CN100418535C - Aescin medicine composition and its prepn process and use - Google Patents
Aescin medicine composition and its prepn process and use Download PDFInfo
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- CN100418535C CN100418535C CNB2006100726004A CN200610072600A CN100418535C CN 100418535 C CN100418535 C CN 100418535C CN B2006100726004 A CNB2006100726004 A CN B2006100726004A CN 200610072600 A CN200610072600 A CN 200610072600A CN 100418535 C CN100418535 C CN 100418535C
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- aescine
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Abstract
The present invention relates to aescin medicine composition and its preparation process and use. The aescin product of purity over 90 % may be compounded with medicine carrier to form composition with obvious synergistic effect, reduced stimulation of aescin on blood vessels and muscles, and obviously raised effects of diminishing inflammation, antagonizing effusion, improving blood circulation, etc. The composition features its less stimulation, high safety, high treating index, etc.
Description
Technical field
The invention belongs to drug world, particularly pharmaceutical composition of aescine and preparation method thereof and its purposes.
Background technology
Aescine claims aescine acid again, for extract the general name of total saponins, β-aescine or the different aescine etc. that obtain from Hippocastanaceae buckeye seed.At present manyly be applied to clinically with total aescine (Totalescin) sodium, mainly contain 4 kinds of main components.China's national standard goes out the peak successively by liquid chromatograph, successively called after aescine A (this day this aspect escin I
a), aescine B (escin I
b), aescine C (isoescin I
a) and aescine D (isoescin I
a).Aescine A and B are β-type aescine, and its structure is basic identical, but and C
21-hydroxyl becomes the organic acid difference of ester, is the crotonic acid or the angelic acid of positive each other trans isomer, thereby aescine A and B can merge with structural formula (1) and represent.Aescine C and D are respectively the C of aescine A and B
21Acetas is indexed into C on the-hydroxyl
28The isomer of-hydroxyl; Aescine C and D be isomer each other also, is Crypto-type (abnormal shape) aescine, claims different aescine or special-shaped aescine again, can merge with structure (2) and represent.
Total aescine is the material that contains β-aescine and different aescine simultaneously, has antiinflammatory, exudation and improves the blood circulation isoreactivity, has been widely used in cerebral edema, traumatic edema, venous return obstacle or burn etc. that the treatment a variety of causes causes.But because of the strong stimulation effect of aescine, can not be used for intramuscular injection, and during the vein repetitively administered, also easily cause phlebitis, again because of LD to muscle and mucosa
50Smaller, Ti (therapeutic index relatively) only is about 5, and therapeutic dose and toxic dose are more approaching, have limited this medicine and have used clinically.Document CN1575797A discloses use aescine treatment postoperative intestine functional and has recovered.Document CN1548052A discloses use aescine treatment pulmonary's acute inflammation and pulmonary edema.
On this basis, there are many pieces of documents to disclose again to the structural modification of aescine chemical compound and the applied in any combination by isomer composition.Japanese kokai publication hei JP10-17591 discloses the inflammatory applications of β-aescine.CN1073573C has isolated from β-aescine on this basis has hypotoxic two isomerized unification compounds on glycosyl.CN1156278C discloses and has contained β-aescine and different aescine isomer.CN1376675A discloses by on the basis of aescine, with behind arginine salt and the aescine salify to solve compound dissolution and its angiospastic toxicity of reduction.
Document (Arzneim-Forsch 20 (2) 209-215,1970) show with experiment: β-aescine is in different aescine isomerization process, in the time of its active reduction, its toxicity also reduces in proportion, concentration ratio arrival 6 when β-type and special-shaped aescine: 4-5: (form α-aescine this moment) during 5 scopes, this mixture has a therapeutic index that equates with β-aescine to claw due to the rat Ovum Gallus domesticus album is swollen, and to the therapeutic activity of the swelling of burning than nearly 1 times of β-aescine height.Therefore document thinks that its therapeutic activity had superposition when β-type and special-shaped aescine coexisted in certain ratio range.
In May, 05, our factory has been submitted the patent application (application number is 2005101055854) of relevant lysine aescin saponin to State Intellectual Property Office, this application discloses lysine aescin saponin and has compared with aescine, have better antiinflammatory, exudation and improve the blood circulation isoreactivity, and can effectively reduce the zest of aescine to blood vessel and muscle, improve the safety in utilization and the therapeutic index of medicine, but its preparation process relative complex.The full text content of No. 2005101055854 applications is drawn the reference for the application.
Summary of the invention
Purpose one of the present invention provides a kind of aescine compositions of low stimulation, and described compositions is made up of aescine or its pharmaceutically acceptable salt, pharmaceutical carrier and pharmaceutically acceptable carrier.
Further, described aescine is selected from β-aescine, different aescine or total aescine, is preferably total aescine.
Further, the β-aescine in total aescine and the weight ratio of different aescine are controlled at 3-9: 7-1 is preferably 4-8: 6-2, more preferably 5-7: 5-3 is preferably 5: 5-6: 4.
Further, described pharmaceutical carrier is selected from one or more in glutathion, lysine acetate, lysine hydrochloride, human albumin or the mannitol, is preferably lysine hydrochloride, lysine acetate or glutathion.
Further, the weight ratio of aescine and pharmaceutical carrier is 1-10: 10-1, is preferably 2-9: 9-2, more preferably 3-8: 8-3, other is preferably 4-7: 7-4 most preferably is 5-6.5: 1.
Aescine and pharmaceutical carrier use in conjunction, not only can reduce the toxic and side effects and the zest of chemical compound, and the antiinflammatory of raising aescine, exudation and the sanguimotor curative effect of improvement, its therapeutic index and safety are significantly improved, and pharmaceutical carrier can improve blood-brain barrier permeability, the fine chemical compound that carries sees through blood brain barrier, make medicine can enter in the brain, be used for the treatment of brain inflammation, brain oozes out, cerebral edema, traumatic edema, the venous return obstacle, burn, postoperative intestine functional recovers, pulmonary's acute inflammation or pulmonary edema, and also it can be prepared into ointment, external preparation such as spray or gel is in order to handle trauma wounds.Example hydrochloric acid lysine or lysine acetate injection are the treatment craniocerebral trauma; the cerebral protective agent of chronic brain tissue ischemia, anoxia disease of brain; and aescine has antiinflammatory, exudation, improves pharmacological actions such as blood circulation; to treating the cerebral edema cephalophyma that the various causes of disease cause significant curative effect is arranged; and alleviate injury of kidney to the renal insufficiency person; reduce toxicity, improve the safe dose of medicine.Therefore, lysine and aescine coupling have the complementary action on the pharmacology, and the present application human animal experiment proves, the weight ratio of aescine and lysine is at 1-10: in the 10-1 scope, not only can alleviate the blood vessel and the muscular irritation effect of aescine, can also improve its antiinflammatory, exudation and improve effects such as blood circulation.As seen, characteristics such as pharmaceutical composition of the present invention has low to stimulate, safety low-poison, high therapeutic index are widened the scope of application of medicine greatly.
Further, described pharmaceutically acceptable salt is selected from sodium salt or potassium salt, is preferably sodium salt, more preferably total aescine.
Compositions of the present invention can be various dosage form well known in the art, and adopts the preparation technique of this area routine to prepare.Being fit to pharmaceutical composition of the present invention comprises and is applicable to enteral (for example oral or rectally), part and parenteral or by sucking the preparation of spraying to mammal (comprising the people) administration, forms such as for example oral, injection, implantation, external are preferably injection.
Further, be fit to injection of the present invention and be selected from injection, injectable sterile powder or aseptic block, concentrated solution for injection or lyophilized formulations; Be preferably lyophilized formulations or injection.
Further, be fit to oral formulations of the present invention and be selected from tablet, suspension, oral liquid, capsule, granule, pill, powder, drop pill, syrup, mixture, distillate medicinal water, effervescent, paste or medicinal tea etc.; Be preferably powder, suspension, granule, tablet, capsule or effervescent.
Because pharmaceutical composition of the present invention has alleviated the zest and the toxic and side effects of aescine, make the aescine that is not suitable for directly acting on trauma wounds can be directly used in the processing trauma wounds, be used for the treatment of wound, traumatic wound, inflammation, ooze out, effect such as edema.
Further, be suitable for external preparation of the present invention and be selected from spray, membrane, gel, patch, colloid, emplastrum, plaster, cream, ointment, liniment, lotion, suppository, liniment or coagulate unguentum etc., be preferably gel or coagulate unguentum.
Described pharmaceutically acceptable carrier is well known usual excipients or the adjuvant that is used to prepare above-mentioned preparation, and excipient that oral formulations or external preparation are commonly used or adjuvant include but are not limited to filler (claim not only diluent), lubricant (but also claiming fluidizer or antitack agent), dispersant, wetting agent, binding agent, regulator, solubilizing agent, antioxidant, antibacterial, emulsifying agent, correctives, odorant etc.Binding agent, for example syrup, arabic gum, gelatin, sorbitol, tragacanth, cellulose and derivant thereof, gelatine size, syrup, starch slurry or polyvinylpyrrolidone etc.; Filler, for example lactose, Icing Sugar, dextrin, starch and derivant thereof, cellulose and derivant thereof, inorganic calcium salt, sorbitol or glycine etc.; Lubricant, for example micropowder silica gel, magnesium stearate, Pulvis Talci, aluminium hydroxide, boric acid, hydrogenated vegetable oil, Polyethylene Glycol etc.; Disintegrating agent, for example starch and derivant thereof, polyvinylpyrrolidone or microcrystalline Cellulose, preferred starch derivatives is carboxymethyl starch sodium, Explotab, pregelatinized Starch, modified starch, hydroxypropyl starch, corn starch; Wetting agent, for example sodium lauryl sulphate, water or alcohol etc.
Excipient or adjuvant that described injection is commonly used include but are not limited to: antioxidant, for example sodium sulfite, sodium sulfite, dibutyl benzoic acid, V
COr sodium pyrosulfite; Antibacterial, for example 0.5% phenol, 0.3% cresol or 0.5% chlorobutanol; Acid-base modifier, for example hydrochloric acid, citric acid, potassium hydroxide (sodium), sodium citrate; Buffer agent is as phosphoric acid dioxy sodium or sodium hydrogen phosphate; Isoosmotic adjusting agent is as sodium chloride or glucose; Emulsifying agent, for example Tween-80, do not have that sour Pyrusussuriensis is smooth, pluronic gram F-68, lecithin, fabaceous lecithin; Solubilizing agent, for example tween 80, glycerol etc.; Dispersant is as water, alcoholic solution etc.
In addition, also active component and pharmaceutically acceptable slow controlled release carrier can be prepared its sustained-release preparation according to the preparation method of sustained-release preparation well known in the art, as add the blocker coating or with making micropill after the active principle microcapsulesization again, as slow-release micro-pill or controlled release micro pill; Described slow controlled release carrier includes but are not limited to oil agent, hydrophilic colloid or the coating blocker etc. of mixing, and described oil to mix agent be glyceryl monostearate, castor oil hydrogenated, Dormant oils, polysiloxanes, dimethyl siloxane; Described hydrophilic colloid is cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, or PVP, arabic gum, tragcanth or carbopol etc.; Described coating blocker is ethyl cellulose (EC), hydroxypropyl methylcellulose (HMPC), polyvinylpyrrolidone (PVP), cellulose acetate-phthalate (CAP), acrylic resin etc.
The unit dose of pharmaceutical composition of the present invention (in aescine) is selected from 5mg, 10mg, 15mg or 20mg." unit dose " of the present invention is meant the least unit that can use separately in the processes such as clinical, operation, production, use, as, grain, sheet, ball etc.
Further, " related substance " content in the pharmaceutical composition of the present invention is no more than 10.0%, preferably is no more than " 9.0% ", more preferably no more than 8.0%.
State Food and Drug Administration is in order to guarantee the drug quality of aescine related preparations, and regulation is measured with the high performance liquid chromatography normalization method, and except that aescine A, B, C and D and solvent peak, the content of other " related substance " must not surpass 10%.And described " related substance " is meant with high performance liquid chromatography normalization method mensuration, material except that aescine A, B, C and D and solvent peak mainly comprises following two class materials: a class is inherent other type β-aescine or the different aescine except that structural formula (1) or (2) of extract; Another kind of is the seven folic alcohol compounds that aescine A, B, C and D and other type β-aescine or different aescine hydrolysis form, and the generation of seven folic alcohol compounds is relevant with process conditions and selection of process parameters.Because of other types β-aescine is subject to the influence of temperature and solution PH, in aqueous solution or Diluted Alcohol, very easily be isomerizated into different aescine, and different aescine facile hydrolysis is seven folic alcohol compounds.Therefore, the present invention passes through the generation of control second class " related substance ", and removes other type β-aescine of part, controls the content of " related substance " in the aescine.
The present invention adopts highly purified aescine or its pharmaceutically acceptable salt directly to mix with pharmaceutical carrier, obtain compositions, not only processing technology is simple, reduce manufacturing procedure, improve stability of drug, and aescine and pharmaceutical carrier coupling, has good synergistic function, can significantly improve safety and effectiveness, as improve the antiinflammatory of aescine, exudation and the sanguimotor activity of improvement, and significantly reduce the zest of its blood vessel and muscle, and significantly increase the amount of aescine by blood brain barrier, improve curative effect to brain edema and trauma wounds.
Another object of the present invention provides a kind of highly purified aescine, and the purity of described aescine is not less than 93.0%, preferably is not less than 95.0%, more preferably is not less than 98.0%, most preferably is not less than 98.5%.
Another object of the present invention provides a kind of method for preparing the high-purity aescine, 1) ion exchange: with the distilled water solution of aescine potassium, sodium salt-mixture crude product, by the Hydrogen cation exchange column, cold preservation is placed and is separated out crystallization or add seeded crystallization, promptly; Or
2) add the mineral acid sedimentation method: with the distilled water solution of aescine potassium, sodium salt-mixture crude product, add acid solution, regulating aqueous solution pH is 1-3, and cold preservation is placed and separated out crystallization or add seeded crystallization, and preferred described acid solution is sulphuric acid or hydrochloric acid; Or
3) liquid chromatography: aescine potassium sodium salt-mixture or aescine acid crude are dissolved in the alcoholic solution, by reversed-phase high-performance liquid chromatography or fast liquid chromatography, separate through mobile phase, the mobile phase in aescine A, B, C and D peak district appears in collection, vacuum distilling is removed acetic acid and alcohols, cold preservation is placed and is separated out crystallization or add seeded crystallization, promptly; Preferred described alcoholic solution is selected from ethanol, methanol, acetonitrile or isopropyl alcohol etc., more preferably ethanol or methanol; Described mobile phase is selected from the solution of methanol or ethanol composition, is preferably 50% ethanol or 70% methanol solution that contain 1% acetic acid, and the preferred column filler is C18 or C8 bonded silica gel; Or
4) aescine potassium sodium salt-mixture or aescine acid crude are dissolved in the alcoholic solution, pass through normal-phase chromatography, with silica gel or aluminium oxide is adsorbent, with chloroform-methanol-water or isopropyl alcohol-water or ethyl acetate-methanol-water or n-butyl alcohol-acetic acid-water is mobile phase, the mobile phase in aescine A, B, C and D peak district appears in collection, behind the vacuum concentration, cold preservation is placed and is separated out crystallization or add seeded crystallization, promptly.
Another object of the present invention provides a kind of method for preparing high-purity aescine salt, it is characterized in that, highly purified aescine is dissolved in the high concentration alcoholic solution, add equivalent alkaline matter alcoholic solution, cold preservation is placed and is separated out crystallization or add seeded crystallization, promptly.
Further, the purity that limits aescine salt is not less than 93.0%, preferably is not less than 95.0%, more preferably is not less than 98.0%, most preferably is not less than 98.5%.
Further, the concentration of described alcoholic solution is 80-99v/v%, is preferably 85-95v/v%, more preferably 90v/v%.
Further, preferred described alcoholic solution is selected from ethanol, methanol, acetonitrile or isopropyl alcohol etc., more preferably ethanol or methanol.
Further, described alkaline matter is selected from sodium hydroxide or potassium hydroxide, is preferably sodium hydroxide.
Another object of the present invention provides a kind of low stimulation aescine preparation of compositions method, behind aescine and pharmaceutical carrier uniform mixing, adds suitable pharmaceutically acceptable carrier, according to the conventional preparation method processing of required preparation, promptly.As with behind aescine and the pharmaceutical carrier uniform mixing, be dissolved in the injection water, the lyophilization aqueous solution promptly gets its lyophilized formulations; Or, place the levigate mixing of ball mill or colloid mill with melt into aqueous solution behind aescine and the pharmaceutical carrier uniform mixing, promptly get its Emulsion or oral formulations.
Further, described aescine is selected from β-aescine, different aescine or total aescine, is preferably total aescine.
Further, the β-aescine in total aescine and the weight ratio of different aescine are controlled at 3-9: 7-1 is preferably 4-8: 6-2, more preferably 5-7: 5-3 is preferably 5: 5-6: 4.
Further, described pharmaceutical carrier is selected from one or more in glutathion, lysine acetate, lysine hydrochloride, human albumin or the mannitol, is preferably lysine hydrochloride, lysine acetate or glutathion.
Further, the weight ratio of aescine and pharmaceutical carrier is 1-10: 10-1, is preferably 2-9: 9-2, more preferably 3-8: 8-3, other is preferably 4-7: 7-4 most preferably is 5-6.5: 1.
Further, described pharmaceutically acceptable salt is selected from sodium salt or potassium salt, is preferably sodium salt, more preferably total aescine.
Further, the preparation that is fit to the present composition is selected from oral formulations, injection or external preparation, is preferably injection.
Further, be fit to injection of the present invention and be selected from injection, injectable sterile powder or aseptic block, concentrated solution for injection or lyophilized formulations; Be preferably lyophilized formulations or injection.
Further, be fit to oral formulations of the present invention and be selected from tablet, suspension, oral liquid, capsule, granule, pill, powder, drop pill, syrup, mixture, distillate medicinal water, effervescent, paste or medicinal tea etc.; Be preferably powder, suspension, granule, tablet, capsule or effervescent.
Further, be suitable for external preparation of the present invention and be selected from spray, membrane, gel, patch, colloid, emplastrum, plaster, cream, ointment, liniment, lotion, suppository, liniment or coagulate unguentum etc., be preferably gel or coagulate unguentum.
Another object of the present invention is to provide the aescine compositions in preparation at preparation antiinflammatory, exudation with improve application in the blood circulation medicine.
Further, the pharmacy of pharmaceutical composition of the present invention is used and is comprised the application that is used for preparing treatment brain edema drugs, as be used for the treatment of that brain inflammation, brain ooze out, diseases such as brain edema, traumatic edema, venous return obstacle, burn, postoperative intestine functional recovery, pulmonary's acute inflammation, pulmonary edema, craniocerebral trauma, chronic brain tissue ischemia or anoxia disease of brain.
Further, the pharmacy of pharmaceutical composition of the present invention is used and to be comprised and be used for preparing the application of handling the trauma wounds medicine, as is used for the treatment of wound, traumatic wound, inflammation, oozes out or disease such as edema.
Drug dose of the present invention or weight ratio are all carried out longitudinal comparison according to corresponding aescine or lysine as mete-wand and are got, and when total aescine or its salt are compared, are mete-wand with total aescine just; When β-aescine or its salt are compared, be mete-wand just with β-aescine; When different aescine or its salt are compared, be mete-wand just, as when relating to the dosage of lysine, lysine hydrochloride or lysine acetate or weight ratio with different aescine, all with lysine as mete-wand.
Except as otherwise noted, percentage ratio of the present invention all is weight percentage.
The specific embodiment
Specify the present invention below with reference to embodiment, the embodiment of the invention only is used to illustrate technical scheme, and limits essence of the present invention.
Embodiment 1Prepare aescine potassium sodium salt-mixture with the cholesterol sedimentation method
The Semen Aesculi fine powder is with 5 times of amounts, concentration is extracted three times for the 50v/v%-70v/v% alcoholic solution stirs, each 4 hours, collect merge extractive liquid,, vacuum reclaims ethanol to 1/5 of extracting liquid volume, extract β-aescine content in the concentrated solution with high effective liquid chromatography for measuring, mass ratio with β-aescine and cholesterol is 1: 1.2 then, under stirring condition, add cholesterol, add back restir 2 hours, placement is spent the night, next day centrifugal collection cholesterol deposit, be washed to colourless, after 60 ℃ of oven dry,, make cholesterol dissolve in solvent with chloroform or O for toluene, and the salt of aescine (sodium, potassium salt) still exist with solid-state form, with 90%-95% ethyl alcohol recrystallization twice, get white aescine salt (sodium, potassium salt), purity is 98.5%.
Embodiment 2The preparation of β-aescine and different aescine
1. the cholesterol sedimentation method
The Semen Aesculi fine powder, with 5 times of amounts, concentration is that 50v/v%～70v/v% Diluted Alcohol stirs extraction three times, each 4 hours, collect merge extractive liquid,, vacuum reclaims ethanol to 1/5 of extracting liquid volume, extracts β-aescine content in the concentrated solution with high effective liquid chromatography for measuring, and the mass ratio with β-aescine and cholesterol is 1: 1.2 then, under stirring condition, add cholesterol, added the back restir 2 hours, placement is spent the night, next day centrifugal collection cholesterol deposit, be washed to colourlessly, after 60 ℃ of oven dry, precipitate is done the back with chloroform or O for toluene, cholesterol is dissolved in the solvent, and the salt of aescine (sodium, potassium salt) still exist with solid-state form.After flinging to residual solvent, use water dissolution,, get the milky colloidal solution by the hydrogen type cation exchange resin post, add 0.5% acetic acid by liquor capacity, crystallization is separated out in cold preservation, behind the filter collection,, be able to the β-aescine crystallization of structural formula (1) expression with a small amount of cold distilled water flush away acetic acid.Yield is 0.8～1.3%, and content is 90～95%.
Solution merges behind the solution of elimination cholesterol deposit and the filtering β-aescine, passes through D
101Macroporous adsorptive resins behind water flush away acetic acid, inorganic salt, the pigment, reclaims ethanol with the ethanol elution vacuum, and crystallization is separated out in cold preservation, and yield is 0.2～0.7%, and content is 88～93%.
With methanol: 1% vinegar acid liquid (7: 3) is that mobile phase is, total aescine that extraction is obtained is dissolved in the mobile phase, goes up anti-phase ODS post, and the preparation of carrying out high performance liquid chromatography or fast liquid chromatography with mobile phase separates.Press the described order of aescine national standard, collect aescine A and aescine B position successively, vacuum concentration gained concentrated solution is placed at cold place, separates out crystallization, and the filter collection is used distilled water wash, and 40 ℃ of vacuum dryings get β-aescine, and content is 99.1%.Physicochemical property is as follows:
mp.223～225℃
FAB-MS(m/z)1153(M+Na)
+
13C-NMR(δ/ppm)：91.2(C
3)，122.6(C
12)，142.8(C
13)，79.2(C
21)，74.5(C
22)，64.0(C
28)；171.8(C
6′)，171.0(C
1″″)。
1H-NMR(δ/ppm)：5.38(H-12)，4.42(H-16β)，2.97(H-18)，6.49(H-21)，6.13(H-22)
Press the described order of aescine national standard, collect aescine C and aescine D position successively, the different aescine of vacuum concentration gained position concentrated solution carries out D
101Macroporous adsorbent resin column chromatography after the absorption, is used the distilled water washing resin post, remove acetic acid or sodium acetate after, use ethanol elution, eluent boils off ethanol in 50 ℃ of following vacuum, 40 ℃ of vacuum dryings, the pure product of different aescine, its content is 98.8%.Its physicochemical characteristics is as follows:
mp.217～219℃
FAB-MS(m/z)：1153(M+Na)
+
13C-NMR(δ/ppm)：91.2(C
3)，122.8(C
12)，142.8(C
13)，81.6(C
21)，71.5(C
22)，66.5(C
28)；171.8(C
6′)，170.6(C
1″′)。
1H-NMR(δ/ppm)：2.82(H-18)，4.47(H-22)，4.72(H-16β)，5.44(H-12)。
Embodiment 2Prepare aescine acid with the ore deposit Acid precipitation
The Semen Aesculi fine powder is that the 50v/v%-70v/v% Diluted Alcohol stirs and extracts three times with 5 times of amounts, concentration for, concentration, each 4 hours, collect merge extractive liquid,, 50 ℃ of vacuum reclaim ethanol to original volume 1/5th, filter, add 2mol sulphuric acid in the filtrate, the pH of regulator solution is to 1-2.8, cold preservation is placed and is separated out crystallization, gets white aescine acid crystal.Purity is 97.0%.
Embodiment 3The preparation of high-purity aescine
1, be that 98.5% aescine salt (potassium, sodium salt) is dissolved in the distilled water with purity, obtain concentration and be about 2% aqueous solution, aqueous solution is by the Hydrogen cation exchange column, aescine salt is about 0.8-1.2: 1.2-0.8 with the weight resin ratio, obtain the solution that pH is about 2.0-2.8, place at cold place or crystallization is separated out in the cold preservation placement.Crystallization is dissolved in the 95v/v% ethanol again, adds equivalent sodium hydroxide ethanol liquid, and place at cold place or crystallization is separated out in the cold preservation placement, and obtaining purity is 99.0% aescine crystallization.
2, be that 97.5% aescine salt (potassium, sodium salt) is dissolved in the distilled water with purity, obtain concentration and be about 2% aqueous solution, add 2mol sulphuric acid or hydrochloric acid, the pH to 1-3 of regulator solution, place at cold place or cold preservation is placed and separated out crystallization.Crystallization is dissolved in the 96v/v% ethanol again, adds equivalent sodium hydroxide ethanol liquid, and place at cold place or cold preservation is placed and separated out crystallization, obtains purity and be 98.5% aescine crystallization.
3, be that 96.5% aescine (potassium, sodium salt) is dissolved in 50% ethanol or 70% methanol with purity, with 50% ethanol that contains 1% acetic acid or 70% methanol is mobile phase, by being that filler high performance liquid chromatography or fast liquid chromatography separate with C18 or C8 bonded silica gel, the mobile phase in aescine A, B, C, D district appears in collection, 50 ℃ of vacuum distillinges are removed acetic acid and alcohols, and place at cold place or crystallization is separated out in the cold preservation placement.Crystallization is dissolved in the 97v/v% ethanol again, adds equivalent sodium hydroxide ethanol liquid, and place at cold place or cold preservation is placed and separated out crystallization, obtains purity and be 99.2% aescine crystallization.
4, be that 95.5% aescine (potassium, sodium salt) is dissolved in 50% ethanol or 70% methanol with purity, is adsorbent by positive high performance liquid chromatogram or fast liquid chromatography with silica gel or aluminium oxide, with chloroform-methanol-water or isopropyl alcohol-water or ethyl acetate-methanol-water or n-butyl alcohol-acetic acid-water is that mobile phase is separated, obtain aescine A, B, C, D component, make saponin sodium by aforementioned salifying method, purity is 98.9%.
Embodiment 4The preparation of the notoginsenoside sodium freezing-dried preparation of unit dose
Take by weighing aescine according to table 1, add an amount of lysine hydrochloride or lysine acetate, it is dissolved in the water for injection, lyophilization promptly.
The composition of the notoginsenoside sodium freezing-dried preparation of table 1
Below verify the excellent anti-inflammatory activity and the low toxicity of The compounds of this invention by the pharmacologically active testing experiment.
Test example 1The comparison of the aescine anti-inflammatory activity of " related substance " different content
The content of " related substance " is respectively 7%, 10%, 13%, 15%, 17%, 20% 6 samples and the relation between its anti-inflammatory activity in the research aescine.
Body weight is 300 of the healthy male mouse of kunming of 25-30g, is divided into big group of six samples according to the content of " related substance " in the aescine, and the intravenous injection dosage range is 0.125-1.00mg.kg
-1Or 0.15-1.20mg.kg
-1Aescine 0.4ml, big group of each sample is divided into 4 dosage groups by geometric progression, 10 mices of each dosage group, this is tested described drug dose and all carries out longitudinal comparison according to aescine as mete-wand, and establish the equal-volume normal saline, and calculate ED from 4 groups of results as the blank group
50
Intravenous injection various dose aescine sodium solution or normal saline are after 30 minutes, every Mus auris dextra is smeared dimethylbenzene 0.06ml, after 2 hours, put to death mice successively, lay the ears disk with 9.00mm diameter card punch, weigh, obtain the swelling degree (it is heavy that auris dextra deducts left ear) of each Mus, the results are shown in Table 2-8.
Table 2 " related substance " content is the anti-inflammatory activity of 7% aescine
Table 3 " related substance " content is the anti-inflammatory activity of 10% aescine
Table 4 " related substance " content is the anti-inflammatory activity of 13% aescine
Table 5 " related substance " content is the anti-inflammatory activity of 15% aescine
Table 6 " related substance " content is the anti-inflammatory activity of 17% aescine
Table 7 " related substance " content is the anti-inflammatory activity of 20% aescine
Illustrate:
* *Expression P＜0.001,
*Expression P＜0.01
Antiinflammatory ED with the aescine of various content
50Be summarized in table 8.
The relation of " related substance " content and anti-inflammatory activity in table 8 aescine
Learnt by table 8: " related substance " content in the aescine is higher, its ED
50Bigger, anti-inflammatory activity is lower, and promptly " related substance " content becomes negative correlation with the anti-inflammatory activity of aescine.
Test example 2The aescine of " related substance " different content is to the comparison of blood vessel irritation
The content of " related substance " is respectively 7%, 10%, 13%, 17%, 20% 5 samples and the relation between its blood vessel irritation in the research aescine.
Body weight is 2 kilograms 18 of healthy rabbits, is divided into 6 groups, and 3 every group, contain this aescine sodium sample each 1mg from rabbit the same side auricular vein normal saline solution 1ml of injected sample slowly every day, injected continuously 11 days.With the normal saline is blank, the blood vessel irritation result that detects by an unaided eye, 20 ℃ of experimental temperatures.The results are shown in Table 9.
Table 9 " related substance " content and aescine vascular stimulation reaction relation
Annotate: irritant reaction is not observed in-number expression; The relative extent of irritant reaction is observed in+number expression.
Learn that by table 9 greater than the high aescine of " related substance " content, i.e. blood vessel irritation reaction is opposite with its anti-inflammatory activity to blood vessel irritation for the low aescine of " related substance " content.Therefore, in order to keep aescine antiinflammatory, exudation and to improve curative effects such as blood circulation, and remove the zest of its blood vessel and muscle, the present invention adopts aescine directly to mix with lysine and pharmaceutically acceptable carrier, makes its compositions.
Test example 3Aescine-lysine hydrochloride compositions or aescine-lysine acetate compositions is to the stimulation research of blood vessel
Aescine-lysine hydrochloride compositions represents that with NaEsc-Lys.Hcl aescine-lysine acetate compositions is represented with NaEsc-Lys.HAC.
Body weight is that 2 kilograms 24 of rabbit are divided into 8 groups, and 3 every group, various compositionss are that benchmark calculates dosage with contained aescine, and every rabbit 1ml every day: 5mg is for three days on end from same auricular vein injection.Test method is as follows:
Slowly inject NaEsc-Lys.Hcl (10: 1) compositions physiological salt liquid 1ml from the edge vein of picking up the ears for first group, contain aescine 5mg.
Second group of method according to first group injected NaEsc-Lys.Hcl (1: 1) compositions physiological salt liquid 1ml, contains aescine 5mg.
The 4th group shines first group of methods injection NaEsc-Lys.Hcl (1: 6.5) compositions physiological salt liquid 1ml, contains aescine 5mg.
The 5th group shines first group of methods injection NaEsc-Lys.HAC (1: 10) compositions physiological salt liquid 1ml, contains seven leaf soap sodium 5mg.
The 6th group shines first group of methods injection aescine physiological salt liquid 1ml, contains aescine 5mg.
The 7th group according to the first group of methods injecting normal saline 1ml.
The 8th group of compositions physiological salt liquid 1ml according to first group of methods injection NaEsc-Lys.HAC (10: 1) contains aescine 5mg.
The 9th group shines first group of methods injection NaEsc-Lys.Hcl (10: 0.5) compositions physiological salt liquid 1ml, contains aescine 5mg.
The 4th day, put to death animal, cut administration ear edge, observe medicine to the venous stimulation, and do the pathology cut sections for microscopic examination.Obtain following result:
1, injection aescine-hydrochloric acid relies first to five group of ammonia compositions and all animals of the 8th group to there is no tangible irritant reaction, pathology section examination result is similar substantially to normal saline group (the 7th group), do not see that blood vessel and peripheral cell thereof have degeneration, downright bad and obvious pathological abnormalities.
2, serious congestion and edema all appears in 6 animals of the 6th group and the 9th group, and most of injection site shows puce, and pathological section shows serious degeneration, necrosis and thrombosis.
3, the ear of 3 animals of the 7th group of injecting normal saline there is no the obvious stimulation reaction, and pathological section shows that circumvascular cell is normal substantially, does not see the situation of pathological abnormalities.
Learn from test example 3: the compositions, the weight ratio of lysine hydrochloride or lysine acetate and aescine≤1/10 o'clock, the molecular proportion of lysinate and aescine 〉=1 is got the compositions that is equivalent to the 5mg aescine and is dissolved in normal saline 1ml, and lysinate concentration is greater than 0.5mg ml
-1, this moment, aescine and lysine were completed into double salt, and animal experiment shows can eliminate the stimulation of aescine to blood vessel.In the compositions, lysinate and aescine weight ratio equal at 0.5/10 o'clock, and its molecular proportion is 0.5: 1, have 1/2 amount aescine to become free state, get and be equivalent to 5mg aescine composition of sodium and be dissolved among the normal saline 1ml, lysinate concentration is 0.25mgml
-1, this moment, animal experiment showed that blood vessel is had the obvious stimulation reaction.Clinical aescine maximum dose level is no more than 20mg, when NaEsc-Lys.HAC (1: 6.5) composition freeze-drying agent is used to instil, when the transfusion volume was no more than 250ml, every ml transfusion contained the above lysinate of 0.50mg, can avoid the stimulation of aescine to blood vessel; And the composition of NaEsc-Lys.HAC is higher than at 1: 6.5 o'clock, the one, and cause freezing preceding aseptic filtration speed too slow, be unfavorable for producing, and the lysinate too high levels in the compositions, increase the zest of compositions to muscle, reduce its safety.
Test example 4The anti-inflammatory activity research of aescine-lysinate compositions
Test method is with test example 1, and test dose is mete-wand with contained aescine in the compositions all, and specimen in use is the aescine-lysine hydrochloric acid salt composite of various proportionings.The results are shown in Table 10-15:
The anti-inflammatory activity of table 10NaEsc-Lys.Hcl compositions (10: 1)
The anti-inflammatory activity of table 11NaEsc-Lys.Hcl compositions (1: 10)
The anti-inflammatory activity of table 12NaEsc-Lys.Hcl compositions (1: 1)
The anti-inflammatory activity of table 13NaEsc-Lys.Hcl compositions (1: 3)
The anti-inflammatory activity of table 14NaEsc-Lys.Hcl compositions (1: 6.5)
Illustrate:
* *Expression P＜0.001,
*Expression P＜0.01
NaEsc-Lys.Hcl compositions antiinflammatory ED with various proportionings compositions
50Be summarized in table 15.
The NaEsc-Lys.Hcl combination anti-inflammatory activity that the various proportionings of table 15 are formed
Learn the ED of the NaEsc-Lys.Hcl compositions that various proportionings are formed from table 15
50All less than simple aescine group, illustrate that the anti-inflammatory activity of all compositionss all is higher than the aescine with same amount " related substance ", visible lysine hydrochloride and aescine coupling have obvious role in synergism.
Test example 5The NaEsc-Lys.Hcl compositions is to the protective effect of cerebral ischemia
Body weight is 80 of the healthy wistar rats of 150-200g, is divided into eight groups, 10 every group, wherein one group is the cerebral ischemic model group, and one group is Sham-operated control group, and other 6 groups is the treatment group, treatment group dosage all calculates with contained aescine, and testing used dosage is 0.5mg.kg
-1Animal elder generation lumbar injection urethane anesthesia (1mg.kg before the operation
-1), preceding 5 minutes of bilateral carotid arteries ligation by the vena femoralis injection administration.After the ligation 3 hours, with sacrifice of animal.Broken end is got brain and is weighed, and dries to constant weight at 110 ℃ then.Calculate brain water content according to the following equation: brain water content=(weight in wet base-dry weight) * 100/ weight in wet base.The results are shown in Table 16.
The NaEsc-Lys.Hcl compositions that the various proportionings of table 16 are formed is to the protective effect of rat cerebral ischemia
Illustrate:
*Expression P＜0.01
Learn by table 16, aescine and lysine compositions thereof all have inhibitory action to the cerebral edema that ischemia causes, and the cerebral edema that compositions causes ischemia has stronger inhibitory action, and the composition proportioning of compositions is 10: 1-1: in 10 scopes to the suppression ratio of cerebral edema substantially on same level, do not have significant difference.In addition, the synergistic function of lysine hydrochloride or lysine acetate and aescine is basic identical in the compositions.
Test example 6The exudation test of NaEsc-Lys.Hcl compositions
Body weight is 120 of the healthy kunming mices of 23-26g, and male and female half and half are divided into 12 groups, 10 every group.The dosage 1.0-1.5mg.kg of administration group
-1, calculate with the contained aescine of compositions, simultaneously with the equal-volume normal saline as blank.Each 0.4ml of intravenous drug solution or normal saline, after 1 hour, intravenous injection 1% azovan blue normal saline, peritoneal injection 1% acetum 0.2ml puts to death mice successively after 20 minutes simultaneously, cuts off the abdominal cavity, use normal saline 6ml, gradation washing abdominal cavity merges cleaning mixture, adds normal saline 10ml, centrifugal 300rpm * 20 minute, get supernatant, measure absorbance at the 590nm place, the result is referring to table 17.
The exudation effect of table 17 aescine lysine compositions
Illustrate:
*Show P＜0.01
Learnt by table 17: the drug effect of aescine can be strengthened because of the existence of lysine, and aescine and lysine coupling have synergistic function, and the synergistic function of lysine hydrochloride or lysine acetate and aescine is basic identical in the compositions.
Test example 7The antiinflammatory of lysine hydrochloride aescine composition of sodium and lysine aescin saponin chemical compound, the active comparative study of exudation
Lysine hydrochloride aescine composition of sodium represents that with NaEsc-Lys.Hcl wherein the weight ratio of lysine hydrochloride and aescine is 10: 1.The lysine aescin saponin chemical compound represents that with Lys.Esc wherein the content of lysine is 10%.The method of exudation activity research is with test example 6, and the anti-inflammatory activity research method is with test example 1.The exudation of the two, anti-inflammatory activity comparative result see Table 18-19.
The exudation specific activity of table 18 lysine hydrochloride aescine composition of sodium and lysine aescin saponin
Illustrate: compare with blank assay,
*P＜0.01, drug dose are mete-wand with the aescine.
The anti-inflammatory activity of table 19 lysine hydrochloride aescine composition of sodium and lysine aescin saponin relatively
Illustrate: compare with blank assay,
*P＜0.01, drug dose are mete-wand with the aescine.
18-19 learns by table, lysine hydrochloride is identical with the drug effect of the lysine aescine that contains 10% lysine with 10: 1 compositionss of aescine, and all can both eliminate the stimulation of aescine to blood vessel and muscle, the two has identical medical value, but the production technology of compositions is fairly simple, do not need heat treated, thereby be beneficial to medicine stability.
Test example 8The aescine compositions is to the research of intravenous tension increase effect
25 of ripe healthy dogs, phenobarbital 30mgkg
-1After the body weight intravenous anesthesia, carefully separate the Canis familiaris L. saphena, clip proximal part vein treaty 2cm is long, careful separation is fascia and connective tissue around it, be prepared into spiral vein bar, be fixed in the 10ml isolated organ bath of freshly prepared gram-Guo Shi liquid, 37 ℃ ± 1 ℃ of temperature control also feeds 95%O
2And 5%CO
2Mist.The vein bar links through tonotransducer and balance recorder, and before the experiment beginning, adds-preload of 50mg to vein.Medicine to the tensile influence of vein bar with to 10
-5The percent of mol/L norepinephrine (NA) reaction is expressed: promptly with 1.0 * 10
-5Tension variation ceiling effect when the vein bar that the NA of mol/L causes shrinks is 100, and under the different pharmaceutical mass action, vein bar tension variation compares with it, calculates the percent that the vein shrink tension changes under each dosage group effect.Each administration must add after a last dose response is complete again.Test dose is counted benchmark with aescine.Weight ratio (6.5: the 1) compositions of total aescine, lysine and total aescine sees Table 20 to intravenous tension increase effect.
Total aescine compositions of table 20 lysine and of the increase effect of total aescine to intravenous tension
Learnt that by table 20 the total aescine composition of sodium of lysine has the effect that increases intravenous tension, its action intensity is basic identical with total aescine.Improving blood circulation is the important physiologically active of aescine, is that aescine improves the blood circulation important motivity and increase intravenous tension.This experiment shows: lysine is made compositions with total aescine, and what do not influence aescine improves the blood circulation activity.
Test example 9The lysine aescin saponin compositions is to the irritation test of lagophthalmos
The equal aescine of drug dose of the present invention carries out longitudinal comparison as measurement criteria, is solvent with the sterile saline, and liquor strength is 0.2w/w%.Eye drops, every lagophthalmos difference administration 0.1ml.
Body weight is 2 kilograms a healthy rabbits, with the eyeball of every rabbit of lens examination, answers the preceding NIP of confirmatory test, no cornea defective, no conjunctival damage before the administration.Then with 6 of satisfactory rabbit, be divided into three groups of the total seven leaf soap composition of sodium groups (compositions 1) of lysine acetate, the total seven leaf soap composition of sodium groups (compositions 2) of lysine hydrochloride and total aescine groups, every group 2, wherein the weight ratio of acetic acid (or hydrochloric acid) lysine and total seven leaf soap sodium is 6.5: 1 in the compositions.All splash into medicinal liquid at left eye, right eye splashes into sterile saline in contrast.After lagophthalmos splashes into medicinal liquid, allow rabbit passive closed 10 seconds, the irritant reaction of observing lagophthalmos after 1,24,48,72 hours.
The eye irritation test method criterion of " new drug (Western medicine) the preclinical study guideline compilation " issued according to Ministry of Public Health bureau of drug administration judges, the results are shown in Table 21 after 1 hour.The listed result of table 21 all is the irritant reaction that the administration of rabbit left eye showed after 1 hour, and the equal vacuum response of the right eye of its normal saline.After 24 hours, it is normal that its left eye all recovers.
Table 21 aescine compositions and total aescine are to the irritation test result of lagophthalmos
Learnt by table 21: total aescine composition of sodium of 0.2% lysine acetate and the total aescine composition of sodium of 0.2% hydrochloric acid have slight stimulation to the lagophthalmos ball, and 0.2% total aescine has the moderate stimulation to the lagophthalmos ball.
To sum up, Sodium Aescinate of the present invention is compared with Sodium Aescinate with the composition of lysine hydrochloride or Lysine Acetate, has the following advantages:
1, composition can be eliminated Sodium Aescinate to the spread effect of blood vessel.
2, composition can increase anti-inflammatory, the impervious effect that goes out, suppresses encephaledema.
3, composition has significant synergistic function, and drug effect strengthens, thereby can reduce dosage, thereby can Reduce the toxic and side effect of Sodium Aescinate.
Claims (16)
- One kind prepare aescine potassium sodium salt-mixture method, comprise the steps:1) the Semen Aesculi fine powder is with 5 times of amounts, concentration is extracted three times for the 50v/v%-70v/v% alcoholic solution stirs, each 4 hours, collect merge extractive liquid,, vacuum reclaims ethanol to 1/5 of extracting liquid volume, extract β-aescine content in the concentrated solution with high effective liquid chromatography for measuring, mass ratio with β-aescine and cholesterol is 1: 1.2 then, add cholesterol under stirring condition, added the back restir 2 hours, placement is spent the night, next day centrifugal collection cholesterol deposit, be washed to colourless, after 60 ℃ of oven dry, with chloroform or O for toluene, make cholesterol dissolve in solvent, and the sodium of aescine, potassium salt still exists with solid-state form;2) with 90%-95% ethyl alcohol recrystallization twice, promptly.
- 2. method for preparing aescine comprises:1) ion exchange: the aescine potassium salt-mixture dissolving crude product that will prepare according to the method for claim 1 forms distilled water solution in distilled water, and by the Hydrogen cation exchange column, cold preservation is placed and separated out crystallization or add seeded crystallization; Or2) add the mineral acid sedimentation method: the aescine potassium salt-mixture dissolving crude product that will prepare according to the method for claim 1 forms distilled water solution in distilled water, add acid solution, regulating aqueous solution pH is 1-3, and cold preservation is placed and separated out crystallization or add seeded crystallization; Or3) liquid chromatography: the aescine potassium sodium salt-mixture crude product that will prepare according to the method for claim 1 is dissolved in the alcoholic solution, by high performance liquid chromatography or fast liquid chromatography, separate through mobile phase, the mobile phase in aescine A, B, C and D peak district appears in collection, vacuum distilling is removed acetic acid and alcohols, and cold preservation is placed and separated out crystallization or add seeded crystallization; OrThe aescine potassium sodium salt-mixture crude product that 4) will prepare according to the method for claim 1 is dissolved in the alcoholic solution, pass through normal-phase chromatography, with silica gel or aluminium oxide is adsorbent, with chloroform-methanol-water or isopropyl alcohol-water or ethyl acetate-methanol-water or n-butyl alcohol-acetic acid-water is mobile phase, the mobile phase in aescine A, B, C and D peak district appears in collection, behind the vacuum concentration, cold preservation is placed and is separated out crystallization or add seeded crystallization.
- 3. preparation method as claimed in claim 2 is characterized in that adding the acid solution that adds in the mineral acid sedimentation method and is selected from sulphuric acid or hydrochloric acid.
- 4. preparation method as claimed in claim 2 is characterized in that alcoholic solution described in the liquid chromatography is selected from ethanol, methanol or isopropyl alcohol.
- 5. preparation method as claimed in claim 4, wherein said alcoholic solution are ethanol or methanol.
- 6. preparation method as claimed in claim 2 is characterized in that mobile phase described in the liquid chromatography is selected from the solution of methanol or ethanol composition.
- 7. preparation method as claimed in claim 6, wherein said mobile phase are 50% ethanol or 70% methanol that contains 1% acetic acid.
- 8. preparation method as claimed in claim 2 is characterized in that chromatographic column filler is C18 or C8 bonded silica gel in the liquid chromatography.
- 9. a method for preparing aescine salt comprises the steps:To be dissolved in the alcoholic solution of 80-99v/v% according to the aescine that each described method of claim 2-8 prepares, add the alcoholic solution of equivalent alkaline matter, place at cold place, promptly gets its crystallization.
- 10. method according to claim 9, the concentration of described alcoholic solution are 85-95v/v%.
- 11. method according to claim 10, the concentration of described alcoholic solution are 90v/v%.
- 12. according to each described method of claim 9-11, described alcoholic solution is selected from ethanol, methanol, propylene glycol or glycerol.
- 13. method according to claim 12, described alcoholic solution are ethanol or methanol.
- 14. method according to claim 9, described alkaline matter is selected from sodium hydroxide or potassium hydroxide.
- 15. method according to claim 14, described alkaline matter are sodium hydroxide.
- 16. a method for preparing β-aescine comprises the steps:1) operates according to the step 1) in the claim 1;2) fling to residual solvent, use water dissolution then, by the hydrogen type cation exchange resin post, get the milky colloidal solution, add 0.5% acetic acid by liquor capacity, crystallization is separated out in cold preservation, behind the filter collection, with a small amount of cold distilled water flush away acetic acid, gets β-aescine crystallization.
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| CN102532241A (en) * | 2010-12-24 | 2012-07-04 | 苏州宝泽堂医药科技有限公司 | Method for purifying sodium aescinate |
| CN102836133B (en) * | 2012-08-31 | 2014-03-12 | 武汉普生制药有限公司 | Sodium aescinate freeze-dried powder injection and preparation method thereof |
| CN104622740B (en) * | 2015-01-14 | 2017-05-31 | 武汉爱民制药股份有限公司 | Purposes of the Horse chest Nut P.E in cosmeceutical is prepared |
| CN105878173B (en) * | 2016-04-13 | 2018-10-19 | 武汉爱民制药股份有限公司 | A kind of Sodium Aescinate liniment |
| WO2018029292A1 (en) * | 2016-08-11 | 2018-02-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method for treating glioma |
| CN106580891B (en) * | 2016-11-15 | 2019-08-27 | 武汉爱民制药股份有限公司 | A kind of Aescinate B injection and preparation method thereof |
| CN106511282B (en) * | 2016-11-15 | 2019-05-14 | 武汉爱民制药股份有限公司 | A kind of Aescinate A injection and preparation method thereof |
| CN108218948B (en) * | 2016-12-22 | 2021-01-15 | 深圳翰宇药业股份有限公司 | Preparation method of sodium aescinate |
| CN109045054A (en) * | 2018-09-14 | 2018-12-21 | 西南交通大学 | The new application of otoginsenoside |
| CN116159134A (en) * | 2023-01-31 | 2023-05-26 | 四川大学 | Application of aescin and/or salt compound thereof as adjuvant in vaccine |
| CN116999450A (en) * | 2023-09-18 | 2023-11-07 | 河北中医药大学 | Application of aescin and its derivative in preparing antidepressant |
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