CN1857295A - Complex salt or composition medicine of breviscapine and basic amino acid for treating cardiac and cerebral vascular diseases - Google Patents
Complex salt or composition medicine of breviscapine and basic amino acid for treating cardiac and cerebral vascular diseases Download PDFInfo
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- CN1857295A CN1857295A CN 200610020537 CN200610020537A CN1857295A CN 1857295 A CN1857295 A CN 1857295A CN 200610020537 CN200610020537 CN 200610020537 CN 200610020537 A CN200610020537 A CN 200610020537A CN 1857295 A CN1857295 A CN 1857295A
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Abstract
The present invention relates to complex salt or composition medicine of breviscapine and basic amino acid for treating cardiac and cerebral vascular diseases. The composition medicine consists of breviscapine 1 weight portions, and basic amino acid 0.01-100 weight portions, and proper amount of supplementary material. It may be prepared into powder for injection, injection, oral liquid, capsule and other suitable clinical preparation forms. The composition medicine of the present invention has obviously raised dissolubility and bioavailability of breviscapine, high medicine effect, obvious synergistic effect and wide clinical application foreground.
Description
Technical field
The present invention relates to be used for the treatment of in the medical technical field breviscapine and basic amino acid double salt or the composition medicine of cardiovascular and cerebrovascular disease, specifically be by 1 part of breviscapine (percentage by weight), basic amino acid is arginine, histidine, a kind of in the material such as tryptophan and lysine or 0.01～100 part in several aminoacid of combining by arbitrary proportion arbitrarily wherein, double salt or composition medicine that compatibility forms.
Background technology
Cardiovascular and cerebrovascular disease is the highest disease of mortality rate in the world today, seizes the above life of 12,000 ten thousand people every year, accounts for more than 25% of the dead sum in the whole world, and thousands of patient is disabled.And the age obviously be tending towards the young and the middle agedization, especially social high speed development, sickness rate greatly increases due to dietary structure change and environmental pollution and the various psychological illness, brings very big loss and misery for society and family.As seen, cardiovascular and cerebrovascular disease serious threat human beings'health and life.Especially in the big and medium-sized cities of China, the cardiovascular and cerebrovascular disease mortality rate has accounted for more than 50% of the population cause of the death, and the apoplexy mortality rate is surprisingly high especially, and China's apoplexy survivor has more than 5,000,000 people approximately, wherein existing disability in various degree more than 75%.
Breviscapine (Breviscapine) is the extract of Compositae Erigeron breviscapus (Vant.) Hand.-Mazz. platymiscium (Erigron breviscapus (vaniot) Hand Mazz) Herba Erigerontis, its main component is a scutellarin (scutellarin) promptly 4,5,6-trihydroxyflavone-7-0-glucuronide, other contains a spot of breviscapine.A large amount of these effective constituents that studies show that have good cardiovascular and cerebrovascular vessel activity.A lot of preparations such as Herba Erigerontis tablet, breviscapine injection, breviscapine capsule and dispersible preparation thereof etc. have been applied to clinical.Its major function is for improving the brain blood circulation, and the cerebral blood flow increasing amount reduces vascular resistance and anti-platelet aggregation, paralysis and sequela thereof due to the treatment occlusive cerebrovascular; Blood circulation promoting and blood stasis dispelling, removing obstruction in the collateral to relieve pain.Be used for apoplexy sequela, coronary heart disease and angina pectoris.
But because its molecule belongs to polysubstituted flavonoid structure, molecular rigidity is strong, dissolubility is relatively poor in water, not only influenced its dissolubility and stability in various preparations, as clarity of injection etc., and breviscapine absorption in vivo and metabolism have been influenced, thereby limited its route of administration, reduced its bioavailability, also occur ill effects such as anaphylaxis, urticaria, limbs fatigue, xerostomia, weak, cardiovascular response and hyperpyrexia, shiver with cold infusion reaction in the clinical use, make this medicine be subjected to bigger influence aspect the clinical expansion use.
Summary of the invention
The purpose of this invention is to provide the breviscapine and basic amino acid double salt or the composition medicine that are used for the treatment of cardiovascular and cerebrovascular disease.Mainly be by 1 part of breviscapine (percentage by weight), basic amino acid is arginine, histidine, a kind of in the material such as tryptophan and lysine or 0.01～100 part in several aminoacid of combining by arbitrary proportion arbitrarily wherein, compatibility forms the medicine of double salt or compositions.Can add pharmaceutically acceptable various pharmaceutic adjuvant in the described medicine, make ejection preparation, comprise injectable powder, liquid drugs injection and transfusion or make oral liquid, capsule, pill, drop pill, micropill (grain), tablet, granule, and clinical other suitable dosage forms such as long-acting slow-release and dispersion fast dissolving dosage form.
The present invention is the acidic-group carboxyl activity of utilizing in the breviscapine flavonoid glycosides molecular structure, can with basic amino acid commonly used, as arginine (Arginine), histidine (histidine), tryptophan (trypophan) and lysine (Lysine) etc. form more stable double salt or compositions.These basic amino acids, because its intramolecule all can form the molecule inner salt structure, thereby itself has an extremely strong water solublity, in addition and breviscapine can form acylate between the molecule again, its hydrophilic significantly strengthens, increased the dissolubility of breviscapine in water greatly, thereby widened the route of administration of this medicine, reduce or avoid its adverse side effect, increase its medicine and stability of formulation thereof, significantly improve its bioavailability, guaranteed the good efficacy that this medicine is obtained in clinical use.And the prescription screening of such double salt or complex, preparation technology, stability, content control all-round exploration and research have been carried out with everyways such as its quality standard and preliminary pharmacology.
In the present invention, breviscapine and basic amino acid can form organic acid ammonia salt (double salt) by the quantitative proportioning principle of chemical equation mole (1: 1), also can form the combination material by other arbitrary proportion.For example in its process, at first breviscapine being sent out by chemosynthesis should, generate double salt or compositionss such as breviscapine arginine salt, breviscapine histidine salt, breviscapine tryptophan salt and breviscapine lysinate with basic amino acid, again with newly-generated chemical compound, press research process such as galenic pharmacy principle and preparation technology thereof, quality detection, be made into suitable various pharmaceutical preparatioies.And by paper chromatography, ultra-violet absorption spectrum, infrared absorption spectroscopy, even X-ray diffracting spectrum carries out the structure evaluation one by one to it.Also it physicochemical property that comprises dissolubility, stability etc. is studied, conclusion is good.In double salt or compositions synthetic reaction, we further investigate the material ratio of multiple breviscapine and basic amino acid, and by product content being measured with relatively stable, the amount ratio that filters out breviscapine and basic amino acid should be when 1: 1 or its left and right sides, water solublity the best, stability are also better.Simultaneously because the double salt or the compositions that make belong to acylate, and certain oxidisability and hygroscopy are arranged, so we have adopted N
2Deng inert gas shielding, and after reaction, can add antioxidant such as a small amount of dimension C or sodium sulfite, better effects if.
Breviscapine and basic amino acid double salt of the present invention or compositions are when all kinds of preparation of preparation, pharmaceutic adjuvant in the constituent is meant pharmaceutical field acceptable carrier or material, as diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, lubricant, stabilizing agent and the correctives etc. of routine.
The dosage form of medicine of the present invention is an injection, comprise freeze-dried powder, aqueous injection and large and small transfusion, or make oral formulations, comprise oral liquid, capsule, drop pill, micropill (grain), pill, tablet, granule and patch, and clinical other suitable dosage forms such as fast dissolving dosage form such as long-acting slow-release and dispersion.
The invention has the advantages that:
(1), passes through chemosynthesis reaction, prepare organic double salt of this medicine or compositions, owing to be the outstanding feature of two salt based structures, help improving its molecular polarity, improve its bioavailability, strengthen its curative effect, indication the present invention can obviously improve clinical effective rate, and further improves patient's life quality.
(2), prepared double salt or composition medicine, stability is high, has solved the unsettled shortcoming of breviscapine, has improved the pharmacokinetic parameters and the metabolic pathway thereof of medicine, has strengthened patient's compliance, has reduced untoward reaction and side effect.
(3), owing to improved water solublity, will solve technical barriers such as breviscapine injection clarity more satisfactorily, can obviously reduce or avoid the incidence rate of infusion reaction.
The specific embodiment
The preparation of embodiment 1, breviscapine arginine double salt
Take by weighing breviscapine 230mg, under tepor, be dissolved in fully in the 60ml dehydrated alcohol, stir step feeding down, add L-arginine 116.0mg.Put coldly slightly, stir down, drip sodium carbonate liquor, monitoring PH changes, to PH=7～9.Continue the stirring and refluxing reaction, 3～4h.Reaction finishes, and rotation is steamed and removed reaction dissolvent, and residue adds 60ml～100ml ethanol behind vacuum drying 2h, fully concussion, and decompress filter behind the decompression filtrate recycling ethanol, adds refrigerated distilled water, stirs, and vibrates 10 minutes, puts sucking filtration, merging filtrate slightly.Filtrate is through supersound process 15～30min, reuse 0.22 μ m filtering with microporous membrane, and filtrate is with the distilled water standardize solution promptly.Or with filtrate through lyophilization, the white crystalline powder of breviscapine arginine salt.Product structure is through infrared, ultraviolet, and detections such as nuclear-magnetism and elementary analysis are confirmed.Product is soluble in water, is slightly soluble in alcohol, is insoluble to organic solvents such as ether.
Embodiment 2, the preparation of breviscapine lysine double salt aqueous injection
Take by weighing breviscapine lysine double salt 150g, add and make with extra care injection water 20000ml, dissolving, filtration, preparation 2ml/ props up, and sterilization gets 10000 of aqueous injection.Every contains breviscapine lysine double salt 15mg.
Embodiment 3, the preparation of breviscapine lysine powder injection
Take by weighing breviscapine lysine double salt 200g, dextran S
40160g adds injection water 25000ml dissolving, through 0.22 μ m filtering with microporous membrane, measures content, and is distributed into every 2.5ml specification.Lyophilization promptly gets 10000 of breviscapine lysine double salt injectable powder, and every contains breviscapine lysine double salt 20mg.
Embodiment 4, breviscapine histidine double salt capsule must prepare
Take by weighing breviscapine histidine double salt 60g, add appropriate amount of starch, 60% ethanol is made wetting agent, crosses 20 mesh sieves and granulates, and 60 ℃ of oven dry, granulate divides in the capsule of packing into, makes 2000 capsules promptly.Every contains breviscapine histidine double salt 30mg.
Embodiment 5, the capsular preparation of breviscapine arginine double salt long-acting slow-release
Get breviscapine arginine double salt 600g, lactose 50g, polyvinylpyrrolidone 15g, hydroxypropyl emthylcellulose 80g, Pulvis Talci 50g.With hydroxypropyl emthylcellulose and breviscapine mixing, and add lactose, make micropill with polyvinylpyrrolidone liquid, the fill capsule makes 1000 grain lengths and imitates slow releasing capsule.Every contains breviscapine arginine double salt 600mg.
Claims (4)
1, the breviscapine and basic amino acid or the compositions that are used for the treatment of cardiovascular and cerebrovascular disease.It is characterized in that described medicine forms (percentage by weight) by following composition: 1 part of breviscapine, part (W is a basic amino acid in W0.01～100, be a kind of or wherein several the combinations arbitrarily in the materials such as arginine, histidine, tryptophan and lysine by arbitrary proportion), all the other are pharmaceutic adjuvant.
2,, it is characterized in that this medicine can be applicable to treat all clinical practice indications of breviscapine that comprise the treating cardiac and cerebral vascular diseases disease according to described breviscapine and basic amino acid double salt of claim 1 or composition medicine.
3,, it is characterized in that described breviscapine comprises lamp-dish flower acetic, oil lamp cycle of sixty years element or Herba Erigerontis flavone extract interior according to claims 1 described breviscapine and basic amino acid double salt or composition medicine.
4, according to described breviscapine and basic amino acid double salt or the composition medicine that is used for the treatment of cardiovascular and cerebrovascular disease of claim 1, it is characterized in that adding in the described medicine constituent the pharmaceutically various pharmaceutic adjuvants of acceptable, make ejection preparation, comprise injectable powder, aqueous injection and transfusion, or make oral formulations, capsule, pill, drop pill, micropill (grain), tablet, granule and patch, and clinical other suitable dosage forms such as long-acting slow-release and the agent of dispersion rapid release.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610020537 CN1857295A (en) | 2006-03-22 | 2006-03-22 | Complex salt or composition medicine of breviscapine and basic amino acid for treating cardiac and cerebral vascular diseases |
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| CN 200610020537 CN1857295A (en) | 2006-03-22 | 2006-03-22 | Complex salt or composition medicine of breviscapine and basic amino acid for treating cardiac and cerebral vascular diseases |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101513400B (en) * | 2008-02-22 | 2012-05-16 | 兰州大学 | Ampelopsin and basic amino acid solubilizing system and antitumor activity research |
| CN105456284A (en) * | 2016-01-05 | 2016-04-06 | 李春华 | Medicine for treating coughs |
| CN108785253A (en) * | 2017-05-04 | 2018-11-13 | 上海交通大学 | A kind of preparation method of Scutellarein liposome |
-
2006
- 2006-03-22 CN CN 200610020537 patent/CN1857295A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101513400B (en) * | 2008-02-22 | 2012-05-16 | 兰州大学 | Ampelopsin and basic amino acid solubilizing system and antitumor activity research |
| CN105456284A (en) * | 2016-01-05 | 2016-04-06 | 李春华 | Medicine for treating coughs |
| CN105456284B (en) * | 2016-01-05 | 2018-06-15 | 李春华 | A kind of drug for treating cough |
| CN108785253A (en) * | 2017-05-04 | 2018-11-13 | 上海交通大学 | A kind of preparation method of Scutellarein liposome |
| CN108785253B (en) * | 2017-05-04 | 2021-11-05 | 上海交通大学 | Preparation method of scutellarin aglycone liposome |
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Open date: 20061108 |