US 20120195942A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0195942 A1 Heger et al. (43) Pub. Date: Aug. 2, 2012

(54) DOSAGE FORMS OF ACTIVE INGREDIENTS Publication Classi?cation CONTAINING HYDROXYSTILBENE FOR (51) Int Cl TREATING MENOPAUSAL COMPLAINTS A 61K 31/05 (2006.01) (76) Inventors: Peter Heger, Ubstadt-Weiher (DE); A61K 9/00 (200601) Reinhard Rettenberger ‘461p 13/02 (200601) Goppingen- (DE),_ Carl-Friedrich’ . . A61P 15/00 (2006.01) spaich Heiningen (DE) A61P 25/00 (2006.01) ’ A61K 31/7034 (2006.01) (21) App1.No.: 13/445,087 C12” 5/071 (201001) (22) Filed: Apr. 12, 2012 (52) US. Cl...... 424/400; 514/733; 514/25; 435/375 Related US. Application Data (63) Continuation of application No. 11/883,667, ?led on Apr. 25, 2008, noW Pat. No. 8,168,220, ?led as appli- (57) ABSTRACT cation No. PCT/EP2006/000957 on Feb. 3, 2006. ______The 1nvent1on provldes novel hydroxystllbene-contalning (30) Foreign Application Priority Data dosage forms, processes for producing these dosage forms and the use thereof for the treatment of menopausal symp Feb. 4, 2005 (DE) ...... 1020050052681 toms in Women, juvenile oligomenerrhea and dysmenerrhea, Feb. 4, 2005 (DE) ...... 102005005271 .1 primary and secondary amenorrhea 0r endometn'tis. Patent Application Publication Aug. 2, 2012 Sheet 1 0f 4 US 2012/0195942 A1

[Z13 female Big 40' 30

20

10

Piceatanno! Resveralrol

~9- ~!&- Pineatanno! * Rhapontlgenln

+Deoxyrhapontigenin v ‘ ‘ ~$-cls~Rhapontigen1n -+- ERr731 extract

LUBE-13 ‘HIDE-12 1.005-11 1.00510 1.06509 1.00508 LUBE-07 1.00506 ‘MODE-O5 1.00504 LUBE-O3 1.00E-O2M

Fig. 2 Patent Application Publication Aug. 2, 2012 Sheet 2 0f 4 US 2012/0195942 A1

300 %Activity 250 ’~"" - V ‘ E1 Deoxyrhapontigenin ‘ E cis-Rhaponliganln El Resvarairoi E! Plcealannol

150

100

50

Negative control Postive control 1.00E-08 1.00E-07 'LOOE-OS 1.00E-05 Fig. 3

0,08 ~

(ng/m!) 0,06 -

0,04 -

0.02 '

i (5

'_ - ; v y ' | I I * l /' / 0 2 4 6 8 10 22 23 24 Time after intake of ERr 731@ (h)

Fig, 4 Patent Application Publication Aug. 2, 2012 Sheet 3 of4 US 2012/0195942 A1

400 HEC~1B~cells 1 ERr 731@

300 — ‘ink in‘: 1 D 200 ~ .- ~ 3’ I

100 " r -.

o 010100‘ .-:'...E2 01 1

ERr 731 [pg/mi]

Fig. 5a

H E (3-1 B c e II S trans~Rha p0 ntigen'm

400

‘ 300

200

100

0 011150 E2 0.0002 0.002 0.026 0.26 2.0 091ml (0.01) (0.001) (0.01) (0.1) (1) (10) (0M) trans—

Fig. 5b Patent Application Publication Aug. 2, 2012 Sheet 4 0f 4 US 2012/0195942 A1

mam E2 0,0002 0.002 0.024 0.244 2.44 ugimi (0.01) (0.001) {0.01) (0.1) (1) (10) (NW Deoxyrhapontigenin

Fin 5% US 2012/0195942 A1 Aug. 2, 2012

DOSAGE FORMS OF ACTIVE INGREDIENTS 2000; 283: 485-491, Ross et al. J Natl Cancer Inst 2000; 92: CONTAINING HYDROXYSTILBENE FOR 328-332, ColditZ et al. N Engl J Med 1995; 332: 1589-1593, TREATING MENOPAUSAL COMPLAINTS Magnusson et al. Int] Cancer 1999; 81: 339-344). [0005] The receptor (ER) mediates the activity of [0001] This application is a continuation of US. applica in regulating a number of important physiological tion Ser. No. 11/883,667, Allowed, Which is the US. national processes, including the development and function of the phase application, pursuant to 35 U.S.C. §371, of PCT inter female reproductive system. Whereas stimulation of pro national application Ser. No. PCT/EP2006/000957, ?led Feb. cesses in these tissues has important health advantages, the 3, 2006, designating the United States and published in Ger cancer risk may be increased by stimulation of other tissues man on Aug. 10, 2006 as publication WO 2006/082073 A1, such as the breast and the uterus, especially in the pen- and Which claims priority to German application Ser. Nos. DE 10 postmenopause. The ER family comprises tWo subtypes, 2005 005 268.1, ?led Feb. 4, 2005 and DE 10 2005 005 271.1, namely ERG. and ER[3. Studies With ER-selective knockout ?led Feb. 4, 2005. The entire contents of the aforementioned mice have shoWn that the typical unWanted estrogen effects patent applications are incorporated herein by this reference. [0002] The invention relates to novel hydroxystilbene-con such as endometrial hyperplasia and breast cancer are medi taining dosage forms, processes for producing these dosage ated by ERot, or as ER[3 acts as a negative regulator of ERG. forms and the use thereof for the treatment of menopausal and is important for protecting against hyperproliferation and symptoms in Women, juvenile oligomenorrhea and dysmen carcinogenesis in tissues in Which both receptors are coex orrhea, primary and secondary amenorrhea or endometritis. pressed (HeWitt et al. Breast Cancer res 2003; 2: 345-352, Frasor et al. Endocrinology 2003; 144: 3159-3166, Lindberg BACKGROUND OF THE INVENTION et al. Mol Endocrinol 2003; 17: 203-208). [0003] The menopause is an impairment of ovarian func [0006] Based on the results of clinical and experimental tion accompanied by high levels of follicle-stimulating hor studies, increasing numbers of Women refuse to use HRT for mone (FSH) and loWer levels of estradiol (E2). The time up to their menopausal symptoms. In addition, HRT is not indi the last menstruation is also referred to as “perimenopause”. cated for treating Women Who already have an endocrine During this period, most Women notice cycle irregularities dependent tumor, or shoW a high cancer risk, especially breast Which last for 1 to 5 years. In most Western countries, about cancer and endometrial cancer. For these reasons, novel 80% of perk and postmenopausal Women suffer from hot active ingredients for treating menopausal symptoms Which ?ushes, in about 30% of them the hot ?ushes are so severe and frequent that the quality of life is noticeably impaired thereby. are free of the potential risks associated With HRT, especially The exact physiological cause of hot ?ushes is unknown also on long-term use, are very desirable. (Ginsburg. Obstetrics and Gynecology Clinics of North [0007] There are a number of so-called America 1994; 21 (2): 381-390). Hot ?ushes folloW a release Which have claims to be effective in relation to reducing hot of gonadotropin-releasing hormone (GnRH) from the hypo ?ushes and sWeating episodes. For most of these herbal prod thalamus and are not linked to changes in the level of estradiol ucts, the results of clinical studies, Where in fact available, are and . They are accompanied by the release of lutein contradictory or shoW no e?icacy by comparison With pla iZing hormone (LH), corticotrophin, groWth hormone and [3-lipotrophin from the pituitary and of dehydroepiandroster cebo. In addition, some constituents of these products may have an estrogenic activity despite their relatively Weak bind one and androstenedion from the adrenal. FSH levels may vary betWeen normal and high (>20 IU/1). ing af?nity for ERG. (e.g. , , and [0004] Hormone replacement therapy (HRT) replaces the ; Muller et al. Toxicol. Sci. 2004; 80: 14-25) and tWo female sex estrogen and progesterone. HRT Was thus represent the risks similar to HRT. It has in fact been employed for many years for the treatment of menopausal observed that long-term treatment With soya phytoestrogens symptoms and for preventing cardiovascular disorders and led to endometrial hyperplasia (Unfer et al., Fertil Steril 2004; osteoporosis in the perk and postmenopause. It Was regarded 82: 145-148). These observations cast doubt on the long-term as effective and safe. HoWever, this is no longer true since safety of phytoestrogens, especially in relation to the large randomiZed controlled studies Were carried out and endometrium. shoWed the contrary (Beral et al., Lancet 2002; 360: 942-944, Collaborative Group, Lancet 1997; 359: 1047-1059). HRT [0008] There is thus a great need for novel active ingredi has no positive effect on the incidence and progression of ents or active ingredient combinations for treating meno coronary heart disease. There is in fact evidence that it pausal symptoms Which do not bind to ERot, i.e. are not increases the risk of cardiovascular disorders in pen- and post procarcinogenic, and do not promote the development of menopausal Women. In a randomiZed, placebo-controlled cardiovascular disorders. double-blind study of primary prevention With estrogen plus [0009] Since 1993, a dry extract ofroots ofRheum rhapon progestin, carried out by the Women’s Health Initiative Zicum has been on the market in Germany under the name (WHI), 100% more thromboses, 41% more strokes and 29% more myocardial infarctions compared With placebo found Extrakt Rheum rhaponlicum (ERr 731®) (proprietary name after HRT (Writing Group for WHI Investigators JAMA Phytoestrol® N) for follicle hormone replacement therapy, 2002; 288: 321-333, ChleboWsky et al. JAMA 2003; 289: for example for treating Women With menopausal symptoms, 3243-3253). In addition, it has been found in randomiZed juvenile oligomenorrhea and dysmenorrhea, primary and controlled studies that HRT is linked to an increased risk of secondary amenorrhea, and endometritis. The constituents of the occurrence of breast cancer (Million Women Study Col the speci?c ERr 731® extract are rhaponticin, deoxyrhapon laborators Lancet 2003; 362: 419-427, Schairer et al. JAMA ticin, rhapontigenin and deoxyrhapontigenin (table 1). US 2012/0195942 A1 Aug. 2, 2012

tion of the solid dosage form is not easily achieved, since TABLE 1 When the size of the dosage form is reduced, the limit for the permissible variation in active ingredient content becomes Composition of the extract ER_r 731 ® increasingly di?icult to comply With. This is true in particular Hydroxystilbene Chemical name CAS No. of active ingredients of the present type, Which are very prone to become inhomogeneous during production of the solid Rhaponticin 3 ,3 ' ,5-Trihydroxy-4'-methoxystilbene 15 5-5 8- 8 dosage form, especially of the active ingredient-containing 3-O-[5-D-glucopyranoside Deoxyrhaponticin 3 ‘,5 -Dihydroxy-4'-methoxystilbene 30197-14-9 tablet core. 3-O-[5-D-glucopyranoside [0014] Since active ingredient release in the intestine is Rhap ontigenin 3,3',5-Trihyd_roxy-4'-methoxystilbene 500-65-2 desired in some cases for the solid dosage forms employed for (trans Rhap ontigenin) the above indication, conventional formulations are provided Deoxyrhapontigenin 3 ‘,5 -Dihydroxy-4'-methoxystilbene 33 62 6-0 8-3 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® 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 stomach ache. Crack resistant but plasticizer groups strongly in?uences the biological activity of the free, gastro-resistant solid formulations Would therefore like hydroxystilbenes. The pharmacological effect of the hydrox Wise be desirable. ystilbenes is moreover dependent on the presence of a glucose [0015] 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 R1 treatment of acute symptoms such as suddenly occurring migraines or hot ?ushes is not optimal. In addition, conven tional solid dosage forms can be administered only systemi HO \ 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 R3 dosage forms, especially gastro-resistant tablets, is possible to only a limited extent because they are not divisible, Which R1 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 OCH3 OH O-Glc Deoxyrhaponticin OCH3 H O-Glc [0016] Against the provision of dosage forms Which are not Rhapontigenin OCH3 OH OH designed for oral administration, such as, for example, gels Deoxyrhap ontigenin OCH 3 H OH for local application, is also the fact that it has to date been OH OH O-Glc (astringenin) OH OH OH assumed that the resveratrol and piceatannol precursors such as rhaponticin and deoxyrhaponticin are pharmacologically inactive per se 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 2 835 185 describes a complex rhubarb extract 731® are degraded in the body for example after oral admin obtainable from rhizomes of Rheum rhaponlicum, 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 hydroxystil 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 (Park et al, Arch. Pharm. Res. 2002, 25 (4), 528-533). Weight rhaponticin, 10-35% by Weight deoxyrhaponticin, Metabolism of rhaponticin to 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® hydroalcoholic extraction of rhizomes of Rheum rhaponti (proprietary name Phytoestrol® 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 ab solute active ingredient content in the commercial prod content of astrangin comprises 1 1% 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 unde?ned constituents. It is additionally asserted in [0013] The size of the dosage form additionally has disad PR 2 835 185 that the speci?c 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 US 2012/0195942 A1 Aug. 2, 2012

to have individually. The extract described therein is alleged ents and can be administered locally, can be individually to have antioxidant, antitumor, antiin?ammatory and estro dosed better and more accurately, make the active ingredient genic properties. However, in fact, FR 2 835 185 does not bioavailable more quickly and shoW feWer side effects such as provide a veri?able technical teaching for the asserted phar gastric problems and allergies because of the absence of macological usability, to say nothing of the asserted syner additions such as plasticiZers. In addition, such liquid or gistic effect of the complex drug extract described therein. semisolid 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 [0024] FIG. 1 shoWs the formulation of piceatannol and ment of disorders connected With free radicals, such as, for resveratrol in vivo in male and female dogs 24 hours after example, accelerated aging, cancer, arteriosclerosis, administration of 100 mg of ERr 731/kg of body Weight. Wrinkles, in?ammatory phenomena and the like, are com [0025] FIG. 2 shoWs the estrogenic activity of 178-estradiol pletely lacking. The asserted suitability of a combination of compared With resveratrol, cis- and trans-rhapontigenin, the rhubarb extract described therein With a hop extract rich in deoxyrhapontigenin, piceatannol and ERr 731® in a recom prenyl ?avonoids for the treatment of diseases standing With binant yeast screen stably expressing ER-ot. The concentra free radicals and/ or for the treatment of hormonal imbalance tions Qi axis) are molar concentrations With the exception of such as amenorrhea, menopause, hot ?ushes etc., is not the ERr 731® concentration, Which is indicated in ug/ml. proved by any data either. It is moreover entirely unclear [0026] FIG. 3 shoWs the estrogenic activity of 17[3-estra Which of the components actually present in the extract diol compared With resveratrol, cis- and trans -rhapontigenin, described therein (rhaponticin, deoxyrhaponticin, astrangin, deoxyrhapontigenin, piceatannol and ERr 731®, indicated as piceatannol, anthracenosides, and the unanalyZed constitu activity of alkaline phosphatase in ishikaWa cells transiently ents present in a content of 10%) contribute to the asserted With ER-ot. The concentrations (X axis) are molar concentra pharmacological activity or, Where appropriate, are in fact tions With the exception of ERr 731® concentration, Which is absolutely necessary for the asserted synergism. The actual indicated in ug/ml. disclosure of FR 2 835 185 should therefore be restricted to [0027] FIG. 4 shoWs the result of a pharmacokinetic inves the preparation of a speci?c, complex rhubarb extract by tigation on the ingredient rhaponticin in ERr 731® in the hydroalcoholic extraction of rhizomes of Rheum rhaponti blood of a female subject after oral administration of ERr cum and the preparation of speci?c hydroxystilbene deriva 731®. Rhaponticin Was detectable in the blood, but not tives, and the production of various pharmaceutical formula rhapontigenin. Likewise, the metabolite thereof piceatannol tions. In addition, there are doubts Whether the complex Was undetectable in the blood under the experimental condi extract disclosed in ER 2 835 185 can in fact be processed tions. satisfactorily to tablets complying With the quality standards [0028] FIG. 5 shoWs the result of experiments on the acti of the pharmaceutical industry. vation of the [3 (ER[3) by the active ingre [0018] There is thus a need for improved dosage forms for dient combination ERr 731® in the human endometrial car the extract ERr 731 and other compositions With similar cinoma cell line HEC-1B (FIG. 5a); the aglycones trans active ingredients for more ef?cient treatment of various rhapontigenin (FIG. 5b) and deoxyrhapontigenin (FIG. 50) menopausal disorders Which no longer have one or more of are effective only at higher concentrations (E2:estradiol; the disadvantages described above. RLU:relative luciferase units); *:p<0.05; **:p<0.01 SUMMARY OF THE INVENTION DETAILED DESCRIPTION OF THE INVENTION [0019] This object has surprisingly been achieved by pro 1. Preferred Aspects of the Invention viding solid dosage forms, Which can easily be produced, of ERr 731® and comparable active ingredients and active [0029] The invention relates to a solid dosage form, com ingredient combinations, Which may additionally have a prising an active ingredient-containing solid core With a phar higher active ingredient content. The above object has also maceutically acceptable carrier and an active ingredient con been achieved by providing for the ?rst time semisolid and tent of about 1 to 20% by Weight, based on the total Weight of liquid dosage forms of the active ingredients and combina the core, Where the active ingredient is a hydroxystilbene tions thereof described above. containing active ingredient or a hydroxystilbene-containing [0020] This is because the folloWing has surprisingly been active ingredient combination, selected from prodrugs of res found: veratrol and piceatannol (precursors), such as, in particular, [0021] a) Smaller solid dosage forms With a higher relative rhaponticin, deoxyrhaponticin, cis- and trans-rhapontigenin, active ingredient content, Which have a surprisingly small deoxyrhapontigenin and astringin; and re sveratrol and piceat percentage variation in the active ingredient content, can be annol; and the stereoisomeric forms thereof, in each case in produced. the form of their salts or in the phenol form and functional [0022] b) Smaller solid dosage forms With a higher relative derivatives, and combinations of these compounds. active ingredient content and gastro-resistant coating are in [0030] Resveratrol and piceatannol prodrugs in the sense of addition more crack resistant than conventional tablets and the invention are in particular substances Which can be con can be formulated Without plasticiZer in the coating, Whereby ver‘ted, partly or Wholly, into resveratrol and/ or piceatannol in feWer side effects occur, such as gastric problems and aller vivo, such as, for example, in humans and/or another mam gies, because of the absence of plasticiZers. mal, such as, for example, dog. Possibilities in this connection [0023] c) Because of the surprisingly found activity of res are sugar-containing () or sugar-free (aglycones) veratrol and piceatannol precursors such as rhaponticin and natural or synthetic precursors of resveratrol or piceatannol. deoxyrhaponticin per se, it is possible to provide liquid or Typical examples of sugar-containing precursors include semisolid formulations Which include these active ingredi rhaponticin, astringin and deoxyrhaponticin. Typical US 2012/0195942 A1 Aug. 2, 2012

examples of sugar-free precursors include rhapontigenin and cum, Rheum reliculalum, Aslragalus complanalus, Cassia deoxyrhapontigenin. The terms “prodrug” or “precursor” are, garrelliana and Picea silchensis. however, not to be understood as functional restriction in the [0035] The skilled person is additionally aWare that genera/ context of the invention. As proven by the experimental species differing in provenance and differing in age (e.g. results described hereinafter, in particular the “precursors” of harvest at various times of the vegetation period) can be the invention per se display advantageous pharmacological employed, in turn possibly in?uencing the nature, amount effects. and composition of the active ingredients and mixtures Which [0031] The active ingredients are preferably substantially can be isolated therefrom. It is likeWise possible in principle present in the trans form. Salts are in particular the alkali to use various plant parts, such as roots, rhiZomes, leaves metal and alkaline earth metal phenolates of the above com and/or stalks. pounds Which have one or more free phenolic hydroxyl [0036] The active ingredient or the active ingredient com groups. If a plurality of hydroxyl groups is present, these can bination is particularly advantageously obtainable from the be partly or completely in the salt form. roots and/ or other plant parts, especially of Rheum rhaponti [0032] The active ingredient to be employed according to cum. the invention or the active ingredient combination is in this [0037] In a further embodiment, the active ingredient com connection chemically synthesiZed or, in particular, is an bination substantially comprises rhaponticin and deox ingredient Which can be isolated from natural or recombinant yrhaponticin, it being possible for the active ingredient com plants or an ingredient combination Which can be isolated bination in particular substantially to comprise rhaponticin therefrom and contains at least one of the abovementioned and deoxyrhaponticin in a ratio by Weight of about 10:1 to hydroxystilbene compounds. The resulting plant extracts or 1:10, such as, for example, in a range ofabout 5:1 to 1:5 or 4:1 individual components thereof can also be subjected to to 1:4 or 3:1 to 1:3 or2:1 to 1:2 or about 1:1. derivatiZation reactions in order to obtain so -called functional [0038] In a speci?c dosage form the active ingredient com derivatives. These are in particular derivatives Which can be bination of substantially rhaponticin and deoxyrhaponticin is converted back in the human or animal body, after adminis present in a ratio by Weight of about 2:1 to 1:2. tration, into the underivatiZed starting compound again. Men [0039] A further preferred active ingredient combination tion should be made in particular of ethers and ester deriva may comprise rhaponticin and deoxyrhaponticin, in particu tives of the compounds used according to the invention. It is lar in the ratios of amounts indicated above, and rhapontige moreover possible for individual ones or all of the etheri?able nin and/or deoxyrhapontigenin. The quantitative proportion or esteri?able groups in a molecule (especially the phenolic of rhapontigenin and/or deoxyrhapontigenin in the total and glucosidic hydroxy groups) to be derivatiZed. Examples active ingredient content may vary over a Wide range and is, of suitable derivatives and their preparation are described for for example, in the range of about 0.01 to 20% by Weight, in example in PR 2 835 185, Which is incorporated herein by particular 0.1 to 5% by Weight, based on the total active reference. Thus, mention may be made of: esters of saturated ingredient content. or unsaturated, aliphatic or aromatic carboxylic acids having [0040] Preference is further given to active ingredient com up to 25 carbon atoms, such as 1 to 25 carbon atoms, such as, binations Which have a total hydroxystilbene content, in par for example, saturated C6-C22 fatty acids (such as, for ticular a total content of deoxyrhaponticin, deoxyrhapontige example, saturated unbranched fatty acids selected from cap nin, rhaponticin and rhapontigenin, or a total content of roic acid, enanthic acid, caprylic acid, pelargonic acid, capric rhaponticin and deoxyrhaponticin, of more than 90% by acid, undecanoic acid, lauric acid, tridecanoic acid, myristic Weight, such as, for example, 91 to 100% by Weight, or 92 to acid, pentadecanoic acid, palmitic acid, margaric acid, stearic 99 or 93 to 98 or 94 to 97% by Weight. acid, nonadecanoic acid, arachidic acid, behenic acid); or [0041] In a further preferred embodiment there is use of an silyl ethers, Where the silicon atom carries three identical or active ingredient combination Which is substantially free of different, straight-chain or branched, saturated or unsaturated aglycone derivatives of rhaponticin and deoxyrhaponticin, hydrocarbon radicals having up to 20 carbon atoms, such as, such as, in particular, resveratrol and piceatannol. “Substan for example, C l-C2O alkyl or C2-C2O alkenyl. tially free” means an aglycone content of less than 5% by [0033] An active ingredient combination of at least tWo of Weight, in particular less than 2% by Weight, such as, for the abovementioned compounds is preferably employed, example, less than 1% by Weight or 0.1°/o by Weight, such as such as, for example, 2, 3, 4, 5, 6, 7 or 8 individual com 0 to 0.05% by Weight, in each case based on the total content pounds, Where the group of resveratrol precursors (especially of rhaponticin plus deoxyrhaponticin. deoxyrhaponticin and deoxyrhapontigenin) and of piceatan [0042] In a further preferred embodiment an active ingre nol precursors (especially rhaponticin and rhapontigenin) is dient combination used is a plant dry extract Which has a high represented in each case by one compound. content of glycosides, in particular glycosides of the type [0034] In a preferred embodiment, the active ingredient or described above. Glycosides are in particular the above-de the active ingredient combination is obtainable from plants scribed glycosidic precursors of resveratrol and piceatannol. Which are selected from natural plants and plants Which have These are present for example in a content of from 30 to 100% been modi?ed by breeding or recombinant, genetically modi by Weight, 50 to 100% by Weight, but preferably in contents ?ed plants, Which have a content of at least one of the desired of more than 76% by Weight, such as 76 to 99% by Weight or ingredients Which is higher by comparison With the corre 80 to 98% by Weight or 85 to 96% by Weight, in each case sponding unmodi?ed plant. These plants are in particular based on the total Weight of the dry extract. selected from plant of the genus Rheum spp., Aslragalus spp., [0043] Preference is further given to active ingredient com Cassia spp. or Picea spp. or active ingredient-containing binations Which have a content of less than 0.5% by Weight, plant parts. Nonlimiting examples of suitable species of these such as, for example, 0-0.49% by Weight or 0.001 to 0.3 or genera are Rheum undulalum, Rheum palmalum, Rheum 0.01 to 0.2 or 0.01 to 0.1% by Weight ofanthraquinone and/or Zalaricum, Rheum o?icinale, Rheum willrockii, Rheum allai anthraquinoids (in each case based on the dry Weight of the US 2012/0195942 A1 Aug. 2, 2012

active ingredient combination). Anthraquinoids are in this [0061] a) providing an active ingredient-containing part of connection to be understood in the Widest sense as substances a medicinal plant, Where appropriate in comminuted form, having a basic anthraquinone structure. [0062] b) adding an aqueous extractant thereto, [0044] A “dry extract” in the sense of the invention is one [0063] c) after the extractant has acted, obtaining a liquid Where the residual moisture content, i.e. the residual content extract phase from the mixture and, Where appropriate, of Water and/or organic liquid (such as extractant), is less than repeating the extraction several times, and about 5% by Weight, in particular less than 2% by Weight, [0064] d) removing the extractant from the liquid extract such as, for example, 0 to 1.5% by Weight or 0.1 to 0.5% by phases obtained in this Way. Weight, in each case based on the total Weight of the resulting [0065] This preferably entails carrying out an extraction dry extract. With an aqueous extractant at a pH of the mixture in the [0045] Nonlimiting examples of suitable solid dosage alkaline range. forms are those Where the active ingredient combination con [0066] The extracted medicinal plant is selected in particu sists substantially of about lar from plants of the genus Rheum spp, Aslragalus spp, [0046] 60-66% by Weight rhaponticin Cassia spp or Picea spp. [0047] 30-35% by Weight deoxyrhaponticin [0067] In a preferred variant of the preparation process, the [0048] 0-2% by Weight rhapontigenin; total amount of the active ingredient or of the active ingredi [0049] 0-2% by Weight deoxyrhapontigenin. ent combination is mixed in portions With the pharmaceuti [0050] Preferred solid dosage forms have a total active cally acceptable carrier, such as, for example, Avicel or a ingredient content of about 2 to 20 mg per dose unit. comparable cellulose-based carrier, in particular microcrys [0051] The invention relates in particular to solid dosage talline cellulose, and the mixing process is repeated after each forms Which have a sugar-free, in particular mono- or disac addition of carrier, but at least one or tWice. In particular, a charide-free, such as, for example, lactose-free, core. ball mill is used in this case for mixing over a period of from 30 minutes to 3 hours, such as, for example, 1 to 2 hours. It is [0052] 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 [0053] 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 [0068] In a further variant of the process, the active ingre ers such as , such as, for example, diethyl . dient core is provided With a gastro-resistant, preferably plas Coating compositions suitable in particular for producing gastro-resistant, plasticiZer-free coatings are selected from ticiZer-free, coating. knoWn natural and synthetic coating compositions (cf., for [0069] In a further preferred variant in this connection, the example, Voigt, PharmaZeutische Technologie, 7th edition core is sugar-coated. 1993, Ullstein Mosby, Berlin). Particularly suitable coating [0070] The invention also relates to liquid dosage forms compositions are, Without being restricted thereto, shellac comprising an active ingredient or an active ingredient com and cellulose derivatives such as hydroxypropylmethylcellu bination as de?ned above in a content of about 0.1 to 20 lose derivatives such as, for example, hydroxypropylmethyl mg/ml, such as, for example, 0.5 to 15 or 1 to 10 or 2 to 5 cellulose acetate succinate, obtainable under the proprietary mg/ml, in a solvent mixture comprising Water and a pharma ceutically acceptable alcohol such as, in particular, ethanol. name AQOAT. The solvent mixture is preferably a Water/ethanol mixture [0054] 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 mg120 mg, a core Weight of 84 mg110 mg and an active liquid dosage forms are formulated in particular as drops for ingredient content of about 3 to 10 mg. oral administration. [0055] Further preferred solid dosage forms are those hav [0071] 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 de?ned above in a content of about 1 to 12, or 2 to ing 15% by Weight, such as, for example, 10.1 to 4 or 10.5 to 6, mg of active ingredient or active ingredient combination 3 or 11 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 speci?ed 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 [0056] 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 [0057] 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 [0072] The invention also relates to a composition compris [0058] b) the mixture is consolidated to give the active ing a solid, semisolid or liquid dosage forms as de?ned above. ingredient core. Compositions in the sense of the invention are in particular [0059] 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. [0073] A further aspect of the invention relates to the use of [0060] The active ingredient used according to the inven a solid, semisolid or liquid dosage form as de?ned 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 de?ned above for the treatment of meno US 2012/0195942 A1 Aug. 2, 2012

pausal symptoms in Women, especially for the treatment of [0080] In the production of the compositions, active ingre menopausal symptoms in the pre- or postmenopause, and dients of the invention are usually mixed With an excipient or menopausal symptoms owing to a natural or therapeutically diluted. Excipients may be solid, or semisolid materials induced menopause. Menopausal symptoms are in this con Which serve as vehicle, carrier, adsorbent or medium for the nection in particular hot ?ushes, sWeaty episodes, sleep dis active ingredient or the active ingredient combinations. orders, irritability, psychological and mental exhaustion, [0081] Examples of suitable excipients include, unless sexual problems and urinary tract symptoms. The invention indicated otherWise, lactose, dextrose, sucrose, sorbitol, man also relates to their use for treating juvenile oligomenorrhea nitol, starches, gum acacia, calcium phosphate, alginates, and dysmenorrhea, primary and secondary amenorrhea or tragacanth, gelatin, calcium silicate, microcrystalline cellu endometritis. lose, polyvinylpyrrolidone, cellulose and methylcellulose. [0074] Owing to the excellent tolerability of the active The formulations may in addition comprise usual pharmaceu ingredients or active ingredient combinations described tically acceptable ancillary substances such as lubricants, for above, the invention also relates to the use during long-term example talloW, magnesium stearate and mineral oil; Wetting therapy, Which is possible Without limitation in time. The agents; emulsifying and suspending agents; preservatives daily dose to be administered in this connection can be in the such as methyl and propyl hydroxybenZoates; antioxidants; range from 0.1 to 20 mg or 0.5 to 15 mg, 1 to 10 or 4 to 8 mg antiirritants; insulating agents; tablet-coating aids; emulsion of active ingredient or active ingredient combination such as, stabiliZers; ?lm formers; gel fomers; odor-masking agents; for example, ERr 731®. taste correctives; resins; hydrocolloids; solvents; solubiliZ [0075] A treatment in the sense of the invention includes ers; neutraliZers; permeation promoters; pigments; quater both an acute and a preventive administration of compositions nary ammonium compounds; refatting and superfatting of the invention. agents; ointment, cream or oil bases; silicone derivatives; [0076] Finally, the present invention also relates to the use spreading aids; stabiliZers; sterilants; tablet excipients such as of the active ingredients or active ingredient combinations binders, ?llers, lubricants, disintegrants or coatings; propel described above, e. g. formulated in one of the dosage forms lants; dessicants; opaci?ers; thickeners; Waxes; plasticizers. described above, for selective activation of ERB, i.e. activa An arrangement concerning this is based on expert knoWl tion of ERB Without simultaneous substantial or detectable edge as set forth for example in Fiedler, H. P., Lexikon der activation of ERG. in vivo or in vitro. Hilfsstoffe fiir PharmaZie, Kosmetik und angrenZende Gebi [0077] The invention therefore relates in particular also to ete, 4th edition, Aulendorf: ECV-Editio-Kantor-Verlag, the use of an active ingredient or of an active ingredient 1996; cf. also Hager’s Handbuch der PharmaZeutischen combination as de?ned above (such as in particular of ERr Praxis, Springer Verlag, Heidelberg. 731 or similar combinations comprising rhaponticin and/or [0082] Solvents Which are suitable according to the inven deoxyrhaponticin) for treating one of the disorder de?ned tion for producing formulations and Which should be particu above by selective activation of ERB, i.e. activation of ERB larly mentioned are monohydric or polyhydric alcohols such Without simultaneous substantial or detectable activation of as, in particular, ethanol, glycerol and mixtures thereof With ERot. Water, such as, for example 1 to 50% by volume ethanol in Water. 2. Further Speci?c Re?nements of Formulations [0083] Dosage forms or pharmaceutical compositions of According to the Invention the invention are produced by using generally knoWn meth ods of pharmaceutical technology as described for example in Voigt, PharmaZeutische Technologie, 7th edition 1993, Ull a) Dosage Forms stein Mosby, Berlin. [0078] The teaching of the invention is directed especially [0084] 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 [0079] 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 de?ned above. pastes or patches, and liquid pharmaceutical forms such as [0085] 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, [0086] 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 US 2012/0195942 A1 Aug. 2, 2012

solidating the mixture to give the active ingredient core. This yrhaponticin and deoxyrhapontigenin) and of piceatannol entails dissolving or dispersing the active ingredient or the precursors (especially rhaponticin and rhapontigenin) each active ingredient combination in an inert liquid, mixing it being represented by one compound. With the carrier and removing the solvent during or after the [0099] 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 [0087] 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® dry extract in a suitable solvent such the total Weight of the resulting dry extract. A “dry extract” in as, for example, a Water/alcohol 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 [0088] Semisolid dosage forms of the invention, such as, as extractant) is less than about 5% by Weight, in particular for example, gels, are produced for example by dissolving the less than 2% by Weight, such as, for example, 0 to 1.5% by active ingredient(s), such as, for example, an ERr 731® dry Weight or 0.1 to 0.5% by Weight, in each case based on the extract, in a suitable solvent such as, for example, a Water/ total Weight of the resulting dry extract. alcohol mixture, alcohol or glycerol, and incorporating the [0100] A further preferred embodiment provides an extract solution into the previously sWollen gel former, Where appro Which is substantially free of aglycone derivatives of rhapon priate together With further conventional additions. ticin and deoxyrhaponticin, such as, in particular, resveratrol [0089] The mode and duration of administration of the and piceatannol. “Substantially free” means an aglycone con medicaments of the invention are subject to the decision of the tent of less than 5% by Weight, in particular less than 2% by treating physician. The latter can establish a suitable dose and Weight such as, for example, less than 1% by Weight or 0.1% an appropriate do sage regimen depending on the chosen route by Weight, such as 0 to 0.05% by Weight, in each case based of administration, on the ef?cacy of the speci?c active ingre on the total Weight of rhaponticin and deoxyrhaponticin. dient composition, the nature and severity of the disorder to [0101] Active ingredient combinations Which are further be treated, the patient’s condition and his response to the preferably prepared are those having a total hydroxystilbene therapy. For example, a suitable single dose may comprise content of more than 90% by Weight such as, for example, 91 about 0.1 to 50 mg, such as, for example, 2 to 12 mg, of active to 100% by Weight, or 92 to 99 or 93 to 98 or 94 to 97% by ingredient or active ingredient combination as de?ned above, Weight. and be administered 1 to 3 times a day until the desired result [0102] Further active ingredient combinations Which are of the treatment is to be observed. preferably prepared are those having a content of less than b) Preparation of a Drug Extract Which can be Used Accord 0.5% by Weight, such as, for example, 0-0.49% by Weight or ing to the Invention 0.001 to 0.3 or 0.01 to 0.2 or 0.01 to 0.1% by Weight, of [0090] Drug extracts Which can be used according to the anthraquinone and/or anthraquinoids (in each case based on invention are preferably prepared by the dry Weight of the active ingredient combination). [0091] a) providing a hydroxystilbene-containing part of Anthraquinoids are in this case to be understood in the Widest a medicinal plant, Where appropriate in comminuted sense as substances having a basic anthraquinone structure. form, [01 03] In a preferred embodiment, the medicinal plant to be [0092] b) adding an aqueous, organic or aqueous-organic extracted is selected from natural plants and plants modi?ed extractant thereto, by breeding or recombinant, genetically modi?ed plants [0093] c) after the extractant has acted, obtaining a liquid Which have a content of at least one of the desired ingredients extract phase from the mixture, and Where appropriate Which is higher by comparison With the corresponding repeating the extraction several times, and unmodi?ed plant. These plants are selected in particular from [0094] d) removing the extractant from the liquid extract plants of the genus Rheum spp., Aslragalus spp., Cassia spp. phases obtained in this Way. or Picea spp. or active ingredient-containing plant parts. Non [0095] In particular, the extract obtained in this Way limiting examples of suitable species of these genera are includes at least one compound selected from rhaponticin, Rheum undulalum, Rheum palmalum, Rheum Zalaricum, deoxyrhaponticin, rhapontigenin, deoxyrhapontigenin as salt Rheum o?icinale, Rheum willrockii, Rheum allaicum, Rheum or in phenolic form, in a stereoisomeric form thereof, such as reliculalum, Aslragalus complanalus, Cassia garrelliana and cis or trans form, or as mixture of such stereoisomeric forms. Picea silchensis. It is additionally preferred to employ [0096] HoWever, the extracted hydroxystilbenes are prefer medicinal plants as single varieties. ably substantially in the trans form. Salts are in particular the [0104] The skilled Worker is additionally aWare that genera/ alkali metal and alkaline earth metal phenolates of the above species differing in provenance and differing in age (i.e. har compounds Which have one or more free phenolic hydroxyl vest at various times of the vegetation period) can be groups. If a plurality of hydroxyl groups is present, they may employed, in turn possibly in?uencing the nature, amount be partly or completely in the salt form. and composition of the hydroxystilbenes and mixtures Which [0097] The resulting plant extracts or individual compo can be isolated therefrom. It is likeWise possible in principle nents thereof can, as already mentioned, also be subjected to to use various plant parts such as roots, rhiZomes, leaves derivatiZation reactions in order to obtain so -called functional and/or stalks. derivatives . [0105] The respective plant part or mixture of plant parts [0098] An active ingredient combination of at least tWo of can, if expedient, be mechanically treated such as, for the abovementioned compounds is preferably obtained, such example, ground, chopped, reeled, crushed or cut. If expedi as, for example, 2, 3, 4, 5, 6, 7 or 8 individual compounds, ent, predrying is also possible, such as, for example, 2 hours With the group of resveratrol precursors (especially deox to 2 days at 30 to 500 C., in order to reduce the liquid content. US 2012/0195942 A1 Aug. 2, 2012

[0106] 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 rhaponli [0118] The precipitate can be Washed for example With cum. puri?ed Water, and this serves in particular to remove remain [0107] The invention relates in particular to a process in ing acid. Which a hydroxystilbene-containing percolate is prepared [0119] Remaining liquid is removed from the extract by from the drug. A “percolation” means a continuous extraction drying, eg 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 per se, eg in a drying oven. Freeze drying is extract. likeWise possible. [0108] An alternative possibility is also a continuous or [0120] 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. [0109] The temperature during the extraction according to EXPERIMENTAL SECTION the invention is usually in the range from 10 to 50° C., such as, General Methods for example, 25 to 35° C. The pressure is usually atmospheric pressure. If a speeding up of the rate of extraction or quality of [0121] 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 [0110] The extraction may take, depending on the chosen a) Sample Preparation: conditions such as the nature of the drug, batch siZe, extrac tant and temperature used, from 1 hour to several days, such [0122] 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 amber glass vessel, treated in an [0111] 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 [0123] 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 [0112] In one variant of the process, an extraction is carried the folloWing system parameters: out With an aqueous extractant Which is substantially free of [0124] Sample loop: 20 [1.1 organic solvent, such as, in particular, Water, preferably puri [0125] Column: Lichrospher 5p. RP 18, 250><4 mm ?ed Water, at a pH of the mixture in the alkaline range, With [0126] Precolumn: Lichrospher 5p. RP 18, 5x4 mm the pH of the mixture being in particular in the range from [0127] Column temperature: 250 C. about 11 to 12, such as, for example, about 11.3 to 11.8. [0128] Eluent A: Acetonitrile/dist. Water/phosphoric acid [0113] The pH of the mixture is adjusted for example With 85%, 15/85/0.05 (parts by volume) the aid of an inorganic base selected from alkali metal and [0129] Eluent B: Acetonitrile/dist. Water/phosphoric acid alkaline earth metal hydroxides such as, for example, calcium 85%, 80/20/0.05 (parts by volume) hydroxide or calcium oxide. It is possible for this purpose for [0130] Flow rate: 1.5 ml/min example to prepare a concentrated quicklime solution by [0131] Column ?ushing: 15 min With eluent 50% B; equili dissolving 3 to 8 parts of CaO in 20 parts of puri?ed Water. bration time 15 min This solution is strongly alkaline and has a pH in the range [0132] Detection: 310 nm from about 12 to 13, such as, for example, of about 12.4 to [0133] HPLC: Kontron Kroma 2000 12 .6. [0114] The ratio of the amounts of introduced drug to base Gradient: such as, for example, calcium hydroxide (calculated as cal cium oxide) can be according to the invention in the range [0134] fromabout5:1 to 20:1, suchas about8:1 to 12:1 or9:1 to 11:1. [0115] The process is preferably carried out in such a Way that the desired hydroxystilbenes are precipitated from the Time % B resulting alkaline liquid extract phase, for example by adjust ing the pH of the extract to a value in the range from about 3 0.0 0 0.5 0 to 4, such as, for example, 3.2 to 3.8, or 3.4-3.6, and, Where 7.5 75 appropriate, subsequently removing the precipitate, Washing 8.5 100 Where appropriate and drying Where appropriate. 9.5 0 [0116] Used for the acidi?cation is any inorganic or organic 12.5 0 acid, such as, for example, hydrochloric acid or sulfuric acid, but in particular organic acids such as formic acid or acetic [0135] The retention times resulting under the system con acid. ditions indicated above are as folloWs: [0117] Before removal of the precipitate it may be expedi Rhaponticin: about 5.5 min ent to leave the batch to stir for some hours or days in order to Deoxyrhaponticin: about 6.8 min US 2012/0195942 A1 Aug. 2, 2012

Rhapontigenin: about 7.2 min [0147] Homogeneous mixing of the quicklime With the Deoxyrhapontigenin: about 9.0 min drug alters the pH of the mixture. It is then in the range from [0136] For a quantitative determination, the respective peak 11.3 to 11.8, thus preventing precipitation of rhaponticin, areas are found and compared With the corresponding peak because the phenolic form has been converted into a pheno areas of a standard extract of knoWn composition. late form. Despite the high oxalic acid content, the pH can be kept in the alkaline range. This is attributable to the fact that Preparation Example 1 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 [0148] Rhaponticin is extracted from the root by the sub Hydroxide Solution sequent percolation With puri?ed Water. After completion of the percolation, a pH of 3 .4 to 3.6 is adjusted by adding acetic [0137] 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 rhaponticin through 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 stand for 5 days. It is then ?ltered. Rhaponticin remains as Drug (radix rheum rhaponricum) 50.0 kg Calcium oxide 5.0 kg yelloWish substance on the ?lter. Puri?ed Water 190.0 kg [0149] 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. [0138] The yield Which can be achieved in this case is betWeen 2 and 3 kg per 50 kg of drug. Preparation Example 2 [0139] The preparation takes place in the folloWing steps: Preparation of a Dry Extract from Rhapontic Rhu [0140] a) Firstly 5 kg of calcium oxide are introduced into barb Root With Various Organic Solvents a plastic tub and made into a slurry With 20 kg of puri?ed Water. The formation of calcium hydroxide (quicklime) [0150] The constituents mainly detectable in the rhapontic Which takes place under these conditions leads to a large rise rhubarb root used as drug here belong to the group of hydrox in temperature of the solution. The calcium hydroxide can ystilbenes. Present from this group in the roots are rhaponti therefore be used further only after cooling. The temperature cin (Rh) With a content of about 6% and deoxyrhaponticin of the solution is then 30° C. to 35° C. (DRh) With a content of about 4%. [0141] b) 50 kg of drug are introduced into a mixer, and the [0151] It is possible by exposure to the solvent systems abovementioned quicklime is added. In order to remove the indicated beloW, in a 100-fold quantity at room temperature quicklime as completely as possible from the plastic tub, it is for 10 minutes With shaking or stirring, to extract the propor rinsed With 10 kg of puri?ed Water. This Washing liquid is tions summarized beloW: likeWise put in the mixer. [0142] c) The drug homogeneously mixed With quicklime is introduced into a percolator and covered With 160 kg of puri?ed Water. The percolator remains closed for 48 hours. Ethanol 86% R11 100.8% DRh 99.5% The percolate is then collected in a suitable vessel at a How Ethanol 15% R11 77.1% rate of 50 ml/min. The percolation is continued until no fur DRh 75.5% ther percolate emerges. The drug mass is not squeeZed out Acetone Rh 88.3% after completion, but is discarded. DRh 96.6% Water, alkaline Rh 75.5% [0143] d) While monitoring continuously, concentrated (pH 11, adjusted With CaO solution) DRh 60.5% acetic acid is added to the percolate until a pH in the range from 3 .4 to 3.6 is reached. In order to achieve precipitation of the extract Which is as complete as possible, the mixture is left [0152] No useful results Were achieved With heptane. to stand for 5 days. [0153] The respective yields of crude extracts in propor [0144] e) The dry extract is obtained by ?ltration through tions by mass (based on drug employed) are as folloWs: Buchner funnels under applied vacuum. Finally, the extract is Washed With 10 to 20 kg of puri?ed Water. [0145] f) The dry extract obtained after ?ltration is dried in Ethanol 86% 35.5% a drying oven at 40° C. until a residual moisture tolerance not Ethanol 15% 32.2% exceeding 1% is reached. Acetone 21.4% [0146] Rhaponticin is readily soluble in aqueous solutions Heptane 0% 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 [0154] 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 1/3 in bound form), this must be constituents rhaponticin (about 30%) and deoxyrhaponticin neutralized during the isolation in order to prevent the pH (about 22%), comprises a further stilbene, Which has not as drifting into the acidic range and thus to inhibit premature yet been investigated, in a proportion of about 20% in the precipitation of the rhaponticin. This is achieved by using extract. Besides these, the aglycones rhapontigenin (about calcium oxide. The latter is employed as quicklime solution 8%) and deoxyrhapontigenin (about 2%) and a further 9 With a pH of 12.4-12.6. compounds Which total about 20% are obtained. US 2012/0195942 A1 Aug. 2, 2012

[0155] 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. [0156] Extraction With alkaline Water (cf. conditions in [0166] 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 [0157] 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 15% by Weight (deter dry extract. Rhapontigenin and deoxyrhapontigenin together mined according to Ph. Eur. 5th edition 2005 (SO/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 of2.5%. [0167] The mixture of Avicel® 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 Production of a Solid Dosage FormiMinitablet stated tabletting aids (Without magnesium stearate), mixed in a suitable mixer (e.g. drum hoop mixer of type Standard RR 1. Production of the Tablet Core: M 200, from Engelsmann AG/LudWigshafen) for at least 30 min. Addition of magnesium stearate is folloWed by mixing [0158] A solid tablet core is produced using the folloWing again for at least 5 min. active ingredients and ancillary substances in the stated ratios of amounts (Prparts by Weight). The ingredients are mixed [0168] The compression takes place in a suitable tablet press (e.g. rotary of type Perfecta Fette 2000, from Fette/ and tabletted in three different Ways: SchWarZenbeck): a) Tablet Core Formulation: Core Weight: 84 mg14.2 mg maximum variation Punch: 7 mm diameter, domed [0159] [0169] The ERr-731 content per core is about 4 mg15%.

2. Production of the Gastro-Resistant Coated Tablet

Puri?ed dry extract according to 3.6 P [0170] 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 ®) Microcrystalline cellulose (e.g. Avicel ®) 57.0 P (140%) late and diethyl phthalate, dissolved in isopropanol and ethyl Sorbitol 8.0 P (140%) acetate, is applied to the tablet cores using a coating system. Talc 2.5 P (140%) [0171] Macrogol is dissolved in puri?ed Water. The ingre Makrogol 6000 (polyglycol) 1.6 P (140%) dients sugar (sucrose or isomalt), calcium carbonate, talc, Polyvidone (K value about 25, e.g. Kollidon ® 25) 1.6 P (140%) Sodium dodecyl sulfate (e.g. Texapon ® K 12) 0.5 P (140%) titanium dioxide and the tWo povidones are mixed and stirred Magnesium stearate (vegetable) 0.8 P (140%) into the liquid. The suspension is stirred in a jet ?oW mixer (e.g. Rototron of type RTA 70-50) for 20 minutes. 75.6 P (140%) [0172] The sugar-coating suspension is applied to the sealed core With the aid of an automatic coater. The process is [0160] It is possible by varying the Weighed amount of ERr repeated until an average Weight of 150 mg per coated core is 731® and/ or varying the amount of microcrystalline cellulose reached. Finally, the polishing Wax is applied and then rolling to obtain any desired ERr 73 1 ® contents in the untreated core is continued until a high gloss is obtained. (such as, for example, 2, 4, 6, 8, 10, 12 mg per tablet). [0173] Final Weight of the gastro-resistant coated tablet: 150 mg17.5 mg maximum variation. b) Mixing of Drug and Carrier [0174] In this Way, tWo different tablet forms4one con taining sugar and onesugar-freeiare produced, employing Mixing Variant a: the respective ancillary substances in the parts by Weight [0161] 1.2 P of ERr 731® are triturated in portions With indicated beloW. Avicel® in a ball mill and then, after addition of the other a) Gastro-Resistant Coated Minitablet4Containing Sugari ancillary substances, mixed and tabletted as described beloW. With PlasticiZer in the Coating [0162] Mixing Variant b: [0163] ERr 731® (1 g/l ofsolvent) is dissolved in a suitable Ancillary Substances: solvent (e.g. ethanol/Water mixture 86% v/v ethanol) and [0175] adsorbed on Avicel®, dried (at 400 C. for at least 48 hours) and, after addition of the other ancillary substances, mixed and tabletted as described beloW. [0164] Mixing Variant c: Coating: Eudragit L12.5% dry matter 1.350 kg (140%) Diethyl phthalate 1.749 kg (140%) [0165] The total amount of Avicel® is divided into three Cellulose acetate phthalate 7.770 kg (140%) equal portions. The ?rst portion is mixed With the total Isopropyl alcohol 75.600 kg (140%) amount of ERr 731® and triturated in a laboratory ball mill Ethyl acetate 77.600 kg (140%) (e.g. type 1-25 LK, Alpine, Augsburg) for at least 120 min Talc 2.000 kg (140%) Sugar coating: Talc 7.182 kg (140%) utes. The second portion of Avicel® is then added, and the Sugar 28.747 kg (140%) mixture is again triturated in the laboratory ball mill for at Calcium carbonate 6.410 kg (140%) least 120 minutes. After addition of the third portion of Titanium dioxide E 171 0.635 kg (140%) Avicel®, brief mixing is again carried out. Subsequently, US 2012/0195942 A1 Aug. 2, 2012

-continued -continued Povidone (K value about 25, 0.756 kg (140%) Ancillary Substances: kg (140%) e.g. Kollidon ® 25) Povidone (K value about 90) 0.332 kg (140%) Macrogol 35,000 0.635 Macrogol 35,000 0.635 kg (140%) Water 10.500 Water 10.500 kg (140%) Polish: 95% carnauba Wax 0.108 Polish: 95% carnauba Wax, 0.108 kg (140%) 5% bleached Wax 5% bleached Wax (e.g. Capol 1295 PH) (e.g. Capol 1295 PH)

_ _ _ _ [0182] a) Variant B b) Gastro-Resistant Coated MinitabletiSugar-FreeiWith PlasticiZer in the Coating

AIlCill ary Substances: Ancillary substances: kg 140% [0176] Coating: Eudragit L12.5% dry matter 0.400 Aqoat Hydroxypropylmethylcellulose 5 .420 acetate succinate Coating: DiethylEudragit phthalate L12.5% dry matter 1.7491350 kg (140%) gfnrg?dlltiizrholEthp plygw 55'000

Cellulose acetate phthalate 7.770 kg (140%) Sugar coating:. Talcano 0 9.182' Isopropyl alcohol 75.600 kg (140%) Sn at 28 747 Ethyl acetate 77.600 kg (140%) C 1? . b t 6'410 Sugar coating: Talc 7.482 kg (140%) Ti 01pm caring?ln 0'635 Sorbitol and/or isomalt 28.747 kg (140%) l amilm OX1 e ' Calcium carbonate 6.410 kg (140%) Polyvldqn? (K Valu? about 25’ 0'756 Titanium dioxide E 171 0.635 kg (140%) ;'g' if“??? @125? b t 90) 0 332 Povidone (K value about 25, 0.756 kg (140%) 0V1 0H6 Va 116' a on ' ?ig- Konidon ® 25) Macrogol 35,000 0.635 Povidone (K value about 90) 0.332 kg (140%) . _ Wat?r 10500 Macrogol 35,000 0.635 kg (140%) Polish. 95% carnauba Wax 0.108 5% bleached Wax Water 10.500 kg (140%) ( C l 1295 PH) Polish: 95% carnauba Wax, 0.108 kg (140%) 6'g' apo 5% bleached Wax (e.g. Capol 1295 PH) Formulation Example 3

Formulation Example 2 Production of a Solid Dosage FormiMinitablet Sugar-Free Without PlasticiZer Production of a Solid Dosage FormiMinitablet Containing Sugar Without PlasticiZer [0183] a) prodllction of the Tablet Core . [0184] Production takes place in analogy to formulation [0177] a) Production of the Tablet Core example 1, but using isomalt instead of Avicel. [0178] Production takes place in analogy to formulation [0185] a) Production of the Gastro-Resistant Coated Tablet example 1. [0186] Production takes place in analogy to formulation [0179] a) Production of the Gastro-Resistant Coated Tablet example 2, but using isomalt instead Of Sugar. [0180] Production takes place in analogy to formulation [0187] a) Variant A example 1, but With use of shellac (Variant A) or Aqoat (Vari ant B) instead of cellulose acetate phthalate/diethyl phthalate Anomaly Substances: kg (140%) (plasticiZer). [0181] a) Variant A Coating: Eudragit L12.5% dry matter 0.400 CAPOL 5270 PH 8% 60.000 (shellac solution) = 4.8 kg dry matter (shellac) Isopropyl alcohol 4.000 Ancillary substances: kg (140%) Ethanol 96% 3200

I I Talc 2.000 Coating: Eudragit L12.5% dry matter 0.400 Sugar coating: T310 7182 CAPOL 5270 PH 8% 60.000 Isomalt 28 747 (Shdlac Solution) : Calcium carbonate 6:410 4-8 kg dry matter (Shellac) Titaiiiiiiii oxide E 171 0.635 Isopropyl aolcohol 4'000 Polyvidone (K value about 25, 0.756 E?lw‘nol 96A) 3'200 e.g. Kollidon ® 25) I _ Ta 0 2'000 Povidone (K value: about 90) 0.332 Sugar coating. Talc 7.182 Macrogol 35,000 0635 Suga? 28-747 Water 10.500 CIalClPm caIrbOInam 6'410 Polish: 95% carnauba Wax 0.108 Titanium dioxideE 171 0.635 5% bl?ach?d Wax Polyvidone (K value about 25, (6 g capol 1295 PH) e.g. KOllidOn ® 25) 0.756 ' ' Povidone (K value: about 90) 0.332 US 2012/0195942 A1 Aug. 2, 2012

[0188] b) Variant B a) Variant A: Formulation:

Ancillary substances: kg (140%) [0193] Coating: Eudragit L12.5% dry matter 0.400 Aqoat 5.420 Distilled Water 12.500 Gelatin 1 part Isopropyl alcohol 4.000 Puri?ed Water 2 parts Ethanol 86% 55.000 Glycerol 85% (+ERr 731 ®) 5 parts Talc .2000 Sugar coating: Talc 7.182 Isornalt 28.747 Calcium carbonate 6.410 b) Variant B: Titanium oxide E 171 0.635 Polyvidone (K value about 25, 0.756 e.g. Kollidon ® 25) [0194] Same formulation but With suitable preservatives Povidone (K value: about 90) 0.332 such as, for example, sorbate, benZoate. PHB ester. Macrogol 35,000 0.635 [0195] The gelatin is introduced in each case into puri?ed Water 10.500 Water and alloWed to sWell until the mixture has become Polish: 95% carnauba Wax 0.108 5% bleached Wax glassy. Glycerol 85% With active ingredient is then added and (e.g. Capol 1295 PH) heated, but not above 65° C. The suppositories are then cast in a conventional Way.

Formulation Example 4 Formulation Example 6

Production of a Semisolid Dosage FormiVaginal Production of a Liquid Dosage FormiDrops Gel [0196] a) Dissolving Tests With ERr 7310 in Ethanol and [0189] Production takes place using conventional methods Glycerol: by the tWo following variants: Content of the Extract: a) Variant A: [0197] 61.9% rhaponticin [0190] Hydroxypropylmethylcellulose (hypromellose [0198] 29.9% deoxyrphaponticin [0199] TestA: 200 mg of dry extract in 50 ml of glycerol R: USP) or another gel former is alloWed to sWell With 2-10% by Weight in puri?ed Water. The ERr 73 1® (preparation example 1), dissolved in glycerol, is then incorporated. The amount of glycerol may be up to 50% of the Weight of the gel. ERr 731® 55.1% rhaponticin (89.0% oftheory) 27.1% deoxyrhaponticin (90.6% oftheory) 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 to the gel. Adjustment of the pH is also possible. As alterna [0200] Test B: 200 mg of dry extract in 50 ml of ethanol tive to glycerol it is also possible to use 30-86% by volume 30% R; ethanol. b) Variant B: 52.2% rhaponticin (84.3% oftheory) 25.2% deoxyrhaponticin (84.2% oftheory) [0191] Carbomer (Carbopol) is dissolved With 0.5-5% by Weight in puri?ed Water, and the desired pH is adjusted (e.g. [0201] Test C: 200 mg of dry extract in 50 ml of ethanol KOH, NaOH, NH3). If necessary, a preservative (e.g. sorbic 50% R; acid and its salts) is admixed. After formation of a clear gel, ERr 731® (preparation example 1) is dissolved up to 0.5% by Weight in 30-86% by volume ethanol and added. As alterna tive to ethanol, it is also possible to use glycerol. 5 8. 8% rhaponticin (95.0% oftheory) 29.0% deoxyrhaponticin (97.0% oftheory) Formulation Example 5 [0202] Test D: 200 mg of dry extract in 50 ml of ethanol Production of a Semisolid Dosage FormiVaginal 86% R; Suppositories

[0192] Suppositories With a size of 1 to 15 g With a content 59. 8% rhaponticin (96.6% oftheory) of 1 to 12 mg of ERr 731° (preparation example 1) dissolved 29.5% deoxyrhaponticin (98.7% oftheory) in glycerol (85% n 20/D:1.45085) are produced in a conven tional Way by tWo different variants. US 2012/0195942 A1 Aug. 2, 2012

b) Production of Drops: hormones and anti steroids on alkaline phosphatase activity in [0203] Drops are produced by dissolving dry extract human endometrial cancer cells (IshikaWa Line). Cancer Res. 46: 2771-2774, and modi?cations described in Wober J, according to test B in ethanol 30% R and ?ltering Where WeillWange I, Vollmer G (2002) Stimulation of alkaline phos appropriate. phatase activity in IshikaWa cells induced by various phy Test Example 1 toestrogens and synthetic estrogens. J. Biochem. Mol. Biol. 83:227-233. In Vivo Metabolism of the Dry Extract ERr 731® [0211] Table 2 presents the concentrations for the positive control (17[3-estradiol) and the test substances used in the [0204] For further elucidation of the mode of action, ERr 731® Was administered orally by capsule to 3 male and 3 assay. female dogs (pure-bred beagles, Weight 6-9 kg, age 6-8 months) in a dose of 100 mg of ERr 731°/kg of body Weight. TABLE 2 At various time intervals, blood Was taken from the animals Test substance Concentration (M)l and blood plasma Was obtained. The plasma Was investigated for ERr 731® ingredients and metabolites. It Was surprisingly Estradiol 10’6 Resveratrol 1073-10’5 possible to detect both in male and in female animals signi? trans-Rhapontigenin 1073-10’5 cant amounts of the metabolite piceatannol and small Deoxyrhap ontigenin 1078-10’5 amounts of the metabolite resveratrol. Maximum plasma lev Piceatannol 104-10’5 els of these metabolites Were reached after about 24 h. The cis-Rhapontigenin 1073-10’5 plasma levels of piceatannol Were distinctly higher than those Extract ERr 731 ® 0.00001-10 of resveratrol. The results of the test at the 24 h timepoint are lException: The concentration for the extract ERr 731 is indicated in [lg/ml depicted in FIG. 1. [0212] The results of test B) are depicted in FIG. 3. Test Example 2 [0213] Both tests are conclusive because all the positive and negative controls shoW their predicted effects (cf. FIGS. 2 and Investigation of the Activation of the Estrogen 3). The results of the tWo test systems described above dem Receptor ERG. by ERr 731® and the Ingredients or onstrate that neither ERr 73 1 ° nor its ingredients and metabo Metabolites Thereof lites have a signi?cant effect on the activation of ERG. (cf. [0205] It Was intended to ansWer the question of Whether FIGS. 2 and 3). It can thus be assumed that the activity of ERr ERr 731 activates ERot. The extract ERr 731® and the ingre 7310 is based on a molecular mechanism independent of dients or metabolites thereof (trans-rhapontigenin, deox ERot. yrhapontigenin, resveratrol, piceatannol and cis-rhapontige nin) Were therefore investigated, comparing With 176 Test Example 3 estradiol, for the estrogenic activity in established model Pharmacokinetics of ERr 731® Ingredients in systems. Female Subjects Test A): [0214] The intention Was to check Whether, after oral intake of ERr 731°, one of the ingredients of this active ingredient [0206] In a ?rst series of experiments, a recombinant yeast combination can be found again in the blood, in order to screen Was used (cf. E. Routledge and J. P. Sumpter, Ostro demonstrate that at least one of the constituents of this active genic activity of surfactants and some of their degradation ingredient combination or its metabolites is bioavailable. products assessed using a recombinant yeast screen, Envi [0215] A volunteer took 10 tablets of ERr 731o (dosage:40 rom. Tox. Chem. 1996). mg of ERr 731°) With liquid in the morning (8.00 h). Subse [0207] Saccharomyces cerevisiae cells Were stably trans quently, 10 ml of blood Was taken at various times (as indi fected With human ERG. both With a reporter gene consisting cated in FIG. 1) and the plasma Was obtained by centrifuga of the respective responsive promoter element fused to the tion. LacZ gene Which codes for [3-galactosidase. Estrogen treat [0216] These plasma samples Were processed as folloWs: ment (With estrogen or With a substrate having an estrogen 500 pl of plasma Were mixed With 25 pl of an internal standard like effect) of the cells activates, mediated by the estrogen Working solution (2.5 ng/ul rhaponticin or rhapontigenin in receptor, [3-galactosidase, leading to a red coloration of the methanol) and then mixed With 500 [1.1 of isotonic NaCl solu yeast cells, Which can be measured at 565 nm. tion and 2.5 ml of diethyl ether/butanol (9/1; v/v). After [0208] The test results are summariZed in FIG. 2. shaking and centrifugation (10 minutes at 4600 rpm), about 2 ml of the supernatant Were removed and dried under a stream Test B): of nitrogen (at 60° C.). The pellet Was taken up in 50 pl of [0209] In a second series of experiments, the data of the methanol. Addition of 200 pl of distilled Water Was folloWed estrogenicity measurement Were veri?ed by determining the by reneWed mixing, and 200 [11 Were pipetted into autosam induction of alkaline phosphatase in IshikaWa cells (human pler tubes (light-protected). 30 pl of the samples Were injected endometrial adenocarcinoma cells) Which had been trans for analysis into an LC-MS/MS system (PE Sciex API 3000). fected With an ERot-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 ERot-mediated response. mobile phase. [0210] The test is based on the description by Holinka C F, [0217] The analyZed results are summarized in FIG. 4. Hata H, Kuramoto H, Gurpide E (1986) Effects of steroid Rhaponticin Was detected in the blood, With a maximum at US 2012/0195942 A1 Aug. 2, 2012

3-4 hours (FIG. 4), Whereas rhapontigenin could not be [0224] Park et al,Arch. Pharm. Res. 2002, 25 (4), 528-533). found. Since rhaponticin is one of the main ingredients of ERr A further surprising fact is that the active ingredient combi 73 l®, it can be assumed that rhaponticin is an activity-code nation ERr 7310 has greater activity than the corresponding termining ingredient of ERr 73l®. This is all the more sur aglycones rhapontigenin and deoxyrhapontigenin. In addi prising since it Was previously assumed that only the agly tion the latter are not detectable under physiological condi cones, but not the glycosylated hydroxystilbenes, are active tions (tests not shoWn). (Park et al., Arch Pharm Res. 2002; 25:528-533). [0225] It has thus been possible to shoW for the ?rst time by the present invention the direct pharmacological activity of Test Example 4 the glycosides rhaponticin and deoxyrhaponticin (as main constituents of ERr 73 l®). Estrogen Receptor [3 (ER[3) Activation by ERr 73l® and Its Metabolites in the ER[3-Expressing Endome What is claimed is: trial Adenocarcinoma Cell Line HEC-lB 1. A solid dosage form comprising an active-ingredient containing solid core With a pharmaceutically acceptable car [0218] HEC-lB cells, a human endometrial adenocarci rier and an active ingredient content of about 1 to 20% by noma cell line, do not express either ERG. or ER[3. They Weight, based on the total Weight of the core, Wherein the therefore represent a possible Way of investigating, in a active ingredient is a hydroxystilbene-containing active human and endometrial context, ligand-dependent effects of ingredient or a hydroxystilbene-containing active ingredient substances on the transactivation mechanisms in relation to combination selected the group consisting of precursors of different receptor subtypes and different estrogen-responsive resveratrol and piceatannol, resveratrol, piceatannol, stereoi promoters. someric forms thereof and functional derivatives thereof, in [0219] An established ER[3/mC3 -luciferase system Was each case in the form of their salts or in the phenol form. employed. For this purpose, HEC-lB cells Were applied in 2. The solid dosage form as claimed in claim 1, Wherein the 24-Well plates With a density of 95 000 cells/Well (in Dulbec active ingredient or the active ingredient combination is co’s modi?ed Essential Medium (DMEM/Fl2)). The next obtainable from roots of Rheum rhaponlicum. day, they Were cotransfected With an ER[3-containing con 3. The solid dosage form as claimed in claim 1, Where the struct (hER[3/pSG2) and a triple-ERE-containing promoter/ active ingredient combination substantially comprises luciferase construct (mC3-Luc/pGL2) (Hillisch et al. Dis rhaponticin and deoxyrhaponticin in a ratio of about 2:28 to secting physiological roles of and 28:2 by Weight. beta With potent selective ligands from structure-based design. Mol. Endocrinol. 2004 July; 18:1599-609). The tran 4. The solid dosage form as claimed in claim 1, Wherein the active ingredient combination substantially consists of sient transfection took place using DOTAP (N-[l-(2,3-dio approximately 60-66% by Weight rhaponticin, 30-35% by leoyloxy)]-N,N,N-trimethylammoniumpropane methyl-sul Weight deoxyrhaponticin, 0-2% by Weight rhapontigenin; fate, Roth) as described by the manufacturer. and 0-2% by Weight deoxyrhapontigenin. [0220] After 24 hours, the cells Were treated With appropri 5. The solid dosage form as claimed in claim 1, Wherein the ate concentrations of the substances or substance mixtures to be investigated. l7[3-Estradiol (E2; 10 nm) served as positive total active ingredient content is about 2 to 20 mg per dose control, and a comparable volume of dimethyl sulfoxide unit. (DMSO) Was employed as solvent control. The incubation 6. The solid dosage form as claimed in claim 1, Wherein the time Was 24 hours. The cells Were then lysed. The Luciferase core is lactose-free core. Assay® kit (Promega) Was used to determine the luciferase 7. The solid dosage form as claimed in claim 1 in the form activity on the one hand, and the BCA0 kit (Sigma) Was used of a pill, of a tablet, of an extrudate or of granules. to determine the protein content on the other hand. The result 8. The solid dosage form as claimed in claim 1, Which has ing speci?c luciferase activities of the substances to be inves a gastro-resistant coating. tigated Were then compared With the DMSO control (100%). 9. The solid dosage form as claimed in claim 8, Wherein the [0221] At least three transfection experiments Were carried coating comprises substantially no plasticiZer. out for each test substance. After calculation of the relative 10. The solid dosage form as claimed in claim 1, having a luciferase activity in relation to the negative control (DMSO) total Weight in the range of about 150 mg120 mg, a core for each single experiment (set at 100%), the corresponding Weight of 84 mg:l0 mg and an active ingredient content of averages and standard deviations are formed. The results are about 3 to 10 mg per dose unit. represented graphically in the form of a bar diagram. Stu 11. The solid dosage form as claimed in claim 1, having a dent’s test Was used to calculate the signi?cance, the latter uniformity of active ingredient content (averaged over 10 or being ?xed as folloWs: * p<0.05; ** p<0.0l; *** p<0.00l. 20 randomly selected individual dose units) not exceeding [0222] The results for ERr 7310 are depicted in FIG. 5a, for 15% by Weight based on the total Weight of the dose unit. trans -rhapontigenin in FIG. 5b and for deoxyrhapontigenin in 12. A process for producing a solid dosage unit as claimed FIG. 50. They shoW that the substances activate the ER[3 in claim 1, comprising: do se-dependently and thus can be employed according to the a) mixing the active ingredient or the active ingredient invention. combination With a pharmaceutically acceptable carrier; [0223] The results of the tests described above demonstrate and the surprising ?nding that, contrary to previous assumptions, b) consolidating the mixture to give the active ingredient the “precursors” of resveratrol and piceatannol, i.e. the gly core. cosides rhaponticin and deoxyrhaponticin (as main constitu 13. The process as claimed in claim 12, Wherein the active ents of ERr 73l®) can be taken up per se by human cells. ingredient or active ingredient combination is dissolved or Skilled Workers have previously assumed that these glycones dispersed in an inert liquid and mixed With the carrier, and the are non-absorbable (cf. solvent is removed during or after the consolidating step. US 2012/0195942 A1 Aug. 2, 2012

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 or an 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 dosage form as claimed in claim 27 and a pharmaceutically 17. The process as claimed in claim 14, Wherein the extrac acceptable carrier. tion With the aqueous extractant is carried out at a pH of the 33. A method of treating menopausal symptoms, juvenile mixture in the alkaline range. oligomenorrhea and dysmenorrhea, primary and secondary 18. The process as claimed in claim 14, the medicinal plant amenorrhea or endometritis in a subject comprising admin is selected fromplants of the genus Rheum sp., Aslragalus sp., istering to the subject a solid dosage form, a liquid dosage Cassia sp. and Picea sp. form or a semisolid dosage form, Wherein the solid dosage 19. The process as claimed in claim 12, Wherein the total form, liquid dosage form or semisolid dosage form comprises amount of the active ingredient or of the active ingredient the hydroxystilbene-containing active ingredient or a hydrox combination is mixed in portions With the pharmaceutically ystilbene-containing active ingredient combination as acceptable carrier, and mixing is carried out after each addi claimed in claim 1. tion of carrier. 34. The method of claim 33, Wherein the active ingredient 20. The process as claimed in claim 19, Wherein mixing is or active ingredient combination brings about treatment by carried out after each addition With a ball mill over a period of selective activation of ERB. from 30 minutes to 3 hours. 35. The method of claim 33, Wherein the menopausal 21. The process as claimed in claim 12, Wherein the active symptoms occur in perk or postmenopause. ingredient core is provided With a gastro-resistant coating. 36. The method of claim 35, Wherein the menopausal 22. The process as claimed in claim 21, Where the coating symptoms are selected from the group consisting of hot comprises substantially no plasticiZer. ?ushes, sWeating episodes, sleep disorders, irritability, psy 23. The process as claimed in claim 12, Wherein the core is chological and mental exhaustion, sexual problems and uri sugar-coated. nary tract symptoms. 24. A liquid do sage form comprising an active ingredient or 37. The method of claim 33, Wherein the menopausal an active ingredient combination as claimed in claim 1 in a symptoms are the result of natural or therapeutically induced proportion of about 0.1 to 20 mg/ml in a solvent mixture menopause. comprising Water and a pharmaceutically acceptable alcohol. 38. A method for selective activation of ERB in vivo or in 25. The liquid dosage form as claimed in claim 24, Wherein vitro comprising contacting a cell With the hydroxystilbene the solvent mixture is a Water/ ethanol mixture With an ethanol containing active ingredient or a hydroxystilbene-containing content of from 10 to 50% by volume. active ingredient combination as claimed in claim 1. 26. The liquid dosage form as claimed in claim 24, formu lated as drops for oral administration. * * * * *