CN102976943B - The alpha-crystal form material of salvianolic acid A, method for making and pharmaceutical composition and purposes - Google Patents
The alpha-crystal form material of salvianolic acid A, method for making and pharmaceutical composition and purposes Download PDFInfo
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Abstract
The present invention discloses the alpha-crystal form solid matter of compound salvianolic acid A; Also disclose the preparation method of alpha-crystal form solid matter sample; Relate to the pharmaceutical composition adopting crystal-form substances to manufacture out as active constituents of medicine, and it prevents and treats the application in the medicine of cardio-cerebrovascular, immunity system, hyperlipidaemia, diabetes and complication thereof in preparation. Salvianolic acid A molecular structure.
Description
Technical field
The present invention relates to the two kinds of crystal-form substances existence forms having found salvianolic acid A in the solid state; Relate to the preparation method of alpha-crystal form sample and the beta crystal sample having invented salvianolic acid A solid matter.
The present invention relates to and utilize the brilliant type solid matter of brilliant type salvianolic acid A to develop the clinical application in the diseases such as cardio-cerebrovascular, immunity system, hyperlipidaemia, diabetes and complication thereof of medicine and composition thereof as active fraction preparation. Particularly owing to the brilliant type solid matter of salvianolic acid A have impact on the absorption rate of effective ingredient in organism, enhances Plasma Concentration in organism thus reach and improve clinical drug preventive and therapeutic effect.
Background technology
Salvianolic acid A, systematic naming method: 3-{2-[2-(3,4-dihydroxy-phenyl)-vinyl]-3,4-dihydroxy-phenyl}-acrylicAcid1-carboxy-2-(3,4-dihydroxy-phenyl)-ethylester.
Molecular structure is as follows:
Prior art mainly discloses preparation technology and the formulation of salvianolic acid A.
Chinese Patent Application No. 200810000904.9 discloses Beijing Ke Laibo pharmaceutical developments limited liability company and institute of materia medica of the Chinese Academy of Medical Sciences combines the method for Radix Salviae Miltiorrhizae extract of salvianolic acid A " preparation be rich in " of invention[1], it is disclosed that the extraction preparation method (as follows) of salvianolic acid A. The present invention utilizes this extracting method to obtain to research and develop two kinds of brilliant type solid matters on salvianolic acid A basic substance, and its main extraction step is as follows:
(1) in salvia piece or first powder, add appropriate Extraction solvent and carry out refluxing extraction or diafiltration; Filter, obtain extracting solution, extracting solution is concentrated; Add ethanol, stirring while adding, it is 40 ~ 90% to reaching determining alcohol, places, precipitation is left standstill, gets supernatant concentration, obtain concentrated solution; Or at a certain temperature, add finings, stir, filter, filtrate is concentrated, obtains concentrated solution.
(2) concentrated solution is incubated 6 ~ 72 hours at the temperature of 40 ~ 100 �� of C.
(3) it is 1 ~ 6 by solution acid for adjusting pH value after above-mentioned insulation; With organic solvent extraction, obtaining extraction liquid, described organic solvent is preferably trichloromethane, ethyl acetate, propyl acetate or butylacetate; Reclaim organic solvent, obtain extract.
(4) by above-mentioned extract dissolution with solvents; Adsorb through chromatographic column, it is preferable that the filler in chromatographic column is macroporous resin, gel or polymeric amide; Wash-out; Collect and merge the component containing salvianolic acid A, dry, salvianolic acid A must be rich in and obtain Radix Salviae Miltiorrhizae extract.
At Chinese patent CN1830947A(publication number) in disclose kingdom shake invention " extracting method of a kind of salvianolic acid A "[2]. It relates to the extracting method having invented a kind of salvianolic acid A, and the receipts rate height of salvianolic acid A is prepared in its invention, and purity is good, stable performance, and in extract, salvianolic acid A content can reach more than 80%, and can realize scale operation.
At Chinese patent CN101121658A(publication number) in disclose kingdom shake invention " preparing the control method of salvianolic acid A "[3]. Wherein relating to and invented a kind of control method preparing salvianolic acid A, its inventive method is by controlling the content of salvianolic acid A in final extract so that final extract performance is more stable, and required requirements for pharmaceuticals is lower, more logical and applicable suitability for industrialized production.
At Chinese patent CN1887849A(publication number) in disclose Zhengda Qingchunbao Pharmaceutical Co., Ltd invention " preparation method of danshen root salvianolic acid A "[4]. Wherein relating to the preparation method having invented a kind of danshen root salvianolic acid A, its invention has extraction yield height, and purity is good, and in extract, salvianolic acid A content can reach more than 90%, and constant product quality can be used for scale operation.
At Chinese patent CN101041620A(publication number) in disclose Zhengda Qingchunbao Pharmaceutical Co., Ltd invention " preparation method of danshen root salvianolic acid A "[5]. Wherein relating to the preparation method having invented a kind of danshen root salvianolic acid A, its invention has extraction yield height, and purity is good, and in extract, salvianolic acid A content can reach more than 90%, and constant product quality is applicable to scale operation.
At Chinese patent CN101019824A(publication number) in disclose " a kind of combination of oral medication containing danshen root salvianolic acid A and its preparation method " of the invention of Beijing book on Chinese herbal medicine researches on natural drugs institute[6]. Wherein relate to and invented a kind of combination of oral medication and its preparation method that contain danshen root salvianolic acid A.
At Chinese patent CN101049298A(publication number) in disclose positive space (Hong Kong) international corporation invention " the micro-ball of salvianolic acid A and salvianolic acid A capsule "[7]. Wherein relate to the preparation technology having invented the micro-ball of a kind of salvianolic acid A and capsule, and pharmacological action.
At Chinese patent CN1994277A(publication number) in disclose " a kind of solid preparation of salvianolic acid A of red sage root and its preparation method " of the invention of Beijing book on Chinese herbal medicine researches on natural drugs institute[8]. Wherein relate to and invented a kind of solid preparation of salvianolic acid A of red sage root and its preparation method.
At Chinese patent CN1987452A(publication number) in disclose " a kind of detection and analytic method for red sage root dan phenolic acid A " that Beijing book on Chinese herbal medicine researches on natural drugs invents[9]. Wherein relate to and invented a kind of detection and analytic method for red sage root dan phenolic acid A, comprise red rooted salvia, pharmaceutical preparation containing the red sage root, danshen root salvianolic acid A sample, pharmaceutical preparation containing danshen root salvianolic acid A high performance liquid chromatography detection analyze.
At Chinese patent CN101125123A(publication number) in disclose " a kind of red sage root A magnesium injection preparation and its preparation method " that Beijing book on Chinese herbal medicine researches on natural drugs invents[10]. Wherein relate to and invented a kind of red sage root A magnesium injection preparation and its preparation method.
At Chinese patent CN100999470A(publication number) in disclose Beijing book on Chinese herbal medicine researches on natural drugs " preparation method of a kind of danshen root salvianolic acid A and preparation and the purposes " invented[11]. Wherein relate to method, quality controlling means and the pharmaceutical composition thereof having invented from salviamiltiorrhizabung, extracted danshen root salvianolic acid A.
At Chinese patent CN101019878A(publication number) in disclose " a kind of injectable pharmaceutical compositions containing danshen root salvianolic acid A and its preparation method " of the invention of Beijing book on Chinese herbal medicine researches on natural drugs institute[12]. Wherein relate to and invented a kind of injectable pharmaceutical compositions and its preparation method that contain danshen root salvianolic acid A.
At Chinese patent CN1994288A(publication number) in disclose Beijing book on Chinese herbal medicine researches on natural drugs institute invention " red sage root salvianolic acid A tablet of a kind of Cardiovarscular and its preparation method "[13]. Wherein relate to the red sage root salvianolic acid A tablet and its preparation method of having invented a kind of Cardiovarscular.
At Chinese patent CN1969822A(publication number) in disclose Beijing book on Chinese herbal medicine researches on natural drugs institute invention " red sage root A magnesium injection preparation of a kind of Cardiovarscular and its preparation method "[14]. Wherein relate to the red sage root A magnesium injection preparation and its preparation method of having invented a kind of Cardiovarscular.
At Chinese patent CN101130498A(publication number) in disclose Zhejiang University invention " extracting and purifying method of a kind of salvianolic acid A "[15]. Wherein relating to the extracting and purifying method having invented a kind of salvianolic acid A, the final extract yield of its inventive method reaches more than 0.3%, and the purity of salvianolic acid A reaches more than 90%, avoids the column chromatography steps in previous methods.
At Chinese patent CN1110139A(publication number) in disclose Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences invention " salvianolic acid A is used for the treatment of tumour novelty teabag "[16]. Wherein relate to and having invented as salvianolic acid A has opened up new purposes, it is contemplated that salvianolic acid A is applied to clinical cancer therapy can obtain more excellent curative effect.
It is the document about salvianolic acid A Advance on Pharmacological Activities mostly by literature search, has no the report of its solid crystal-form substances preparation method aspect.
Summary of the invention
Salvianolic acid A molecular structure is as follows:
Present invention finds the two of salvianolic acid A kind new crystal solid matter existence form; Invent the preparation method of the two kinds of new crystal solid matters producing salvianolic acid A; Relate to the pharmaceutical composition adopting two kinds of new crystal solid matters to manufacture out as active constituents of medicine and play better clinical prevention effect in diseases such as control cardio-cerebrovascular, immunity system, hyperlipidaemia, diabetes and complication thereof.
One of the object of the invention: be to provide the alpha-crystal form solid matter of salvianolic acid A and the existence of beta crystal solid matter and describing mode.
The two of the object of the invention: be to provide the alpha-crystal form solid matter of salvianolic acid A and the preparation method of beta crystal solid matter sample.
The three of the object of the invention: be to provide pharmaceutical composition effect of making the most of the advantage in the clinical prevention of the diseases such as cardio-cerebrovascular, immunity system, hyperlipidaemia, diabetes and complication thereof that containing salvianolic acid A two kinds of brilliant type solid matters manufacture as medicine effective active composition.
The four of the object of the invention: there is provided human body dosage every day of the medicinal composition using the brilliant type solid matter of salvianolic acid A to manufacture out as active constituents of medicine within the scope of 1 ~ 100mg.
The five of the object of the invention: be to provide tablets, capsule, pill, the injection of the various confession Clinical practice that the brilliant type solid matter employing salvianolic acid A manufactures out as active constituents of medicine, delay and release or controlled-release pharmaceutical formulation type.
The six of the object of the invention: have in organism after being to provide the pharmaceutical preparation oral administration route of administration of the brilliant type solid matter employing salvianolic acid A as active constituents of medicine exploitation preparation and significantly absorb and Plasma Concentration advantage.
The seven of the object of the invention: be to provide the clinical prevention effect that the brilliant type solid matter employing salvianolic acid A is prepared the pharmaceutical composition and pharmaceutical preparation thereof and made the most of the advantage in the control etc. of cardio-cerebrovascular, immunity system, hyperlipidaemia, diabetes and complication thereof as active constituents of medicine.
The eight of the object of the invention: be to provide the advantage clinical treatment effect that the brilliant type solid matter employing salvianolic acid A prepares, as active constituents of medicine and with phenolic acids or flavonoid or other chemical substances, the pharmaceutical composition and pharmaceutical preparation plays in diseases prevention and treatment.
The nine of the object of the invention: be to provide the advantage clinical treatment effect that the brilliant type solid matter that employs salvianolic acid A prepares, as active constituents of medicine, the pharmaceutical composition with Chinese medicine or Chinese medical extract and pharmaceutical preparation plays in diseases prevention and treatment.
1. the alpha-crystal form solid sample morphological specificity of salvianolic acid A:
The alpha-crystal form solid of 1.1 salvianolic acid As of the present invention, its chemical purity and crystal form purity are all greater than 90% and containing recrystallisation solvent, when use powder x-ray diffraction analysis adopts CK��Diffraction peak position 2-Theta value (��) or d value during radiation experiments conditionDiffraction peak relative intensity peak high level (Height%) or peak area value (Area%) have following expression. Table 1 is the powder x-ray diffraction peak value table of the alpha-crystal form solid sample of salvianolic acid A, and accompanying drawing 1 is the x-ray diffractogram of powder spectrum of the alpha-crystal form solid sample of salvianolic acid A.
The powder x-ray diffraction peak value of the alpha-crystal form solid sample of table 1 salvianolic acid A
��
The alpha-crystal form solid matter of 1.2 salvianolic acid As that the present invention relates to, when using the KBr compressing tablet of infrared spectra to analyze 3365.5,1688.9,1603.2,1520.0,1491.0,1445.1,1356.0,1284.2,1258.2,1190.5,1112.6,1070.8,1042.8,971.3,935.2,864.9,809.2,756.7,722.6,627.6,592.0,521.5,485.2,454.0cm-1There is absorption peak at place, wherein 3365.5,1491.0,1258.2,1190.5,1070.8,809.2,592.0,521.5,485.2,454.0cm-1Peak is the characteristic absorbance peak position of the alpha-crystal form solid matter presenting salvianolic acid A. Accompanying drawing 2 is the infrared absorpting light spectra of the alpha-crystal form solid sample of salvianolic acid A.
, there are two endotherm(ic)peaks in the alpha-crystal form solid matter of 1.3 salvianolic acid As that the present invention relates to, its transformation value is respectively about 78 �� of about C and 178 �� of about C in its DSC collection of illustrative plates. Accompanying drawing 3 is the DSC spectrogram of the alpha-crystal form solid sample of salvianolic acid A.
2. the beta crystal solid sample morphological specificity of salvianolic acid A:
The beta crystal solid matter of 2.1 salvianolic acid As that the present invention relates to, its chemical purity and crystal form purity are all greater than 90% and containing crystal water or recrystallisation solvent, when use powder x-ray diffraction analysis adopts CK��Diffraction peak position 2-Theta value (��) or d value during radiation experiments conditionDiffraction peak relative intensity peak high level (Height%) or peak area value (Area%) have following expression. Table 2 is the powder x-ray diffraction peak value table of the beta crystal solid sample of salvianolic acid A, and accompanying drawing 4 is the x-ray diffractogram of powder spectrum of the beta crystal solid sample of salvianolic acid A.
The powder x-ray diffraction peak value of the beta crystal solid sample of table 2 salvianolic acid A
��
The beta crystal solid sample of 2.2 salvianolic acid As that the present invention relates to, when using the microlens of infrared spectra to analyze 3364.7,1862.8,1722.1,1687.3,1603.0,1520.0,1492.3,1444.5,1355.0,1284.2,1259.4,1189.3,1112.0,1072.2,1042.7,971.8,936.5,865.2,809.5,757.3,722.2,627.8,591.9cm-1There is absorption peak at place, wherein 3364.7,1862.8,1722.1,1492.3,1259.4,1189.3,1072.2,809.5,591.9cm-1Peak is the characteristic absorbance peak position of the beta crystal solid matter presenting salvianolic acid A. Accompanying drawing 5 is the infrared absorpting light spectra of the beta crystal sample of salvianolic acid A.
, there is an endotherm(ic)peak in the beta crystal solid matter of 2.3 salvianolic acid As that the present invention relates to, its transformation value is about 178 �� of about C in its DSC collection of illustrative plates. Accompanying drawing 6 is the DSC spectrogram of the beta crystal solid sample of salvianolic acid A.
3. the alpha-crystal form solid sample preparation method of salvianolic acid A:
3.1 the invention also discloses the preparation method of the alpha-crystal form solid matter of salvianolic acid A, utilize the single solvent being selected from acetonitrile, DMF, dioxane, propyl carbinol, Virahol, dehydrated alcohol, methyl alcohol, tetrahydrofuran (THF), formic acid, 95% ethanol, ethyl acetate, water, DMSO or n-propyl alcohol 14 kinds of solvents, at 15 �� of C ~ 80 �� C temperature, salvianolic acid A sample is dissolved completely, and the recrystallization preparation technology when envrionment temperature 4 �� of C ~ 80 �� C, ambient moisture 10% ~ 75%, normal pressure or vacuum experiment obtains the alpha-crystal form solid matter of salvianolic acid A.
3.2 the invention also discloses another kind of preparation method of the alpha-crystal form solid matter of salvianolic acid A, the mixed organic solvents system being selected from acetonitrile, DMF, dioxane, propyl carbinol, Virahol, dehydrated alcohol, methyl alcohol, tetrahydrofuran (THF), formic acid, 95% ethanol, ethyl acetate, water, DMSO or n-propyl alcohol 14 kinds of solvents is utilized to be dissolved completely by salvianolic acid A sample at 15 �� of C ~ 80 �� C temperature, and the recrystallization preparation technology through envrionment temperature 4 �� of C ~ 80 �� C, ambient moisture 10% ~ 75%, normal pressure or vacuum experiment when obtains the alpha-crystal form solid matter of salvianolic acid A.
3.3 the invention also discloses the 3rd kind of preparation method of the alpha-crystal form solid matter of salvianolic acid A, adopt physical mechanics lattice damage and molecular transposition rotating crystal method prepare the alpha-crystal form solid matter of salvianolic acid A or are prepared the alpha-crystal form solid matter of salvianolic acid A by the pressure condition of change physics, temperature condition.
3.4 the invention also discloses the 4th kind of preparation method of the alpha-crystal form solid matter of salvianolic acid A, adopt the single solvent being selected from acetonitrile, DMF, dioxane, propyl carbinol, Virahol, dehydrated alcohol, methyl alcohol, tetrahydrofuran (THF), formic acid, 95% ethanol, ethyl acetate, water, DMSO or n-propyl alcohol 14 kinds of solvents or mixed solvent system that salvianolic acid A sample dissolves completely the alpha-crystal form solid matter adopting cold spray or thermal spray process to prepare salvianolic acid A fast again at 15 �� of C ~ 80 �� C temperature.
Need the problem illustrated: due to can be used for preparing the single organic solvent of alpha-crystal form salvianolic acid A sample and have 14 kinds, two or more solvent combination have hundreds of, often kind of organic solvent boiling point values is different, salvianolic acid A sample solubility is different, causes the variate-value such as the envrionment temperature of its experiment when using the alpha-crystal form sample preparing salvianolic acid A when different solvents, humidity, time can there is some difference property and constant interval scope.
4. the beta crystal solid sample preparation method characteristic of salvianolic acid A:
The present invention discloses the beta crystal solid matter preparation method of salvianolic acid A, the alpha-crystal form solid matter sample of the salvianolic acid A of the present invention is placed in 95 ~ 115 �� of C thermostat containers through within 40 ~ 80 minutes, turn brilliant after namely prepare the beta crystal solid matter sample of salvianolic acid A.
5. the brilliant type composition of salvianolic acid A, dosage and pharmaceutical preparations composition feature:
5.1 the present invention relates to the various pharmaceutical compositions using the brilliant type solid sample of salvianolic acid A as active constituents of medicine, and the brilliant type of described salvianolic acid A is selected from the alpha-crystal form of the alpha-crystal form of salvianolic acid A, the beta crystal of salvianolic acid A and salvianolic acid A and beta crystal composition mixes the mixed crystal of acquisition in any proportion. These pharmaceutical compositions can also contain phenolic acids, flavonoid and other chemical substances as active constituents of medicine; Or containing Chinese medicine or Chinese medical extract combined composition as active constituents of medicine.
The dosage scope of the 5.2 brilliant type solid samples employing salvianolic acid A that the present invention relates to, its, dosage was 1 ~ 100mg salvianolic acid A crystal-form substances every day every day. comprise the pharmaceutical composition using the alpha-crystal form composition of salvianolic acid A as active constituents of medicine, or using the beta crystal composition of salvianolic acid A as the pharmaceutical composition of active constituents of medicine, or the pharmaceutical composition of mixed crystal composition as active constituents of medicine of acquisition is mixed in any proportion using the alpha-crystal form composition of salvianolic acid A and beta crystal composition, and with the brilliant type solid matter of salvianolic acid A and phenolic acids, flavonoid and other combination of chemicals compositions are as the pharmaceutical composition of thing activeconstituents, or using the brilliant type solid matter of salvianolic acid A and Chinese medicine or Chinese medical extract combined composition as the pharmaceutical composition of active constituents of medicine,
5.3 the present invention relates to and use the crystal-form substances composition of salvianolic acid A as the various pharmaceutical preparations of active constituents of medicine, it may also be useful to manufactures out the tablet for Clinical practice, capsule, pill, injection containing one or more pharmaceutical excipients, slow release or controlled-release pharmaceutical formulation type. Brilliant type solid matter containing salvianolic acid A can be dosage scope every day.
6. the absorption of the brilliant type oral administration of salvianolic acid A and Plasma Concentration feature:
Use the brilliant type solid matter of salvianolic acid A of the present invention to develop the various pharmaceutical preparation and pharmaceutical composition prepared as active constituents of medicine by oral administration route, and there is obvious absorption advantage and the salvianolic acid A component content in blood after oral administration administration, can be made in organism to reach the Plasma Concentration requirement of effective disease preventing and treating fast.
7. the oral administration of the brilliant type composition of salvianolic acid A and pharmacodynamic profile:
7.1 the present invention relates to the brilliant type solid pharmaceutical of salvianolic acid A affect the fasting blood sugar of diabetes B rat model, it is characterized in that by biological study test find when give diabetes B rat model oral salvianolic acid A crystalline substance type solid pharmaceutical after 2 weeks its fasting blood sugar have significant reducing effect. Accompanying drawing 7 is diabetes B rat model and oral gives the fasting plasma glucose changing value before and after the brilliant type solid pharmaceutical of salvianolic acid A.
7.2 the present invention relates to the brilliant type solid pharmaceutical of salvianolic acid A affect the body weight value of diabetes B rat model, it is characterized in that by biological study test find when give diabetes B rat model oral salvianolic acid A crystalline substance type solid pharmaceutical after 3 weeks its body weight value have remarkable ascendant trend. Accompanying drawing 8 is diabetes B rat model and oral gives the body weight change value before and after the brilliant type solid pharmaceutical of salvianolic acid A.
It is have obvious absorption advantage after oral administration in organism that the alpha-crystal form solid sample oral administration of 7.3 use salvianolic acid As absorbs feature, and makes salvianolic acid A component content in blood reach the concentration requirement of effective disease preventing and treating fast. The alpha-crystal form solid matter (100mg/kg) of the oral salvianolic acid A of rat afterwards blood plasma Drug-time curve see accompanying drawing 9. The alpha-crystal form solid matter (100mg/kg) of the oral salvianolic acid A of rat afterwards blood peak concentration of drug be greater than 300ng/ml, rat serum still can detect after administration 12h prototype medicine, all distribute in each main tissue of rat after the brilliant type composition of salvianolic acid A is oral, the results are shown in accompanying drawing 10.
The clinical advantage effect that the brilliant type solid matter of 7.4 salvianolic acid As is played by oral administration route as active constituents of medicine in the diseases such as control cardio-cerebrovascular, immunity system, hyperlipidaemia, diabetes and complication thereof, its reason is that the brilliant type of salvianolic acid A solid matter have impact on the absorption rate of effective ingredient in organism, enhances Plasma Concentration in organism, make content reach the concentration requirement of effective disease preventing and treating fast, thus reach the effective preventive and therapeutic effect improving medicine in clinical.
Need the problem illustrated: the present invention relates to and use the brilliant type solid matter of salvianolic acid A to have multifactor impact perhaps on dosage as active constituents of medicine, such as: the difference causing dosage every day for the purposes difference of prevention and therapy; Ill kind is different from ill severity and causes the different of dosage every day; The difference of patient's sex, age, body surface area, route of administration, administration number of times, therapeutic purpose are different and cause the difference of dosage every day. In addition, the absorption existed between crystal form samples and Plasma Concentration are not equal, also cause the present invention using the brilliant type composition of salvianolic acid A different as suitable dose scope every day of active constituents of medicine. During use should according to reality prevention with treat different situations demand formulate different brilliant type salvianolic acid A effective constituent total dose schemes, and can be divided into repeatedly or single administration mode complete.
The present invention is the brilliant type solid matter having found new salvianolic acid A unlike the prior art, it has been found that the application in clinical of the brilliant type solid matter existence of salvianolic acid A and preparation method and pharmaceutical composition thereof. Start with from the research of the solid matter existence of salvianolic acid A, by brilliant type triage techniques, the raw material aspect of effective ingredient is found, finds that solid matter exists kind and status flag, crystalline substance type research is combined with pharmacodynamic study, provides basic scientific research data for finding, find, develop the brilliant type solid pharmaceutical of the salvianolic acid A with optimal clinical curative effect.
Research in the past shows, the aspects such as acute and chronic cerebrovascular, cardiovascular disease, hepatitis, liver cirrhosis, tumour are all demonstrated improvement and therapeutic action by salvianolic acid A. By biological study, this patent has found that salvianolic acid A reduces blood sugar apart from also having outside above biological activity, promotes that grape cell sugar absorbs and improves the new clinical effects such as the weight of animals. Salvianolic acid A crystal-form substances facilitates the absorption of solid pharmaceutical thus enables salvianolic acid A better play it and the clinical of various disease is prevented effect.
Accompanying drawing explanation
The x-ray diffractogram of powder spectrum of the alpha-crystal form solid sample of Fig. 1 salvianolic acid A
The infrared absorpting light spectra of the alpha-crystal form solid sample of Fig. 2 salvianolic acid A
The DSC collection of illustrative plates of the alpha-crystal form solid sample of Fig. 3 salvianolic acid A
The x-ray diffractogram of powder spectrum of the beta crystal solid sample of Fig. 4 salvianolic acid A
The infrared absorpting light spectra of the beta crystal solid sample of Fig. 5 salvianolic acid A
The DSC collection of illustrative plates of the beta crystal solid sample of Fig. 6 salvianolic acid A
Figure 72 patients with type �� DM rat model and oral give the fasting plasma glucose changing value before and after the brilliant type solid pharmaceutical of salvianolic acid A
Figure 82 patients with type �� DM rat model and oral give the body weight change value before and after the brilliant type solid pharmaceutical of salvianolic acid A
Plasma Concentration after the alpha-crystal form solid sample of the oral salvianolic acid A of Fig. 9 rat
Figure 10 rat oral pill phenolic acid A(100mg/kg) content in each tissue after 5,20,60 minutes
Embodiment
The following examples are used for illustrating further the present invention, but this and do not mean that any limitation of the invention.
Embodiment 1
The preparation method 1 of the alpha-crystal form solid sample of salvianolic acid A:
The alpha-crystal form solid sample preparation method of salvianolic acid A, it is characterized in that first using that salvianolic acid A sample is dissolved completely by acetone or alcohol solvent under 15 ~ 25 �� of C normal temperature states, control temperature in 45 �� of C utilize vacuum filtration or revolve steaming method the solvent in sample taken out fast filter or steam dry, sample again drying technique finally prepare the alpha-crystal form solid sample of salvianolic acid A.
The preparation method 2 of the alpha-crystal form solid sample of salvianolic acid A:
The alpha-crystal form solid sample preparation method of salvianolic acid A, it is characterized in that first using n-propyl alcohol add water ratio for 2:1 under 15 ~ 25 �� of C normal temperature states, salvianolic acid A sample is dissolved completely after being configured to mixing solutions, control temperature in 45 �� of C utilize vacuum filtration or revolve steaming method the solvent in sample taken out fast filter or steam dry, sample again drying technique finally prepare the alpha-crystal form solid sample of salvianolic acid A.
The preparation method 3 of the alpha-crystal form solid sample of salvianolic acid A:
The alpha-crystal form solid sample preparation method of salvianolic acid A, it is characterized in that first using solid sample as preparing raw material, adopt physical mechanics lattice damage and molecular transposition rotating crystal method prepare the alpha-crystal form solid matter of salvianolic acid A or are prepared the alpha-crystal form solid sample of salvianolic acid A by the pressure condition of change physics, temperature condition.
The preparation method 4 of the alpha-crystal form solid sample of salvianolic acid A:
The alpha-crystal form solid sample preparation method of salvianolic acid A, it is characterized in that first using acetone solvent to be dissolved completely by salvianolic acid A sample under 15 ~ 25 �� of C normal temperature states, then adopt cold spray or thermal spray process to prepare the alpha-crystal form solid sample of brilliant type salvianolic acid A fast.
Embodiment 2
The preparation method 1 of the beta crystal solid sample of salvianolic acid A:
The beta crystal solid sample preparation method of salvianolic acid A, it is characterized in that being placed in 105 �� of C thermostat containers by the alpha-crystal form solid sample of salvianolic acid A through the heating of 60 minutes turn brilliant after namely obtain the beta crystal solid sample of salvianolic acid A.
Embodiment 3
The pharmacodynamic profile of the brilliant type composition oral administration of salvianolic acid A:
Laboratory animal: SD male rat 120, body weight 180 ~ 200g, it is purchased from Beijing Wei Tonglihua experimental technique company limited, obtaining diabetes B rat model by modeling experiment, in detection rat blood serum, the blood biochemical index such as blood lipid level and SOD, MDA such as TG, TC, LDL-C, NEFA proves diabetes B rat modeling success.
Experimental technique: to diabetes B rat rat, after fasting 12h, gavage gives salvianolic acid A the brilliant each 3mg/kg of type solid pharmaceutical respectively, once a day, successive administration 6 weeks. Before administration and after administration 3 days, 1 week, 2 weeks, 6 weeks on an empty stomach time eye socket get blood, measurement rat body weight during 3 days, 1 week, 2 weeks, 3 weeks empty stomaches, is specifically shown in Fig. 7 and Fig. 8 before administration and after administration. Experimental result shows: the oral brilliant type solid pharmaceutical of salvianolic acid A that gives can obviously reduce rat fasting blood-glucose value and improve rat body weight, shows good pharmacodynamic profile.
Embodiment 4
The brilliant type of salvianolic acid A and brilliant type solid pharmaceutical are in rat body absorption characteristic sum Plasma Concentration feature:
Laboratory animal adopts the SD male rat of body weight 195 �� 10g, and normal condition is raised, and freely drinks water, and after fasting 12h, gavage gives salvianolic acid A alpha-crystal form solid (by 100mg/kg dosage) physiological salt liquid. Rat oral pill phenolic acid A(100mg/kg) within latter 5,10,15,30,45,60,75,90,180,360,720 minutes, get blood, each time point surveys Plasma Concentration, and blood plasma Drug-time curve is shown in Fig. 9. Rat oral pill phenolic acid A(100mg/kg) afterwards blood peak concentration of drug be 318ng/mL, rat serum still can detect after administration 12h salvianolic acid A prototype.
Get male SD rat, it is divided into 3 groups at random, often organize 6. Oral pill phenolic acid A100mg/kg, after administration 5,20 and 60min put to death animal. Divide immediately core, liver, spleen, lung, kidney, brain, stomach, large intestine, small intestine, muscle, fat, testis, bladder. Precise weighing, through biological sample process after, measure tissue in salvianolic acid A concentration, rat oral pill phenolic acid A(100mg/kg) afterwards each Tissue distribution characteristics see Figure 10. As seen from the figure, after the oral salvianolic acid A of rat, wider at distribution in vivo. Wherein the highest with liver, kidney and lung concentration.
After rat administration 5min respectively organize drug concentration from high to low sequence for for: the liver > kidney > lung > stomach > small intestine > spleen > large intestine > heart, does not detect in remaining tissue.
After administration 20min respectively organize drug concentration from high to low sequence for being kidney > liver > lung > stomach > small intestine > spleen > brain > large intestine > heart > testis > muscle > fat.
After administration 60min respectively organize drug concentration from high to low sequence for being liver > kidney > lung > small intestine > spleen > large intestine > stomach > heart > brain > testis > muscle > fat > bladder.
Embodiment 5
The preparation method 1 of the alpha-crystal form medicinal composition solid dosage tablet of salvianolic acid A:
A kind of drug regimen method for preparing tablet thereof of alpha-crystal form solid matter as effective constituent employing salvianolic acid A, the alpha-crystal form solid sample that it is characterized in that employing salvianolic acid A as active constituents of medicine, use several vehicle as the adjunct ingredient preparing medicinal composition tablet, proportioning makes the tablet samples that every sheet contains the alpha-crystal form solid pharmaceutical composition 5 ~ 60mg of salvianolic acid A according to a certain percentage, and table 3 is the formula rate of conventional tablet:
The bulk drug of the alpha-crystal form solid medicinal composition tablet of table 3 salvianolic acid A and accessory formula
The method that the alpha-crystal form solid matter of the salvianolic acid A of some amount and vehicle auxiliary material are prepared into various dose tablet is by several vehicle auxiliary material and bulk drug Homogeneous phase mixing, add 1% sodium cellulose glycolate solution and make soft material in right amount, sieve granulation, wet grain is dried and the whole grain that sieves, and adds Magnesium Stearate and talcum powder mixes rear compressing tablet and get final product.
The preparation method 2 of the alpha-crystal form medicinal composition solid dosage capsule of salvianolic acid A:
A kind of drug regimen capsule preparations preparation method of alpha-crystal form solid sample as effective constituent employing salvianolic acid A, it is characterized in that using the alpha-crystal form solid sample of salvianolic acid A as active constituents of medicine, using several vehicle as the adjunct ingredient preparing medicinal composition tablet, proportioning makes the capsule preparations of the alpha-crystal form pharmaceutical cpd 5 ~ 50mg containing salvianolic acid A in every capsules according to a certain percentage, and table 4 is the formula rate of conventional capsule preparation:
The bulk drug of the alpha-crystal form solid medicinal composition capsule preparations of table 4 salvianolic acid A and accessory formula
By the method that the alpha-crystal form solid matter of the salvianolic acid A of some amount and vehicle auxiliary material are prepared into capsule preparations it is: several vehicle auxiliary material is mixed with the alpha-crystal form solid material medicine of salvianolic acid A, add 1% sodium cellulose glycolate solution appropriate, make wet grain and dry the whole grain that sieves, adding Magnesium Stearate to mix, insertion capsule obtains; Or do not use granulation step, and directly the alpha-crystal form solid material medicine of salvianolic acid A is mixed with several vehicle auxiliary material, after sieving, directly load capsule and obtain.
Embodiment 6
The dosage of the alpha-crystal form medicinal composition of salvianolic acid A:
The pharmaceutical composition that the alpha-crystal form material of salvianolic acid A manufactures as active constituents of medicine, use salvianolic acid A alpha-crystal form sample its daily dosage be 15mg, can be prepared into 3 times/each 1 5mg every day, every day 2 times/each 1 7.5mg, every day 1 time/each 1 15mg common or slow control formula tablet type.
The dosage 2 of the alpha-crystal form medicinal composition of salvianolic acid A:
The pharmaceutical composition that the alpha-crystal form material of salvianolic acid A manufactures as active constituents of medicine, use salvianolic acid A alpha-crystal form sample its daily dosage be 30mg, can be prepared into 3 times/each 1 10mg every day, every day 2 times/each 1 15mg, every day 1 time/each 1 30mg common or slow control formula tablet type.
Claims (10)
1. the alpha-crystal form solid matter of salvianolic acid A compound, it is characterised in that, its chemical purity and crystal form purity are all greater than 90% and containing recrystallisation solvent, when use powder x-ray diffraction analysis adopts CuK��Diffraction peak position 2-Theta value (��) or d value during radiation experiments conditionDiffraction peak relative intensity peak high level (Height%) or peak area value (Area%) have following expression:
; When using infrared spectra to analyze 3365.5,1688.9,1603.2,1520.0,1491.0,1445.1,1356.0,1284.2,1258.2,1190.5,1112.6,1070.8,1042.8,971.3,935.2,864.9,809.2,756.7,722.6,627.6,592.0,521.5,485.2,454.0cm-1Place has absorption peak to exist, wherein 3365.5,1491.0,1258.2,1190.5,1070.8,809.2,592.0,485.2,521.5,485.2,454.0cm-1Peak is the absorption peak position that the alpha-crystal form solid matter of salvianolic acid A presents brilliant type feature; When using dsc to analyze,
There is 1 endotherm(ic)peak and 1 exothermic peak in its DSC collection of illustrative plates, its transformation value is respectively at about 78 DEG C and about 178 DEG C.
2. prepare the method for the alpha-crystal form solid matter of the salvianolic acid A compound described in claim 1, it is characterized in that, first use and it is selected from acetonitrile, DMF, dioxane, propyl carbinol, Virahol, dehydrated alcohol, methyl alcohol, tetrahydrofuran (THF), formic acid, 95% ethanol, ethyl acetate, water, the single solvent of DMSO or n-propyl alcohol, at 15 DEG C��80 DEG C temperature, salvianolic acid A sample is dissolved completely, and through envrionment temperature 4 DEG C��80 DEG C, ambient moisture 10%��75%, utilize vacuum filtration or revolve steaming method and the solvent in sample is taken out fast filter or steams the dry alpha-crystal form solid matter obtaining salvianolic acid A.
3. prepare the method for the alpha-crystal form solid matter of the salvianolic acid A compound described in claim 1, it is characterized in that, first use and it is selected from acetonitrile, DMF, dioxane, propyl carbinol, Virahol, dehydrated alcohol, methyl alcohol, tetrahydrofuran (THF), formic acid, 95% ethanol, ethyl acetate, water, in DMSO or n-propyl alcohol any two or more in different sorts solvent salvianolic acid A sample is dissolved completely at 15 DEG C��80 DEG C temperature through the mixed solvent system that different ratio combination is made and through envrionment temperature 4 DEG C��80 DEG C, ambient moisture 10%��75%, utilize vacuum filtration or revolve steaming method and the solvent in sample is taken out fast filter or steams the dry alpha-crystal form solid matter obtaining salvianolic acid A.
4. prepare the method for the alpha-crystal form solid matter of the salvianolic acid A compound described in claim 1, it is characterised in that, adopt physical mechanics lattice damage and molecular transposition rotating crystal method to prepare the alpha-crystal form solid matter of salvianolic acid A.
5. prepare the method for the alpha-crystal form solid matter of the salvianolic acid A compound described in claim 1, it is characterized in that, first use the single solvent being selected from acetonitrile, DMF, dioxane, propyl carbinol, Virahol, dehydrated alcohol, methyl alcohol, tetrahydrofuran (THF), formic acid, 95% ethanol, ethyl acetate, water, DMSO or n-propyl alcohol to be dissolved completely by salvianolic acid A sample; Or use two or more mixed solvent systems made through different ratio combination any being selected from acetonitrile, DMF, dioxane, propyl carbinol, Virahol, dehydrated alcohol, methyl alcohol, tetrahydrofuran (THF), formic acid, 95% ethanol, ethyl acetate, water, DMSO or n-propyl alcohol different sorts solvent that salvianolic acid A sample dissolves completely the alpha-crystal form solid matter adopting cold spray or thermal spray process to prepare salvianolic acid A fast again at 15 DEG C��80 DEG C temperature.
6. a pharmaceutical composition, it is characterized in that, using the crystal form samples of salvianolic acid A as active constituents of medicine, the crystal form samples of described salvianolic acid A be selected from the salvianolic acid A described in claim 1 alpha-crystal form composition or containing the alpha-crystal form composition of salvianolic acid A and the beta crystal composition of salvianolic acid A mix the mixed crystal composition of acquisition in any proportion as described in the appended claim 1; The beta crystal composition of wherein said salvianolic acid A, when use powder x-ray diffraction analysis adopts CuK��Diffraction peak position 2-Theta value (��) or d value during radiation experiments conditionDiffraction peak relative intensity peak high level (Height%) or peak area value (Area%) have following expression:
��
7. according to claim 6 Chinese traditional medicine composition, it is characterised in that, described pharmaceutical composition is selected from tablet, capsule, pill, injection, delays and release or controlled-release pharmaceutical formulation.
8. the alpha-crystal form material of the salvianolic acid A described in claim 1 prevents and treats the application in the medicine of diseases of cardiovascular and cerebrovascular systems, disease of immune system, diabetes and complication thereof in preparation.
9. the application of the mixed crystal composition that the alpha-crystal form composition of the salvianolic acid A described in claim 1 and the beta crystal composition of salvianolic acid A mix acquisition in any proportion in the medicine of preparation control diseases of cardiovascular and cerebrovascular systems, disease of immune system, diabetes and complication thereof; The beta crystal composition of wherein said salvianolic acid A, when use powder x-ray diffraction analysis adopts CuK��Diffraction peak position 2-Theta value (��) or d value during radiation experiments conditionDiffraction peak relative intensity peak high level (Height%) or peak area value (Area%) have following expression:
��
10. application according to the arbitrary item of claim 8-9, it is characterised in that, described diseases of cardiovascular and cerebrovascular systems comprises hyperlipidaemia.
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| CN102432467B (en) * | 2011-09-30 | 2014-01-15 | 吴谢军 | Salvianolic acid A magnesium salt, preparation method and use of the salvianolic acid A magnesium salt, and salvianolic acid A magnesium salt-containing freeze-dried powder injection composition |
| CN108341747B (en) * | 2017-01-24 | 2021-06-18 | 浙江永宁药业股份有限公司 | Crystal form of salvianolic acid A and preparation method thereof |
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| CN1788748A (en) * | 2004-12-17 | 2006-06-21 | 雅安三九药业有限公司 | Injection formulation containing raw material herb red sage root and its quality control method |
| CN1958555A (en) * | 2006-10-30 | 2007-05-09 | 王煜 | Method for preparing salviol acid A |
| CN101019878A (en) * | 2007-03-27 | 2007-08-22 | 北京本草天源药物研究院 | Injection medicine composite containing salvianolic acid A and its prepn |
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| CN1397276A (en) * | 2002-08-07 | 2003-02-19 | 沈阳药科大学 | Preparing process and medical application of SLA-A contained in red sage root and its composition |
| CN1788748A (en) * | 2004-12-17 | 2006-06-21 | 雅安三九药业有限公司 | Injection formulation containing raw material herb red sage root and its quality control method |
| CN1958555A (en) * | 2006-10-30 | 2007-05-09 | 王煜 | Method for preparing salviol acid A |
| CN101019878A (en) * | 2007-03-27 | 2007-08-22 | 北京本草天源药物研究院 | Injection medicine composite containing salvianolic acid A and its prepn |
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