CN102114044B - Artificially processed bear bile powder and preparation method thereof - Google Patents
Artificially processed bear bile powder and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a preparation method of bear bile, which comprises the following steps: incising a wound on the gall bladder of a bear, forming a fistula with muscular tissues and binding up; and extruding a fistula orifice after healing so as to collect the bile. The method can be used for non-continuous, timing, quantitative and long-term collection, and can avoid affecting the utilization of the bile of the bear. The invention discloses high-quality bear bile powder and the preparation method thereof. The bear bile powder shows bright yellow fluorescence under a 365nm ultraviolet lamp and has three chromatographic peaks under 198nm. The preparation method of the powder comprises the steps of standing the bile, separating and drying the powder, and then crushing and screening the powder so as to get the bear bile powder. The prepared bear bile powder is pure in color and luster of appearance, high in the content of tauroursodeoxycholic acid, does not absorb moisture and is convenient to store, transport and process.
Description
Technical field
The present invention relates to a kind of method of bile, production method and gallbladder powder of gallbladder powder of extracting in the animal body, especially a kind ofly in the body of Bears, extract the method for bile, production method and the high-quality Fel Ursi powder of Fel Ursi powder.
Background technology
Fel Ursi is the dry bile in ursidae animal black bear Selenarctos thibetanus (G.Cuvier), northeast brown bear Ursus arctos lasiotus Gray or the brown bear Ursus arctos L. gallbladder.In China, main product Yunnan, Heilungkiang, Jilin.In addition, the ground such as Guizhou, Sichuan, Qinghai, Tibet, Xinjiang, Gansu, Hubei, Hunan, Shaanxi, Fujian also produce.Main Ingredients and Appearance in the Fel Ursi is the alkali metal salt of bile acids, in addition, also contains cholesterol and bile pigments.Tauroursodeoxycholic acid that can about 20% from the black bear gallbladder is the main component of Fel Ursi, be hydrolyzed then give birth in sulfonic acid and ursodeoxycholic acid.Fel Ursi contains again a small amount of chenodeoxy cholic acid and cholic acid.Ursodeoxycholic acid is the stereoisomers of crane deoxycholic acid, is the special composition of Fel Ursi, can distinguish with the gallbladder of its beast.
Fel Ursi energy heat-clearing and toxic substances removing makes eye bright, and has spasmolytic, convulsion, choleretic effect, in addition, hemophilus influenza, escherichia coli, streptococcus pneumoniae, alpha streptococcus, Pseudomonas aeruginosa, micrococcus catarrhalis etc. is all had inhibitory action.All bringing into play pharmacological action and health-care effect aspect treatment cholelithiasis, acute icterohepatitis and chronic hepatitis B, acute conjunctivitis and cataract, anti-cerebral thrombosis and cerebral ischemia, antitumor, antiulcer, antiviral, antipyretic-antalgic, blood fat reducing and anti-ageing the waiting for a long time.
Traditional preparation method is to kill Bears to get gallbladder always, causes medicine source animal to be on the brink of extinction.In the later stage eighties 20th century, domestic-developed and the Fel Ursi capsule of progressively use living are made art with Louing and are inserted drainage tube and gather bile (the Tube Drain acquisition method is arranged) or have Tube Drain to get continuously bile technology (the continuous drain acquisition method of pipe is arranged), produce drainage bear bile powder.The technical deficiency that has continuously Tube Drain to produce Fel Ursi powder is that drainage tube retains in the Bears body for a long time, causes easily wound local inflammation and infection; There is simultaneously the Tube Drain continuous acquisition also to affect self metabolism of Fel Ursi.
The patent No. be ZL 01112258.7 disclosure of the Invention a kind of preparation method of artificial bear bile powder; extract by biological with poultry bile; obtain respectively tauroursodeoxycholic acid component, cholochrome composition and bile acid component, process in proportion after then these components being measured and be mixed with artificial bear bile powder.Although artificial bear bile powder contains some Main Ingredients and Appearances in the natural Fel Ursi, its component is single, and complicated process of preparation is not suitable for large-scale industrial production.
Present commercially available Fel Ursi powder is expensive, the easy moisture absorption, and tauroursodeoxycholic acid content is lower in the Fel Ursi powder, makes it be subject to great restriction in the application aspect medicine and the health care.
The present invention adopts artificial pipeless drainage to gather Fel Ursi, and the method can obviously reduce the infection of gallbladder, improves the quantity and quality of bile, reduces because there being pipe to retain destruction to gallbladder; Simultaneously, can also reduce the operation number of times of black bear.Cut wound by the surgery fistulation at gallbladder, and after forming fistula with muscular tissue, can be used for every day discontinuous, gather at regular time and quantity, make bile fully concentrated in gallbladder, thereby obtain high-quality bile.Even long-term the collection can not utilize bile (required for its physiology and growth promoter) to impact to black bear self yet.
The Fel Ursi powder that the bile that extracts by the method is made, appearance luster is pure, and is nonhygroscopic, be beneficial to accumulating and be processed into peroral dosage form, and in the Fel Ursi powder tauroursodeoxycholic acid content apparently higher than present commercially available common Fel Ursi powder.
Summary of the invention
Primary and foremost purpose of the present invention is to provide a kind of method of extracting bile in the body of Bears and a kind of artificial Fel Ursi powder and preparation method thereof for the problem that above-mentioned prior art exists, active constituent content in the artificial Fel Ursi powder of the present invention is high, water content is low, nonhygroscopic, be suitable for storage, deposit and transport, and the curative effect of Fel Ursi powder is high, has obviously improved its effect.
For realizing purpose of the present invention, one aspect of the present invention provides a kind of method of extracting bile in the body of Bears.
Wherein, cut wound at the gallbladder of Bears, and form fistula with muscular tissue, tighten; Squeeze the fistula mouth after the recovery from illness and gather bile.
Wherein, at the downward 1～10cm of the ventrimeson xiphoid-process place of Bears, percutaneous incision undertissue pulls out gallbladder; Cut the wound of 1～3cm at gallbladder, and form fistula with muscular tissue, tighten.
Particularly, in the downward 1～10cm of ventrimeson xiphoid-process place, percutaneous incision undertissue, blunt separation muscle cuts sarolemma, peritoneum, pulls out gallbladder; Cut the wound of 1～3cm at gallbladder, and form fistula with muscular tissue, tighten with the stitching thread appropriateness; Again fixedly gallbladder and gallbladder skin; Difference peritoneal suture, fat, sarolemma, muscle and skin; Then the art mouth cleans and sterilizes.
Wherein, revived 2～4 hours the nutritional solution of feeding at the Bears postoperative.
Particularly, nutritional solution is hydromel, sucrose solution or egg water.
Wherein, in 1-15 days after surgery, give intramuscular injection or oral antibiotic to Bears.
Wherein, every day, the timing acquiring Fel Ursi was 1～3 time, and gathering total amount every day is 50～200mL.
Wherein, Bears is black bear, is preferably the black bear that cultivates in the Asia, more preferably cultivates the black bear in Fujian province.
The present invention provides a kind of artificial Fel Ursi powder on the other hand, is bright orange green fluorescence under 365nm, namely is bright orange green fluorescence under the ultraviolet light of 365nm.
Particularly, the ultraviolet characteristic absorption wavelength of the effective ingredient tauroursodeoxycholic acid of described Fel Ursi powder is 198nm; In the chromatographic peak that occurs thereafter, also having the uv absorption wavelength of 2 chromatographic peaks also is 198nm.
Wherein, Fel Ursi powder adopts in the chromatographic peak of high effective liquid chromatography for measuring, and retention time is that the ultraviolet characteristic absorption wavelength of 3.3-3.4 minute chromatographic peak is 198nm and 226nm behind the methanol solvate peak; Wherein, the chromatographic condition of described high performance liquid chromatography: mobile phase-methanol 0.03mol/L sodium dihydrogen phosphate (65: 30); Transfer PH4.4 with phosphoric acid; Flow velocity: 1.0ml/min; Detect wavelength: 210nm; Detector: Agilent 1100 DAD; Column temperature: 30 ℃; Pillar: Hypersil ODS sum 4.6 * 250mm.
Particularly, the ultraviolet characteristic absorption peak that also contains 249nm and 494nm.
Wherein, tauroursodeoxycholic acid content 〉=40% in the described Fel Ursi powder, preferred 〉=40-60%, more preferably 40-45%.
Particularly, the moisture of described Fel Ursi powder≤2%.
High-quality Fel Ursi powder of the present invention, gather the ultraviolet fingerprint at each peak through high performance liquid chromatography DAD detector, the uv absorption spectrum wavelength of main effective ingredient tauroursodeoxycholic acid and other 2 main chromatographic peaks all is 198nm, 3.5 telling the uv absorption wavelength of the impurity chromatographic peak at peak is 198nm, 226nm, all the other impurity peaks are all without ultraviolet absorption peak;
Wherein, described Fel Ursi powder is at first water-soluble after, adopt ethyl acetate extraction, obtain acetic acid ethyl ester extract and the water-soluble substances of Fel Ursi powder, wherein, the uv absorption wavelength of described acetic acid ethyl ester extract is 262nm; The uv absorption wavelength of described water-soluble substances is 249nm and 494nm;
Wherein, described Fel Ursi powder with dissolve with methanol, is then removed insoluble part, get Fel Ursi powder dissolve with methanol thing, the uv absorption wavelength of described dissolve with methanol thing is 249nm and 262nm.
High-quality Fel Ursi powder of the present invention through thin layer chromatography, can detect 7 blue-fluorescence speckles under the 254nm uviol lamp, its Rf value is respectively 0.96,0.8, and 0.7,0.54,0.46,0.4,0.2; Can detect 9 sapphirine fluorescence speckles under the 365nm uviol lamp, its Rf value is respectively 0.96,0.84, and 0.76,0.56,0.5,0.4,0.7,0.18,0.1.Wherein, Rf value is 0.18 sapphirine fluorescence speckle, is its peculiar speckle.
Another aspect of the invention provides a kind of production method of artificial Fel Ursi powder, comprises the steps:
1) Fel Ursi is left standstill clarification, obtain supernatant;
2) supernatant is carried out remove impurity and process, obtain the water solublity Fel Ursi;
3) the water solublity Fel Ursi is carried out dried, pulverize, sieve, and get final product.
Wherein, step 1) temperature that leaves standstill clarification described in is 4～10 ℃, and time of repose is 2～24 hours; Step 2) adopting centrifugal, filtration or adsorption treatment method that the Fel Ursi supernatant is carried out described remove impurity in processes; Step 3) dried described in is selected oven dry, vacuum drying, spray drying or lyophilization.
Particularly, the rotating speed that described centrifugal remove impurity is processed is 10000～12000rpm, and the time is 10-120min; Described filtration treatment is pressure filtration, and the relative pressure of filtration treatment is 0.1～0.3MPa; It is to adopt macroporous adsorbent resin to carry out adsorption-edulcoration that described adsorption-edulcoration is processed.
Wherein, the filtering accuracy of filtration treatment is the 0.2-0.5 micron; Described macroporous resin is chosen as D101 type macroporous resin.
Particularly, described macroporous adsorbent resin is 1～80: 1 with the ratio of the weight of Fel Ursi supernatant.
Wherein, described vacuum drying relative pressure be-0.05～-0.095MPa; Baking temperature is 30～60 ℃; Be 8-60 hour drying time.
Particularly, described bake out temperature is 60～80 ℃; Drying time is 24～48 hours.
Particularly, described lyophilization is-40 ℃ of lower pre-freezes 3～5 hours, then-40～-15 ℃ of lower sublimation dryings 18～24 hours, and then lower dry 12～20 hours in-15～30 ℃ with Fel Ursi.
Especially, cryodesiccated relative pressure is 2-20MPa.
Particularly, with the water solublity Fel Ursi at effluxvelocity 300～990 meter per seconds, temperature be 30～60 ℃, relative pressure be-0.04～-carry out described spray drying under the condition of 0.09MPa.
Wherein, described Fel Ursi powder through the pulverizing after the dried is crossed 100～180 mesh sieves.
The present invention provides a kind of artificial Fel Ursi powder that is prepared from according to the method described above on the other hand.
Wherein, Fel Ursi powder is bright orange green fluorescence under 365nm, namely is bright orange green fluorescence under the ultraviolet light of 365nm.
Particularly, the ultraviolet characteristic absorption wavelength of the effective ingredient tauroursodeoxycholic acid of described Fel Ursi powder is 198nm; In the chromatographic peak that occurs thereafter, also having the uv absorption wavelength of 2 chromatographic peaks also is 198nm.
Wherein, Fel Ursi powder adopts in the chromatographic peak of high effective liquid chromatography for measuring, and retention time is that the ultraviolet characteristic absorption wavelength of 3.3-3.4 minute chromatographic peak is 198nm and 226nm behind the methanol solvate peak; Wherein, the chromatographic condition of described high performance liquid chromatography: mobile phase-methanol 0.03mol/L sodium dihydrogen phosphate (65: 30); Transfer PH4.4 with phosphoric acid; Flow velocity: 1.0ml/min; Detect wavelength: 210nm; Detector: Agilent 1100 DAD; Column temperature: 30 ℃; Pillar: Hypersil ODS sum 4.6 * 250mm.
Particularly, the ultraviolet characteristic absorption peak that also contains 249nm and 494nm.
Wherein, tauroursodeoxycholic acid content 〉=40% in the described Fel Ursi powder, preferred 〉=40-60%, more preferably 40-45%.
Particularly, the moisture of described Fel Ursi powder≤2%.
Further aspect of the present invention provides a kind of high-quality Fel Ursi powder of manually purifying.
Wherein, Fel Ursi powder is burnished gold or the foresythia powder of hyaloid gloss, is glassy yellow fluorescence and nonhygroscopic.
Wherein, tauroursodeoxycholic acid content 〉=40% in the described Fel Ursi powder, preferred 〉=40-60%, more preferably 40-45%.
Another aspect of the invention provides a kind of artificial Fel Ursi powder for the preparation of the application in treatment and prevention hepatitis, hepatic fibrosis, cholelithiasis, antitumor, antiviral, oculopathy, the antipyretic analgesics.
Advantage of the present invention is as follows:
1, by the artificial pipeless drainage technology, cut wound at the gallbladder of Bears, and form fistula with muscular tissue, tighten; Squeeze the fistula mouth after the recovery from illness and gather bile.That the method can be used for is discontinuous, at regular time and quantity and long-term the collection, and can not utilize bile to impact to Bears self.
2, the artificial Fel Ursi powder appearance luster of the present invention's preparation is pure, nonhygroscopic, hydroscopicity≤2%; Tauroursodeoxycholic acid content is high in the Fel Ursi powder, reaches more than 40%, and its effective ingredient tauroursodeoxycholic acid content is significantly higher than at present commercially available common Fel Ursi powder, is beneficial to accumulating and the processing of Fel Ursi powder, especially is beneficial to the preparation of peroral dosage form.
3, the preparation method of artificial Fel Ursi powder of the present invention is simple, and process conditions are gentle, and with low cost, expense is low.
Description of drawings
Fig. 1: reversed phase high efficiency lamellae: RP-18F
254, developing solvent chloroform-acetone-glacial acetic acid (7: 2: 1), exhibition is apart from 5cm.Fluorescence photo under the uviol lamp 254nm; The ratio of volume is 7: 2: 1
Fig. 2: reversed phase high efficiency lamellae: RP-18F
254, developing solvent chloroform-acetone-glacial acetic acid (7: 2: 1), exhibition is apart from 5cm.Fluorescence photo under the uviol lamp 365nm;
Fig. 3: the Fel Ursi powder high-efficient liquid phase chromatogram of the embodiment of the invention 4 preparations;
Fig. 4: the Fel Ursi powder high performance liquid chromatography of the embodiment of the invention 4-3D figure;
Fig. 5: the Fel Ursi powder of the embodiment of the invention 4 is schemed (uv absorption wavelength 198nm) at the high performance liquid chromatography of 2.635 minutes methanol solvate chromatographic peak of retention time-3D;
Fig. 6: the Fel Ursi powder of the embodiment of the invention 4 is schemed (uv absorption wavelength 198nm, 226nm) at the high performance liquid chromatography of 3.355 minutes chromatographic peak of retention time-3D;
Fig. 7: the Fel Ursi powder of the embodiment of the invention 4 is schemed (tauroursodeoxycholic acid uv absorption wavelength 198nm) at the high performance liquid chromatography of 11.02 minutes chromatographic peak of retention time-3D;
Fig. 8: the Fel Ursi powder of the embodiment of the invention 4 is schemed (uv absorption wavelength 198nm) at the high performance liquid chromatography of 20.74 minutes chromatographic peak of retention time-3D;
Fig. 9: the Fel Ursi powder of the embodiment of the invention 4 is schemed (uv absorption wavelength 198nm) at the high performance liquid chromatography of 31.218 minutes chromatographic peak of retention time-3D;
Figure 10: Fel Ursi powder is fluorescence photo figure under the 254nm uviol lamp;
Figure 11: Fel Ursi powder is fluorescence photo figure under the 356nm uviol lamp.
The photo description of reference numerals:
1. the Fel Ursi powder sample of the embodiment of the invention 4 preparation; 2. reference examples 1 Fel Ursi powder sample; 3. reference examples 2 Fel Ursi powder samples
The specific embodiment mode
Below further set forth the beneficial effect of medicine of the present invention by test example, these test examples have comprised the pharmacodynamics test of medicine of the present invention.
Test example 1 Fel Ursi powder antitumor action
Test material:
The embodiment of the invention 4 preparation Fel Ursi powders, the 1g/ bottle; The first contrast Fel Ursi powder, 10g/ bag (reference examples 1 Fel Ursi powder, the production of Moschus moschiferous institute is supported in Sichuan Province); The second contrast Fel Ursi powder, 5g/ bottle (Fel Ursi powder of reference examples 2, the black precious Pharmaceutical in Heilongjiang Province limited company produces); Positive control drug: cyclophosphamide (CTX, Hua Lian, Shanghai pharmacy group produces).
1. to the tumor-inhibiting action of B16 murine melanoma
1) test method:
Take the logarithm under the aseptic condition B16 murine melanoma cultured cell of trophophase is prepared into 2.5 * 10
5The B16 murine melanoma cultured cell suspension of/ml.
Get 70 of C57BL/6 mices, body weight 150-200g, male and female half and half, inoculation B16 murine melanoma cultured cell suspension, inoculum concentration is 0.2ml/ mice; Postvaccinal second day is divided into 7 groups at random with mice, and 10 every group, i.e. the high, medium and low dosage group of administration, the first contrast Fel Ursi powder, the second contrast Fel Ursi powder, positive control medicine group and negative control group carboxymethyl cellulose (CMC); The high, medium and low dosage group of administration is oral respectively to give Fel Ursi powder of the present invention, is administered once every other day administration high dose group 260mg/kg; Dosage group 130mg/kg in the administration; Administration low dose group 65mg/kg; The first contrast Fel Ursi powder oral administration is administered once every other day, and dosage is 260mg/kg, and the second contrast Fel Ursi powder oral administration is administered once every other day, and dosage is 260mg/kg, and positive drug group lumbar injection gives CTX100mg/kg, and be administered once every day; Negative control group is oral the CMC suspension of weight such as to give, and is administered once every other day, and each is organized mice and puts to death after 3 weeks of administration, cuts open the lungs of getting mice, the colony number that every mice lungs of instrumentation shift.
Tumor control rate calculates: the average colony number of tumor with each group mice, calculate tumor control rate by following formula:
The average colony number of the tumor control rate %=[(matched group-average colony number of administration group)/the average colony number of matched group] * 100%.
2) result of the test:
The anti metastasis curative effect comparative result of different dosing group sees Table 1.
Table 1 Fel Ursi powder is to mouse melanoma B16 clinical trial (n=3)
* *Compare p value＜0.01 with negative control group.
Result of the test shows: the Fel Ursi powder of the present invention's preparation has obvious inhibitory action to mouse melanoma B16, high dose group 260mg/kg (being equivalent to clinical dosage 1.0g/60kg/ day) tumour inhibiting rate can reach 56.57%, obviously be better than Isodose first the contrast Fel Ursi powder (the 260mg/kg tumour inhibiting rate is 44.07%
#P value＜0.05), the second contrast Fel Ursi powder (the 260mg/kg tumour inhibiting rate is 43.64%,
#P value＜0.05).
2. to the tumor-inhibiting action of human hepatoma QGY
1) test method:
Get under the aseptic condition and pass second filial generation QGY tumor source in the eugonic body, make 1-2 * 10 at 1: 6 with the homogenate method
7/ ml human hepatoma QGY cultured cell suspension, homogenate is through 100 order stainless steel sift net filtrations, and is for subsequent use.
(Shanghai City Chinese Academy of Sciences Experimental Animal Center provides nude mouse, the quality certification number: SCXK 2003-0003) routine disinfection, after the anesthesia, under the xiphoid-process of center, abdominal cavity, cut skin and abdominal cavity, expose liver, with the injection 0.05ml of syringe liver cell suspension, close the abdominal cavity, layer-by-layer suture abdominal cavity and skin.The nude mouse of postoperative places laminar-flow rack to raise, and the apparatus of used feedstuff, bedding and padding, cage tool and contact etc. all should use behind the autoclave sterilization.Second day after operation is divided into 7 groups at random with nude mouse, and 6 every group, i.e. the high, medium and low dosage group of administration, the first contrast Fel Ursi powder group, the second contrast Fel Ursi powder group, positive drug group and negative control group; The high, medium and low dosage group of administration is oral respectively to give Fel Ursi powder of the present invention, is administered once every other day administration high dose group 260mg/kg; Dosage group 130mg/kg in the administration; Administration low dose group 65mg/kg; The first contrast Fel Ursi powder group oral administration is administered once every other day, and dosage is 260mg/kg, the second contrast Fel Ursi powder group oral administration is administered once every other day, and dosage is 260mg/kg, positive drug group cyclophosphamide group lumbar injection gives cyclophosphamide 100mg/kg, and be administered once every day; Negative control group is oral every other day the weight carboxymethyl cellulose (CMC) such as to give once, observes the life span in each treated animal 45 days, compares the statistics increase in life span with negative control group.
2) experimental result is calculated:
Test is respectively organized mice and calculated its increase in life span by following formula: increase in life span %=administration group the average survival time sky/negative control group the average survival time sky * 100% the results are shown in Table 2.
Table 2 Fel Ursi powder is to human hepatoma QGY inhibition test (n=3)
* *Compare p value＜0.01 with negative control group; Increase in life span＞125% is above in antitumor effectively.
Result of the test shows: the Fel Ursi powder of the present invention's preparation has obvious prolongation tumor bearing nude mice vital rates to human hepatoma QGY, high dose group 260mg/kg (being equivalent to clinical dosage 1.0g/60kg/ day) extending life rate is 142.93%, (the 260mg/kg tumour inhibiting rate is 129.33% to show the one group of Fel Ursi powder of contrast that is better than Isodose
#P value＜0.05), contrast two groups of Fel Ursi powders (the 260mg/kg tumour inhibiting rate is 130.02%,
#P value＜0.05).
Test example 2 Fel Ursi powder antivirus actions
Test material:
The embodiment of the invention 4 preparation Fel Ursi powder 1g/ bottles; The first contrast Fel Ursi powder, 10g/ bag (reference examples 1 Fel Ursi powder, the production of Moschus moschiferous institute is supported in Sichuan Province); The second contrast Fel Ursi powder, 5g/ bottle (Fel Ursi powder of reference examples 2, the black precious Pharmaceutical in Heilongjiang Province limited company produces); Positive control drug: ribavirin tablet (Xiamen Cod-liver Oil Factory produces, batch number: 03048402, and the accurate word H19993827 of traditional Chinese medicines).
Strain: influenza virus FM
1Strain is purchased from Inst. of Viruses, China Preventive Medicine Science Academy; Parainfluenza virus is purchased from Inst. of Viruses, China Preventive Medicine Science Academy;
Main agents: culture medium, IMDM (U.S. Sigma product); Hyclone (Changchun Biological Products Institute's product); Trypsin, (Japanese Northeast Co., Ltd. produces, the packing of Solution on Chemical Reagents in Shanghai factory).
Laboratory animal:
The ICR mice, male and female half and half, 3-4W age, 18-22g is provided by the Bethune of Jilin University medical board Experimental Animal Center.The laboratory animal quality certification number: SCXK (Ji) 2003-0001.
1. the determination test of anti-mice influenza virus lung index
Test method:
The ICR mice is divided into 8 groups at random, 10/group, Fel Ursi powder administration of the present invention is high, in, low dose group, negative control group, model group and positive drug (ribavirin tablet) group, the first contrast Fel Ursi powder group, the second contrast Fel Ursi powder group, begin gastric infusion the previous day in infecting, Fel Ursi powder administration of the present invention is high, in, low dose group 260mg/kg/d, 130mg/kg/d, 65mg/kg/d, model control group and negative control group gavage the distilled water of equal volume (0.03ml), positive drug (ribavirin tablet) group 58.5mg/kg/d, the first contrast Fel Ursi powder group 260mg/kg/d, the second contrast Fel Ursi powder group 260mg/kg/d; The administration second day, difference collunarium influenza virus infection and parainfluenza virus 15LD under the ether light anaesthesia
50(0.03ml), negative control group is not carried out the processing that collunarium infects virus, only gavages the distilled water of equal volume (0.03ml); Successive administration 4d, then record dissects in infecting rear 96h respectively, gets lung and weighs, and calculates the lung index, compares with model control group, organizes a t check, according to the statistical significance determine effect.Test repeats 3 times, and result of the test sees Table 3,4.
Table 3 Fel Ursi powder is to the effect of mice viral pneumonia
Table 4 Fel Ursi powder is to the effect of mice parainfluenza virus toxicity pneumonia
2. anti-mouse lung influenza A virus, parainfluenza virus breed and the antigen titre determination test
Animal grouping, drug dose, medication, viral infection method are with above-mentioned " determination test of anti-mice influenza virus lung index ".After infecting viral 72h, take off neck and put to death mice, dissect and get lung, Potter-Elvehjem Tissue Grinders grinds, normal saline is made 10% lung tissue suspension, the centrifuging and taking supernatant, doubling dilution drips after on the titer plate by the 0.2ml/ hole, every hole adds 0.2ml 1% chicken erythrocyte suspension, mixing is put room temperature 30min, observed and recorded blood clotting titre.As terminal point, and represent its titre with the suspension extension rate during take red cell agglutination (++).The results are shown in Table 5,6.
The impact of table 5 Fel Ursi powder infected by influenza Pneumonia Mice lung tissue blood clotting titre
Table 6 Fel Ursi powder is on the impact of parainfluenza virus toxicity Pneumonia Mice lung tissue blood clotting titre
Result of the test shows: the Antiviral assay in vivo result shows that Fel Ursi powder that the present invention prepares can obviously reduce the lung exponential sum blood clotting titre of influenza virus and the caused Mouse Virus Pneumonia of parainfluenza virus, remarkable with the model group comparing difference, the antivirus action of Fel Ursi powder of the present invention is remarkable.
Test example 3 Fel Ursi powder refrigeration functions
Test material:
The embodiment of the invention 4 preparation Fel Ursi powders, the 1g/ bottle; The first contrast Fel Ursi powder, 10g/ bag (reference examples 1 Fel Ursi powder, the production of Moschus moschiferous institute is supported in Sichuan Province); The second contrast Fel Ursi powder, 5g/ bottle (Fel Ursi powder of reference examples 2, the black precious Pharmaceutical in Heilongjiang Province limited company produces); Positive control drug: acetaminophen (Dongbei Pharmaceutical General Factory production, 20/box, lot number: 20090311).
1. beer yeast is caused the impact of rat fever
Test method:
Male Wistar rat, body weight 180～200g.Measure normal anus temperature 2 times (every minor tick 1h) with WSC-411P type portable digital temperature measurer respectively before the test, get the meansigma methods of twice measurement as the normal body temperature of rat.Then select body temperature 70 of 36.5～38 ℃ rats, be divided at random 7 groups: model (0.5% carboxymethyl cellulose) group, Fel Ursi powder high dose group 200mg/kg of the present invention, middle dosage group 100mg/kg, low dose group 50mg/kg, the first contrast Fel Ursi powder group 200mg/kg, the second contrast Fel Ursi powder group 200mg/kg and positive drug acetaminophen (100mg/kg) group, 10 every group.Each organizes the equal back of rat subcutaneous injection 10% draft beer yeast suspension 10ml/kg pyrogenicity.After injecting 10% draft beer yeast suspension 6.0h, the high, medium and low dosage group of Fel Ursi powder of the present invention, the first contrast Fel Ursi powder group, the second contrast Fel Ursi powder group and equal gastric infusion of positive drug group, model group gavage equal-volume 0.5% carboxymethyl cellulose.Respectively at after the administration 1,2,3 and 4h measure the anus temperature.Observe the body temperature situation of change, and organize a t check by analgesic percentage rate and process, the difference between relatively each is organized, result of the test sees Table 7.
Result of the test shows:
1. after respectively organizing rat skin lower injection 10% draft beer yeast suspension 6h, fervescence all about 1.5 ℃, with comparing difference before the pyrogenicity remarkable (p＜0.001), shows that beer yeast causes the rat fever model and is successfully established;
2. compare with model group, Fel Ursi powder high dose group 200mg/kg of the present invention after administration 1,2,3 and 4h rat fever due to the beer yeast suspension is all had obvious cooling effect, common Fel Ursi powder (i.e. the first contrast Fel Ursi powder, the second contrast Fel Ursi powder) 200mg/kg dosage group to rat fever due to the beer yeast suspension then without obvious cooling effect (p＞0.05);
Fel Ursi powder low dose group 50mg/kg of the present invention and middle dosage group 100mg/kg after administration 1,2,3 and 4h to rat fever due to the beer yeast suspension then without significantly cooling effect (p＞0.05), the middle dosage group no significant difference of common Fel Ursi powder (i.e. the first contrast Fel Ursi powder, the second contrast Fel Ursi powder) 200mg/kg dosage group and Fel Ursi powder of the present invention shows that the cooling-down effect of Fel Ursi powder of the present invention improves.
2. Fel Ursi powder causes the impact of fever in rabbits on typhoid fever, paratyphoid fever vaccine
Experimental technique:
Male Japan large ear rabbit, body weight 1.5～2.0kg.Measure normal anus temperature 2 times with WSC-411P type portable digital temperature measurer respectively before the test, get average as normal body temperature.Then select body temperature 48 of 38～39.6 ℃ Japan large ear rabbits, be divided at random 8 groups, that is: blank (normal saline) is organized, model contrast (0.5% carboxymethyl cellulose) group, Fel Ursi powder high dose group 104mg/kg of the present invention, middle dosage group 52mg/kg, low dose group 26mg/kg, the first contrast Fel Ursi powder group 104mg/kg, the second contrast Fel Ursi powder group 104mg/kg and positive drug acetaminophen (50mg/kg) group.Place in the holder large ear rabbit fixing.The blank group is by auricular vein injecting normal saline 1ml/kg; Model control group, each medicine group auricular vein injection typhoid fever, paratyphoid fever vaccine 0.8ml/kg.Treating (needs 1～1.5h when the rabbit fervescence surpasses 1 ℃ approximately, this experiment is limited to 1h), blank group and model group gavage give 0.5% carboxymethyl cellulose 1ml/kg, administration group respectively gavage gives the high, medium and low dosage Fel Ursi powder of the present invention, the first contrast Fel Ursi powder and the second contrast Fel Ursi powder, positive control drug acetaminophen, after administration 30,60,90,120,180 and 240min measure the anus temperature, observe the body temperature situation of change, and organize a t check by analgesic percentage rate and process, relatively the difference between each group the results are shown in Table 8.
Experimental result shows:
1, behind large ear rabbit auricular vein injection typhoid fever, the paratyphoid fever vaccine 1h, fervescence shows that typhoid fever, paratyphoid fever vaccine can prepare rabbit fever models about 1 ℃;
2, compare with the blank group, the body temperature of model group continues to raise in 240min, compare with model group, Fel Ursi powder of the present invention, the first contrast Fel Ursi powder, second contrast Fel Ursi powder 30～240min after administration all have obvious refrigeration function to fever in rabbits due to typhoid fever, the paratyphoid fever vaccine, and be best with the 104mg/kg dosage group solution thermal effect of the Fel Ursi powder of the present invention's preparation.
The anti-carbon tetrachloride of test example 4 Fel Ursi powders causes the test of rat liver fibrosis effect
Test material:
The embodiment of the invention 4 preparation Fel Ursi powders, the 1g/ bottle; The first contrast Fel Ursi powder, 10g/ bag (reference examples 1 Fel Ursi powder, the production of Moschus moschiferous institute is supported in Sichuan Province); The second contrast Fel Ursi powder, 5g/ bottle (Fel Ursi powder of reference examples 2, the black precious Pharmaceutical in Heilongjiang Province limited company produces); Positive drug: FUFANG BIEJIA RUANGAN PIAN (NeiMenggu FuRuiZhong MengYao Science Co., Ltd, 0.5g/ sheet, lot number: 20090112).
Test method:
Get 82 of cleaning level male SD rats, body weight 150-200g.With wherein 72 adopt 15% carbon tetrachloride solution (be dissolved in the vegetable oil with the analytical pure carbon tetrachloride, be made into the 150ml/L solution for standby) 1ml/100g body weight gavages, 2 times/week, week for 7 weeks.Put to death at random 2 rats after 7 weeks of modeling, get liver and do histopathologic examination, confirm to have caused Liver Fibrosis Model.The rat of modeling success is divided into 7 groups at random, i.e. model group, positive drug group, administration high dose group, middle dosage group, low dose group, the first contrast Fel Ursi powder group, the second contrast Fel Ursi powder group stop modeling and begin gastric infusion.Get 10 rats of other not modeling as the blank group.
Gavage gives medicine Fel Ursi powder high dose 200mg/kg of the present invention, middle dosage 100mg/kg, low dosage 50mg/kg and the first contrast Fel Ursi powder 200mg/kg, the second contrast Fel Ursi powder 200mg/kg respectively, once a day; Positive drug group then gavage gives soft liver sheet 1g/kg, the equal gavage of blank group and model group gives isometric distilled water, all rat oral gavage volumes are 10ml/kg, continuous 8 weeks of gastric infusion, observe the animal ordinary circumstance every day, take a blood sample next day on an empty stomach after the last administration, separation of serum, detect AST, ALT index in the serum with automatic clinical chemistry analyzer, the results are shown in Table 9.
Table 9 is on the impact of hepatic fibrosis rats liver function due to the carbon tetrachloride and hydroxyproline content
Annotate: compare with model group,
*P＜0.05,
*P＜0.01
The testing result explanation:
1, the liver function of the Liver Fibrosis Model rat of being induced by carbon tetrachloride has obvious damage, and AST, ALT and hydroxyproline content water mean pole are higher than Normal group (P＜0.01) significantly in the model group rat blood serum.And after high, the middle dosage group treatment of medicine of the present invention in the rat blood serum AST, ALT and hydroxyproline content level compare with model group remarkable reduction all arranged.
2, the liver function of medicine of the present invention Liver Fibrosis Model rat that carbon tetrachloride is induced improves significantly.The therapeutic equivalence of common Fel Ursi powder (i.e. the first contrast Fel Ursi powder, the second contrast Fel Ursi powder) is in the middle dosage group of medicine of the present invention.
The test of the anti-acute liver effect of test example 5 Fel Ursi powders
Test material:
The embodiment of the invention 4 preparation Fel Ursi powders, the 1g/ bottle; The first contrast Fel Ursi powder, 10g/ bag (reference examples 1 Fel Ursi powder, the production of Moschus moschiferous institute is supported in Sichuan Province); The second contrast Fel Ursi powder, 5g/ bottle (Fel Ursi powder of reference examples 2, the black precious Pharmaceutical in Heilongjiang Province limited company produces); Positive drug: (Zhejiang Prov WanBang Pharmaceutical Co., Ltd produces bifendate drop pill, the 1.5mg/ ball; Lot number: 20090316)
Experimental technique:
Get cleaning level NIH mice (high-new medical animal experiment center, Changchun, the quality certification number: the moving word 10-5115 of doctor), 160, body weight 22～25g, be divided at random 8 groups, every group 20,3 groups of of the present invention group of Fel Ursi powder low dose group (65mg/kg), middle dosage group (130mg/kg), high dose group (260mg/kg); The first contrast Fel Ursi powder group (260mg/kg) and the second contrast Fel Ursi powder group (260mg/kg); Blank group: normal saline 320mg/kg; Model group: canavaline 20mg/kg; Positive drug group: bifendate drop pill (150mg/kg).
Fel Ursi powder of the present invention, the first contrast Fel Ursi powder, the second contrast Fel Ursi powder, positive drug are prepared into aseptic suitable concentration solution according to dosage behind water dissolution.Except the blank group, all the other mices in the experiment first day with 20mg/kg dosage intravenous injection concanavalin A, Con A, medication group solution and blank normal saline be all by 1.2ml/kg per os gavage, every day 1 time.For three days on end, detect plasma A LT activity, IFN-γ and TNF-alpha content, experimental result sees Table 10.
Table 10 is on the impact of immune hepatic injury mice plasma ALT, IFN-γ due to the canavaline and TNF-α
Annotate: compare with model group,
*P＜0.05,
*P＜0.01
The testing result explanation: ALT activity, IFN-γ and the TNF-alpha content of of the present invention group of Fel Ursi powder high dose group mice all are starkly lower than model group, have significant difference (t=5.19 is arranged, 3.63,15.90, P＜0.05,0.01), show that it has preferably protective effect to canavaline induced mice immunologic liver injury; Simultaneously, mice TNF-alpha content and positive drug group show also that without significant difference of the present invention group of Fel Ursi powder has preferably protective effect to canavaline induced mice immunologic liver injury.
Test material:
The embodiment of the invention 4 preparation Fel Ursi powders, the 1g/ bottle; The first contrast Fel Ursi powder, 10g/ bag (reference examples 1 Fel Ursi powder, the production of Moschus moschiferous institute is supported in Sichuan Province); The second contrast Fel Ursi powder, 5g/ bottle (Fel Ursi powder of reference examples 2, the black precious Pharmaceutical in Heilongjiang Province limited company produces); Positive drug: (Jilin Province wins peaceful medical company limited production to chloromycetin eyedrops, and 8ml/ props up; Lot number: 20090112); Cause scorching medicine: (analytical pure, Solution on Chemical Reagents in Shanghai factory produces dimethylbenzene, lot number: 20080915)
Experimental technique:
Take by weighing respectively Fel Ursi powder of the present invention, the first contrast Fel Ursi powder and second each 10g of contrast Fel Ursi powder, with the sterile water for injection dissolving, cross 0.22 μ m filter membrane, surely be dissolved in 100 milliliters of vials, for subsequent use after the sterilization.Be diluted to respective concentration by requirement of experiment during test.
42 of large ear rabbits, male, body weight 2.3-3.0kg.At first splash into stupid 1 of 8% diformazan on the conjunctiva of right eye capsule of every white rabbit, closed one's eyes for 30 seconds, then use the injection normal saline flushing 3 times, make the conjunctivitis white rabbit.White rabbit is divided into 7 groups at random, 6 every group.(1.5%) 3 group of of the present invention group of Fel Ursi powder low dose group (0.5%), middle dosage group (1%), high dose group; The first contrast Fel Ursi powder group (1.5%) and the second contrast Fel Ursi powder group (1.5%); Positive drug group, model group, every group respectively eye drip give the present invention 1.5% high dose bear bile powder eye drop, 1.0% middle dosage bear bile powder eye drop, 0.5% low dosage bear bile powder eye drop and the first contrast Fel Ursi powder liquid of 1.5%, the second contrast Fel Ursi powder liquid of 1.5%; Positive drug group then eye drip gives 0.25% chloromycetin eyedrops; Model group is with injection normal saline eye drip, and every day, eye drip was 3 times, drips continuously 2, and after splashing into proinflammatory agent dimethylbenzene 48 hours, judges inflammation degree and the curative effect of medication of right eye take left eye as contrast, and the result carries out the H check, sees table 11 for details.
The inflammation degree is judged as follows: 0 grade of conjunctival sac is without congestion and edema, and without the secretions increase phenomenon, it is transparent clear to resemble film.Without edema, muddiness.1 grade: conjunctiva Mild edema and hyperemia, but corneal transparency is clear; The II level: the conjunctiva moderate is red and swollen, the cornea Mild edema; The III level: conjunctiva is obviously red and swollen, companion's corneal edema, and eye discharge showed increased 1 IV level: conjunctival sac is seriously red and swollen, the excessive or companion's purulent secretion of secretions, corneal edema, muddiness.
The impact of table 11 Fel Ursi powder xylol zest eye knot, corneal injury
As seen from Table 11, eye conjunctiva and the corneal injury of xylol Induced by Stimulation, the bear bile powder eye drop of the present invention's preparation has good therapeutical effect, and wherein 1% and 1.5% concentration all has significant curative effect (comparing P＜0.01 with model group); The eye drop of the first contrast combination the second matched group Fel Ursi powder preparation also has antiinflammatory action, but curative effect is lower than of the present invention group (comparing P＜0.05 with model group).
Below in conjunction with specific embodiment, further set forth the present invention.Be not used in but these embodiment only limit to the present invention is described and limit the scope of the invention.
To cultivate after the adult black bear of the foster Moschus moschiferous institute in Sichuan Province is finished the cleaning of art section, defeathering, sterilization, in the downward 1cm of ventrimeson xiphoid-process place, percutaneous incision undertissue, blunt separation muscle, cut sarolemma, peritoneum, gallbladder is slowly pulled out, cut the wound of 1cm at gallbladder, and form fistula with muscular tissue, tighten with the stitching thread appropriateness; Again fixedly gallbladder and gallbladder skin; Difference peritoneal suture, fat, sarolemma, muscle and skin; Then the art mouth cleans and sterilizes.Art was revived rear 2 hours, gave black bear feed hydromel or sucrose solution and egg water; Postoperative gives black bear intramuscular injection or oral antibiotic in one week, prevents traumatic infection, and notes the reasonably combined nutrient fodder of quantitative feeding.Slightly squeeze the fistula mouth after the recovery from illness and gather bile, regularly gather Fel Ursi 1 time without Tube Drain every day, and gathering total amount every day is 50ml, gathers altogether 30 days, and gained Fel Ursi total amount is 1500ml.
To cultivate after the adult black bear of the black precious Pharmaceutical in Heilongjiang Province limited company is finished the cleaning of art section, defeathering, sterilization, in the downward 5cm of ventrimeson xiphoid-process place, percutaneous incision undertissue, blunt separation muscle, cut sarolemma, peritoneum, gallbladder is slowly pulled out, cut the wound of 2cm at gallbladder, and form fistula with muscular tissue, tighten with the stitching thread appropriateness; Again fixedly gallbladder and gallbladder skin; Difference peritoneal suture, fat, sarolemma, muscle and skin; Then the art mouth cleans and sterilizes.Art was revived rear 3 hours, gave black bear feed hydromel or sucrose solution and egg water; Postoperative gives black bear intramuscular injection or oral antibiotic in one week, prevents traumatic infection, and notes the reasonably combined nutrient fodder of quantitative feeding.Slightly squeeze the fistula mouth after the recovery from illness and gather bile, regularly gather Fel Ursi 2 times without Tube Drain every day, and gathering total amount every day is 100ml, gathers altogether 30 days, and gained Fel Ursi total amount is 3000ml.
To cultivate after the adult black bear of Fujian Province Gui Zhentang Pharmaceutical limited company is finished the cleaning of art section, defeathering, sterilization, in the downward 10cm of ventrimeson xiphoid-process place, percutaneous incision undertissue, blunt separation muscle, cut sarolemma, peritoneum, gallbladder is slowly pulled out, cut the wound of 3cm at gallbladder, and form fistula with muscular tissue, tighten with the stitching thread appropriateness; Again fixedly gallbladder and gallbladder skin; Difference peritoneal suture, fat, sarolemma, muscle and skin; Then the art mouth cleans and sterilizes.Art was revived rear 4 hours, gave black bear feed hydromel or sucrose solution and egg water; Postoperative gives black bear intramuscular injection or oral antibiotic in one week, prevents traumatic infection, and notes the reasonably combined nutrient fodder of quantitative feeding.Slightly squeeze the fistula mouth after the recovery from illness and gather bile, regularly gather Fel Ursi 3 times without Tube Drain every day, and gathering total amount every day is 200ml, gathers altogether 30 days, and gained Fel Ursi total amount is 6000ml.
To leave standstill 2 hours at 4 ℃ available from the Fel Ursi of supporting the Moschus moschiferous institute in Sichuan Province, the supernatant of getting after leaving standstill adopts high speed centrifuge to carry out centrifugal treating, and centrifugal liquid is the water solublity Fel Ursi, and centrifugal rotational speed is 12000 rev/mins, centrifugation time 30 minutes;
The water solublity Fel Ursi is placed vacuum drier (SZG-4500), at 30 ℃, relative pressure be-0.06MPa under, vacuum drying was pulverized after 8 hours, crossed 120 mesh sieves, namely obtained moisture content and be 2% Fel Ursi powder finished product.
Fel Ursi powder is the burnished gold powder with hyaloid gloss, and is nonhygroscopic, observes in uviol lamp 365nm place to be glassy yellow fluorescence; Through thin layer chromatography (1 time, reversed phase high efficiency lamellae: RP-18F
254, the chromatography developing solvent: the ratio of chloroform-acetone-glacial acetic acid volume is 7: 2: 1), under the 254nm uviol lamp, can detect 7 blue-fluorescence speckles, its R
fValue is respectively 0.96,0.8, and 0.7,0.54,0.46,0.4,0.2; Under the 365nm uviol lamp, can detect 9 sapphirine fluorescence speckles, its R
fValue is respectively 0.96,0.84, and 0.76,0.56,0.5,0.4,0.7,0.18,0.1.Wherein, R
fValue is 0.18 sapphirine fluorescence speckle, is its peculiar speckle.The thin layer chromatography spectrogram is seen Fig. 1,2.
To leave standstill 24 hours at 10 ℃ available from the Fel Ursi of the black precious Pharmaceutical limited company in the Heilongjiang Province, the supernatant of getting after leaving standstill adopts high speed centrifuge to carry out centrifugal treating, centrifugal liquid is the water solublity Fel Ursi, and centrifugal rotational speed is 10000 rev/mins, centrifugation time 45 minutes;
The water solublity Fel Ursi is placed vacuum drier (SZG-4500), and under 60 ℃, relative pressure-0.09MPa pressure, vacuum drying was pulverized after 48 hours, crossed 150 mesh sieves, namely got moisture content and be 1% Fel Ursi powder finished product.
Fel Ursi powder is the burnished gold powder with hyaloid gloss, and is nonhygroscopic, observes in uviol lamp 365nm place to be glassy yellow fluorescence; Through thin layer chromatography (1 time, reversed phase high efficiency lamellae: RP-18F
254, the chromatography developing solvent: the ratio of chloroform-acetone-glacial acetic acid volume is 7: 2: 1), under the 254nm uviol lamp, can detect 7 blue-fluorescence speckles, its R
fValue is respectively 0.96,0.8, and 0.7,0.54,0.46,0.4,0.2; Under the 365nm uviol lamp, can detect 9 sapphirine fluorescence speckles, its R
fValue is respectively 0.96,0.84, and 0.76,0.56,0.5,0.4,0.7,0.18,0.1.Wherein, R
fValue is 0.18 sapphirine fluorescence speckle, is its peculiar speckle.
To leave standstill 5 hours at 4 ℃ available from the Fel Ursi of supporting the Moschus moschiferous institute in Sichuan Province, getting supernatant after leaving standstill is that 0.2 micron titanium plate titanium rod filter filters by filtering accuracy under relative pressure 0.3MPa, filtrate is adopted extractum spray dryer (ZLG300 type), at effluxvelocity 300 meter per seconds, under 60 ℃, relative pressure-0.09MPa, with the instantaneous drying of hypersonic velocity, then pulverize, cross 180 mesh sieves, namely get moisture content and be 1.5% Fel Ursi powder finished product.
Fel Ursi powder is the burnished gold powder with hyaloid gloss, and is nonhygroscopic, observes in uviol lamp 365nm place to be glassy yellow fluorescence; Through thin layer chromatography (1 time, reversed phase high efficiency lamellae: RP-18F
254, the chromatography developing solvent: the ratio of chloroform-acetone-glacial acetic acid volume is 7: 2: 1), under the 254nm uviol lamp, can detect 7 blue-fluorescence speckles, its R
fValue is respectively 0.96,0.8, and 0.7,0.54,0.46,0.4,0.2; Under the 365nm uviol lamp, can detect 9 sapphirine fluorescence speckles, its R
fValue is respectively 0.96,0.84, and 0.76,0.56,0.5,0.4,0.7,0.18,0.1.Wherein, R
fValue is 0.18 sapphirine fluorescence speckle, is its peculiar speckle.
The Fel Ursi that Fujian Province Gui Zhentang Pharmaceutical limited company is produced left standstill 10 hours at 8 ℃, get that to leave standstill supernatant be that 0.5 micron titanium plate titanium rod filter filters by filtering accuracy under relative pressure 0.1MPa, filtrate is adopted extractum spray dryer (ZLG300 type), at effluxvelocity 990 meter per seconds, under 30 ℃, relative pressure-0.06MPa, with the instantaneous drying of hypersonic velocity, then pulverize, cross 120 mesh sieves, namely get moisture content and be 1% Fel Ursi powder finished product.
Fel Ursi powder is the burnished gold powder with hyaloid gloss, and is nonhygroscopic, observes in uviol lamp 365nm place to be glassy yellow fluorescence; Through thin layer chromatography (1 time, reversed phase high efficiency lamellae: RP-18F
254, the chromatography developing solvent: the ratio of chloroform-acetone-glacial acetic acid volume is 7: 2: 1), under the 254nm uviol lamp, can detect 7 blue-fluorescence speckles, its R
fValue is respectively 0.96,0.8, and 0.7,0.54,0.46,0.4,0.2; Under the 365nm uviol lamp, can detect 9 sapphirine fluorescence speckles, its R
fValue is respectively 0.96,0.84, and 0.76,0.56,0.5,0.4,0.7,0.18,0.1.Wherein, R
fValue is 0.18 sapphirine fluorescence speckle, is its peculiar speckle.
To leave standstill 12 hours at 10 ℃ available from the Fel Ursi of supporting the Moschus moschiferous institute in Sichuan Province, get supernatant and D101 type industry macroporous adsorbent resin mix homogeneously after leaving standstill, wherein supernatant is 1: 1 with the ratio of the weight portion of D101 type industry macroporous adsorbent resin, be washed with water to macroporous resin effluent anacholia color, the gained effluent carries out the temperature programming lyophilization in gland type freezer dryer (FD-1), at first-40 ℃ of lower pre-freezes 3 hours, then, at-40 ℃, relative pressure is to distil under the 20Pa, dry 18 hours; Then at-15 ℃, relative pressure is vacuum drying 20 hours under the 5Pa, crosses 100 mesh sieves after pulverizing, and namely gets moisture content and be 2% Fel Ursi powder finished product.
Fel Ursi powder is the burnished gold powder with hyaloid gloss, and is nonhygroscopic, observes in uviol lamp 365nm place to be glassy yellow fluorescence; Through thin layer chromatography (1 time, reversed phase high efficiency lamellae: RP-18F
254, the chromatography developing solvent: the ratio of chloroform-acetone-glacial acetic acid volume is 7: 2: 1), under the 254nm uviol lamp, can detect 7 blue-fluorescence speckles, its R
fValue is respectively 0.96,0.8, and 0.7,0.54,0.46,0.4,0.2; Under the 365nm uviol lamp, can detect 9 sapphirine fluorescence speckles, its R
fValue is respectively 0.96,0.84, and 0.76,0.56,0.5,0.4,0.7,0.18,0.1.Wherein, R
fValue is 0.18 sapphirine fluorescence speckle, is its peculiar speckle.
To leave standstill 18 hours at 4 ℃ available from the Fel Ursi of the black precious Pharmaceutical limited company in the Heilongjiang Province, get supernatant and D101 type industry macroporous adsorbent resin mix homogeneously after leaving standstill, wherein supernatant is 1: 80 with the ratio of the weight portion of D101 type industry macroporous adsorbent resin, be washed with water to macroporous resin effluent anacholia color, the gained effluent carries out the temperature programming lyophilization in gland type freezer dryer (FD-1 type), at first-40 ℃ of pre-freezes 5 hours, then at-15 ℃, relative pressure is to distil under the 15Pa, dry 24 hours, then at 30 ℃, relative pressure is under the 10Pa, vacuum drying 12 hours is crossed 180 mesh sieves after pulverizing, namely get moisture content and be 1% Fel Ursi powder finished product.
Fel Ursi powder is the burnished gold powder with hyaloid gloss, and is nonhygroscopic, observes in uviol lamp 365nm place to be glassy yellow fluorescence; Through thin layer chromatography (1 time, reversed phase high efficiency lamellae: RP-18F
254, the chromatography developing solvent: the ratio of chloroform-acetone-glacial acetic acid volume is 7: 2: 1), under the 254nm uviol lamp, can detect 7 blue-fluorescence speckles, its R
fValue is respectively 0.96,0.8, and 0.7,0.54,0.46,0.4,0.2; Under the 365nm uviol lamp, can detect 9 sapphirine fluorescence speckles, its R
fValue is respectively 0.96,0.84, and 0.76,0.56,0.5,0.4,0.7,0.18,0.1.Wherein, R
fValue is 0.18 sapphirine fluorescence speckle, is its peculiar speckle.
To leave standstill 8 hours at 6 ℃ available from the Fel Ursi of supporting the Moschus moschiferous institute in Sichuan Province, the supernatant of getting after leaving standstill adopts high speed centrifuge to carry out centrifugal treating, makes the water solublity Fel Ursi, and centrifugal rotational speed is 12000 rev/mins, centrifugation time 60 minutes;
The water solublity Fel Ursi of gained at 60 ℃ of oven dry 24h, is crossed 180 mesh sieves after pulverizing, namely get moisture content and be 2% Fel Ursi powder finished product.
Fel Ursi powder is the burnished gold powder with hyaloid gloss, and is nonhygroscopic, observes in uviol lamp 365nm place to be glassy yellow fluorescence; Through thin layer chromatography (1 time, reversed phase high efficiency lamellae: RP-18F
254, the chromatography developing solvent: the ratio of chloroform-acetone-glacial acetic acid volume is 7: 2: 1), under the 254nm uviol lamp, can detect 7 blue-fluorescence speckles, its R
fValue is respectively 0.96,0.8, and 0.7,0.54,0.46,0.4,0.2; Under the 365nm uviol lamp, can detect 9 sapphirine fluorescence speckles, its R
fValue is respectively 0.96,0.84, and 0.76,0.56,0.5,0.4,0.7,0.18,0.1.Wherein, R
fValue is 0.18 sapphirine fluorescence speckle, is its peculiar speckle.
To leave standstill 24 hours at 10 ℃ available from the Fel Ursi of the black precious Pharmaceutical limited company in the Heilongjiang Province, the supernatant of getting after leaving standstill is to be that 0.2 micron titanium plate titanium rod filter filters by filtering accuracy under the 0.3MPa in relative pressure, filtrate is behind 80 ℃ of oven dry 48h, pulverize 100 mesh sieves, namely got moisture content and be 1% Fel Ursi powder finished product.
Fel Ursi powder is the burnished gold powder with hyaloid gloss, and is nonhygroscopic, observes in uviol lamp 365nm place to be glassy yellow fluorescence; Through thin layer chromatography (1 time, reversed phase high efficiency lamellae: RP-18F
254, the chromatography developing solvent: the ratio of chloroform-acetone-glacial acetic acid volume is 7: 2: 1), under the 254nm uviol lamp, can detect 7 blue-fluorescence speckles, its R
fValue is respectively 0.96,0.8, and 0.7,0.54,0.46,0.4,0.2; Under the 365nm uviol lamp, can detect 9 sapphirine fluorescence speckles, its R
fValue is respectively 0.96,0.84, and 0.76,0.56,0.5,0.4,0.7,0.18,0.1.Wherein, R
fValue is 0.18 sapphirine fluorescence speckle, is its peculiar speckle.
Embodiment 12
To leave standstill 18 hours at 4 ℃ available from the Fel Ursi of supporting the Moschus moschiferous institute in Sichuan Province, get supernatant and D101 type industry macroporous adsorbent resin mix homogeneously after leaving standstill, wherein supernatant is 1: 50 with the ratio of the weight portion of D101 type industry macroporous adsorbent resin, be washed with water to macroporous resin effluent anacholia color, the gained effluent adopts extractum spray dryer (ZLG300 type) to carry out spray drying, at effluxvelocity 600 meter per seconds, 45 ℃, under relative pressure-0.07MPa, with the instantaneous drying of hypersonic velocity, cross 120 mesh sieves after pulverizing, namely get moisture content and be 1.5% Fel Ursi powder finished product.
Fel Ursi powder is the burnished gold powder with hyaloid gloss, and is nonhygroscopic, observes in uviol lamp 365nm place to be glassy yellow fluorescence; Through thin layer chromatography (1 time, reversed phase high efficiency lamellae: RP-18F
254, the chromatography developing solvent: the ratio of chloroform-acetone-glacial acetic acid volume is 7: 2: 1), under the 254nm uviol lamp, can detect 7 blue-fluorescence speckles, its R
fValue is respectively 0.96,0.8, and 0.7,0.54,0.46,0.4,0.2; Under the 365nm uviol lamp, can detect 9 sapphirine fluorescence speckles, its R
fValue is respectively 0.96,0.84, and 0.76,0.56,0.5,0.4,0.7,0.18,0.1.Wherein, R
fValue is 0.18 sapphirine fluorescence speckle, is its peculiar speckle.
Reference examples 1
The Fel Ursi that the adult black bear of supporting the Moschus moschiferous institute and providing with Sichuan Province produces directly carries out in contrast example 2 of Fel Ursi powder that vacuum drying treatment makes.
Fel Ursi powder is yellow powder, without hyaloid gloss, through thin layer chromatography (1 time, reversed phase high efficiency lamellae: RP-18F
254, the chromatography developing solvent: the ratio of chloroform-acetone-glacial acetic acid volume is 7: 2: 1), under the 254nm uviol lamp, can detect 5 blue-fluorescence speckles, its R
fValue is respectively 0.96,0.54, and 0.46,0.4,0.2; Under the 365nm uviol lamp, can detect 8 sapphirine fluorescence speckles, its R
fValue is respectively 0.96,0.84,0.76,0.56,0.5,0.4,0.7,0.1, and the thin layer chromatography spectrogram is seen Fig. 1,2.
Reference examples 2
The Fel Ursi that the adult black bear that provides with the black precious Pharmaceutical in Heilongjiang Province limited company produces directly carries out in contrast example 2 of Fel Ursi powder that vacuum drying treatment makes.
Fel Ursi powder is yellow powder, without hyaloid gloss, through thin layer chromatography (1 time, reversed phase high efficiency lamellae: RP-18F
254, the chromatography developing solvent: the ratio of chloroform-acetone-glacial acetic acid volume is 7: 2: 1), under the 254nm uviol lamp, can detect 7 blue-fluorescence speckles, its R
fValue is respectively 0.96,0.8, and 0.7,0.54,0.46,0.4,0.2; Under the 365nm uviol lamp, can detect 8 sapphirine fluorescence speckles, its R
fValue is respectively 0.96,0.84,0.76,0.56,0.5,0.4,0.7,0.1, and the thin layer chromatography spectrogram is seen Fig. 1,2.
Reference examples 3
With Fujian Province Gui Zhentang Pharmaceutical limited company produce the Fel Ursi that produces of adult black bear directly carry out in contrast example 3 of Fel Ursi powder that vacuum drying treatment makes.
Fel Ursi powder is yellow powder, without hyaloid gloss, through thin layer chromatography (1 time, reversed phase high efficiency lamellae: RP-18F
254, the chromatography developing solvent: the ratio of chloroform-acetone-glacial acetic acid volume is 7: 2: 1), under the 254nm uviol lamp, can detect 7 blue-fluorescence speckles, its R
fValue is respectively 0.96,0.8, and 0.7,0.54,0.46,0.4,0.2; Under the 365nm uviol lamp, can detect 8 sapphirine fluorescence speckles, its R
fValue is respectively 0.96,0.84, and 0.76,0.56,0.5,0.4,0.7,0.1.
The assay of effective ingredient in experimental example 1 Fel Ursi powder
Adopt the People's Republic of China's Ministry of Public Health ministry standard (new drug is become a full member the 11st) to measure the content of the main effective ingredient tauroursodeoxycholic acid of high-quality Fel Ursi powder sample.Chromatographic condition: mobile phase-methanol 0.03mol/L sodium dihydrogen phosphate (65: 30); Transfer PH4.4 with phosphoric acid; Flow velocity: 1.0ml/min; Detect wavelength: 210nm; Detector: Agilent 1100 DAD; Column temperature: 30 ℃; Pillar: Hypersil ODS sum 4.6 * 250mm.Accurately weighed embodiment 4-12, reference examples 1,2 prepared Fel Ursi powders, every part of 25mg respectively with dissolve with methanol and surely be dissolved in the 10ml measuring bottle, gets respectively 5 microlitres and injects high performance liquid chromatograph and measure effective ingredient tauroursodeoxycholic acid (C in the finished product
26H
45NO
8S) the assay result is as shown in table 12.
Table 12 Fel Ursi powder tauroursodeoxycholic acid content detection result
The mensuration of experimental example 2 Fel Ursi powder different component uv absorption wavelength
Get respectively prepared each 4g of Fel Ursi powder of embodiment 5, reference examples 1, reference examples 2, after 3 times of water gagings dissolvings, with equivalent ethyl acetate extraction 3 times, the combined ethyl acetate phase, the acetic acid ethyl acetate extract water bath method gets the Fel Ursi powder acetic acid ethyl ester extract, dissolves to get laboratory sample a with acetonitrile again; Water layer, the water bath method water layer, residue dry method loading is carried out silica gel column chromatography, and eluant is: the ratio of volume is acetone-water-glacial acetic acid of 1: 2: 0.01, and the eluant consumption is 5 times of column volumes; Then, take out the silica gel in the chromatographic column, take out the silica gel of the superiors' fluorescence part of silicagel column, with methanol-eluted fractions, get laboratory sample c with water dissolution again behind the eluent evaporate to dryness;
Other gets prepared each 4g of Fel Ursi powder of embodiment 5, reference examples 1, reference examples 2, behind dissolve with methanol, removes insoluble part, gets Fel Ursi powder dissolve with methanol thing laboratory sample b;
Laboratory sample a, b, c divide and take uv-spectrophotometric instrument scanning, and it the results are shown in Table 13.
Table 13 Fujian high-quality Fel Ursi powder and different places of production Fel Ursi powder uv absorption wavelength measurement result
The mensuration of experimental example 3 Fel Ursi powder high performance liquid chromatography ultraviolet fingerprint
Getting Fel Ursi powder sample 25mg among the embodiment 4 is dissolved in methanol and surely is dissolved in the 10ml measuring bottle, then get 20 microlitres, inject high performance liquid chromatograph, gather the ultraviolet fingerprint at each peak, chromatographic condition: mobile phase-methanol 0.03mol/L sodium dihydrogen phosphate (65: 30) with Agilent 1100 DAD detectors; Transfer PH4.4 with phosphoric acid; Flow velocity: 1.0ml/min; Detect wavelength: 210nm; Detector: Agilent 1100 DAD; Column temperature: 30 ℃; Pillar: Hypersil ODS sum 4.6 * 250mm.The uv absorption spectrum wavelength that confirms main effective ingredient tauroursodeoxycholic acid and other 2 main chromatographic peaks all is 198nm, having retention time only is 198nm, 226nm at the uv absorption wavelength of 3.36 minutes chromatographic peak, and high-efficient liquid phase chromatogram 3, the ultraviolet 3D spectrogram of the Fel Ursi powder of the embodiment that measures 4 are seen respectively Fig. 4-9; Each peak absorbing wavelength sees Table 14.
The measurement result of table 14 Fel Ursi powder high performance liquid chromatography ultraviolet fingerprint
| Chromatographic peak number | Appearance time (min) | Relative area % | Absorbing wavelength (nm) |
| 1 (methanol peak) | 2.54 | 21.04 | 198 |
| 2 | 2.90 | 4.95 | —— |
| 3 | 3.17 | 1.72 | —— |
| 4 | 3.36 | 2.65 | 198，226 |
| 5 | 3.58 | 2.96 | —— |
| 6 | 4.02 | 0.89 | —— |
| 7 | 4.98 | 0.64 | —— |
| 8 | 7.12 | 0.72 | —— |
| 9 | 11.02 | 37.71 | 198 |
| 10 | 20.74 | 2.98 | 198 |
| 11 | 31.22 | 23.73 | 198 |
The hydroscopicity of experimental example 4 Fel Ursi powders is measured
With the Fel Ursi powders of embodiment 4-12, reference examples 1,2 preparations, according to " [oven drying method] in the Chinese pharmacopoeia carried out the determination of moisture of Fel Ursi powder, and to calculate its water absorption rate be moisture content.
Get each test sample 2g of Fel Ursi powder of embodiment 4-12, reference examples 1,2 preparations, be tiled in respectively in the flat weighing bottle that is dried to constant weight, thickness is no more than 5mm, and is accurately weighed; Open bottle cap 100～105 ℃ of dryings 5 hours, bottle cap is built, in the dislocation exsiccator, cooled off accurately weighed weight 30 minutes; At said temperature dry 1 hour again, cooling was weighed, and was no more than till the 5mg to double difference of weighing.According to the weight that subtracts mistake, calculate the percent that contains moisture in the test sample.Measurement result sees Table 15.
The moisture absorption result of table 15 Fel Ursi powder
| Group | Hydroscopicity (%) |
| |
1.01 |
| |
1.15 |
| |
1.40 |
| |
1.52 |
| |
1.11 |
| |
1.22 |
| |
1.35 |
| |
1.23 |
| Embodiment 12 | 1.18 |
| Reference examples 1 | 5.02 |
| Reference examples 2 | 6.15 |
The fluorescence color observation experiment of Fel Ursi powder under experimental example 5 ultraviolet lights
The Fel Ursi powder of embodiment 4, reference examples 1,2 preparations is placed under the ultraviolet light of 254nm, 365nm simultaneously, observe the fluorescence color of Fel Ursi powder.Observed result is shown in table 16, fluorescence photo such as Figure 10,11.
Fluoroscopic examination result under the table 16 Fel Ursi powder ultraviolet light
Claims (8)
1. the preparation method of an artificial Fel Ursi powder comprises following in sequence step:
1) Fel Ursi is left standstill clarification, obtain supernatant, the temperature that wherein leaves standstill clarification is 4～10 ℃, and time of repose is 2～24 hours;
2) adopt centrifugal method that supernatant is carried out remove impurity and process, obtain the water solublity Fel Ursi, wherein, centrifugation rate is 10000～12000rpm, and the time is 10-120min;
3) the water solublity Fel Ursi is carried out dried, pulverizes, sieve, and get final product,
The Fel Ursi powder that obtains is burnished gold or the foresythia powder of hyaloid gloss, is glassy yellow fluorescence under 365nm, moisture absorption ratio≤2%.
2. the preparation method of an artificial Fel Ursi powder comprises following in sequence step:
1) Fel Ursi is left standstill clarification, obtain supernatant, the temperature that wherein leaves standstill clarification is 4～10 ℃, and time of repose is 2～24 hours;
2) adopt filter method that supernatant is carried out remove impurity and process, obtain the water solublity Fel Ursi, wherein, the relative pressure of filtration is 0.1～0.3MPa, and filtering accuracy is the 0.2-0.5 micron;
3) the water solublity Fel Ursi is carried out dried, pulverizes, sieve, and get final product,
The Fel Ursi powder that obtains is burnished gold or the foresythia powder of hyaloid gloss, is glassy yellow fluorescence under 365nm, moisture absorption ratio≤2%.
3. the preparation method of an artificial Fel Ursi powder comprises following in sequence step:
1) Fel Ursi is left standstill clarification, obtain supernatant, the temperature that wherein leaves standstill clarification is 4～10 ℃, and time of repose is 2～24 hours;
2) adopt adsorption method that supernatant is carried out remove impurity and process, obtain the water solublity Fel Ursi, wherein, adopt D101 type macroporous resin to carry out described adsorption-edulcoration and process;
3) the water solublity Fel Ursi is carried out dried, pulverizes, sieve, and get final product,
The Fel Ursi powder that obtains is burnished gold or the foresythia powder of hyaloid gloss, is glassy yellow fluorescence under 365nm, moisture absorption ratio≤2%.
4. such as the arbitrary described preparation method of claim 1-3, it is characterized in that dried selection oven dry, vacuum drying, spray drying or the lyophilization described in the step 3).
5. preparation method as claimed in claim 4 is characterized in that described bake out temperature is 60～80 ℃.
6. preparation method as claimed in claim 4, it is characterized in that described vacuum drying relative pressure be-0.05～-0.095MPa; Baking temperature is 30～60 ℃.
7. preparation method as claimed in claim 4, it is characterized in that described lyophilization for Fel Ursi-40 ℃ of lower pre-freezes 3～5 hours, then-40～-15 ℃ of lower sublimation dryings 18～24 hours, and then lower dry 12～20 hours in-15～30 ℃.
8. artificial Fel Ursi powder is characterized in that being prepared from according to method as described in arbitrary such as claim 1-4.
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| CN105784854B (en) * | 2014-12-23 | 2020-06-16 | 重庆药友制药有限责任公司 | Method for detecting related substances in tauroursodeoxycholic acid |
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| CN108635375A (en) * | 2018-07-14 | 2018-10-12 | 齐光伟 | Prevent or treats hepatopathy and liver fibrosis and improve the bear gall powder and purposes of liver function |
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| CN108653332A (en) * | 2018-07-14 | 2018-10-16 | 齐光伟 | Inhibition thrombosis and platelet aggregation and the bear gall powder and purposes for preventing cerebral ischemia |
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| CN110368403A (en) * | 2019-07-17 | 2019-10-25 | 上海凯宝药业股份有限公司 | The application in preparing anti-inflammatory drugs of bioconversion bear gall powder |
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