CN1626067A - Preparation of honokiol, magnolol or their admixture and usage in preparing medication for treating cardiovascular and cerebrovascular diseases - Google Patents
Preparation of honokiol, magnolol or their admixture and usage in preparing medication for treating cardiovascular and cerebrovascular diseases Download PDFInfo
- Publication number
- CN1626067A CN1626067A CN 200310121303 CN200310121303A CN1626067A CN 1626067 A CN1626067 A CN 1626067A CN 200310121303 CN200310121303 CN 200310121303 CN 200310121303 A CN200310121303 A CN 200310121303A CN 1626067 A CN1626067 A CN 1626067A
- Authority
- CN
- China
- Prior art keywords
- magnolol
- honokiol
- mixture
- group
- cerebral
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- VVOAZFWZEDHOOU-UHFFFAOYSA-N honokiol Natural products OC1=CC=C(CC=C)C=C1C1=CC(CC=C)=CC=C1O VVOAZFWZEDHOOU-UHFFFAOYSA-N 0.000 title claims abstract description 351
- 239000003814 drug Substances 0.000 title claims abstract description 49
- 208000026106 cerebrovascular disease Diseases 0.000 title claims abstract description 22
- 230000002526 effect on cardiovascular system Effects 0.000 title claims abstract description 14
- 208000024172 Cardiovascular disease Diseases 0.000 title claims abstract description 11
- FVYXIJYOAGAUQK-UHFFFAOYSA-N honokiol Chemical compound C1=C(CC=C)C(O)=CC=C1C1=CC(CC=C)=CC=C1O FVYXIJYOAGAUQK-UHFFFAOYSA-N 0.000 title claims description 111
- BYTORXDZJWWIKR-UHFFFAOYSA-N Hinokiol Natural products CC(C)c1cc2CCC3C(C)(CO)C(O)CCC3(C)c2cc1O BYTORXDZJWWIKR-UHFFFAOYSA-N 0.000 title claims description 108
- 238000002360 preparation method Methods 0.000 title claims description 41
- 229940079593 drug Drugs 0.000 title abstract description 31
- 239000000203 mixture Substances 0.000 claims abstract description 98
- 238000002347 injection Methods 0.000 claims abstract description 41
- 239000007924 injection Substances 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 22
- 208000029078 coronary artery disease Diseases 0.000 claims abstract description 9
- 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 8
- 201000001429 Intracranial Thrombosis Diseases 0.000 claims abstract description 8
- 206010003119 arrhythmia Diseases 0.000 claims abstract description 6
- 230000006793 arrhythmia Effects 0.000 claims abstract description 6
- 206010019280 Heart failures Diseases 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 51
- 239000000284 extract Substances 0.000 claims description 41
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 36
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 33
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 26
- 206010008118 cerebral infarction Diseases 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 20
- 230000002490 cerebral effect Effects 0.000 claims description 17
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 235000010265 sodium sulphite Nutrition 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- 238000009472 formulation Methods 0.000 claims description 12
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 11
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 10
- 229930003268 Vitamin C Natural products 0.000 claims description 10
- 230000000302 ischemic effect Effects 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 10
- 235000019154 vitamin C Nutrition 0.000 claims description 10
- 239000011718 vitamin C Substances 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 9
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- 201000006474 Brain Ischemia Diseases 0.000 claims description 8
- 206010008088 Cerebral artery embolism Diseases 0.000 claims description 8
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 8
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 8
- 201000010849 intracranial embolism Diseases 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 150000002989 phenols Chemical class 0.000 claims description 8
- 229920001993 poloxamer 188 Polymers 0.000 claims description 8
- 206010008132 Cerebral thrombosis Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- -1 polyoxyethylene Polymers 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 6
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 claims description 6
- 239000008389 polyethoxylated castor oil Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000012546 transfer Methods 0.000 claims description 6
- 239000001856 Ethyl cellulose Substances 0.000 claims description 5
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 5
- 229920001249 ethyl cellulose Polymers 0.000 claims description 5
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- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
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- 239000008107 starch Substances 0.000 claims description 4
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- 239000004094 surface-active agent Substances 0.000 claims description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical group OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 3
- 241000218378 Magnolia Species 0.000 claims description 3
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- 239000003480 eluent Substances 0.000 claims description 3
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- 239000000796 flavoring agent Substances 0.000 claims description 3
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- 229960003511 macrogol Drugs 0.000 claims description 3
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
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Abstract
An application of the magnolol or its mixture in preparing the medicines for preventing and treating cardiovascular and cerebrovascular diseases (coronary heart disease, angina pectoris, arrhythmia, senile heart failure, cerebral thrombus, etc), the process for extracting magnolol, and the prepared medicines in the form of injection, slow-releasing form, release-controllable form, etc. are disclosed.
Description
Invention field
The present invention relates to honokiol, magnolol and/or its mixture purposes in preparation prevention or treatment cardiovascular and cerebrovascular diseases medicament, described cardiovascular and cerebrovascular disease is a coronary heart disease, angina pectoris, old heart failure, cerebral ischemia diseases such as arrhythmia and cerebral embolism, cerebral infarction, cerebral thrombosis.
Background technology
Cortex Magnoliae Officinalis is dried bark, root bark and the branch skin of Magnoliacea plant Cortex Magnoliae Officinalis Magnolia officinalis Rehd.et Wils, magnolia officinalis rehd.et wils.var.biloba rehd.et wils. Magnolia officinalis Rehd.et Wils.var.biloba Rehd.et Wils..Cortex Magnoliae Officinalis bitter in the mouth, suffering, warm in nature.Return spleen, stomach, lung, large intestine channel.Have dampness expectorant, the therapeutic method to keep the adverse QI flowing downwards and remove functions such as full.Be used for the humidity hysteresis damaging the spleen and stomach, the wrist painful abdominal mass is vomited and diarrhoea, stagnation of QI due to dyspepsia, and abdominal distention constipation, phlegm retention is breathed with cough.Therefore Cortex Magnoliae Officinalis all has been used for the treatment of digestive system disease since the successive dynasties.
The active component research of Cortex Magnoliae Officinalis mainly lays particular emphasis on Lignanoids compounds and alkaloid compound.Magnolol, honokiol are the main effective ingredient in the Cortex Magnoliae Officinalis, in the past studies show that it has various active such as of flaccid muscles, anxiety and maincenter inhibition, antimicrobial antiphlogistic activity, anti-arrhythmia, antioxidation, antitumor, has the rat brain of making electric wave as magnolol, honokiol to become the high-amplitude slow wave; Magnolol can suppress the chicken spinal reflex fully; When magnolol, honokiol have that maincenter suppresses and the maincenter myorelaxant effects, heavy dose of (100 and 250mg/kg, lumbar injection), the lax and righting reflex loss of mouse muscle was reached about 3 hours; Magnolol has significant antibacterial activity to gram-positive bacteria, acid resistance bacterium, yeast-like fungi and filamentous fungi; Magnolol and honokiol can both resist arrhythmia; Experiment finds that magnolol can pass through to discharge the endothelium derivation relaxing factor and the vasodilator smooth muscle, suppresses the calcium influx by pressure gate open (dependency)-calcium channel; Can suppress norepinephrine (NE) inductive rat chest aorta position phasic property and the contraction of tetanic property; Can suppress the inductive Ca-dependent rat aorta of high potassium and shrink, and have tangible dose-effect relationship.Magnolol and honokiol are the effective antiplatelet factors, and its mechanism is to have suppressed moving of thromboxane B2 and the interior calcium of platelet cell.
The toxic and side effects of Cortex Magnoliae Officinalis is detected in the report to Cortex Magnoliae Officinalis decoct and alkaloids composition magnocurarine thereof.The Cortex Magnoliae Officinalis decoct once irritates stomach 60g/kg for mice, observes 3 days, does not see death.Because the contained toxic component of Cortex Magnoliae Officinalis is mainly magnocurarine, it absorbs very slow in gastrointestinal tract, and is after the absorption, promptly by renal excretion, lower at blood level.The LD of Cortex Magnoliae Officinalis decoct mouse peritoneal injection
50Be 6.12 ± 0.038g/kg.And the LD of magnocurarine lumbar injection
50Be 45.55mg/kg.It is 4.25 ± 1.25g/kg that the Cortex Magnoliae Officinalis decoct is given the MLD of the quiet notes of cat, and under general muscle relaxant amount, the laboratory animal electrocardiogram does not have influence, and heavy dose can cause respiration inhibition and death.And magnolol, honokiol and composition thereof are not seen the toxicity report.
Summary of the invention
An object of the present invention is to provide the magnolol of formula I, the honokiol of formula II or its mixture, or the acceptable salt or derivatives thereof of its pharmacy is used for preparing the purposes of preventing or treating the medicine of cardiovascular and cerebrovascular disease:
The inventor finds by test, honokiol, magnolol or their mixture can prolong electricity irritation rat carotid artery thrombus formation time, anticoagulant, reduce malonaldehyde (MDA) content in the mouse brain ischemical reperfusion injury hindbrain, alleviate intraluminal middle cerebral artery occlusion in rats is blocked (MCAO) damage, can be effective to prevention or treatment cardiovascular and cerebrovascular disease, as coronary heart disease, angina pectoris, old heart failure, cerebral ischemia diseases such as arrhythmia and cerebral embolism, cerebral infarction, cerebral thrombosis.Therefore, the invention provides magnolol, honokiol or its mixture and be used for preparation prevention or treatment cerebral ischemia diseases, in particular for the purposes in the medicine of preparation prevention or treatment coronary heart disease, angina pectoris, cerebral thrombosis, cerebral infarction or cerebral embolism.
Honokiol of the present invention, magnolol or its mixture can or adopt new method of the present invention to extract from the plant Cortex Magnoliae Officinalis with known extracting method.Chinese patent CN 85103128A discloses the extracting method of magnolol and honokiol, comprise that the solution of using inorganic base such as sodium hydroxide, potassium hydroxide etc. earlier directly extracts magnolol and honokiol from raw material, adding a kind of mineral acid example hydrochloric acid, nitric acid or sulphuric acid then in extracting solution makes them emanate out in the acid solution middle reaches, a kind of organic solvent of reuse is refining, obtains the mixed crystallization of magnolol and honokiol.
Chinese patent application 01130129.5 discloses a kind of method of refining effective ingredient, it is characterized in that the Cortex Magnoliae Officinalis extract with magnolol and magnolol total content 10.0-50.0% is a raw material, be 20-50Pa successively in vacuum, it is 1-5Pa with vacuum that temperature is 80-120 ℃, temperature is to carry out molecular distillation under 100-250 ℃ the condition, obtains hypocrystalline or crystallized product.The response rate of this method is more than 90%, and magnolol and honokiol content are at 80.0-99.0%.
More than two patents be incorporated herein by reference at this paper comprehensively.
Under the situation of the mixture of honokiol and magnolol, the ratio of magnolol and honokiol can be arbitrarily, and preferred ratio can be magnolol: honokiol=1-8: 8-1.
In yet another aspect, the present invention also provides a kind of new method of extracting magnolol and honokiol from the plant Cortex Magnoliae Officinalis, may further comprise the steps:
Get magnolia medicament, use alcohol reflux, filter, merging filtrate, reclaim under reduced pressure is used organic solvent extraction to nothing alcohol flavor behind the concentrated solution dilute with water, and the extract reclaim under reduced pressure gets grease to doing, defat, recrystallization obtains the total phenols coarse-grain again.Can extract the total phenols coarse-grain simply, apace with method of the present invention, its extraction rate reached is more than 90%, and total phenol content reaches 90%～98%.
In yet another aspect, the present invention also provides a kind of method of separating honokiol and magnolol, comprise above-mentioned total phenols coarse-grain, be dissolved in an amount of ethanol, mix sample with column chromatography with polyamide, upper prop, 0.5%～2% sodium hydroxide gradient elution, eluent transfers to acidity with dilute hydrochloric acid, and with the eluting that TLC monitors active component, merges same section, use organic solvent extraction respectively, the evaporated under reduced pressure solvent, the white needle that obtains with the organic solvent recrystallization is the honokiol part, with mixed solvent repeatedly the white plates crystallization of recrystallization gained be the magnolol part.
In addition, the inventor studies show that by the internal metabolism to magnolol, honokiol and composition thereof, the oral absorption of magnolol, honokiol and composition thereof is very poor, generally have only about 4～8%, and owing to magnolol, honokiol and composition thereof have very strong bacteriostasis, take for a long time and will cause the unusual of human body normal flora, therefore, the inventor adopts dispersion technology that magnolol, honokiol and composition thereof are prepared into solid dispersed formulation, its oral absorption is reached more than 50%, improved the bioavailability of effective ingredient greatly.Simultaneously magnolol, honokiol and composition thereof are prepared into injection, adopt the method for intravenous injection or intramuscular injection to make medicine directly act on diseased region, have characteristics fast and efficiently, can reduce amount of drug greatly simultaneously, reduce its side effect.
In addition, the inventor shows by the pharmacokinetic to magnolol, honokiol and composition thereof, the blood plasma medicine of magnolol, honokiol and composition thereof curve for the moment is three Room open models or two Room open models, eliminate in its body rapidly, therefore for keeping blood drug level, the inventor adopts slow release or controlled-release technology, and it is long and steady that effective blood drug concentration is held time, the release that makes medicine is near zero level or first-rate, and can reduce amount of drug.
Another purpose of the present invention provides the injection that contains magnolol, honokiol or its mixture, said preparation comprises magnolol, honokiol or its mixture 0.1～10%, surfactant 0.1～30%, solubilizing agent 1～50%, antioxidant 0.1～1%, chelating agent 0.01～0.03%, surplus are water for injection.If there is not a specified otherwise, all percentage ratios used in the present invention are that the weight percentage of benchmark represents that promptly the content of various compositions is weight percentage in the preparation with the weight of described preparation all.
Surfactant described in the injection of the present invention is selected from Tween 80, and Tween 65, cremophorEL (polyoxyethylene castor oil), pluronic F-68 etc., or their mixture.Solubilizing agent for example comprises Polyethylene Glycol, glycerol, propylene glycol, ethanol, amino acid salts, lactose, mannitol, sorbitol, glucose, dextran etc., or their mixture.Antioxidant for example comprises vitamin C, sodium sulfite, sodium pyrosulfite etc., or their mixture.Chelating agent for example comprises edta salt, citrate etc.
In a preferred embodiment, injection of the present invention comprises magnolol, honokiol or its mixture 0.1～10%, Macrogol 200 (or 300,400) 1～30%, glycerol or propylene glycol or ethanol or their mixture 10～50%, sodium sulfite, sodium pyrosulfite, vitamin C or their mixture 0.1～1%, EDTA disodium salt 0.01～0.03%.
In another preferred embodiment, injection of the present invention comprises magnolol, honokiol or the two mixture 0.1～10%, pluronic F-68 0.2～10%, glycerol, propylene glycol, ethanol or their mixture 1～50%, sodium sulfite, sodium pyrosulfite, vitamin C or their mixture 0.1～1%, EDTA disodium salt 0.01～0.03%.
In still another preferred embodiment, injection of the present invention comprises magnolol, honokiol or the two mixture 0.1～10%, cremophorEL 1～20%, glycerol, propylene glycol, ethanol or their mixture 1～50%, sodium sulfite, sodium pyrosulfite, vitamin C or their mixture 0.1～1%, EDTA disodium salt 0.01～0.03%.
Another object of the present invention also provides the solid dispersed formulation of magnolol, honokiol or the two mixture, comprise magnolol, honokiol or the two mixture 5～50%, water-solubility carrier (PEG, polyvinylpyrrolidone, pluronic F-68, carbamide, the joint vector of saccharide and saccharide thereof and PEG) 95～50% solid dispersion of making, then this solid dispersion preparation technique routinely is prepared into drop pill, or with other adjuvants, be mixed with into tablet, capsule or granule as disintegrating agent, swelling adjuvant and diluent etc.
Another object of the present invention also provides the slow releasing preparation of magnolol, honokiol or the two mixture, comprises magnolol, honokiol or the mixture of the two 5～50%, high polymer adjuvant (PEG, methylcellulose, hydroxypropyl cellulose, ethyl cellulose, PVP, hydroxypropyl emthylcellulose) 90～45%, sucrose, starch, magnesium stearate, after Pulvis Talci etc. 1～5% mix, make slow releasing tablet or slow releasing capsule by preparation technique.
Magnolol of the present invention, honokiol or the mixture of the two be with the form administration of injection, infusion preparation or dispersant, and with slow releasing preparation or controlled release preparation form administration.
The dosage of magnolol of the present invention, honokiol or the mixture of the two depends on patient's body weight, age, the state of an illness, factors such as disease specific.As guidance, under the situation of injection, magnolol of the present invention, honokiol or the mixture daily dose of the two can be 0.01 μ g-20mg/kg body weight, can divide and advance medicine or successive administration for 1-3 time.
Description of drawings
Fig. 1 is the dissolution rate in vitro of solid dispersed formulation.
Fig. 2 is the dissolution rate in vitro of slow releasing tablet.
The specific embodiment
Further specify the present invention by the following examples, should be noted that, these embodiment only are used for illustrative purposes, do not constitute any restriction to the scope of the invention.
One, preparation embodiment
The preparation of embodiment 1 Cortex Magnoliae Officinalis extract
Get magnolia medicament, be ground into coarse powder, measure 95% alcohol reflux 3 times with 10 times, filter, merging filtrate, reclaim under reduced pressure is used chloroform extraction to there not being the alcohol flavor behind the concentrated solution dilute with water, the extract reclaim under reduced pressure is to doing, get grease, use defat with petroleum ether then, reuse chloroform recrystallization obtains the total phenols coarse-grain, its extraction ratio is greater than 90%, the content of total phenols adopts HPLC method mensuration, and [octadecylsilane chemically bonded silica is a filler, methanol: 0.05% phosphoric acid solution (77: 23), detection wavelength: 294, flow velocity: 1ml/min], its magnolol, honokiol content sum is between 90～98%.
Embodiment 2 honokiols separate with magnolol
Get the total phenols coarse-grain of embodiment 1, be dissolved in an amount of ethanol, mix sample with column chromatography with polyamide, upper prop, 0.5%～2% sodium hydroxide gradient elution, eluent transfers to acidity with dilute hydrochloric acid, and TLC monitors active component, merge same section, use chloroform extraction respectively, the chloroform solution evaporated under reduced pressure.White needle with cyclohexane extraction recrystallization gained is the honokiol part, with petroleum ether-ether repeatedly the white plates crystallization of recrystallization gained be the magnolol part, the content of gained honokiol adopts the HPLC method, and [octadecylsilane chemically bonded silica is a filler, methanol: 0.05% phosphoric acid solution (77: 23), detect wavelength: 294, flow velocity: 1ml/min] assay, content is greater than 99.0%, and yield is greater than 90.0%; Gained magnolol content adopts HPLC method assay, and content is greater than 99.5%, and yield is greater than 90.0%.
Embodiment 3 injections
Magnolol, honokiol or the two mixture 0.2%, PEG200 10%, glycerol 50%, sodium sulfite 0.2%, EDTA disodium salt 0.03% and water surplus.
Preparation method: precision takes by weighing medicine, adds Macrogol 200 and glycerol, is stirred to medicine and dissolves fully, add the aqueous solution of sodium sulfite and EDTA, stir, add water for injection to ormal weight, stir to clear and bright, regulate pH value to neutral with dilute hydrochloric acid or dilute sodium hydroxide.Filter embedding, sterilization.
Embodiment 4 injections
Magnolol, honokiol or the two mixture 10%, PEG200 30%, propylene glycol 50%, sodium pyrosulfite 1%, EDTA disodium salt 0.01% and water surplus.
Preparation method is with embodiment 3.
Embodiment 5 injections
Magnolol, honokiol or the two mixture 1.0%, PEG200 2%, ethanol 10%, vitamin C 0.2%, EDTA disodium salt 0.03% and water surplus.
Preparation method is with embodiment 3.
Embodiment 6 injections
Magnolol, honokiol or the two mixture 1.0%, pluronic F-68 10%, glycerol 50%, sodium pyrosulfite 0.2%, EDTA disodium salt 0.03% and water surplus.
Preparation method is with embodiment 3.
Embodiment 7 injections
Magnolol, honokiol or the two mixture 0.5%, pluronic F-68 10%, ethanol 50%, sodium sulfite 0.2%, EDTA disodium salt 0.03% and water surplus.
Preparation method is with embodiment 3.
Embodiment 8 injections
Magnolol, honokiol or the two mixture 0.5%, cremophor EL 1%, glycerol 15%, vitamin C 1.0%, EDTA disodium salt 0.03% and water surplus.
Preparation method is with embodiment 3.
Embodiment 9 injections
Magnolol, honokiol or the two mixture 1.0%, cremophor EL 10%, propylene glycol 20%, sodium sulfite 0.2%, EDTA disodium salt 0.03% and water surplus.
Preparation method is with embodiment 3.
Magnolol, honokiol or the two mixture 5.0%, cremophor EL 20%, ethanol 50%, sodium pyrosulfite 0.2%, EDTA disodium salt 0.03% and water surplus.
Preparation method is with embodiment 3.
Embodiment 11 injections
Magnolol, honokiol or the two mixture 10.0%, cremophor EL 20%, propylene glycol 30%, sodium sulfite 0.2%, EDTA disodium salt 0.03% and water surplus.
Preparation method is with embodiment 3.
Embodiment 12-14 drop pill
Magnolol, honokiol or the two mixture 25.0%, Polyethylene Glycol (PEG)-6000 or PEG-12000 or PEG20000 75%, the embodiment 12-14 that the PEG of different molecular weight is corresponding different.
Preparation method: with the Polyethylene Glycol heating and melting, add accurate claim fixed magnolol, honokiol or the two mixture then, stir to make and be dissolved into clear solution, drip and make drop pill.
Embodiment 15 slow releasing tablets
Magnolol, honokiol or the two mixture 10.0%, PEG-6000 30%, ethyl cellulose (EC) 10%, hydroxypropyl methylcellulose (HPC) 25%, starch 20%, Pulvis Talci 4%, magnesium stearate 1%
Preparation method: get mixed solvent (95% ethanol: CH
2Cl
2=1: 1) an amount of, add magnolol, honokiol or the two mixture, stir and make its dissolving, add the PEG6000 stirring and make its dissolving, decompression and solvent recovery, add EC, HPC, the starch mix homogeneously is made granule, add Pulvis Talci, the magnesium stearate mix homogeneously, tabletting, promptly.
Two, the light stability of injection and heat stability are investigated the result
1, we have investigated the light stability of above-mentioned preparation as follows, get each three of three batches of injection of embodiment 3,6 and 9 respectively, are positioned under the condition of 4000lx and shine, get 0 respectively, each one of 5,10 days three batch sample are carried out visual examination and assay.Three batch sample visual examinations are achromaticity and clarification respectively, and measures content of effective with the content of each time point percentage calculation of content to zero time respectively, and the result is as follows:
Embodiment 3 100.00% 100.53% 101.98%
Embodiment 6 100.00% 100.79% 97.79%
Embodiment 9 100.00% 100.78% 99.22%
As seen, above-mentioned preparation is very stable under above-mentioned illumination experiment condition.
To sum up: preparation stability meets the requirements.
2, we have investigated the heat stability of above-mentioned preparation as follows, get each three of three batches of injection of embodiment 3,6 and 9 respectively, are positioned over 60 ℃ condition heated at constant temperature, get 0 respectively, 30,90 days three batch samples are carried out visual examination and assay.Three batch sample visual examinations are achromaticity and clarification and measure content of effective with the content of each time point percentage calculation of content to zero time respectively respectively, and the result is as follows:
0 day 30 days 90 days
Embodiment 3 100% 102.86% 102.53%
Embodiment 6 100% 104.25% 104.68%
Embodiment 9 100% 101.72% 100.02%
As seen, above-mentioned preparation is very stable equally under the accelerated tests condition.
To sum up: preparation stability meets the requirements.
Three, distribution experimental result in the body
We have carried out the experiment that distributes in the rat body to the injection of embodiment 3,6,9, and the result shows that above-mentioned injection can be distributed to rapidly in each histoorgan, and is wherein the highest with the brain abundance, is kidney, heart and liver secondly.Illustrate that medicine can effectively be distributed in the diseased region of human body.The results are shown in Table 1.
Distribution behind the above-mentioned injection of table 1 intravenous injection 20mg/kg in each tissue
Time (minute) brain liver heart kidney
2??????????26.01±2.84????????56.27±????????????????????58.52±5.81??????53.91±
20.51????????????????????????????20.22
5??????????26.98±3.08????????38.43±????????????????????28.48±0.47??????33.25±5.27
12.39
10?????????20.86±1.51????????6.32±3.02??????15.30±1.97??????16.35±1.42
15?????????16.41±1.51????????9.55±1.34??????10.86±1.33??????13.45±0.82
30?????????9.41±1.02?????????3.08±1.07??????6.28±1.00???????5.51±0.92
60?????????4.95±0.32?????????2.89±0.60??????4.86±0.82???????2.54±0.83
120????????1.19±0.16?????????0.75±0.46??????2.08±0.37???????1.03±0.21
Four, the dissolution rate in vitro of magnolol, honokiol and the two mixture solid dispersible preparation is measured and is measured in the intravital bioavailability of rat.
By " 2000 editions one appendix XC of Chinese pharmacopoeia " dissolution method " carries out, rotating speed 100r/min, 37 ± 0.5 ℃ of bath temperatures, dissolution medium is the simulated gastric fluid 900ml of pH1.2, dosage is solid dispersed formulation and the conventional tablet of content of dispersion 30mg, described solid dispersed formulation is the drop pill of embodiment 12, and its dissolution rate the results are shown in Table 2 and Fig. 1.
The dissolution rate in vitro of table 2 solid dispersed formulation and conventional tablet (%) (n=6)
Time solid dispersed formulation dissolution rate ordinary tablet dissolution rate
1?????????????8.04?????????????????0.4
2?????????????25.81????????????????1.35
5?????????????39.9?????????????????2.31
10????????????55.58????????????????8.69
20????????????64.98????????????????18.96
30????????????73.31????????????????22.01
45????????????85.64????????????????26.91
60????????????92.88????????????????30.1
Five, the dissolution rate of slow releasing tablet is measured
By " " dissolution method " carries out 2000 editions appendix XC of Chinese pharmacopoeia, rotating speed 50r/min, 37 ± 0.5 ℃ of bath temperatures, dissolution medium is distilled water 900ml, dosage is the solid dispersed formulation of content of dispersion 30mg, used slow releasing tablet is that embodiment 15 is obtained, and its dissolution rate the results are shown in Figure 2.
Six, the pharmacodynamics test of magnolol, honokiol and the two mixture
1, honokiol is to the influence of electricity irritation rat carotid artery thrombus formation time
Experimental technique: body weight is that 50 of the SD male rats of 300 ± 20g are divided into 5 groups at random: heavy dose of group (honokiol 5 * 10-5g/kg), middle dosage group (honokiol 5 * 10-6g/kg), small dose group (honokiol 5 * 10-7g/kg), positive drug control group (aspirin 5 * 10-3g/kg) and blank group (0.9% normal saline).15% urethane anesthetized rat.It is fixing that rat is lain on the back, and the capable 2cm otch of cervical region separates right carotid, and it is standby to wear plastic strip.The tongue intravenous administration clocks, and the right carotid of standby separator well is connected with the thrombosis analyzer.10min gives 2mA galvanism blood vessel 3min after the administration, the record thrombus formation time.The blank group gives 0.9% normal saline of equal volume.Experimental result is referring to table 3.
Table 3 honokiol is to the influence (n=10) of electricity irritation rat carotid artery thrombus formation time
Group dosage (g/kg) thrombus formation time min
Blank group/8.9 ± 1.1
Positive drug control group 5 * 10
-313.4 ± 5.3
*
The heavy dose of group 5 * 10 of honokiol
-515.9 ± 4.7
*
Dosage group 5 * 10 in the honokiol
-611.4 ± 3.1
*
Honokiol small dose group 5 * 10
-710.9 ± 3.4
*Represent P＜0.05,
*Represent P＜0.01
2, honokiol is to the influence of platelet aggregation in the rabbit body
Experimental technique: body weight is that 30 of the adult male rabbit of 3.0～4.0kg are divided at random: heavy dose of group (honokiol 1.2 * 10-5g/kg), middle dosage group (honokiol 1.2 * 10-6g/kg), small dose group (honokiol 1.2 * 10-7g/kg), positive drug control group (aspirin 1.2 * 10-3g/kg) and blank group (0.9% normal saline), measure 6 rabbits for every group, measure next group dosage at interval behind the 72h.Rabbit is weighed, and the ear medium-sized artery is got blood 4ml (anticoagulant in 1: 9 of 3.8% sodium citrate).The auricular vein administration, behind the administration 15min once more the ear medium-sized artery get blood 2ml (anticoagulant in 1: 9 of 3.8% sodium citrate) in test tube.With the centrifugal PRP (platelet rich plasma) that obtains of anticoagulation; The centrifugal again PPP (platelet poor plasma) that obtains of lower floor.Get PPP respectively and PRP places platelet aggregation instrument, transfer the PRP turbidity with the PPP of self animal, make each PRP turbidity identical, PRP adds collagen (the empty mg/ml of final concentration) and causes platelet aggregation, record maximum agglutination rate at 37 ℃ of incubation 1min.Experimental result is referring to table 4.
Table 4 honokiol is to the influence (n=6) of platelet aggregation in the rabbit body
The suppression ratio (%) of group dosage (g/kg) platelet aggregation
Blank group 6.1 ± 33.5
Positive drug control group 5 * 10
-395.1 ± 7.6
*
The heavy dose of group 5 * 10 of honokiol
-577.4 ± 29.4
*
Dosage group 5 * 10 in the honokiol
-670.8 ± 27.3
*
Honokiol small dose group 5 * 10
-760.6 ± 24.9
*
*Represent P＜0.05,
*Represent P＜0.01
3, honokiol is to the influence of MDA in the mouse brain ischemical reperfusion injury hindbrain
Experimental technique: choose body weight and be 60 of the ICR male mices of 25～35g, be divided into 6 groups at random: heavy dose of group (honokiol 7 * 10-5g/kg), middle dosage group (honokiol 7 * 10-6g/kg), small dose group (honokiol 7 * 10-7g/kg), blank group (0.9% normal saline), positive drug control group (vitamin E 0.5g/kg) and sham operated rats.Mice is weighed, chloral hydrate anesthesia, it is fixing to lie on the back, cervical region 3cm otch separates bilateral common carotid arteries 30min, unclamp bulldog clamp and unclamp bulldog clamp after 30 minutes, mice immediately in ice bath down broken end get brain, cerebral tissue-40 is ℃ frozen, measures with pending MDA; The blank group gives the normal saline of equal volume; Positive drug control group is continuous gastric infusion 5 days, and once a day, dosage 0.5g/kg carried out the ischemia-reperfusion operation in 1 hour in last administration.Sham operated rats is only isolated common carotid artery, does not press from both sides to close not administration, and it is frozen to get cerebral tissue behind the 1h.
Cerebral tissue 0-4 ℃ is thawed, and the thiobarbituricacid method is measured MDA level in the cerebral tissue, represents with the 532nm absorbance.Experimental result is referring to table 5.
Table 5 honokiol is to the influence (n=10) of MDA in the mouse brain ischemical reperfusion injury hindbrain
Group dosage (g/kg) OD (A532) value
Blank group 0.302 ± 0.03
Sham operated rats 0.223 ± 0.03
*
Positive drug control group 0.5 0.247 ± 0.03
*
The heavy dose of group 7 * 10 of honokiol
-50.243 ± 0.03
*
Dosage group 7 * 10 in the honokiol
-60.257 ± 0.05
*
Honokiol small dose group 7 * 10
-70.279 ± 0.04
*Represent P＜0.05,
*Represent P＜0.01
4, honokiol blocks the influence of (MCAO) damage to intraluminal middle cerebral artery occlusion in rats
Experimental technique: with body weight is that the 300-350g male SD rat is divided into 6 groups at random, every group 10, be respectively heavy dose of group (honokiol 5 * 10-5g/kg), middle dosage group (honokiol 5 * 10-6g/kg), small dose group (0.9% normal saline) and sham operated rats.Administering mode is the tongue intravenous administration, divides three administrations, 24h behind 3h and the ischemia behind the preceding 15min of ischemia, the ischemia.
Concrete operations are as follows:
Operation group rat is weighed, 7% chloral hydrate (350mg/kg, ip) anesthesia, tongue intravenously administrable.Cervical region center row 2cm operative incision, isolate common carotid artery, external carotid artery and internal carotid artery, threading and ligation common carotid artery proximal part and external carotid artery insert the about 22mm of internal carotid artery place with the nylon wire of the good length of labelling, and with surgical thread ligation, fixing, layer-by-layer suture skin.Postoperative 3h is the tongue intravenously administrable once more, the administration for the third time of postoperative 24h anesthesia back tongue vein, 15min sacrificed by decapitation after the administration, get brain section under the ice bath, 2%TTC dyeing, section, take pictures, photo ischemic area and non-ischemic area are cut weighed at last, calculate the ischemia ratio.Sham operated rats is only gone otch, separates carotid artery, plug wire not, and not administration is sewed up back 24h and is got brain.The normal saline group is consistent with the operation of operation group, gives the normal saline of equal volume when being administration.Experimental result is referring to table 6.
Table 6. honokiol blocks the influence (n=10) of (MCAO) damage to intraluminal middle cerebral artery occlusion in rats
| Group | Dosage (g/kg) | Cerebral infarct size (%) |
| The blank group | 42.92±14.08 | |
| Sham operated | 0 | |
| Positive drug control group | 1.2 | 9.94±11.70 ** |
| The heavy dose of group of honokiol | 5×10 -5 | 15.48±15.36 ** |
| Dosage group in the honokiol | 5×10 -6 | 15.75±14.16 ** |
| The honokiol small dose group | 5×10 -7 | 22.94±16.67 * |
*：P＜0.05，
**：P＜0.01
5, magnolol is to the influence of electricity irritation rat carotid artery thrombus formation time
Experimental technique: body weight is that 50 of the SD male rats of 300 ± 20g are divided into 5 groups at random: heavy dose of group (magnolol 2.5 * 10-5g/kg), middle dosage group (magnolol 2.5 * 10-6g/kg), small dose group (magnolol 2.5 * 10-7g/kg), positive drug control group (aspirin 5 * 10-3g/kg) and blank group (0.9% normal saline).15% urethane anesthetized rat.It is fixing that rat is lain on the back, and the capable 3cm otch of cervical region separates right carotid, and it is standby to wear plastic strip.The tongue intravenous administration clocks, and the right carotid of standby separator well is connected with the thrombosis analyzer.10min gives 2mA galvanism blood vessel 3min after the administration, the record thrombus formation time.The blank group gives 0.9% normal saline of equal volume.Experimental result is referring to table 7.
Table 7. magnolol is to the influence (n=10) of electricity irritation rat carotid artery thrombus formation time
Group dosage (g/kg) thrombus formation time min
Blank group/8.3 ± 1.8
Positive drug control group 5 * 10
-312.9 ± 4.4
*
The heavy dose of group 2.5 * 10 of magnolol
-517.3 ± 5.1
*
Dosage group 2.5 * 10 in the magnolol
-612.4 ± 4.3
*
Magnolol small dose group 2.5 * 10
-710.9 ± 4.1
*：P＜0.05，
**：P＜0.01
6, magnolol is to the influence of platelet aggregation in the rabbit body
Experimental technique: 30 of adult male rabbit, body weight 3.0～4.0kg, random packet, experiment is divided into: heavy dose of group (magnolol 2.5 * 10-5g/kg), middle dosage group (magnolol 2.5 * 10-6g/kg), small dose group (magnolol 2.5 * 10-7g/kg), positive drug control group (aspirin 1.2 * 10-3g/kg) and blank group (0.9% normal saline), measure 6 rabbits for every group, measure next group dosage at interval behind the 72h.Rabbit is weighed, and the ear medium-sized artery is got blood 4ml (anticoagulant in 1: 9 of 3.8% sodium citrate).The auricular vein administration, behind the administration 15min once more the ear medium-sized artery get blood 2ml (anticoagulant in 1: 9 of 3.8% sodium citrate) in test tube.With the centrifugal PRP (platelet rich plasma) that obtains of anticoagulation; The centrifugal again PPP (platelet poor plasma) that obtains of lower floor.Get PPP respectively and PRP places platelet aggregation instrument, transfer the PRP turbidity with the PPP of self animal, make each PRP turbidity identical, PRP adds collagen (final concentration 3mg/ml) and causes platelet aggregation at 37 ℃ of incubation 1min, the record maximum agglutination rate.Experimental result is referring to table 8.
Table 8. magnolol is to the influence (n=6) of platelet aggregation in the rabbit body
The suppression ratio (%) of group dosage (g/kg) platelet aggregation
Blank group 6.1 ± 33.5
Positive drug control group 1.2 * 10
-395.1 ± 7.6
*
The heavy dose of group 2.5 * 10 of magnolol
-593.4 ± 12.3
*
Dosage group 2.5 * 10 in the magnolol
-678.9 ± 9.0
*
Magnolol small dose group 2.5 * 10
-770.3 ± 8.9
*
*Represent P＜0.05,
*Represent P＜0.01
7, magnolol is to the influence of MDA in the mouse brain ischemical reperfusion injury hindbrain
Experimental technique: choosing body weight is 60 of 25～35g ICR male mices, is divided into 6 groups at random: heavy dose of group (magnolol 5 * 10
-5G/kg), middle dosage group (magnolol 5 * 10
-6G/kg), small dose group (magnolol 5 * 10
-7G/kg), blank group (0.9% normal saline), positive drug control group (vitamin E 0.5g/kg) and sham operated rats.Mice is weighed, chloral hydrate anesthesia, and it is fixing to lie on the back, and cervical region 3cm otch separates bilateral common carotid arteries, and threading is standby.Magnolol administration group is closed bilateral common carotid arteries 30min with noinvasive small artery folder folder, unclamp bulldog clamp 30min and form reperfusion injury, in ischemia and when logical more respectively tail vein injection be administered once, unclamp bulldog clamp after 30 minutes, mice breaks end down in ice bath immediately and gets brain, cerebral tissue-40 is ℃ frozen, measures with pending MDA; The blank group gives the normal saline of equal volume; Positive drug control group is continuous gastric infusion 5 days, and once a day, dosage is 0.5g/kg, carries out the ischemia-reperfusion operation in 1 hour in last administration.Sham operated rats is only isolated common carotid artery, does not press from both sides to close not administration, and it is frozen to get cerebral tissue behind the 1h.
Cerebral tissue is thawed for 0～4 ℃, and the thiobarbituricacid method is measured MDA level in the cerebral tissue, represents with the 532nm absorbance.Experimental result is referring to table 9.
Table 9. magnolol is to the influence (n=10) of MDA in the mouse brain ischemical reperfusion injury hindbrain
Group dosage (g/kg) OD (A532) value
Blank group 0.302 ± 0.03
Sham operated rats 0.223 ± 0.03
*
Positive drug control group 0.5 0.247 ± 0.03
*
The heavy dose of group 5 * 10 of magnolol
-50.246 ± 0.02
*
Dosage group 5 * 10 in the magnolol
-60.251 ± 0.03
*
Magnolol small dose group 5 * 10
-70.269 ± 0.06
*：P＜0.05，
**：P＜0.01
8, magnolol blocks the influence of (MCAO) damage to intraluminal middle cerebral artery occlusion in rats
Experimental technique: with body weight is that the male SD rat of 300～350g is divided into 6 groups at random, every group 10, be respectively heavy dose of group (magnolol 5 * 10-5g/kg), middle dosage group (magnolol 5 * 10-6g/kg), small dose group (magnolol 5 * 10-7g/kg), positive drug control group (Radix Salviae Miltiorrhizae Injection 1.2g/kg), blank group (0.9% normal saline) and sham operated rats.Administering mode is the tongue intravenous administration, divides three administrations, 24h. behind 3h and the ischemia behind the preceding 15min of ischemia, the ischemia.
Concrete operations are as follows:
Operation group rat is weighed, 7% chloral hydrate (350mg/kg, ip) anesthesia, tongue intravenously administrable.Cervical region center row 2cm operative incision, isolate common carotid artery, external carotid artery and internal carotid artery, threading and ligation common carotid artery proximal part and external carotid artery insert the about 22mm of internal carotid artery place with the nylon wire of the good length of labelling, and with surgical thread ligation, fixing, layer-by-layer suture skin.Postoperative 3h is the tongue intravenously administrable once more, the administration for the third time of postoperative 24h anesthesia back tongue vein, 15min sacrificed by decapitation after the administration, get brain section under the ice bath, 2%TTC dyeing, section, take pictures, photo ischemic area and non-ischemic area are cut weighed at last, calculate the ischemia ratio.Sham operated rats is only gone otch, separates carotid artery, plug wire not, and not administration is sewed up back 24h and is got brain.The normal saline group is consistent with the operation of operation group, gives the normal saline of equal volume when being administration.Experimental result is referring to table 11.
Table 11. magnolol blocks the influence (n=10) of (MCAO) damage to intraluminal middle cerebral artery occlusion in rats
Group dosage (g/kg) cerebral infarct size (%)
Blank group 42.92 ± 14.08
Sham operated rats 0
Three nine-day periods after the winter solstice Radix Salviae Miltiorrhizae Injection matched group 1.2 9.94 ± 11.70
*
The heavy dose of group 5 * 10 of magnolol
-510.05 ± 12.63
*
Dosage group 5 * 10 in the magnolol
-612.72 ± 13.24
*
Magnolol small dose group 5 * 10
-721.29 ± 15.31
*
*Represent P＜0.05,
*Represent P＜0.01
9, Cortex Magnoliae Officinalis extract (mixture of magnolol and honokiol) is to the influence of electricity irritation rat carotid artery thrombus formation time
Experimental technique: body weight is that 50 of the male rats of 300 ± 20g SD are divided into 5 groups at random: heavy dose of group [(content is 95%, and Cortex Magnoliae Officinalis extract content is by magnolol)] (Cortex Magnoliae Officinalis extract 1 * 10-4g/kg), middle dosage group (Cortex Magnoliae Officinalis extract 1 * 10-5g/kg), small dose group (Cortex Magnoliae Officinalis extract 1 * 10-6g/kg), positive drug control group (aspirin 5 * 10-3g/kg) and blank group (0.9% normal saline).15% urethane anesthetized rat.It is fixing that rat is lain on the back, and the capable 3cm otch of cervical region separates right carotid, and it is standby to wear plastic strip.The tongue intravenous administration clocks, and the right carotid of standby separator well is connected with the thrombosis analyzer.10min gives 2mA galvanism blood vessel 3min after the administration, the record thrombus formation time.The blank group gives 0.9% normal saline of equal volume.Experimental result is referring to table 12.
Table 12. Cortex Magnoliae Officinalis extract is to the influence (n=10) of electricity irritation rat carotid artery thrombus formation time
Group dosage (g/kg) bolt formation time min
Blank group/8.9 ± 1.1
Positive drug control group 5 * 10
-313.4 ± 5.3
*
The heavy dose of group 1 * 10 of Cortex Magnoliae Officinalis extract
-419.3 ± 5.9
*
Dosage group 1 * 10 in the Cortex Magnoliae Officinalis extract
-516.2 ± 4.6
*
Cortex Magnoliae Officinalis extract small dose group 1 * 10
-615.4 ± 3.1
*
*Represent P＜0.05,
*Represent P＜0.01
10, Cortex Magnoliae Officinalis extract is to the influence of platelet aggregation in the rabbit body
Experimental technique: 30 of adult male rabbit, body weight 3.0～4.0kg, random packet, experiment is divided into: heavy dose of group (Cortex Magnoliae Officinalis extract 4 * 10-5g/kg), middle dosage group (Cortex Magnoliae Officinalis extract 4 * 10-6g/kg), small dose group (Cortex Magnoliae Officinalis extract 4 * 10-7g/kg), positive drug control group (aspirin 1.2 * 10-3g/kg) and blank group (0.9% normal saline), measure 6 rabbits for every group, measure next group dosage at interval behind the 72h.Rabbit is weighed, and the ear medium-sized artery is got 4ml (anticoagulant in 1: 9 of 3.8% sodium citrate).The auricular vein administration, behind the administration 15min once more the ear medium-sized artery get blood 2ml (anticoagulant in 1: 9 of 3.8% sodium citrate) in test tube.With the centrifugal PRP (platelet rich plasma) that obtains of anticoagulation; The centrifugal again PPP (platelet poor plasma) that obtains of lower floor.Get PPP respectively and PRP places platelet aggregation instrument, transfer the PRP turbidity with the PPP of self animal, make each PRP turbidity identical, PRP adds collagen (final concentration 3mg/ml) and causes platelet aggregation at 37 ℃ of incubation 1min, the record maximum agglutination rate.Experimental result is referring to table 13.
Table 13. Cortex Magnoliae Officinalis extract is to the influence (n=6) of platelet aggregation in the rabbit body
Group
The suppression ratio (%) of dosage (g/kg) platelet aggregation
Blank group 6.1 ± 33.5
Positive drug control group 1.2 * 10
-395.1 ± 7.6
*
The heavy dose of group 4 * 10 of Cortex Magnoliae Officinalis extract
-587.8 ± 9.7
*
Dosage group 4 * 10 in the Cortex Magnoliae Officinalis extract
-682.8 ± 7.9
*
Cortex Magnoliae Officinalis extract small dose group 4 * 10
-776.1 ± 4.5
*
*：P＜0.05，
**：P＜0.01
11, Cortex Magnoliae Officinalis extract is to the influence of MDA in the mouse brain ischemical reperfusion injury hindbrain
Experimental technique: choose 60 of ICR male mices, body weight 25～35g is divided into 6 groups at random: heavy dose of group (Cortex Magnoliae Officinalis extract 1 * 10-4g/kg), middle dosage group (Cortex Magnoliae Officinalis extract 1 * 10-5g/kg), small dose group (Cortex Magnoliae Officinalis extract 1 * 10-6g/kg), blank group (0.9% normal saline), positive drug control group (vitamin E 0.5g/kg) and sham operated rats.Mice is weighed, chloral hydrate anesthesia, and it is fixing to lie on the back, and cervical region 3cm otch separates bilateral common carotid arteries, and threading is standby.Cortex Magnoliae Officinalis extract administration group is closed bilateral common carotid arteries 30min with noinvasive small artery folder folder, unclamp bulldog clamp 30min and form reperfusion injury, in ischemia and when logical more respectively tail vein injection be administered once, unclamp bulldog clamp after 30 minutes, mice breaks end down in ice bath immediately and gets brain, cerebral tissue-40 is ℃ frozen, measures with pending MDA; The blank group gives the normal saline of equal volume; Positive drug control group is continuous gastric infusion 5 days, and once a day, dosage is 0.5g/kg, carries out the ischemia-reperfusion operation in 1 hour in last administration.Sham operated rats is only isolated common carotid artery, does not press from both sides to close not administration, and it is frozen to get cerebral tissue behind the 1h.
Cerebral tissue is thawed for 0～4 ℃, and the thiobarbituricacid method is measured MDA level in the cerebral tissue, represents with the 532nm absorbance.Experimental result is referring to table 14.
Table 14. Cortex Magnoliae Officinalis extract is to the influence (n=10) of MDA in the mouse brain ischemical reperfusion injury hindbrain
Group dosage (g/kg) OD (A532) value
Blank group 0.302 ± 0.03
Sham operated rats 0.223 ± 0.03
*
Positive drug control group 0.5 0.247 ± 0.03
*
The heavy dose of group 1 * 10 of Cortex Magnoliae Officinalis extract
-40.227 ± 0.05
*
Dosage group 1 * 10 in the Cortex Magnoliae Officinalis extract
-50.231 ± 0.04
*
Cortex Magnoliae Officinalis extract small dose group 1 * 10
-60.243 ± 0.06
*
*：P＜0.05，
**：P＜0.01
12, Cortex Magnoliae Officinalis extract blocks the influence of (MCAO) damage to intraluminal middle cerebral artery occlusion in rats
Experimental technique: with body weight is that the male SD rat of 300～350g is divided into 6 groups at random, every group 10, be respectively heavy dose of group (Cortex Magnoliae Officinalis extract 1 * 10-4g/kg), middle dosage group (Cortex Magnoliae Officinalis extract 1 * 10-5g/kg), small dose group (Cortex Magnoliae Officinalis extract 1 * 10-6g/kg), positive drug control group (Radix Salviae Miltiorrhizae Injection 1.2g/kg), blank group (0.9% normal saline) and sham operated rats.Administering mode is the tongue intravenous administration, divides three administrations, 24h. behind 3h and the ischemia behind the preceding 15min of ischemia, the ischemia.
Concrete operations are as follows:
Operation group rat is weighed, 7% chloral hydrate (350mg/kg, ip) anesthesia, tongue intravenously administrable.Cervical region center row 2cm operative incision, isolate common carotid artery, external carotid artery and internal carotid artery, threading and ligation common carotid artery proximal part and external carotid artery insert the about 22mm of internal carotid artery place with the nylon wire of the good length of labelling, and with surgical thread ligation, fixing, layer-by-layer suture skin.Postoperative 3h is the tongue intravenously administrable once more, the administration for the third time of postoperative 24h anesthesia back tongue vein, 15min sacrificed by decapitation after the administration, get brain section under the ice bath, 2%TTC dyeing, section, take pictures, photo ischemic area and non-ischemic area are cut weighed at last, calculate the ischemia ratio.Sham operated rats is only gone otch, separates carotid artery, plug wire not, and not administration is sewed up back 24h and is got brain.The normal saline group is consistent with the operation of operation group, gives the normal saline of equal volume when being administration.Experimental result is referring to table 15.
Table 15. Cortex Magnoliae Officinalis extract blocks the influence (n=10) of (MCAO) damage to intraluminal middle cerebral artery occlusion in rats
Group dosage (g/kg) cerebral infarct size (%)
Blank group 42.92 ± 14.08
Sham operated rats 0
Radix Salviae Miltiorrhizae Injection matched group 1.2 9.94 ± 11.70
*
The heavy dose of group 1 * 10 of Cortex Magnoliae Officinalis extract
-410.53 ± 10.60
*
Dosage group 1 * 10 in the Cortex Magnoliae Officinalis extract
-511.15 ± 12.03
*
Extract magnolol small dose group 1 * 10
-612.25 ± 11.05
*
*：P＜0.05，
**：P＜0.01
13, the clinical meaning of the pharmacodynamic index of above-mentioned honokiol, magnolol and composition thereof
1) honokiol, magnolol and composition thereof are to platelet aggregation and thrombotic effect
Platelet aggregation and artery thrombosis play an important role in the morbidity of coronary heart disease and cerebral infarction with in reaccessing, anticoagulant is a requisite medicine for the treatment of and prevent these two big class diseases clinically, share with the thrombolytic medicine and can strengthen the thrombolytic effect, and the generation that prevents or delay to block again.Honokiol, magnolol and composition thereof have very strong anticoagulant and thrombotic effect, can become the medicine of new control cardiovascular and cerebrovascular disease, especially to coronary heart disease, angina pectoris, ischemic cardiovascular and cerebral vascular diseases such as cerebral embolism, cerebral infarction, cerebral thrombosis have very effective treatment and preventive effect.
2) honokiol, magnolol and composition thereof are to the influence of cerebral ischemia reperfusion injury
Need to carry out the revascularization that thromboembolism treatment makes obstruction behind cerebral ischemia and the cerebral embolism, recover blood supply, the oxygen supply of cerebral tissue, this process can be brought out the generation of oxygen-derived free radicals, makes lipid peroxidation, thereby increases the weight of the damage of brain cell.Malonaldehyde (MDA) is the metabolite of lipid peroxidation; honokiol, magnolol and composition thereof can reduce the level of the MDA of ischemia-reperfusion mouse brain tissue; show that it can be used as the protective agent of cerebral ischemia reperfusion injury; prevent or when alleviating revascularization to brain tissue injury; especially to described coronary heart disease; angina pectoris, old heart failure, ischemic cardiovascular and cerebral vascular diseases such as arrhythmia and cerebral embolism, cerebral infarction, cerebral thrombosis have notable therapeutic effect.
3) honokiol, magnolol and composition thereof block the influence of (MCAO) cerebral ischemic model to intraluminal middle cerebral artery occlusion in rats
Common clinically brain lacks the property apoplexy to be caused owing to mesencephalic arteries blocks, this model class is similar to people's cerebral infarction, honokiol, magnolol and composition thereof can obviously reduce the cerebral infarct size of MCAO rat, can be clinically as preventing and treating the new drug of cerebral infarction, especially cerebral infarction there is very effective therapeutic effect, for coronary heart disease, angina pectoris notable therapeutic effect is arranged also equally.
Claims (16)
1, magnolol, honokiol or its mixture or its pharmaceutically acceptable salt are used for preparing the purposes of prevention or treatment cardiovascular and cerebrovascular diseases medicament, described cardiovascular and cerebrovascular disease especially is a coronary heart disease, angina pectoris, old heart failure, arrhythmia, and cerebral ischemia diseases such as cerebral embolism, cerebral infarction, cerebral thrombosis.
2, purposes according to claim 1, wherein said cardiovascular and cerebrovascular disease are the cerebral ischemia diseases of ischemic cardiovascular and cerebral vascular disease, especially cerebral thrombosis, cerebral infarction or cerebral embolism.
3, the method of a kind of extraction separation magnolol and honokiol, may further comprise the steps: get magnolia medicament, use alcohol reflux, filter, merging filtrate, reclaim under reduced pressure is to there not being the alcohol flavor, use chloroform extraction behind the concentrated solution dilute with water, the extract reclaim under reduced pressure gets grease, defat to doing, recrystallization obtains the total phenols coarse-grain again, then the total phenols coarse-grain is dissolved in an amount of ethanol, mixes sample with polyamide, upper prop with column chromatography, 0.5%～2% sodium hydroxide gradient elution, eluent transfers to acidity with dilute hydrochloric acid, and TLC monitors active component, merges same section, use chloroform extraction respectively, the chloroform solution evaporated under reduced pressure is the honokiol part with the white needle of cyclohexane extraction recrystallization gained, with petroleum ether-ether repeatedly the white plates crystallization of recrystallization gained be the magnolol part.
4, a kind of injection that contains magnolol, honokiol or its mixture, it is characterized in that: the percentage by weight of each component is in the preparation, magnolol, honokiol or its mixture 0.1～10%, surfactant 0.1～30%, solubilizing agent 1～50%, antioxidant 0.1～1%, chelating agent 0.01～0.03%, water for injection surplus.
5, injection according to claim 4, described surfactant is selected from Tween 80, and Tween 65, cremophor EL (polyoxyethylene castor oil), pluronic F-68, or their mixture.
6, according to the arbitrary described injection of claim 4-5, described solubilizing agent is selected from poly-7 glycol, glycerol, propylene glycol, ethanol, amino acid salts, lactose, mannitol, sorbitol, glucose, dextran, or their mixture.
7, according to the arbitrary described injection of claim 4-6, described antioxidant is selected from vitamin C, sodium sulfite, sodium pyrosulfite, or their mixture.
8, according to the arbitrary described injection of claim 4-7, described chelating agent is selected from edta salt or citrate.
9, according to the arbitrary described injection of claim 4-8, comprise magnolol, honokiol or its mixture 0.1～10%, Macrogol 200～400 1～30%, glycerol or propylene glycol or ethanol or their mixture 10～50%, sodium sulfite, sodium pyrosulfite, vitamin C or their mixture 0.1～1%, EDTA disodium salt 0.01～0.03%.
10, according to the arbitrary described injection of claim 4-9, comprise magnolol, honokiol or the two mixture 0.1～10%, pluronic F-68 0.2～10%, glycerol, propylene glycol, ethanol or their mixture 1～50%, sodium sulfite, sodium pyrosulfite, vitamin C or their mixture 0.1～1%, EDTA disodium salt 0.01～0.03%.
11, according to the arbitrary described injection of claim 4-10, comprise magnolol, honokiol or the two mixture 0.1～10%, cremophor EL 1～20%, glycerol, propylene glycol, ethanol or their mixture 1～50%, sodium sulfite, sodium pyrosulfite, vitamin C or their mixture 0.1～1%, EDTA disodium salt 0.01～0.03%.
12, a kind of contain magnolol, honokiol or its mixture solid dispersed formulation, it is characterized in that: the percentage by weight of each component is in the preparation, magnolol, honokiol or the two mixture 5～50%, water-solubility carrier 50～95%.
13, solid dispersed formulation according to claim 12, described water-solubility carrier are selected from PEG, polyvinylpyrrolidone, pluronic F-68, carbamide, the joint vector of saccharide and saccharide thereof and PEG.
14,, solid dispersed formulation preparation technique routinely can be prepared into drop pill, or be prepared into tablet, capsule or granule with disintegrating agent, swelling adjuvant and mixing diluents according to the arbitrary described solid dispersed formulation of claim 12-13.
15, a kind of slow releasing preparation that contains magnolol, honokiol or its mixture, it is characterized in that: the percentage by weight of each component is in the preparation, comprises magnolol, honokiol or the mixture of the two 5～50%, high polymer adjuvant 95～50%.
16, slow releasing preparation according to claim 15, described high polymer adjuvant is selected from PEG, methylcellulose, hydroxypropyl cellulose, ethyl cellulose, PVP, hydroxypropyl emthylcellulose, especially can with sucrose, starch, magnesium stearate, after Pulvis Talci mixed, preparation technique made slow releasing tablet or slow releasing capsule routinely.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2003101213030A CN100374107C (en) | 2003-12-11 | 2003-12-11 | Preparation of honokiol, magnolol or their admixture and usage in preparing medication for treating cardiovascular and cerebrovascular diseases |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2003101213030A CN100374107C (en) | 2003-12-11 | 2003-12-11 | Preparation of honokiol, magnolol or their admixture and usage in preparing medication for treating cardiovascular and cerebrovascular diseases |
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| CN1626067A true CN1626067A (en) | 2005-06-15 |
| CN100374107C CN100374107C (en) | 2008-03-12 |
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| CNB2003101213030A Expired - Fee Related CN100374107C (en) | 2003-12-11 | 2003-12-11 | Preparation of honokiol, magnolol or their admixture and usage in preparing medication for treating cardiovascular and cerebrovascular diseases |
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| WO2006129898A1 (en) * | 2005-05-30 | 2006-12-07 | Korea Institute Of Oriental Medicine | A mass separation method of magnolol from magnoliae cortex ormagnoliae radix |
| CN102178666A (en) * | 2011-03-21 | 2011-09-14 | 四川大学 | Application of Honokiol to preparing drugs for preventing or treating intracranial space occupying lesion and intracranial tissues and organs inflammation |
| CN102267877A (en) * | 2011-09-05 | 2011-12-07 | 于华忠 | Method for extracting and separating magnolol and honokiol from leaf of magnolia officinalis |
| CN104095817A (en) * | 2014-07-22 | 2014-10-15 | 武汉工程大学 | Nanoparticles containing magnolol or honokiol as well as preparation method and application of nanoparticles |
| CN104739932A (en) * | 2013-12-31 | 2015-07-01 | 瑞普（天津）生物药业有限公司 | Preparation method of mangnolia officinalis perfusion fluid for dairy cow mastitis |
| CN105012242A (en) * | 2015-07-21 | 2015-11-04 | 南京中医药大学 | Solid dispersion prepared from magnolol, honokiol or mixture of magnolol and honokiol and preparation method of solid dispersion by hot-melt extrusion |
| CN105726521A (en) * | 2014-12-10 | 2016-07-06 | 瑞普（天津）生物药业有限公司 | Emulsion containing magnolol or honokiol, and preparation method of emulsion |
| CN109771431A (en) * | 2018-02-10 | 2019-05-21 | 成都贝诺科成生物科技有限公司 | The new application of honokiol derivative |
| CN109875983A (en) * | 2018-12-10 | 2019-06-14 | 广州医科大学附属第二医院 | A kind of agonist of aldehyde dehydrogenase 2 |
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| CN112933302A (en) * | 2021-02-02 | 2021-06-11 | 四川大学华西医院 | Multifunctional biomedical coating material based on traditional Chinese medicine magnolia officinalis and preparation method thereof |
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| WO2006129898A1 (en) * | 2005-05-30 | 2006-12-07 | Korea Institute Of Oriental Medicine | A mass separation method of magnolol from magnoliae cortex ormagnoliae radix |
| US7608741B2 (en) * | 2005-05-30 | 2009-10-27 | Korea Institute Of Oriental Medicine | Mass separation method of magnolol from Magnoliae cortex radix |
| CN102178666A (en) * | 2011-03-21 | 2011-09-14 | 四川大学 | Application of Honokiol to preparing drugs for preventing or treating intracranial space occupying lesion and intracranial tissues and organs inflammation |
| CN102267877A (en) * | 2011-09-05 | 2011-12-07 | 于华忠 | Method for extracting and separating magnolol and honokiol from leaf of magnolia officinalis |
| CN104739932A (en) * | 2013-12-31 | 2015-07-01 | 瑞普（天津）生物药业有限公司 | Preparation method of mangnolia officinalis perfusion fluid for dairy cow mastitis |
| CN104095817A (en) * | 2014-07-22 | 2014-10-15 | 武汉工程大学 | Nanoparticles containing magnolol or honokiol as well as preparation method and application of nanoparticles |
| CN105726521A (en) * | 2014-12-10 | 2016-07-06 | 瑞普（天津）生物药业有限公司 | Emulsion containing magnolol or honokiol, and preparation method of emulsion |
| CN105012242A (en) * | 2015-07-21 | 2015-11-04 | 南京中医药大学 | Solid dispersion prepared from magnolol, honokiol or mixture of magnolol and honokiol and preparation method of solid dispersion by hot-melt extrusion |
| CN109771431A (en) * | 2018-02-10 | 2019-05-21 | 成都贝诺科成生物科技有限公司 | The new application of honokiol derivative |
| CN109875983A (en) * | 2018-12-10 | 2019-06-14 | 广州医科大学附属第二医院 | A kind of agonist of aldehyde dehydrogenase 2 |
| CN111789811A (en) * | 2020-08-07 | 2020-10-20 | 火人科创(北京)药物研发有限公司 | Injection solution and freeze-dried powder of honokiol for injection and preparation method thereof |
| CN112933302A (en) * | 2021-02-02 | 2021-06-11 | 四川大学华西医院 | Multifunctional biomedical coating material based on traditional Chinese medicine magnolia officinalis and preparation method thereof |
| CN112933302B (en) * | 2021-02-02 | 2022-06-03 | 四川大学华西医院 | Multifunctional biomedical coating material based on traditional Chinese medicine magnolia officinalis and preparation method thereof |
| CN115414339A (en) * | 2022-10-10 | 2022-12-02 | 深圳市中医院 | Application of honokiol in preparation of medicine for treating kidney diseases |
| CN116270473A (en) * | 2023-05-25 | 2023-06-23 | 成都金瑞基业生物科技有限公司 | Co-carried liposome and preparation method thereof |
| CN116270473B (en) * | 2023-05-25 | 2023-12-19 | 成都金瑞基业生物科技有限公司 | Co-carried liposome and preparation method thereof |
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| CN100374107C (en) | 2008-03-12 |
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