US 200900.48184A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0048184A1 Heger et al. (43) Pub. Date: Feb. 19, 2009

(54) METHOD FOR PRODUCING A DRUG (30) Foreign Application Priority Data EXTRACT THAT CONTAINS HYDROXYSTILBENE Feb. 4, 2005 (DE) ...... 10-2005-005-268.1 Feb. 4, 2005 (DE) ...... 10-2005-005-271.1 (76) Inventors: Peter Heger, Ubstadt-Weiher (DE): Reinhard Rettenberger, Publication Classification Goppingen (DE); Carl-Friedrich Spaich, Heiningen (DE) (51) A63L/70Int. Cl. (2006.01) Correspondence Address: CD7G 3/00 (2006.01) EDWARDS ANGELL PALMER & DODGE LLP A63L/05 (2006.01) P.O. BOX SS874 A6IP5/24 (2006.01)

(21) Appl. No.: 11F883,687 (52) U.S. Cl...... 514/25:536/18.5:568/729; 514/733 y x- - - 9 (22) PCT Filed: Feb. 3, 2006 (57) ABSTRACT (86). PCT No.: PCT/EP06/00955 The invention relates to a method for producing drug extracts that contain hydroxyStilbene from a vegetable drug and to the S371 (c)(1), use of various agents for pharmaceutical and non-pharmaceu (2), (4) Date: May 30, 2008 tical purposes. US 2009/0048.184 A1 Feb. 19, 2009

METHOD FOR PRODUCING A DRUG Such as amenorrhea, menopause, hot flushes etc., is not EXTRACT THAT CONTAINS proved by any data either. It is moreover entirely unclear HYDROXYSTILBENE which of the components actually present in the extract described therein (rhaponticin, deoxyrhaponticin, astrangin, piceatannol, anthracenosides, and the unanalyzed constitu 0001. The invention relates to a process for producing a ents present in a content of 10%) contribute to the asserted hydroxyStilbene-containing drug extract from a herbal drug pharmacological activity or, where appropriate, are in fact and the use of the drug extracts produced in this way for absolutely necessary for the asserted synergism. The actual producing various compositions for pharmaceutical and non disclosure of FR 2835 185 should therefore be restricted to pharmaceutical purposes. the preparation of a specific, complex rhubarb extract by hydroalcoholic extraction of rhizomes of Rheum rhaponti BACKGROUND OF THE INVENTION cum and the preparation of specific hydroxyStilbene deriva 0002 The collective term hydroxystilbenes encompasses tives, and the production of various pharmaceutical formula a large group of compounds which can be obtained as natural tions. constituents of herbal drugs or by chemical synthesis and 0006 Numerous further publications (cf., for example, Some of which have pharmacological activity. Babu et al., Bioorg. Med. Chem. Lett. 14 (2004), 3841-3845: 0003. Thus, for example, Aggarwal et al. describe in a Matsuda et al., Bioorg. Med. Chem. 9 (2001), 41-50) propose review article (Anticancer Research, 24, 2004) resveratrol the use of methanol as extractant for extracting the constitu and structurally similar compounds and the natural sources ents of Rheum rhizoma. thereof. 0007 EP-A-1 140 097 describes the isolation of trihy 0004 Because of the potential pharmacological use of droxyStilbene compounds from plant material by extraction naturally occurring hydroxyStilbenes and hydroxyStilbene with aqueous solvent, followed by a specific combination of mixtures, there is a need to develop processes making it chromatographic steps. The aqueous solvent is in particular possible to isolate desired hydroxy stilbenes reliably and an alcohol-water mixture comprising 75% alcohol. Pure reproducibly on the industrial scale and moreover inadequate water is not used as extractant. Typical extracted plants are purity and yield. Vitis vinifera and Polygonum cuspidatum. 0005 FR 2835 185 describes a complex rhubarb extract 0008. However, the extracts obtained according to the obtainable from rhizomes of Rheum rhaponticum, which is prior art have very complex compositions, have only limited said to be characterized in that it comprises at least 50% suitability as such for medical use, and require further puri hydroxy stilbenes, with at least 50% of these hydroxy stil fication steps. benes consisting of rhaponticin, deoxyrhaponticin, astrangin 0009. There is thus a need for an improved process for and piceatannol. A preferred extract comprises 15-50% by producing hydroxyStilbene-containing drug extracts. weight rhaponticin, 10-35% by weight deoxyrhaponticin, 5-10% by weight astrangin and 0.1-3% by weight piceatan SUMMARY OF THE INVENTION nol. This extract is, as illustrated in the examples, prepared by 0010. The object of the present invention is to provide an hydroalcoholic extraction of rhizomes of Rheum rhaponti efficient process for producing a hydroxyStilbene-containing cum. The total content of rhaponticin and deoxyrhaponticin drug extract. An object of the invention is in particular to which can be obtained thereby is only 76% by weight. The produce a drug extract which is particularly pure and includes content of astrangin comprises 11% by weight, the content of as predominant hydroxyStilbene constituents the glycone piceatannol comprises 3% by weight, and the content of forms (glycosides) of hydroxyStilbenes such as, in particular, anthracenosides comprises 0.5% by weight. In addition rhaponticin and deoxyrhaponticin. thereto, this extract appears to comprise about 10% by weight 0011. It has surprisingly been possible to achieve the further undefined constituents. It is additionally asserted in above object by providing an extraction process which is FR 2835 185 that the specific extract therein has, as a result of alleged synergistic effects of the various ingredients of the described in detail in the following sections. extract, biological properties which are considerably Superior DETAILED DESCRIPTION OF THE INVENTION to the effect of the individual hydroxy stilbenes, especially those effects which the ingredients described therein are said to have individually. The extract described therein is alleged 1. Preferred Aspects of the Invention to have antioxidant, antitumor, antiinflammatory and estro 0012. The invention relates to a process for producing a genic properties. However, in fact, FR 2835 185 does not hydroxyStilbene-containing drug extract, where provide a verifiable technical teaching for the asserted phar 0013 a) a hydroxy stilbene-containing part of a medicinal macological usability, to say nothing of the asserted Syner plant, where appropriate in a form comminuted in a conven gistic effect of the complex drug extract described therein. tional way, is provided, The experimental section describes merely individual formu 0014 b) an aqueous, organic or aqueous-organic extract lation examples of capsules, tablets or creams. In particular, ant is added thereto, experimental data proving the alleged usability for the treat 0015 c) after the extractant has acted, a liquid extract ment of disorders connected with free radicals, such as, for phase is obtained from the mixture, and the extraction is example, accelerated aging, cancer, arteriosclerosis, repeated several times where appropriate, and wrinkles, inflammatory phenomena and the like, are com 0016 d) the extractant is removed from the liquid extract pletely lacking. The asserted suitability of a combination of phases obtained in this way. the rhubarb extract described therein with a hop extract rich in 0017 Aparticular aspect is a process in which the hydrox prenyl flavonoids for the treatment of diseases standing with yStilbene-containing part of a medicinal plant comprises at free radicals and/or for the treatment of hormonal imbalance least one piceatannol and/or resveratrol prodrug. US 2009/0048.184 A1 Feb. 19, 2009

0018 Hydroxystilbenes in the sense of the invention 0023 The resulting plant extracts or individual compo include in particular Sugar-containing (glycosides) and Sugar nents thereof can also be subjected to derivatization reactions free (aglycones) prodrugs (i.e. precursors or derivatives) of in order to obtain so-called functional derivatives. These are resveratrol and piceatannol. Resveratrol and piceatannol pro in particular derivatives which can be converted back in the drugs in the sense of the invention are in particular also human or animal body, after administration, into the substances which can be converted into resveratrol and/or underivatized starting compound again. Mention should be piceatannol in vivo. Such as, for example, in humans and/or made in particular of ethers and ester derivatives of the com another mammal. Such as, for example, dog. Typical glyco pounds used according to the invention. It is moreover pos sides in this connection are rhaponticin, deoxyrhaponticin sible for individual ones or all of the etherifiable or esterifi and astringin; typical aglycone precursors are rhapontigenin able groups in a molecule (especially the phenolic and and deoxyrhapontigenin, without being restricted thereto (cf. glycosidic hydroxyl groups) to be derivatized. Examples of also Table 1 and following structural formula). suitable derivatives and their preparation are described for 0019. The terms “prodrug” or “precursor are, however, example in FR 2835 185, which is incorporated herein by not to be understood as functional restriction in the context of reference. Thus, mention may be made of without being the invention. As can be proven by various experimental restricted thereto: esters of saturated or unsaturated, aliphatic results, in particular the “precursors' of the invention perse or aromatic carboxylic acids having up to 25 carbon atoms, likewise display advantageous pharmacological effects. Such as 1 to 25 carbon atoms, such as, for example, Saturated C-C fatty acids (such as, for example, saturated 0020. It is possible according to the invention for hydrox unbranched fatty acids selected from caproic acid, enanthic yStilbenes to be present as salt or in phenolic form, in a acid, caprylic acid, pelargonic acid, capric acid, undecanoic Stereoisomeric form Such as cis or transform, or as mixture of acid, lauric acid, tridecanoic acid, myristic acid, pentade Such stereoisomeric forms in the drug, or to be obtained as canoic acid, palmitic acid, margaric acid, Stearic acid, nona products of the process. decanoic acid, arachidic acid, behenic acid); or silyl ethers, where the silicon atom carries three identical or different, TABLE 1. straight-chain or branched, Saturated or unsaturated hydro Hydroxystilbene Chemical name CAS No. carbon radicals having up to 20 carbon atoms, such as, for example, C-Co alkyl or C-Coalkenyl. Rhaponticin 3,3',5-Trihydroxy-4'-methoxystilbene- 155-58-8 3-O--D-glucopyranoside 0024. An active ingredient combination of at least two of Deoxyrhaponticin 3',5-Dihydroxy-4'-methoxystilbene-3- 30197-14-9 the abovementioned compounds is preferably obtained, such O--D-glucopyranoside as, for example, 2, 3, 4, 5, 6, 7 or 8 individual compounds, Rhapontigenin 3,3',5-Trihydroxy-4'-methoxystilbene SOO-6S-2 with the group of resveratrol precursors (especially deox (trans Rhapontigenin) yrhaponticin and deoxyrhapontigenin) and of piceatannol Deoxyrhapontigenin 3',5-Dihydroxy-4'-methoxystilbene 33626-08-3 precursors (especially rhaponticin and rhapontigenin) each being represented by one compound. RI 0025. A further preferred embodiment of the process of the invention provides an extract which has a high content of HO glycosides, in particular glycosides of the type described N R2 above, such as, for example, a content of from 30 to 100% by weight, 50 to 100% by weight, 60 to 99% by weight or 80 to 98% by weight or 85 to 96% by weight, in each case based on the total weight of the resulting dry extract. R3 0026. A “dry extract” in the sense of the invention is RI R2 R3 present in particular when the residual moisture content of water and/or organic liquid (Such as extractant) is less than Resveratrol OH H OH about 5% by weight, in particular less than 2% by weight, Rhaponticin OCH OH O-Glc such as, for example, 0 to 1.5% by weight or 0.1 to 0.5% by Deoxyrhaponticin OCH H O-Glc Rhapontigenin OCH OH OH weight, in each case based on the total weight of the resulting Deoxyrhapontigenin OCH H OH dry extract. Astringin OH OH O-Glc 0027. A further preferred embodiment provides an extract Piceatannol OH OH OH (astringenin) which is substantially free of aglycone derivatives of rhapon ticin and deoxyrhaponticin, such as, in particular, resveratrol and piceatannol. “Substantially free” means anaglycone con 0021. The invention relates in particular to a process tent of less than 5% by weight, in particular less than 2% by where the resulting extract includes at least one compound weight such as, for example, less than 1% by weight or 0.1% selected from rhaponticin, deoxyrahponticin, rhapontigenin, by weight, such as 0 to 0.05% by weight, in each case based deoxyrhapontigenin as Salt or in phenolic form, in a stereoi on the total weight of rhaponticin and deoxyrhaponticin. Someric form, or as mixture of Such stereoisomeric forms. 0028 Active ingredient combinations which are further 0022. The extracted hydroxy stilbenes are, however, pref preferably prepared are those having a total hydroxy stilbene erably substantially present in the trans form. Salts are in content, in particular a total content of deoxyrhaponticin, particular the alkali metal and alkaline earth metal phenolates deoxyrhapontigenin, rhaponticin and rhapontigenin, or a of the above compounds which have one or more free phe total content of rhaponticin and deoxyrhaponticin, of more nolic hydroxyl groups. If a plurality of hydroxyl groups is than 90% by weight such as, for example, 91 to 100% by present, these can be partly or completely in the salt form. weight, or 92 to 99 or 93 to 98 or 94 to 97% by weight. US 2009/0048.184 A1 Feb. 19, 2009

0029. Further active ingredient combinations which are a wide range and from extraction step to extraction step. The preferably prepared are those having a content of less than ratio by weight of drug to extractant is typically in the range 0.5% by weight, such as, for example, 0-0.49% by weight or from 10:1 to about 1:200 or about 1:2 to 1:50, or 1:4 to 1:10. 0.001 to 0.3 or 0.01 to 0.2 or 0.01 to 0.1% by weight, of 0039. In one variant of the process, an extraction is carried anthraquinone and/or anthraquinoids (in each case based on out with an aqueous extractant which is Substantially free of the dry weight of the active ingredient combination). organic solvent, such as, in particular, water, preferably puri Anthraquinoids are in this case to be understood in the widest fied water, at a pH of the mixture in the alkaline range, with sense as Substances having a basic anthraquinone structure. the pH of the mixture being in particular in the range from 0030. In a preferred embodiment, the medicinal plant is about 11 to 12, such as, for example, about 11.3 to 11.8. selected from natural plants and plants modified by breeding 0040. The pH of the mixture is adjusted for example with or recombinant, genetically modified plants which have a the aid of an inorganic base selected from alkali metal and content of at least one of the desired ingredients which is alkaline earth metal hydroxides such as, for example, calcium higher by comparison with the corresponding unmodified hydroxide or calcium oxide. It is possible for this purpose for plant. These plants are selected in particular from plants of the example to prepare a concentrated quicklime solution by genus Rheum spp., Astragalus spp., Cassia spp. or Picea spp. dissolving 3 to 8 parts of CaO in 20 parts of purified water. or active ingredient-containing plant parts. Nonlimiting This solution is strongly alkaline and has a pH in the range examples of suitable species of these genera are Rheum undu from about 12 to 13, such as, for example, of about 12.4 to latum, Rheum palmatum, Rheum tataricum, Rheum offici 12.6. male, Rheum wittrockii, Rheum altaicum, Rheum reticulatum, 0041. The ratio of the amounts of introduced drug to base Astragalus complanatus, Cassia garrettiana and Picea Sitch Such as, for example, calcium hydroxide (calculated as cal ensis. It is additionally preferred to employ medicinal plants cium oxide) can be according to the invention in the range as single varieties. from about 5:1 to 20:1, such as about 8:1 to 12:1 or 9:1 to 11:1. 0031. The skilled worker is additionally aware that genera/ 0042. The process is preferably carried out in such a way species differing in provenance and differing in age (i.e. har that the desired hydroxy stilbenes are precipitated from the Vest at various times of the vegetation period) can be resulting alkaline liquid extract phase, for example by adjust employed, in turn possibly influencing the nature, amount ing the pH of the extract to a value in the range from about 3 and composition of the hydroxystilbenes and mixtures which to 4, such as, for example, 3.2 to 3.8, or 3.4-3.6, and, where can be isolated therefrom. It is likewise possible in principle appropriate, Subsequently removing the precipitate, washing to use various plant parts such as roots, rhizomes, leaves where appropriate and drying where appropriate. and/or stalks. 0043. Used for the acidification is any inorganic or organic 0032. The respective plant part or mixture of plant parts acid, such as, for example, hydrochloric acid or Sulfuric acid, can, if expedient, be mechanically treated prior to the extrac but in particular organic acids Such as formic acid or acetic tion Such as, for example, ground, chopped, reeled, crushed or acid. cut. If expedient, predrying is also possible. Such as, for 0044 Before removal of the precipitate it may be expedi example, 2 hours to 2 days at 30 to 50° C., in order to reduce ent to leave the batch to stir for some hours or days in order to the liquid content. achieve precipitation which is as quantitative as possible of 0033. The hydroxyStilbene-containing part of the medici the desired extracted ingredients. nal plant used for the extraction is in particular the root of the 0045. The precipitate can be washed for example with medicinal plant, such as, for example, of Rheum rhapOnti purified water, and this serves in particular to remove remain Cit. ing acid. 0034. The invention relates in particular to a process in 0046 Remaining liquid is removed from the extract by which a hydroxyStilbene-containing percolate is produced drying, e.g. at 30 to 50° C. or 35 to 45°C., for example over from the drug. A "percolation” means a continuous extraction a period of from 1 to 100 hours, until the residual moisture is of soluble substances from a drug by continual renewal of the in the range indicated above. The drying takes place in a Solvent. This results in a permanent concentration gradient, so manner known perse, e.g. in a drying oven. Freeze drying is that a large part of all the soluble Substances goes into the likewise possible. eXtract. 0047. In a further variant of the process, the extractant 0035 An alternative possibility is also a continuous or used is a polar aprotic organic solvent or aqueous or nonaque periodic mixing of the batch Such as, for example, by stirring ous solvent mixtures comprising at least one of these organic or shaking. Solvents. 0036. The temperature during the extraction according to 0048. The organic solvent is preferably selected from the invention is usually in the range from 10 to 50° C., such as, C-C alkanols and di-(C-C) ketones and mixtures thereof, for example, 25 to 35°C. The pressure is usually atmospheric Such as, in particular, methanol, ethanol, n- or i-propanol, pressure. If a speeding up of the rate of extraction or quality of aqueous alcohol Such as in particular with a water content of the extract can be achieved, the pressure may also be varied from 1 to 90% by weight or 10 to 30% by weight or 5 to 14% during the extraction, such as, for example, raised or lowered. by weight, Such as aqueous ethanol, and ketones Such as 0037. The extraction may take, depending on the chosen acetone and methyl ethyl ketone. conditions such as the nature of the drug, batch size, extrac 0049. The organic or aqueous-organic liquid extract phase tant and temperature used, from 1 hour to several days, Such obtained in this case is in particular further purified in a as, for example, 10 to 72 hours. manner known per se, such as, for example, by chromatog 0038. The extraction process can if necessary be repeated raphy, and/or the extractant is removed, and dried as several times in order to ensure that isolation in particular of described above. the desired ingredients is as complete as possible. The ratio by 0050. The extract produced according to the invention can weight of introduced drug to liquid extractant may vary over be used directly, without further after-treatment, for produc US 2009/0048.184 A1 Feb. 19, 2009

ing the composition desired in each case. Further treatment of range from 0.1 to 20 mg or 0.5 to 15 mg, 1 to 10 or 4 to 8 mg the constituents, such as, for example, a derivatization Such of active ingredient or active ingredient combination Such as, as, for example, esterification, deglycosylation, conversion for example, ERr 731(R). into a Suitable salt, is possible in principle, however. 0066. The invention relates in particular also to a process 0051. The invention further relates to the use of a hydrox for producing the compositions defined above, where initially yStilbene-containing drug extract obtainable by a process as an extraction process as defined above is carried out, and the defined above for producing a composition Such as, for hydroxyStilbene-containing drug extract resulting therefrom example, selected from medicaments such as homeopathic is formulated in a manner known per se together with con remedies, other medicinal plant preparations, dietary Supple ventional ancillary Substances to one of the abovementioned ments and dietetic food products. compositions. 0052. The medicament or pharmaceutical composition may in particular include a solid dosage form. 2. Further Specific Refinements of Formulations Produced 0053. This solid dosage form includes in particular an According to the Invention active ingredient-containing Solid core with a pharmaceuti cally acceptable carrier and an active ingredient content of 2.1 Medicaments about 1 to 20% by weight, such as, for example, 2 to 15 or 5 0067. The invention also includes the production of phar to 10% by weight, based on the total weight of the core, where maceutical compositions (medicaments). Such as homeo the “active ingredient' includes a hydroxystilbene-contain pathic remedies, for the treatment of an individual, preferably ing extract which has been produced in the above manner and a mammal, in particular a human, productive or domestic which comprises hydroxyStilbene constituents of the drug as animal. Thus, the active ingredients or active ingredient com defined above, especially piceatannol and/or resveratrol pro binations described above are usually administered in the drugs. form of pharmaceutical compositions which comprise a phar 0054 The active ingredient combination in the composi maceutically acceptable excipient with at least one active tion of the invention includes in particular substantially ingredient of the invention, in particular a mixture of a plu rhaponticinand deoxyrhaponticin in a ratio of about 2:1 to 1:2 rality of active ingredients of the invention, and, where appro by weight. priate, further active ingredients. These compositions can be 0055 Examples of active ingredient combinations obtain administered for example by the oral, local, rectal, transder able according to the invention consist Substantially of about mal. Subcutaneous, intravenous, intramuscular, intraperito 0056 60-66% by weight rhaponticin neal, intracutaneous or intranasal route. 0057 30-35% by weight deoxyrhaponticin 0068 Examples of suitable pharmaceutical formulations 0.058 0-2% by weight rhapontigenin and are solid pharmaceutical forms such as oral powders, dusting powders, granules, tablets, such as coated tablets, gastro 0059 0-2% by weight deoxyrhapontigenin. resistant coated tablets, dry-coated, inlay and layered tablets, 0060 A dosage form may according to the invention have pastilles, chewable tablets, Suckable tablets, Sachets, cachets, a total active ingredient content of about 2 to 20 mg. Such as, Sugar-coated tablets, capsules such as hard and soft gelatin for example, 3 to 15 or 4 to 10 mg, per dose unit. capsules, pessaries, Suppositories or vaginal pharmaceutical 0061 A preferred solid dosage form additionally has a forms, semisolid pharmaceutical forms such as ointments, lactose-free core. creams, hydrogels, pastes or patches, and liquid pharmaceu 0062 Solid dosage forms which are preferably produced tical forms such as solutions, emulsions, especially oil-in are in the form of a pill, of a tablet, of an extrudate or of water emulsions, Suspensions, for example lotions, prepara granules. tions for injection and infusion, eye drops and ear drops, nose 0063 A further preferred solid dosage form additionally drops, nasal spray and tinctures. It is also possible to use has a gastro-resistant coating. implanted delivery devices for administering inhibitors of the 0064. The invention further relates to the use of a hydrox invention. Liposomes, microspheres or polymer matrices can yStilbene-containing drug extract produced by a process as also be used in addition. defined above for producing a composition for the treatment 0069. In the production of the compositions, active ingre of menopausal symptoms in women, juvenile oligomenor dients or active ingredient combinations of the invention are rhea and dysmenorrhea, primary and secondary amenorrhea usually mixed with an excipient or diluted. Excipients may be or endometritis, of prostate cancer and disorders of the lower Solid, semisolid or liquid materials which serve as vehicle, urogenital tract, of cancer, of chronic inflammatory disorders, carrier, adsorbent or medium for the active ingredient or the of depressions and anxiety, of osteoporosis, and of headaches active ingredient combinations. and migraine, especially for the treatment of menopausal 0070. Examples of suitable excipients include lactose, symptoms in the peri- or postmenopause, such as, in particu dextrose, Sucrose, Sorbitol, mannitol, starches, gum acacia, lar, of hot flushes, Sweating episodes, sleep disorders, irrita calcium phosphate, alginates, tragacanth, gelatin, calcium bility, psychological and mental exhaustion, sexual problems silicate, microcrystalline cellulose, polyvinylpyrrolidone, and urinary tract symptoms. The compositions produced cellulose, cellulose derivatives Such as, for example, methyl according to the invention are particularly Suitable for the cellulose, water, syrups and methylcellulose. The formula treatment of menopausal symptoms owing to a natural or tions may in addition comprise pharmaceutically acceptable therapeutically induced menopause. carriers or usual ancillary Substances such as lubricants, for 0065. Owing to the excellent tolerability of the active example tallow, magnesium Stearate and mineral oil; wetting ingredients or active ingredient combinations described agents; emulsifying and Suspending agents; preservatives above, the invention also relates to the use during long-term Such as methyl and propyl hydroxybenzoates; antioxidants; therapy, which is possible without limitation in time. The antiirritants; chelating agents; tablet-coating aids; emulsion daily dose to be administered in this connection can be in the stabilizers; film formers; gel formers; odor-masking agents; US 2009/0048.184 A1 Feb. 19, 2009

taste correctives; resins; hydrocolloids; solvents; solubiliz 0077 Liquid dosage forms of the invention are produced ers; neutralizers; permeation promoters; pigments; quater for example by dissolving the active ingredient(s) such as, for nary ammonium compounds; refatting and Superfatting example, an ERr731(R) dry extract in a suitable solvent such agents; ointment, cream or oil bases; silicone derivatives; as, for example, a waterfalcohol mixture, where appropriate spreading aids; stabilizers; sterilants; Suppository bases; tab together with further conventional additions. Active ingredi let excipients such as binders, fillers, lubricants, disintegrants ent contents of from 0.1 to 20 or 1 to 10 mg/ml are usually or coatings; propellants; dessicants; opacifiers; thickeners; adjusted in this case. waxes; plasticizers; white oils. 0078 Semisolid dosage forms of the invention, such as, 0071. An arrangement concerning this is based on expert for example, gels, are produced for example by dissolving the knowledge as set forth for example in Fiedler, H. P. Lexikon active ingredient(s), such as, for example, an ERr 731(R) dry der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende extract, in a suitable solvent such as, for example, a water/ Gebiete, 4th edition, Aulendorf. ECV-Editio-Kantor-Verlag, alcohol mixture, alcohol or glycerol, and incorporating the 1996; cf. also Hager's Handbuch der PharmaZeutischen Solution into the previously Swollengel former, where appro Praxis, Springer Verlag, Heidelberg. priate together with further conventional additions. Active 0072. In a preferred embodiment, a pharmaceutical com ingredient contents of from 1 to 12 or 2 to 6 mg per gram of the position which comprises a solid dosage form is provided. formulation are usually adjusted in this case. This solid dosage form in turn includes an active ingredient 0079 Solvents which should be particularly mentioned as containing Solid core with a pharmaceutically acceptable car Suitable according to the invention for producing formula rier and an active ingredient content of about 1 to 20% by tions are monohydric or polyhydric alcohols such as, in par weight, based on the total weight of the core, where the active ticular, ethanol, glycerol and mixtures thereof with water, ingredient or the active ingredient combination includes a such as, for example, 10 to 50% by volume ethanol in water. compound selected from resveratrol and piceatannol pro 0080 Dosage forms or pharmaceutical compositions of drugs; and resveratrol and piceatannol; and the stereoiso the invention are produced by using generally known meth meric forms thereof, in each case in the form of their salts or ods of pharmaceutical technology as described for example in in the phenol form, or combinations of at least two of these Voigt, PharmaZeutische Technologie, 7th edition 1993, Ull compounds. Preferred active ingredient combinations are as stein Mosby, Berlin. defined above. 0081. The mode and duration of administration of the 0073. This solid dosage form has for example a total active medicaments of the invention are subject to the decision of the ingredient content of about 1 to 20 mg, such as, for example, treating physician. The latter can establish a suitable dose and 2 to 10 mg, per dose unit and can be in the form of a pill, a an appropriate dosage regimen depending on the chosen route tablet, an extrudate or granules, and for example be Sugar of administration, on the efficacy of the specific active ingre coated. If desired, it may also have a gastro-resistant coating. dient composition, the nature and severity of the disorder to 0074 The solid dosage form is produced for example by be treated, the patient's condition and his response to the mixing the active ingredient or the active ingredient combi therapy. For example, a suitable single dose may comprise nation with the pharmaceutically acceptable carrier, and con about 0.1 to 50 mg, such as, for example, 2 to 12 or 2 to 20 mg. Solidating the mixture to give the active ingredient core. This of active ingredient or active ingredient combination as entails dissolving or dispersing the active ingredient or the defined above, and be administered 1 to 3 times a day until the active ingredient combination in an inert liquid, mixing it desired result of the treatment is to be observed. with the carrier and removing the solvent during or after the consolidation. The active ingredient core can then be pro 2.2 Dietary Supplements and Food Products vided where appropriate with a gastro-resistant coating I0082. The compositions of the invention also include in before the core is Sugar-coated in a conventional way. Such particular dietary Supplements and food products, especially coatings are for example free of plasticizers such as phtha functional or dietetic food products. The food products of the lates, such as, for example, diethyl phthalate. Coating com invention have besides a function mainly related to nutritional positions suitable in particular for producing gastro-resistant, value in addition a function related to active ingredients relat plasticizer-free coatings are selected from known natural and ing in particular to the active ingredient combination of the synthetic coating compositions (cf., for example, Voigt, Phar invention. They are therefore referred to as functional or mazeutische Technologie, 7th edition 1993, Ullstein Mosby, dietetic food products or foodstuffs. Dietary supplements Berlin). Particularly suitable coating compositions are, with serve to supplement the daily diet with the active ingredient out being restricted thereto, shellac and cellulose derivatives combination of the invention, in which case the function Such as hydroxypropylmethylcellulose derivatives such as, related to nutritional value of the dietary supplement becomes for example, hydroxypropylmethylcellulose acetate Succi of less intrinsic importance. nate, obtainable under the proprietary name AQOAT. I0083. The formulation base for dietary supplements and 0075 Mention should be made in particular of a solid food products of the invention likewise includes physiologi dosage form with a total weight in the range of about 150 mg cally acceptable ancillary Substances in the widest sense, Such t20 mg, a core weight of 84 mg. t10 mg and an active as, for example, the abovementioned excipients. Ancillary ingredient content of about 3 to 10 mg. Substances in the sense according to the invention may also 0076 Further suitable solid dosage forms are those having have a nutritional value and therefore generally be used as a uniformity of active ingredient content (averaged over 10 or dietary component. Nutrients, especially essential nutrients, 20 randomly selected individual dose units) not exceeding may also belong thereto. +5% by weight, such as, for example, +0.1 to 4 or +0.5 to 3 or I0084. Nutritional components ordinarily comprise one or +1 to 2% by weight, based on the active ingredient content in more amino acids, carbohydrates or fats and are suitable for the dosage form (e.g. determined as specified in Ph. Eur, 5th human and/or animal nutrition. They include single compo edition 2005 (5.0/2.09.06.00)). nents, frequently vegetable, but also animal, products, espe US 2009/0048.184 A1 Feb. 19, 2009

cially Sugars, where appropriate in the form of syrups, fruit ultrasonic bath for 15 minutes and made up to 50 ml with the preparations such as fruit juices, nectar, fruit pulps, purees or solvent mixture and then diluted 1:10 with the solvent mix dried fruits, for example applejuice, grapefruit juice, orange ture. juice, apple puree, tomato sauce, tomato juice, tomato puree: cereals products such as wheat flour, rye flour, oat flour, b) Procedure for the Chromatography: cornflour, barley flour, spelt flour, corn syrup, and Starches 0093. A high-pressure liquid chromatography (HPLC) is from said cereals; dairy products such as milk protein, whey, carried out on a portion of the solution obtained above, with yogurt, lecithin and lactose. the following system parameters: 0085 Examples of essential nutrients are in particular Vitamins, provitamins, minerals, trace elements, amino acids and fatty acids. Essential amino acids which may be men tioned are isoleucine, leucine, lysine, methionine, phenylala Sample loop: 20 ul Column: Lichrospher 51 RP 18, 250 x 4 mm nine, threonine, tryptophan and valine. These also include Precolumn: Lichrospher 51 RP 18, 5 x 4 mm semiessential amino acids which must be supplied for Column temperature: 25o C. example during growth phases or deficiency states, such as Eluent A: Acetonitrile/dist. wateriphosphoric acid 85%, arginine, histidine, cysteine and tyrosine. Trace elements 15/85/0.05 (parts by volume) Eluent B: Acetonitrile/dist. wateriphosphoric acid 85%, which may be mentioned are: essential trace elements and 80/20/0.05 (parts by volume) minerals such as: iron, copper, Zinc, chromium, selenium, Flow rate: 1.5 ml/min calcium, magnesium, Sodium, potassium, manganese, cobalt, Column flushing: 15 min with eluent 50% B; equilibration time molybdenum, iodine, silicon, fluorine, chlorine, phosphorus, 15 min Detection: 310 mm tin, nickel, Vanadium, arsenic, lithium, lead, boron. Fatty HPLC: Kontron Kroma 2000 acids which may be mentioned as essential for humans are: Time % B linoleic acid and linolenic acid, ARA (arachidonic acid) and DHA (docosahexaenoic acid) for infants and possibly EPA Gradient: O.O O O.S O (eicosapentaenoic acid) and DHA also for adults. A compre 7.5 75 hensive list of vitamins is to be found in “Referenzwerte fir 8.5 1OO die Nährstoffzufuhr, 1st Edition, Umschau Braus Verlag, 9.5 O Frankfurt am Main, 2000, edited by the Deutsche Gesell 12.5 O schaft für Ern?hrung. I0086 Examples of suitable formulations for dietary The retention times resulting under the system conditions Supplementation are capsules, tablets, pills, powder Sachets, indicated above are as follows: liquid ampoules and bottles with dropper inserts, and the pharmaceutical forms mentioned above. 0087 Food product formulations ordinarily have the usual form and are made available for example as breakfast prepa Rhaponticin: about 5.5 min Deoxyrhaponticin: about 6.8 min rations, in the form of mueslis or bars, sports drinks, complete Rhapontigenin: about 7.2 min meals, dietetic preparations such as diet drinks, diet meals Deoxyrhapontigenin: about 9.0 min and diet bars. 0088 Dietary supplements and food products of the inven tion are produced by methods familiar to the skilled worker For a quantitative determination, the respective peak areas are and requiring no further explanation (cf. for example, Hans found and compared with the corresponding peak areas of a Dieter Belitz et al. Lehrbuch der Lebensmittelchemie. standard extract of known composition. Springer-Lehrbuch 5th revised edition 2001. XLIV. 1059 publisher: SPRINGER, BERLIN) PREPARATION EXAMPLE1 0089. The content of active ingredients/active ingredient Preparation of the Dry Extract ERr 731 from combinations of the invention in the above dietary supple Rhapontic Rhubarb Root with an Aqueous Calcium ments and food products can vary over a wide range and is for Hydroxide Solution example in a range from 0.01 to 10% by weight, such as, for example, 0.1 to 1% by weight. 0094. A dry extract is prepared from rhapontic rhubarb 0090 The invention is now explained in more detail by root employing the following: means of the following nonlimiting production and formula tion examples. Drug (radix rheum rhaponticum) 50.0 kg EXPERIMENTAL SECTION Calcium oxide 5.0 kg Purified water 190.0 kg General Methods: Acetic acid (as necessary to adjust the required pH) 0091) Determination of Stilbenes by High-Pressure Liq The yield which can be achieved in this case is between 2 and uid Chromatography (HPLC) in the Dry Extract from 3 kg per 50 kg of drug. Rhapontic Rhubarb Root 0.095 The preparation takes place in the following steps: a) Sample Preparation: 0096 a) Firstly 5 kg of calcium oxide are introduced into a plastic tub and made into a slurry with 20 kg of purified 0092 50 mg of extract, mixed with 40 ml of a mixture of water. The formation of calcium hydroxide (quicklime) acetone and water (1:1) in an amberglass vessel, treated in an which takes place under these conditions leads to a large rise US 2009/0048.184 A1 Feb. 19, 2009 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%. 0097 b) 50 kg of drug are introduced into a mixer, and the abovementioned quicklime is added. In order to remove the 0107. It is possible by exposure to the solvent systems quicklime as completely as possible from the plastic tub, it is indicated below, in a 100-fold quantity at room temperature rinsed with 10 kg of purified water. This washing liquid is for 10 minutes with shaking or stirring, to extract the propor likewise put in the mixer. tions summarized below: 0098 c) The drug homogeneously mixed with quicklime is introduced into a percolator and covered with 160 kg of purified water. The percolator remains closed for 48 hours. Ethanol 86% Rh 100.8% The percolate is then collected in a suitable vessel at a flow DRh 99.5% rate of 50 ml/min. The percolation is continued until no fur Ethanol 15% Rh 77.19% ther percolate emerges. The drug mass is not squeezed out DRh 75.5% Acetone Rh 88.3% after completion, but is discarded. DRh 96.6% 0099 d) While monitoring continuously, concentrated Water, alkaline Rh 75.5% acetic acid is added to the percolate until a pH in the range (pH 11, DRh 60.5% from 3.4 to 3.6 is reached. In order to achieve precipitation of adjusted with CaO solution) the extract which is as complete as possible, the mixture is left to stand for 5 days. 0100 e) The dry extract is obtained by filtration through No useful results were achieved with heptane. Büchner funnels under applied vacuum. Finally, the extract is 0108. The respective yields of crude extracts in propor washed with 10 to 20 kg of purified water. tions by mass (based on drug employed) are as follows: 0101 f) The dry extract obtained after filtration is dried in a drying oven at 40°C. until a residual moisture tolerance not exceeding 1% is reached. Ethanol 86% 35.5% 0102 Rhaponticin is readily soluble in aqueous solutions Ethanol 15% 32.2% with an alkaline pH range, whereas it is precipitated as yel Acetone 21.4% lowish substance in the acidic pH range (pH 3.4-3.6). Use is Heptane O% made of this for its isolation. Since, besides other organic Water, alkaline 4.5% acids, the root in particular has a high content of oxalic acid (2/3 in water-soluble and /3 in bound form), this must be Extraction of rhapontic rhubarb root with ethanol-water mix neutralized during the isolation in order to prevent the pH drifting into the acidic range and thus to inhibit premature tures leads to an extract which, besides the main constituents precipitation of the rhaponticin. This is achieved by using rhaponticin (about 30%) and deoxyrhaponticin (about 22%), calcium oxide. The latter is employed as quicklime solution comprises a further stilbene, which has not as yet been inves with a pH of 12.4-12.6. tigated, in a proportion of about 20% in the extract. Besides 0103 Homogeneous mixing of the quicklime with the these, the aglycones rhapontigenin (about 8%) and deox drug alters the pH of the mixture. It is then in the range from yrhapontigenin (about 2%) and a further 9 compounds which 11.3 to 11.8, thus preventing precipitation of rhaponticin, total about 20% are obtained. because the phenolic form has been converted into a pheno 0.109 The results on extraction with acetone are funda late form. Despite the high oxalic acid content, the pH can be mentally the same. kept in the alkaline range. This is attributable to the fact that the calcium hydroxide reacts with oxalic acid and forms 0110 Extraction with alkaline water (cf. conditions in insoluble and nontoxic calcium oxalate. preparation example 1) leads to an extract of greater purity. 0104 Rhaponticin is extracted from the root by the sub 0111. The main constituents rhaponticin and deox sequent percolation with purified water. After completion of yrhaponticin are present in a proportion of about 97% in the the percolation, a pH of 3.4 to 3.6 is adjusted by adding acetic dry extract. Rhapontigenin and deoxyrhapontigenin together acid. This pH shift from the alkaline to the acidic range leads amount to a proportion of 1.1% of the extract, whereas the to a precipitation of rhaponticin through conversion back into stilbene which has not yet been investigated is present in a the phenolic form. In order to achieve precipitation of rhapon ticin which is as complete as possible, the mixture is left to proportion of only 0.2%. A further 3 compounds are present stand for 5 days. It is then filtered. Rhaponticin remains as in a proportion of 2.5%. yellowish substance on the filter. 0105. The above statements about rhaponticin apply cor FORMULATION EXAMPLE1 respondingly to the other hydroxyStilbene active ingredients isolated according to the invention. Production of a Solid Dosage Form Minitablet PREPARATION EXAMPLE 2 1. Production of the Tablet Core: Preparation of a Dry Extract from Rhapontic Rhu 0112 A solid tablet core is produced using the following barb Root with Various Organic Solvents active ingredients and ancillary Substances in the stated ratios 0106 The constituents mainly detectable in the rhapontic of amounts (P-parts by weight). The ingredients are mixed rhubarb root used as drug here belong to the group of hydrox and tabletted in three different ways: US 2009/0048.184 A1 Feb. 19, 2009

a) Tablet Core Formulation: 0113 Core weight: 84 mg - 4.2 mg maximum variation Punch: 7 mm diameter, domed Purified dry extract according to 3.6 P preparation example 1 The ERr-731 content per core is about 4 mg +5%. from rhapontic rhubarb root (ERr 731 (R) Microcrystalline cellulose (e.g. Avicel (R) 57.0 P(+40%) 2. Production of the Gastro-Resistant Coated Tablet Sorbitol 8.0 P (40%) Talc 2.5 P(+40%) Makrogol 6000 (polyglycol) 1.6 P (40%) 0.124. After removal of dust from the tablet cores with Polyvidone (Kvalue about 25, e.g. Kollidon (R 25) 1.6 P (40%) Eudragit, a gastro-resistant coating of cellulose acetate phtha Sodium dodecyl sulfate (e.g. Texapon (R) K12) 0.5 P(+40%) late and diethyl phthalate, dissolved in isopropanol and ethyl Magnesium stearate (vegetable) 0.8 P (40%) acetate, is applied to the tablet cores using a coating system. 0.125 Macrogol is dissolved in purified water. The ingre 75.6 P(+40%) dients Sugar (sucrose or isomalt), calcium carbonate, talc, titanium dioxide and the two povidones are mixed and stirred 0114. It is possible by varying the weighedamount of ERr into the liquid. The Suspension is stirred in a jet flow mixer 731(R) and/or varying the amount of microcrystalline cellulose (e.g. Rototron of type RTA 70-50) for 20 minutes. to obtain any desired ERr 731(R) contents in the untreated core 0.126 The Sugar-coating Suspension is applied to the (such as, for example, 2, 4, 6, 8, 10, 12 mg per tablet). sealed core with the aid of an automatic coater. The process is repeated until an average weight of 150 mg per coated core is b) Mixing of Drug and Carrier reached. Finally, the polishing wax is applied and then rolling 0115 Mixing Varianta: is continued until a high gloss is obtained. 0116 1.2 P of ERr 731(R) are triturated in portions with (O127 Final Weight of the Gastro-Resistant Coated Tablet: Avicel(R) in a ball mill and then, after addition of the other I0128 150 mg +7.5 mg maximum variation. ancillary substances, mixed and tabletted as described below. I0129. In this way, two different tablet forms—one con 0117. Mixing Variant b: taining Sugar and one Sugar-free-are produced, employing 0118 ERr 731(R) (1 g/l of solvent) is dissolved in a suitable the respective ancillary Substances in the parts by weight solvent (e.g. ethanol/water mixture 86% V/v ethanol) and indicated below. adsorbed on Avicel(R), dried (at 40°C. for at least 48 hours) a) Gastro-Resistant Coated Minitablet—Containing Sugar— and, after addition of the other ancillary Substances, mixed with Plasticizer in the Coating and tabletted as described below. 0119 Mixing Variant c. 0120. The total amount of Avicel(R) is divided into three Ancillary Substances: equal portions. The first portion is mixed with the total Coating: Eudragit L12.5% dry matter 1.350 kg (40%) amount of ERr731(R) and triturated in a laboratory ball mill Diethyl phthalate 1.749 kg (40%) (e.g. type 1-25 LK. Alpine, Augsburg) for at least 120 min Cellulose acetate phthalate 7.770 kg (40%) utes. The second portion of Avicel(R) is then added, and the Isopropyl alcohol 75.600 kg (40%) mixture is again triturated in the laboratory ball mill for at Ethyl acetate 77.600 kg (40%) Talc 2.000 kg (40%) least 120 minutes. After addition of the third portion of Sugar coating: Talc 7.182 kg (40%) Avicel(R), brief mixing is again carried out. Subsequently, Sugar 28.747 kg (40%) after addition of the other ancillary Substances, mixing and Calcium carbonate 6.410 kg (40%) tabletting are carried out as described below. Titanium dioxide E 171 0.635 kg (40%) Povidone 0.756 kg (40%) 0121. It is surprisingly possible with this mixing variant to (Kvalue about 25, e.g. reduce markedly the tendency to inhomogeneity and, even Kollidon (R 25) with Small dose units, to adjust an extremely uniform active Povidone (K value about 90) 0.332 kg (40%) Macrogol 35,000 0.635 kg (40%) ingredient content of not more than +5% by weight (deter Water 10.500 kg (40%) mined according to Ph. Eur, 5th edition 2005 (5.0/2.09.06. Polish: 95% carnauba wax, 0.108 kg (40%) 00)). 5% bleached wax (e.g. Capol 1295 PH) c) Tabletting: 0122) The mixture of Avicel(R) and active ingredient is b) Gastro-Resistant Coated Minitablet Sugar-Free with sieved through a sieving machine (sieve diameter 1.2 mm) Plasticizer in the Coating into a suitable mixing container and, after addition of the stated tabletting aids (without magnesium Stearate), mixed in a suitable mixer (e.g. drum hoop mixer of type Standard RR M 200, from Engelsmann AG/Ludwigshafen) for at least 30 Ancillary Substances: min. Addition of magnesium Stearate is followed by mixing Coating: Eudragit L12.5% dry matter 1.350 kg (40%) Diethyl phthalate 1.749 kg (40%) again for at least 5 min. Cellulose acetate phthalate 7.770 kg (40%) 0123. The compression takes place in a suitable tablet Isopropyl alcohol 75.600 kg (40%) press (e.g. rotary of type Perfecta Fette 2000, from Fette/ Ethyl acetate 77.600 kg (40%) Schwarzenbeck): US 2009/0048.184 A1 Feb. 19, 2009 9

-continued -continued Ancillary Substances: b) Wariant B Sugar coating: Talc 7.482 kg (40%) Ancillary Substances: kg (40%) Sorbitol and for isomalt 28.747 kg (40%) Calcium carbonate 6.410 kg (40%) Distilled water 12.SOO Titanium dioxide E 171 0.635 kg (40%) Isopropyl alcohol 4.OOO Povidone 0.756 kg (40%) Ethanol 86% 55.000 (Kvalue about 25, e.g. Sugar coating: Talc 9.182 Kollidon (R 25) Sugar 28.747 Povidone (K value about 90) 0.332 kg (40%) Calcium carbonate 6.410 Macrogol 35,000 0.635 kg (40%) Titanium oxide E 171 O.63S Water 10.500 kg (40%) Polyvidone 0.756 Polish: 95% carnauba wax, 0.108 kg (40%) (Kvalue about 25, e.g. 5% bleached wax Kollidon (R 25) (e.g. Capol 1295 PH) Povidone (K value: about 90) O.332 Macrogol 35,000 O.63S Water 1O.SOO Polish: 95% carnauba wax O.108 FORMULATION EXAMPLE 2 5% bleached wax (e.g. Capol 1295 PH) Production of a Solid Dosage Form Minitablet Containing Sugar Without Plasticizer 1. Production of the Tablet Core FORMULATION EXAMPLE 3 0130 Production takes place in analogy to formulation Production of a Solid Dosage Form Minitablet example 1. Sugar-Free Without Plasticizer 2. Production of the Gastro-Resistant Coated Tablet 1. Production of the Tablet Core I0132) Production takes place in analogy to formulation 0131 Production takes place in analogy to formulation example 1, but using isomalt instead of Avicel. example 1, but with use of shellac (variant A) or Aqoat (vari ant B) instead of cellulose acetate phthalate/diethyl phthalate 2. Production of the Gastro-Resistant Coated Tablet (plasticizer)lasticizer). 0.133 Production takes place in analogy to formulation example 2, but using isomalt instead of Sugar.

a) VariantA Ancillary Substances: kg (40%) a) VariantA Coating: Eudragit L12.5% dry matter O.400 Ancillary Substances: kg (40%) CAPOL S270 PH8% 6O.OOO (shellac solution) = Coating: Eudragit L12.5% dry matter O.400 4.8 kg dry matter (shellac) CAPOL S27O PH8% 6O.OOO Isopropyl alcohol 4.OOO (shellac solution) = Ethanol.96% 3.200 4.8 kg dry matter (shellac) Talc 2.OOO Isopropyl alcohol 4.OOO Sugar coating: Talc 7.182 Ethanol.96% 3.200 Sugar 28.747 Talc 2.OOO Calcium carbonate 6.410 Sugar coating: Talc 7.182 Titanium dioxide E 171 O.63S Isomalt 28.747 Polyvidone 0.756 Calcium carbonate 6.410 (Kvalue about 25, e.g. Titanium oxide E 171 O.63S Kollidon (R 25) Polyvidone 0.756 Povidone (Kvalue: about 90) O.332 (Kvalue about 25, e.g. Macrogol 35,000 O.63S Kollidon (R 25) Water 1O.SOO Povidone (Kvalue: about 90) O.332 Polish: 95% carnauba wax O.108 Macrogol 35,000 O.63S 5% bleached wax Water 1O.SOO (e.g. Capol 1295 PH) Polish: 95% carnauba wax O.108 5% bleached wax (e.g. Capol 1295 PH)

b) Wariant B Ancillary Substances: kg (40%) b) Wariant B Coating: Eudragit L12.5% dry matter O4(OO Ancillary Substances: kg (40%) Aqoat S.42O Hydroxypropylmethylcellulose Coating: Eudragit L12.5% dry matter O.400 acetate Succinate Aqoat S.42O US 2009/0048.184 A1 Feb. 19, 2009

-continued b) Wariant B a) Variant A: Formulation: Ancillary Substances: kg (40%) Gelatin 1 part Distilled water 12.SOO Purified water 2 parts Isopropyl alcohol 4.OOO Glycerol 85% (+ERr 731 (R) 5 parts Ethanol 86% 55.000 Talc 2.OOO Sugar coating: Talc 7.182 Isomalt 28.747 Calcium carbonate 6.410 b) Variant B: Titanium oxide E 171 O.63S 0.138 Same formulation but with suitable preservatives Polyvidone 0.756 (Kvalue about 25, e.g. such as, for example, sorbate, benzoate, PHB ester. Kollidon (R 25) 0.139. The gelatin is introduced in each case into purified Povidone (Kvalue: about 90) O.332 water and allowed to swell until the mixture has become Macrogol 35,000 O.63S glassy. Glycerol 85% with active ingredient is then added and Water 1O.SOO Polish: 95% carnauba wax O.108 heated, but not above 65°C. The suppositories are then cast in 5% bleached wax a conventional way. (e.g. Capol 1295 PH) FORMULATION EXAMPLE 6 Production of a Liquid Dosage Form Drops FORMULATION EXAMPLE 4 0140) a) Dissolving Tests with ERr 731(R) in Ethanol and Glycerol: Production of a Semisolid Dosage Form Vaginal 0.141 Content of the extract: Gel 0142 61.9% rhaponticin 0.143 29.9% deoxyrphaponticin 0134) Production takes place using conventional methods by the two following variants: a) Variant A: Test A: 200 mg of dry extract in 50 ml of glycerol R: 55.1% rhaponticin (89.0% of theory) 0135) Hydroxypropylmethylcellulose (hypromellose 27.1% deoxyrhaponticin (90.6% of theory) USP) or another gel former is allowed to swell with 2-10% by Test B: 200 mg of dry extract in 50 ml of ethanol 30% R: weight in purified water. The ERr 731(R) (preparation example 52.2% rhaponticin (84.3% of theory) 1), dissolved in glycerol, is then incorporated. The amount of 25.2% deoxyrhaponticin (84.2% of theory) glycerol may be up to 50% of the weight of the gel. ERr 731(R) Test C: 200 mg of dry extract in 50 ml of ethanol 50% R: can be dissolved up to 0.5% by weight in glycerol. If neces 58.8% rhaponticin (95.0% of theory) sary, preservatives (e.g. Sorbic acid and its salts) can be added 29.0% deoxyrhaponticin (97.0% of theory) to the gel. Adjustment of the pH is also possible. As alterna Test D: 200 mg of dry extract in 50 ml of ethanol 86% R: tive to glycerol it is also possible to use 30-86% by volume 59.8% rhaponticin (96.6% of theory) ethanol. 29.5% deoxyrhaponticin (98.7% of theory) b) Variant B: 0.136 Carbomer (Carbopol) is dissolved with 0.5-5% by b) Production of Drops: weight in purified water, and the desired pH is adjusted (e.g. 0144 Drops are produced by dissolving dry extract KOH, NaOH, NH). If necessary, a preservative (e.g. sorbic according to test B in ethanol 30% R and filtering where acid and its salts) is admixed. After formation of a clear gel. appropriate. ERr 731(R) (preparation example 1) is dissolved up to 0.5% by 1. A process for producing a hydroxyStilbene-containing weight in 30-86% by volume ethanol and added. As alterna drug extract, comprising: tive to ethanol, it is also possible to use glycerol. a) providing a hydroxyStilbene-containing part of a medicinal plant, FORMULATION EXAMPLE 5 b) adding an aqueous extractant to the hydroxyStilbene containing part of the medicinal plant to form a mixture, Production of a Semisolid Dosage Form Vaginal c) extracting the mixture by allowing the extractant to act, Suppositories wherein the extracting is carried out at a pH of the mixture in the alkaline range, thereby obtaining a liquid 0.137 Suppositories with a size of 1 to 15 g with a content extract phase from the mixture, and of 1 to 12 mg of ERr 731(R) (preparation example 1) dissolved d) removing the extractant from the liquid extract phase, in glycerol (85% in 20/D=1.45085) are produced in a conven thereby producing a hydroxyStilbene-containing drug tional way by two different variants. eXtract. US 2009/0048.184 A1 Feb. 19, 2009

2. The process as claimed in claim 1, wherein the resulting 19. The process as claimed in claim 18, wherein the active extract includes at least one compound selected from rhapon ingredient combination Substantially includes rhaponticin ticin, deoxyrhaponticin, rhapontigenin, deoxyrhapontigenin and deoxyrhaponticin in a ratio of about 2:1 to 1:2 by weight. as Salt or in phenolic form. 20. The process as claimed in claim 18, wherein the solid 3. The process as claimed in claim 1, wherein the medicinal dosage form consists substantially of about plantis selected from plants of the genus Rheum sp., Astraga 60-66% by weight rhaponticin; lus sp., Cassia sp. or Picea sp. 30-35% by weight deoxyrhaponticin; 4. The process as claimed in claim 1, wherein the hydrox 0-2% by weight rhapontigenin; and yStilbene-containing part of the medicinal plant is the root of 0-2% by weight deoxyrhapontigenin. Rheum rhaponticum. 21. The process as claimed in claim 17, wherein the dosage 5. The process as claimed in claim 1, wherein a hydrox form has a total active ingredient content of about 2 to 20 mg yStilbene-containing percolate is produced from the drug. per dose unit. 6. The process as claimed in of claim 1, wherein the pH of 22. The process as claimed in claim 17, wherein the solid the mixture is in the range from about 11 to 12. dosage form has a lactose-free core. 7. The process as claimed in claim 1, wherein the pH of the 23. The process as claimed in claim 17, wherein the solid mixture is adjusted with the aid of an inorganic base selected dosage form is in the form of a pill, a tablet, an extrudate or from alkali metal and alkaline earth metal hydroxides. granules. 8. The process as claimed in claim 7, wherein the base is 24. The process as claimed in claim 17, wherein the solid calcium hydroxide. dosage form has a gastro-resistant coating. 9. The process as claimed in claim 8, wherein the ratio of 25. The process as claimed in claim 17, wherein the medi the amounts of introduced drug to calcium hydroxide (calcu cament is selected from the group consisting of gels and lated as calcium oxide) is in the range from about 5:1 to 20:1. Solutions. 10. The process as claimed in any of claim 1, wherein the 26. A process for producing a pharmaceutical composition hydroxy stilbene is precipitated from the resulting alkaline for the treatment of menopausal symptoms, juvenile oligo liquid extract phase. menorrhea and dysmenorrhea, primary and secondary amen orrhea or endometritis, prostate cancer, disorders of the lower 11. The process as claimed in claim 10, wherein the pH of urogenital tract, cancer, chronic inflammatory disorders, the extract is adjusted to a value in the range from about 3 to depression, anxiety, osteoporosis, or headaches and migraine, 4. comprising: 12. The process as claimed in either of claim 10, wherein the precipitate is removed, washed and dried. a) producing a hydroxystilbene-containing drug extract 13. The process as claimed in any of claim 1, wherein the according to a process as claimed in claim 1; and precipitate is derivatized, where appropriate after further b) formulating the extract to give the pharmaceutical com purification. position 27. The process as claimed in claim 26 wherein the meno 14. The process as claimed in claim 13, wherein the deriva pausal symptoms are in peri- or postmenopause. tization includes an esterification. 28. The process as claimed in claim 26, wherein the meno 15. The process as claimed in claim 13, wherein the deriva pausal symptoms are selected from the group consisting of tization includes an etherification. hot flushes, Sweating episodes, sleep disorders, irritability, 16. A process for producing a composition selected from psychological and mental exhaustion, sexual problems and the group consisting of medicaments, medicinal plant prepa urinary tract symptoms. rations, dietary Supplements and dietetic food products, 29. The process as claimed in claim 28, wherein the meno comprising: pausal symptoms are the result of natural or therapeutically a) producing a hydroxyStilbene-containing drug extract induced menopause. according to a process as claimed in claim 1; and 30. A method for treating a disorderina Subject comprising b) formulating the extract to give the composition. administering to a Subject a pharmaceutical composition 17. The process as claimed in claim 16, wherein the medi comprising a hydroxyStilbene-containing drug extract pro cament includes a Solid, semisolid or liquid dosage form. duced by a process as claimed in claim 1, wherein the disorder 18. The process as claimed in claim 17, wherein the solid is selected from the group consisting of menopausal Symp dosage form includes an active ingredient-containing Solid toms, juvenile oligomenorrhea and dysmenorrhea, primary core with a pharmaceutically acceptable carrier, and has an and secondary amenorrhea or endometritis, prostate cancer, active ingredient content of about 1 to 20% by weight based disorders of the lower urogenital tract, cancer, chronic on the total weight of the core, where the active ingredient inflammatory disorders, depression, anxiety, osteoporosis, includes at least one compound selected from rhaponticin, headaches and migraine. deoxyrhaponticin, rhapontigenin, deoxyrhapontigenin, and 31. The process as claimed in claim 1, further comprising the stereoisomeric forms thereof, in each case as Salt or in providing the hydroxyStilbene-containing part of the medici phenolic form, and combinations of at least two of these nal plant in comminuted form. compounds, and additionally where appropriate at least one 32. The process as claimed in claim 1, wherein the extract compound selected from resveratrol, piceatannol, astringin, ing of the liquid extract phase is repeated several times. the stereoisomeric forms thereof, in each case as Salt or in phenolic form. c c c c c