CN102260313B - Amorphous ginsenoside Rb1 and preparation method thereof - Google Patents
Amorphous ginsenoside Rb1 and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the field of medicines and discloses an amorphous ginsenoside Rb1 which has an X-ray diffraction pattern shown in figure 1. The invention also provides a preparation method of the amorphous ginsenoside Rb1. The preparation method comprises the following steps: dissolving ginsenoside Rb1 in a solvent, wherein the solvent is lower alkanol or a mixture of lower alkanol and water; and recovering the solvent while decompressing to obtain the amorphous ginsenoside Rb1. The preparation method provided by the invention is simple to operate and is easy to realize industrial production. The X-ray powder diffraction analysis, IR (infrared) analysis and HPLC (high-performance liquid chromatography) analysis show that the amorphous ginsenoside Rb1 prepared by the preparation method is amorphous, has high purity (up to 98% or above) and good solubility, and has good medicinal application prospects.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of amorphous state ginsenoside Rb1 and preparation method thereof.
Background technology
The ginsenoside Rb1 is the main active ingredient of extracting from pseudo-ginseng, and ginsenoside Rb1's pharmacological action has anti-aging effects, be mainly manifested in improve sexual function, improve adrenal function, anti-stress effect, anti peroxidation of lipid; The reperfusion injury that resists myocardial ischemia, the ginsenoside Rb1 has the calcium ion retardation, and myocardial cell's apoptosis is significantly reduced; The ginsenoside Rb1 can regulate air flue, vascular smooth muscle tension force by the NO approach, suppresses capillary vessel and oozes out and neutrophil adhesion, the ischemia-reperfusion lung injury that causes to reduce ischemic, anoxic.The ginsenoside Rb1 can reduce the release of synaptic vesicle Excitatory Neurotransmitter that anoxic causes etc., helps to reduce extracellular L-glutamic acid level, thereby alleviates its excititoxic, the neuroprotective cell; , the ginsenoside Rb1 can promote Schwann Cell Increase, thereby promotes peripheral nerve-cell regeneration; The ginsenoside Rb1 has the effects such as the cerebral tissue of raising acetyl choline content and increase M cholinocepter number, strengthens the choline system function, improves neural plasticity, thereby improves learning and memory function.
Solid pharmaceutical polymorphic state is the important content of drugs existence, for most chemicalses, generally all has polymorphism.Different crystal-form substances affects physico-chemical property and the biological activity of medicine.Amorphous state (amorphous) is that material exists a kind of form in the polymorphism, also is a kind of special crystal formation state.Such with the crystalline state material, also can there be different forms in the metamict of solid pharmaceutical, and this phenomenon is referred to as the polymorphism of solid matter amorphous state, is called again amorphous polymorphic (polyamorphous).Lv Yangyu Du Guan China (" crystal formation medicine ", the People's Health Publisher, in October, 2009) point out, form the polymorphic material of amorphous state reason may with compound structure type or structure phase, the moiety of chemical substance, three kinds of factor analysis of chemical substance Intermolecular Forces.
As everyone knows, the active substance of amorphous form is better and dissolving is faster than the active substance solvability of corresponding crystalline forms, and compares with the active substance of crystallized form, and amorphous active substance has better bioavailability.When the inventor uses the X-ray diffraction method to test to above-mentioned ginsenoside Rb1 of the prior art, find that it has X ray diffracting spectrum as shown in Figure 2, it is a kind of amorphous state, available data shows, the ginsenoside Rb1's of this amorphous state solubleness is relatively poor, and bioavailability is low.
Summary of the invention
The object of the present invention is to provide a kind of amorphous state ginsenoside Rb1.Compare with amorphous state ginsenoside Rb1 of the prior art, the ginsenoside Rb1 of the present invention's preparation has preferably solubleness, and purity is high.
A kind of amorphous state ginsenoside Rb1, it has X ray diffracting spectrum as shown in Figure 1.
The present invention also provides described amorphous state ginsenoside Rb1's preparation method, comprising:
Step 1: the ginsenoside Rb1 is dissolved in the solvent, and described solvent is the mixture of low-level chain triacontanol or low-level chain triacontanol and water;
Step 2: decompression and solvent recovery obtains the amorphous state ginsenoside Rb1.
As preferably, described low-level chain triacontanol is the alkanol that contains 1-4 carbon atom.
As preferably, water-content is 2wt%～5wt% in the mixture of described low-level chain triacontanol and water.
Preferably, the water-content of described low-level chain triacontanol is 3.5wt%～4.5wt%.
As preferably, described low-level chain triacontanol is one or more the mixture in methyl alcohol, ethanol, Virahol, the propyl carbinol.
Preferably, step 1 also comprises solvent is heated to its step below boiling point.
Preferably, the mass body volume concentrations of ginsenoside Rb1 in described solvent is 0.1g/ml～0.5g/ml.
Preferred, described ginsenoside Rb1's mass body volume concentrations is 0.1g/ml～0.3g/ml.
Preferably, described ginsenoside Rb1's mass body volume concentrations is 0.15g/ml～0.25g/ml.
The unformed state that it has been generally acknowledged that solid pharmaceutical can not have diversified form as the crystalline state material.But in fact, also can there be different forms in the unformed state of material, and this phenomenon is called the polymorphism of solid matter unformed shape, referred to as unformed polymorphic (polyamorphous).The reason that forms unformed polymorphic material may be to contain more polar group (glucosyl group and hydroxyl) in our sample, under unformed state, molecule is subject to the impact of polar group reactive force, thereby the Intermolecular Forces that different trend therefore occurred produces another kind of unformed state.
Amorphous state ginsenoside Rb1 provided by the invention has improved its solubleness and bioavailability.Its preparation method simply is easy to repetition, is fit to industrial-scale production.
Description of drawings:
Fig. 1 is the armorphous ginsenoside Rb1's of the present invention X-ray powder diffraction figure.
Fig. 2 is amorphous state ginsenoside Rb1's of the prior art X-ray powder diffraction figure.
Fig. 3 is amorphous state ginsenoside Rb1's of the present invention infrared spectrogram.
Fig. 4 is amorphous state ginsenoside Rb1's of the prior art infrared spectrogram.
Fig. 5 is amorphous state ginsenoside Rb1's of the present invention high-efficient liquid phase chromatogram.
Embodiment:
The invention discloses a kind of amorphous state ginsenoside Rb1 and preparation method thereof, those skilled in the art can use for reference this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are deemed to be included in the present invention.Product of the present invention and method are described by preferred embodiment, the related personnel obviously can change or suitably change and combination methods and applications as herein described within not breaking away from content of the present invention, spirit and scope, realizes and use the technology of the present invention.
A kind of amorphous state ginsenoside Rb1 provided by the invention has X ray diffracting spectrum as shown in Figure 1.
According to the present invention, the step for preparing amorphous state ginsenoside Rb1 of the present invention comprises:
Step 1: the ginsenoside Rb1 is dissolved in the solvent, and described solvent is the mixture of low-level chain triacontanol or low-level chain triacontanol and water;
Step 2: decompression and solvent recovery obtains the amorphous state ginsenoside Rb1.
According to the present invention, the ginsenoside Rb1's who uses for the present invention source, there is no particular restriction in the present invention, can use method well known to those skilled in the art to extract, the ginsenoside Rb1 preferably uses the ginsenoside Rb1 of nominal purity, purity is preferably greater than 98wt%, more preferably greater than 99.9wt%.
According to the present invention, first the ginsenoside Rb1 is dissolved in the carbon atom number and is 1～4, water-content is in the low-level chain triacontanol of 2wt%～5wt%, when dissolving, can under heating condition, carry out, preferably low-level chain triacontanol is heated to the temperature below the boiling point, the ginsenoside Rb1 is dissolved.Described low-level chain triacontanol can be a kind of in methyl alcohol, ethanol, Virahol, propyl carbinol, the side chain butanols or their mixture.Wherein, the water-content of low-level chain triacontanol is preferably 3.5wt～4.5wt%.When the dissolving ginsenoside Rb1, the mass body volume concentrations of ginsenoside in low-level chain triacontanol is preferably 0.1g/ml～0.5g/ml, and more preferably 0.1g/ml～0.3g/ml most preferably is 0.15g/ml～0.25g/ml.
After being dissolved in the ginsenoside Rb1 in the moisture low-level chain triacontanol, the reclaim under reduced pressure low-level chain triacontanol is to dry, during the reclaim under reduced pressure low-level chain triacontanol, for recovered temperature, be preferably the following temperature of boiling point of low-level chain triacontanol, preferably be lower than 5～10 ℃ of boiling points, there is no particular restriction for decompression pressure, as long as low-level chain triacontanol can be reclaimed.
Experimental result shows, after the present invention uses low-level chain triacontanol dissolving ginsenoside Rb1, after reclaiming low-level chain triacontanol again, the ginsenoside that obtains is proved to be and has improved solubleness, this is because the part water molecules has formed the crystalline hydrate of ginsenoside in the ginsenoside Rb1, has therefore improved ginsenoside Rb1's bioavailability and solubleness.According to the present invention, if when using water-content to be lower than the low-level chain triacontanol of 2wt%, then owing to can not form fully hydrate, therefore can not effectively improve ginsenoside Rb1's solubleness; If when using water-content to be higher than the low-level chain triacontanol of 5wt%, then owing to also can contain more moisture among the ginsenoside Rb1 after the reclaim under reduced pressure, can not form dry ginsenoside Rb1.
Below in conjunction with embodiment, further set forth the present invention:
Under heating condition, with 5g ginsenoside Rb1 ginsenoside Rb1, Kunming Medicine Group Stock Co., Ltd provides, purity 98.8%.) be dissolved in the 25ml methyl alcohol, stir about dissolved it in 10 minutes fully, under heating condition, solution was extremely done with the Rotary Evaporators decompression and solvent recovery, obtained the even armorphous ginsenoside Rb1 of 5g, yield 100%.
Under heating condition, the 5g ginsenoside Rb1 is dissolved in the mixture of 25ml ethanol and propyl carbinol, stir about dissolved it in 10 minutes fully, under heating condition, solution is extremely done with the Rotary Evaporators decompression and solvent recovery, obtained the even armorphous ginsenoside Rb1 of 5g, yield 100%.
Embodiment 3
Get the 5g ginsenoside Rb1 and be dissolved in the methyl alcohol that the 25ml water content is 2wt%, stirred 10 minutes, the ginsenoside Rb1 is dissolved fully, in above-mentioned dissolution process methyl alcohol is heated to 50 ℃ of insulations, then reclaim under reduced pressure methyl alcohol is extremely done under 50 ℃ of conditions.
Embodiment 4
Get the 5g ginsenoside Rb1 and be dissolved in the methyl alcohol that the 25ml water content is 5wt%, stirred 10 minutes, the ginsenoside Rb1 is dissolved fully, in above-mentioned dissolution process methyl alcohol is heated to 50 ℃ of insulations, then reclaim under reduced pressure methyl alcohol is extremely done under 50 ℃ of conditions.
Embodiment 5:X ray powder diffraction is analyzed
Instrument: Rigaku D/MAX-2200 type diffractometer
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 measurement of X-ray diffraction is based on diffraction and the interference of the electronics of dot matrix atom.Lattice structure is by the reflective display of X ray picture.Because its unordered result, armorphous material does not show spike in diffractogram, only has level and smooth curve to characterize.
Raw material ginsenoside Rb1 (hereinafter to be referred as material sample) to prior art carries out the X-ray diffraction test, and the result because it is metamict, does not therefore show spike as shown in Figure 2 in diffracting spectrum, level and smooth curve is only arranged.
The sample of getting embodiment 1 preparation carries out the X-ray diffraction test, the result as shown in Figure 1, the result of Fig. 1 shows that amorphous ginsenoside Rb1 provided by the invention has different X-ray diffraction results.Material sample shown in Figure 2 is higher than 20 ° of later positions at 2 θ and seamlessly transits; Compare with the material sample among Fig. 2, the X ray among Fig. 1 is that position between 23 °～30 ° has depression at 2 θ, is position between 35 °～45 ° at 2 θ, obvious structure cell peak occurred.
Embodiment 6: infrared spectra (IR) is analyzed
Instrument: Shimadzu FTIR-8400S infrared spectrometer
Amorphous state ginsenoside Rb1's of the present invention (pressing potassium bromide troche) infrared spectra, as shown in Figure 3, the ginsenoside Rb1 of prior art infrared spectra, as shown in Figure 4, illustrate that both are same materials.
Embodiment 7: amorphous state ginsenoside Rb1 purity detecting of the present invention
Instrument and reagent reagent: Agilent1100 high performance liquid chromatograph.
Chromatographic column: Luna C18150 * 4.6mm.
Acetonitrile is chromatographic grade, the HPLC water steaming distilled water of attaching most importance to.
Ginsenoside Rb1's reference substance: lot number: 8420-200102 is provided by Nat'l Pharmaceutical ﹠ Biological Products Control Institute;
The ginsenoside Rb1, embodiment 1-4 preparation.
Chromatographic condition and system suitability: be weighting agent with octadecylsilane chemically bonded silica; Take acetonitrile-water) (19: 81) be moving phase; The detection wavelength is 203nm.Number of theoretical plate calculates by the ginsenoside Rb1 should be not less than 3000.
Measure: get the about 10mg of this product, accurately weighed, put in the 50ml measuring bottle, add dissolve with methanol and be diluted to scale, shake up, precision is measured 20 μ l injection liquid chromatographies, the record color atlas; Other gets the about 10mg of ginsenoside Rb1's reference substance, measures with method, presses external standard method with calculated by peak area, and get final product.The results are shown in Table 1.
Table 1, amorphous state ginsenoside Rb1 purity detecting result of the present invention
| | Embodiment | 1 | |
Embodiment 3 | Embodiment 4 |
| Content (%) | 98.7 | 98.5 | 99.0 | 99.1 |
The result is shown in Fig. 5 and upper table, and armorphous ginsenoside Rb1's of the present invention content is up to more than 98%.
Embodiment 8: amorphous state ginsenoside Rb1 of the present invention and ginsenoside Rb1's solubleness are relatively
Get the amorphous state ginsenoside Rb1 of the present invention of embodiment 1-4 preparation, the ginsenoside Rb1 is an amount of, add respectively water, 0.9% sodium chloride aqueous solution, each 10ml of 3% Osmitrol, jolting is 30 minutes respectively, make it be dissolved to state of saturation, get mentioned solution, the HPLC method is measured ginsenoside Rb1's content.The results are shown in Table 2.
Table 2, amorphous state ginsenoside Rb1 of the present invention and ginsenoside Rb1's solubleness are relatively
| Condition/content (mg/ml) | Water | 0.9% sodium chloride aqueous solution | 3% N.F,USP MANNITOL is water-soluble |
| Amorphous state ginsenoside Rb1 of the present invention | 40.15 | 44.82 | 48.29 |
| The ginsenoside Rb1 | 33.65 | 35.18 | 40.57 |
Upper table shows that in the solubleness comparative studies, amorphous state ginsenoside Rb1 solubleness of the present invention is better in different solutions for amorphous state ginsenoside Rb1 of the present invention and ginsenoside Rb1.
Embodiment 9
Amorphous state ginsenoside Rb1 of the present invention and ginsenoside Rb1 induce the impact of rabbit extracorporeal platelet aggregation to compare on ADP
Instrument: LBY-NJ2 blood pool instrument: Pulisheng Instruments Co., Ltd., Beijing; LG10-2.4A supercentrifuge: Beijing supercentrifuge factory.
Reagent: adenosine diphosphate (ADP) (ADP): Sigma company product; Sodium Citrate: Tianjin chemical reagent three factories, lot number: 061107; Sodium chloride injection: Kuming Nanjiang Pharmacy Co., Ltd, lot number: A08070412; Chloral Hydrate (analytical pure): the special chemical in Rui Jin, Tianjin company limited, lot number: 20060917; Tween-80 (chemical pure CP): Chemical Reagent Co., Ltd., Sinopharm Group, lot number: F20050324.
Animal: healthy rabbits, ♀
Dual-purpose, body weight 2-2.5kg, Sichuan Province's medical scientific institute Institute of Botany provides product batch number: Dossy-2009-10.
Test sample: implement the amorphous state ginsenoside Rb1 of 1-4 preparation, the ginsenoside Rb1 is provided by Kunming pharmacy group.Being mixed with high density with distilled water before the experiment is that 3.5700mg/ml, middle concentration are that 1.7850mg/ml, lower concentration are that 0.8925mg/ml is as the solution of final concentration.Normal group is selected physiological saline, wherein adds tween 30 μ l in the tested medicine of each dosage and the physiological saline among every l0ml.Tested medicine all is mixed with clear and bright solution before treated in vitro.
Statistical method: the measurement data one-way analysis of variance, adopt statistical software to carry out statistical study, relatively adopt the Dunnett check between many groups.
Method: the Chloral Hydrate intraperitoneal injection of anesthesia rabbit with 10%, get blood from arteria carotis communis, be collected in the disposable plastic tube, adopt 3.2% Sodium Citrate anti-freezing, blood and antithrombotics volumetric ratio are 9: 1, put upside down immediately mixing (can not firmly rock) after getting.Blood adopts respectively the centrifugal 6min of 800r/min in room temperature, and the gained upper plasma is the PRP of different rotating speeds.With the centrifugal 15min of 3000r/min, upper strata liquid is PPP to residual blood again.In the process of the test, the platelet count among the PRP is controlled at and is about 500,000 mm
-3
Adopt platelet aggregation instrument to measure by BornShi turbidimetry principle.Get respectively different rotating speeds PPP 300 μ l in than zeroing in the turbid cup, get PRP 270 μ l and add solvent or tested liquid 30 μ l, incubation 5min in 37 ℃ of preheating gates in another in than turbid cup.During mensuration the PPP cup is inserted in the test hole and returns to zero, take out the PPP cup and insert the PRP cup, and add stirrer in PRP, then adding final concentration under the instrumentation prompting is the inductor ADP 10 μ l of 15 μ mol/L, induced platelet is assembled, and measures thrombocyte MA in the 5min
[3]L-Arginine is calculated as follows: assemble inhibiting rate (%)=(1-administration group aggregation rate/control group aggregation rate) * 100%.
Amorphous state ginsenoside Rb1 of the present invention and ginsenoside Rb1 the results are shown in Table 3 to the impact that ADP induces the effect of rabbit extracorporeal platelet aggregation:
Table 3, amorphous state ginsenoside Rb1 of the present invention and ginsenoside Rb1 on ADP induce rabbit extracorporeal platelet aggregation rate impact (
N=6)
Annotate: each group is compared with Normal group: * * P＜0.01;
As can be seen from Table 3: amorphous state ginsenoside Rb1 high density of the present invention and middle concentration and ginsenoside Rb1's high density and Normal group compare, and difference all has significant (P＜0.01); Compare no significant difference (P＞0.05) between amorphous state ginsenoside Rb1 of the present invention and ginsenoside Rb1's group.But from inhibiting rate, amorphous state ginsenoside Rb1 effect of the present invention is good than the ginsenoside Rb1.
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (8)
1. an amorphous state ginsenoside Rb1 is characterized in that, has X ray diffracting spectrum as shown in Figure 1.
2. amorphous state ginsenoside Rb1's claimed in claim 1 preparation method is characterized in that, comprising:
Step 1: the ginsenoside Rb1 is dissolved in the solvent, and described solvent is the mixture of low-level chain triacontanol and water, and water-content is 2wt%～5wt% in the mixture of described low-level chain triacontanol and water, and described low-level chain triacontanol is the alkanol that contains 1-4 carbon atom;
Step 2: decompression and solvent recovery obtains the amorphous state ginsenoside Rb1.
3. preparation method according to claim 2 is characterized in that, the water-content of described low-level chain triacontanol is 3.5wt%～4.5wt%.
4. according to claim 2 or 3 described preparation methods, it is characterized in that described low-level chain triacontanol is one or more the mixture in methyl alcohol, ethanol, Virahol, the propyl carbinol.
5. preparation method according to claim 4 is characterized in that, step 1 also comprises solvent is heated to its step below boiling point.
6. preparation method according to claim 5 is characterized in that, the mass body volume concentrations of ginsenoside Rb1 in described solvent is 0.1g/ml～0.5g/ml.
7. preparation method according to claim 6 is characterized in that, described ginsenoside Rb1's mass body volume concentrations is 0.1g/ml～0.3g/ml.
8. preparation method according to claim 6 is characterized in that, described ginsenoside Rb1's mass body volume concentrations is 0.15g/ml～0.25g/ml.
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| CN101445544A (en) * | 2007-11-28 | 2009-06-03 | 北京本草天源药物研究院 | Method for preparing ginsenoside Rb<1> |
| CN101463061A (en) * | 2007-12-21 | 2009-06-24 | 中国医学科学院药物研究所 | Ginseng saponin Rg1 and Rb1 in pseudo-ginseng and preparation of total saponin thereof |
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| CN101445544A (en) * | 2007-11-28 | 2009-06-03 | 北京本草天源药物研究院 | Method for preparing ginsenoside Rb<1> |
| CN101463061A (en) * | 2007-12-21 | 2009-06-24 | 中国医学科学院药物研究所 | Ginseng saponin Rg1 and Rb1 in pseudo-ginseng and preparation of total saponin thereof |
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