CN1565443A - Daphnetin cyclodextrin clathrate compound, formulation and its preparation method - Google Patents
Daphnetin cyclodextrin clathrate compound, formulation and its preparation method Download PDFInfo
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- CN1565443A CN1565443A CN 03124551 CN03124551A CN1565443A CN 1565443 A CN1565443 A CN 1565443A CN 03124551 CN03124551 CN 03124551 CN 03124551 A CN03124551 A CN 03124551A CN 1565443 A CN1565443 A CN 1565443A
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- daphnetin
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- cyclodextrin
- cyclodextrin clathrate
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Abstract
The invention discloses a daphnetin cyclodextrin clathrate compound, the preparation and the process for preparing same, wherein the daphnetin and cyclodextrin or other derivative (such as beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin) are employed to prepare the clathrate compound with improved stability.
Description
Technical field
The present invention relates to medical technical field, definitely utilize cyclodextrin or derivatives thereof and daphnetin to form clathrate or improve dissolubility, the stability of daphnetin in water saying so, thereby make cyclodextrin clathrate and preparation thereof by adding cyclodextrin or derivatives thereof.
Background technology
Daphnetin is the coumarin kind compound of extraction separation from thymelaeceae plant Daphne Giraldii Nitsche Daphne giraldii Nitsche root bark and peel of stem, has the expansion coronary vasodilator, coronary blood flow increasing, reduce myocardial oxygen consumption, improve myocardial metabolism and promote cardiac function to recover, expansion peripheral vessel and anti-artery thrombosis and the effect of inhibition platelet aggregation; And excited hypophysis---the antiinflammatory action of interrenal system arranged; Analgesia, tranquilizing soporific and antibacterial action are still arranged in addition.Be a kind of extremely promising medicine, have great exploitation and be worth.
The existing dosage form of daphnetin is the daphnetin capsule at present, the clinical auxiliary treatment that is used for the treatment of thromboangiitis obliterans and other obliterative vascular diseases and coronary heart disease; And the Daphne Giraldii Nitsche injection of one of injection that the sterile water solution of Daphne Giraldii Nitsche root bark and peel of stem is made has expelling wind and removing dampness, blood circulation promoting and blood stasis dispelling, the function of dispersing cold for relieving pain is used for wind-cold damp pathogen invasion and attack and diseases such as the rheumatic arthritis that causes, pain that rheumatoid arthritis causes and sciatica; Another injection Daphne giraldii Nitsche injection liquid has expelling wind and removing dampness, and the promoting blood circulation and stopping pain function is used for limbs joint swelling, cold type of pain or twinge, movable joint stuffiness, overcast and rainy increasing the weight of, tongue with ecchymosis, deep and stringy pulse person; Rheumatic arthritis, rheumatoid arthritis belong to above-mentioned patient.Because daphnetin is molten in the methanol part omitted, slightly soluble in ethanol, insoluble in water, make injection and need add solubilizing agent tween 80 etc. to increase the dissolubility of daphnetin in water, transfusion be should not make, thereby the clinical practice and the curative effect of this medicine influenced.We use the modern pharmaceutical technology for this reason, adopt novel enclose rings of material dextrin or derivatives thereof that its enclose is formed cyclodextrin clathrate and makes corresponding dosage forms, clinical safety, stable, the evident in efficacy medicine of providing is provided, benefit the common people, this is significant to inheriting and develop motherland's medicine legacy.
Summary of the invention
The purpose of this invention is to provide a kind of daphnetin cyclodextrin clathrate and preparation thereof, it has good absorbing, bioavailability height, curative effect height, the little characteristics of side effect.
The present invention selects the cyclodextrin or derivatives thereof, as beta-schardinger dextrin-, HP-, hydroxyethyl-, methyl-beta-schardinger dextrin-, iodic acid group-beta-cyclodextrin, by glucoside-beta-schardinger dextrin-of other plant extract or synthetic etc. as the enclose material, daphnetin is made cyclodextrin clathrate.
Daphnetin cyclodextrin clathrate of the present invention, the weight ratio of daphnetin and cyclodextrin or derivatives thereof is: 1: any ratio in the 1-200 scope.
The preparation method of daphnetin clathrate can adopt any in solvent method, polishing, ultrasonic method, freeze-drying, the spray drying method etc. among the present invention.
The preparation of daphnetin clathrate of the present invention: daphnetin can carry out enclose with The suitable solvent dissolving back adding, also can directly add.
The made daphnetin cyclodextrin clathrate of the present invention can be prepared into various dosage forms, as oral formulations (comprising tablet, capsule, granule, pill, mixture, drop pill etc.), injection (comprising injection, aseptic powder injection or freeze-dried powder and transfusion etc.) also can be made into suppository, spray etc.
The said oral formulations of the present invention can be conventional formulation, also can be slow releasing preparation/controlled release preparation.
In " injection " of the present invention, can contain antioxidant, antioxidant is nitrogen, carbon dioxide gas, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, disodiumedetate, cysteine etc.
In " injection " of the present invention, can contain the excipient of 3-20%.
The present invention's said " injection " can adopt clathrates such as daphnetin hydroxypropyl-beta-cyclodextrin inclusion.
The present invention's said " injection " mainly contains daphnetin cyclodextrin clathrate, water for injection.
The present invention's said " freeze-dried powder " mainly contains daphnetin cyclodextrin clathrate and proppant or excipient, waits one or more to mix as " mannitol ", " lactose ", " dextran ", " sorbitol " and uses, get by lyophilization.
The present invention's said " aseptic powder injection " mainly contains daphnetin cyclodextrin clathrate and suitable proppant or excipient, wait one or more to mix as " mannitol ", " lactose ", " dextran ", " sorbitol " and use, the powder that obtains by " lyophilization " or " spray drying " carries out aseptic subpackaged getting.
The present invention's said " transfusion " mainly contains daphnetin cyclodextrin clathrate, water for injection and the instrumentality that oozes such as an amount of, oozes instrumentality as acceptable etc. on sodium chloride, glucose and other pharmaceuticss, gets through preparation.
The invention solves the water solublity problem of daphnetin, stability improves greatly.Daphnetin clathrate of the present invention can be used for making various preparations, has advantage efficiently, made oral formulations can be routine/release preparation, made injection has solubilizing agents such as no organic solvent, no tween 80, avoided the toxicity of tween 80, unit volume Chinese medicine content height, good effect, the advantage that toxic and side effects is low to body.
Concrete enforcement
Embodiment 1: the preparation of daphnetin Benexate Hydrochloride: amount takes by weighing daphnetin, beta-schardinger dextrin-according to the above ratio; Add suitable quantity of water/second alcohol and water, heating is stirred/ultrasonic to the stipulated time, stops heating, continue to stir/ultrasonic to the stipulated time, and cold preservation 24 hours, sucking filtration, washing, the precipitate cold drying, promptly.
Embodiment 2: the preparation of daphnetin hydroxypropyl-beta-cyclodextrin inclusion: amount takes by weighing daphnetin, HP-according to the above ratio, add suitable quantity of water/second alcohol and water, heating, stir/ultrasonic, stop heating, continue to stir/ultrasonic to the stipulated time to the stipulated time, membrane filtration with reuse 0.22 μ behind the membrane filtration of 0.45 μ, the solution of gained gets white powder, i.e. daphnetin hydroxypropyl-beta-cyclodextrin inclusion after vacuum drying/spray drying/lyophilization.
Embodiment 3: the preparation of daphnetin hydroxyethyl-clathrate: amount takes by weighing daphnetin, hydroxyethyl-according to the above ratio, add suitable quantity of water/second alcohol and water, heating, stir/ultrasonic, stop heating, continue to stir/ultrasonic to the stipulated time to the stipulated time, membrane filtration with reuse 0.22 μ behind the membrane filtration of 0.45 μ, the solution of gained gets white powder, i.e. daphnetin hydroxyethyl-clathrate after vacuum drying/spray drying/lyophilization.
Embodiment 4: get an amount of daphnetin cyclodextrin clathrate and an amount of auxiliary materials and mixing pelletizing press sheet, get various daphnetin sheets.Mixing tabletting after selecting for use different materials to granulate can get the release sheet.
Embodiment 5: get an amount of daphnetin cyclodextrin clathrate and appropriate amount of auxiliary materials mixing, directly granulate/make micropill after, encapsulated, promptly get capsule.After made micropill carried out coating with different coating materials, mixing, encapsulated, promptly get the release capsule.
Embodiment 6: get an amount of daphnetin cyclodextrin clathrate and an amount of substrate mixing and make suppository.
Embodiment 7: get an amount of daphnetin hydroxypropyl-beta-cyclodextrin inclusion and be dissolved in the water for injection, add an amount of lactose and 0.1-0.2% active carbon, stirred 10-40 minute, behind the depyrogenation, filtering decarbonization is with 0.22 μ m filtering with microporous membrane, transfer to ormal weight with water for injection, gained solution is sub-packed in the cillin bottle, carries out lyophilization, gets freeze-dried powder.
Embodiment 8: get an amount of daphnetin hydroxypropyl-beta-cyclodextrin inclusion and be dissolved in the water for injection, add an amount of mannitol and 0.1-0.2% active carbon, stirred 10-40 minute, behind the depyrogenation, filter carbon removal, with 0.22 μ m filtering with microporous membrane, transfer to ormal weight with water for injection, gained solution is sub-packed in the cillin bottle, carries out lyophilization, gets freeze-dried powder.
Embodiment 9: get an amount of daphnetin hydroxypropyl-beta-cyclodextrin inclusion and be dissolved in the water for injection, add the 0.1-0.2% active carbon, stirred 10-40 minute, behind the depyrogenation, filter carbon removal, with 0.22 μ m filtering with microporous membrane, transfer to ormal weight with water for injection, the packing of gained solution, flowing steam sterilization 30 minutes gets injection.
Embodiment 10: get an amount of daphnetin hydroxy propyl-Beta-thick spermatophore compound of ring and be dissolved in the water for injection, add an amount of glucose for injection and 0.1-0.3% active carbon, stirred 10-40 minute, behind the depyrogenation, filter carbon removal, with 0.22 μ m filtering with microporous membrane, transfer to ormal weight with water for injection, gained solution is sub-packed in the infusion bottle, sterilizes 30 minutes for 115 ℃, gets the daphnetin glucose injection.
Embodiment 11: get an amount of daphnetin hydroxypropyl-beta-cyclodextrin inclusion and be dissolved in the water for injection, add an amount of sodium chloride for injection and 0.1-0.3% active carbon, stirred 10-40 minute, behind the depyrogenation, filter carbon removal, with 0.22 μ m filtering with microporous membrane, transfer to ormal weight with water for injection, gained solution is sub-packed in the infusion bottle, sterilizes 30 minutes for 115 ℃, gets the daphnetin sodium chloride injection.
Claims (10)
1. a daphnetin cyclodextrin clathrate, preparation and preparation method, it is characterized in that: utilize cyclodextrin/its derivant (as beta-schardinger dextrin-, HP-, hydroxyethyl-, methyl-beta-schardinger dextrin-, sulfonic acid group-beta-cyclodextrin, by the glucose group-beta-cyclodextrin of other plant extract or synthetic) to form clathrate and prepare the daphnetin cyclodextrin clathrate with daphnetin, improve dissolubility and the stability of daphnetin in water, and make oral formulations, suppository, spray, four kinds of dosage forms of injection.
2. daphnetin cyclodextrin clathrate according to claim 1, preparation and preparation method is characterized in that: used " cyclodextrin or derivatives thereof " and the weight ratio of " daphnetin " are 1-200: any in 1.
3. daphnetin cyclodextrin clathrate according to claim 1, preparation and preparation method is characterized in that: said oral formulations comprises tablet, pill, mixture, drop pill, capsule, can be conventional formulation, also can be the release preparation; Said injection comprises injection, freeze-dried powder, aseptic powder injection, transfusion.
4. according to claim 1,3 described daphnetin cyclodextrin clathrate, preparation and preparation method, it is characterized in that: said " injection " mainly contains daphnetin cyclodextrin clathrate and water for injection.
5. according to claim 1,3 described daphnetin cyclodextrin clathrate, preparation and preparation method, it is characterized in that: said " freeze-dried powder " mainly contains daphnetin cyclodextrin clathrate, suitable proppant/excipient, gets by lyophilization.
6. according to claim 1,3 described daphnetin cyclodextrin clathrate and preparations thereof, it is characterized in that: said " aseptic powder injection " mainly contains daphnetin cyclodextrin clathrate, suitable proppant/excipient, and the powder that obtains by lyophilization/spray drying carries out aseptic subpackaged getting.
7. according to claim 1,3 described daphnetin cyclodextrin clathrate, preparation and preparation method, it is characterized in that: said " transfusion " mainly contains daphnetin cyclodextrin clathrate, water for injection, the instrumentality (as the instrumentality that oozes such as acceptable on sodium chloride, glucose and other pharmaceuticss) that oozes such as an amount of.
8. daphnetin cyclodextrin clathrate according to claim 1, preparation and preparation method is characterized in that: the preparation of said daphnetin cyclodextrin clathrate can be adopted any of solvent method, polishing, freeze-drying, spray drying method, ultrasonic method.
9. daphnetin cyclodextrin clathrate according to claim 1, preparation and preparation method, it is characterized in that: in the said injection, can contain antioxidant (as nitrogen, carbon dioxide gas, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, disodiumedetate, cysteine).
10. daphnetin cyclodextrin clathrate according to claim 1, preparation and preparation method, it is characterized in that: in the said injection, can contain 3-20% excipient (as mannitol, lactose, dextran, sorbitol a kind of/several mixing use).
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| Application Number | Priority Date | Filing Date | Title |
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| CN 03124551 CN1565443A (en) | 2003-06-10 | 2003-06-10 | Daphnetin cyclodextrin clathrate compound, formulation and its preparation method |
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| CN 03124551 CN1565443A (en) | 2003-06-10 | 2003-06-10 | Daphnetin cyclodextrin clathrate compound, formulation and its preparation method |
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| CN 03124551 Pending CN1565443A (en) | 2003-06-10 | 2003-06-10 | Daphnetin cyclodextrin clathrate compound, formulation and its preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103181909A (en) * | 2011-12-31 | 2013-07-03 | 中国人民解放军军事医学科学院毒物药物研究所 | Daphnetin slow-release composition and preparation method thereof |
| CN107668036A (en) * | 2017-10-31 | 2018-02-09 | 西南大学 | Tobacco bacterial wilt controlling agent containing dephnetin and preparation method and application |
-
2003
- 2003-06-10 CN CN 03124551 patent/CN1565443A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103181909A (en) * | 2011-12-31 | 2013-07-03 | 中国人民解放军军事医学科学院毒物药物研究所 | Daphnetin slow-release composition and preparation method thereof |
| CN103181909B (en) * | 2011-12-31 | 2015-03-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Daphnetin slow-release composition and preparation method thereof |
| CN107668036A (en) * | 2017-10-31 | 2018-02-09 | 西南大学 | Tobacco bacterial wilt controlling agent containing dephnetin and preparation method and application |
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