CN100431533C - Medicinal composition containing backuchiol for treating female osteoporosis - Google Patents

Medicinal composition containing backuchiol for treating female osteoporosis Download PDF

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Publication number
CN100431533C
CN100431533C CNB2005100515507A CN200510051550A CN100431533C CN 100431533 C CN100431533 C CN 100431533C CN B2005100515507 A CNB2005100515507 A CN B2005100515507A CN 200510051550 A CN200510051550 A CN 200510051550A CN 100431533 C CN100431533 C CN 100431533C
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bakuchiol
fructus psoraleae
extract
contain
osteoporosis
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CN1827090A (en
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林汉钦
丁秀玉
张温良
赵建良
黄信文
林清亮
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XINGHUI MEDICINE INDUSTRY Co Ltd
Sinphar Pharmaceutical Co Ltd
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XINGHUI MEDICINE INDUSTRY Co Ltd
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Abstract

The present invention provides a new use of a single bakuchiol compound or an extract containing bakuchiol for curing or preventing osteoporosis. The use has a specific example of a medicinal composition for curing or preventing osteoporosis. The medicinal composition of the present invention has dosage types of a transdermal absorption type, an oral administration preparation type, an injection type and a slow release preparation type. The present invention simultaneously reveals a new use of the bakuchiol compound or the extract containing bakuchiol for curing or preventing mammary cancer.

Description

The medical composition that is used for the treatment of female osteoporosis that comprises Bakuchiol
Technical field
The present invention is that relevant a kind of Bakuchiol that contains is as the medical composition of effective ingredient with osteoporosis after doing prevention or treating women's menolipsis and women's breast carcinoma disease.The also relevant a kind of Fructus Psoraleae extract that prevents or treat female osteoporosis and breast carcinoma of the present invention.
Background technology
Fructus Psoraleae is a leguminous plant Psoralea corilifolia mature fruit, and at traditional Chinese medicine, its purposes classifies as tonic (Tonic).Fructus Psoraleae has many chemical constituents and has many pharmacological actions to be put down in writing by document.In the chemistry main constituent, except that fats, psoralen (Psoralen) is arranged still, isopsoralen (Isopsoralen) and Bakuchiol (Bakuchiol), other composition then are micro constitutent.The Bakuchiol that wherein has phenol card class formation comes into one's own; therefore its pharmacological action of considerable document description is arranged; for example: mutation (antimutation); protection hepatocyte (Hepatoprotection); antioxidation (antioxidation); weak estrogen action (weak estrogen like effect); cytotoxic effect (cytotoxic effect); nucleic acid polymerization enzyme inhibition (DNA polymerase inhibitor); diabetes effect (antihyperglycemic effect) is controlled in anti-inflammatory effect (anti-inflammation).
Aspect patent, Japan Patent 11-71231 number discloses Bakuchiol can restraint of tyrosinase (Tyrosinase), therefore is used for skin-lightening cosmetic and uses.Japan Patent then discloses its bacteriostasis 2000-327581 number and 2001-233707 number, therefore is used for the therapeutic agent of sterilizing oral agent (sterilizing oral cavity) and veteran's disease pathogen (anti-legionella agent) and Drug resistance staphylococcus (anti-MRSAagent) respectively.Japan then discloses it 3-20218 number and has cytotoxicity, therefore is used for clavus (anti-corn agent) therapeutic agent.The fats composition (lipids) that Japan Patent discloses in the Fructus Psoraleae for 7-109225 number has bone strength to strengthen and bone calcification effect (bonecalcification).
Data show at present with the caused osteoporosis of estrogen for want of after estrogen (estrogen) the treatment women menolipsis, can make the women who receives treatment have higher probability to suffer from breast carcinoma than the women who does not receive treatment.Therefore have one to press for and develop a kind of medicine and can treat after women's menolipsis the caused osteoporosis of estrogen for want of, can not make the women who receives treatment have higher probability to suffer from breast carcinoma simultaneously than the women who does not receive treatment.Certainly, a kind ofly can treat women's breast carcinoma, treating after women's menolipsis for want of simultaneously, the medicine of the caused osteoporosis of estrogen also is useful.
Summary of the invention
Main purpose of the present invention is used for the treatment of or the new purposes of protect against osteoporosis at the extract that a kind of single Bakuchiol chemical compound is provided or contains Bakuchiol.One object lesson of this purposes is the medical composition of treatment or prevention of osteoporosis disease.Medical composition of the present invention can contain single Bakuchiol or contain the Bakuchiol extract, can be used in osteoporosis treatment or preventive use, and its dosage form can be percutaneous absorption, peroral dosage form, injection type or slow release formulation.
Another main purpose of the present invention is used for the treatment of or prevents and treats the new purposes of breast carcinoma a kind of single Bakuchiol chemical compound being provided or containing the extract of Bakuchiol.One object lesson of this purposes is the medical composition of treatment or prevention breast carcinoma.Medical composition of the present invention can contain single benefit bone phenol or contain the Bakuchiol extract, can be used in breast cancer treatment or preventive use, and its dosage form can be percutaneous absorption, peroral dosage form, injection type or slow release formulation.
The present invention is with the cell in vitro culture experiment, the discovery Bakuchiol has the human breast cancer cell of inhibition propagation situation is promptly arranged under low dosage, this result shows that Bakuchiol is fit to do breast cancer treatment or control agent to the selective inhibitory action of some human breast cancer cell, show that also effect is different from Korea S scholar discovery in the past to Bakuchiol to human breast cancer cell: Bakuchiol is to the toxic action of five kinds of different people cancerous cell (lung (A549), ovary (SK-OV-3), skin (SK-MEL-2), nervus centralis (XF498), large intestine (HCT)), its inhibition concentration (ED 5o) all between 10~15 μ g/cc (Arch.Pharm.Res.15,356-359 (1992)), the close demonstration Bakuchiol of this inhibition concentration is not had a selectivity to these cancerous cell toxicity, and this research is not studied human breast cancer cell.
The present invention is in the animal experiment mode in addition, with the caused osteoporosis of estrogen (estrogen) for want of after the female Mus ovariectomy simulation women menolipsis, found that Bakuchiol (5mg/kg) under low dosage has treatment osteoporosis effect, its effect machine transfers to and suppresses bone absorption (boneresorption).This discovery is different from the past Japanese scholar and finds: promptly the fats composition (lipids) in the Fructus Psoraleae has only the bone calcification effect (bone calcification) of enhancing but sclerotin (bone mass) be there is no any increase effect (Japan Patent 7-109225 number and Planta med.62,150-153 (1996)).The ideal state of the treatment of osteoporosis is that medicine can promote bone formation (bone formation) effect or bone resorption (bone resorption) inhibitory action.The similar estrogen of the effect of Bakuchiol (eStrogen) can prevent and treat bone absorption, obviously is better than the bone calcification effect of this fats.
From another angle, use the estrin treatment osteoporosis after women's menolipsis, have an opportunity to suffer from the breast carcinoma risk, Bakuchiol has treatment or prevention of osteoporosis disease, has the breast cancer cell toxic action concurrently.Therefore, for breast carcinoma/osteoporosis that the women easily suffers from, Bakuchiol is the treatment and the prophylactic agent of suitable potentialization.
Many the past data in literature can illustrate that the Fructus Psoraleae extract can utilize silica gel column chromatography (Silicagel column chromatography) fractionation of fatty constituents (lipids) and Bakuchiol.Because the two chemical property difference is easy to utilize thin chromatography (TLC) to detect, the former can't be detected but the detection of available iodine (I2) reagent by ultra-violet lamp detector (UV lamp), and the then very easy use uviol lamp of the latter detects.Therefore in embodiment 1, use single solvent mixed liquor, can purifies and separates fats and/or Bakuchiol chemical compound.
The present invention is used for the treatment of the medical composition of female osteoporosis, the Bakuchiol with following formula (I) or its medicine as the effective ingredient that comprise female osteoporosis treatment effective dose are allowed ester or salt, and and common medical allowable carrier or the diluent that uses of this effective ingredient:
Described medical composition contains the Bakuchiol (I) of 1~300mg.
Described medical composition is oral, injection, percutaneous absorption type or slow release formulation.
Described medical composition is to be prepared by Fructus Psoraleae.
Described medical composition contains the Bakuchiol (I) of 5 weight %~weight 95%, and does not contain psoralen and isopsoralen in fact.
Described effective ingredient is to be prepared by following steps:
I) with the powdered Fructus Psoraleae of organic solvent extraction;
Ii) concentrated extract; And
Iii) with step I i) resulting concentrate separates with silica gel chromatography, and obtain containing Bakuchiol (I), and do not contain the extract of psoralen and isopsoralen in fact.
Described medical composition is used for the treatment of this women's breast carcinoma simultaneously.
A kind of use has Bakuchiol or its medicine of following formula (I) and allows that ester or salt prepare the purposes of the medicine that is used for the treatment of female osteoporosis:
Figure C20051005155000071
Described medicine contains the Bakuchiol (I) of 1~300mg.
Described medicine is oral, injection, percutaneous absorption type or slow release formulation.
Described Bakuchiol (I) is to be prepared by Fructus Psoraleae.
Described medicine contains the Bakuchiol (I) of 5 weight %~95 weight %, and does not contain benefit in fact
Bone fat element and isopsoralen.
Described effective ingredient is to be prepared by following steps:
I) with the powdered Fructus Psoraleae of organic solvent extraction;
Ii) concentrated extract; And
Iii) with step I i) resulting concentrate separates with silica gel chromatography, and obtain containing Bakuchiol (I), and do not contain the extract of psoralen and isopsoralen in fact.
Described medicine is used for the treatment of this women's breast carcinoma simultaneously.
Embodiment
The method that a kind of preparation of finishing according to a preferred embodiment of the present invention contains the Bakuchiol extract comprises the following step:
A) with organic solvent, normal hexane, acetone, ethyl acetate, methanol, ethanol or the powdered Fructus Psoraleae of above-mentioned organic solvent mixture extraction (Psoralea corilifolia);
B) concentrated extract, again the gained concentrate is separated with silica gel chromatography, and with normal hexane: the mixed solution of ethyl acetate (9: 1) carries out elution as eluant, can be in regular turn (1) fatty constituents and (2) contain the eluate (eluate) of Bakuchiol, or merge and collect to such an extent that contain the eluate of (1) fats composition and (2) Bakuchiol simultaneously.Concentrated eluate promptly gets the extract that contains Bakuchiol, or contains the extract of (1) fats composition and (2) Bakuchiol simultaneously.
Wherein step b) gained eluate is with thin chromatography Analysis and Identification, its chromatography value (Rf)>0.29 of the eluate of fatty constituents.And contain the eluate of Bakuchiol chemical compound, its chromatography value (Rf)=0.29.Composition is to detect with uviol lamp or iodine, and the chromatography developping solution then is a normal hexane: ethyl acetate=9: 1
The present invention can further be understood by following examples, and these embodiment but not are used to limit the scope of the invention as illustrative purposes only.
Embodiment 1 explanation utilizes Fructus Psoraleae to make material, through extraction and separable lipoid material and the Bakuchiol of obtaining of chromatography.Embodiment 2 explanations utilize two kinds of breast cancer cells of people (a kind of is estrogen-dependent type, and another kind is the estrogen independent form), suppress human breast cancer cell growth situation with cell in vitro training method proof Bakuchiol.Embodiment 3 explanation utilizations are extractd animal ovary and are carried out Bakuchiol antagonism osteoporosis situation.
Description of drawings
Fig. 1: Bakuchiol is to the bone volume influence of trabecular bone in the proximal tibia, and error line is wherein represented 1.0 standard errors, the meansigma methods that the high expression of post is every group.
Fig. 2: Bakuchiol is to the bone density influence of tibia, and error line is wherein represented 1.0 standard errors, the meansigma methods that the high expression of post is every group.
Fig. 3: (error line is wherein represented 1.0 standard errors to Bakuchiol for ES/BS, influence %), the meansigma methods that the high expression of post is every group to the erosion bone surface percentage ratio of trabecular bone in the proximal tibia.
The specific embodiment
Embodiment 1
Behind commercially available Psoralea corylifolia grinds, to get 300 grams and utilize 2.4 liters of extractions of acetone, isolated by filtration is solid Liquid phase. Repeat aforementioned extraction and Solid-Liquid Separation three times, merging filtrate, and acetone extract liquid is concentrated Get oily extract 72.11 grams, utilize the silicone tube column chromatography that these concentrate 22 grams are separated, (9.6 * 25cm) are filled with 300g silica gel to this silica gel tubing string, and silica gel is available from Merck company, code name Silica gel 60, particle diameter 70~230 meshes (mesh). With n-hexane/ethyl acetate (9: 1), acetone, Methyl alcohol is made elutriant (eluent) in regular turn, collects one bottle for per 300 milliliters, and eluate (eluate) is with silica gel Thin chromatography (developping solution is n-hexane/ethyl acetate (9: 1)), detector is ultraviolet lamp or iodine reagent, Detect composition, with the eluat merging of identical component.
Carry out 25 bottles of silicone tube column chromatographies (1~25 bottle) with n-hexane/ethyl acetate (9: 1) mixed liquor; The 1st bottle to the 7th bottle does not present UV Absorption point mark on thin layer is analysed, obviously be the fats composition, Merging concentrates and can get 6.116 gram grease, and the 8th bottle to the 20th bottle only contains single purple on thin layer is analysed Outer light absorption point mark (chromatography value (Rf) is 0.29) merges the Bakuchiol that can get grease after concentrating 4.543 gram. In addition can get 10 bottles (26~35 bottles) with the acetone elutriant, the methyl alcohol elutriant get 10 bottles (36~45 bottles). Merge and do not contain Bakuchiol eluate (21~45 bottles), can get 11.04 grams through concentrating. By Above-mentioned test can get following result: the per kilogram corylifolia L can get the 240.36g extract, extraction Rate is 24.04%. The per kilogram medicinal material can get fats composition 66.82g, and content is 6.68%. Every public affairs The jin medicinal material can get Bakuchiol 49.64g, and content is 4.96%, and other Psoralea corylifolia composition has 123.9g, Content is 12.4%.
Resulting Bakuchiol is confirmed by following physico-chemical property:
EI-MS m/z(rel.int.%):256([m]+,24),173(100); UV(EtoH)λmax(logε):260nm(4.26);IR(KBr)v max 3350,1650, 1530,1245,1010,980,922cm -1;13C-NMR(δ,CDCl3):C-1(25.6),C-2 (131.2),C-3(124.8),C-4(23.2),C-5(41.2),C-6(42.5),C-7(135.7),C-8 (126.5),C-9(130.7),C-10(127.3),C-11(115.4),C-12(154.6),C-13(115.4), C-14(127.3),C-15(23.3),C-16(145.9),C-17(111.8),C-18(17.6). 1H-NMR(δmult.(J in Hz),CDCl3):H-1(1.61,S),H-3(5.15,t(7.3)),H-4 (1.99,q(7.3)),H-5(1.53,m),H-7(6.08,d(16.2)),H-8(6.28,d(16.2)),H-10 (7.26,d(8.5)),H-11(6.80,d(8.5)),H-13(6.80,d(8.5)),H-14(7.26,d(8.5)), H-15(1.23,S),H-16(5.91,dd(10.7,17.4)),H-17(5.06,m),H-18(1.71,S)
Figure C20051005155000092
Embodiment 2
The vitro cytotoxicity experiment:
Material: DMEM, the RPMI culture medium, L-glutaminate (L-glutamine), penicillin (Penicillin), streptomycin (Streptomycin), (fetal-bovine serum is available from Gibco company FBS) to hyclone.Cultivating plastic products is available from Corning company.Tamoxifon is available from Sigma-Aldrich company.CCK-8 reagent (Cell Counting Kit-8, new water solublity Tetrazolium salt) is available from Dojindo Moleaular Technologies company.Other reagent is the reagent level, is available from Sigma company or E.Merck company.
Cell/cell culture:
Human breast cancer cell strain T47D or MDA-MB231 are available from ATCC (American TypeCulture Collection), the T47D cell strain is estrogen-dependent type (ER-Positive), and the MDA-MB231 cell strain is non-estrogen-dependent type (ER-negative).The T47D cell culture is in the RPMI culture medium, include 10% active carbon-glucosan and remove hyclone (Charcoal-dextranstripped fetal bovine serum, CD-FBS) the MDA-MB231 cell then is incubated at the DMEM culture medium, includes two kinds of cells of 10%CD-FBS and all contains in the 5%CO2 incubator in 37 ℃ and cultivate.Cells involved hypertrophy mensuration then by adding trypan blue (trypan blue) reagent in culture medium, utilizes blood counting instrument to measure living cells quantity.
Cell toxicity test:
Have on 96 grooves at every dish, add cell suspending liquid 198 microlitres (containing 20,000 cells of T47D or 10,000 cells of MDA-MB231), plate is placed in the incubator (37 ℃, 5%CO 2) cultivate after 24 hours, adding 2 microlitre variable concentrations medicines (matched group then is medicine solvent DMSO) in groove, each concentration or contrast solvent are made 6 times (n=6).In incubator, cultivate after 48 hours, absorb culture medium, add new culture medium 100 microlitres, cultivate after 1 hour in the incubator, each groove adds 5 microlitre CC-K-8 reagent, in incubator, after 4 hours, utilize ELISA Reader instrument to survey the absorptance (Absorbance) (absorptance is the meansigma methods of 6 summations) of 450nm.Utilize concentration and absorptance can make the curve chart of corresponding each drug level (value of taking the logarithm) of cell survivaling number (absorptance), by figure the survive concentration (IC of number (matched group is 100%) of cell 50% that can be inhibited 50), the result is as shown in Table 1.
The result:
By in the table one as can be seen, Bakuchiol is to people's breast cancer cell T47D and the IC of MDA-MB-231 5oBe respectively 5.00 and 0.62 μ g/cc.The Prior Art quoted of summary of the invention discloses as described above, and Bakuchiol is to the IC of other people cancerous cell (as ovary, skin, nervus centralis, large intestine, lung) 50Be 10-15 μ g/cc, with respect to all high 2~3 times of concentration of human breast cancer cell (to the T47D cell) or 16~24 times (to MDA-MB-231 cell).So show that Bakuchiol to people's breast carcinoma effectively and have a selectively acting.Compare as Tamoxifen in addition, also show that Bakuchiol is better than the effect of Tamoxifen with clinical use.
Table one, Bakuchiol are to the human cancer cell toxic action
Figure C20051005155000111
Embodiment 3
The experiment on mice of Bakuchiol protect against osteoporosis
One, animal and ovarian resection: the female Mus of Wistar virgin with 16 ages in week is tested, be divided into five groups as follows:
First group of baseline control group (Baseline group): 8 mouse are arranged, the feeding feedstuff.
Second group of false operation group (Sham group): 10 mouse are arranged, and feeding does not add the feedstuff of medicine.
The 3rd group of removal ovary matched group (OVA group): 8 mouse are arranged, and feeding does not add the feedstuff of medicine.
The 4th group of removal ovary experiment A group (OVA+A group): 9 mouse are arranged, and feeding adds the feedstuff of medicine (5mg/kg).
The 5th group of removal ovary experiment B group (OVA+B group): 9 mouse are arranged, and feeding adds the feedstuff of medicine (15mg/kg).
Ovariectomy is with reference to Wronski method (Wronski et al., Endocrinology, 123 (2), 681-686 (1988)), with female Mus oophorectomize; False operation group mouse carries out with above-mentioned method, but does not have spay; Baseline control group mouse does not operate.
Two, contain the preparation of medicine feedstuff: behind the feedstuff and trial drug, starch and suitable quantity of water mix homogeneously pulverized, and be pressed into pastille feed block (the standard mouse feedstuff that U.S. purina company produces of the long 5.0cm of internal diameter 1.5cm x, include 1% calcareous and 1.2% phosphate), air-dry back is standby.Do not add the medicine feedstuff with method for preparing yet, only do not add the test medicine.And feed to mouse with single-blind fashion.
Three, process of the test: in pairing feeding mode, be experimental group, matched group, with false operation group feeding equivalent feedstuff, throw continuously and gave two months, drinking-water is unrestricted, and experiment 21 ℃ and 12 hours day and night the laboratory in cycle carry out, animal is sacrificed the back and measures osseous tissue form and bone density after two months.The morphometry of osseous tissue: all osseous tissues and form are to carry out (Lin et al according to international habitual metering system, Calcif Tissue Int, 67,373-377 (2000)), tissue dyes with Villanueva earlier, again with after London resin (London resin) embedding treatment, with microtome (Jung-K microtome, Leica Ltd., USA) the decalcification skeleton is not cut into 7 μ m thin slices, measures bone volume (BV/TV) and erosion bone surface percentage ratio (ES/BS%) etc. with fluorescence microscope and light microscope, and with Osteomeasures software (3.0version, Atlanta USA) analyzes (shown in Fig. 1 and 2).Bone density (Apparent bonedensity) test: behind the mouse sacrifice, take out tibia and femur, test its bone density (Danielsen et al., Calcif Tissue Int, 52,26-33 (1993)) with the Archimedian floatation principle; Measuring skeleton weight in air is W-air, and skeleton weight is W-water in the survey water in water, bone density=[W-air/ (W-air-W-water)] g/cm 3(as shown in Figure 2).
Four, data analysis: meansigma methods (mean) that data are represented and standard error (SD) are that (SPSS Inc, Chicago USA) calculates, and carries out comparing between many groups with Bonferronnitest again with one-way ANOVA earlier via SPSS 8.0.
Five, experimental result: shown in Fig. 1 and 2, change the removal ovary rat (OVX+A that situation is given Bakuchiol as can be seen by bone volume (Fig. 1) and bone density (Fig. 2), OVX+B) all there is statistics to go up the meaning increase more for bone volume of medicine removal ovary rat (OVX) and bone density, wherein organizes p<0.001 (bone volume) and p<0.05 (bone density) of OVX+A and OVX+B group with respect to OVX.Fig. 1 and 2 data show Bakuchiol can effectively prevent the osteoporosis that the estrogen forfeiture is caused.Bakuchiol effect machine changes then can change by erosion bone surface percentage ratio to be found out, the mouse of giving Bakuchiol as shown in Figure 3 mainly is to reach via the erosion bone effect (bone resorption) that stops Osteoclasts (Osteoclast) to prevent bone-loss, wherein organizes p<0.001 of OVX+A and OVX+B group with respect to OVX.

Claims (8)

1. medical composition that is used for the treatment of female osteoporosis, form by effective ingredient with common medical allowable carrier or the diluent that uses of this effective ingredient, described effective ingredient is Bakuchiol shown in the formula (I) that derives from Fructus Psoraleae or contains Bakuchiol shown in the formula (I) but do not contain the Fructus Psoraleae extract of psoralen and isopsoralen that the content of Bakuchiol in compositions is 1~300mg shown in its Chinese style (I);
Figure C2005100515500002C1
2. medical composition as claimed in claim 1, wherein this medical composition is to be prepared by Fructus Psoraleae.
3. medical composition as claimed in claim 2, it contains the Bakuchiol (I) of 5 weight %~95 weight %.
4. medical composition as claimed in claim 3, wherein effective ingredient is to be prepared by following steps:
I) with the powdered Fructus Psoraleae of organic solvent extraction;
Ii) concentrated extract; And
Iii) with step I i) resulting concentrate separates with silica gel chromatography, and obtain containing Bakuchiol (I), and do not contain the extract of psoralen and isopsoralen.
A use have the Bakuchiol of following formula (I) or derive from Fructus Psoraleae contain Bakuchiol shown in the formula (I) but the Fructus Psoraleae extract that do not contain psoralen and isopsoralen prepares the purposes of the medicine that is used for the treatment of female osteoporosis:
Figure C2005100515500002C2
Wherein this medicine contains the Bakuchiol (I) of 1~300mg.
6. purposes as claimed in claim 5, wherein this Bakuchiol (I) is to be prepared by Fructus Psoraleae.
7. purposes as claimed in claim 6, wherein this medicine contains the Bakuchiol (I) of 5 weight %~95 weight %.
8. purposes as claimed in claim 7, wherein effective ingredient is to be prepared by following steps:
I) with the powdered Fructus Psoraleae of organic solvent extraction;
Ii) concentrated extract; And
Iii) with step I i) resulting concentrate separates with silica gel chromatography, and obtain containing Bakuchiol (I), and do not contain the extract of psoralen and isopsoralen.
CNB2005100515507A 2005-03-04 2005-03-04 Medicinal composition containing backuchiol for treating female osteoporosis Expired - Fee Related CN100431533C (en)

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Publication number Priority date Publication date Assignee Title
JPH041148A (en) * 1990-04-17 1992-01-06 Asahi Denka Kogyo Kk Optically active alkenyl-substituted heptane derivative
JP4001148B2 (en) * 2005-04-01 2007-10-31 株式会社ジェイテクト Electric power steering device

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Publication number Priority date Publication date Assignee Title
JPH041148A (en) * 1990-04-17 1992-01-06 Asahi Denka Kogyo Kk Optically active alkenyl-substituted heptane derivative
JP4001148B2 (en) * 2005-04-01 2007-10-31 株式会社ジェイテクト Electric power steering device

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* Cited by examiner, † Cited by third party
Title
补骨脂化学成分及药理研究进展. 黄剑,赵陆华,邹巧根,相秉仁.药学进展,第24卷第4期. 2000
补骨脂化学成分及药理研究进展. 黄剑,赵陆华,邹巧根,相秉仁.药学进展,第24卷第4期. 2000 *

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