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WO2013007807A1 - Fractions de cimicifuga sélectionnées pour le traitement de l'ostéoporose - Google Patents

Fractions de cimicifuga sélectionnées pour le traitement de l'ostéoporose Download PDF

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Publication number
WO2013007807A1
WO2013007807A1 PCT/EP2012/063748 EP2012063748W WO2013007807A1 WO 2013007807 A1 WO2013007807 A1 WO 2013007807A1 EP 2012063748 W EP2012063748 W EP 2012063748W WO 2013007807 A1 WO2013007807 A1 WO 2013007807A1
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WO
WIPO (PCT)
Prior art keywords
cimicifuga
fractions
fraction
bone
liquid
Prior art date
Application number
PCT/EP2012/063748
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German (de)
English (en)
Inventor
Wolfgang Wuttke
Daniel INTELMANN
Markus Schuh
Guenther Stecher
Gudrun ABEL
Franz Jakob
Regina EBERT
Dana SEIDLOVÀ-WUTTKE
Original Assignee
Bionorica Se
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
Priority claimed from EP11173710A external-priority patent/EP2545932A1/fr
Application filed by Bionorica Se filed Critical Bionorica Se
Publication of WO2013007807A1 publication Critical patent/WO2013007807A1/fr

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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)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the invention relates to Cimicifuga fractions for the prophylaxis and treatment of osteoporosis in humans and animals,
  • Cimicifuga extracts are already known for the treatment of diseases based on aqueous-ethanolic extracts. In particular, their dry extracts are used as phytopharmaceuticals.
  • HRT Hormone replacement therapy
  • Cimicifuga extracts are already described as estrogen-like organ-selective drug in WO1999047149A1.
  • WO200236140A discloses that preparations of Cimieifuga are therapeutically effective in the presence of urinary incontinence. Furthermore, WO1999047149A1 discloses the suitability of Cimicifuga extracts as an organ-selective drug for the treatment of osteoporosis and atherosclerosis.
  • Osteoporosis are particularly suitable.
  • Solvents can be obtained by liquid-liquid extraction against water, an organo-selective extract from the organic phase, while the aqueous (residual) phase shows no activity (detection by a
  • Extract is suitable for treatment of estrogen deficiency, including for the treatment of osteoporosis.
  • fractions which show a bone-protective and anti-osteoporic action, both for the aqueous residual phase and for the organic phase could surprisingly be obtained by means of a chromatographic step.
  • the chromatographic step In a preferred embodiment, the
  • chromatographic step based on a solid (stationary) phase in particular by means of a column chromatography or phase chromatography, in particular a
  • Reverse phase chromatography especially normal pressure silica-reversed phase chromatography, e.g. by means of a RP-C18 column.
  • a RP-C18 column e.g. by means of a RP-C18 column.
  • HPLC High performance liquid chromatography
  • the chromatographic step allows the provision of fractions having a high content of active ingredients, which are also advantageously enriched, so that an effective lower dose level can be achieved over the prior art.
  • the invention therefore relates to a process for the production of bone-protective and anti-osteoporic Cimicifuga fractions from a Cimicifuga extract, wherein at least one chromatographic step is carried out.
  • a liquid-liquid extraction (LLE for short) of Cimicifuga takes place, wherein a first solvent is water or aqueous
  • Solvent is an organic solvent.
  • Organic solvents may preferably be such as Dichloromethane, ether, diethyl ether, tert. Butyl methyl ether (TBME), pentane, hexane, heptane.
  • TBME Butyl methyl ether
  • the first solvent is water
  • the second solvent has such a preferred polarity as dichloromethane.
  • the invention relates to a method for the production of bone-protective and anti-osteoporotic Cimicifuga fractions, wherein in a first step
  • the invention relates to a process for the preparation of bone-protective and anti-osteoporotic Cimicifuga fractions, wherein in a first step
  • the chromatographic step may be repeated. It is further preferred that the aqueous phase have high proportions of water and a pH of 7 to 9, preferably 8 to 8.5. If necessary, the pH value can be adjusted by means of a base (eg NaHCC> 3). In a further embodiment of the invention, the chromatographic step may preferably be carried out on the respective aqueous (C001 / R) or lipophilic (C001 / S) fraction.
  • fractions are obtained, which achieve at the same dosage / amount / patient increased efficacy against C001 / R or C001 / S.
  • Particularly advantageous such (sub) fractions (C001 / S1-3, see Table 1) can be obtained from the lipophilic fraction containing saponins, actin and / or deoxyactein, in particular, these ingredients are effective
  • Saponins actein and / or deoxyactone enriched.
  • Cimipronidine or cyclocimipronidine are enriched, even if saponins, actin and / or deoxyactein are present.
  • fractions enriched with saponins, actin and / or deoxyactein, cimipronidine, cyclocimipronidine are particularly advantageous
  • inventive (sub) fractions from the aqueous phase show a beneficial effect against
  • Hot flushes such as for peri- or post-menopausal complaints or climacteric complaints, are described.
  • the invention also relates to a medicament containing Cimicifuga fractions for use in the
  • the invention particularly relates to a pharmaceutical
  • a liquid-liquid extraction of Cimicifuga with an aqueous phase takes place against an organic phase and ii. ) the organic fraction (C001 / S) obtained is separated by at least one chromatographic step, and such fractions are obtained which contain saponins, actein and / or deoxyactein, if appropriate also petasiphenone,
  • the aqueous fraction (C001 / R) obtained is separated by at least one chromatographic step, and such fractions are obtained which contain cimipronidine or
  • Cyclocimipronidine if necessary, continue to contain caffeic acid, methylserotonin, (iso) ferulic acid, fulkiic acid, petasiphenone, petasiphenol, cimiciphenone, Cimiracemat, cimicifugic acid, fukinolic acid; iii. ) optionally the fractions obtained from ii.) are combined.
  • Cimicifuga racemosa (CR) - too Native American female root - understood, this is about 2 m tall and has silvery-white flowers that form long clusters.
  • the dried rootstock is used medicinally with the roots (drug).
  • C. foetida C. dahurica
  • C. heracleifolia C. simplex
  • C. japonica C. europaea
  • C. europaea C.
  • acerina C. elata, C. rubifolia.
  • rhizomes, roots, stems, leaves and / or petals of the plants can be used.
  • the skilled person is able to produce from Cimicifuga plant parts, in particular root, suitable "Cimicifuga extracts” according to claim 1, as already commercially available, eg Klimadynon® (supra.)
  • a suitable (aqueous-ethanolic) extract as "CR BNO 1055 ".
  • extracts or fractions according to the invention can be prepared by means of organic solvents, such as alcohols, in particular
  • Dry extracts e.g. the well-known "BNO 1055".
  • Cimicifuga or Cimicifuga extracts may be: triterpenes such as acetol and
  • Cimicigenolderivate polyphenols, such as caffeic acid and its derivatives, chlorogenic acid, piscidic acid, fucinoleic acid, ferulic and isoferulic acid, Cimicifugin Textren, formononetin, alkaloids
  • the Cimicifuga fractions can be prepared by the method according to the invention. Therefore, the invention relates to Cimicifuga fractions obtainable by a process according to the invention or the Cimicifuga fractions are obtained by a process according to the invention. Therefore, the invention relates to a process for the preparation of a medicament (pharmaceutical) or pharmaceutical
  • Cimicifuga fractions in particular for use in the treatment and prophylaxis of osteoporosis in humans and animals, if necessary. Containing other auxiliaries and additives.
  • the invention also relates to a medicament according to the invention for the treatment and prophylaxis of osteoporosis containing Cimicifuga fractions for the treatment and prophylaxis of osteoporosis in humans and animals, if necessary.
  • Other auxiliaries and additives are also included.
  • the invention therefore relates to a pharmaceutical
  • Formulation containing a medicament according to the invention also called “active ingredient” or “composition”
  • active ingredient also called “active ingredient” or “composition”
  • particularly suitable pharmacologically acceptable carriers include buffered Saline solutions, water, emulsions such as oil / water emulsions, various types of detergents, sterile
  • compositions comprising such carriers can be formulated by known conventional methods. These pharmaceutical compositions can be administered to an individual / patient in a suitable dose. Administration can be oral, parenteral, intravenous, intraperitoneal, subcutaneous, intramuscular, local, intranasal, or intradermal, or via a catheter at one site in an artery. The type of dosage is from
  • the type of dosage depends on various factors, e.g. the body size or the weight, the body surface, the age, the
  • Gender or the general health of the patient, but also on the specific agent to be administered, the duration and route of administration, and other medications that may be administered in parallel.
  • the medicaments according to the invention can be in the form of
  • the dosage units may be, for example, 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose
  • a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half, a third or a quarter of a daily dose.
  • Carriers are solid, semi-solid or liquid
  • Preferred pharmaceutical formulations are tablets, dragees, capsules, pills, granules, suppositories, solutions, juice, suspensions and emulsions, pastes, ointments, gels,
  • Tablets, dragees, capsules, pills and granules may contain the active ingredient (s) in addition to the usual excipients, such as a) fillers and extenders, e.g. Starches, lactose, cane sugar, glucose, mannitol and silicic acid, b) binders, e.g.
  • Polyvinylpyrrolidone c) humectants, e.g. Glycerine, d) disintegrants, e.g. Agar-agar, calcium carbonate and
  • Sodium carbonate e) dissolution inhibitor, e.g. Paraffin and f) absorption enhancer, e.g. quaternary ammonium compounds, g) wetting agents, e.g. Cetyl alcohol, glycerol monostearate, h) adsorbents, e.g. Kaolin and bentonite and i)
  • dissolution inhibitor e.g. Paraffin
  • absorption enhancer e.g. quaternary ammonium compounds
  • wetting agents e.g. Cetyl alcohol, glycerol monostearate
  • adsorbents e.g. Kaolin and bentonite and i)
  • Lubricants for example talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under a) to i).
  • the tablets, dragees, capsules, pills and granules can be mixed with the usual, optionally opacifying
  • Coated tablet in particular a calcium coated tablet, as disclosed in WO2002100422.
  • the active ingredient (s) may optionally also be incorporated with one or more of the excipients listed above
  • microencapsulated form is a microencapsulated form.
  • Suppositories may contain, besides the active ingredient (s), the usual water-soluble or water-insoluble excipients, e.g. Polyethylene glycols, fats, e.g. Cocoa fat and higher esters (e.g., C14 alcohol with C16 fatty acid) or
  • Ointments, pastes, creams and gels may contain, in addition to the active substance (s), the usual excipients, e.g.
  • Powders and sprays may contain, in addition to the active substance (s), the usual excipients, for example lactose, talc, Silica, aluminum hydroxide, calcium silicate and
  • Sprays may additionally contain the usual propellants.
  • Solutions and emulsions may contain, in addition to the active substance (s), the customary carriers such as solvents, solubilizers and emulsifiers, e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal,
  • solvents e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame
  • Fatty acid esters of sorbitan or mixtures of these substances Fatty acid esters of sorbitan or mixtures of these substances.
  • Suspensions may in addition to the active substance or the
  • liquid diluents e.g., liquid diluents
  • ethyl alcohol ethyl alcohol
  • propylene glycol ethylene glycol
  • suspending agent e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose,
  • Formulations may also include colorants,
  • Cimicifuga extracts Preservatives and odor and flavor additives, such as peppermint oil and eucalyptus oil and sweeteners, such as saccharin included.
  • Cimicifuga extracts for the preparation of the Cimicifuga extracts according to the invention and moreover reference is made to the technical teachings which are the subject of EP 1368605B1, EP 0753306B1.
  • the following examples and figures serve to illustrate the invention, without the invention to these examples
  • Cimicifuga racemosa dry extract (C001) was over
  • Dichloromethane-water (pH 8.5) worked up in two fractions.
  • the water fraction (C001 / R) contains both the simple phenylpropanoids and the cimicifugic acids, while in the dichloromethane phase (C001 / S) the saponins are enriched.
  • FIGURE 1 also shows an analytical comparison between different Cimicifuga extracts prepared at different times (lanes 1-5).
  • the subfractionation is carried out by means of a workup of the LLE fractions over normal pressure silica
  • fractions are applied to a silica gel RP-C18 packed glass column and then eluted with increasing methanol concentration.
  • a fraction collector are 20 ml aliquots
  • the saponin fraction is dissolved in methanol (1 ml per gram
  • the residual fraction is suspended in 10% methanol (1.25 ml per gram of residual fraction) and applied to the column in this form. Elution is carried out successively with 10%, 30% and 70% methanol. After combining the corresponding aliquots, the 3 subfractions R1 (72% of the residual fraction used), R2 (19%), and R3 (9%) are present.
  • Cimicifuga fractions esp. C001 / R1, C001 / R2 and C001 / R3 and C001 / S1, C001 / S2 and C001 / S3:
  • the Struts analysis determines the connectivity of the trabecular bone.
  • the ratio between the trabeculae points (NODES) and the trabecular ends (STRUTS) serves as a measure. The more Nodi and the less free trabecular ends can be determined, the more stable is the Trachea Net.
  • NODES node points
  • Strokes (STRUTS) simplified.
  • a node is defined as a point of association of three or more trabeculae.
  • a free end is defined as a point at which no
  • Struts as the individual trabeculae, are expressed as percent of the total
  • Residual fractions (C001 / R / 1-3) have a bone-protective effect (FIG. 4),
  • a Quantitative Computed Tomography enables rapid and accurate determination of rat bone mineral density.
  • 200,000 cells / well were seeded on 6-well plates and adipogenously differentiated after reaching confluence with 1, 10, 100 and 1000 ng / ml with C001, C001 / S and C001 / R for 3 weeks (DMEM (hG); % Penicillin / streptomycin; 10% fetal Calf serum; 0.1% indomethacin, dexamethasone and IBMX; 0.01% insulin). Subsequently, the cultures were stained with oil red. The quantitative evaluation was carried out with the
  • the cells to be stimulated were seeded in 6-well plates at a concentration of 100,000 cells / well and cultured until reaching confluence (80%) at 37 ° C. Then there was a two-week differentiation to adipocytes with and without extract and then a four-week
  • Transdifferentiation capacity in favor of osteogenic differentiation increases at all concentrations tested, regardless of the time of stimulation (see FIGURE 8).
  • 10 reference standard isoferulic acid (phenylpropanoid)
  • 11 reference standard deoxyactein (saponin).
  • FIG. 3 shows the spongosia density measured by qCT in the metaphysis of the tibia with respect to the fractions and subtractions according to FIG. Legend after Figure 2.
  • FIG. 4 shows the spongosia density measured by qCT in the metaphysis of the tibia with respect to the fractions and subtractions according to FIG. Legend after Figure 2.
  • Figure 5 shows the effect of the subcutaneous temperature on the ovx rats to the fractions and subfractions according to. Legend after Figure 2.
  • Figure 8 Transdifferentiation studies of 100 ng / ml and 1000 ng / ml C001 / S in hMSCs

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne des fractions de cimicifuga pour la prophylaxie et le traitement de l'ostéoporose chez l'homme et l'animal, des médicaments les contenant et leurs procédés de production.
PCT/EP2012/063748 2011-07-12 2012-07-12 Fractions de cimicifuga sélectionnées pour le traitement de l'ostéoporose WO2013007807A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP11173710A EP2545932A1 (fr) 2011-07-12 2011-07-12 Fractions de cimicifuga sélectionnées pour le traitement de l'ostéoporose
EP11173710.2 2011-07-12
EP11192016.1 2011-12-05
EP11192016 2011-12-05

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WO2013007807A1 true WO2013007807A1 (fr) 2013-01-17

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105954439A (zh) * 2016-04-22 2016-09-21 广西壮族自治区梧州食品药品检验所 一种ase方法提取升麻中异阿魏酸的方法
CN105954381A (zh) * 2016-04-22 2016-09-21 广西壮族自治区梧州食品药品检验所 一种升麻中异阿魏酸的测定方法
IT201900000343A1 (it) 2019-01-10 2020-07-10 Herbal E Antioxidant Derivatives S R L Ed In Forma Abbreviata H&Ad S R L Composizioni per il trattamento della menopausa, osteopenia e osteoporosi, disturbi metabolici e vascolari legati al climaterio

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Cited By (3)

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CN105954381A (zh) * 2016-04-22 2016-09-21 广西壮族自治区梧州食品药品检验所 一种升麻中异阿魏酸的测定方法
IT201900000343A1 (it) 2019-01-10 2020-07-10 Herbal E Antioxidant Derivatives S R L Ed In Forma Abbreviata H&Ad S R L Composizioni per il trattamento della menopausa, osteopenia e osteoporosi, disturbi metabolici e vascolari legati al climaterio

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