CN103012345B - Luteolin alpha crystal form substance, preparation method thereof as well as pharmaceutical composition and application thereof - Google Patents
Luteolin alpha crystal form substance, preparation method thereof as well as pharmaceutical composition and application thereof Download PDFInfo
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- CN103012345B CN103012345B CN201210535776.4A CN201210535776A CN103012345B CN 103012345 B CN103012345 B CN 103012345B CN 201210535776 A CN201210535776 A CN 201210535776A CN 103012345 B CN103012345 B CN 103012345B
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Abstract
The invention discloses an alpha crystal form substance of luteolin with chemical name of 5,7,3',4'-tetrahydroxy flavone) compound and a preparation method thereof, a pharmaceutical composition containing mixed crystal forms of luteolin alpha crystal forms and (alpha+beta) mixed crystal forms in any proportion and an application of the luteolin crystal form substance used as effective pharmaceutical ingredients in preparation of medicines used for preventing and treating nervous system disease, cardiocerebral vascular system disease, digestive system disease, inflammation and infectious diseases.
Description
Technical field
The invention discloses two kinds of crystal-form substances of compound of luteolin and preparation method thereof, the pharmaceutical composition that contains luteolin alpha-crystal form, beta crystal and (alpha+beta) mixing crystal formation, and luteolin crystal-form substances is as effective ingredient, the application in nervous system disorders, diseases of cardiovascular and cerebrovascular systems, digestive system, disease of immune system, inflammation and infectious diseases.
Background technology
Luteolin (chemical name: 5,7,3', 4'-kaempferol; English name: Luteolin)
Luteolin molecular structure
At Chinese patent CN1613445(publication number) in recorded " application in suppressing intestinal peristalsis medicine of luteolin and derivative thereof " of Dalian Inst of Chemicophysics, Chinese Academy of Sciences's invention
[1].Wherein, related to the application in suppressing intestinal peristalsis medicine of luteolin and derivative thereof.
At Chinese patent CN1785991(publication number) in recorded the invention of Chuanda Huaxi Pharmaceutical Industry Co., Ltd. Sichuan Prov. and Sichuan University " a kind of anti inflammatory detoxication luteolin kind new medicine and preparation method thereof "
[3].Wherein, related to a kind of anti inflammatory detoxication luteolin kind derivative and preparation method thereof.
At Chinese patent CN1947747(publication number) in recorded the invention of yellow Zhenhua " pharmaceutical composition of being made by luteolin and the capsule of weeping forsythia and its production and use "
[3].Wherein, related to the preparation method of the pharmaceutical composition that luteolin, the capsule of weeping forsythia or Fructus Forsythiae extract form and its in antibacterial, antiviral, anti-inflammatory, antitumor, analgesia, relieving cough and reducing sputum, antipyretic, protect the liver, the aspect effect such as hemostasis, reducing blood-fat, anti-oxidant, immunomodulatory.
Summary of the invention
One of the object of the invention: two kinds of crystal formation solid matter samples that are to provide luteolin alpha-crystal form and beta crystal.
Two of the object of the invention: the process of preparing that is to provide two kinds of crystal formation solid matter samples of luteolin alpha-crystal form and beta crystal.
Three of the object of the invention: be to provide and contain luteolin alpha-crystal form sterling, beta crystal sterling or mixed solid pharmaceutical and the composition thereof of the different crystal forms forming by (alpha+beta) crystal formation by different ratios proportioning, comprise the different pharmaceutical dosage forms such as tablet, capsule, pill, injection, sustained release preparation, controlled release preparation.
Four of the object of the invention: be to provide the solid crystal formation medicine that contains luteolin alpha-crystal form, beta crystal, (alpha+beta) crystal formation in performance pharmacological agent mechanism and produce the impact of specific absorption difference.
Five of the object of the invention: be to provide the effect of luteolin crystal-form substances in preventing and treating nervous system disorders, diseases of cardiovascular and cerebrovascular systems or other class disease, and the therapeutic action that improves Plasma Concentration performance in organism in treatment various diseases process due to crystal formation effect.
Six of the object of the invention: be to provide and use luteolin alpha-crystal form, beta crystal and (alpha+beta) mixing crystal formation solid matter and the common raw material as effective ingredient of flavonoid chemical substance (or other class chemical substance) combination that becomes to grade (containing different chemical composition kind, different content proportioning), exploitation compound chemical medicine and the various pharmaceutical preparation thereof made, and be applied to prevent and treat nervous system disorders, diseases of cardiovascular and cerebrovascular systems, digestive system, disease of immune system or and other class diseases etc.
Seven of the object of the invention: be to provide and use luteolin alpha-crystal form, beta crystal and (alpha+beta) mixing crystal formation solid matter and the common raw material as effective ingredient of herbal medicine (containing Chinese medicine compound prescription, Chinese medicinal materials, extract part etc.) combinations of substances (containing different sorts, different content proportioning), exploitation herbal mixture medicine and the various pharmaceutical preparation thereof made, and be applied to prevent and treat nervous system disorders, diseases of cardiovascular and cerebrovascular systems, digestive system, disease of immune system or and other class diseases etc.
This patent has been found two kinds of different crystal forms (alpha-crystal form and beta crystal) solid matter existence of compound of luteolin, and has invented the preparation method of two kinds of crystal form samples; The present invention finds that two kinds of crystal formation solid matters of luteolin exist absorptivity difference in vivo, wherein beta crystal specific absorption is greater than alpha-crystal form, the comparable alpha-crystal form of specific absorption of beta crystal improves more than 1.5 times, in performance pharmacological agent, on because specific absorption is different, and the Plasma Concentration causing thus changes and causes medicine biological action difference.
In addition, the present invention has also found that luteolin crystal-form substances is different from the medical active effect of above-mentioned 3 patent reports, by neuroprotective, monoamine oxidase restraining effect, the re-absorbed restraining effect of neurotransmitter 5-HT, performance prevents and treats nervous system disorders and senile nervous system disorders, comprises the nerve degenerative diseases such as Parkinson's disease, senile dementia; Luteolin crystal-form substances also has good therapeutic action in diseases of cardiovascular and cerebrovascular systems, disease of immune system, digestive system, inflammatory reaction and infectious diseases simultaneously.
Technical characterictic
1. the morphological specificity of alpha-crystal form luteolin sample:
1.1. luteolin alpha-crystal form solid matter of the present invention, is characterized in that (CuK when using powder x-ray diffraction analysis
αradiation), show as diffraction peak position: 2-Theta value (°) or d value
with diffraction peak relative intensity: crystalline state solid matter when peak height value (Height%) or peak area value (Area%) have following characteristic peaks (table 1, Fig. 1):
The powder x-ray diffraction characteristic peaks of table 1 alpha-crystal form luteolin sample
1.2. luteolin alpha-crystal form solid matter of the present invention, when using DSC collection of illustrative plates (Fig. 2) to analyze, is characterized in that having two endotherm(ic)peaks in its DSC collection of illustrative plates, and transformation value is respectively about 162 ° of C left and right and 339 ° of C.
1.3. luteolin alpha-crystal form solid matter of the present invention, when using KBr compressing tablet to analyze, the infrared absorption spectrum (Fig. 3) obtaining is characterized in that its infrared absorption exists: 3419.3, 3108.5, 3070.8, 2978.1, 2902.9, 2817.9, 2763.1, 2694.6, 2629.0, 1655.3, 1611.4, 1576.8, 1502.0, 1457.3, 1443.2, 1401.3, 1366.7, 1313.3, 1266.1, 1251.8, 1191.8, 1165.0, 1138.3, 1120.9, 1097.5, 1031.7, 999.2, 953.9, 931.6, 876.9, 861.2, 838.4, 815.7, 791.2, 758.1, 685.6, 666.9, 642.1, 602.6, 565.1, 520.1, 472.1, 457.4, 422.7cm
-1there is an absorption peak at place, wherein 3419.3,3108.5,3070.8,2978.1,2902.9,2763.1,2694.6,2629.0,1457.3,1191.8,953.5,931.6,758.1,666.9,472.1cm
-1peak is the principal character absorption peak of luteolin alpha-crystal form solid matter.
2. the morphological specificity of beta crystal luteolin sample:
2.1. luteolin beta crystal solid matter of the present invention, is characterized in that (CuK when using powder x-ray diffraction analysis
αradiation), show as diffraction peak position: 2-Theta value (°) or d value
with diffraction peak relative intensity: solid matter when peak height value (Height%) or peak area value (Area%) have following characteristic peaks (table 2, Fig. 4):
The powder x-ray diffraction characteristic peaks of table 2 beta crystal luteolin sample
2.2. luteolin beta crystal solid matter of the present invention, when using DSC collection of illustrative plates (Fig. 5) to analyze, is characterized in that having two endotherm(ic)peaks in its DSC collection of illustrative plates, and its transformation value is respectively about 147 ° of C left and right and 337 ° of C.
2.3. luteolin beta crystal solid matter of the present invention, when using KBr compressing tablet to analyze, the infrared absorption spectrum (Fig. 6) obtaining is characterized in that its infrared absorption exists: 3416.2, 3043.0, 2973.3, 2896.5, 2814.0, 2748.1, 2691.9, 2622.0, 1655.6, 1610.7, 1575.6, 1502.1, 1442.2, 1363.9, 1299.6, 1264.5, 1189.9, 1163.8, 1138.4, 1119.6, 1095.4, 1030.4, 998.3, 945.6, 876.0, 860.5, 837.0, 815.3, 789.6, 761.5, 685.3, 641.2, 601.4, 563.2, 518.1, 492.9, 456.7, 422.8cm
-1there is an absorption peak at place, wherein 3416.2,3043.0,2973.3,2896.5,2748.1,2691.9,2622.0,1299.6,1189.9,945.6,761.5,492.9cm
-1peak is the principal character absorption peak of luteolin beta crystal solid matter.
3. the pharmacodynamic profile of luteolin sample:
3.1 suppress activity of monoamine oxidase.The mixing crystal formation solid matter sample that luteolin alpha-crystal form sterling of the present invention, beta crystal sterling, the combination of (alpha+beta) crystal formation arbitrary proportion obtain, it is characterized in that having inhibition brain Inner activity of monoamine oxidase, the metabolism of minimizing to neurotransmitter, improve the partial concn of brain Inner neurotransmitter, reach the effect of performance treatment disease.
3.2 suppress neurotransmitter 5-HT heavily absorbs.The mixing crystal formation solid matter sample that luteolin alpha-crystal form sterling of the present invention, beta crystal sterling, the combination of (alpha+beta) crystal formation arbitrary proportion obtain, it is characterized in that having and suppress brain Inner nerve synapse to the re-absorbed restraining effect of neurotransmitter 5-HT, improve the neurotransmitter concentration in nerve synapse gap, the effect of performance disease preventing and treating.
3.3 in addition, and luteolin crystal-form substances is at cardiovascular and cerebrovascular, anti-inflammatory, immunosuppression, anti-infective and strengthen the aspects such as gastrointestinal function and all can bring into play preventive and therapeutic effect.
4. the bioavailability feature of luteolin sample:
Luteolin alpha-crystal form sterling of the present invention and beta crystal sterling all can be passed through oral absorption, but bioavailability there are differences, the bioavailability of oral beta crystal sterling is higher more than 1.5 times than alpha-crystal form, and two kinds of crystal formations combine in any proportion the mixed crystal solid matter sample obtaining and also have different bioavailability difference.
5. the dosage of luteolin sample and pharmaceutical preparation feature:
Further aspect of the present invention also relates to usings the pharmaceutical composition of the compounds of this invention as active ingredient.Pharmaceutical preparation feature of the present invention is to contain the mixing crystal formation solid sample that luteolin alpha-crystal form sterling, beta crystal sterling, the combination of (alpha+beta) crystal formation arbitrary proportion obtain, it is characterized in that every day dosage in 2000mg scope with interior pharmaceutical composition.Pharmaceutical composition of the present invention, contain effective dose as claim 1(alpha-crystal form) and or claim 4(beta crystal) and claim 7(alpha+beta mixing crystal formation) as described in luteolin solid matter and pharmaceutically acceptable carrier.Pharmaceutical composition also contains flavonoid chemical substance, or also contains herbal medicine material.Described herbal medicine material comprises Chinese medicine compound prescription, Chinese medicinal materials, extract part.This pharmaceutical composition includes the different pharmaceutical dosage forms such as tablet, capsule, pill, injection, sustained release preparation, controlled release preparation.
This pharmaceutical composition can be according to method preparation well known in the art.Can be suitable for any formulation of human or animal's use by the pharmaceutically acceptable solid of the compounds of this invention and one or more or liquid excipient and/or assistant agent being combined, making.The content of the compounds of this invention in its pharmaceutical composition is generally 0.1-95 % by weight.
The compounds of this invention or the pharmaceutical composition that contains it can unit dosage form administrations, route of administration can be enteron aisle or non-enteron aisle, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For the compounds of this invention is made to tablet, can be widely used various vehicle well known in the art, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet further can also be made to coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
For capsule is made in administration unit, effective constituent the compounds of this invention can be mixed with thinner, glidant, mixture is directly placed in to hard capsule or soft capsule.Also can by effective constituent the compounds of this invention first with thinner, tamanori, disintegrating agent granulation or micropill, then be placed in hard capsule or soft capsule.Also the capsule that can be used for preparing the compounds of this invention for the preparation of each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind of the compounds of this invention tablet.
For the compounds of this invention is made to injection, can water, ethanol, Virahol, propylene glycol or their mixture as solvent and add the conventional solubilizing agent in appropriate this area, solubility promoter, pH to adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.
In addition,, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives or other additive.
For reaching medication object, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.
The dosage of the compounds of this invention pharmaceutical composition is according to character and the severity that will prevent or treat disease, the individual instances of patient or animal, and route of administration and formulation etc. can have large-scale variation.In general, the appropriate dose scope of the every day of the compounds of this invention is 0.001-150mg/Kg body weight, is preferably 0.1-100mg/Kg body weight, and more preferably 1-60mg/Kg body weight, most preferably is 2-30mg/Kg body weight.Above-mentioned dosage can a dose unit or is divided into several dose unit administrations, and this depends on doctor's clinical experience and comprises the dosage regimen of using other treatment means.
Compound of the present invention or composition can be taken separately, or merge and use with other treatment medicine or symptomatic drugs.When compound of the present invention and other medicine existence synergy, should adjust according to practical situation its dosage.
Accompanying drawing explanation
The x-ray diffractogram of powder spectrum of Fig. 1 alpha-crystal form luteolin sample
The DSC collection of illustrative plates of Fig. 2 alpha-crystal form luteolin sample
The infrared absorption pattern of Fig. 3 alpha-crystal form luteolin sample
The x-ray diffractogram of powder spectrum of Fig. 4 beta crystal luteolin sample
The DSC collection of illustrative plates of Fig. 5 beta crystal luteolin sample
The infrared absorption pattern of Fig. 6 beta crystal luteolin sample
Different time blood Chinese traditional medicine concentration after Fig. 7 luteolin Oral Administration in Rats (300mg/kg)
Fig. 8 luteolin (5 μ g/ml) is to monoamine oxidase and the re-absorbed restraining effect of 5-HT
Embodiment
For better explanation technical scheme of the present invention, spy provides following examples, but the present invention is not limited to this content.
Crystal formation preparation
Embodiment 1
The preparation method 1 of luteolin alpha-crystal form sample:
A preparation method for luteolin alpha-crystal form sample, is characterized in that using the single solvent systems such as chloroform, acetone, ethyl acetate, propyl carbinol, acetonitrile, tetrahydrofuran (THF), dioxane, Glacial acetic acid, formic acid, ether, methylene dichloride, toluene, benzene, normal hexane, hexanaphthene, dioxane, DMF, sherwood oil, ammoniacal liquor, n-propyl alcohol, water.First luteolin sample is dissolved completely, is placed on temperature range at 4 ° of C to 350 ° of C, relative humidity scope 90% with interior environment under, through recrystallization growth time 1 day to 60 days, the alpha-crystal form solid sample finally preparing.
Embodiment 2
The preparation method 2 of luteolin alpha-crystal form sample:
A kind of preparation method of luteolin alpha-crystal form sample, it is characterized in that using methyl alcohol, ethanol, Virahol, 95% ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, acetonitrile, tetrahydrofuran (THF), dioxane, Glacial acetic acid, formic acid, ether, methylene dichloride, toluene, benzene, normal hexane, hexanaphthene, dioxane, DMF, sherwood oil, ammoniacal liquor, n-propyl alcohol, water equal solvent kind, the mixed solvent system of making from different proportionings through various combination (two or more solvent is used).First luteolin sample is dissolved completely, is placed on temperature range at 4 ° of C to 350 ° of C, relative humidity scope 90% with interior environment under, through recrystallization growth time 1 day to 60 days, the alpha-crystal form solid sample finally preparing.
Embodiment 3
The preparation method 1 of luteolin beta crystal sample:
The preparation method of luteolin beta crystal sample, is characterized in that using luteolin alpha-crystal form solid sample as raw material, through solid abrasive, heating etc., turns the beta crystal solid sample that brilliant technique and other physics rotating crystal method prepare.
Embodiment 4
The preparation method 2 of luteolin beta crystal sample:
The preparation method of luteolin beta crystal sample, it is characterized in that using the single solvent systems such as chloroform, acetone, ethyl acetate, propyl carbinol, acetonitrile, tetrahydrofuran (THF), dioxane, Glacial acetic acid, formic acid, ether, methylene dichloride, toluene, benzene, normal hexane, hexanaphthene, dioxane, DMF, sherwood oil, ammoniacal liquor, n-propyl alcohol, water by after luteolin sample dissolution, re-use cold spray method and obtain fast beta crystal solid sample.
Preparation
Embodiment 5
The preparation method 1(tablet of combined pharmaceutical formulation):
A kind of preparation method of combined pharmaceutical formulation, it is characterized in that using the bulk drug of several vehicle using luteolin alpha-crystal form sterling, beta crystal sterling or the solid matter that mixed by different ratios proportioning by (alpha+beta) crystal formation as medicinal composition, make every content of dispersion at the tablet of 10 ~ 500mg, table 3 provides tablet formulation:
The preparation formula of table 3 luteolin medicinal composition tablet
The method that luteolin alpha-crystal form sterling, beta crystal sterling or the bulk drug that mixed by different ratios proportioning by (alpha+beta) crystal formation is prepared into tablet formulation is: several vehicle are mixed with bulk drug, add 1% sodium cellulose glycolate solution appropriate, make soft material, the granulation of sieving, wet grain is dried, and the whole grain that sieves, adds Magnesium Stearate and talcum powder to mix, compressing tablet, obtains.
Embodiment 6
The preparation method 2(capsule of combined pharmaceutical formulation):
A kind of preparation method of combined pharmaceutical formulation, it is characterized in that using the bulk drug of several vehicle using luteolin alpha-crystal form sterling, beta crystal sterling or the solid matter that mixed by different ratios proportioning by (alpha+beta) crystal formation as medicinal composition, make every content of dispersion at the capsule of 10 ~ 500mg, table 4 provides capsule formula:
The preparation formula of table 4 luteolin medicinal composition capsule
The method that luteolin alpha-crystal form sterling, beta crystal sterling or the bulk drug that mixed by different ratios proportioning by (alpha+beta) crystal formation is prepared into capsule preparations is: several vehicle are mixed with bulk drug, add 1% sodium cellulose glycolate solution appropriate, make wet grain, dry, whole grain sieves, add Magnesium Stearate, mix, insert capsule and make.Or do not use granulation step, and directly that bulk drug and several mixed with excipients is even, after sieving, directly incapsulate and make.
Pharmacological evaluation
Embodiment 7
The luteolin solid material medicine of alpha-crystal form and beta crystal Absorption Characteristics and Plasma Concentration feature in vivo:
To clean level rat stomach Inner, give pure alpha-crystal form, pure beta crystal, (alpha+beta) mixing crystal formation luteolin solid material medicinal powder end, dosage is 300mg/kg, after administration, in different time points, extract rat artery hematometry content of luteolin (table 5, Fig. 7).Result proves: the luteolin bulk drug of different crystal forms under the condition of oral same dosage, the drug level in blood and the asynchronism(-nization) of concentration of peaking, wherein the Plasma Concentration of alpha-crystal form is starkly lower than the Plasma Concentration of beta crystal.
The Plasma Concentration (HPLC detection) of different time after table 5 Oral Administration in Rats luteolin different crystal forms sample
Embodiment 8
Luteolin (5 μ g/ml) is to monoamine oxidase and the re-absorbed restraining effect of 5-HT:
By Bioexperiment, prove that luteolin (5 μ g/ml) has obvious restraining effect to monoamine oxidase respectively, heavily absorbs and also has obvious restraining effect (Fig. 8) 5-HT simultaneously.Illustrate that luteolin has therapeutic action to nervous system disorders and diseases of cardiovascular and cerebrovascular systems, particularly nerve degenerative diseases and senile nervous system disease have preventive and therapeutic effect.
Embodiment 9
Adopt 6-OHDA (6-OHDA) damage SD rat brain dopaminergic neuron, preparation Parkinson's disease (PD) model, with apomorphine (APO) abdominal injection (0.5mg/kg) induction PD symptom, visible animal is all of a tremble, the back of a bow, perpendicular tail, tremble, movable slow, grasp, smell the symptom of visiting and rotatablely move etc.The number of turns rotatablely moving by recording animal, evaluates animal movement behavior disorder degree, and result proves, animal model is successfully prepared.Luteolin to the circling behavior of animal pattern without obvious effect, and with positive drug madopar there was no significant difference relatively, the results are shown in Table 6.
The circling behavior impact of table 6 luteolin on 6-OHDA damage SD rat
Embodiment 10
Adopt 6-OHDA (6-OHDA) damage SD rat brain dopaminergic neuron, preparation Parkinson's disease (PD) model, with apomorphine (APO) abdominal injection (0.5mg/kg) induction PD symptom, visible animal is all of a tremble, the back of a bow, perpendicular tail, tremble, movable slow, grasp, smell the symptoms such as spy.By recording the myoelectrical activity of animal hindlimb muscle, evaluate degree and the drug effect of PD symptom.Result is visible, and luteolin can significantly reduce animal pattern muscular tremor frequency and amplitude, and (with model group comparison, P<0.05), effect is better than positive drug madopar, the results are shown in Table 7.
The tremble impact of table 7 luteolin on 6-OHDA damage SD rat
Note: with model group comparison, * P<0.05, * * P<0.01.
Claims (10)
1. the alpha-crystal form of luteolin, is characterized in that, uses powder x-ray diffraction analysis to adopt CuK
αradiation experiments condition, diffraction peak position: 2-Theta value (°) or d value
with diffraction peak relative intensity: peak height value (Height%) or peak area value (Area%) have following feature:
2. one kind contains luteolin alpha-crystal form as claimed in claim 1 and two kinds of crystal form samples of luteolin beta crystal mixing crystal formation solid matter that combination obtains after physical mixed in any proportion; Wherein said luteolin beta crystal, is used powder x-ray diffraction analysis to adopt CuK
αradiation experiments condition, diffraction peak position: 2-Theta value (°) or d value
with diffraction peak relative intensity: peak height value (Height%) or peak area value (Area%) have following feature:
3. the preparation method of luteolin alpha-crystal form according to claim 1, it is characterized in that, use chloroform, acetone, ethyl acetate, propyl carbinol, acetonitrile, tetrahydrofuran (THF), dioxane, Glacial acetic acid, formic acid, ether, methylene dichloride, toluene, benzene, normal hexane, hexanaphthene, DMF, sherwood oil, ammoniacal liquor, n-propyl alcohol, water single solvent system; First luteolin sample is dissolved completely, is placed on temperature range at 4 ℃ to 350 ℃, relative humidity scope 90% with interior environment under, through recrystallization growth time 1 day to 60 days, the alpha-crystal form solid sample finally preparing.
4. the preparation method of luteolin alpha-crystal form according to claim 1, it is characterized in that, use methyl alcohol, ethanol, Virahol, chloroform, acetone, ethyl acetate, propyl carbinol, acetonitrile, tetrahydrofuran (THF), dioxane, Glacial acetic acid, formic acid, ether, methylene dichloride, toluene, benzene, normal hexane, hexanaphthene, DMF, sherwood oil, ammoniacal liquor, n-propyl alcohol, water solvent kind, the mixed solvent system of making by different proportionings through two or more solvent; First luteolin sample is dissolved completely, is placed on temperature range at 4 ℃ to 350 ℃, relative humidity scope 90% with interior environment under, through recrystallization growth time 1 day to 60 days, the alpha-crystal form solid sample finally preparing.
5. a pharmaceutical composition, the luteolin alpha-crystal form as claimed in claim 1 and the pharmaceutically acceptable carrier that contain effective dose.
6. a pharmaceutical composition, the mixing crystal formation solid matter as claimed in claim 2 and the pharmaceutically acceptable carrier that contain effective dose.
7. according to the pharmaceutical composition of claim 5 or 6, it is characterized in that, described pharmaceutical composition is selected from tablet, capsule, pill or injection.
8. according to the pharmaceutical composition of claim 5 or 6, it is characterized in that, described pharmaceutical composition is selected from sustained release preparation or controlled release preparation.
9. the luteolin alpha-crystal form of claim 1 and claim 2 mixes the application of crystal formation solid matter in the medicine of preparation prevention and or treatment nervous system disorders, diseases of cardiovascular and cerebrovascular systems, digestive system, disease of immune system, inflammation and infectious diseases.
10. according to the application of claim 9, it is characterized in that, described nervous system disorders is Parkinson's disease, senile dementia, depression, anxiety; Described diseases of cardiovascular and cerebrovascular systems is hypertension, cerebral thrombosis, hyperlipidemia, Intracerebral hemorrhage, coronary heart disease; Described digestive system is gastritis, intestinal peristalsis; Described disease of immune system is diabetes, asthma.
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| CN110693870A (en) * | 2018-07-10 | 2020-01-17 | 南方医科大学 | Application of luteolin in preparation of medicine for relieving insulin beta intracellular reticulum stress |
| CN109198628A (en) * | 2018-10-10 | 2019-01-15 | 陶燃 | A kind of composition and application thereof for treating depression and anxiety disorder |
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| KR100675999B1 (en) * | 1998-10-30 | 2007-01-29 | 메르크 파텐트 게엠베하 | Method for producing luteolin and luteolin derivatives |
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2007
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1544427A (en) * | 2003-11-20 | 2004-11-10 | 黑龙江大学 | Luteolin semi-synthesis method |
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| A Short and Facile Synthetic Route to Hydroxylated Flavones. New Syntheses of Apigenin,Tricin, and Luteolin;Dhanapalan Nagarathnam and Mark Cushman;《J. Org. Chem.》;19911231;第56卷;4884-4887 * |
| Dhanapalan Nagarathnam and Mark Cushman.A Short and Facile Synthetic Route to Hydroxylated Flavones. New Syntheses of Apigenin,Tricin, and Luteolin.《J. Org. Chem.》.1991,第56卷4884-4887. * |
| 多舌飞蓬黄酮成分的研究;张印俊等;《中草药》;19981231;第29卷(第12期);798-800 * |
| 张印俊等.多舌飞蓬黄酮成分的研究.《中草药》.1998,第29卷(第12期),798-800. * |
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| 木犀草素和奥洛波尔的合成;戈夏等;《中国医药工业杂志》;20031231;第34卷(第4期);159-161 * |
| 腐婢根化学成分研究;郑宗忠等;《亚热带植物科学》;20021231;第31卷(第3期);9-11 * |
| 郑宗忠等.腐婢根化学成分研究.《亚热带植物科学》.2002,第31卷(第3期),9-11. * |
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| CN103012345A (en) | 2013-04-03 |
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