CN103421002A - Berberine hydrochloride crystal D form substance, preparation method, pharmaceutical compositions and applications - Google Patents
Berberine hydrochloride crystal D form substance, preparation method, pharmaceutical compositions and applications Download PDFInfo
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- CN103421002A CN103421002A CN2012101606895A CN201210160689A CN103421002A CN 103421002 A CN103421002 A CN 103421002A CN 2012101606895 A CN2012101606895 A CN 2012101606895A CN 201210160689 A CN201210160689 A CN 201210160689A CN 103421002 A CN103421002 A CN 103421002A
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Abstract
The invention discloses a novel crystal D form substance of Berberine hydrochloride compound (chemical name: 5,6-dihydro-9,10 dimethoxy phenyl [g]-1,3-benzodioxole [5,6-a] quinolizine ydrochloride, English name: Berberine hydrochloride), a preparation method, pharmaceutical compositions and applications, concretely discloses a novel crystal D form solid substance state of Berberine hydrochloride compound, a preparation method for novel crystal D form solid substance samples, and applications of Berberine hydrochloride crystal form substance as an active component in preparation of medicines preventing nervous system diseases, cardiovascular system diseases, digestive system diseases, immune system diseases, inflammation and infectious diseases. The molecular structural formula of Berberine hydrochloride is shown in the specification.
Description
Technical field
The present invention relates to find a kind of new brilliant D type material existence form that the berberine hydrochloride compound exists under solid state; Relate to the preparation method who has invented the new brilliant D type of a kind of berberine hydrochloride; Relate to and invented the pharmaceutical composition that contains the new brilliant D type of berberine hydrochloride and contain the mixing crystal formation of the brilliant D type of arbitrary proportion; The invention still further relates to the berberine hydrochloride crystal-form substances as effective ingredient, in preparation, prevent and treat the application in nervous system disorders, diseases of cardiovascular and cerebrovascular systems, digestive system, disease of immune system, inflammation and infectious disease medicament.
Background technology
Berberine hydrochloride compound (chemical name: 5,6-dihydro-9,10 dimethoxy phenyl [g]-1,3-benzo dioxole [5,6-a] quinolizine hydrochloride; English name: Berberine hydrochloride)
The berberine hydrochloride molecular structural formula
At Chinese patent CN101245064(publication number) in put down in writing " preparation method of berberine hydrochloride " of the invention such as Chen Zaixin
[1], wherein related to the preparation method of berberine hydrochloride.
At Chinese patent CN101812061A(publication number) in put down in writing the invention such as Fu Jianming " being produced the method for N-1 by berberine hydrochloride "
[2], wherein relate to the preparation method to the berberine hydrochloride derivative.
At Chinese patent CN1634048(publication number) in put down in writing " berberine hydrochloride granule for masking flavor and the preparation thereof " of Sun Yazhou invention
[3], wherein relate to the preparation of berberine hydrochloride granule for masking flavor and preparation thereof, belong to the pharmaceutics field.
At Chinese patent CN101467999(publication number) in put down in writing " a kind of compound preparation of berberine hydrochloride " of the invention such as Wu Hongyun
[4], wherein relate to and relate to a kind of compound preparation of berberine hydrochloride composition and application.
At Chinese patent CN1682720(publication number) in put down in writing the invention such as Chen Xiaojian " a kind of berberine hydrochloride dispensing tablet and preparation method thereof "
[5], wherein related to a kind of berberine hydrochloride dispensing tablet and preparation method thereof.
At Chinese patent CN1582926(publication number) in put down in writing the invention such as Wu Haiyan " Berberine Hydrochloride Microcapsules and preparation method thereof "
[6], wherein relate to preparation and the application thereof of Berberine Hydrochloride Microcapsules.
At Chinese patent CN1931137(publication number) in put down in writing " Berberine hydrochloride taste masked Pill and its preparation " of the invention such as Han Zhiqiang
[7], wherein related to and a kind ofly for masked berberine hydrochloride micro pill, comprised a series of excipient substance.
At Chinese patent CN101683322(publication number) in put down in writing " method of preparing nano berberine hydrochloride liposome by supercritical carbon dioxide method " of the invention such as An Xueqin of East China University of Science
[8], wherein related to a kind of method of preparing nano berberine hydrochloride liposome by supercritical carbon dioxide method.
At Chinese patent CN101108167(publication number) in put down in writing " ammonium sulphate gradient-film evaporation method prepares the method for berberine hydrochloride long circulating liposomes " of the inventions such as An Xueqin of Nanjing Normal University
[9], wherein related to the method that ammonium sulphate gradient-film evaporation method prepares the berberine hydrochloride long circulating liposomes.
The article that the people such as Lin Xiang deliver " Protoberberine Alkoloids molecular configuration and structural research in the coptis have been put down in writing in Chinese periodical " natural product and exploitation "
[10]", wherein related to the preparation method of berberine hydrochloride crystal type A.
Put down in writing abroad the article that the people such as B.M.Kajiuki deliver " Five Salts of Berberine " in periodical " Acta.Cryst.C ", wherein related to the crystal B-type of berberine hydrochloride containing 4 molecular crystal water, and the crystal C type that contains 1 molecules of ethanol half molecular water
[11].
The present invention has found the new brilliant D type solid matter state of a kind of berberine hydrochloride different from above-mentioned patent or literature research Reporting and preparation method.
Research purpose of the present invention is to start with from the crystal formation solid matter existence research of berberine hydrochloride, by crystal formation triage techniques, crystal formation evaluated biological activity technology, find on the active ingredient raw materials aspect of medicine, find that the crystal formation solid matter exists kind and status flag, crystal-form substances is combined with pharmacodynamic study, for the advantage medicinal crystal-form solid matter of finding, finding, exploitation has the berberine hydrochloride of optimal clinical curative effect provides the basic science data; Simultaneously, also for from berberine hydrochloride solid pharmaceutical raw material basis application country or international intellecture property invention patent protection, providing scientific basis.
Summary of the invention
One of the object of the invention: the new crystal solid matter existence and the describing mode that are to provide the brilliant D type of berberine hydrochloride.
Two of the object of the invention: the preparation method who has been to provide a kind of new crystal solid matter of the brilliant D type of berberine hydrochloride.
Three of the object of the invention: the solid pharmaceutical and the composition thereof that are to provide the mixing crystal formation that contains the brilliant D type sterling of berberine hydrochloride or contain the brilliant D type of arbitrary proportion.
Four of the object of the invention: be to provide use berberine hydrochloride crystal formation solid matter as active constituents of medicine every day dosage in 100 ~ 1000mg scope.
Five of the object of the invention: be to provide use berberine hydrochloride crystal formation solid matter to manufacture out as active constituents of medicine various for clinical tablet, capsule, pill, injection, slowly-releasing or controlled release preparation medicine.
Six of the object of the invention: be to provide the berberine hydrochloride crystal-form substances and bring into play the effective therapeutic action of medicine because crystal-form substances improves Plasma Concentration in organism in treatment lysis.
Seven of the object of the invention: be to provide the raw material of the mixing crystal formation solid matter of the brilliant D type of use berberine hydrochloride or brilliant D type as effective ingredient, the application in preparation prevents and treats nervous system disorders, diseases of cardiovascular and cerebrovascular systems, digestive system, disease of immune system or reaches other class disease medicaments.
This patent has been invented a kind of new brilliant D type solid matter existence of berberine hydrochloride compound, and has invented the preparation method of this crystal form samples; In addition, the present invention has found that berberine hydrochloride prevents and treats the application in nervous system disorders, diseases of cardiovascular and cerebrovascular systems, digestive system, disease of immune system, inflammation and infectious disease medicament in preparation.
Technical characterictic
1. the brilliant D type sample morphological specificity of berberine hydrochloride:
1.1 the brilliant D type of berberine hydrochloride of the present invention solid matter, is characterized in that (CuK when using powder x-ray diffraction analysis
αRadiation), show as the diffraction peak position: the 2-Theta value (°) or the d value
With the diffraction peak relative intensity: solid matter while thering is following characteristic peaks of peak height value (Height%) or peak area value (Area%) (table 1, Fig. 1):
The powder x-ray diffraction peak value of the brilliant D type of table 1 berberine hydrochloride sample
1.2 the brilliant D type of berberine hydrochloride of the present invention solid sample, it is characterized in that, while using infrared spectra to be analyzed 3549,3308,3049,3024,2998,2945,2912,2844,2363,2112,1931,1633,1619,1598,1567,1504,1479,1458,1442,1422,1388,1362,1332,1301,1270,1228,1214,1141,1102,1064,1033,1002,974,961,925,909,891,872,826,778,768,752,731,711,660cm
-1± 2cm
-1Absorption peak be the diffuse reflectance infrared spectroscopy peak position (Fig. 2) that the brilliant D type of berberine hydrochloride crystal formation solid matter presents.
1.3 the brilliant D type solid matter of berberine hydrochloride of the present invention, is characterized in that when using the means of differential scanning calorimetry technical Analysis, shows as in the DSC collection of illustrative plates that temperature rise rate is 10 ° of C of per minute without obvious endotherm(ic)peak (Fig. 3).2. the preparation method characteristic of the brilliant D type of berberine hydrochloride sample:
2.1 the preparation method of the brilliant D type of the berberine hydrochloride described in claim 1 the present invention relates to sample, is characterized in that at 4 ° of C ~ 80 ° C of envrionment temperature, ambient moisture 10% ~ 75%, the berberine hydrochloride sample applied to the brilliant D type solid matter that mechanical pressure is ground 3 ~ 48 hours acquisition berberine hydrochlorides.
2.2 the preparation method of the brilliant D type of the berberine hydrochloride as claimed in claim 1 the present invention relates to, is characterized in that using chloroform, methylene dichloride, acetone, ether single solvent system; Or chloroform, acetone, ether, dichloromethane solvent kind, the mixed solvent system of making by different proportionings through two or more solvent is after the berberine hydrochloride sample dissolution, and removes fast solvent method or spray method obtain brilliant D type solid sample under envrionment temperature 10 ° of C ~ 80 ° C, ambient moisture 10% ~ 75%, normal pressure or vacuum experiment conditions.
3. the crystal formation composition of berberine hydrochloride, dosage and pharmaceutical preparations composition feature:
3.1 the mixed crystal solid matter of a berberine hydrochloride compound, the brilliant D type of the berberine hydrochloride that contains arbitrary proportion composition.
3.2 the pharmaceutical composition the present invention relates to, is characterized in that, the brilliant D type of the berberine hydrochloride that contains effective dose, or contain berberine hydrochloride mixed crystal solid matter and pharmaceutically acceptable carrier.
3.3 the pharmaceutical composition the present invention relates to, using berberine hydrochloride crystal formation solid matter as active constituents of medicine, every day, dosage was in 100 ~ 1000mg scope.
3.4 the pharmaceutical composition the present invention relates to, is characterized in that, described pharmaceutical composition is tablet, capsule, pill, injection, sustained release preparation, controlled release preparation.
3.5 the brilliant D type of the berberine hydrochloride mixed crystal composition that the present invention relates to the brilliant D type of berberine hydrochloride or contain arbitrary proportion is prevented and treated the application in nervous system disorders, diseases of cardiovascular and cerebrovascular systems, digestive system, disease of immune system, inflammation and infectious disease medicament in preparation.
The accompanying drawing explanation
The x-ray diffractogram of powder spectrum of the brilliant D type of Fig. 1 berberine hydrochloride sample
The infrared absorpting light spectra of the brilliant D type of Fig. 2 berberine hydrochloride sample
The DSC collection of illustrative plates of the brilliant D type of Fig. 3 berberine hydrochloride sample
Embodiment
For better explanation technical scheme of the present invention, the spy provides following examples, but the present invention is not limited to this.
The preparation method 1 of the brilliant D type of berberine hydrochloride sample:
The brilliant D type sample preparation methods of berberine hydrochloride, it is characterized in that under normal temperature and pressure, under the environment of 45% humidity, 10g berberine hydrochloride bulk drug is put into to ball mill to be ground 5 hours, obtain 9.5g berberine hydrochloride solid matter, the sample obtained is carried out to powder x-ray diffraction analysis, and its diffracting spectrum is consistent with Fig. 1, shows that the gained sample is the brilliant D type of berberine hydrochloride solid matter.
Embodiment 2
The preparation method 2 of the brilliant D type of berberine hydrochloride sample:
The brilliant D type sample preparation methods of berberine hydrochloride, it is characterized in that under normal temperature and pressure, under the environment of 45% humidity, berberine hydrochloride bulk drug 300mg is dissolved in acetone solvent fully, filters, 50 ° of C rotary evaporated to dryness, obtain 270mg berberine hydrochloride solid matter, the sample obtained is carried out to powder x-ray diffraction analysis, and its diffracting spectrum is consistent with Fig. 1, shows that the gained sample is the brilliant D type of berberine hydrochloride solid matter.
Embodiment 3
The preparation method 3 of the brilliant D type of berberine hydrochloride sample:
The brilliant D type sample preparation methods of berberine hydrochloride, it is characterized in that under normal temperature and pressure, under the environment of 45% humidity, berberine hydrochloride bulk drug 200mg is dissolved in the trichloromethane solvent fully, filters, 60 ° of C rotary evaporated to dryness, obtain 170mg berberine hydrochloride solid matter, the sample obtained is carried out to powder x-ray diffraction analysis, and its diffracting spectrum is consistent with Fig. 1, shows that the gained sample is the brilliant D type of berberine hydrochloride solid matter.
Embodiment 4
The preparation method 4 of the brilliant D type of berberine hydrochloride sample:
The brilliant D type sample preparation methods of berberine hydrochloride, it is characterized in that under normal temperature and pressure, under the environment of 45% humidity, berberine hydrochloride bulk drug 300mg is dissolved in to acetone fully: in the mixed solvent of trichloromethane (2: 1), filter, 60 ° of C rotary evaporated to dryness, obtain 280mg berberine hydrochloride solid matter, the sample obtained is carried out to powder x-ray diffraction analysis, and its diffracting spectrum is consistent with Fig. 1, shows that the gained sample is the brilliant D type of berberine hydrochloride solid matter.
Embodiment 5
The preparation method 1(tablet of combined pharmaceutical formulation):
A kind of preparation method of medicinal composition tablet, the mixed crystal solid matter that it is characterized in that using the brilliant D type sterling of berberine hydrochloride or contain the brilliant D type of arbitrary proportion as the bulk drug of medicinal composition, use several vehicle as the adjunct ingredient for preparing the medicinal composition tablet, proportioning is made the tablet samples of every content of dispersion at 50 ~ 500mg according to a certain percentage, and table 2 provides the tablet formulation ratio:
The preparation formula of table 2 berberine hydrochloride composite medicine tablet
The method that the brilliant D type sterling of berberine hydrochloride or the mixed crystal bulk drug that contains the brilliant D type of arbitrary proportion is prepared into to 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, add Magnesium Stearate and talcum powder to mix, compressing tablet, obtain.
The preparation method 2(capsule of combined pharmaceutical formulation):
A kind of preparation method of medicinal composition capsule, the mixed crystal solid matter that it is characterized in that using the brilliant D type sterling of berberine hydrochloride or contain the brilliant D type of arbitrary proportion as the bulk drug of medicinal composition, use several vehicle as the adjunct ingredient for preparing the medicinal composition capsule, proportioning is made the capsule sample of every content of dispersion at 50 ~ 500mg according to a certain percentage, and table 3 provides the capsule formula ratio:
Bulk drug and the accessory formula of the brilliant D type of table 3 berberine hydrochloride medicinal composition capsule preparations
The method that the brilliant D type sterling of berberine hydrochloride or the mixed crystal bulk drug that contains the brilliant D type of arbitrary proportion is prepared into to tablet formulation is: several vehicle are mixed with bulk drug, add 1% sodium cellulose glycolate solution appropriate, make wet grain and dry the whole grain that sieves, add Magnesium Stearate to mix, insert capsule and make; Or do not use granulation step, and directly the berberine hydrochloride bulk drug is mixed with several vehicle auxiliary materials, after sieving, directly incapsulate and make.
Embodiment 6
The dosage 1(tablet of berberine hydrochloride crystal formation medicinal composition):
The pharmaceutical composition that uses crystal formation berberine hydrochloride sample to manufacture as active constituents of medicine, it is characterized in that using the activeconstituents of brilliant D type berberine hydrochloride as medicine, every day, dosage was 600mg, can be prepared into respectively 3 times/each 1 200mg conventional tablet every day, every day 2 times/each 1 200mg conventional tablet or every day 1 time/each 1 600mg the tablet type.
The dosage 2(capsule of berberine hydrochloride crystal formation medicinal composition):
The pharmaceutical composition that uses crystal formation berberine hydrochloride sample to manufacture as active constituents of medicine, it is characterized in that using the activeconstituents of brilliant D type berberine hydrochloride as medicine, every day, dosage was 100mg, can be prepared into respectively 2 times/each 1 50mg capsule every day, every day 1 time/each 1 100mg capsule.
The problem that needs explanation: the berberine hydrochloride crystal formation pharmaceutical composition the present invention relates to has many factor impacts on the dosage of effective constituent, for example: the difference that causes dosage every day for the purposes of preventing and treat is different; Ill character is different from ill severity and cause the different of dosage every day; The difference of Gender, 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, and also causing the present invention is the 0.01-150mg/kg body weight in appropriate dose scope every day of using crystal formation berberine hydrochloride composition, is preferably the 1-100mg/kg body weight.Should formulate different brilliant D type berberine hydrochloride effective constituent total dose schemes from treatment different situations demand according to actual prevention during use, and can be divided into repeatedly or the single administration mode completes.
Reference
1. Chinese patent, publication number CN101245064
2. Chinese patent, publication number CN101812061A
3. Chinese patent, publication number CN1634048
4. Chinese patent, publication number CN101467999
5. Chinese patent, publication number CN1682720
6. Chinese patent, publication number CN1582926
7. Chinese patent, publication number CN1931137
8. Chinese patent, publication number CN101683322
9. Chinese patent, publication number CN101108167
10. woods Xiang, Lei Xianrong, Yang Jianhua, Li Hui, Protoberberine Alkoloids molecular configuration and structural research [J] in the coptis; Research and development of natural products; 2009,21:87-90
11.B.M.Kajiuki,W.Jones.Five?Salts?of?Berberine.Acta.Cryst.(1995).C51,1234-1240。
Claims (10)
1. the brilliant D type solid matter of a berberine hydrochloride, is characterized in that, (CbuK when using powder x-ray diffraction analysis
αRadiation), diffraction peak position: the 2-Theta value (°) or the d value
With the diffraction peak relative intensity: peak height value (Height%) or peak area value (Area%) have following feature:
2. according to the brilliant D type of the berberine hydrochloride in claim 1 solid matter, it is characterized in that, while using infrared spectra to be analyzed 3549,3308,3049,3024,2998,2945,2912,2844,2363,2112,1931,1633,1619,1598,1567,1504,1479,1458,1442,1422,1388,1362,1332,1301,1270,1228,1214,1141,1102,1064,1033,1002,974,961,925,909,891,872,826,778,768,752,731,711,660cm
-1± 2cm
-1Absorption peak be the diffuse reflectance infrared spectroscopy peak position that the brilliant D type of berberine hydrochloride crystal formation solid matter presents.
3. according to the brilliant D type of the berberine hydrochloride solid matter of any one in claim 1-2, it is characterized in that, while using the means of differential scanning calorimetry technical Analysis, show as in the DSC collection of illustrative plates that temperature rise rate is 10 ° of C of per minute without obvious endotherm(ic)peak.
4. the mixed crystal solid matter of a berberine hydrochloride compound, is characterized in that, the brilliant D type of the berberine hydrochloride described in the claim 1 that contains arbitrary proportion.
5. the preparation method of the brilliant D type of the described berberine hydrochloride of claim 1, is characterized in that, at 4 ° of C ~ 80 ° C of envrionment temperature, ambient moisture 10% ~ 75%, the berberine hydrochloride sample is applied mechanical pressure or grinds obtain.
6. the preparation method of the brilliant D type of the described berberine hydrochloride of claim 1, is characterized in that, uses the single solvent system that is selected from trichloromethane, methylene dichloride, acetone, ether; Or be selected from trichloromethane, methylene dichloride, acetone, ether solvent, the mixed solvent system of making by different proportionings through two or more solvent is after the berberine hydrochloride sample dissolution, and removes fast solvent method or spray method obtain brilliant D type solid sample under envrionment temperature 10 ° of C ~ 80 ° C, ambient moisture 10% ~ 75%, normal pressure or vacuum experiment conditions.
7. a pharmaceutical composition, is characterized in that, the brilliant D type of the berberine hydrochloride as claimed in claim 1 that contains effective dose, or contain berberine hydrochloride mixed crystal solid matter as claimed in claim 4 and pharmaceutically acceptable carrier.
8. according to the pharmaceutical composition of claim 7, it is characterized in that, berberine hydrochloride crystal formation bulk drug every day dosage in 100 ~ 1000mg scope.
9. according to the pharmaceutical composition of claim 7, it is characterized in that, described pharmaceutical composition is tablet, capsule, pill, injection, sustained release preparation or controlled release preparation.
10. the brilliant D type of the berberine hydrochloride of claim 1 composition is prevented and treated the application in the medicine of nervous system disorders, diseases of cardiovascular and cerebrovascular systems, digestive system, disease of immune system, inflammation and infectious diseases in preparation.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012101606895A CN103421002A (en) | 2012-05-22 | 2012-05-22 | Berberine hydrochloride crystal D form substance, preparation method, pharmaceutical compositions and applications |
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| CN2012101606895A CN103421002A (en) | 2012-05-22 | 2012-05-22 | Berberine hydrochloride crystal D form substance, preparation method, pharmaceutical compositions and applications |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115477647A (en) * | 2022-10-26 | 2022-12-16 | 山西医科大学 | Berberine fumarate crystal form, preparation method, composition and application thereof |
| CN115572292A (en) * | 2022-10-26 | 2023-01-06 | 山西医科大学 | Berberine succinate crystal form, preparation method, composition and application thereof |
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| CN1165822A (en) * | 1996-05-22 | 1997-11-26 | 湖南省桑植县药材公司 | Process for extracting berberine hydrochloride |
| CN101153039A (en) * | 2006-09-30 | 2008-04-02 | 中国科学院上海药物研究所 | 13, 13a- dihydro berberine derivant, pharmaceutical composition and uses of the same |
| CN101928285A (en) * | 2010-08-05 | 2010-12-29 | 重庆市中药研究院 | Method for extracting major alkaloids from rhizoma coptidis |
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2012
- 2012-05-22 CN CN2012101606895A patent/CN103421002A/en active Pending
Patent Citations (3)
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| CN1165822A (en) * | 1996-05-22 | 1997-11-26 | 湖南省桑植县药材公司 | Process for extracting berberine hydrochloride |
| CN101153039A (en) * | 2006-09-30 | 2008-04-02 | 中国科学院上海药物研究所 | 13, 13a- dihydro berberine derivant, pharmaceutical composition and uses of the same |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115477647A (en) * | 2022-10-26 | 2022-12-16 | 山西医科大学 | Berberine fumarate crystal form, preparation method, composition and application thereof |
| CN115572292A (en) * | 2022-10-26 | 2023-01-06 | 山西医科大学 | Berberine succinate crystal form, preparation method, composition and application thereof |
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Application publication date: 20131204 |