingredient content of not more than +5% by weight (deter dry extract. Rhapontigenin and deoxyrhapontigenin together mined according to Ph. Eur, 5th edition 2005 (5.0/2.09.06. amount to a proportion of 1.1% of the extract, whereas the 00)). stilbene which has not yet been investigated is present in a proportion of only 0.2%. A further 3 compounds are present c) Tabletting: in a proportion of 2.5%. 0151. The mixture of Avicel(R) and active ingredient is sieved through a sieving machine (sieve diameter 1.2 mm) Formulation Example 1 into a suitable mixing container and, after addition of the stated tabletting aids (without magnesium Stearate), mixed in Production of a Solid Dosage Form Minitablet a suitable mixer (e.g. drum hoop mixer of type Standard RR M 200, from Engelsmann AG/Ludwigshafen) for at least 30 1. Production of the Tablet Core: min. Addition of magnesium Stearate is followed by mixing 0141. A solid tablet core is produced using the following again for at least 5 min. active ingredients and ancillary Substances in the stated ratios 0152 The compression takes place in a suitable tablet of amounts (P-parts by weight). The ingredients are mixed press (e.g. rotary of type Perfecta Fette 2000, from Fette/ and tabletted in three different ways: Schwarzenbeck): Core weight: 84 mg-4.2 mg maximum variation a) Tablet Core Formulation: Punch: 7 mm diameter, domed 0142 0153. The ERr-731 content per core is about 4 mg-5%. 2. Production of the Gastro-Resistant Coated Tablet

Purified dry extract according to 3.6 P 0154. After removal of dust from the tablet cores with preparation example 1 from Eudragit, a gastro-resistant coating of cellulose acetate phtha rhapontic rhubarb root (ERr 731 (R) late and diethyl phthalate, dissolved in isopropanol and ethyl Microcrystalline cellulose (e.g. Avicel (R) 57.0 P(+40%) acetate, is applied to the tablet cores using a coating system. Sorbitol 8.0 P (40%) Talc 2.5 P(+40%) 0155 Macrogol is dissolved in purified water. The ingre Makrogol 6000 (polyglycol) 1.6 P (40%) dients Sugar (sucrose or isomalt), calcium carbonate, talc, Polyvidone (Kvalue about 25, e.g. Kollidon (R 25) 1.6 P (40%) titanium dioxide and the two povidones are mixed and stirred Sodium dodecyl sulfate (e.g. Texapon (R) K12) 0.5 P(+40%) into the liquid. The Suspension is stirred in a jet flow mixer Magnesium stearate (vegetable) 0.8 P (40%) (e.g. Rototron of type RTA 70-50) for 20 minutes. 75.6 P(+40%) 0156 The Sugar-coating Suspension is applied to the sealed core with the aid of an automatic coater. The process is repeated until an average weight of 150 mg per coated core is 0143. It is possible by varying the weighedamount of ERr reached. Finally, the polishing wax is applied and then rolling 731(R) and/or varying the amount of microcrystalline cellulose is continued until a high gloss is obtained. to obtain any desired ERr 731(R) contents in the untreated core 0157 Final weight of the gastro-resistant coated tablet: (such as, for example, 2, 4, 6, 8, 10, 12 mg per tablet). 0158 150 mg-7.5 mg maximum variation. 0159. In this way, two different tablet forms—one con b) Mixing of Drug and Carrier taining Sugar and one Sugar-free-are produced, employing 0144) Mixing Variant a: the respective ancillary Substances in the parts by weight (0145 1.2 P of ERr 731(R) are triturated in portions with indicated below. Avicel(R) in a ball mill and then, after addition of the other a) Gastro-Resistant Coated Minitablet—Containing Sugar— ancillary substances, mixed and tabletted as described below. with Plasticizer in the Coating 0146 Mixing Variant b: 0147 ERr 731(R) (1 g/l of solvent) is dissolved in a suitable solvent (e.g. ethanol/water mixture 86% V/v ethanol) and adsorbed on Avicel(R), dried (at 40°C. for at least 48 hours) Ancillary Substances: and, after addition of the other ancillary Substances, mixed Coating: Eudragit L12.5% dry matter 1.350 kg (40%) and tabletted as described below. Diethyl phthalate 1.749 kg (40%) Cellulose acetate phthalate 7.770 kg (40%) 0148 Mixing Variant c: Isopropyl alcohol 75.600 kg (40%) 0149. The total amount of Avicel(R) is divided into three Ethyl acetate 77.600 kg (40%) equal portions. The first portion is mixed with the total Talc 2.000 kg (40%) amount of ERr731(R) and triturated in a laboratory ball mill US 2014/0099368 A1 Apr. 10, 2014

-continued -continued Ancillary Substances: Ancillary Substances: kg (40%) Sugar coating: Talc 7.182 kg (40%) Sugar coating: Talc 7.182 Sugar 28.747 kg (40%) Sugar 28.747 Calcium carbonate 6.410 kg (40%) Calcium carbonate 6.410 Titanium dioxide E 171 0.635 kg (40%) Titanium dioxide E 171 O.63S Povidone (Kvalue about 0.756 kg (40%) Polyvidone (Kvalue about 25, 25, e.g. Kollidon (R 25) e.g. Kollidon (R 25) 0.756 Povidone (Kvalue about 0.332 kg (40%) Povidone (Kvalue: about 90) O.332 90) Macrogol 35,000 O.63S Macrogol 35,000 0.635 kg (40%) Water 1O.SOO Water 10.500 kg (40%) Polish: 95% carnauba wax O.108 Polish: 95% carnauba wax, 0.108 kg (40%) 5% bleached wax 5% bleached wax (e.g. Capol 1295 PH) (e.g. Capol 1295 PH) (0165 a) Variant B b) Gastro-Resistant Coated Minitablet Sugar-Free with Plasticizer in the Coating Ancillary Substances: kg (40%) Coating: Eudragit L12.5% dry matter O400 Ancillary Substances: Aqoat Hydroxypropylmethylcellulose S.42O Coating: Eudragit L12.5% dry matter 1350 kg (40%) acetate Succinate Diethyl phthalate 1.749 kg (40%) Distilled water 12.SOO Cellulose acetate phthalate 7.770 kg (40%) Isopropyl alcohol 4.OOO Isopropyl alcohol 75.600 kg (40%) Ethanol 86% 55.000 Ethyl acetate 77.600 kg (40%) Sugar coating: Talc 9.182 Sugar coating: Talc 7.482 kg (40%) Sugar 28.747 Sorbitol and or isomalt 28.747 kg (40%) Calcium carbonate 6.410 Calcium carbonate 6.410 kg (40%) Titanium oxide E 171 O.63S Titanium dioxide E 171 0.635 kg (40%) Povidone (Kvalue about 0.756 kg (40%) Polyvidone (Kvalue about 25, 0.756 25, e.g. Kollidon (R 25) e.g. Kollidon (R 25) Povidone (Kvalue about 0.332 kg (40%) Povidone (Kvalue: about 90) O.332 90) Macrogol 35,000 O.63S Macrogol 35,000 0.635 kg (40%) Water 1O.SOO Water 10.500 kg (40%) Polish: 95% carnauba wax O.108 Polish: 95% carnauba wax, 0.108 kg (40%) 5% bleached wax 5% bleached wax (e.g. Capol 1295 PH) (e.g. Capol 1295 PH) Formulation Example 3 Formulation Example 2 Production of a Solid Dosage Form Minitablet Sugar-Free without Plasticizer Production of a Solid Dosage Form Minitablet Containing Sugar without plasticizer (0166 a) Production of the Tablet Core 0.167 Production takes place in analogy to formulation (0160 a) Production of the Tablet Core example 1, but using isomalt instead of Avicel. 0161 Production takes place in analogy to formulation 0168 a) Production of the Gastro-Resistant Coated Tablet example 1. 0169 Production takes place in analogy to formulation 0162 a) Production of the Gastro-Resistant Coated Tablet example 2, but using isomalt instead of Sugar. 0163 Production takes place in analogy to formulation (0170 a) Variant A example 1, but with use of shellac (variant A) or Aqoat (vari ant B) instead of cellulose acetate phthalate/diethyl phthalate (plasticizer). Ancillary Substances: kg (40%) 0164 a) Variant A Coating: Eudragit L12.5% dry matter O400 CAPOL S27O PH8% 6O.OOO (shellac solution) = 4.8 kg dry matter (shellac) Ancillary Substances: kg (40%) Isopropyl alcohol 4.OOO Ethanol.96% 3.200 Coating: Eudragit L12.5% dry matter O400 Talc 2.OOO CAPOL S270 PH8% 6O.OOO Sugar coating: Talc 7.182 (shellac solution) = Isomalt 28.747 4.8 kg dry matter (shellac) Calcium carbonate 6.410 Isopropyl alcohol 4.OOO Titanium oxide E 171 O.63S Ethanol.96% 3.200 Polyvidone (Kvalue about 25, 0.756 Talc 2.OOO e.g. Kollidon (R 25) US 2014/0099368 A1 Apr. 10, 2014

-continued in glycerol (85% in 20/D=1.45085) are produced in a conven tional way by two different variants. Ancillary Substances: kg (40%) Povidone (Kvalue: about 90) O.332 a) Variant A: Macrogol 35,000 O.63S Water 1O.SOO (0176) Polish: 95% carnauba wax O.108 5% bleached wax (e.g. Capol 1295 PH) Formulation: (0171 b) Variant B Gelatin 1 part Purified water 2 parts Glycerol 85% (+ERr 731 (R) 5 parts

Ancillary Substances: kg (40%) Coating: Eudragit L12.5% dry matter O400 b) Variant B: Aqoat S.42O Distilled water 12.SOO 0177 Same formulation but with suitable preservatives Isopropyl alcohol 4.OOO such as, for example, sorbate, benzoate, PHB ester. Ethanol 86% 55.000 Talc 2.OOO 0.178 The gelatin is introduced in each case into purified Sugar coating: Talc 7.182 water and allowed to swell until the mixture has become Isomalt 28.747 glassy. Glycerol 85% with active ingredient is then added and Calcium carbonate 6.410 Titanium oxide E 171 O.63S heated, but not above 65°C. The suppositories are then cast in Polyvidone (Kvalue about 25, 0.756 a conventional way. e.g. Kollidon (R 25) Povidone (Kvalue: about 90) O.332 Formulation Example 6 Macrogol 35,000 O.63S Water 1O.SOO Polish: 95% carnauba wax O.108 Production of a Liquid Dosage Form Drops 5% bleached wax (0179 a) Dissolving Tests with ERr 731(R) in Ethanol and (e.g. Capol 1295 PH) Glycerol: 0180 Content of the extract: Formulation Example 4 0181 61.9% rhaponticin 0182 29.9% deoxyrphaponticin Production of a Semisolid Dosage Form Vaginal Gel 0183 Test A:200 mg of dry extract in 50 ml of glycerol R: 0172 Production takes place using conventional methods by the two following variants: 55.1% rhaponticin (89.0% of theory) a) Variant A: 27.1% deoxyrhaponticin (90.6% of theory) 0173 Hydroxypropylmethylcellulose (hypromellose USP) or another gel former is allowed to swell with 2-10% by 0184 Test B: 200 mg of dry extract in 50 ml of ethanol weight in purified water. The ERr 731(R) (preparation example 30% R: 1), dissolved in glycerol, is then incorporated. The amount of glycerol may be up to 50% of the weight of the gel. ERr 731(R) can be dissolved up to 0.5% by weight in glycerol. If neces sary, preservatives (e.g. Sorbic acid and its salts) can be added 52.2% rhaponticin (84.3% of theory) to the gel. Adjustment of the pH is also possible. As alterna 25.2% deoxyrhaponticin (84.2% of theory) tive to glycerol it is also possible to use 30-86% by volume ethanol. 0185 Test C: 200 mg of dry extract in 50 ml of ethanol b) Variant B: 50%. R: (0174 Carbomer (Carbopol) is dissolved with 0.5-5% by weight in purified water, and the desired pH is adjusted (e.g. KOH, NaOH, NH). If necessary, a preservative (e.g. sorbic 58.8% rhaponticin (95.0% of theory) acid and its salts) is admixed. After formation of a clear gel. 29.0% deoxyrhaponticin (97.0% of theory) ERr 731(R) (preparation example 1) is dissolved up to 0.5% by weight in 30-86% by volume ethanol and added. As alterna 0186. Test D: 200 mg of dry extract in 50 ml of ethanol tive to ethanol, it is also possible to use glycerol. 86% R: Formulation Example 5 Production of a Semisolid Dosage Form Vaginal 59.8% rhaponticin (96.6% of theory) Suppositories 29.5% deoxyrhaponticin (98.7% of theory) 0175 Suppositories with a size of 1 to 15 g with a content of 1 to 12 mg of ERr 731(R) (preparation example 1) dissolved US 2014/0099368 A1 Apr. 10, 2014

b) Production of Drops: 0194 The test is based on the description by Holinka CF, Hata H. Kuramoto H, Gurpide E (1986) Effects of steroid 0187 Drops are produced by dissolving dry extract hormones and antisteroids on alkaline phosphatase activity in according to test B in ethanol 30% R and filtering where human endometrial cancer cells (Ishikawa Line). Cancer Res. appropriate. 46:2771-2774, and modifications described in Wober J, We?B wange I, Vollmer G (2002) Stimulation of alkaline phos Test Example 1 phatase activity in Ishikawa cells induced by various phy toestrogens and synthetic estrogens. J. Steroid Biochem. Md. In Vivo Metabolism of the Dry Extract ERr 731(R) Biol. 83:227-233. 0188 For further elucidation of the mode of action, ERr 0.195 Table 2 presents the concentrations for the positive 731(R) was administered orally by capsule to 3 male and 3 control (17 B-estradiol) and the test substances used in the female dogs (pure-bred beagles, weight 6-9 kg, age 6-8 assay. months) in a dose of 100 mg of ERr 731(R/kg of body weight. At various time intervals, blood was taken from the animals TABLE 2 and blood plasma was obtained. The plasma was investigated for ERr 731(R) ingredients and metabolites. It was surprisingly Test substance Concentration (M) possible to detect both in male and in female animals signifi Estradiol 1O-6 Resveratrol 10-8-10-5 cant amounts of the metabolite piceatannol and Small trans-Rhapontigenin 108-10-5 amounts of the metabolite resveratrol. Maximum plasma lev Deoxyrhapontigenin 108-10-5 els of these metabolites were reached after about 24 h. The Piceatannol 107-10-5 plasma levels of piceatannol were distinctly higher than those cis-Rhapontigenin 10-8-10-5 of resveratrol. The results of the test at the 24 h timepoint are Extract ERr 731 (R) OOOOO1-10 depicted in FIG. 1. Exception: The concentration for the extract ERr 731 is indicated in Lugiml Test Example 2 (0196. The results of test B) are depicted in FIG. 3. 0.197 Both tests are conclusive because all the positive and Investigation of the Activation of the Estrogen negative controls show their predicted effects (cf. FIGS. 2 and Receptor ERC. by ERr 731(R) and the Ingredients or 3). The results of the two test systems described above dem Metabolites Thereof onstrate that neither ERr 731(R) nor its ingredients and metabolites have a significant effect on the activation of ERC. 0189 It was intended to answer the question of whether (cf. FIGS. 2 and 3). It can thus be assumed that the activity of ERr 731(R) activates ERO. The extract ERr 731(R) and the ERr 731(R) is based on a molecular mechanism independent of ingredients or metabolites thereof (trans-rhapontigenin, ERO. deoxyrhapontigenin, resveratrol, piceatannol and cis-rhapon tigenin) were therefore investigated, comparing with 17B Test Example 3 estradiol, for the estrogenic activity in established model systems. Rharmacokinetics of ERr 731(R) Ingredients in Female Subjects Test A): 0.198. The intention was to check whether, after oral intake (0190. In a first series of experiments, a recombinant yeast of ERr 731(R), one of the ingredients of this active ingredient screen was used (cf. E. Routledge and J. P. Sumpter, Ostro combination can be found again in the blood, in order to genic activity of Surfactants and some of their degradation demonstrate that at least one of the constituents of this active products assessed using a recombinant yeast screen, Envi ingredient combination or its metabolites is bioavailable. rom. Tox. Chem. 1996). (0199. A volunteer took 10 tablets of ERr 731(R) (dos 0191 Saccharomyces cerevisiae cells were stably trans age=40 mg of ERr 731(R) with liquid in the morning (8.00 h). fected with human ERC. both with a reporter gene consisting Subsequently, 10 ml of blood was taken at various times (as of the respective responsive promoter element fused to the indicated in FIG. 1) and the plasma was obtained by centrifu Lacz gene which codes for B-galactosidase. Estrogen treat gation. ment (with estrogen or with a substrate having an estrogen 0200. These plasma samples were processed as follows: like effect) of the cells activates, mediated by the estrogen 500 ul of plasma were mixed with 25ul of an internal standard receptor, R-galactosidase, leading to a red coloration of the working Solution (2.5 ng/ul rhaponticin or rhapontigenin in yeast cells, which can be measured at 565 nm. methanol) and then mixed with 500 ul of isotonic NaCl solu tion and 2.5 ml of diethyl ether/butanol (9/1; V/v). After 0192 The test results are summarized in FIG. 2. shaking and centrifugation (10 minutes at 4600 rpm), about 2 nil of the Supernatant were removed and dried under a stream Test B): of nitrogen (at 60° C.). The pellet was taken up in 50 ul of 0193 In a second series of experiments, the data of the methanol. Addition of 200 ul of distilled water was followed estrogenicity measurement were verified by determining the by renewed mixing, and 200 ul were pipetted into autosam induction of alkaline phosphatase in Ishikawa cells (human pler tubes (light-protected).30pul of the samples were injected endometrial adenocarcinoma cells) which had been trans for analysis into an LC-MS/MS system (PE Sciex API3000). fected with an ERC.-containing reporter gene construct. The Chromatographic separation of the analytes took place on a activity of alkaline phosphatase, which is assessed using the Phenomenex Polymer X column with a gradient of an ammo chromogenic Substrate 4-nitrophenyl phosphate, represents nium buffer Solution and an acetonitrile/methanol mixture as an ERC.-mediated response. mobile phase. US 2014/0099368 A1 Apr. 10, 2014

0201 The analyzed results are summarized in FIG. 4. Skilled workers have previously assumed that these glycones Rhaponticin was detected in the blood, with a maximum at are non-absorbable (cf. Parketal, Arch. Pharm. Res. 2002, 25 3-4 hours (FIG. 4), whereas rhapontigenin could not be (4), 528-533). A further surprising fact is that the active ingre found. Since rhaponticin is one of the mainingredients of ERr dient combination ERr 731(R) has greater activity than the 731(R), it can be assumed that rhaponticin is an activity-code corresponding aglycones rhapontigenin and deoxyrhaponti termining ingredient of ERr 731(R). This is all the more sur genin. In addition the latter are not detectable under physi prising since it was previously assumed that only the agly ological conditions (tests not shown). cones, but not the glycosylated hydroxyStilbenes, are active 0208. It has thus been possible to show for the first time by (Parket al., Arch Pharm Res. 2002; 25:528-533). the present invention the direct pharmacological activity of the glycosides rhaponticin and deoxyrhaponticin (as main Test Example 4 constituents of ERr 731(R). What is claimed is: Estrogen Receptor B (ERB) Activation by ERr 731(R) 1. A solid dosage form comprising an active-ingredient and its Metabolites in the ERB-Expressing containing Solid core with a pharmaceutically acceptable car Endometrial Adenocarcinoma Cell Line HEC-1B rier and an active ingredient content of about 1 to 20% by 0202 HEC-1B cells, a human endometrial adenocarci weight, based on the total weight of the core, wherein the noma cell line, do not express either ERC. or ERB. They active ingredient is a hydroxyStilbene-containing active therefore represent a possible way of investigating, in a ingredient or a hydroxyStilbene-containing active ingredient human and endometrial context, ligand-dependent effects of combination selected the group consisting of precursors of Substances on the transactivation mechanisms in relation to resveratrol and piceatannol, resveratrol, piceatannol, Stereoi different receptor subtypes and different estrogen-responsive someric forms thereof and functional derivatives thereof, in promoters. each case in the form of their salts or in the phenol form. 0203. An established ERB/mC3-luciferase system was 2. The solid dosage form as claimed in claim 1, wherein the employed. For this purpose, HEC-1B cells were applied in active ingredient or the active ingredient combination is 24-well plates with a density of 95000 cells/well (in Dulbec obtainable from roots of Rheum rhaponticum. co's modified Essential Medium (DMEM/F12)). The next 3. The solid dosage form as claimed in claim 1, where the day, they were cotransfected with an ERB-containing con active ingredient combination Substantially comprises struct (hERB/pSG2) and a triple-ERE-containing promoter/ rhaponticin and deoxyrhaponticin in a ratio of about 2:28 to luciferase construct (mC3-Luc?pGL2) (Hillisch et al. Dis 28:2 by weight. secting physiological roles of estrogen receptor alpha and 4. The Solid dosage form as claimed in claim 1, wherein the beta with potent selective ligands from structure-based active ingredient combination Substantially consists of design. Mol. Endocrinol. 2004 July; 18:1599-609). The tran approximately 60-66% by weight rhaponticin, 30-35% by sient transfection took place using DOTAP (N-1-(2,3-dio weight deoxyrhaponticin, 0-2% by weight rhapontigenin: leoyloxy)-N.N.N-trimethylammoniumpropane methyl-sul and 0-2% by weight deoxyrhapontigenin. fate, Roth) as described by the manufacturer. 5. The solid dosage form as claimed in claim 1, wherein the 0204 After 24 hours, the cells were treated with appropri total active ingredient content is about 2 to 20 mg per dose ate concentrations of the Substances or Substance mixtures to unit. be investigated. 17 B-Estradiol (E2; 10 nm) served as positive 6. The solid dosage form as claimed in claim 1, wherein the control, and a comparable volume of dimethyl sulfoxide core is lactose-free core. (DMSO) was employed as solvent control. The incubation 7. The solid dosage form as claimed in claim 1 in the form time was 24 hours. The cells were then lysed. The Luciferase of a pill, of a tablet, of an extrudate or of granules. Assay(R) kit (Promega) was used to determine the luciferase 8. The solid dosage form as claimed in claim 1, which has activity on the one hand, and the BCAR) kit (Sigma) was used a gastro-resistant coating. to determine the protein content on the other hand. The result 9. The solid dosage form as claimed in claim8, wherein the ing specific luciferase activities of the Substances to be inves coating comprises Substantially no plasticizer. tigated were then compared with the DMSO control (100%). 10. The Solid dosage form as claimed in claim 1, having a 0205 At least three transfection experiments were carried total weight in the range of about 150 mgt20 mg, a core out for each test substance. After calculation of the relative weight of 84 mgit 10 mg and an active ingredient content of luciferase activity in relation to the negative control (DMSO) about 3 to 10 mg per dose unit. for each single experiment (set at 100%), the corresponding 11. The Solid dosage form as claimed in claim 1, having a averages and standard deviations are formed. The results are uniformity of active ingredient content (averaged over 10 or represented graphically in the form of a bar diagram. Stu 20 randomly selected individual dose units) not exceeding dent's test was used to calculate the significance, the latter +5% by weight based on the total weight of the dose unit. being fixed as follows: *p<0.05; **p<0.01: ***p<0.001. 12. A process for producing a solid dosage unit as claimed 0206. The results for ERr 731(R) are depicted in FIG. 5a, in claim 1, comprising: for trans-rhapontigenin in FIG. 5b and for deoxyrhapontige a) mixing the active ingredient or the active ingredient nin in FIG.5c. They show that the substances activate the ERB combination with a pharmaceutically acceptable carrier; dose-dependently and thus can be employed according to the and invention. b) consolidating the mixture to give the active ingredient 0207. The results of the tests described above demonstrate COC. the Surprising finding that, contrary to previous assumptions, 13. The process as claimed in claim 12, wherein the active the “precursors” of resveratrol and piceatannol, i.e. the gly ingredient or active ingredient combination is dissolved or cosides rhaponticin and deoxyrhaponticin (as main constitu dispersed in an inert liquid and mixed with the carrier, and the ents of ERr 731(R) can be taken up per se by human cells. Solvent is removed during or after the consolidating step. US 2014/0099368 A1 Apr. 10, 2014

14. The process as claimed in claim 12, wherein the active 27. A semisolid dosage form comprising an active ingre ingredient or the active ingredient combination is prepared dient oran active ingredient combination as claimed in claim by: 1 in a proportion of about 1 to 12% by weight in a conven a) providing an active ingredient-containing part of a tional semisolid carrier. medicinal plant; 28. The semisolid dosage form as claimed in claim 27, b) adding an aqueous extractant thereto; formulated as vaginal gel or vaginal Suppositories. c) after the extractant has acted, obtaining a liquid extract 29. A pharmaceutical composition comprising a solid dos phase from the mixture; and age form as claimed in 1 and a pharmaceutically acceptable d) removing the extractant from the liquid extract phases, carrier. thereby preparing the active ingredient combination. 30. The pharmaceutical composition of claim 29, wherein 15. The process as claimed in claim 14, wherein the active the solid dosage form is produced as claimed in 39. ingredient-containing part of a medicinal plant is provided in 31. A pharmaceutical composition comprising a liquid comminuted form. dosage form as claimed in claim 24 and a pharmaceutically 16. The process as claimed in claim 14, further comprising acceptable carrier. repeating the extraction several times. 32. A pharmaceutical composition comprising a semisolid 17. The process as claimed in claim 14, wherein the extrac dosage form as claimed in claim 27 and a pharmaceutically tion with the aqueous extractant is carried out at a pH of the acceptable carrier. mixture in the alkaline range. 33. A method of treating menopausal symptoms, juvenile 18. The process as claimed in claim 14, wherein the oligomenorrhea and dysmenorrhea, primary and secondary medicinal plant is selected from plants of the genus Rheum amenorrhea or endometritis in a Subject comprising admin sp., Astragalus sp., Cassia sp. and Picea sp. istering to the Subject a solid dosage form, a liquid dosage 19. The process as claimed in claim 12, wherein the total form or a semisolid dosage form, wherein the Solid dosage amount of the active ingredient or of the active ingredient form, liquid dosage form or semisolid dosage form comprises combination is mixed in portions with the pharmaceutically the hydroxyStilbene-containing active ingredient or a hydrox acceptable carrier, and mixing is carried out after each addi yStilbene-containing active ingredient combination as tion of carrier. claimed in claim 1. 20. The process as claimed in claim 19, wherein mixing is 34. The method of claim 33, wherein the active ingredient carried out after each addition with a ball mill over a period of or active ingredient combination brings about treatment by from 30 minutes to 3 hours. selective activation of ERB. 21. The process as claimed in claim 12, wherein the active 35. The method of claim 33, wherein the menopausal ingredient core is provided with a gastro-resistant coating. symptoms occur in peri- or postmenopause. 22. The process as claimed in claim 21, where the coating 36. The method of claim 35, wherein the menopausal comprises Substantially no plasticizer. symptoms are selected from the group consisting of hot 23. The process as claimed in claim 12, wherein the core is flushes, Sweating episodes, sleep disorders, irritability, psy Sugar-coated. chological and mental exhaustion, sexual problems and uri 24. Aliquid dosage form comprising an active ingredientor nary tract symptoms. an active ingredient combination as claimed in claim 1 in a 37. The method of claim 33, wherein the menopausal proportion of about 0.1 to 20 mg/ml in a solvent mixture symptoms are the result of natural or therapeutically induced comprising water and a pharmaceutically acceptable alcohol. menopause. 25. The liquid dosage form as claimed in claim 24, wherein 38. A method for selective activation of ERB in vivo or in the solvent mixture is a waterlethanol mixture with an ethanol vitro comprising contacting a cell with the hydroxyStilbene content of from 10 to 50% by volume. containing active ingredient or a hydroxyStilbene-containing 26. The liquid dosage form as claimed in claim 24, formu active ingredient combination as claimed in claim 1. lated as drops for oral administration. k k k k k