CN101474157A - Asiatic acid injectable sustained-release microballoons and preparation method thereof - Google Patents
Asiatic acid injectable sustained-release microballoons and preparation method thereof Download PDFInfo
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- CN101474157A CN101474157A CNA2009100956669A CN200910095666A CN101474157A CN 101474157 A CN101474157 A CN 101474157A CN A2009100956669 A CNA2009100956669 A CN A2009100956669A CN 200910095666 A CN200910095666 A CN 200910095666A CN 101474157 A CN101474157 A CN 101474157A
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Abstract
The invention relates to the technical field of pharmaceutical preparation, in particular to an asiatic acid sustained-release microsphere used for injection and a preparation method thereof. A biodegradable chitosan is taken as a carrier, an asiatic acid is taken as principal agent, and the asiatic acid sustained-release microsphere used for injection is obtained by the technology of cross-linked emulsion. Due to the obtained medicament carried microspheres, the surfaces are relatively smooth; the particle diameters range from 20mum to 110mum; and the medicament loading rate of the microspheres ranges from 4.8% to 15.6%. The asiatic acid microsphere has the characteristics that the burst effect is modest (the burst size on the first day is smaller than 15%); the release rate is stable; the sustained release time is long (4-10 weeks); and the asiatic acid microsphere is biodegradable. The implantation and the removal by operation before and after the medicament is used are avoided.
Description
Technical field
The present invention relates to technical field of medicine, relate in particular to a kind of can prolong drug action time, biodegradable asiatic acid injectable sustained-release microballoons preparation.
Background technology
Herba Centellae is dry herb or the whole herb with root of samphire Herba Centellae Centella asiatica (L) Urban, effect (Zhang Leilei with clearing away heat-damp and promoting diuresis, removing toxic substances and promoting subsidence of swelling, Deng. Herba Centellae chemical constitution study [J]. Chinese herbal medicine, 2005,36 (12): 1761-1763.), its effective ingredient asiaticoside, asiaticoside and asiatic centella total glucoside extract etc. can significantly soften connective tissue and make this even tissue growth, are usually used in the treating acne (WS relevant with beautifying skin
3-B-2596-97-2002 drug standard), be widely used in clinical in China, Europe and south east asia.
The Herba Centellae common oral preparation needs frequent drug administration, needs day 3 administrations of clothes as the asiaticoside tablet that has gone on the market, generally needs 3-6 month the course of treatment, and this brings very big inconvenience for taking medicine of patient.And the easier fluctuation that causes blood drug level of multiple dosing, cause " peak valley " phenomenon, thereby cause the increase of toxic and side effects.Though oral slow-releasing preparation can partly be avoided this phenomenon, also need administration every day at least 1 time (Wang Shenghao, etc. contain Chinese medicine slow releasing preparation of asiatic pennywort herb water-soluble active ingredient and preparation method thereof, patent No. ZL200510050001.8).
The asiaticoside drug effect is clear and definite, but its oral absorption is relatively poor, and blood drug level is extremely low.Lot of documents report asiatic acid is the Chinese medicine asiaticoside plays main pharmacodynamics in vivo behind biotransformation material base (Marquart, FX, et al.Stimulation of collagen synthesis in fibroblastscultures by an extract of Centalla asiatica:specific effect on the freepraline pool[J] .Tissue Res, 1990,24:107-120; Grimaldi R, et al.Pharmacokinetics of the total triterpenic fraction from Centellaasiatica after single and multiple administrations to healthyvolunteers.A new assay for asiatic acid[J] .J Ethnopharmacol, 1990,28:235-241; Rush, WR, et al.The comparative steady-state bioavai-lability ofthe active ingredients of Madecassol[J] .Eur J Drug MetabPharm, 1993,8 (4): 323-326.), its effect is stronger than asiaticoside.Therefore, the present invention with the Chinese medicine asiatic acid (chromatographic purity〉90%, commercially available) be principal agent, adopt advanced microball preparation technology, prepare a kind of interval long period drug administration by injection Chinese medicine asiatic acid Atrigel (can stablize and discharge 4-10 week) once, can yet be regarded as solves the effective way of patient dependence.
Summary of the invention
The objective of the invention is provides a kind of asiatic acid injectable sustained-release microballoons and preparation method thereof at the deficiencies in the prior art.
For achieving the above object, the present invention adopts following technical scheme:
A kind of asiatic acid injectable sustained-release microballoons is characterized in that the medicine of described microsphere parcel is an asiatic acid, and microsphere supported is chitosan.The microsphere features smooth surface that is obtained, particle size distribution are between 20-110 μ m, and drug loading is 4.8-15.6%, can stablize to discharge 4-10 week.
Above-mentioned asiatic acid injectable sustained-release microballoons preparation method is characterized in that comprising following process:
1. be solvent with 2% glacial acetic acid solution, add chitosan (molecular weight is 46-200kDa), abundant swelling, stirring and dissolving is filtered, and discards insoluble matter, makes into 5% concentration (W/V).
2. asiatic acid (particle diameter＜10 μ m, chromatographic purity is greater than 90%) is added to mix homogeneously in above-mentioned 5% chitosan solution as water (the asiatic acid addition is the 0.5-2 doubly (W/W) of chitosan); Under the mechanical agitation condition (800-1200r/min), water slowly is added drop-wise in the oil phase that contains emulsifying agent, and keep and stir 5-10min, make to form water-in-oil type (W/O) emulsion, wherein emulsifier span 80 is 1:50 with the w/v of oil phase liquid paraffin body.
3. under 200r/min stirred, 25-30 ℃ of control temperature dripped cross-linking agent 25% glutaraldehyde solution to emulsion, and dripping quantity is 1-2ml, solidifies 1-6h.Collect microspheres with solid, through petroleum ether, distilled water, petroleum ether/isopropyl alcohol (1:1) and petroleum ether, vacuum drying promptly obtains the asiatic acid sustained-release micro-spheres.
The invention has the beneficial effects as follows: the present invention has characteristics such as simple to operate, preparing technique process is stable and cheap for manufacturing cost.Thus obtained microsphere surface compact, particle diameter between 20-110 μ m, narrow diameter distribution; Drug loading is between 4.8-15.6%.This asiatic acid microsphere has more burst effect little (first day burst size＜15%), and rate of release is stable, continues to discharge long (4-10 week) and has characteristics such as biodegradable, have long-acting significantly, slow releasing function.The carrier material chitosan that is adopted has characteristics such as safe without toxic side effect, biocompatibility are good, biodegradability, therefore can avoid the operation before and after the medication to implant and take out, and good research and application and development prospect are arranged.
Description of drawings
Fig. 1 is the stereoscan photograph of asiatic acid microsphere;
Fig. 2 is the particle size distribution figure of asiatic acid microsphere;
Fig. 3 is for pH7.4 phosphate buffer (containing 1% sodium lauryl sulphate) being the outer release profiles of asiatic acid microsphere of release medium.
The specific embodiment
Asiatic acid injectable sustained-release microballoons of the present invention, the medicine of microsphere parcel is an asiatic acid, microsphere supported is chitosan.By the conditions such as cross-linking reaction time, carrier molecule amount and mixing speed of control microsphere, preparation surface compact and slick Chinese medicine asiatic acid microsphere are to reach " burst effect " that lower microsphere, significantly to delay the purpose of drug release.
The preparation process of asiatic acid injectable sustained-release microballoons of the present invention is as follows:
1. be solvent with 2% glacial acetic acid solution, add chitosan, abundant swelling, stirring and dissolving is filtered, and discards insoluble matter, makes into 5% concentration (W/V).
2. asiatic acid (particle diameter＜10 μ m, chromatographic purity is greater than 90%) is added to mix homogeneously in above-mentioned 5% chitosan solution as water (the asiatic acid addition is the 0.5-2 doubly (W/W) of chitosan); Under the mechanical agitation condition (800-1200r/min), water slowly is added drop-wise in the oil phase that contains emulsifying agent, and keeps and stir 5-10min, make to form water-in-oil type (W/O) emulsion.
3. under 200r/min stirred, 25-30 ℃ of control temperature dripped cross-linking agent to emulsion, and dripping quantity is 1-2ml, solidifies 1-6h.Collect microspheres with solid, washing is dry, promptly obtains the asiatic acid sustained-release micro-spheres.
Wherein, the chitosan molecule weight range is 46-200kDa; Emulsifying agent is a sorbester p17, and oil phase is a liquid paraffin; The w/v of sorbester p17 and liquid paraffin is 1:50; Cross-linking agent is 25% glutaraldehyde solution; Through petroleum ether, distilled water, petroleum ether/isopropyl alcohol (1:1) and petroleum ether, vacuum drying obtains microsphere respectively.
Be described in further detail below in conjunction with embodiment:
Embodiment 1
Take by weighing chitosan (molecular weight 200kDa) 1g, add the abundant swelling of 2% glacial acetic acid solution 20ml, stirring and dissolving is filtered, and discards insoluble matter, makes into 5% concentration (W/V).448mg asiatic acid (particle diameter＜10 μ m) is joined in above-mentioned 5% chitosan solution of 4ml, and mix homogeneously is as water.(900r/min) slowly is added drop-wise in the liquid paraffin (80ml) that contains 1.6g Span-80 under the mechanical agitation condition, keeps and stirs 5min, makes to form water-in-oil type (W/O) emulsion; Under 200r/min stirred, 25-30 ℃ of control temperature added 1.5ml 25% glutaraldehyde solution, solidifies 1h, filters, and uses petroleum ether, distilled water, petroleum ether/isopropyl alcohol (1:1) and petroleum ether respectively, and vacuum drying promptly obtains the asiatic acid sustained-release micro-spheres.This microsphere drug loading is 15.6%, 24h cumulative release (first day burst size): 9.6%.
Take by weighing chitosan (molecular weight 126kDa) 1g, add the abundant swelling of 2% glacial acetic acid solution 20ml, stirring and dissolving is filtered, and discards insoluble matter, makes into 5% concentration (W/V).224mg asiatic acid (particle diameter＜10 μ m) is joined in the above-mentioned 4ml5% chitosan solution, and mix homogeneously is as water.(1000r/min) slowly is added drop-wise in the liquid paraffin (80ml) that contains 1.6g Span-80 under the mechanical agitation condition, keeps and stirs 10min, makes to form water-in-oil type (W/O) emulsion; Under 200r/min stirred, 25-30 ℃ of control temperature added 2ml 25% glutaraldehyde solution, solidifies 3h, filters, and uses petroleum ether, distilled water, petroleum ether/isopropyl alcohol (1:1) and petroleum ether respectively, and vacuum drying promptly obtains the asiatic acid sustained-release micro-spheres.This microsphere drug loading is 7.8%, 24h cumulative release (first day burst size): 10.5%.
Embodiment 3
Take by weighing chitosan (molecular weight 126kDa) 1g, add the abundant swelling of 2% glacial acetic acid solution 20ml, stirring and dissolving is filtered, and discards insoluble matter, makes into 5% concentration (W/V).224mg asiatic acid (particle diameter＜10 μ m) is joined in above-mentioned 4ml5% chitosan (molecular weight 12.6KDa) solution, and mix homogeneously is as water.(1000r/min) slowly is added drop-wise in the liquid paraffin (80ml) that contains 1.6g Span-80 under the mechanical agitation condition, keeps and stirs 10min, makes to form water-in-oil type (W/O) emulsion; Under 200r/min stirred, 25-30 ℃ of control temperature added the 1.5ml25% glutaraldehyde solution, solidifies 6h, filters, and uses petroleum ether, distilled water, petroleum ether/isopropyl alcohol (1:1) and petroleum ether respectively, and vacuum drying promptly obtains the asiatic acid sustained-release micro-spheres.This microsphere drug loading is 8.4%, 24h cumulative release (first day burst size): 8.0%.
Take by weighing chitosan (molecular weight 200kDa) 1g, add the abundant swelling of 2% glacial acetic acid solution 20ml, stirring and dissolving is filtered, and discards insoluble matter, makes into 5% concentration (W/V).224mg asiatic acid (particle diameter＜10 μ m) is joined in above-mentioned 4ml 5% chitosan solution, and mix homogeneously is as water.(800r/min) slowly is added drop-wise in the liquid paraffin (80ml) that contains 1.6g Span-80 under the mechanical agitation condition, keeps and stirs 5min, makes to form water-in-oil type (W/O) emulsion; Under 200r/min stirred, 25-30 ℃ of control temperature added the 1ml25% glutaraldehyde solution, solidify 3h, filter, use petroleum ether, distilled water, petroleum ether/isopropyl alcohol (1:1) and petroleum ether respectively, vacuum drying promptly obtains the asiatic acid chitosan sustained-release microsphere.This microsphere drug loading is 11.1%, 24h cumulative release (first day burst size): 6.9%.
Embodiment 5
Take by weighing chitosan (molecular weight 46kDa) 1g, add the abundant swelling of 2% glacial acetic acid solution 20ml, stirring and dissolving is filtered, and discards insoluble matter, makes into 5% concentration (W/V).112mg asiatic acid (particle diameter＜10 μ m) is joined in above-mentioned 4ml 5% chitosan solution, and mix homogeneously is as water.(800r/min) slowly is added drop-wise in the liquid paraffin (80ml) that contains 1.6g Span-80 under the mechanical agitation condition, keeps and stirs 5min, makes to form water-in-oil type (W/O) emulsion; Under 200r/min stirred, 25-30 ℃ of control temperature added 1ml 25% glutaraldehyde solution, solidify 6h, filter, use petroleum ether, distilled water, petroleum ether/isopropyl alcohol (1:1) and petroleum ether respectively, vacuum drying promptly obtains the asiatic acid chitosan sustained-release microsphere.This microsphere drug loading is 4.8%, 24h cumulative release (first day burst size): 14.4%.
Embodiment 6
Get the about 25mg of the microsphere for preparing according to embodiment 4,5 parts of the same form place releasing tube respectively, add 5ml pH7.4 phosphate buffer (containing 1%SDS), place the constant temperature air bath shaker, keep 37 ℃, and rotating speed is 50r/min.Respectively at 0.5d, 1d, 4d, 13d, 24d, 28d, 33d, 37d, 41d, 45d, 49d, 53d, 57d, the 61d sampling, the centrifugal 10min of 5500r/min takes out whole supernatant, adds the 5ml release medium again, takes out liquid and detects through HPLC.The result shows that the cumulative release amount of the 61st day (greater than 2 months) is 88.6% ± 4.11.The release in vitro design sketch is seen accompanying drawing 3.
Claims (2)
1, a kind of asiatic acid injectable sustained-release microballoons is characterized in that the medicine of described microsphere parcel is an asiatic acid, and microsphere supported is chitosan.The microsphere features smooth surface that is obtained, particle size distribution are between 20-110 μ m, and drug loading is 4.8-15.6%, can stablize to discharge 4-10 week.
2, asiatic acid injectable sustained-release microballoons as claimed in claim 1 is characterized in that comprising following process:
(1). with 2% glacial acetic acid solution is solvent, adds chitosan (molecular weight is 46-200kDa), abundant swelling, stirring and dissolving is filtered, and discards insoluble matter, makes into 5% concentration (W/V).
(2). asiatic acid (particle diameter＜10 μ m, chromatographic purity is greater than 90%) is added to mix homogeneously in above-mentioned 5% chitosan solution as water (the asiatic acid addition is the 0.5-2 doubly (W/W) of chitosan); Under the mechanical agitation condition (800-1200r/min), water slowly is added drop-wise in the oil phase that contains emulsifying agent, and keep and stir 5-10min, make to form water-in-oil type (W/O) emulsion, wherein emulsifier span 80 is 1:50 with the w/v of oil phase liquid paraffin body.
(3). under 200r/min stirred, 25-30 ℃ of control temperature dripped cross-linking agent 25% glutaraldehyde solution to emulsion, and dripping quantity is 1-2ml, solidifies 1-6h.Collect microspheres with solid, through petroleum ether, distilled water, petroleum ether/isopropyl alcohol (1:1) and petroleum ether, vacuum drying promptly obtains the asiatic acid sustained-release micro-spheres.
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| CN102784096A (en) * | 2011-05-18 | 2012-11-21 | 上海现代药物制剂工程研究中心有限公司 | Asiatic acid self-microemulsifying drug delivery system and its preparation method |
| CN104352442A (en) * | 2014-10-18 | 2015-02-18 | 福州大学 | Mifepristone chitosan sustained release microspheres and preparation method thereof |
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| CN110201217A (en) * | 2019-06-13 | 2019-09-06 | 西安医学院 | A kind of hemostatic microsphere and preparation method thereof for cervical erosion post-surgical trauma bleeding |
| CN112107561A (en) * | 2019-12-10 | 2020-12-22 | 江苏一全药业有限公司 | Medicinal preparation containing chitosan, medicinal transdermal patch and preparation method thereof |
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2009
- 2009-01-19 CN CN 200910095666 patent/CN101474157B/en not_active Expired - Fee Related
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| CN102784096B (en) * | 2011-05-18 | 2016-10-12 | 上海现代药物制剂工程研究中心有限公司 | A kind of Asiatic acid self-microemulsifyindrug drug delivery system and preparation method thereof |
| CN102784096A (en) * | 2011-05-18 | 2012-11-21 | 上海现代药物制剂工程研究中心有限公司 | Asiatic acid self-microemulsifying drug delivery system and its preparation method |
| CN104352442A (en) * | 2014-10-18 | 2015-02-18 | 福州大学 | Mifepristone chitosan sustained release microspheres and preparation method thereof |
| CN104352442B (en) * | 2014-10-18 | 2017-07-04 | 福州大学 | A kind of mifepristone chitosan sustained-release microsphere preparation and preparation method thereof |
| CN105832675A (en) * | 2016-03-24 | 2016-08-10 | 湖北民族学院 | Selenium-supported chitosan microsphere controllably sustained-releasing selenium negative ions and preparation method thereof |
| CN105832675B (en) * | 2016-03-24 | 2018-10-26 | 湖北民族学院 | A kind of load selenium chitosan microball of controllable sustained-release selenium anion and preparation method thereof |
| CN110201217B (en) * | 2019-06-13 | 2021-12-07 | 西安医学院 | Hemostatic microsphere for cervical erosion postoperative wound bleeding and preparation method thereof |
| CN110201217A (en) * | 2019-06-13 | 2019-09-06 | 西安医学院 | A kind of hemostatic microsphere and preparation method thereof for cervical erosion post-surgical trauma bleeding |
| CN112107561A (en) * | 2019-12-10 | 2020-12-22 | 江苏一全药业有限公司 | Medicinal preparation containing chitosan, medicinal transdermal patch and preparation method thereof |
| CN112107561B (en) * | 2019-12-10 | 2021-07-23 | 江苏一全药业有限公司 | Medicinal preparation containing chitosan, medicinal transdermal patch and preparation method thereof |
| CN113288884A (en) * | 2019-12-10 | 2021-08-24 | 江苏一全药业有限公司 | Medicinal preparation containing chitosan, medicinal transdermal patch and preparation method thereof |
| CN112315943A (en) * | 2020-11-19 | 2021-02-05 | 广东海洋大学 | Asiaticoside-chitosan-sodium alginate microspheres, preparation method and application thereof |
| CN112315943B (en) * | 2020-11-19 | 2022-02-25 | 广东海洋大学 | Asiaticoside-chitosan-sodium alginate microspheres, preparation method and application thereof |
| WO2022105301A1 (en) * | 2020-11-19 | 2022-05-27 | 广东海洋大学 | Asiaticoside-chitosan-sodium-alginate microsphere, and preparation method therefor and use thereof |
| CN115804822A (en) * | 2022-12-16 | 2023-03-17 | 广东恒诚制药股份有限公司 | A method for preparing granule containing Chinese medicinal composition with appetite stimulating and spleen invigorating effects |
| CN115804822B (en) * | 2022-12-16 | 2023-08-18 | 广东恒诚制药股份有限公司 | A method for preparing granule containing Chinese medicinal composition for stimulating appetite and invigorating spleen |
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