CN103073615A - Oleanolic acid kushenin compound salt and preparation method thereof - Google Patents
Oleanolic acid kushenin compound salt and preparation method thereof Download PDFInfo
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- CN103073615A CN103073615A CN2012103557959A CN201210355795A CN103073615A CN 103073615 A CN103073615 A CN 103073615A CN 2012103557959 A CN2012103557959 A CN 2012103557959A CN 201210355795 A CN201210355795 A CN 201210355795A CN 103073615 A CN103073615 A CN 103073615A
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- oleanolic acid
- kurarinone
- composite salt
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- organic solvent
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Abstract
The invention provides an oleanolic acid kushenin compound salt and a preparation method thereof, and is used in the preparation of drugs for the treatment of liver diseases. The composite salt is prepared by reaction in organic solvent, and crystallization in acetone or ethanol.
Description
Technical field
The present invention relates to medicine composite salt that is used for the treatment of hepatitis and preparation method thereof, specifically the compound Salt And Preparation Method of Oleanolic Acid kurarinone.
Background technology
Oleanolic Acid and kurarinone are the clinical medicine that is used for the treatment of hepatopathy.
Oleanolic Acid is to be distributed widely in botanic a kind of natural product chemistry composition, toxicity is very low, has multiple biological activity---and antiviral, anti-inflammatory, enhancing immunity and Immunosuppression (immune two-way conciliation effect), suppress platelet aggregation, reducing blood-fat, hypoglycemic, protect the liver, protect kidney, anti AIDS virus etc.This medicine of 20 century 70s begins to be used for the treatment of hepatitis, research is found, Oleanolic Acid can make the hepatic tissue of degeneration necrosis recover normal, alleviate the L-Ala vigor and descend, the liver tissues inflammatory habituation, gamma-globulin descends in the blood, and can promote liver cell regeneration, the necrotic area is repaired rapidly, and therefore, Oleanolic Acid is widely used in treatment icterohepatitis, chronic persistent hepatitis, viral hepatitis and chronic active hepatitis clinically.
Kurarinone (Oxymatyine) is the compound that extensively is present in the natural drugs such as kuh-seng, Herba Sophorae alopecuroidis.Modern pharmacological research shows, it has the effects such as antitumor, antiviral, anti-inflammatory, adjusting immunity, especially at liver disease field special effects such as hepatitis virus resisting and liver injury, anti-hepatic fibrosis, to chemical drugs---the efficacy of interferon therapy effect is similar, and untoward reaction is few.Studies confirm that kurarinone has the dual function of clear and definite anti-hepatitis B virus and anti-hepatic fibrosis, obtain satisfactory effect after clinical employing kurarinone or the Oxymatrine Injection treatment.Kurarinone is not only inhibited to copying of hepatitis B virus, also various liver injuries is had certain provide protection, and it is heavier and with the patient of jaundice to can be used for liver dysfunction.In addition, kurarinone can also suppress collagen mobility and control hepatic fibrosis.Through for many years research, 1998, Ministry of Health's approval Oxymatyine was five kind new medicines for the treatment of chronic hepatitis B.
Oleanolic Acid, kurarinone are the hepatosis treating medicine of using clinically for many years, but all have many weak points.The formulation of Oleanolic Acid monomer component is single, and bioactive application is also single.The most frequently used in the formulation is tablet, is pill secondly.Because poorly water-soluble causes bioavailability very low, affects body to the absorption of Oleanolic Acid.Multinomial studies have shown that can be improved bioavailability by Oleanolic Acid being made salt or being prepared derivative.Studies show that the solubleness of Oleanolic Acid sodium salt in water improves greatly, the solubleness of prodrug in water of Oleanolic Acid dibasic acid monoester disodium one class increases several times than Oleanolic Acid, has effectively strengthened and has fallen enzyme, liver protection effect.The kurarinone water absorbability is strong, brings many insoluble problems for the application of medicine.
Trimly pier tartaric acid kurarinone composite salt provided by the invention preferably resolves above problem, and the bioavailability of not only having improved Oleanolic Acid is low, the single and bibulous shortcoming of kurarinone of formulation, and also curative effect is higher than single medicine far away.
The present invention provides the pharmaceutical composition that contains Oleanolic Acid kurarinone composite salt simultaneously, can add the pharmaceutical preparation that suitable auxiliary material is made certain forms, comprises tablet, capsule, powder pin or large and small injection.
Summary of the invention
The object of the invention is to overcome Oleanolic Acid and the weak point of kurarinone in application of single component, provide bioavailability high, good stability, curative effect is better than the Oleanolic Acid kurarinone composite salt of single component.
A kind of Oleanolic Acid kurarinone composite salt is characterized in that: Oleanolic Acid and kurarinone mol ratio 1:1.
Oleanolic Acid kurarinone composite salt of the present invention has following structural formula:
The present invention also aims to provide the preparation method of Oleanolic Acid kurarinone composite salt.
The present invention also aims to provides the pharmaceutical composition that is comprised of above-mentioned composite salt, and the preparation of making.
The preparation method of above-mentioned composite salt provided by the invention is as follows:
1. get an amount of Oleanolic Acid and kurarinone (mol ratio 1:1), add in an amount of organic solvent under the room temperature, be stirred to abundant dissolving, slowly join in the acetone or dehydrated alcohol of vigorous stirring, separate out the white powder precipitation, continue stirring and make crystallization complete, filter, a small amount of acetone or absolute ethanol washing precipitation, crystallization namely gets Oleanolic Acid kurarinone composite salt in 50～70 ℃ of dryings.
Among the above-mentioned preparation method, organic solvent is a kind of in methyl alcohol, ethanol, propyl alcohol, tetrahydrofuran (THF), the chloroform, the perhaps aqueous solution of their any concentration, and this organic solvent can dissolve Oleanolic Acid fully, can dissolve kurarinone again, is preferably ethanol.
Preparation in accordance with the present invention, the Oleanolic Acid kurarinone composite salt that obtains can add the pharmaceutical preparation that suitable auxiliary material is made certain forms, comprises tablet, capsule, powder pin or large and small injection.
The present invention finds by research, after Oleanolic Acid and kurarinone form composite salt, has greatly improved the water absorbability of kurarinone, has improved Oleanolic Acid bioavailability in vivo, and absorption is good, thereby drug dose significantly reduces.Simultaneously, research finds, above-mentioned composite salt can more significant reduction blood in alanine aminotransferase, the effect of prompting composite salt hepatitis virus resisting is better than single component, this also may be relevant with the medicine synergistic function of Oleanolic Acid and kurarinone.
Embodiment
The following example is intended to further describe for example the present invention, rather than limits by any way the present invention.
Embodiment 1
Take by weighing Oleanolic Acid 100g, kurarinone 57.9g adds in the 600mL95% ethanol under the room temperature, be stirred to abundant dissolving, slowly join in the acetone of 1200mL vigorous stirring, separate out the white powder precipitation, continue stirring and make crystallization complete, filter, a small amount of washing with acetone precipitation, crystallization gets white powder crystallization 145g in 60 ℃ of dryings 4 hours, be Oleanolic Acid kurarinone composite salt, yield is 91.8%.
Embodiment 2
Take by weighing Oleanolic Acid 100g, kurarinone 57.9g adds in the 700mL50% ethanol under the room temperature, be stirred to abundant dissolving, slowly join in the acetone of 1200mL vigorous stirring, separate out the white powder precipitation, continue stirring and make crystallization complete, filter, a small amount of washing with acetone precipitation, crystallization gets white powder crystallization 140g in 50 ℃ of dryings 6 hours, be Oleanolic Acid kurarinone composite salt, yield is 88.7%.
Embodiment 3
Get the Oleanolic Acid kurarinone composite salt raw material 4.0g among the embodiment 3, add the dissolving of an amount of water for injection after, add again activated carbon 0.04g, heated and boiled 30 minutes filters, and adds water to 800mL, NaOH solution with 0.1% is regulated pH to 6.0～6.5, leaves standstill 2h, filters, filtrate injects water to 1000mL, stirs filtering with microporous membrane, (10 mL/ prop up in embedding, 4 mg/mL), sterilization namely gets Oleanolic Acid kurarinone composite salt injection liquid.Usage and dosage is every day 1 time, each 20～40mg, intravenous injection or add the glucose solution iv drip of physiological saline or 5～10%.
Claims (6)
1. an Oleanolic Acid kurarinone composite salt is characterized in that: Oleanolic Acid and kurarinone mol ratio 1:1.
2. method for preparing the described Oleanolic Acid kurarinone of claim 1 composite salt, it is characterized in that comprising following steps: even up pier tartaric acid and kurarinone mol ratio 1:1, add in an amount of organic solvent under the room temperature, be stirred to abundant dissolving, slowly join in the acetone or dehydrated alcohol of vigorous stirring, separate out the white powder precipitation, continue stirring and make crystallization complete, filter, a small amount of acetone or absolute ethanol washing precipitation, crystallization namely gets Oleanolic Acid kurarinone composite salt in 50～70 ℃ of dryings.
3. method according to claim 2 is characterized in that used organic solvent is a kind of in methyl alcohol, ethanol, propyl alcohol, tetrahydrofuran (THF), the chloroform, perhaps the aqueous solution of their any concentration.
4. method according to claim 2 is characterized in that used organic solvent is ethanol.
5. a pharmaceutical composition is characterized in that said composition contains the Oleanolic Acid kurarinone composite salt as claimed in claim 1 as effective constituent, and pharmaceutically acceptable carrier.
6. pharmaceutical composition according to claim 6 adds the pharmaceutical preparation that suitable auxiliary material is made certain forms, comprises tablet, capsule, powder pin or large and small injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103557959A CN103073615A (en) | 2012-09-24 | 2012-09-24 | Oleanolic acid kushenin compound salt and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2012103557959A CN103073615A (en) | 2012-09-24 | 2012-09-24 | Oleanolic acid kushenin compound salt and preparation method thereof |
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| CN103073615A true CN103073615A (en) | 2013-05-01 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2012103557959A Pending CN103073615A (en) | 2012-09-24 | 2012-09-24 | Oleanolic acid kushenin compound salt and preparation method thereof |
Country Status (1)
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1712411A (en) * | 2004-06-22 | 2005-12-28 | 江苏恒瑞医药股份有限公司 | Compound salt of glycyrrhizin and kurarinol, its production and use |
| CN101012267A (en) * | 2005-09-05 | 2007-08-08 | 江苏正大天晴药业股份有限公司 | Glycyrrhizic acid matrine salt and glycyrrhizic acid marine salt, its preparing method and use |
-
2012
- 2012-09-24 CN CN2012103557959A patent/CN103073615A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1712411A (en) * | 2004-06-22 | 2005-12-28 | 江苏恒瑞医药股份有限公司 | Compound salt of glycyrrhizin and kurarinol, its production and use |
| CN101012267A (en) * | 2005-09-05 | 2007-08-08 | 江苏正大天晴药业股份有限公司 | Glycyrrhizic acid matrine salt and glycyrrhizic acid marine salt, its preparing method and use |
Non-Patent Citations (1)
| Title |
|---|
| 廖丹丹等: "苦参碱衍生物的研究进展", 《广州化工》 * |
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Application publication date: 20130501 |