CN101993462A - Scutellarin crystal I and preparation method thereof - Google Patents
Scutellarin crystal I and preparation method thereof Download PDFInfo
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- CN101993462A CN101993462A CN2009101648557A CN200910164855A CN101993462A CN 101993462 A CN101993462 A CN 101993462A CN 2009101648557 A CN2009101648557 A CN 2009101648557A CN 200910164855 A CN200910164855 A CN 200910164855A CN 101993462 A CN101993462 A CN 101993462A
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Abstract
The invention relates to the field of pharmaceutical chemistry, and discloses a scutellarin crystal I. X-ray powder diffraction analysis, differential scanning calorimetry (DSC) and thermogravimetric and differential thermal analysis (TG-DTA), and infrared ray (IR) and high performance liquid chromatography (HPLC) analysis prove that the scutellarin crystal I is in a novel crystal form. The scutellarin crystal I has high purity, stability for light, moist and heat, and high stability in alkaline solution; and an acute toxicity test proves that the scutellarin crystal I has high safety. The invention also provides a method for preparing the crystal. The method is easy to operate and has low production cost; the using amount of a crystallization solvent is smaller than that of the crystallization solvent in the conventional crystallization method; industrial production is easy to realize; and the scutellarin content of the prepared scutellarin crystal I is over 98 percent.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, particularly a kind of lamp-dish flower acetic crystallization I and this crystalline method of preparation.
Background technology:
Herba Erigerontis has another name called Herba Erigerontis, and because of spending like oil lamp, root is gained the name like the root of Chinese wild ginger.Herb for the short booth bitter fleabane of composite family bitter fleabane platymiscium [Erigeron breviscapus (vant.) Hand.-Mazz.].This medicinal material head is stated from " the southern regions of the Yunnan Province book on Chinese herbal medicine ", has recorded in that " Chinese pharmacopoeia version in 2005, Yunnan is among the people to be usually used in treating wound, rheumatalgia, toothache, stomachache, flu etc.Twentieth century seventies, to hypertension, Intracerebral hemorrhage, cerebral thrombosis, cerebral embolism polyneuritis, chronic arachnoiditis and sequela thereof had better curative effect, and rheumatism, coronary heart disease are also had certain curative effect through clinical verification.The main active ingredient of having determined the treatment cardiovascular and cerebrovascular diseases is Breviscarpine (Breviscapine).Breviscarpine mainly contains oil lamp cycle of sixty years element (Apigenin-7-O-glucuronside) and lamp-dish flower acetic (Scutellarin has another name called scutellarin); Lamp-dish flower acetic content is greater than 75% (HPLC mensuration) in the commercially available Breviscarpine.The content of lamp-dish flower acetic in Herba Erigerontis medicinal material dry product is about about 0.4%-0.5%, and lamp-dish flower acetic treatment cardiovascular and cerebrovascular diseases drug effect is definite.
The plain structural formula of oil lamp cycle of sixty years is shown below:
The lamp-dish flower acetic structural formula is shown below:
Owing to Breviscarpine series product determined curative effect, use constantly and enlarge, the demand of raw material is risen year by year.At present, annual handle dried medicinal material more than 6000 tons, the market requirement is more than 10000 tons, 4000 tons of breach; Wild resource is limited, and sharply reduces.
The artificial growth Herba Erigerontis occupies cultivated land, and also has problems such as disease and pest sickness rate height (80%-95%), germplasm degeneration variation, cost remain high, and has limited the popularization that this method is produced lamp-dish flower acetic greatly.And it is higher that the plant extract separation method obtains high-purity scutellarin (HPLC content is greater than 98.0%) cost, and purity be cannot say for sure to demonstrate,prove.
The patent No. be CN1298728C, CN1303092C, CN1317289C, CN1317290C, CN100352826C, CN100366629C patent disclosure utilize the method for plant extract Breviscarpine feed purification lamp-dish flower acetic, its principle is according to containing carboxylic acid functional in the lamp-dish flower acetic molecule, adopt the basic solvent dissolving to form salt, remove by filter impurity, filtrate is extracted lamp-dish flower acetic with the method refined plant of Acid precipitation.If the control of pH value is bad, then can produce degraded product when existing the adding basic solvent to regulate the lamp-dish flower acetic salify in this process for refining, add alkaline reagents and will cause lamp-dish flower acetic generation ultraviolet to be offset; The normal mineral ion difficulty of introducing is removed; The refining sad filter of sample, problems such as difficult drying cause the suitability for industrialized production difficulty.
In addition, owing to still contain a certain amount of oil lamp cycle of sixty years element in the plant extract Breviscarpine raw material, still contain carboxylic acid functional in its molecule, thus still contain a certain amount of oil lamp cycle of sixty years element in the refining lamp-dish flower acetic that obtains, obtain highly purified lamp-dish flower acetic technically time you in difficulty.
Summary of the invention
The objective of the invention is to solve the low defective of existing lamp-dish flower acetic purity, a kind of highly purified lamp-dish flower acetic crystallization I is provided.Lamp-dish flower acetic crystallization I of the present invention uses Cu-K α radiation, λ=1.5405A, and the x-ray powder diffraction spectral signature of representing with 2 θ angles is as follows:
| 2θ | I/I 0％ | 2θ | I/I 0％ |
| 7.88 | 34 | 26.62 | 62 |
| 9.30 | 36 | 27.50 | 17 |
| 9.94 | 48 | 28.84 | 52 |
| 14.2 | 97 | 30.42 | 12 |
| 15.92 | 100 | 31.44 | 16 |
| 18.98 | 24 | 32.98 | 12 |
| 20.12 | 24 | 34.60 | 10 |
| 21.14 | 30 | 36.88 | 10 |
| 21.56 | 14 | 38.50 | 24 |
| 22.36 | 10 | 40.82 | 18 |
| 22.92 | 25 | 44.00 | 10 |
| 25.74 | 73 | 46.38 | 20 |
Described x-ray powder diffraction 2 θ positions 15.92 place's diffraction peak intensities are 100%.
The infrared absorpting light spectra of described lamp-dish flower acetic crystallization I is at 3511cm
-1, 3373cm
-1, 2920cm
-1, 2885cm
-1, 1721cm
-1, 1662cm
-1, 1608cm
-1, 1590cm
-1, 1575cm
-1, 1558cm
-1, 1498cm
-1, 1467cm
-1, 1442cm
-1, 1418cm
-1, 1400cm
-1, 1362cm
-1, 1304cm
-1, 1286cm
-1, 1249cm
-1, 1224cm
-1, 1198cm
-1, 1183cm
-1, 1150cm
-1, 1119cm
-1, 1101cm
-1, 1084cm
-1, 1041cm
-1, 846cm
-1, 813cm
-1, 740cm
-1, 720cm
-1, 618cm
-1There is absorption peak at the place.
The dsc analysis endothermic transition temperature of described lamp-dish flower acetic crystallization I is 124-128 ℃.
The fusion and decomposition temperature of described lamp-dish flower acetic crystallization I is 207-209 ℃.
When the TGA of described lamp-dish flower acetic crystallization I analyzes fusion and decomposition with the mass attenuation of 12%-15%.
The present invention also provides the preparation method of described lamp-dish flower acetic crystallization I, may further comprise the steps:
Step 1: in lamp-dish flower acetic, add solvent and acid, the mass volume ratio of lamp-dish flower acetic and described solvent with g/ml count 1: 0.5～5, the mass volume ratio of lamp-dish flower acetic and described acid with g/ml count 1: 10～100, it is fully dissolved;
Step 2: in step 1 gained solution, slowly drip 1-10 doubly to the solvent of separating out of described liquor capacity, leave standstill, slowly separate out crystallization, promptly get described lamp-dish flower acetic crystallization 1.
The described solvent of step 1 is preferably N, one of dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), methylcarbonate or two or more mixtures.
Acid described in the step 1 is preferably one of formic acid, acetate, phosphoric acid, hydrochloric acid, sulfuric acid or its mixed solution.
The preferred gac that accounts for lamp-dish flower acetic quality 1%-5% that adds after the step 1,40-80 ℃ of heating also filtered the processing of decolouring.
Leaving standstill preferred temperature described in the step 2 is 0-40 ℃, continues 2-72 hour.
Separate out described in the step 2 that solvent is preferably water or/and the Fatty Alcohol(C12-C14 and C12-C18) of 1-3 carbon atom more preferably is water and alcoholic acid mixture or water and methanol mixture.
The present invention also provides a kind of pharmaceutical composition, said composition comprises acceptable carrier on the claim 1 described lamp-dish flower acetic crystallization I of significant quantity and the pharmaceutics, makes on the pharmaceutics acceptable forms such as lyophilized injectable powder, enteric coated capsule, enteric coated tablet, sprays, nasal drop etc.
In the described pharmaceutical composition, lamp-dish flower acetic crystallization I contains 5mg～100mg in each preparation unit, and content is 10mg～50mg preferably.
The present invention also provides the lyophilized injectable powder of described pharmaceutical composition, and its composition is by weight:
Lamp-dish flower acetic crystallization I 5～100mg
Described vehicle is preferably one or both the mixture in N.F,USP MANNITOL, the low molecular dextran.
The present invention also provides the capsule of described pharmaceutical composition, and the content composition of described capsule is by weight:
Lamp-dish flower acetic crystallization I 5mg～100mg
Soybean oil 5mg～500mg
Vitamin-E 0.01mg～0.3mg.
Described phosphatide comprises any one in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, the synthetic phosphatide.
The softgel shell composition of described capsule is counted with weight mg:
Gelatin 60mg
Glycerine 20mg
Ethyl p-hydroxybenzoate 0.01mg～0.3mg.
The analysis of X-ray powder diffraction, DSC and the TG-DTA analysis of lamp-dish flower acetic crystallization I of the present invention, IR and HPLC analyze, and with existing lamp-dish flower acetic crystal (scutellarin reference substance, Nat'l Pharmaceutical ﹠ Biological Products Control Institute provides, lot number: 8420-200102) and Breviscarpine (Kunming pharmacy pharmacy Group Plc provides, lot number: 20090301) contrast of X-ray powder diffraction shows, is a kind of new crystal habit.Described lamp-dish flower acetic crystallization I purity height, stable to light, wet, heat etc., good stability in basic solution, acute toxicity test shows that it is safe.
The preparation method of lamp-dish flower acetic crystallization I of the present invention, simple to operate, the recrystallisation solvent amount that the existing crystallization method of the recrystallisation solvent of employing uses is few, and production cost is low, easy suitability for industrialized production, lamp-dish flower acetic content is up to more than 98% among the prepared lamp-dish flower acetic crystallization I.
Description of drawings
Fig. 1: the X-ray powder diffraction pattern of lamp-dish flower acetic crystallization I;
Fig. 2: the DSC of lamp-dish flower acetic crystallization I and TG-DTA figure;
Fig. 3: the IR figure of lamp-dish flower acetic crystallization I;
Fig. 4: the HPLC figure of lamp-dish flower acetic crystallization I;
Fig. 5: the lamp-dish flower acetic crystalline X-ray powder diffraction pattern that Nat'l Pharmaceutical ﹠ Biological Products Control Institute provides;
Fig. 6: the X-ray powder diffraction pattern of the Breviscarpine that Kunming Medicine Group Stock Co., Ltd provides.
Embodiment
The following examples are of the present inventionly further to illustrate, rather than limit.
Get lamp-dish flower acetic and treat highly finished product 1kg, add the N of 2L, dinethylformamide, and add the formic acid of 0.1L, jolting or ultrasonicly make abundant dissolving adds the gac of 0.01kg then, and 60 ℃ of heating several minutes are filtered.Slowly drip 95% ethanol of 6L, 25 ℃ left standstill 72 hours, made and slowly separated out crystallization, filter, and washing, 60 ℃ of drying under reduced pressure get lamp-dish flower acetic highly finished product 0.75kg.The process for refining rate of recovery 70.5%, content 98.8%.
Get lamp-dish flower acetic and treat highly finished product 1kg, add the N,N-dimethylacetamide of 1L, and add the acetate of 0.05L, jolting or ultrasonicly make abundant dissolving adds the gac of 0.02kg then, and 80 ℃ of heating several minutes are filtered.Slowly drip 50% methyl alcohol of 4L, 25 ℃ left standstill 2 hours, made and slowly separated out crystallization, filter, and washing, 40 ℃ of drying under reduced pressure get lamp-dish flower acetic highly finished product 0.83kg.The process for refining rate of recovery 83.2%, content 98.5%.
Get lamp-dish flower acetic and treat highly finished product 1kg, add the dimethyl sulfoxide (DMSO) of 0.5L, and add the phosphoric acid of 0.01L, jolting or ultrasonicly make abundant dissolving adds the gac of 0.05kg then, and 80 ℃ of heating several minutes are filtered.75% ethanol of slow Dropwise 5 L, 0 ℃ left standstill 12 hours, made and slowly separated out crystallization, filter, washing, 60 ℃ of drying under reduced pressure get lamp-dish flower acetic highly finished product 0.9kg.The process for refining rate of recovery 90.5%, content 99.0%.
Get lamp-dish flower acetic and treat highly finished product 1kg, add the N of 5L, dinethylformamide, and add the hydrochloric acid of 0.05L, jolting or ultrasonicly make abundant dissolving adds the gac of 0.03kg then, and 50 ℃ of heating several minutes are filtered.75% Virahol of slow Dropwise 5 0L, 30 ℃ left standstill 24 hours, made and slowly separated out crystallization, filter, washing, 60 ℃ of drying under reduced pressure get lamp-dish flower acetic highly finished product 0.65kg.The process for refining rate of recovery 65.5%, content 99.1%.
Embodiment 5
Get lamp-dish flower acetic and treat highly finished product 1kg, add the methylcarbonate of 0.8L, and add the sulfuric acid of 0.01L, jolting or ultrasonicly make abundant dissolving adds the gac of 0.03kg then, and 40 ℃ of heating several minutes are filtered.Slowly drip 80% methyl alcohol of 3L, 0 ℃ left standstill 24 hours, made and slowly separated out crystallization, filter, and washing, 60 ℃ of drying under reduced pressure get lamp-dish flower acetic highly finished product 0.86kg.The process for refining rate of recovery 86.5%, content 99.3%.
Embodiment 6: the purity testing of lamp-dish flower acetic among the lamp-dish flower acetic crystallization I of the present invention
Instrument and reagent reagent: Shimadzu LC-10ATvp high performance liquid chromatograph: comprise Shimadzu LC-10ATVP pump, FCV-10ALVP+DGU-12A is combined into online de-gassing vessel, the SIL-10ADVP automatic sampler, the SPD-M10AVP diode array detector, the CTO-10ASVP column oven, the CLASS-VP workstation.Chromatographic column: Luna C18150 * 4.6mm.
Methyl alcohol, tetrahydrofuran (THF), phosphoric acid are that chromatographic grade, HPLC water are heavily to steam distilled water.
Scutellarin reference substance: lot number: 8420-200102 is provided by Nat'l Pharmaceutical ﹠ Biological Products Control Institute;
Lamp-dish flower acetic, lot number: 200904-B, 200904-C, 200904-D, thigh mg company limited of Kunming pharmacy group.
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is weighting agent; With methyl alcohol-tetrahydrofuran (THF)-0.1% phosphate aqueous solution) (23: 10: 67) be moving phase; The detection wavelength is 335nm.Number of theoretical plate calculates by the lamp-dish flower acetic peak should be not less than 5000.
Measure: get the about 10mg of this product, the accurate title, decide, and puts in the 50ml measuring bottle, adds dissolve with methanol and be diluted to scale, shakes up, and precision is measured 10ml, puts in the 25ml measuring bottle, adds methyl alcohol and is diluted to scale, shakes up, and precision is measured 10 μ l and injected liquid chromatograph, the record color atlas; Other gets the about 10mg of scutellarin reference substance, measures with method, presses external standard method with calculated by peak area, promptly.
| Crest | Response value | Area under the peak | Peak | Area % | |
| 1 | 7.484 | 2423233 | 136255 | 98.001 | |
| 2 | 11.437 | 24513 | 1083 | 1.099 | |
| Amount to | 2447746 | 137337 | 100 |
The result is shown in Fig. 4 and last table, and the content of lamp-dish flower acetic is up to more than 98% among the lamp-dish flower acetic crystallization I of the present invention.
Embodiment 7: the X-ray diffraction check analysis of crystallization I of lamp-dish flower acetic described in the present invention and existing lamp-dish flower acetic
Instrument: Japanese D/MAX-2200 type diffractometer of science
Target: Cu-K α radiation (λ=1.5405A), 2 θ=2 °～70 °
Step angle: 0.04 °
Pipe is pressed: 36KV
Pipe stream: 30mA
Sweep velocity: 10 °/min
Filter disc: graphite monochromator
The crystallization of lamp-dish flower acetic described in the present invention I uses Cu-K α radiation, λ=1.5405A, the x-ray powder diffraction of representing with 2 θ angles as shown in Figure 1, its spectral signature is as follows:
Existing lamp-dish flower acetic crystal (scutellarin reference substance, Nat'l Pharmaceutical ﹠ Biological Products Control Institute provides, lot number: 8420-200102) use Cu-K α radiation, λ=1.5405A, the x-ray powder diffraction of representing with 2 θ angles as shown in Figure 5, spectral signature is as follows:
| 2θ | Spacing (the d value, A) | I/I 0 |
| 7.32 | 12.07 | 76 |
| 8.92 | 9.91 | 100 |
| 9.40 | 9.40 | 11 |
| 11.12 | 7.95 | 66 |
| 12.18 | 7.26 | 32 |
| 18.22 | 4.86 | 49 |
| 18.74 | 4.73 | 45 |
| 19.34 | 4.58 | 20 |
| 20.76 | 4.27 | 70 |
| 21.24 | 4.18 | 22 |
| 22.60 | 3.93 | 12 |
| 26.16 | 3.40 | 82 |
| 27.24 | 3.27 | 18 |
| 28.54 | 3.12 | 13 |
| 28.84 | 3.09 | 30 |
| 30.52 | 2.93 | 14 |
(Kunming pharmacy pharmacy Group Plc provides Breviscarpine, contains lamp-dish flower acetic 90%, lot number: X-ray powder diffraction 20090301), use Cu-K α radiation, λ=1.5405A, the x-ray powder diffraction of representing with 2 θ angles as shown in Figure 6, spectral signature is as follows:
| 2θ | Spacing (the d value, A) | I/I 0 |
| 7.68 | 11.50 | 16 |
| 9.16 | 9.65 | 17 |
| 9.78 | 9.04 | 33 |
| 14.00 | 6.32 | 48.3 |
| 15.72 | 5.63 | 36.7 |
| 18.84 | 4.71 | 50.5 |
| 20.84 | 4.26 | 38 |
| 21.42 | 4.14 | 33 |
| 22.12 | 4.01 | 11 |
| 22.80 | 3.90 | 17 |
| 25.58 | 3.48 | 100 |
| 26.50 | 3.36 | 82 |
| 27.36 | 3.26 | 17 |
| 28.58 | 3.12 | 24 |
| 32.86 | 2.72 | 11 |
| 34.48 | 2.60 | 12 |
| 38.28 | 2.35 | 10 |
Above analytical results shows that lamp-dish flower acetic crystallization I of the present invention is a kind of new crystal habit.
Embodiment 8: the crystallization of lamp-dish flower acetic described in invention I differential scanning calorimetric (DSC) is analyzed
Instrument: NETZSCH STA 409 PG/PC
Scope: 35-350 ℃
Heat-up rate: 5 ℃/minute
The DSC endothermic transition temperature of lamp-dish flower acetic crystallization I is 124-128 ℃, 207-209 ℃ of fusion and decomposition temperature.
Embodiment 9: thermogravimetric-differential thermal (TGA) is analyzed
Instrument: NETZSCH STA 409PG/PC
TG range: 5mg
DTA range: ± 250 μ V
Reference substance: Al
2O
3
Temperature range: 35-350 ℃
Heat-up rate: 5 ℃/minute
The result shows lamp-dish flower acetic crystallization I fusion and decomposition temperature at 202-215 ℃, and with the mass attenuation of 12%-15%.
Embodiment 10: infrared spectra (IR) is analyzed
Instrument: Shimadzu FTIR-8400S infrared spectrometer
Infrared spectra wave number (the cm of synthetic lamp-dish flower acetic (pressing potassium bromide troche)
-1) be to see shown in Figure 3:
3511，3373，2920，2885，1721，1662，1608，1590，1575，1558，1498，1467，1442，1418，1400，1362，1304，1286，1249，1224，1198，1183，1150，1119，1101，1084，1041，846，813，740，720，618。
Embodiment 11: the stability of lamp-dish flower acetic crystallization I
The active destructive test of lamp-dish flower acetic crystallization I: will carry out respectively with the high-purity scutellarin of a collection of acquisition:
1. strong acid destroys: precision takes by weighing the 0.5mg sample in the 50ml measuring bottle, adds the aqueous hydrochloric acid 1ml of 0.1mol/L, mixes, and places 48 hours for 20-30 ℃;
2. highly basic destroys: precision takes by weighing the 0.5mg sample in the 50ml measuring bottle, adds the aqueous sodium hydroxide solution 1ml of 0.1mol/L, mixes, and places 48 hours for 20-30 ℃;
3. smart strong oxidation destroys: the close 0.5mg sample that takes by weighing adds 30% hydrogen peroxide (H in the 50ml measuring bottle
2O
2) solution 1ml, mix, placed 48 hours for 20-30 ℃;
4. high temperature destroys: precision takes by weighing the 0.5mg sample in the 50ml measuring bottle, puts 100 ℃ of heating 48 hours;
5. intense light irradiation destroys: precision takes by weighing the 0.5mg sample in the 50ml measuring bottle, places 240 hours under the intense light irradiation condition of 4500 ± 500 luxs.With the time taking-up according to the rules of above-mentioned test sample, add methyl alcohol and make dissolving and be diluted to scale, shake up, the unbroken sample of accompanying carries out HPLC and analyzes.
The results are shown in following table:
| Test conditions | The lamp-dish flower acetic peak area | Other degraded product situations |
| Strong acid destroys | 944598 | A new degraded product is arranged |
| Highly basic destroys | 0 | The skew of generation ultraviolet has many degraded products peak. |
| High temperature destroys | 2649851 | Do not find the degraded product peak |
| Strong oxidation destroys | 2571369 | Find a new degraded product |
| Intense light irradiation destroys | 2674321 | Do not find the degraded product peak |
| Do not destroy | 2653287 | An impurity peaks is arranged |
Above test-results shows, this lamp-dish flower acetic crystallization I is stable to light, wet, heat etc., is convenient to produce, store.
Embodiment 12: the stability of solution of lamp-dish flower acetic crystallization I and lamp-dish flower acetic relatively
It is an amount of to get lamp-dish flower acetic crystallization I and Breviscarpine respectively, adds the phosphate buffer solution of pH8.0, pH9.0, pH10.0 respectively, makes constant volume become 100ml, is positioned over 37 ℃, and respectively at sampling in 2,4,6,8,12 hours, the HPLC method was measured lamp-dish flower acetic content.The results are shown in following table:
Last table shows, in high-purity scutellarin crystallization I and the stable comparative studies of lamp-dish flower acetic in the phosphate buffer solution of different meta-alkalescences, the stability of solution of high-purity scutellarin crystallization I is better.
Embodiment 13: lamp-dish flower acetic crystallization I acute toxicity test
Laboratory animal: the ICR mouse, body weight 18-20g, cleaning level, Kunming pharmacy group Experimental Animal Center, laboratory animal produces and occupancy permit number: SCXK (Yunnan) 2005-0006 number, SYXK (Yunnan) 2005-0006 number.
Medicine and reagent: Breviscarpine, Kunming Medicine Group Stock Co., Ltd, lot number: 20090301, contain lamp-dish flower acetic 95.0%; Lamp-dish flower acetic crystallization I contains lamp-dish flower acetic 99.0%, Kunming Medicine Group Stock Co., Ltd, lot number 200904-C.
Method: it is an amount of trial-product to be added 0.5% the CMC-Na aqueous solution, forms suspension, gastric infusion.Observe symptom and the death condition that animal occurs after the mouse administration.
The result: the LD50 of the oral lamp-dish flower acetic crystallization of mouse I is 15.23g/kg, is equivalent to 125 times of clinical administration amount (120mg/ people/sky).The 95% credible 14.98～15.50g/kg that is limited to, the LD50 of mouse oral Breviscapine is 10.45g/kg, is equivalent to 87 times of clinical administration amount (120mg/ people/sky).The 95% credible 9.88～11.02g/kg that is limited to.Above results suggest lamp-dish flower acetic crystallization I oral administration is safe than Breviscarpine.
Embodiment 14
Lamp-dish flower acetic crystallization I form lyophilized injectable powder: 1000 prescriptions
Lamp-dish flower acetic crystallization I 5g
Meglumine 3g
N.F,USP MANNITOL 2g
Be distributed into 1000, water dissolution, lyophilize is promptly.
Lamp-dish flower acetic crystallization I form lyophilized injectable powder: 1000 prescriptions
Lamp-dish flower acetic crystallization I 100g
Meglumine 45g
N.F,USP MANNITOL 1.31kg
Be distributed into 1000, water dissolution, lyophilize is promptly.
Embodiment 16
Lamp-dish flower acetic crystallization I form lyophilized injectable powder: 1000 prescriptions
Lamp-dish flower acetic crystallization I 50g
Meglumine 23g
Low molecular dextran 73g
Be distributed into 1000, water dissolution, lyophilize is promptly.
Embodiment 17
Lamp-dish flower acetic crystallization I form lyophilized injectable powder: 1000 prescriptions
Lamp-dish flower acetic crystallization I 50g
Meglumine 23g
N.F,USP MANNITOL 30g
Low molecular dextran 50g
Be distributed into 1000, water dissolution, lyophilize is promptly.
Embodiment 18
Lamp-dish flower acetic crystallization I form phospholipid complex soft capsule: 1000 prescriptions
Content is formed
Lamp-dish flower acetic crystallization I 5g
Soybean lecithin 5g
Soybean oil 5g
Vitamin-E 0.3g
Softgel shell is formed
Gelatin 65g
Glycerine 25g
Ethyl p-hydroxybenzoate 0.3g
Load soft capsule and become 1000, promptly.
Embodiment 19
Lamp-dish flower acetic crystallization I form phospholipid complex soft capsule: 1000 prescriptions
Content is formed
Lamp-dish flower acetic crystallization I 100g
Ovum Gallus domesticus Flavus lecithin 500g
Soybean oil 500g
Vitamin-E 0.05g
Softgel shell is formed
Gelatin 65g
Glycerine 25g
Ethyl p-hydroxybenzoate 0.01g
Load soft capsule and become 1000, promptly.
Lamp-dish flower acetic crystallization I form phospholipid complex soft capsule: 1000 prescriptions
Content is formed
Lamp-dish flower acetic crystallization I 50g
Dipalmitoyl phosphatidylcholine 75g
Soybean oil 100g
Vitamin-E 0.05g
Softgel shell is formed
Gelatin 65g
Glycerine 25g
Ethyl p-hydroxybenzoate 0.01g
Load soft capsule and become 1000, promptly.
Claims (20)
1. a lamp-dish flower acetic crystallization I is characterized in that, uses Cu-K α radiation, λ=1.5405A, and the x-ray powder diffraction spectral signature of representing with 2 θ angles is as follows:
2. lamp-dish flower acetic crystallization I as claimed in claim 1 is characterized in that, described x-ray powder diffraction 2 θ positions 15.92 place's diffraction peak intensities are 100%.
3. lamp-dish flower acetic crystallization I as claimed in claim 1 is characterized in that its infrared absorpting light spectra is at 3511cm
-1, 3373cm
-1, 2920cm
-1, 2885cm
-1, 1721cm
-1, 1662cm
-1, 1608cm
-1, 1590cm
-1, 1575cm
-1, 1558cm
-1, 1498cm
-1, 1467cm
-1, 1442cm
-1, 1418cm
-1, 1400cm
-1, 1362cm
-1, 1304cm
-1, 1286cm
-1, 1249cm
-1, 1224cm
-1, 1198cm
-1, 1183cm
-1, 1150cm
-1, 1119cm
-1, 1101cm
-1, 1084cm
-1, 1041cm
-1, 846cm
-1, 813cm
-1, 740cm
-1, 720cm
-1, 618cm
-1There is absorption peak at the place.
4. lamp-dish flower acetic crystallization I as claimed in claim 1 is characterized in that, its dsc analysis endothermic transition temperature is 124-128 ℃.
5. lamp-dish flower acetic crystallization I as claimed in claim 1 is characterized in that its fusion and decomposition temperature is 207-209 ℃.
6. lamp-dish flower acetic crystallization I as claimed in claim 1 is characterized in that, when its TGA analyzes fusion and decomposition with the mass attenuation of 12%-15%.
7. the preparation method of the described lamp-dish flower acetic crystallization of claim 1 I may further comprise the steps:
Step 1: in lamp-dish flower acetic, add solvent and acid, the mass volume ratio of lamp-dish flower acetic and described solvent with g/ml count 1: 0.5～5, the mass volume ratio of lamp-dish flower acetic and described acid with g/ml count 1: 10～100, it is fully dissolved;
Step 2: in step 1 gained solution, slowly drip 1-10 doubly to the solvent of separating out of described liquor capacity, leave standstill, slowly separate out crystallization, promptly get described lamp-dish flower acetic crystallization 1.
8. preparation method as claimed in claim 7 is characterized in that, the described solvent of step 1 is N, one of dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), methylcarbonate or two or more mixtures.
9. preparation method as claimed in claim 7 is characterized in that, acid described in the step 1 is one of formic acid, acetate, phosphoric acid, hydrochloric acid, sulfuric acid or its two or more mixed solution.
10. preparation method as claimed in claim 7 is characterized in that, the temperature that leaves standstill described in the step 2 is 0-40 ℃, continues 2-72 hour.
11. preparation method as claimed in claim 7 is characterized in that, adds the gac that accounts for lamp-dish flower acetic quality 1%-5% after the step 1, heating is also filtered.
12. preparation method as claimed in claim 7 is characterized in that, separating out solvent described in the step 2 is that water is or/and the Fatty Alcohol(C12-C14 and C12-C18) of 1-3 carbon atom.
13. preparation method as claimed in claim 7 is characterized in that, separating out solvent described in the step 2 is water and alcoholic acid mixture or water and methanol mixture.
14. a pharmaceutical composition, said composition comprise acceptable carrier on the claim 1 described lamp-dish flower acetic crystallization I of significant quantity and the pharmaceutics.
15. in the pharmaceutical composition as claimed in claim 14, lamp-dish flower acetic crystallization I contains 5mg～100mg in each preparation unit, content is 10mg～50mg preferably.
16. the lyophilized injectable powder as pharmaceutical composition as described in the claim 14 is characterized in that its composition is by weight:
Lamp-dish flower acetic crystallization I 5～100mg
Meglumine 3～45mg
Vehicle 2～1310mg.
17., it is characterized in that described vehicle is one or both the mixture in N.F,USP MANNITOL, the low molecular dextran as lyophilized injectable powder as described in the claim 16.
18. the capsule as pharmaceutical composition as described in the claim 14 is characterized in that, described capsular content is formed and is by weight:
Lamp-dish flower acetic crystallization I 5mg～100mg
Phosphatidase 15 mg～500mg
Soybean oil 5mg～500mg
Vitamin-E 0.01mg～0.3mg.
19. capsule as claimed in claim 18 is characterized in that, described phosphatide comprises any one in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, the synthetic phosphatide.
20., it is characterized in that described capsular softgel shell composition is counted with weight mg as claim 18 or 19 described capsules:
Gelatin 60mg
Glycerine 20mg
Ethyl p-hydroxybenzoate 0.01mg～0.3mg.
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| EP2612671A1 (en) * | 2010-09-02 | 2013-07-10 | Kunming Pharmaceutical Corp. | A clinical preparation of scutellarin and the preparation method thereof |
| CN104288485A (en) * | 2014-09-18 | 2015-01-21 | 大生祥(武汉）中医投资管理有限公司 | Extract applied to ginseng and radix ophiopogonis preparation and preparation method of extract |
| CN105273018A (en) * | 2014-06-17 | 2016-01-27 | 昆明制药集团股份有限公司 | Scutellarin dihydrate crystal II and preparation method thereof |
| CN106967139A (en) * | 2017-05-24 | 2017-07-21 | 昆明龙津药业股份有限公司 | A kind of lamp-dish flower acetic crystal formation and preparation method thereof |
| CN111939167A (en) * | 2019-05-15 | 2020-11-17 | 贵州医科大学 | Scutellarin-phospholipid complex, solid dispersion and microemulsion drug delivery system thereof, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2612671A1 (en) * | 2010-09-02 | 2013-07-10 | Kunming Pharmaceutical Corp. | A clinical preparation of scutellarin and the preparation method thereof |
| EP2612671A4 (en) * | 2010-09-02 | 2014-05-28 | Kunming Pharmaceutical Corp | A clinical preparation of scutellarin and the preparation method thereof |
| CN105273018A (en) * | 2014-06-17 | 2016-01-27 | 昆明制药集团股份有限公司 | Scutellarin dihydrate crystal II and preparation method thereof |
| CN105273018B (en) * | 2014-06-17 | 2018-11-27 | 昆药集团股份有限公司 | A kind of lamp-dish flower acetic dihydrate crystallization II and preparation method thereof |
| CN104288485A (en) * | 2014-09-18 | 2015-01-21 | 大生祥(武汉）中医投资管理有限公司 | Extract applied to ginseng and radix ophiopogonis preparation and preparation method of extract |
| CN106967139A (en) * | 2017-05-24 | 2017-07-21 | 昆明龙津药业股份有限公司 | A kind of lamp-dish flower acetic crystal formation and preparation method thereof |
| CN106967139B (en) * | 2017-05-24 | 2019-07-26 | 昆明龙津药业股份有限公司 | A kind of lamp-dish flower acetic crystal form and preparation method thereof |
| CN111939167A (en) * | 2019-05-15 | 2020-11-17 | 贵州医科大学 | Scutellarin-phospholipid complex, solid dispersion and microemulsion drug delivery system thereof, and preparation method and application thereof |
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| CN101993462B (en) | 2013-12-11 |
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