CN105585576A - Bilobalide K crystal L type and preparation method, composition and application thereof - Google Patents
Bilobalide K crystal L type and preparation method, composition and application thereof Download PDFInfo
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Abstract
The invention discloses a compound bilobalide K crystal L type and a preparation method, composition and application thereof. Specifically, the invention discloses a crystal L type solid matter state form of bilobalide K under a solid state, and a preparation method of a crystal L type solid matter sample. The bilobalide K can be a promising neuroprotective agent and used as a medicine active compound for preparing medicines for preventing and treating various cardiovascular and cerebrovascular diseases, diabetes, immune system diseases and nervous system diseases.
Description
Technical field 0
The present invention relates to find the stastus format of a kind of brilliant L-type that bilobalide K exists under solid state; Relate to and sending outUnderstand the preparation method of brilliant L-type; Relate to having invented and contain the brilliant L-type of bilobalide K and the mix-crystal containing the brilliant L-type of any non-zero proportionsThe pharmaceutical composition of type; The invention still further relates to the brilliant L-type of bilobalide K as effective ingredient, at the various cardiovascular and cerebrovasculars of preparationApplication in disease, diabetes, disease of immune system and the nervous system disease control medicine.
Background technology
Bilobalide K belongs to ginkgo diterpenoid-lactone, and its structural formula is as follows, and this compound is natural paf receptor antagonismAgent. It has protective effect to central nervous system, ischemic injuries, can be used for treating ICVD and relevant diseaseSick.
The molecular structural formula of bilobalide K
At Chinese patent CN101824041 (publication number)[1]In, record the " a kind of silver-colored of traditional Chinese medicine research institute of Guangdong Province inventionThe preparation method of apricot lactone K ", wherein relate to and utilized concentrated rear ethanol or the methanol solution of using of ginkolide B acid adding dehydration to enterRow recrystallization, makes bilobalide K.
At Chinese patent CN102002052 (publication number)[2]In, record Kangyuan Pharmaceutical Co., Ltd., Jiangsu Prov's invention" bilobalide K and compound thereof and preparation method thereof and purposes ", wherein related to the dissolving of ginkolide B, transform, acid addingPrecipitation or concentrated crystallization and the step that sediment or crystallization are recrystallized. Wherein by sediment or ethanol for crystallization, methyl alcohol,Acetone or butanol solution recrystallization can make bilobalide K.
At Chinese patent CN101747338 (publication number)[3]In, record Guangzhou Iger Biotechnology Co's invention" a kind of method for preparing ginkgolide compound ", wherein related to the extraction, column chromatography of bilobalide K, concentrated and heavy knotBrilliant step. Wherein use 95% methanol solution recrystallization can make bilobalide K.
At Chinese patent CN1424315 (publication number)[4]In, record Kangyuan Pharmaceutical Co., Ltd., Jiangsu Prov invention" Ginkgolid and preparation method thereof and the pharmaceutical composition that contains this compound ", has wherein related to separation and purification ginkgoThe method of lactone K. Ginkgolides crude product is carried out to refluxing extraction through ethyl acetate or acetone soln, through column chromatography purification, use stoneAfter oil ether-eluent ethyl acetate, merge concentrate eluant, place and occur precipitation, will precipitate with acetone solution with preparative high-efficient liquidPhase purifying, can obtain bilobalide K.
Document " separation, purifying and the Structural Identification of ginkgoterpene lactone "[5]The middle ethyl acetate backflow with adopting ginkgo leafLiquid, after column chromatography purification, uses CH2Cl2-MeOH wash-out, collects ginkgolides crude product eluent, after recrystallization through preparative RP-HPLC purifying, makes bilobalide K sterling.
In documents such as " DeterminationofthederivativefromginkgolideB "[6-7]Relate toBy ginkolide B, with using RP-HPLC/UV method to separate on half preparative chromatography post after dissolve with methanol solution, mobile phase isMethanol-water, detection wavelength is 216nm, the derivative that has obtained a kind of ginkolide B is bilobalide K.
In " LC/DAD/ESI/MS of micro constitutent analyzes and Structural Identification in ginkgolides extract ", use 70% acetoneSolution dissolves ginkgolides extract completely, after obtain bilobalide K sterling through preparing separation method[8]。
The disclosed bilobalide K solid sample of above-mentioned patent and document, the difference that is bilobalide K through test confirmation is moltenAgent compound. Through patent and literature search both at home and abroad, find no other crystal formation patent or bibliographical information of closing bilobalide K.
The present invention has found a kind of new bilobalide K solids different from above-mentioned patent or literature research ReportingMatter existence, i.e. the brilliant L-type of bilobalide K, it does not contain any crystallization water or recrystallisation solvent, has found the system of this crystalline substance L-typePreparation Method, with and the advantageous characteristic of security and stability aspect.
Research purpose of the present invention is to start with from the crystal formation solid matter existence research of bilobalide K, passes through crystal formationTriage techniques, crystal formation assessment technique, find in the active ingredient raw materials aspect of medicine, find that crystal formation solid matter exists kindWith status flag, crystal-form substances is combined with pharmacodynamic study, be the silver of finding, finding, exploitation has optimal clinical curative effectThe advantage medicinal crystal-form solid matter of apricot lactone K provides basic science data; Meanwhile, be also former from bilobalide K solid drugsOn material material base, application country or international intellectual property invention patent protection provide scientific basis
Summary of the invention
One of the object of the invention: existence and describing mode that the brilliant L-type of bilobalide K is provided.
Two of the object of the invention: the preparation method that the brilliant L-type of bilobalide K is provided.
Three of the object of the invention: provide and contain the brilliant L-type sterling of bilobalide K or contain the mixed of the brilliant L-type of any non-zero proportionsThe solid drugs of synthetic type and composition thereof.
Four of the object of the invention: provide and use the pharmaceutical composition of the brilliant L-type of bilobalide K as active constituents of medicine, itsEvery day, dosage was within the scope of 50 μ g～100mg.
Five of the object of the invention: provide and use the brilliant L-type of bilobalide K to manufacture out as active constituents of medicine raw materialFor clinical tablet, capsule, pill, injection, slowly-releasing or controlled release preparation medicine.
Six of the object of the invention: the advantageous characteristic of the brilliant L-type of bilobalide K aspect security and stability is provided.
Seven of the object of the invention: provide and use the brilliant L-type of bilobalide K as active raw materials, lack at preparation treatment brainApplication in the medicine of courageous and upright disease.
The invention provides the brilliant L-type form of bilobalide K under solid state, the preparation method of brilliant L-type sample; FindThe medicine that the brilliant L-type of use bilobalide K is developed as active fraction preparation and composition thereof are for the preparation of various heart and brain bloodApplication in pipe disease, diabetes, disease of immune system and the nervous system disease control medicine.
Technical characterictic
1. the brilliant L-type solid sample of bilobalide K morphological feature:
The brilliant L-type of 1.1 bilobalide K the present invention relates to, is characterized in that, does not contain any recrystallisation solvent or the crystallization water,When using powder x-ray diffraction analysis to adopt CuKαWhen radiation experiments condition, show as diffraction maximum position: 2-Theta value (°) orD value () and diffraction maximum relative intensity: when peak height value (Height%) or peak area value (Area%) have following characteristic peaksSolid matter (table 1, Fig. 1):
The powder x-ray diffraction peak value of the brilliant L-type of table 1 bilobalide K
The brilliant L-type of 1.2 bilobalide K the present invention relates to, is characterized in that, uses attenuate total reflection Fourier infrared spectrumWhen method is analyzed 3496,3360,2971,2919,2863,1810,1761,1704,1474,1437,1406,1377,1358、1342、1315、1289、1249、1235、1183、1151、1115、1082、1059、1024、1000、984、964、925、902、885、832、798、752、726、717、695、656cm-1There is diffuse reflectance infrared spectroscopy peak, its mid-infrared spectral behavior peak in placeTolerance be ± 2cm-1(Fig. 2).
The brilliant L-type of 1.3 bilobalide K the present invention relates to, is characterized in that, while using means of differential scanning calorimetry technical Analysis,Show as in 30～290 DEG C of temperature ranges, heating rate is to locate to exist at 280 DEG C ± 5 DEG C in the DSC collection of illustrative plates of 10 DEG C per minute1 endothermic peak (Fig. 3).
The brilliant L-type of 1.4 bilobalide K relating to of the present invention, is characterized in that, while using thermogravimetric technical Analysis, shows asIn 30～200 DEG C of temperature ranges, heating rate is not have weightless step (Fig. 4) in the TG collection of illustrative plates of 10 DEG C per minute.
2. the preparation method characteristic of the brilliant L-type sample of bilobalide K:
The preparation method of the brilliant L-types of 2.1 bilobalide Ks that the present invention relates to, is characterized in that, use methyl alcohol, dioxane,The single solvent of ethanol, acetone, ethyl acetate, acetonitrile or oxolane, or by methyl alcohol, ethanol, water, dioxane, acetone, fourIn hydrogen furans and ethyl acetate, two or more combine the mixed solvent of making through different proportionings arbitrarily, 20 DEG C～60 DEG C temperatureLower bilobalide K sample is dissolved completely and through 15 DEG C～65 DEG C of environment temperatures, ambient humidity 10%～75%, vacuum experiment barUnder part, remove fast solvent experiment; After under the hot environment of 100 DEG C～250 DEG C, place at least after 10min, prepareThe brilliant L-type of bilobalide K.
The preparation method of the brilliant L-types of 2.2 bilobalide Ks that the present invention relates to, is characterized in that, use methyl alcohol, dioxane,Ethanol, ethyl acetate or oxolane, as good solvent, make water or n-hexane as anti-solvent, at 20 DEG C～60 DEG C temperatureBilobalide K sample is dissolved completely and sink fast under environment temperature 10-40 DEG C, ambient humidity 10%～75% conditionThe operation of forming sediment leaves standstill 2-12h, sedimentation and filtration under temperature 10-40 DEG C, ambient humidity 10%～75% condition; Gained solid sampleUnder the hot environment of 80 DEG C～250 DEG C, place at least after 10min, prepare the brilliant L-type of bilobalide K.
The preparation method of the brilliant L-type of 2.3 bilobalide K the present invention relates to, is characterized in that, uses the brilliant K type of bilobalide KSample is through 80 DEG C～250 DEG C hot environments, places at least after 10min, obtains the brilliant L-type of bilobalide K.
The preparation method of the brilliant L-type of 2.4 bilobalide Ks that the present invention relates to, is characterized in that, adopts physical mechanics latticeDestroy method obtains the brilliant L-type of bilobalide K. The wherein said preferred ball-milling method of physical mechanics lattice damage method, wherein ball-milling methodRatio of grinding media to material is 1: 10～30: 1, is preferably 6: 1～15: 1; Rotational speed of ball-mill is 100～800r/min, is preferably 300～400r/Min; Milling time is 2-20h, is preferably 8～16h.
3. the crystal formation composition of bilobalide K, dosage and pharmaceutical preparations composition feature:
The mixing crystal formation solid matter of 3.1 bilobalide Ks that the present invention relates to, is characterized in that, contains any non-zero ratioThe brilliant L-type of bilobalide K of example.
3.2 pharmaceutical compositions that the present invention relates to, is characterized in that, the brilliant L-type that contains bilobalide K, or contain ginkgoThe mixed crystal solid matter of lactone K and pharmaceutically acceptable carrier.
3.3 pharmaceutical compositions that the present invention relates to, bilobalide K every day dosage within the scope of 50 μ g～100mg.
3.4 pharmaceutical compositions that the present invention relates to, is characterized in that, described pharmaceutical composition is tablet, capsule, ballAgent, injection, sustained release preparation or controlled release preparation.
3.5 the present invention relates to the brilliant L-type of bilobalide K, or the mixing crystal formation solid matter of bilobalide K, or medicine groupThe application of compound in the various cardiovascular and cerebrovascular diseases of preparation, diabetes, disease of immune system and the nervous system disease control medicine.
4. stability and the security advantages feature of the brilliant L-type of bilobalide K:
The brilliant L-types of 4.1 bilobalide Ks are at high temperature (60 DEG C), high humidity (25 DEG C, RH90% ± 5%), illumination (4500lx ±Under condition 500lx), place 10 days, all do not turn brilliant phenomenon, show good stability.
The brilliant L-type of 4.2 bilobalide Ks, not containing any recrystallisation solvent or the crystallization water, has good security.
Brief description of the drawings
The x-ray diffractogram of powder spectrum of the brilliant L-type of Fig. 1 bilobalide K
The infrared absorpting light spectra of the brilliant L-type of Fig. 2 bilobalide K
The means of differential scanning calorimetry collection of illustrative plates of the brilliant L-type of Fig. 3 bilobalide K
The thermogravimetric collection of illustrative plates of the brilliant L-type of Fig. 4 bilobalide K
Detailed description of the invention
For better explanation technical scheme of the present invention, spy provides following examples, but the present invention is not limited to this.
Embodiment 1
The preparation method 1 of the brilliant L-type sample of bilobalide K:
The brilliant K type of 100mg bilobalide K sample is laid in culture dish, through 250 DEG C of hot environments, places after 30min,Obtain the brilliant L-type of bilobalide K. The sample obtaining is carried out to powder x-ray diffraction analysis, and its diffracting spectrum is consistent with Fig. 1, tableThe brilliant L-type that bright gained sample is bilobalide K.
The preparation method 2 of the brilliant L-type sample of bilobalide K:
Using methanol solvate at 25 DEG C, bilobalide K sample to be dissolved completely, is under the vacuum condition of 30 DEG C in temperature,Solvent steamed fast and prepare bilobalide K solid sample, the sample 50mg making being put into the hot environment of 150 DEG CAfter middle placement 30min, it is carried out to powder x-ray diffraction analysis, its diffracting spectrum is consistent with Fig. 1, shows that gained sample is ginkgoThe brilliant L-type of lactone K.
The preparation method 3 of the brilliant L-type sample of bilobalide K:
Using alcohol solvent at 40 DEG C, bilobalide K sample to be dissolved completely, is under the vacuum condition of 40 DEG C in temperature,Solvent steamed fast and prepare bilobalide K solid sample, the sample 50mg making being put into the hot environment of 180 DEG CAfter middle placement 30min, it is carried out to powder x-ray diffraction analysis, its diffracting spectrum is consistent with Fig. 1, shows that gained sample is for silverThe brilliant L-type of apricot lactone K.
The preparation method 4 of the brilliant L-type sample of bilobalide K:
Using dioxane solvent at 25 DEG C, bilobalide K sample to be dissolved completely, is the vacuum bar of 60 DEG C in temperatureUnder part, solvent steamed fast and prepare bilobalide K solid sample, the sample 50mg making being put into the height of 200 DEG CIn temperature environment, place after 20min, it is carried out to powder x-ray diffraction analysis, its diffracting spectrum is consistent with Fig. 1, shows gained sampleProduct are the brilliant L-type of bilobalide K.
The preparation method 5 of the brilliant L-type sample of bilobalide K:
Using tetrahydrofuran solvent at 20 DEG C, bilobalide K sample to be dissolved completely, is the vacuum bar of 25 DEG C in temperatureUnder part, solvent steamed fast and prepare bilobalide K solid sample, the sample 50mg making being put into the height of 220 DEG CIn temperature environment, place after 10min, it is carried out to powder x-ray diffraction analysis, its diffracting spectrum is consistent with Fig. 1, shows gained sampleProduct are the brilliant L-type of bilobalide K.
The preparation method 6 of the brilliant L-type sample of bilobalide K:
Using ethyl acetate solvent at 50 DEG C, bilobalide K sample to be dissolved completely, is the vacuum bar of 35 DEG C in temperatureUnder part, solvent steamed fast and prepare bilobalide K solid sample, the sample 50mg making being put into the height of 220 DEG CIn temperature environment, place after 20min, it is carried out to powder x-ray diffraction analysis, its diffracting spectrum is consistent with Fig. 1, shows gained sampleProduct are the brilliant L-type of bilobalide K.
The preparation method 7 of the brilliant L-type sample of bilobalide K:
(v/v=2: 1) mixed solvent dissolves bilobalide K sample completely at 50 DEG C, in temperature is to use methanol-waterUnder the vacuum condition of 60 DEG C, solvent is steamed fast and prepare bilobalide K solid sample, the sample 50mg making is putEnter in the hot environment of 220 DEG C and place after 20min, it is carried out to powder x-ray diffraction analysis, its diffracting spectrum is consistent with Fig. 1,Show that gained sample is the brilliant L-type of bilobalide K.
The preparation method 8 of the brilliant L-type sample of bilobalide K:
Use methanol-acetone (v/v=1: 1) mixed solvent dissolves bilobalide K sample completely at 25 DEG C, in temperatureBe, under the vacuum condition of 35 DEG C, solvent is steamed fast and prepare bilobalide K solid sample, by the sample 50mg makingPut into the hot environment of 180 DEG C and place after 20min, it is carried out to powder x-ray diffraction analysis, its diffracting spectrum and Fig. 1 mono-Cause, show that gained sample is the brilliant L-type of bilobalide K.
The preparation method 9 of the brilliant L-type sample of bilobalide K:
Use methanol-acetone (v/v=2: 3) mixed solvent dissolves bilobalide K sample completely at 25 DEG C, in temperatureBe, under the vacuum condition of 35 DEG C, solvent is steamed fast and prepare bilobalide K solid sample, by the sample 50mg makingPut into the hot environment of 160 DEG C and place after 20min, it is carried out to powder x-ray diffraction analysis, its diffracting spectrum and Fig. 1 mono-Cause, show that gained sample is the brilliant L-type of bilobalide K.
The preparation method 10 of the brilliant L-type sample of bilobalide K:
Use Ethanol-Acetic Acid ethyl ester (v/v=3: 2) mixed solvent dissolves bilobalide K sample completely at 60 DEG C,Temperature is, under the vacuum condition of 40 DEG C, solvent is steamed fast and prepare bilobalide K solid sample, by the sample making50mg puts into the hot environment of 200 DEG C and places after 20min, it is carried out to powder x-ray diffraction analysis, its diffracting spectrum and figure1 is consistent, shows that gained sample is the brilliant L-type of bilobalide K.
The preparation method 11 of the brilliant L-type sample of bilobalide K:
Use oxolane-water (v/v=2: 1) mixed solvent dissolves bilobalide K sample completely at 35 DEG C, in temperatureDegree is, under the vacuum condition of 40 DEG C, solvent is steamed fast and prepare bilobalide K solid sample, by the sample making50mg puts into the hot environment of 220 DEG C and places after 15min, it is carried out to powder x-ray diffraction analysis, its diffracting spectrum and figure1 is consistent, shows that gained sample is the brilliant L-type of bilobalide K.
The preparation method 12 of the brilliant L-type sample of bilobalide K:
Use oxolane-acetone (v/v=1: 1) mixed solvent dissolves bilobalide K sample completely at 25 DEG C,Temperature is, under the vacuum condition of 35 DEG C, solvent is steamed fast and prepare bilobalide K solid sample, by the sample making50mg puts into the hot environment of 120 DEG C and places after 40min, it is carried out to powder x-ray diffraction analysis, its diffracting spectrum and figure1 is consistent, shows that gained sample is the brilliant L-type of bilobalide K.
The preparation method 13 of the brilliant L-type sample of bilobalide K:
Use oxolane-acetone (v/v=2: 1) mixed solvent dissolves bilobalide K sample completely at 25 DEG C,Temperature is, under the vacuum condition of 35 DEG C, solvent is steamed fast and prepare bilobalide K solid sample, by the sample making50mg puts into the hot environment of 160 DEG C and places after 30min, it is carried out to powder x-ray diffraction analysis, its diffracting spectrum and figure1 is consistent, shows that gained sample is the brilliant L-type of bilobalide K.
The preparation method 14 of the brilliant L-type sample of bilobalide K:
Use methanol solvate at 25 DEG C, bilobalide K sample to be dissolved completely, use ten times of amount hexane solutions at ringBorder temperature is to carry out rapid precipitation operation under the condition of 20 DEG C, is under 20 DEG C of conditions, to leave standstill 2h, sedimentation and filtration in environment temperature; WillThe solid sample 100mg making puts into the hot environment of 250 DEG C and places after 20min, it is carried out to powder x-ray diffraction and divideAnalyse, its diffracting spectrum is consistent with Fig. 1, shows that gained sample is the brilliant L-type of bilobalide K.
The preparation method 15 of the brilliant L-type sample of bilobalide K:
Use alcohol solvent at 40 DEG C, bilobalide K sample to be dissolved completely, use ten times of amount hexane solutions at ringBorder temperature is to carry out rapid precipitation operation under the condition of 25 DEG C, is under 25 DEG C of conditions, to leave standstill 4h, sedimentation and filtration in environment temperature; WillThe solid sample 100mg making puts into the hot environment of 160 DEG C and places after 30min, it is carried out to powder x-ray diffraction and divideAnalyse, its diffracting spectrum is consistent with Fig. 1, shows that gained sample is the brilliant L-type of bilobalide K.
The preparation method 16 of the brilliant L-type sample of bilobalide K:
Use ethyl acetate solvent at 40 DEG C, bilobalide K sample to be dissolved completely, use ten times of water gaging solution at ringBorder temperature is to carry out rapid precipitation operation under the condition of 10 DEG C, is under 10 DEG C of conditions, to leave standstill 12h, sedimentation and filtration in environment temperature;The hot environment that the solid sample 100mg making is put into 200 DEG C is placed after 10min, it is carried out to powder x-ray diffraction and divideAnalyse, its diffracting spectrum is consistent with Fig. 1, shows that gained sample is the brilliant L-type of bilobalide K.
The preparation method 17 of the brilliant L-type sample of bilobalide K:
Use tetrahydrofuran solvent at 25 DEG C, bilobalide K sample to be dissolved completely, use ten times of amount hexane solutionsBeing to carry out rapid precipitation operation under the condition of 25 DEG C in environment temperature, is under 25 DEG C of conditions, to leave standstill 6h in environment temperature, precipitatesFilter; The hot environment that the solid sample 100mg making is put into 120 DEG C is placed after 30min, it is carried out to powder X-ray ray and spread outPenetrate analysis, its diffracting spectrum is consistent with Fig. 1, shows that gained sample is the brilliant L-type of bilobalide K.
The preparation method 18 of the brilliant L-type sample of bilobalide K:
Under room temperature, take appropriate bilobalide K bulk drug sample and be placed in ball mill agate mortar, select 15 agate ballsQuality, material ball ratio is about 30: 1, and it is 400r/min that drum's speed of rotation is set, and every ball milling 15min stops 2min, grinds after 10h, obtainsObtain the brilliant L-type of bilobalide K.
Embodiment 2
The brilliant L-type stability features of bilobalide K:
Hot test: crystal form samples is put in opening clean surface ware, at 60 DEG C of temperature, places 10 days, and in the 0th day,The 5th day and sampling in the 10th day. Above-mentioned sample point gained sample is carried out to powder x-ray diffraction analysis, and its diffracting spectrum all and Fig. 1Unanimously, show that the brilliant L-type of bilobalide K is stable under hot conditions.
High wet test: crystal form samples is put in opening clean surface ware, at 25 DEG C under relative humidity 90% ± 5% conditionPlace 10 days, and in the 0th day, the 5th day and sampling in the 10th day. Above-mentioned sample point gained sample is carried out to powder x-ray diffraction to be dividedAnalyse, its diffracting spectrum is all consistent with Fig. 1, shows that the brilliant L-type of bilobalide K is stable under super-humid conditions.
Exposure experiments to light: crystal form samples is put in opening clean surface ware, is placed on the lighting box that fluorescent lamp is housed, and in illumination isThe condition of 4500lx ± 500lx is placed 10 days, and in the 0th day, the 5th day and sampling in the 10th day. By above-mentioned sample point gained sampleCarry out powder x-ray diffraction analysis, its diffracting spectrum is all consistent with Fig. 1, shows that the brilliant L-type of bilobalide K is steady under illumination conditionFixed.
Embodiment 3
The preparation method 1 (tablet) of combined pharmaceutical formulation:
A preparation method for composition of medicine tablet, is characterized in that using the brilliant L-type of sterling bilobalide K or contains and appointThe mixed crystal solid matter of the brilliant L-type of meaning ratio as the bulk drug of composition of medicine, use several excipient as preparing composition of medicineThe adjunct ingredient of tablet, proportioning is made the tablet samples of every content of dispersion at 0.1～50mg according to a certain percentage, and table 2 is given sliceAgent prescription ratio:
The preparation formula of table 2 bilobalide K composition of medicine tablet
The brilliant L-type sterling of bilobalide K or the mixed crystal bulk drug that contains the brilliant L-type of arbitrary proportion are prepared into tablet formulationMethod is: several excipient are mixed with bulk drug, add 1% sodium cellulose glycolate solution appropriate, make soft material, mistakeSieve series grain, wet grain is dried, and the whole grain that sieves, adds dolomol and talcum powder to mix, and compressing tablet, to obtain final product.
The preparation method 2 (capsule) of combined pharmaceutical formulation:
A preparation method for composition of medicine capsule, is characterized in that using the brilliant L-type sterling of bilobalide K or contains and appointThe mixed crystal solid matter of the brilliant L-type of meaning ratio as the bulk drug of composition of medicine, use several excipient as preparing composition of medicineThe adjunct ingredient of capsule, proportioning is made the capsule sample of every content of dispersion at 0.1～50mg according to a certain percentage, and table 3 is given plastic emittingCapsule formula ratio:
Bulk drug and the accessory formula of table 3 bilobalide K composition of medicine capsule preparations
The brilliant L-type sterling of bilobalide K or the mixed crystal bulk drug that contains the brilliant L-type of arbitrary proportion are prepared into tablet formulationMethod is: several excipient are mixed with bulk drug, add 1% sodium cellulose glycolate solution appropriate, make wet grain and dryThe dry whole grain that sieves, adds dolomol to mix, and inserts capsule and makes; Or do not use granulation step, and directly by ginkgoThe brilliant L-type bulk drug of ester K mixes with several excipient auxiliary materials, after sieving, directly incapsulates and makes.
The problem of needs explanation: the bilobalide K crystal formation pharmaceutical composition the present invention relates to is at the medicament of giving of active ingredientIn amount, have perhaps multifactor impact, for example: cause the difference of dosage every day for preventing different with the purposes for the treatment of;Ill character is different from the ill order of severity and cause the different of dosage every day; Gender, age, body surface area are notDifferent and cause the difference of dosage every day with, method of administration, administration number of times, therapeutic purposes; In addition between crystal form samples, exist,Absorption and blood concentration not equal, also cause the present invention in suitable dose scope every day that uses bilobalide K crystal formation compositionBe 1 μ g/kg-2mg/kg body weight, be preferably 0.1-2mg/kg body weight. Should be according to actual prevention and treatment different situations when useDemand is formulated the brilliant L-type active ingredient accumulated dose scheme of different bilobalide Ks, and can be divided into repeatedly or single administration mode completeBecome.
Bibliography
1. Chinese patent, publication number CN101824041
2. Chinese patent, publication number CN102002052
3. Chinese patent, publication number CN101747338
4.ChuanxunYuan，JianPan.DeterminationofthederivativefromginkgolideB.NaturalProductResearch，2008，15(22).
5. Chinese patent, publication number CN02128965
6. building Feng Chang, Ling Ya. ginkgoterpene lactone separation, purifying and Structural Identification. Chinese natural drug .2004,2 (1).
7. Yuan passes merit, and Pan sees. and high performance liquid chromatography is investigated the Changing Pattern of ginkolide B and its derivative. chromatogram.2008，26(1).8.WangY，ShengLS，LouFC.AnalysisandstructureidentificationoftraceconstituentinthetotalginkgolidebyUsingLC/DAD/ESI/MS[J].YaoXueBao，2001，36(8).
Claims (16)
1. the brilliant L-type of bilobalide K, is characterized in that, does not contain any recrystallisation solvent or the crystallization water, when using powder X-ray ray to spread outPenetrate to analyze and adopt CuKαWhen radiation experiments condition, diffraction maximum position 2-Theta value (°) or d valueDiffraction maximum relative intensity peakHigh value (Height%) or peak area value (Area%) have following expression:
。
2. the brilliant L-type of bilobalide K according to claim 1, is characterized in that, uses attenuate total reflection fourier infrared lightWhen spectrometry is analyzed, 3496,3360,2971,2919,2863,1810,1761,1704,1474,1437,1406,1377,1358、1342、1315、1289、1249、1235、1183、1151、1115、1082、1059、1024、1000、984、964、925、902、885、832、798、752、726、717、695、656cm-1There is diffuse reflectance infrared spectroscopy peak, its mid-infrared spectral behavior peak in placeTolerance be ± 2cm-1。
3. the brilliant L-type of bilobalide K according to claim 1, is characterized in that, uses means of differential scanning calorimetry technical AnalysisTime, showing as in 30～290 DEG C of temperature ranges, heating rate is to locate at 280 DEG C ± 5 DEG C in the DSC collection of illustrative plates of 10 DEG C per minuteThere is 1 endothermic peak.
4. the brilliant L-type of bilobalide K according to claim 1, is characterized in that, while using thermogravimetric technical Analysis, shows asIn 30～200 DEG C of temperature ranges, heating rate is not have weightless step in the TG collection of illustrative plates of 10 DEG C per minute.
5. a method of preparing the brilliant L-type of bilobalide K as described in claim 1-4 any one, is characterized in that, uses firstThe single solvent of alcohol, dioxane, ethanol, acetone, ethyl acetate or oxolane, or by methyl alcohol, ethanol, water, dioxane,In acetone, oxolane and ethyl acetate, arbitrarily two or more combine the mixed solvent of making through different proportionings, 20 DEG C～At 60 DEG C of temperature, bilobalide K sample is dissolved completely and through 15 DEG C～65 DEG C of environment temperatures, ambient humidity 10%～75%, trueUnder empty experiment condition, remove fast solvent experiment; Gained solid sample is placed under the hot environment of 80 DEG C～250 DEG CLack 10min, prepare the brilliant L-type of bilobalide K.
6. a method of preparing the brilliant L-type of bilobalide K as described in claim 1-4 any one, is characterized in that, uses firstAlcohol, dioxane, ethanol, ethyl acetate or oxolane, as good solvent, make water or n-hexane as anti-solvent, at 20 DEG CAt～60 DEG C of temperature, bilobalide K sample is dissolved completely and through environment temperature 10-40 DEG C, ambient humidity 10%～75% conditionUnder carry out rapid precipitation operation, under environment temperature 10-40 DEG C, ambient humidity 10%～75% condition, leave standstill 2-12h, precipitatedFilter; Gained solid sample is placed at least 10min under the hot environment of 80 DEG C～250 DEG C, prepares the brilliant L of bilobalide KType.
7. a method of preparing the brilliant L-type of bilobalide K as described in claim 1-4 any one, is characterized in that, uses silverThe brilliant K type of apricot lactone K sample is through 80 DEG C～250 DEG C hot environments, places at least after 10min, obtains the brilliant L-type of bilobalide K.
8. a method of preparing the brilliant L-type of bilobalide K as described in claim 1-4 any one, is characterized in that, adopts thingReason mechanics lattice damage method obtains the brilliant L-type of bilobalide K.
9. preparation method according to claim 8, the described preferred ball-milling method of physical mechanics lattice damage method, wherein ball millingThe ratio of grinding media to material of method is 1: 10～30: 1, is preferably 6: 1～15: 1; Rotational speed of ball-mill is 100～800r/min, be preferably 300～400r/min; Milling time is 2-20h, is preferably 8～16h.
10. a mixing crystal formation solid matter for bilobalide K, is characterized in that the claim that contains any non-zero proportionsThe brilliant L-type of the arbitrary described bilobalide K of 1-4.
11. 1 kinds of pharmaceutical compositions, is characterized in that, the crystalline substance of the bilobalide K described in the claim 1 that contains effective doseL-type and pharmaceutically acceptable carrier, or the mixing crystal formation of the bilobalide K described in the claim 10 that contains effective doseSolid matter and pharmaceutically acceptable carrier.
12. according to the pharmaceutical composition of claim 11, it is characterized in that, bilobalide K every day dosage 50 μ g～Within the scope of 100mg.
13. according to the pharmaceutical composition of claim 11, it is characterized in that, the formulation of described composition is tablet, capsule, ballAgent, injection, sustained release preparation or controlled release preparation.
The brilliant L-type of bilobalide K answering in preparation treatment ICVD described in 14. claim 1-4 any oneWith.
The mixing crystal formation solid matter of 15. bilobalide Ks claimed in claim 10 is at the various cardiovascular and cerebrovascular diseases of preparation, glycosuriaApplication in disease, disease of immune system and the nervous system disease control medicine.
Pharmaceutical composition described in 16. claims 11 at preparation various cardiovascular and cerebrovascular diseases, diabetes, disease of immune system andApplication in the nervous system disease control medicine.
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