EP1904075A2 - Extraits de varietes d'epimedium procedes de fabrication et utilisation - Google Patents

Extraits de varietes d'epimedium procedes de fabrication et utilisation

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Publication number
EP1904075A2
EP1904075A2 EP06828796A EP06828796A EP1904075A2 EP 1904075 A2 EP1904075 A2 EP 1904075A2 EP 06828796 A EP06828796 A EP 06828796A EP 06828796 A EP06828796 A EP 06828796A EP 1904075 A2 EP1904075 A2 EP 1904075A2
Authority
EP
European Patent Office
Prior art keywords
extract
epimedium
special
water
aqueous
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06828796A
Other languages
German (de)
English (en)
Inventor
Egon Koch
Clemens Erdelmeier
Hermann Hauer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Willmar Schwabe GmbH and Co KG
Original Assignee
Dr Willmar Schwabe GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr Willmar Schwabe GmbH and Co KG filed Critical Dr Willmar Schwabe GmbH and Co KG
Publication of EP1904075A2 publication Critical patent/EP1904075A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/29—Berberidaceae (Barberry family), e.g. barberry, cohosh or mayapple
    • A61K36/296—Epimedium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Definitions

  • the present invention relates to special extracts (liquid and dry extracts) from Epimedium species, to processes for their preparation, to medicaments and foods containing them, in particular dietetic foods, nutritional supplements and "medical food” and “dietary supplements”, and to the use of the special extracts for Prophylaxis and treatment of disease states that are caused by a lack of estrogens or by a dysregulation of the sex hormone metabolism, in particular of the estrogen metabolism.
  • Irregular menstrual cycles typically occur in women around the age of 45 and mark the onset of menopause. This period characterized by changes in the endocrine system, which may extend over a period of up to 10 years, is known as menopause or climacteric. It is triggered by the decreasing responsiveness of the ovaries to gonadotropins and the cessation of regular follicular maturation. As a result, there is a decrease and finally the final discontinuation of ova ⁇ ellen Ostrogensynthese. Due to the lack of estrogen production develop various deficiency symptoms, such as hot flashes, palpitations, depression, anxiety, headaches, sleep disorders, irritability or concentration disorders. In addition to acute climacteric symptoms, long-term postmenopausal health problems such as osteoporosis and atrophy of the urogenital mucosa and increased susceptibility to cardiovascular disease, stroke, Develop Alzheimer's disease or certain tumor diseases.
  • HET for the treatment of vasomotor and mental climacteric complaints is no longer responsible and is now rejected by many women.
  • HET for the prophylaxis of osteoporosis is to assess, especially since it is usually a long-term treatment. For these reasons, there is a great need for alternative therapy options with a better benefit-risk profile.
  • Substances which interact with the endocrine system in humans or animals and thereby produce an estrogen-like effect by influencing hormone-regulated signaling pathways have been found in many plants. At least 20 different substance groups with estrogenic / anti-estrogenic egg properties from more than 300 plants from more than 16 plant families have been found so far. Most known phytoestrogens belong to the groups of isoflavones, lignans or cumestanes. For numerous phytoestrogens, selective estrogen receptor modulating (SERM) properties are described. In contrast to natural estrogen, these compounds have partial, organ-specific estrogenic activity.
  • SERM selective estrogen receptor modulating
  • phytoestrogens are particularly advantageous, the agomstisch on certain target organs act (eg bones, vessels) or target symptoms (eg hot flashes) act, but at the same time no or estrogen have antagonistic effects on the mammary gland or the uterus.
  • TCM Traditional Chinese medicine
  • epi-medium species ferns Berberidaceae
  • These are Epimedium brevicornum, E. sagittatum, E. pubescens, E. wushanense and E. koreanum, E. davidu, E. hunanense.
  • the first five Epimedium species are part of the Herba Epimedii monograph of the Chinese Pharmacopoeia (Pharmacopoea of the Peoples Republic of China, Vol. I, 2000) and are formulated as a preparation with renal fat for the treatment of impotence, limb weakness, rheumatic pains and climacteric Used complaints.
  • herbs of the Epimedium Gattunq are used by the physicians in the form of various preparations, but not in the form of extracts from extraction with organic solvents for the treatment of impotence, spermorrhea, micturition, fatigue, lumbar and knee pain, infertility, amenorrhoea , Senile depression, rheumatoid arthritis, cardiovascular failure, hypertension, chronic bronchitis, angina pectoris and other diseases.
  • H. Wu, EJLien and LL Lien Progress in Drug Research, Vol.60, 2-57, Ed E. Jucker, 2003).
  • Epimedium species contain primarily Prenylflavonglyko- side as main ingredients.
  • Icariin 1 is a major glycoside and is found in many Epimedium species.
  • Other constituents are its desmethyl analogue epimedoside A 2.
  • free prenylflavones such as icaritine and free nonprenylated flavones such as luteolin occur.
  • chemically non-uniform group of icarisides e.g. Icarisid I3, as a major component group (H.Wu, E.J.Lien and L.L. Lien, in Progress in Drug Research, Vol.60, 2-57, Ed E. Jucker, 2003).
  • US6238707 describes a composition of at least 10 different drugs which also contains epimedium for the treatment of hormonal disorders in women. It is obvious that only a small concentration of the epimedium ingredients can be present in this composition.
  • No. 6,750,248 (corresponding to WO03040134) describes micro-preparative methods for the production and isolation of estrogen-active substances from plants such as, for example, Epimedium species. Also claimed are three estrogen-active compounds that have been microproperatively isolated and characterized from Epimedium herb. It is not known which Epimedium species were included in the herb drug used.
  • the described methods for isolating the claimed estrogenic compounds are very expensive, uneconomical and technologically unusable. These include liquid-liquid distribution, solid-phase fractionation, thin-layer chromatography, flash chromatography, and high performance or high pressure liquid chromatography. For liquid-liquid distribution, however, no concrete suitable solvents are mentioned.
  • amino acid-like or alkaloid-like ingredients in simple Epimedium extracts could now be clearly detected by means of thin layer chromatography (Dragendorff and iodoplatinate reagent) and HPLC.
  • the main compound of this amine or Alkaloidfrakti- on the Aporphinalkaloid Magnoflorin was identified. Magnoflorm has weak curare-like and hypotensive properties. Such compounds may also have excelled cytotoxic properties.
  • These plant extracts are characterized by the fact that they have lower undesirable side effects compared to conventional estrogen-effective extracts and are free of toxicologically questionable amines or alkaloids.
  • Another object of the invention is to provide such extracts which also have improved pharmaceutical properties and thus are better galenically processable and optically acceptable.
  • Another object of the present invention is to provide methods of making these special extracts, as well as drugs and foods containing these special extracts.
  • Corresponding special extracts may e.g. from the following epi-medium species (Fern. Berberidaceae): Epimedium brevicornum, E. sagittatum, E. pubescens, E. wushanense and E. koreanum, E. davidii, E. hunanense, E. grandiflorum, E. acuminatum, E. lotorrhizum, E. wanshanense, E. fragesii, E. sutchuenense, E. diphyllum, E. sempervirens, E. baicaliquizhounense, E. caotum, E. glandulospilosum, E. zushanense, E.
  • Epimedlum species are Epimedium brevicornum, Epimedium sagittatum, Epimedium pubescens, Epimedium wushanense and Epimedium koreanum, which are approved as plants for the drug Herba Epidemii of the Chinese Pharmacopoeia.
  • Epimedium brevicornum for special extracts according to the invention from the leaves of Herba Epimedii, surprisingly, in the context of the present invention, particularly strong estrogenic effects were found.
  • the special extracts according to the invention could be obtained from primary extracts by further separation and purification. It was found that the observed pharmacological effects are caused by the interaction of the prenylated flavone compounds present in the extracts. Due to the strong depletion, in particular of the aporphinal cocoa magnoflorin, the special extracts according to the invention also have lower undesired side effects.
  • the Magnofloringehalt lies in the special invention ene ckenex Exerciseen at less than 0.1 wt .-%, preferably less than 0.05 wt .-% and in particular less than 0.01 wt .-%, based on the dry extract.
  • the preparation of the special extracts according to the invention is carried out by a method comprising:
  • extracts according to the invention having improved pharmaceutical properties can be prepared by pre-extracting (degreasing) the epimedium drug prior to the actual extraction of the special extract by means of an apolar solvent and thus removing lipophilic accompanying substances.
  • the cleaning step A) for the purpose of degreasing can be carried out by pre-extraction of the drug with apolar organic solvents, for example with alkanes, more preferably heptane, or with ethers, more preferably tert. Butyl methyl ether, or with mixtures of alkanes with esters, in particular mixtures of heptane with ethyl acetate of up to 50 wt .-%, or with supercritical CO 2 .
  • the degreased drug thus obtained is then available for further processing.
  • the primary extraction step (B) can be carried out by methods known per se with inorganic or organic solvents. like P. List and PC Schmidt, Technology of Herbal Remedies, Horsch. Verlagsgesellschaft mbH, Stuttgart 1984, Chapter 3, pages 85-95 (the disclosure of which is incorporated herein by express reference), for example with water, alcohols, esters and ketones, in particular methanol, ethanol, ethyl acetate, acetone, CO 2 etc ., And their mixtures, in particular with water, at temperatures from room temperature to 100 0 C with gentle to vigorous mixing within 10 Hin. up to 24 hours.
  • inorganic or organic solvents like P. List and PC Schmidt, Technology of Herbal Remedies, Congress. Verlagsgesellschaft mbH, Stuttgart 1984, Chapter 3, pages 85-95 (the disclosure of which is incorporated herein by express reference), for example with water, alcohols, esters and ketones, in particular methanol, ethanol, ethyl acetate, acetone, CO 2 etc ., And
  • the further cleaning step (C) extracts extract constituents with undesired effects.
  • a Flussig-Flussig distribution with e.g. Ethyl acetate / water, butanone / water, n-butanol / water or methyl ethyl ketone / water, etc.
  • adsorption desorption on ion exchanger e.g. Sephadex LH-20, Diaion HP20, Dowex or Lewatit performed.
  • solvents for the chromatographic separation depending on the particular solid phase, different polarity solvents, e.g.
  • the dry extracts according to the present invention have a dry residue level of at least 95% (m / m) based on the total weight of the dry extract.
  • m / m dry residue level
  • F. Gaedcke, B. Steinhoff, H. Blas ius, Phytopharma ka, Wis sen ttl. Verlagsgesellschaft mbH Stuttgart, 2000 are dry extracts (Extracta sicca) solid preparations which are prepared by evaporation of the solvent used for their preparation.
  • the ratio of drug to solvent in each extraction ranges from about 1: 7 to about 1:10.
  • the extraction in step B) is carried out twice.
  • the alcohols and ketones used in step B) are preferably used as 10-96% (v / v) or (w / w), especially 50-92% (v / v) or (w / w) aqueous mixtures.
  • the solvent used in step B) is preferably selected from the group consisting of aqueous ethanol, aqueous methanol, aqueous acetone and aqueous or water-saturated ethyl acetate.
  • the solvent used in step B) is 70% (v / v) (62% (w / w)) ethanol, 60% (w / w) ethanol or water saturated ethyl acetate.
  • the special extracts obtainable according to the invention, together with customary pharmaceutically acceptable excipients, can be converted into medicaments in the form of e.g. Capsules, film-coated tablets, tinctures and dragées can be processed, wherein filling, binding, blasting, lubricating and coating compositions for film-coated tablets and dragees as well as oils and fats can be used as filling compositions for capsules as customary pharmaceutically acceptable auxiliaries.
  • the special extracts obtainable according to the invention can be used to produce foods, in particular dietetic foods, food supplements and "medical food” and “dietary supplements” in the form of, for example, capsules, film tablets, tablets.
  • foods in particular dietetic foods, food supplements and "medical food” and “dietary supplements” in the form of, for example, capsules, film tablets, tablets.
  • the special extracts obtainable according to the invention can be used (for the preparation of medicaments or foods) for the prophylaxis and treatment of disease states which are caused by a lack of estrogens or by a dysregulation of the sex hormone metabolism, in particular estrogen metabolism.
  • the disease states may be selected from the group consisting of climacteric complaints, sex hormone dependent cancers, benign prostatic hyperplasia, osteoporosis, Alzheimer's disease and cardiovascular diseases, as well as erectile dysfunction and urinary incontinence, the cancers comprising breast cancer, prostate cancer and uterine cancer.
  • Suitable dose ranges for the special extract according to the invention are 10 mg to 5 g, more preferably 50 mg to 2 g of extract per day.
  • the examples given below illustrate the invention and are not intended to be limiting. All percentages are by weight unless otherwise specified.
  • Dragendorff reagent (compare H. Wagner, S. Bladt, Plant Drug Analysis, 2 nd ed., Springer-Verlag Berlin, Heidelberg, New York 1996, p 360)
  • Iodoplatinate reagent (compare H. Wagner, S. Bladt, Plant Drug Analysis, 2 nd ed., Springer-Verlag Berlin, Heidelberg, New York 1996, p 361)
  • Ad 2 When spraying with Jodplatmat the Magnoflorin (Rf range 0.2-0.3) turns purple. Detection limit: 0.01% by weight
  • magnoflorine content determined by HPLC in the total extract (extract 1) was 1.1% by weight, based on the dry extract.
  • the ethyl acetate extract contains a large number of flavonoid-type compounds, while amino- or alkaloid-type compounds are no longer detectable (detection limit 0.01% by weight). The latter are clearly detectable in the separated water phase.
  • Example 2 Preparation of a special dry extract from Herba Epimedii by Flussig-Flussig distribution with methyl ethyl ketone
  • the combined extraction solution obtained in a) was removed from the ethanol on a rotary evaporator at 50 ° C.
  • the aqueous residue was shaken out 3 ⁇ with 270 ml of methyl ethyl ketone each, the methyl ethyl ketone phases were combined and concentrated to dryness on a rotary evaporator.
  • the methyl ethyl ketone extract contains according to TLC and HPLC analysis a variety of flavonoid-like compounds, while amine or alkaloid-like compounds are no longer detectable (detection limit 0.01 wt .-%). The latter are clearly detectable in the separated water phase.
  • Example 3 Production of a special dry extract from Herba Epimedii by liquid-liquid distribution with n-butanol
  • the combined extraction solution obtained in a) was removed on a rotary evaporator at 50 0 C, the ethanol.
  • the aqueous residue was shaken out 3 ⁇ with 270 ml of n-butanol each time, and the n-butanol phases were combined and concentrated to dryness on a rotary evaporator.
  • n-butanol extract 21.1 g (7.0% on the drug, 45% on the total extract)
  • n-butanol extract contains according to TLC and HPLC analysis
  • Example 4 Extraction of Epimedium brevicornum with water-saturated ethyl acetate and preliminary degreasing of the drug 300 g of ground Epimedium brevicornum drug was initially tert with 2.1 kg. Butyl methyl ether at 50 0 C extracted (step A)). The obtained liquid extract was discarded. The remaining defatted drug was extracted after intermediate drying twice with in each case 2.1 kg of water-saturated ethyl acetate with intensive stirring (process step B)).
  • the extract obtained is comparatively brightly colored and has a very good powder flowability, characterized by a very low angle of repose.
  • the extract according to DC and HPLC analysis contains a variety of flavonoid-like compounds, while a- or alkaloid-like compounds are no longer detectable (detection limit 0.01 wt .-%). The latter are clearly detectable in the separated water phase.
  • Example 5 Preparation of a special dry extract from Herba Epimedii by adsorption of alkaloid-like ingredients to an ion exchanger
  • the extract obtained from amines or alkaloids thus obtained contains the same spectrum of flavonoid-like compounds as before treatment with the cation exchanger. Alkaloids or amines were no longer detectable (detection limit 0.01 wt .-%).
  • Example 6 Testing of the Prepared Specialty Dry Extracts For Estrogenic Activity was Performed With A Cellular Estrogen Receptor Assay Assay Using Human Endometrial Carcinoma Cell Lines ECC-I (Bergeron et al., Mol., Cell Endocellol 150, 179-187, 1999). The cells were incubated (37 ° C., 5% CO 2 in air) in DME medium (ICN, 1033126) with addition of fetal calf serum (5%), glutamine (2 mM), antibiotic / antimycotic solution (1%). , Sigma, A-9909) and insulin (0.25 U / ml).
  • the adharently growing cells were removed by trypsinization from the bottom of the tissue culture bottles and adjusted to a density of 5 ⁇ 10 5 cells / ml in complete culture medium. Per well of a 24 well tissue culture plate (TPP, # 9224), 500 ⁇ l of cell suspension was filled.
  • test medium DMEM-F12 [Sigma, D-2906] with addition of Charcol-stripped bovine calf serum [5%], Glutamine [2 mM] and antibiotic / antimycotic solutions were then cultured for a further 24 hours in 500 ⁇ l of fresh test medium, and after extracting 100 ⁇ l of medium, the extracts were added to 10 ⁇ l final concentration in a volume of 50 ⁇ l allocated to the cells give.
  • the cells suspended in ethanol were transferred into 4 ml each of Quicksafe A and the bound radioactivity was measured in a ⁇ -counter (Packard, Tri-Carb 2300 TR). All approaches were done in duplicates.
  • a ⁇ -counter Packard, Tri-Carb 2300 TR. All approaches were done in duplicates.
  • To determine nonspecific binding cells were incubated in the presence of 100 nM unlabelled estradiol. The blank used was samples without labeled estradiol. Percent inhibition of receptor binding was calculated in each case in comparison to a parallel tested solvent control (DMSO, 0.1%). The determination of the half-maximal inhibitory concentration (IC 50 ) was carried out by non-linear regression calculation.
  • the special dry extracts according to the invention are approximately 3 to 6 times more effective with respect to the reference extract. With respect to the value of pure 17 ⁇ -estradiol they are less effective. However, the concentrations of the phytostenes in the organism are many times greater than those of the body's own steroids (17 ⁇ -estradiol) in the above-mentioned conventional dosages, so that the effect of the special dry extracts in the organism corresponds approximately to that of 17 ⁇ -estradiol.

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  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
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  • General Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Botany (AREA)
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  • Alternative & Traditional Medicine (AREA)
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Abstract

L'invention concerne des extraits spéciaux (extraits liquides et secs) de variétés d'Epimedium, des procédés de fabrication de ces extraits, des agents pharmaceutiques et des aliments contenant ces extraits, notamment des aliments diététiques, des compléments alimentaires, des aliments fonctionnels et des compléments diététiques. L'invention concerne également l'utilisation desdits extraits spéciaux pour la prophylaxie et le traitement d'états pathologiques dus à une carence en oestrogènes ou à un dérèglement du métabolisme des hormones sexuelles, notamment du métabolisme des oestrogènes.
EP06828796A 2005-07-15 2006-07-14 Extraits de varietes d'epimedium procedes de fabrication et utilisation Withdrawn EP1904075A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005033241 2005-07-15
PCT/EP2006/006929 WO2007031140A2 (fr) 2005-07-15 2006-07-14 Extraits de varietes d'epimedium procedes de fabrication et utilisation

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EP1904075A2 true EP1904075A2 (fr) 2008-04-02

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EP (1) EP1904075A2 (fr)
WO (1) WO2007031140A2 (fr)

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CN104001004A (zh) * 2014-06-16 2014-08-27 徐艳 一种治疗骨折和骨质疏松的中药组合物及其制备方法和应用
CN105214012A (zh) * 2015-11-16 2016-01-06 陈明海 一种治疗乳腺增生的中药组合物
CN112552356A (zh) * 2020-06-29 2021-03-26 郑州福瑞堂制药有限公司 一种淫羊藿苷制备方法
CN113980065A (zh) * 2021-11-09 2022-01-28 陕西理工大学 从淫羊藿全草中提取淫羊藿苷的方法

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US6071883A (en) * 1998-07-28 2000-06-06 Chen; Huifang Flavone analogues useful as anti-rejection agents
US6916845B2 (en) * 1999-06-17 2005-07-12 Zhongcheng Xin Method for prevention and treatment of male and female sexual dysfunction
US20020013280A1 (en) * 2000-06-16 2002-01-31 Zhongcheng Xin Pharmaceutical composition for preventing and treating sexual dysfunction and vasculargenic disease comprising icariin
US6399579B1 (en) * 2000-08-15 2002-06-04 Hauser, Inc. Compositions comprising icariside I and anhydroicaritin and methods for making the same
US6750248B2 (en) * 2001-11-09 2004-06-15 National University Of Singapore Methods for preparing an estrogenic preparation and isolated estrogenic compounds from a plant and uses thereof
US6476203B1 (en) * 2002-03-14 2002-11-05 Xinxian Zhao Safe pharmaceutical composition for treating and preventing infertility and increasing immune function
CN1151164C (zh) * 2002-09-26 2004-05-26 中国药科大学 具有抗骨质疏松作用的淫羊藿总黄酮的制备方法

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WO2007031140A3 (fr) 2007-08-09

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