CN101669935B - Drug combination containing prunetin and application thereof in drugs - Google Patents
Drug combination containing prunetin and application thereof in drugs Download PDFInfo
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- CN101669935B CN101669935B CN200910206250XA CN200910206250A CN101669935B CN 101669935 B CN101669935 B CN 101669935B CN 200910206250X A CN200910206250X A CN 200910206250XA CN 200910206250 A CN200910206250 A CN 200910206250A CN 101669935 B CN101669935 B CN 101669935B
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Abstract
The invention relates to a drug combination containing pratensein and/or prunetin, which has the effects of preventing and treating cardiovascular systems, osteoporosis and the like via the effects of selective estrogen receptor modulators widely distributed in the bodies. The combination can be used for preparing the drugs for treating cancers and lead compounds. The combination can be orally taken by the patients or be applied to the patients who need the treatment by nasal inhalation or in an external rectal, parenteral or local manner. The daily dose of the combination is 1mg-4mg/kg and the combination can be applied once or more times. The combination can be prepared into solid preparations, liquid preparations, creams, ointments, patches, spraying agents, subcutaneous implants and the like, and can be especially prepared into sustained release tablets, coated tablets and the like having effects on intestinal canals.
Description
The application is that denomination of invention is dividing an application of " a kind of pharmaceutical composition containing pratensein, prunusetin. and in application pharmaceutically ", application number 200510031097.3, the patent application in October 25 2005 applying date.
Technical field
The present invention relates to medical composition and its use, be specifically related to containing the pharmaceutical composition of pratensein (Pratensein), prunusetin. (Prunetin) and in application pharmaceutically.
Background technology
The osajin composition extensively is present in plant, there is multiple biological activity, as effects such as anticancer, reduction blood fat, the effect of plant estrogen sample, raising immunity of organisms, the correlational study of relevant flavones ingredient is paid attention to by Chinese scholars always and is deepened continuously.
Herba Trifolii Pratentis (Trifolium pretense L.) has another name called Herba Trifolii Pratentis, red clover etc., multiplexly do herbage, in herb, containing multiple flavone and osajin component cpd, modern pharmacological research proves, Herba Trifolii Pratentis has significant biological activity, and the activity of having reported has:
1, estrogen sample effect: contain multiple osajin composition in this plant and there is the effect of estrogen sample, as biochanin (biochanin) A and B(are formononetin formononetin), genistein (genistein), Dai (daidzein) etc., but the estrogen-like effects of above-mentioned isoflavone all a little less than, certainly also have research to think the most weak or non-activity of formonetin effect.
2, antitumaous effect: have report to claim this product water extract to rats gavaged or injection, can suppress sarcoma S
45growth; Wherein contained genistein has cytotoxic activity to human nasopharyngeal carcinoma KB cell.
3, effect for reducing blood fat: report shows that genistein can reduce the effect of Triglycerides in Serum and cholesterol, and Biochanin A also can suppress the serum cholesterol rising, and Dai also shows obvious effect for reducing fat.
4, other effect: have bibliographical information this product that the resisting pathogenic microbes effect is arranged, wherein contained trifolirhizin has the antifungal effect.
So far; Herba Trifolii Pratentis total flavones or the Herba Trifolii Pratentis extract of report are the chief component composition mainly with Biochanin A and B; or double a small amount of genistein, the Dai be with; pratensein wherein, the content of prunusetin. are very micro-; generally do not list the content detection scope in, their chemical structural formula is:
Up to the present, yet there are no both at home and abroad pratensein, prunusetin. or its glycoside as the research report of selective estrogen receptor modulators and the report of the medical applications aspect of being correlated with.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of pharmaceutical composition containing pratensein and/or prunusetin., by the selective estrogen receptor modulators effect, has prevention and the effects such as treatment cardiovascular system, osteoporosis and cancer.
Pratensein of the present invention and/or prunusetin. are measured estrogenic activity with classical E-SCREEN method, demonstrate the two and all can promote the propagation of MCF-7 cell, have estrogen-like effects, and activity is 10 of medicine estradiol
-5-10
-3.
Pratensein of the present invention and/or prunusetin. are brought into play selectively acting to some estrogen responsiveness tissue in cardiovascular system is unified skeleton.In vitro tests also confirms that the two all can promote osteoblastic propagation significantly, and can significantly increase cellular matrix calcium and mineralising tuberosity calcium.Show that having prevention and treatment cardiovascular system diseases and osteoporosis aspect can play a role.
Zoopery of the present invention also finds that the toxicity of pratensein or prunusetin. is very low, and during heavy dose of the use, the behavior of animal is also without any significant change.
It is active component that pharmaceutical composition of the present invention contains above-mentioned general formula (1) pratensein, the prunusetin. for the treatment of effective dose, and contains one or more pharmaceutically acceptable carriers.
Pratensein of the present invention and/or prunusetin. and pharmaceutical composition can be used for the medicine of preparation treatment cancer, menopausal osteoporosis, cardiovascular and cerebrovascular disease and lead compound.
Above-mentioned pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, such as: diluent, excipient etc.Its dosage form comprises various solid dosage formss and liquid dosage form.Can also in compositions, add other adjuvant and flavouring agent, sweeting agent etc. in addition.
Pratensein of the present invention, prunusetin. can pharmaceutical composition form by oral, snuffing enters, the mode of rectum or parenteral, local application is applied to the patient who needs this treatment.When oral, can be made into conventional solid preparation as tablet, powder, granule, capsule etc., make liquid preparation as water or oiliness suspending agent etc. or other liquid preparation as syrup etc.; During for parenteral, can be made into solution, water or the oiliness suspending agent etc. of injection.During topical, can be made into cream, ointment, patch, spray, subcutaneous implant etc.Preferred form is tablet, slow releasing tablet, coated tablet, capsule, nasal spray, subcutaneous implant, particularly preferably in the preparation of the specific part slow release of intestinal.
The various dosage forms of pharmaceutical composition of the present invention can be according to the production method preparation of pharmaceutical field routine; for example make pratensein and/or prunusetin. active ingredient mix with one or more carriers, according to different indications, select different way of administration to be made into the required dosage forms of clinical practice.
The active ingredient of pharmaceutical composition of the present invention is pratensein, and prunusetin. preferably contains the active component that weight ratio is 0.1%-99.5%, most preferably contains the active component that weight ratio is 0.5%-95%.
The amount of application of active ingredient of the present invention can be according to adjustment such as the type of age of route of administration, patient, body weight, the disease for the treatment of and the orders of severity, and its, dosage was 1mg-4mg/kg every day, can use by one or many.
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
The specific embodiment
Below with embodiment, further illustrate the present invention, but the present invention is not limited.
Embodiment 1
The estrogenic activity of pratensein (pratensein), prunusetin. (prunetin)
This experiment be take MCF-7 estrogen-dependent breast cancer cell as biological test carrier, adopts classical E-SCREEN method to measure its estrogenic activity.
DMSO solvent control group (feminine gender), 1nM estradiol matched group (positive), pratensein group (1uM, 10uM), prunusetin. group (1uM, 10uM) are established in this experiment.
Result shows: pratensein, prunusetin. can promote the propagation of MCF-7 cell significantly, have estrogen-like effects, but its activity is only 10 of estradiol
-5-10
-3.
Embodiment 2
Pratensein (pratensein), prunusetin. (prunetin) and the interactional molecular simulation of estrogen receptor
Adopt the Computer-Aided Drug Design method, with estrogen receptor (ER β, ER α) as the target model, the method for optimizing with molecular mechanics obtains the activity conformation of pratensein and prunetin molecule, by the molecular docking program, calculates the interaction between receptor and aglucon.
Result shows: pratensein and prunetin all can enter the binding cavity of estrogen receptor, result also point out the two with the adhesion of ER β than the strong 7-10 of the adhesion with ER α doubly.In addition, on molecule, some position is substituted, and its activity is had to certain influence.
Because there are the difference on tissue distribution in human body ER β and ER α, ER β mainly is present in brain, skeleton, bladder and blood vessel epithelial tissue, and prompting pratensein and prunetin may bring into play selectively acting to some and ER α estrogen responsiveness tissue in cardiovascular system is unified skeleton.
Embodiment 3
The impact on osteoblast cultured in vitro of pratensein (pratensein), prunusetin. (prunetin)
Get newborn 1-3 days SD rat skulls and be separated into osteocyte with enzyme digestion, third generation cell is observed the impact on osteoblast cultured in vitro increment, cellular matrix calcium and mineralising tuberosity calcium of pratensein, prunusetin. through mtt assay, methyl thymol blue (MTB) colorimetry.
Result shows: pratensein, prunusetin. 0.1-10umol/L concentration all can promote osteoblastic proliferation significantly, and can significantly increase cellular matrix calcium and mineralising tuberosity calcium.Concrete outcome sees the following form:
* P<0.05, * * P<0.01 and control are relatively;
△p<0.05,
△ △compare with NaF P<0.01
Embodiment 4
Pratensein (pratensein), the application of prunusetin. (prunetin) in field of medicaments
The interactional molecular simulation results suggest of pratensein and prunetin and estrogen receptor, pratensein, prunetin is very likely all a selective estrogen receptor modulators, in conjunction with to the existing achievement in research of selective estrogen receptor modulators, therefore pratensein and the prunetin utmost point are hopeful exploitation becomes prevention or treatment medicine relevant to osteoporosis, prevention or treatment and related to cancer medicine, prevention or treatment and the relevant medicine of relevant disease in menopause, prevention or treatment and diseases of cardiovascular and cerebrovascular systems, protection cardiovascular function medicine, and be used for clinical with various dosage forms uses or various route of administration.
Embodiment 5
The impact of the compositions of pratensein, prunusetin. (1:1) (sample I) on ovariectomized rat
With the anesthesia of 30mg/kg pentobarbital sodium intraperitoneal administration, the rat preserved skin, extract the both sides ovary, and postoperative recuperation started administration after 9 days.Rat is divided into four groups, normal group, model group, sample I 100mg/kg group, estrogen 50 micrograms/kg group, administration every day.Continue 30 days.
Administration rises on the 20th, and rat vaginal smear every day 10 days is observed physiological period.Draw the normal saline solution of 50 microlitres 0.9% with the liquid-transfering gun of 200 microlitres, inject vagina, resorption irrigating solution, the even smear of slide.Dry rear Switzerland dye liquor, the dyeing of Giemsa dye liquor, under 400 times of ultramicroscope, carry out differential counting.After administration 30 days, get serum, measure serum triglycerides, T-CHOL on the animal automatic clinical chemistry analyzer.Measure rat blood serum estrogen, progestogen content.
The impact of sample I on ovariectomized rat serum triglycerides, T-CHOL
The research discovery, medicine has the trend that reduces triglyceride and T-CHOL.
The preliminary experiment result shows, the sample I, to the uterus weight of ovariectomized rat, the variation of vagina physiological period, serum triglycerides, T-CHOL etc., all has certain effect.
Annotate: what the sample I meaned is the compositions of pratensein, prunusetin. (1:1)
Embodiment 6
The preventive effect of sample I to retinoic acid Induced Osteoporosis of Rats disease.
Rat is divided into 6 groups at random, Normal group, model control group, the sample I is low, in, high dose group, positive controls, except Normal group, each organizes all oral retinoic acid 70mg/kg of rat, dose 1ml/100g rat, every day 1 time, continuous 14 days, respectively organize rat oral following sample successively every day simultaneously, Normal group, retinoic acid group is coordinative solvent 10ml/kg, sample I low dose group 4mg/kg, middle dosage group 12mg/kg, high dose group 36mg/kg, positive drug ethoxy Alendronate 50mg/kg, dose is the 1ml/100g rat, every day 1 time, continuous 28 days, weigh weekly therebetween 1 time, adjust the administration consumption with body weight.
Administration finishes, and gets blood system from serum, presses kit method and surveys S-Ca, S-P content, gets the rats with bilateral femur, in the scanning of x-ray borne densitometers, measures bone density (g/cm
2), claim bone heavy (W), survey bone long (L), bone diameter (D), calculate Bone apparent line density (W/L), apparent surface density (W/LD), then dry one hour for 110 ℃, be placed in again interior 200,400,600,800 ℃ of each ashing of muffle furnace 2 hours, after the ashing end is cooling, claim ash heavy (Washg), survey bone ash Ca, bone ash P content after extracting with 6NHCl, the grams with the 100g bone ash containing Ca or P means.
Opposite side femoral head 3%HNO
3make paraffin section after decalcification, HE dyeing, survey the bone trabecula width under microscope.Above result all compares with administration group and model group, and model group and Normal group are relatively.
Experiment interior each treated animal body weight no significant difference of the same day and the 1st week (P > 0.05), 2,4 weeks retinoic acid group weight ratio Normal groups lose weight (P<0.01, P<0.05) after administration, but after medication, each treated animal body weight all obviously increases, wherein low dose group (4mg/kg) has body weight to increase but no statistical significance, and the middle and high dosage group of sample I sample I (12mg/kg, 36mg/kg) and the ethoxy Alendronate group rat body weight of the 2nd, 4 weeks all increase (P<0.05) than model group, each dosage group compares no significant difference mutually.
Model group rat femur bone density is than Normal group low (P<0.01), serum Ca content is also than model group low (P<0.05), the serum paraoxonase changes of contents is little, but medication group rat femur density all increases (P<0.05, P<0.01) than model group, the content of serum calcium and phosphorus all raises than model group, but the middle and high dosage group of sample I no significant difference.The rat femur bone density of positive drug ethoxy Alendronate and serum calcium serum paraoxonase content also have obvious difference (P<0.05, P<0.01) than model group.
The sample I is as follows on the bone index impact of induced by retinoic acid in rats osteoporosis preventive effect:
With matched group, compare, the W of model group, L, d, W/L, W/Ld all obviously descend, with respect to all obviously raisings of W, W/Ld of the middle and high dosage group of model group sample I and ethoxy Alendronate group
With matched group relatively, the bone ash of model group heavily reaches bone Ca and bone P content in ash all to be reduced, but the middle and high dosage group of sample I and ethoxy Alendronate group bone ash weight, bone Ca, all increases relatively of bone P content after medication
Embodiment 7
Method for preparing tablet thereof: active component, lactose and starch mix, and water is evenly moistening, the mixture after moistening are sieved and drying, after sieve, add magnesium stearate, then by the mixture tabletting, and every heavy 250mg, active component content 10mg.
Embodiment 8
Capsule preparation method thereof: active component is mixed with auxiliary agent, sieve, evenly mix in suitable container, the mixture the obtained hard gelatin capsule of packing into, each capsule weight 200mg, active component content 50mg.
Embodiment 9
The injection preparation method: active component and sodium chloride 9mg are dissolved in appropriate water for injection, filter gained solution, in the ampulla of packing under aseptic condition, active component content 10mg.
Embodiment 10
Nasal spray preparation method: active component 1mg, sodium chloride 8mg, EDTA1mg, sodium phosphate buffer (pH6-7) 10mg, Spheron MD 30/70 10mg, heavy distilled water adds to 2ml, add a kind of composition under stirring in the heavy distilled water of proper volume at every turn, after adding water to 2ml., this solution is filtered on sterilizing filter, separate in the bottle of packing into and according to suitable dosage.
Claims (12)
1. the application in preparation prevention or treatment osteoporosis agents as the prunusetin. of unique active component.
2. application as claimed in claim 1 is characterized in that: described osteoporosis is menopausal osteoporosis disease.
3. the pharmaceutical composition for prevention or treatment osteoporosis, is characterized in that this pharmaceutical composition comprises the prunusetin. as unique active component.
4. pharmaceutical composition as claimed in claim 3, it is characterized in that: described pharmaceutical composition is solid dosage forms or liquid dosage form.
5. pharmaceutical composition as claimed in claim 3 is characterized in that: the dosage form of described pharmaceutical composition is the preparation of the specific part slow release at intestinal.
6. pharmaceutical composition as claimed in claim 3, it is characterized in that: described pharmaceutical composition is oral or parenteral pharmaceutical dosage form.
7. pharmaceutical composition as claimed in claim 6, it is characterized in that: described oral pharmaceutical dosage form is tablet, powder, granule, capsule, aqueous suspension agent, oiliness suspending agent or syrup; The solution that described parenteral pharmaceutical dosage form is injection, aqueous suspension agent or oiliness suspending agent.
8. pharmaceutical composition as claimed in claim 7, it is characterized in that: described tablet is slow releasing tablet or coated tablet.
9. pharmaceutical composition as claimed in claim 3 is characterized in that: described pharmaceutical composition is that snuffing enters or the pharmaceutical dosage form of rectum.
10. pharmaceutical composition as claimed in claim 9, it is characterized in that: the pharmaceutical dosage form that described snuffing enters is nasal spray.
11. pharmaceutical composition as claimed in claim 3 is characterized in that: the pharmaceutical dosage form that described pharmaceutical composition is local application.
12. pharmaceutical composition as claimed in claim 11 is characterized in that: the pharmaceutical dosage form of described local application is cream, ointment, patch, spray or subcutaneous implant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910206250XA CN101669935B (en) | 2005-10-25 | 2005-10-25 | Drug combination containing prunetin and application thereof in drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910206250XA CN101669935B (en) | 2005-10-25 | 2005-10-25 | Drug combination containing prunetin and application thereof in drugs |
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|---|---|---|---|
| CNB2005100310973A Division CN100546575C (en) | 2005-10-25 | 2005-10-25 | A kind of pharmaceutical composition that contains pratensein, prunusetin. and in pharmaceutically application |
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| Publication Number | Publication Date |
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| CN101669935A CN101669935A (en) | 2010-03-17 |
| CN101669935B true CN101669935B (en) | 2013-12-11 |
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| CN104208058B (en) * | 2014-08-18 | 2016-05-11 | 李健 | The application of prunetin-3 '-sodium sulfonate in the medicine of preparation treatment male sterility |
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| AU2003217982A1 (en) * | 2002-03-06 | 2003-09-22 | The Medical Research And Education Trust | Botanical extract compositions with anti-cancer or phytoestrogenic activity comprising wogonin, isoliquiritigenin and/or coumestrol |
| CN1984648A (en) * | 2003-03-06 | 2007-06-20 | 医学研究和教育联合企业 | Botanical extract compositions and methods of use |
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