CN101537188B - Pinocembrin and cyclodextrin or cyclodextrin derivative inclusion compound - Google Patents
Pinocembrin and cyclodextrin or cyclodextrin derivative inclusion compound Download PDFInfo
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- CN101537188B CN101537188B CN2008100846823A CN200810084682A CN101537188B CN 101537188 B CN101537188 B CN 101537188B CN 2008100846823 A CN2008100846823 A CN 2008100846823A CN 200810084682 A CN200810084682 A CN 200810084682A CN 101537188 B CN101537188 B CN 101537188B
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Abstract
The invention discloses a pinocembrin and cyclodextrin or cyclodextrin derivative inclusion compound, wherein cyclodextrin or a cyclodextrin derivative is used to include the pinocembrin. The inclusion compound contains the pinocembrin and the cyclodextrin or cyclodextrin derivative in a molar ratio of 1:1-100. The inclusion compound can improve the water solubility of the pinocembrin and give good play of the therapeutic action of the pinocembrin. The inclusion compound is suitable for the preparation of sold dosage forms and liquid dosage forms required by clinics, including infusion solution, water injection, powder injection, oral solution, syrup, tablets, capsules, granules and dispersible tablets. The inclusion compound can be used for preparing drugs for preventing and\or treating cardiovascular and cerebrovascular diseases, particularly brain stroke, as well as drugs for preventing and\or treating bacterial and\or fungal infections.
Description
Technical field
The present invention relates to pinocembrin and cyclodextrin or cyclodextrin derivant clathrate, its preparation method, contain the pharmaceutical composition of this type pinocembrin and cyclodextrin or cyclodextrin derivant clathrate and in the purposes of preparation in the medicine.Belong to medical technical field.
Background technology
Pinocembrin (pinocembrin) has another name called pinocembrin, gives birth to pine element, chemical name 5; 7-dihydroxy flavanone (5,7-Dihydroxyflavanone), 2,3-dihydro-5; 7-dihydroxy-2-phenyl-4H-1-.alpha.-5:6-benzopyran-4-ketone (2,3-Dihydro-5,7-dihydroxy-2-phenyl-4H-1-benzopyran-4-one); Be a kind of water-fast flavanone kind composition, structure is following:
Contain a chiral centre in the pinocembrin chemical constitution, natural pinocembrin stereochemical structure is the S configuration, specific optical rotation [α]
D 15For-45.3 (c, 0.9, acetone is solvent).
(S)-pinocembrin is a kind of natural product that from propolis (propolis), extracts.Nut pine, also found this chemical compound (CombinedChemical Dictionary 2004) in the extract of a lot of plants such as eucalyptus leaves, Radix Acaciae senegalis in addition.Pinocembrin except that from propolis, separate obtain, nut pine, Eucalyptus, red raise etc. also separablely in the plant goes out this chemical compound; But content is all very low, and now pinocembrin also can obtain through synthetic, and this makes come true in a large number (Cheng Yonghao, the Duan Yabo of pinocembrin; Qi Yan, Guo Xiao Yun, Tong Yuanfeng; Du Guanhua, Wu Song, chemical reagent.2006，28(7)：437)。
The bibliographical information pinocembrin is responsive to multiple malignant bacteria and fungus, especially some Resistant strains is shown higher antibacterial effect (Hyun Koo, Pedro L. Rosalen; Jaime A.Cury; Yong K.Park, andWilliam H.Bowen, Antimicrob.Agents & Chemother.2002; 46 (5), 1302-1309).We find that through a large amount of pharmacological testings left-handed pinocembrin has better curative effect to apoplexy, and toxic and side effects very low (Chinese patent 200410037860.9); The activity of synthesising racemation pinocembrin is suitable with left-handed pinocembrin, thereby indirect proof dextrorotation pinocembrin is similar with the pharmacological action of levo form.Pharmacodynamics and toxicological study show, intravenous injection and intraperitoneal injection LD
50Greater than 700 mg/kg, high more than 100 times than effective dose.Therefore, pinocembrin effective, toxicity is little, and pharmacological action relatively has remarkable advantages with existing similar medicine, and indication is multiple disease, has good market prospect.
Because pinocembrin is water insoluble, oral absorption is relatively poor, all has certain difficulty as oral or drug administration by injection.During especially for acute diseases such as treatment apoplexy, need employed pharmaceutical preparation can reach rapid release, quick acting, adopting intravenous injection is the most popular method of treating acute disease clinically.And pinocembrin is processed injection, must at first solve its water-fast problem.
Summary of the invention
Water insoluble for pinocembrin in the solution prior art, oral absorption is relatively poor, is difficult to the technical problem of oral or drug administration by injection, the invention provides following technical scheme:
The invention provides a kind of pinocembrin and cyclodextrin or cyclodextrin derivant clathrate
The invention provides the method for preparation this type pinocembrin and cyclodextrin or cyclodextrin derivant clathrate
The invention provides the pharmaceutical composition that contains this type pinocembrin and cyclodextrin or cyclodextrin derivant clathrate
The invention provides the purposes of going back this type pinocembrin and cyclodextrin or cyclodextrin derivant clathrate.
Particularly; In order to realize the object of the invention; Adopt following technical scheme: a kind of pinocembrin and cyclodextrin or cyclodextrin derivant clathrate: contain pinocembrin and cyclodextrin or cyclodextrin derivative, the molecule mol ratio of pinocembrin and cyclodextrin or cyclodextrin derivative is 1: 1～1: 100; Preferred molecule mol ratio is 1: 1～1: 10.
Said pinocembrin is selected from left-handed pinocembrin, dextrorotation pinocembrin, raceme pinocembrin;
Said cyclodextrin comprises, but is not limited to alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin; Beta-schardinger dextrin-preferably.
Said cyclodextrin derivative comprises, but is not limited to hydroxyethyl-, HP-, dihydroxypropyl-beta-schardinger dextrin-, methyl-beta-schardinger dextrin-, glucose-cyclodextrin, maltose-cyclodextrin, maltotriose-cyclodextrin, carboxymethyl-cyclodextrin, sulfoalkyl-cyclodextrin; HP-preferably.
This clathrate of pinocembrin and cyclodextrin of the present invention or cyclodextrin derivant clathrate can be a liquid or solid, can be developed to clinical multiple solid dosage forms and the liquid dosage form that is suitable for.
The present invention prepares the following technical scheme of employing of pinocembrin and cyclodextrin or cyclodextrin derivant clathrate:
With solvent in cyclodextrin or the cyclodextrin derivative adding; Processing the weight concentration scope is 1～60%, and preferred 5～60% cyclodextrin or the solution of cyclodextrin derivative or suspension add pinocembrin; Stir or ground and mixed, promptly get liquid pinocembrin and cyclodextrin or cyclodextrin derivant clathrate.Liquid pinocembrin and cyclodextrin or cyclodextrin derivant clathrate can be solution or suspension, stir to clarify transparently, promptly get liquid pinocembrin and cyclodextrin or cyclodextrin derivant clathrate solution.
Pinocembrin and cyclodextrin or the lyophilization of cyclodextrin derivant clathrate solution or spray drying or distillation concentrated to remove desolvate, promptly get solid pinocembrin and cyclodextrin or cyclodextrin derivant clathrate.
In preparation solid pinocembrin dextrin or the cyclodextrin derivant clathrate process; Can also liquid pinocembrin and cyclodextrin or cyclodextrin derivant clathrate solution be concentrated into dextrin or cyclodextrin derivative weight concentration scope earlier at 10～15% solution; Carry out lyophilization again, promptly get solid pinocembrin dextrin or cyclodextrin derivant clathrate.
The method for preparing of pinocembrin and cyclodextrin or cyclodextrin derivant clathrate among the present invention also can be that cyclodextrin or cyclodextrin derivative are placed colloid mill or mortar, adds an amount of suitable solvent and stirs; Make into pastel, pinocembrin is added in the above-mentioned pastel, ground 1～5 hour; Get the viscous pastes of homogeneous; Filter, concentrate or lyophilization, promptly get solid pinocembrin and cyclodextrin or cyclodextrin derivant clathrate.
It is at least a that the suitable solvent of dissolving cyclodextrin or cyclodextrin derivative is selected from water, ethanol, methanol, propanol, isopropyl alcohol, ethylene glycol, glycerin, acetone, comprises two or more mixed solvent, wherein water preferably.
Add pinocembrin in the preparation and can be the pinocembrin solid or with the pinocembrin solution of an amount of organic solvent dissolution.
The invention provides a kind of pharmaceutical composition, it comprises acceptable carrier on pinocembrin and cyclodextrin or cyclodextrin derivant clathrate and the pharmacopedics.Pinocembrin and cyclodextrin of the present invention or cyclodextrin derivant clathrate can adopt the known method of this area professional, process the suitable type of service or the dosage form that can be used as the human drug use.。The single dose specification is for containing active medicine pinocembrin 1-1000mg, and preferred single dose specification is for containing active medicine pinocembrin 50-250mg.
Described pharmaceutical composition comprises but is not limited to, liquid dosage form such as the transfusion that liquid pinocembrin and cyclodextrin or cyclodextrin derivant clathrate directly are used to prepare, liquid drugs injection, powder pin, oral liquid, syrup; Solid pinocembrin and cyclodextrin or cyclodextrin derivant clathrate are processed multiple solid dosage formss such as tablet, capsule, granule, dispersible tablet, oral cavity disintegration tablet, buccal tablet.
Preferred liquid dosage form comprises the injection of pinocembrin hydroxypropyl-beta-cyclodextrin inclusion, and the concentration of injection is 0.01～3% (g/ml), and the pH value of injection is 3～10; Can contain pH adjustment agent such as sodium chloride, glucose isosmoticity regulator and hydrochloric acid, sodium hydroxide in the injection.
Described injectable powder comprises the injectable powder of pinocembrin hydroxypropyl-beta-cyclodextrin inclusion, and the pH value after the injectable powder dissolving is 3～10, can contain pH such as proppant such as mannitol, lactose and hydrochloric acid, sodium hydroxide in the injection and adjust.
Beneficial effect of the present invention:
Through cyclodextrin or cyclodextrin derivative pinocembrin is carried out enclose; The pinocembrin molecule is embedded in the tubular structure of cyclodextrin or cyclodextrin derivative molecule; Become the clathrate of pinocembrin and cyclodextrin or cyclodextrin derivative, thereby improved the water solublity of pinocembrin.When being determined at 25 ℃, the dissolubility of pinocembrin hydroxypropyl-beta-cyclodextrin inclusion in water can reach 2000mg/100ml.
Pinocembrin and cyclodextrin of the present invention or cyclodextrin derivant clathrate make this active component of pinocembrin directly apply to solid, liquid dosage form with the form of clathrate.Cyclodextrin or cyclodextrin derivative are the less water solublity pharmaceutic adjuvants of a kind of toxicity, are suitable for processing various liquid preparation and solid preparation with the pinocembrin and cyclodextrin or the cyclodextrin derivant clathrate of its preparation.Pinocembrin and cyclodextrin of the present invention or cyclodextrin derivant clathrate have good water solubility, characteristics that blood vessel irritation is little, are particularly useful for making liquid preparation.It is low to have solved the pinocembrin water solublity, can not directly be used for the technical problem of liquid dosage form, especially injection type.In addition owing to improved water solublity, have the advantages that with the solid preparation of its preparation disintegrate is fast, stripping good, bioavailability is high, be more conducive to clinical practice.
The acute toxicity tests shows: the cyclodextrin clathrate of pinocembrin of the present invention, and for the LD of mouse mainline
50Greater than 700 mg/kg, high more than 100 times than effective dose, and do not see local excitation.The cyclodextrin clathrate safety that pinocembrin of the present invention is described is good, is fit to be prepared into injection type.
Pharmacological tests shows: the cyclodextrin clathrate of pinocembrin of the present invention can improve the neuroethology damage that the rat acute focal cerebral ischemia causes; Alleviate the decline degree of cortex middle cerebral artery supply area cerebral blood flow.Can prepare prevention with or the treatment cardiovascular and cerebrovascular diseases medicament, described cardiovascular and cerebrovascular disease is apoplexy preferably.
Pinocembrin is responsive to multiple malignant bacteria and fungus in the prior art; Especially some Resistant strains are shown higher antibacterial effect, thus inference pinocembrin and cyclodextrin of the present invention or cyclodextrin derivant clathrate can prepare prevention with the treatment antibacterial with or the fungal infection medicine.
Description of drawings
Fig. 1 .DL0108 is to the influence of MCAO surgical injury rat Bederson scoring
Fig. 2 .DL0108 is to the influence of MCAO surgical injury animal nerve symptom scoring
The Rcbf value (A) of the different time sections in cortex medium-sized artery blood supply district behind Fig. 3 .MCAO surgical injury.
Compound D L0108 is to the influence (B) of MCAO surgical injury rat Rcbf value.
Fig. 1-Fig. 3, data are represented with meansigma methods ± S.E.M. analyzes and passes through Dunett ' s check through single factor ANOVA, and n=10.##P＜0.01 vs. blank group,
*P＜0.05 vs. solvent control group.
The specific embodiment
For better understanding technical scheme of the present invention, the spy provides following examples.But can not be interpreted as any restriction of the present invention.Those skilled in the art can make various changes to disclosed technical scheme of the present invention, and this change also belongs to scope of the present invention.
Embodiment 1: preparation liquid pinocembrin hydroxypropyl-beta-cyclodextrin inclusion solution
(1) takes by weighing the 40g HP-, pour in the 400ml distilled water stirring and dissolving into;
(2) take by weighing pinocembrin 1g in addition, add the 20ml anhydrous alcohol solution, this solution is poured in the above-mentioned HP-solution;
(3) mixed liquor stirred 20 minutes down at 40～50 ℃ with the magnetic agitation method, observed solution to clear, promptly got pinocembrin HP-derivative clathrate solution.
Embodiment 2: preparation solid pinocembrin hydroxypropyl-beta-cyclodextrin inclusion
(1), (2), (3) are with embodiment 1.
(4) pinocembrin HP-derivative clathrate solution is carried out lyophilization again, promptly get solid pinocembrin hydroxypropyl-beta-cyclodextrin inclusion.
Embodiment 3: preparation solid pinocembrin hydroxypropyl-beta-cyclodextrin inclusion
(1) takes by weighing the 20g HP-, put into mortar and add the 100ml distilled water, grind and make into pasty state;
(2) take by weighing pinocembrin 3g in addition, add the 20ml anhydrous alcohol solution, this solution is poured in the above-mentioned HP-solution;
(3) mixed liquor was ground 2 hours, obtain the homogeneous pastel, filter, evaporated under reduced pressure promptly gets solid pinocembrin and cyclodextrin derivative clathrate.
Embodiment 4: the sodium chloride transfusion of preparation pinocembrin hydroxypropyl-beta-cyclodextrin inclusion
(1) take by weighing the 20g HP-, pour in the 200ml distilled water, stirring and dissolving adds the 0.5g transfusion and uses active carbon, is heated with stirring to 80 ℃, is incubated 15 minutes, filtering decarbonization;
(2) take by weighing pinocembrin 2g in addition, add the 20ml anhydrous alcohol solution, this solution is poured in the above-mentioned HP-solution;
(3) mixed liquor stirred 20 minutes down at 40～50 ℃ with the magnetic agitation method, observed solution to clear, obtained pinocembrin HP-derivative clathrate solution.
(4) the inclusion complex in solution moisturizing adds sodium chloride for injection 7～8g to 800ml, regulates pH8～9, and regulates PH to 3.5～7 with the hydrochloric acid of 0.05M or the sodium hydroxide of 0.05M, and moisturizing adds 0.1g injection active carbon to 1000ml, stirs 20 minutes.
(5) solution takes off 115 ℃ of charcoal fills, and pressure sterilizing promptly got in 30 minutes.
Embodiment 5: the glucose infusion liquid (1) of preparation pinocembrin hydroxypropyl-beta-cyclodextrin inclusion, (2), (3) are with embodiment 4.
(4) take by weighing glucose for injection 50g, add the water stirring and dissolving and make volume reach 100ml, add the 0.1g active carbon, heat and littlely boiled filtering decarbonization 15 minutes.
(5) Glucose Liquid is poured in the inclusion complex in solution, and moisturizing is regulated pH to 6-7 to 800ml with the hydrochloric acid of 0.05M or the sodium hydroxide of 0.05M, and moisturizing adds 0.1g injection active carbon to 1000ml, stirs 20 minutes.
(6) solution carries out coarse filtration, fine straining with filter or sand filtration rod (aperture 1.0 μ m, 0.45 μ m, 0.22 μ m) respectively, and fill is 115 ℃ then, and pressure sterilizing promptly got in 30 minutes.
Embodiment 6: prepare aseptic powder injection with the pinocembrin hydroxypropyl-beta-cyclodextrin inclusion
(1) indoor in the sterile working, take by weighing the 40g HP-, be dissolved in water into 80ml, add the 0.1g active carbon, heat and littlely boiled filtering decarbonization 15 minutes.
(2) take by weighing pinocembrin 1g in addition, add the 20ml anhydrous alcohol solution, this solution is poured in the above-mentioned HP-solution;
(3) mixed liquor stirred 20 minutes down at 40～50 ℃ with the magnetic agitation method, stirred, and observed solution to clear, obtained pinocembrin HP-derivative clathrate solution.
(4) the inclusion complex in solution moisturizing is to 100ml, crosses 0.22 μ m filter membrane, is sub-packed in the cillin bottle of 10ml (2～3ml/ bottle), inserts in the freeze dryer, and the lyophilization gland promptly gets aseptic powder injection.
Embodiment 7: use the beta-cyclodextrin inclusion compound pinocembrin
Take by weighing the 40g beta-schardinger dextrin-, add the 100ml distilled water, be heated to 40～50 ℃, make the beta-schardinger dextrin-dissolving, add the 1g pinocembrin with the 20ml anhydrous alcohol solution, magnetic agitation was filtered after 2～3 hours, and lyophilization promptly gets beta-schardinger dextrin-pinocembrin clathrate.
Embodiment 8: the preparation of beta-cyclodextrin inclusion compound pinocembrin oral capsule
Take by weighing beta-cyclodextrin inclusion compound pinocembrin 20g, with itself and 80g lactose by equivalent multiplication method mixing, with water dissolution HPMC as binding agent system soft material; 20 mesh sieves are granulated, and 60 ℃ dry down, and dried granule is with 30 mesh sieve granulate; Carry out the intermediate check, active medicine 50mg/ grain is encapsulated by containing, sampling observation; Packing promptly gets.
Embodiment 9: the preparation of beta-cyclodextrin inclusion compound pinocembrin oral tablet
Take by weighing beta-cyclodextrin inclusion compound pinocembrin 20g, with itself and 80g lactose and 5g carboxymethyl starch sodium by equivalent multiplication method mixing, with water dissolution HPMC as binding agent system soft material, the granulation of 20 mesh sieves; 60 ℃ dry down, and dried granule adds micropowder silica gel 1g with 30 mesh sieve granulate, and is evenly mixed; By containing active medicine 50mg/ sheet tabletting, carry out the intermediate check, encapsulated; Sampling observation, packing promptly gets.
Pharmacological evaluation
The pinocembrin hydroxypropyl-beta-cyclodextrin inclusion is to the protective effect of rat acute focal cerebral ischemia injury
Test method: the MCAO model method by bibliographical information make an experiment (Zhang Juntian chief editor, the modern pharmacology experimental technique, combined publication society of China Concord Medical Science University of Beijing Medical University, in October, 1998 front page
Nervous symptoms scoring (Bederson ' s Value)
The scoring of sham operated rats Animal Behavior Science is 0 minute.It is 3.4 ± 0.6 minutes that the solvent control group animal nerve is learned the scoring meansigma methods, and wherein, most animals shows as operation offside forelimb inward turning or interior receipts, and lateral compression is stretched strength to pleural muscle and weakened, and the walking of turn-taking or turn-take once in a while is chosen as 3 fens; The forelimb inward turning only appears in the minority animal in addition and drag descends, and is chosen as 2 fens; The individual animal symptom is heavier, lacks autonomic activities, is chosen as 4 fens.
Chemical compound pinocembrin hydroxypropyl-beta-cyclodextrin inclusion (1mg/kg, 3mg/kg, 10mg/kg; Press the cubage of active component pinocembrin; Code name DL0108, down with) can significantly improve the nerve injury symptom (P＜0.05, P＜0.01) behind the animal brain ischemia; And present dose-effect relationship, and all be superior to positive drug nimodipine (see figure 1).
(hang plate experiment) estimated in motor capacity
Sham operated rats rat time of staying meansigma methods on hang plate is 79.3 ± 10.4sec.After the acute cerebral ischemia damage; Group of solvents rat time of staying on hang plate obviously shortens, and meansigma methods is 4.01 ± 1.42sec, compares with group of solvents; Pinocembrin hydroxypropyl-beta-cyclodextrin inclusion (3mg/kg; 10mg/kg) ability significant prolongation animal presents dose-effect relationship in the hang plate time of staying (P＜0.01), and the action effect of pinocembrin hydroxypropyl-beta-cyclodextrin inclusion (3mg/kg, 10mg/kg) dose groups is superior to positive control medicine nimodipine (see figure 2).
DL0108 is to the influence of acute cerebral ischemia in rats tissue local cerebral blood flow
The MCAO operation causes local cortex medium-sized artery blood supply district blood flow to quickly fall to the 20%-30% of the preceding basic value of operation; Behind the ischemia 24h (before the sacrifice of animal) to receive collateral circulation with the position compensatory; When performing the operation, RCBF rises to some extent; But still being lower than 50% of basic value, the result is shown in figure .3A.
Behind the ischemia 24h of rat cerebral tissue; Group of solvents rCBF value is 47.6 ± 5.7% of a basic value; Compound D L0108 (10mg/kg) administration group, nimodipine group rCBF value rise to 25.7 ± 5.6% and 37.7 ± 5.6% of basic value respectively; Compare with group of solvents and to have significant difference (P＜0.05), the result is shown in figure .3B.
Above result proves: the pinocembrin hydroxypropyl-beta-cyclodextrin inclusion can improve the neuroethology damage that the rat acute focal cerebral ischemia causes; Alleviate the decline degree of cortex middle cerebral artery supply area cerebral blood flow.
Claims (6)
1. pinocembrin and cyclodextrin or cyclodextrin derivant clathrate, it is characterized in that: contain pinocembrin and cyclodextrin or cyclodextrin derivative, the molecule mol ratio of pinocembrin and cyclodextrin or cyclodextrin derivative is 1: 1～1: 100;
Said cyclodextrin derivative is selected from hydroxyethyl-, HP-, dihydroxypropyl-beta-schardinger dextrin-, methyl-beta-schardinger dextrin-, glucose-cyclodextrin, maltose-cyclodextrin, maltotriose-cyclodextrin, carboxymethyl-cyclodextrin, sulfoalkyl-cyclodextrin.
2. according to the pinocembrin and cyclodextrin or the cyclodextrin derivant clathrate of claim 1, it is characterized in that: the molecule mol ratio of pinocembrin and cyclodextrin or cyclodextrin derivative is 1: 1～1: 10.
3. according to pinocembrin and cyclodextrin arbitrary among the claim 1-2 or cyclodextrin derivant clathrate, it is characterized in that:
Said pinocembrin is selected from left-handed pinocembrin, dextrorotation pinocembrin, raceme pinocembrin;
Said cyclodextrin is selected from alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin.
Among the claim 1-3 each described pinocembrin and cyclodextrin or cyclodextrin derivant clathrate the preparation prevention with or the application of treatment in the cardiovascular and cerebrovascular diseases medicament.
5. according to the application of claim 4, it is characterized in that described cardiovascular and cerebrovascular disease is an apoplexy.
Among the claim 1-3 each described pinocembrin and cyclodextrin or cyclodextrin derivant clathrate the preparation prevention with or the treatment antibacterial with or the fungal infection medicine in application.
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| CN101744806B (en) * | 2008-12-11 | 2012-09-12 | 石药集团中奇制药技术（石家庄）有限公司 | Application of pinocembrin raceme in preparation of medicals for cerebral apoplexy |
| MX2011006141A (en) * | 2008-12-11 | 2011-09-21 | Cspc Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd | Use of racemates of pinocembrin in preparing medicaments for treating stroke. |
| CN102988279B (en) * | 2011-09-08 | 2016-06-15 | 石药集团中奇制药技术（石家庄）有限公司 | Pinocembrin and cyclodextrin super molecule inclusion compound and its preparation method |
| CN111330019B (en) * | 2018-12-18 | 2022-03-15 | 中国人民解放军第二军医大学 | Flumazenil clathrate compound and preparation method and application thereof |
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| CN1695608A (en) * | 2004-05-12 | 2005-11-16 | 中国医学科学院药物研究所 | Application of pinocembrin in preparing medication for treating disease relevant to hurt of nerve cell |
| CN1739537A (en) * | 2004-08-26 | 2006-03-01 | 张红军 | Cyclodextrin clathrate of breviscapine and its prepn |
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| CN1695608A (en) * | 2004-05-12 | 2005-11-16 | 中国医学科学院药物研究所 | Application of pinocembrin in preparing medication for treating disease relevant to hurt of nerve cell |
| CN1739537A (en) * | 2004-08-26 | 2006-03-01 | 张红军 | Cyclodextrin clathrate of breviscapine and its prepn |
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