CN103301136A - Combined medical and health-care medicine of naringenin - Google Patents
Combined medical and health-care medicine of naringenin Download PDFInfo
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- CN103301136A CN103301136A CN2013101872366A CN201310187236A CN103301136A CN 103301136 A CN103301136 A CN 103301136A CN 2013101872366 A CN2013101872366 A CN 2013101872366A CN 201310187236 A CN201310187236 A CN 201310187236A CN 103301136 A CN103301136 A CN 103301136A
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- naringenin
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- 229940117954 naringenin Drugs 0.000 title claims abstract description 35
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Abstract
The invention provides an application of natural brassinolide analogues and naringenin in preparation of medicines for preventing or treating mammal diseases (in particular male mammals), or an application in preparation of health-care products for health-care of mammals. In addition, the invention further provides a corresponding medicine or health-care composition and a preparation method thereof.
Description
Technical field
The present invention is the continuation application of No. the 201310086548.8th, Chinese patent, belong to for mammal (as, the people) medical technical field, particularly, the present invention relates to coupling and the mammal pharmaceutical composition thereof of natural brassin lactones analog and naringenin, in the medicine for the preparation for the treatment of or prevention mammalian diseases.
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Background technology
Brassin lactones is called as the sixth-largest class phytohormone in the world, is the growth regulator for plant.Wherein, the brassin lactones of chemosynthesis, described as Chinese patent application CN1217337A, CN1217338A etc., though product homogeneous comparatively, kind is few, mainly is that 28-shows high brassin lactones.
From plant (as, pollen) or other natural origins (as, Cera Flava) brassin lactones that extracts in, it normally contains the mixture of multiple brassin lactones analog, be easy to generate the situation of unstable product quality, even like this concerning the comparatively tolerant project of stability, also the stable effect of difficult acquisition more can't be used for requiring higher project (as being used for body of mammals) for the growth regulator that is used for plant; If further purify, then the preparation cost rising is bigger, is unfavorable for industrialized implementation, thereby has hindered the further large-scale purification of people, and hindered people and gone to study wherein whether each brassin lactones analog has the activity of brassin lactones, more can't imagine mammiferous medicinal application.
The inventor passes through long-term and painstaking efforts, found out the stable flow process of from plant, extracting (purification) brassin lactones analog, study intensively wherein each kind and extracted solvent, although wherein need certain purification process, but only need leaching process one time, finally can collect the highly purified natural brassin lactones analog of multiple separation, thereby the cost of purifying of having made thinner, be conducive to Industry Promotion and implement; The natural brassin lactones analog of these separation can use separately, also can proportioning mixed use the, thereby constant product quality and control easily.Unexpectedly be, on the basis of the highly purified natural brassin lactones analog that has obtained a large amount of separation, the inventor chances on, in these natural brassin lactones analog some, can be used in as mammal with medicine or health product, for example be used for prevention or treatment boar prostatoplasia diseases, or be used for improving boar prostatic hyperplasia situation.
More unexpectedly be, the inventor is from vast as the open sea existing chemical compound, chance on, natural brassin lactones can be worked in coordination with onset with naringenin, thereby can be used for prevention or treatment boar prostatoplasia diseases better, or be used for improving boar prostatic hyperplasia situation.
Summary of the invention
The technical problem to be solved in the present invention has been to provide the application of new medicine or health product, can be used for mammal treatment, prevention or the improvement of (as, people).In addition, the present invention also provides the stable pharmaceutical composition of proportioning or health product, and the method for preparing them.
Particularly, in first aspect, the invention provides natural brassin lactones analog and naringenin unite for the preparation of the prevention or the treatment mammalian diseases medicine in application; In addition, the present invention also provides natural brassin lactones analog and naringenin to unite for the preparation of the application in the health product that improve the mammal situation.
In this article, naringenin (Naringenin; 5,7-Dihydroxy-2-(4-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-one) has structure as shown in figure 14, its CAS registration number is 480-41-1, it is the material that just is synthesized out in generation nineteen twenty, have effects such as antibiotic, antiinflammatory, anticancer, spasmolytic and function of gallbladder promoting (referring to Ber, 1928,61:2608-2613).Up to the present, report is not thought the naringenin of naringenin, especially low concentration, can with the collaborative onset of natural brassin lactones analog of the present invention, be used for prevention or treatment boar prostatoplasia diseases, or be used for improving boar prostatic hyperplasia situation.Naringenin of the present invention can be chemosynthesis, also can extract from plant.
In this article, medicine or health product refer to medicine or the health product used at mammal (especially people), rather than the compositions of using at plant.Obviously, at mammal (especially people) medicine of using or the requirement of health product than the compositions of using at plant require much higherly, the former needs proportioning stable, and the latter can be unstable; The former needs aseptic, and the latter can some bacterium; The former impurity content is low, and the latter can be contained more impurity, so even the key component of the former with the latter is identical, but both are different, perhaps the former can not select the part chosen by latter's requirement in latter's category.
In addition, the difference of medicine and health product is that those skilled in the art are familiar with, and mainly is the difference of administrative examination and approval standard, and the requirement of medicine is higher than health product.
In the application of a first aspect of the present invention, mammal can be people, domestic animal, house pet etc., preferably people.Preferably wherein, mammal is boar, as the man.
In this article, " natural " refers to from the material that limits and extracts from natural origin (as pollen, Cera Flava etc.).In the specific embodiment of the present invention, the brassin lactones analog that provides is from Pollen Brassicae campestris.Certainly, owing to resolved these natural brassin lactones analog, so they are not limited to extraction from natural origin (as pollen, Cera Flava etc.), also can be chemosynthesis.
In the application of a first aspect of the present invention, the natural brassin lactones analog that natural brassin lactones analog preferably separates.In this article, " separation " refer to that natural brassin lactones analog has broken away from or once broken away from naturally occurring environment and exist or existed to be higher than 50% purity.Although thereby natural brassin lactones analog can be mixed into the purity that has reduced itself in the mixture again, but high-purity once, be convenient to make each batch products stable, this relates to the field of personal safety for preparation medicine or health product etc., is particularly important and than the advantage of wanting.Therefore, in the application of a first aspect of the present invention, natural brassin lactones analog is the stable natural brassin lactones analog of proportioning preferably.In this article, " proportioning stable " to refer to the composition of natural brassin lactones analog in the different batches product be identical with content.Because the extracting method of first aspect present invention can separate natural brassin lactones analog, therefore can use separately or proportioning use again, can accomplish that fully proportioning is stable.
Preferably in the application of a first aspect of the present invention, described disease is prostatosis, is more preferably prostatoplasia diseases.This disease especially perplexs middle-aging male.Correspondingly, also preferred in the application of a first aspect of the present invention, described situation is prostate condition, preferably the prostatic hyperplasia situation.
Through inventor further investigation, find to have many natural brassin lactones analog to can be used in mammal with medicine or health product, especially with the naringenin administering drug combinations time, can reinforced effects, thereby can be actual medicinal or health care use.Preferably in the application of a first aspect of the present invention, described natural brassin lactones analog is BR6, BR1, BR2, BR3, BR4 and/or BR5, or their any several mixture.In this article, the structural formula of BR1 as shown in Figure 8, the structural formula of BR2 as shown in Figure 9, the structural formula of BR3 as shown in figure 10, the structural formula of BR4 as shown in figure 11, the structural formula of BR5 as shown in figure 12, the structural formula of BR6 is as shown in figure 13.
The independent medication effect of BR3 can reach capacity, although do not demonstrate cooperative effect during coupling, estimates and the naringenin coupling, can reduce their consumption under the situation that does not influence limit drug effect, so BR3 also is preferred.Preferred in the application of a first aspect of the present invention in addition, described natural brassin lactones analog is BR6, BR1, BR2, BR4 and/or BR5, or their any several mixture.
Also preferred in the application of a first aspect of the present invention in addition, described medicine or health product are compositionss of a second aspect of the present invention.
In second aspect, the invention provides the pharmaceutical composition for prevention or treatment mammal (especially boar) disease, it comprises natural brassin lactones analog and naringenin, and pharmaceutically acceptable carrier; In addition, the present invention also provides the Halth-care composition that is used for improving mammal (especially boar) situation, and it comprises natural brassin lactones analog and naringenin, and acceptable carrier on the health product.
In this article, acceptable carrier has medicine and the known implication of field of health care products technical staff respectively on pharmaceutically acceptable carrier and the health product, refer to respectively not influence (even can strengthen) active component bring into play effect, to people or nontoxic excipient substance or the health product adjuvant of other mammalian safe.Acceptable carrier often can be general on pharmaceutically acceptable carrier and the health product, comprises excipient, solubilizing agent, filler, pH regulator agent and/or correctives.They are applied to the impurity content of adjuvant of plant than routine much lower, and homogeneity is better.
In the compositions of a second aspect of the present invention, the natural brassin lactones analog that natural brassin lactones analog preferably separates.In addition, in the compositions of a second aspect of the present invention, natural brassin lactones analog is the stable natural brassin lactones analog of proportioning preferably.
Preferably in the compositions of a second aspect of the present invention, described disease is prostatosis, is more preferably prostatoplasia diseases.Correspondingly, also preferred in the compositions of a second aspect of the present invention, described situation is prostate condition, preferably the prostatic hyperplasia situation.
Preferably in the compositions of a second aspect of the present invention, the weight ratio of described natural brassin lactones analog and naringenin is 0.1 ~ 10:0.2 ~ 20, and more preferably 0.3 ~ 3:0.6 ~ 6 are more preferably 0.5 ~ 2:1 ~ 4, as 0.8 ~ 1.3:1.5 ~ 2.5, most preferably be 1:2.
The compositions of second aspect present invention can be various preparations (dosage forms), is preferably solid preparation and liquid preparation.Preparation of the present invention can be unit dosage form, as tablet, pill, capsule (comprise continue to discharge or postpone to release releasing pattern), powder, suspensoid, granule, tincture, syrup, emulsion agent, suspension, injection, etc. dosage form and various slow release formulation, thereby be fit to various administering modes, for example oral, non-intestinal injection, mucosa, muscle, intravenous, subcutaneous, ophthalmic, Intradermal or through the form of medication of skin etc.The compositions of preferred a second aspect of the present invention is oral formulations, is more preferably oral liquid, as aqueous solution or contain the aqueous solution of alcohol.
According to the inventor's deep research, preferably in the compositions of a second aspect of the present invention, described natural brassin lactones analog is BR6, BR1, BR2, BR3, BR4 and/or BR5, or their any several mixture.
Also the compositions of preferred a second aspect of the present invention is method preparation by a third aspect of the present invention in addition.
In the third aspect, the invention provides preparation and comprise the mammal of natural brassin lactones analog and naringenin with the method for medicine or health product, it comprises,
(1) extracts broken Pollen Brassicae campestris with 80 ~ 100%(V/V) ethanol waters, keep filtrate (optional wherein filtrate further concentrates) after the solid-liquid separation, obtain pure dissolubility extracting solution;
(2) pure dissolubility extracting solution is mixed with 0 ~ 60%(V/V) ethanol water, add ethyl acetate extraction then, keep ethyl acetate layer and add esterase and carry out incomplete reaction, dry then, obtain ester dissolubility extract;
(3) ester dissolubility extract is splined on silica gel chromatographic column, with the mixed liquid eluting of methanol and ethyl acetate, collects the eluent that contains natural brassin lactones analog, and drying also is dissolved in the methanol, obtains the silicagel column refined solution;
(4) and with the silicagel column refined solution be splined on the C18 reversed phase chromatographic column, with the mixed liquid eluting of acetonitrile and water, collect the eluent that contains BR6, BR1, BR2, BR3, BR4 and/or BR5 respectively; With
(5) with after the eluent drying, mix with naringenin, and mix with acceptable carrier on pharmaceutically acceptable carrier or the health product.
Natural brassin lactones analog such as BR6, BR1, BR2, BR3, BR4 and/or BR5 can be by the described extracting method of the specific embodiment of the present invention eluting successively, and it identifies that collection of illustrative plates is respectively shown in Fig. 2 ~ 7.
In the method for third aspect present invention, in step (1), can use 100%(V/V) ethanol water is (namely, straight alcohol), but the concentration of preferred alcohol aqueous solution is 85 ~ 98%(V/V), be preferably 90 ~ 97%(V/V), more preferably 93 ~ 96%(V/V), most preferably be 95%(V/V).
In the method for third aspect present invention, in step (1), the mode of broken Pollen Brassicae campestris generally is to use the physics crumbling method, comprises ultrasonication, the fragmentation etc. of milling.
In the method for third aspect present invention, in step (1), the ratio of Pollen Brassicae campestris and ethanol water can be optimized, and ratio is low excessively, will use excess ethyl alcohol, needs more expensive concentrating; Ratio is too high, then extracts insufficient.Study through the inventor, preferably in step (1), Pollen Brassicae campestris: the w/v of ethanol water is 50 ~ 200 gram: 200 ~ 500mL, is preferably 80 ~ 150 gram: 250 ~ 450mL, more preferably 90 ~ 120 gram: 280 ~ 350mL most preferably are 100 gram: 300mL.
In step (1), in order to extract fully, can the filtering residue after extracting further to be extracted, and extract filtering residue so repeatedly, merging filtrate.Therefore preferred in the method for third aspect present invention, step (1) further comprises, the filtering residue that obtains after the solid-liquid separation extracts with 80 ~ 100%(V/V) ethanol waters, carries out solid-liquid separation then, keep filtrate and with step (1) in the filtrate that obtains merge.This step can step (1) other extraction steps adopt identical condition, and the filtering residue that obtains after this step solid-liquid separation can further adopt the step identical with this step to extract 0 ~ 5 time, as long as at last all filtrates are merged.
In step (1), the filtrate of filtrate or merging, volume is excessive, the extraction efficiency of step after then being unfavorable for.Therefore preferred in the method for third aspect present invention, in step (1), filtrate further concentrates.Concentrating is that drying under reduced pressure concentrates, and is preferably dry the concentrating of vacuum with 65 ~ 80 ℃ and 0.08 ~ 0.09Mpa, most preferably is with the vacuums of 75 ℃ and 0.085Mpa dry concentrated.After concentrating, preferred alcohols dissolubility extracting solution: the volume ratio of the ethanol water in the step (2) is 0.5 ~ 2:1 ~ 3, is preferably 0.8 ~ 1.5:1.5 ~ 2.5, most preferably is 1:2.
In the method for third aspect present invention, in step (2), can use 0%(V/V) ethanol water is (namely, but the concentration of preferred alcohol aqueous solution is 30 ~ 55%(V/V), is preferably 40 ~ 53%(V/V) pure water),, more preferably 45 ~ 52%(V/V), most preferably be 50%(V/V).
In the method for third aspect present invention, in step (2), the amount of the ethyl acetate of adding can be optimized.Through inventor's research, preferably in step (2), ethanol water: the volume ratio of ethyl acetate is 1 ~ 3:3 ~ 8, is preferably 1.5 ~ 2.5:4 ~ 6, most preferably is 2:5.
In order to extract fully, can further to extract the non-ethyl acetate layer after the extraction (that is, having separated remaining layer behind the ethyl acetate layer), and extract non-ethyl acetate layer so repeatedly, the combined ethyl acetate layer.Therefore preferred in the method for third aspect present invention, step (2) comprises that further the non-ethyl acetate layer that obtains after the extraction adds ethyl acetate extraction, keep ethyl acetate layer and with step (2) in the ethyl acetate layer that obtains merge.Extraction can be carried out 1 ~ 8 time, is preferably 2 ~ 5 times.
Preferably in the method for third aspect present invention, in step (2), esterase also claims lipase, can hydrolyzing triglyceride or fatty acid ester generation list or double glyceride and free fatty.Such enzyme itself is in the field of food extensive use.Lipase preferably extracts the esterase from antibacterial, as can being to buy the lipase obtain from market, also can be directly from antibacterial (as, pseudomonas fluorescens, preferably CGMCC No.1.867(is AS 1.867) bacterial strain) the middle esterase (as referring to Chinese patent application 200810046182.0) that extracts.
Preferably in the method for third aspect present invention, in step (2), saccharifying enzyme also claims glucoamylase, starch chain can be converted into glucose.Such enzyme itself is being brewageed the field extensive use.Saccharifying enzyme preferably extracts the saccharifying enzyme from fungus, as being to buy the saccharifying enzyme that obtains from market, also can be the saccharifying enzyme that directly extracts from fungus (as aspergillus niger).
In this article, " incomplete reaction " refers to the substrate cessation reaction before all transforming that makes enzyme reaction, keeps the multiformity of natural brassin lactones analog thus.Usually complete reaction will be carried out more than 3 hours, therefore preferred in the method for third aspect present invention, in step (2), incomplete reaction is 35 ~ 42 ℃ of reactions 0.5 ~ 2 hour, preferably 37 ~ 41 ℃ of reactions 0.75 ~ 1.5 hour, most preferably 40 ℃ of reactions 1 hour.
Preferably in the method for third aspect present invention, in step (2), drying is drying under reduced pressure, is preferably the vacuum drying with 65 ~ 80 ℃ and 0.08 ~ 0.09Mpa, most preferably is the vacuum dryings with 75 ℃ and 0.085Mpa.
The inventor finds that preliminary purification is advisable with silica gel chromatographic column, and only need initial sum termination time of collection be set according to elution speed can the multiple natural brassin lactones analog of comprehensive collection, simple and easy to do.Preferably in the method for third aspect present invention, in step (3), the filler in the silica gel chromatographic column is 200 ~ 300 order silica gel, most preferably is 300 order silica gel.
In step (3), the potential eluent that can select is of a great variety, through inventor's research, finds that product is more stable with the mixed liquid eluting of methanol and ethyl acetate.Preferably in the method for third aspect present invention, in step (3), methanol in the mixed liquid: the volume ratio of ethyl acetate is 3 ~ 8:0.5 ~ 1.5, is preferably 4 ~ 7:0.8 ~ 1.3, most preferably is 5:1.
Preferably in the method for third aspect present invention, in step (3), drying is drying under reduced pressure, is preferably the vacuum drying with 65 ~ 80 ℃ and 0.08 ~ 0.09Mpa, most preferably is the vacuum dryings with 75 ℃ and 0.085Mpa.
In step (4), the potential eluent that can select is of a great variety, through inventor's research, finds can effectively separate various natural brassin lactones analog with the mixed liquid eluting of acetonitrile and water.Preferably in the method for third aspect present invention, in step (4), acetonitrile in the mixed liquid: the volume ratio of water is 60 ~ 90:10 ~ 40, is preferably 70 ~ 80:20 ~ 30, most preferably is 75:25.
It is highly purified extracting the natural brassin lactones analog that obtains with the step in the method for third aspect present invention.Preferably in the method for third aspect present invention, in step (4), greater than 90%, be preferably greater than 95%, more preferably greater than 98%, most preferably greater than 99% suc as formula the purity of the natural brassin lactones analog shown in BR6, BR1, BR2, BR3, BR4 and/or the BR5.
The excellent effect that the present invention obtains is, once extracts, and finally can collect the highly purified natural brassin lactones analog of multiple separation, thereby the cost of having made thinner; It is stable to extract (purification) flow process, and the natural brassin lactones analog of multiple separation can be used separately, also can proportioning is mixed uses constant product quality and control easily reaches the requirement of human medicine or health product; Brassin is used for the restriction of plant in the breakthrough prior art, widen its more purposes of high added value, can be used in treatment or prevention mammalian diseases, especially prostate (hypertrophy) disease, perhaps can be used in and improve mammal situation, especially prostate (hypertrophy) situation; Natural brassin lactones analog and naringenin Synergistic have not only improved effect, can reduce dosage, more can so that originally do not possess the natural brassin lactones analog that patent medicine is worth (as, BR5) also can have the value of associating patent medicine.
For the ease of understanding, below will the present invention be described in detail by concrete drawings and Examples.It needs to be noted that instantiation and accompanying drawing only are in order to illustrate, not constitute limitation of the scope of the invention.Obviously those of ordinary skill in the art can illustrate according to this paper, within the scope of the invention the present invention is made various corrections and change, and these corrections and change are also included in the scope of the present invention.In addition, the present invention has quoted the prior art document, and these documents also are in order more clearly to describe the present invention, and their full text content is all included the present invention in and carried out reference, just look like they full text in description of the present invention repeated description the same excessively.
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Description of drawings
Fig. 1 has shown the purification collection of illustrative plates of natural brassin lactones analog.
Fig. 2 ~ 7 have shown that the mass spectrum of each natural brassin lactones analog identifies collection of illustrative plates, wherein, the mass-spectrogram of BR1 as shown in Figure 2, BR2 as shown in Figure 3, BR3 as shown in Figure 4, BR4 as shown in Figure 5, BR5 as shown in Figure 6, BR6 is as shown in Figure 7.
Fig. 8 ~ 13 have shown the structural formula of each natural brassin lactones analog, wherein BR1 as shown in Figure 8, BR2 as shown in Figure 9, BR3 as shown in figure 10, BR4 as shown in figure 11, BR5 as shown in figure 12, BR6 is as shown in figure 13.
Figure 14 has shown the structural formula of naringenin.
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The specific embodiment
Extraction and the evaluation of embodiment 1 natural brassin lactones analog
Get Pollen Brassicae campestris 100 grams, add 95%(V/V) ethanol 300mL, ultrasonication is filtered, and keeps filtrate; Filtering residue adds 95%(V/V) ethanol 300mL, ultrasonication is filtered, and keeps filtrate.Merging filtrate, being concentrated into volume in 75 ℃, the vacuum drying of 0.085Mpa is 100mL, gets the pollen alcohol extract.
With 50%(V/V) ethanol 200mL is added in the pollen alcohol extract, and mix homogeneously adds the 500mL ethyl acetate extraction then, keeps upper strata (ethyl acetate layer); Lower floor continues to add the 500mL ethyl acetate extraction, keeps upper strata (ethyl acetate layer).The combined ethyl acetate layer adds 300mL and concentrates enzyme liquid (2500U/L; Referring to Chinese patent application 200810046182.0) handled 1 hour in 40 ℃ of stirrings (45rpm), in 75 ℃, the vacuum drying of 0.085Mpa, get ester dissolubility extract then.
Get ester dissolubility extract and be splined on silica gel chromatographic column (2.6cm * 40cm, 300 order silica gel), add mobile phase (namely, the mixed liquid of methanol and ethyl acetate, methanol: the volume ratio of ethyl acetate is 5:1) eluting, the control flow velocity is 4ml/ minute, collect the eluent that flowed out in the 40th minute to the 150th minute, it is fully dry in 75 ℃, the vacuum of 0.085Mpa to merge the back, is dissolved in the 10mL methanol, gets the silicagel column refined solution.
Then, the silicagel column refined solution is splined on the C18 reversed phase chromatographic column, and (column parameter is 50mm * 25cm, 5 μ m), add mobile phase (that is, the mixed liquid of acetonitrile and water, acetonitrile: the volume ratio of water is 75:25) eluting, the control flow velocity is 10ml/min, the eluting collection of illustrative plates has wherein been indicated peak and the elution time thereof of each natural brassin lactones analog as shown in Figure 1, can collect corresponding natural brassin lactones analog (BR6, BR1, BR2, BR3, BR4, BR5) respectively in each elution time.The good stability of said extracted flow process, the overall efficiency height can once obtain above-mentioned 6 kinds of natural brassin lactones analog.
Collect natural brassin lactones analog BR1, BR2, BR3, BR4, BR5 and BR6, (mass-spectrogram of BR1 as shown in Figure 2 with the high resolution mass spec checking, BR2 as shown in Figure 3, BR3 as shown in Figure 4, BR4 as shown in Figure 5, BR5 as shown in Figure 6, BR6 is as shown in Figure 7) correct, each analog purity all is higher than 99%, entrust Institute of Analysis of Sichuan University according to standard method (mass spectral analysis (GB/T 6041-2002) then, infrared spectrum analysis (GB/T6040-2002), superconduction pulse fourier transform nmr spectrum (JY/T 007-1996) and molecule absorption spectrophotometric analysis (GB/T 9721-2006)) test, parse the chemical constitution of each natural brassin lactones analog, wherein BR1 as shown in Figure 8, BR2 as shown in Figure 9, BR3 as shown in figure 10, BR4 as shown in figure 11, BR5 as shown in figure 12, BR6 is as shown in figure 13.
In addition the chemical compound of above-mentioned purification is blended into the brassin analog and (abbreviates " BR mixes " or " BR mixture " as; Wherein the weight ratio of BR1:BR2:BR3:BR4:BR5 and BR6 is 0.4:0.4:0.4:0.4:0.4:98)
Get natural brassin lactones analog BR1, BR2, BR3, BR4, BR5 and the BR6 of embodiment 1 preparation respectively, and BR mixture, use a spot of anhydrous alcohol solution respectively, adding distil water is diluted to drug level and is then: 0.005mg/mL, and wherein the dehydrated alcohol volumetric concentration is: 0.0125%; Take a morsel in addition dehydrated alcohol with distilled water be mixed with volumetric concentration be 0.0125% ethanol water in contrast.
Use the SPF level NIH that reaches large bio tech ltd available from Chengdu to test with age in days SD rat childhood (male and female half and half) with wean mice (male and female half and half) and SPF level of age in days.Process of the test is: mice or rat are divided into 8 groups at random, and (wherein the BR monomer is 6 groups, 1 group in BR mixture, 1 group of blank), every group 10, male and female half and half, each group of BR is irritated stomach with 0.1mg/kg, the blank group is irritated the isopyknic above-mentioned ethanol water of stomach 1 time every day, 3 times weekly, 4 weeks of administration altogether, during weigh in and observe the animal physiological state.Duration of test, animal is equal freely the ingest general common irradiated feed of the large and small Mus of SPF level and drink pure water.
Table 1 mice body weight change result (
, n=10)
Table 2 rat body weight result of variations (
, n=10)
The result is shown in table 1 and 2, under each Measuring Time point, large and small Mus body weight (variation) does not all have significant difference between each observation group, the animal that does not also observe each group of BR in addition occurs with respect to the abnormal physiology situation that has of blank group, shows that it is safe that 6 groups of BR monomers and BR mixture use animal.
The experiment of embodiment 3 anti-prostatic hyperplasias
Get natural brassin lactones analog BR1, BR2, BR3, BR4, BR5 and the BR6 of embodiment 1 preparation respectively, use a spot of anhydrous alcohol solution respectively, adding distil water is diluted to drug level and is then: 0.005mg/mL, and wherein the dehydrated alcohol volumetric concentration is: 0.0125%;
Get naringenin (can be available from the bright Bioisystech Co., Ltd of the Xi'an rising sun, HPLC purity is greater than 98%), be diluted to drug level with adding distil water and be: 0.01mg/mL;
It is that 0.0125% ethanol water is as blank that the dehydrated alcohol that takes a morsel is mixed with volumetric concentration with distilled water;
Use the SPF level NIH male mice (buying body weight 18-22g) that reaches large bio tech ltd available from Chengdu to test, duration of test, animal is equal freely the ingest general common irradiated feed of SPF level mice and drink pure water.
Process of the test is:
6 mices of picked at random are as the modeling matched group, injectable drug not, and only with distilled water subcutaneous injection (10mL/Kg), 1 time/day, amounted to for 3 weeks; Remaining animal all carries out modeling, and sub-cage rearing and with Testosterone Propionate subcutaneous injection modeling (5mg/Kg) 1 time/day, amounted to for 3 weeks at random.After the last modeling administration 24 hours, 6 of picked at random and modeling matched group in the animal of modeling, put to death the back of weighing respectively, gets prostate and claim weight in wet base, calculates two groups prostate index (prostate index=prostate weight in wet base (mg)/mice body weight (g)).The result shows that the mice prostate index (mg/g) of modeling is 0.90 ± 0.29, is significantly higher than modeling matched group (its prostate index (mg/g) is 0.57 ± 0.17).This shows that prostatic hyperplasia has taken place the animal of modeling.
Then, the mice of 105 successful modelings of remainder is divided into 8 groups at random, and (wherein the BR monomer is 6 groups, 1 group of naringenin, 6 groups of BR and naringenin administering drug combinations, 1 group of blank), 5 every group of administering drug combinations group and naringenin groups, all the other every group 10, each sample sets of BR is irritated stomach 1 time with 0.1mg/kg every day, the blank group is irritated the stomach equal-volume every day as the ethanol water of blank 1 time, the naringenin group is irritated stomach 1 time with 0.2mg/kg every day, corresponding BR and the 0.2mg/kg naringenin of each administering drug combinations group difference gastric infusion 0.1mg/kg every day, and administration is 20 altogether.Weigh after 24 hours and put to death mice in the last administration, get prostate and claim weight in wet base, calculate the suppression ratio of prostate index and prostatic hyperplasia.
Prostate index after the medication of table 3 prostatic hyperplasia mice
| Individually dosed group | The BR1 group | The BR2 group | The BR3 group | The BR4 group | The BR6 group | The BR5 group | The naringenin group | Blank group | The modeling matched group |
| Mice prostate index (mg/g) | 0.70 | 0.68 | 0.56 | 0.70 | 0.67 | 0.82 | 0.79 | 0.87 | 0.57 |
| Prostatic hyperplasia suppression ratio (%) | 57 | 63 | 103 | 57 | 67 | 17 | 27 | 0 | 100 |
| With naringenin administering drug combinations group | The BR1 group | The BR2 group | The BR3 group | The BR4 group | The BR6 group | The BR5 group | ? | ? | ? |
| Mice prostate index (mg/g) | 0.63 | 0.63 | 0.57 | 0.65 | 0.59 | 0.72 | ? | ? | ? |
| Prostatic hyperplasia suppression ratio (%) | 80 | 80 | 100 | 73 | 93 | 50 | ? | ? | ? |
The result shows, for individually dosed, the mice of prostatic hyperplasia modeling success is treated respectively through BR1, BR2, BR3, BR4 and BR6, can both reduce the prostate index, be used for the treatment of prostatic hyperplasia, wherein especially best with the BR3 effect, the independent effect of BR5 and naringenin all a little less than, do not have actual medical value; For the administration of associating naringenin, BR1, BR2, BR3, BR4, BR5 and BR6 treat respectively, can both reduce the prostate index, be used for the treatment of prostatic hyperplasia, wherein naringenin and BR1, BR2, BR4, BR5 and BR6 administering drug combinations can both be worked in coordination with the inhibition prostatic hyperplasia, and BR3 is the limit because independent medication effect has been effective, so estimate and the naringenin coupling, can under the situation that does not influence limit drug effect, can reduce their consumption.
Claims (10)
1. be used for the pharmaceutical composition of prevention or treatment mammal (especially boar) disease, it comprises natural brassin lactones analog and naringenin, and pharmaceutically acceptable carrier.
2. be used for improving the Halth-care composition of mammal (especially boar) situation, it comprises natural brassin lactones analog and naringenin, and acceptable carrier on the health product.
3. claim 1 or 2 described compositionss, wherein said natural brassin lactones analog is BR6, BR1, BR2, BR3, BR4 and/or BR5, or their any several mixture.
4. claim 1 or 2 described compositionss, it is oral formulations, preferably oral liquid.
5. claim 1 or 2 described compositionss, wherein said disease is prostatosis, preferably prostatoplasia diseases; Perhaps, described situation is prostate condition, preferably the prostatic hyperplasia situation.
6. natural brassin lactones analog and naringenin are united for the preparation of the medicine of prevention or treatment mammal (especially boar) disease or be used for improving the application of the health product of mammal (especially boar) situation.
7. the described application of claim 6, wherein said disease is prostatosis, preferably prostatoplasia diseases; Perhaps, described situation is prostate condition, preferably the prostatic hyperplasia situation.
8. the described application of claim 6, wherein said natural brassin lactones analog is BR6, BR1, BR2, BR3, BR4 and/or BR5, or their any several mixture.
9. the described application of claim 6, wherein said medicine or health product are arbitrary described compositionss of claim 1 ~ 5.
10. preparation comprises the mammal of natural brassin lactones analog and naringenin with the method for medicine or health product, and it comprises,
(1) extracts broken Pollen Brassicae campestris with 80 ~ 100%(V/V) ethanol waters, keep filtrate (optional wherein filtrate further concentrates) after the solid-liquid separation, obtain pure dissolubility extracting solution;
(2) pure dissolubility extracting solution is mixed with 0 ~ 60%(V/V) ethanol water, add ethyl acetate extraction then, keep ethyl acetate layer and add esterase and carry out incomplete reaction, dry then, obtain ester dissolubility extract;
(3) ester dissolubility extract is splined on silica gel chromatographic column, with the mixed liquid eluting of methanol and ethyl acetate, collects the eluent that contains natural brassin lactones analog, and drying also is dissolved in the methanol, obtains the silicagel column refined solution;
(4) the silicagel column refined solution is splined on the C18 reversed phase chromatographic column, with the mixed liquid eluting of acetonitrile and water, collects the eluent that contains BR6, BR1, BR2, BR3, BR4 and/or BR5 respectively; With
(5) with after the eluent drying, mix with naringenin, and mix with acceptable carrier on pharmaceutically acceptable carrier or the health product.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1491653A (en) * | 2003-08-28 | 2004-04-28 | 中山大学肿瘤防治中心 | New use of brassinolide in reversing multiple medicine resistance of tumour cell |
| WO2009024103A2 (en) * | 2007-08-22 | 2009-02-26 | Ustav Organicke Chemie A Biochemie Akademie Ved Ceske Republiky, V.V.I. | Natural brassinosteroids for use for treating hyperproliferation, treating proliferative diseases and reducing adverse effects of steroid dysfunction in mammals, pharmaceutical composition and its use |
| CN102860302A (en) * | 2012-09-24 | 2013-01-09 | 发事达(南通)化工有限公司 | Brassinolide water-dispersible effervescent tablets and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1491653A (en) * | 2003-08-28 | 2004-04-28 | 中山大学肿瘤防治中心 | New use of brassinolide in reversing multiple medicine resistance of tumour cell |
| WO2009024103A2 (en) * | 2007-08-22 | 2009-02-26 | Ustav Organicke Chemie A Biochemie Akademie Ved Ceske Republiky, V.V.I. | Natural brassinosteroids for use for treating hyperproliferation, treating proliferative diseases and reducing adverse effects of steroid dysfunction in mammals, pharmaceutical composition and its use |
| CN102860302A (en) * | 2012-09-24 | 2013-01-09 | 发事达(南通)化工有限公司 | Brassinolide water-dispersible effervescent tablets and preparation method thereof |
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