CN101036644A - Pharmaceutical composition containing arctigenin and preparation method - Google Patents
Pharmaceutical composition containing arctigenin and preparation method Download PDFInfo
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- CN101036644A CN101036644A CN 200710135648 CN200710135648A CN101036644A CN 101036644 A CN101036644 A CN 101036644A CN 200710135648 CN200710135648 CN 200710135648 CN 200710135648 A CN200710135648 A CN 200710135648A CN 101036644 A CN101036644 A CN 101036644A
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- arctigenin
- cyclodextrin
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Abstract
A composition for medicine having arctigenin and a method for preparing the same, in particular the arctigenin is involved in a cyclodextrin derivative, which mixture ratio is in a range of 1g:3g-30g, and the composition can effectively increase solubility and bioavailability of the arctigenin.
Description
Technical field
The present invention relates to a kind of Pharmaceutical composition that contains arctigenin and preparation method thereof, be specially arctigenin and cyclodextrin clathrate.
Background technology
Fructus Arctii ArctiumlappaL. is Compositae (Compositae) burdock, and its seed, root, Ye Junke are used as medicine.The medicinal part that Fructus Arctii is commonly used is its fruit, claims Fructus Arctii.Its acrid in the mouth hardship, cold.The effect of tool dispelling wind and heat pathogens, lung qi dispersing rash, subduing swelling and detoxicating is used for saturating, the diseases such as rubella is had an itch, carbuncle sore tumefacting virus of anemopyretic cold, cough with copious phlegm, laryngopharynx swelling and pain, macule.Mainly contain lignanoid and glycoside thereof in the Fructus Arctii.The kind of the lignanoid that occurring in nature has been found has a lot, studies show that in recent years: the physiology and the pharmacologically active of the lignanoid of different types of structure are not quite similar.Lignan component in the Fructus Arctii mainly contains arctiin and arctigenin (arctigenin).Arctigenin molecular formula: C
21H
24O
6Molecular weight: 372; Structural formula is as follows:
The molecular structure of arctigenin
It is reported that the high-load composition arctiin in the oral Fructus Arctii of rat (Arctium lappa) seed is converted into the metabolite arctigenin through the rat intestinal microbial population, show that arctiin is an aglycon active precursor material.The active report of arctigenin mainly contains following several respects: 1, antiviral and antiinflammatory; 2) immunoregulation effect; 3) hypoglycemic activity; 4) antitumor action.
Because arctigenin is fat-soluble compound, its preparation uses especially that drug administration by injection is restricted, and finds relevant report as yet.The present invention has solved the arctigenin solubility problem by experimental study, has enlarged the range of application of arctigenin, and has improved the bioavailability of arctigenin.
Summary of the invention:
The purpose of this invention is to provide a kind of Pharmaceutical composition that contains arctigenin and preparation method thereof, under the prerequisite that does not change the arctiin meta structure, increase the arctigenin water solublity, overcome the poorly soluble defective of arctigenin, and increase its bioavailability.It is characterized in that: select cyclodextrin derivative as the enclose material, arctigenin is made clathrate, increase the dissolubility of arctigenin in water with this.The ratio of cyclodextrin and arctigenin can be 3g-30g: any ratio of 1g scope.The ratio of further preferred cyclodextrin and arctigenin is 3g-10g: 1g.Said cyclodextrin derivative comprises: the alpha-cyclodextrin derivant of various substitution values, beta-cyclodextrin derivative, hydroxypropyl-gamma-cyclodextrin derivant and sulfobutyl ether-beta-cyclodextrin derivant etc., wherein the hydroxyl HP-is a preferred cyclodextrin.
Technical solution of the present invention is that arctigenin is added the appropriate amount of organic dissolving, under stirring state, is added drop-wise in the water-soluble cyclodextrin derivative solution, continues to mix solution, makes cyclodextrin derivative that the arctigenin enclose is complete.Preparation has better water miscible preparation thus.
Concrete technology is as follows:
Get the arctigenin of 1 weight portion, with about 150 weight portions, 60% ethanol heating for dissolving; Get the cyclodextrin derivative of 3-30 weight portion, add the water stirring and dissolving of twice cyclodextrin derivative amount, be thick to cyclodextrin derivative solution.
Two parts of solution are put into water-bath, under the high-speed stirred situation, the arctigenin drips of solution is added in the cyclodextrin derivative solution.Continue agitating solution, until being thick.Obtain the arctigenin cyclodextrin mixt.
The arctigenin cyclodextrin clathrate adds one or more pharmaceutic adjuvants and can be made into dosage form on any pharmaceutics, as oral tablet, capsule; Injection of injection or the like.
Arctigenin compositions antiinflammatory weight range is everyone 125-500mg every day, and usage can intravenous injection, also can be oral.Because this dosage is to calculate according to animal pharmacological test to get that in view of the diversity of animals and human beings body, the clinical consumption in historical facts or anecdotes border can allow to adjust to some extent.
The specific embodiment:
The following example is intended to further describe for example the present invention, rather than limit the present invention by any way, under the prerequisite that does not deviate from the spirit and principles in the present invention, any change that those of ordinary skills that the present invention did are realized easily all will fall within the claim scope that awaits the reply of the present invention.
Arctigenin self-control of the present invention.HP-adopts the commercially available product that moral upright biochemical worker in Xi'an provides among the embodiment.Hydroxypropyl-alpha-cyclodextrin, hydroxypropyl-gamma-cyclodextrin are available from the safe imperial biochemical company limited in Guangzhou.
Preparation example 1: preparation arctiin
Fructus Arctii is worn into coarse powder, through petroleum ether, ethyl acetate and 80% ethanol reflux, extract, successively, reclaims solvent respectively, gets the ethanol extract part.This extract water is transferred to certain volume, use n-butanol extraction, reclaim n-butyl alcohol, get n-butyl alcohol extract, get the dried cream of above-mentioned n-butyl alcohol extract, carry out macroporous adsorbent resin column chromatography (ratio of dried cream and resin is 1: 30).Wash with water to eluent colourlessly earlier, it is colourless to its liquid to use 30% ethanol elution then instead, reclaims to concentrate behind the ethanol to leave standstill, and occurs the pale powder granule then.Pale powder is by the silica gel H post (dry column-packing) that reduces pressure, with chloroform-methanol (9: 1) eluting, reclaim solvent after, the pure white crystallization be arctiin, it is 98.3% that the HPLC method records purity.
Preparation example 2: preparation arctigenin
Get in the preparation example 1 arctiin and add heating for dissolving in the sterilized water, put coldly, add an amount of Snailase, 37 ℃ of constant temperature shaking tables were cultivated 36 hours, added ethanol and ended enzyme digestion reaction, with the enzymolysis solution evaporated under reduced pressure, residue adds the chloroform dissolving, get chloroform solution, reclaim solvent and get degradation product, with the gained degradation product by the silica gel H post (dry column-packing) that reduces pressure, with the chloroform-methanol gradient elution, after reclaiming solvent, get the pure white crystallization and be arctigenin, it is 98.2% that the HPLC method records purity.
Embodiment 1:
Get arctigenin 100mg, make it dissolving with the about 15mL heating of 60% ethanol; Take by weighing HP-3.0g, add stirring and dissolving under the water 5mL room temperature.Drip arctigenin solution.Add solution, continue to stir, be thick until solution, drying under reduced pressure, promptly.
Embodiment 2:
Get arctigenin 100mg, make it dissolving with the about 15mL heating of 70% ethanol; Take by weighing HP-0.3g, add stirring and dissolving under the water 15mL room temperature.Drip arctigenin solution.Add solution, continue to stir, be thick until solution, drying under reduced pressure, promptly.
Embodiment 3:
Get arctigenin 100mg, make it dissolving with the about 15mL heating of 65% ethanol; Take by weighing HP-1.0g, add stirring and dissolving under the water 10mL room temperature.Drip arctigenin solution.Add solution, continue to stir, be thick until solution, drying under reduced pressure, promptly.
Embodiment 4:
Get arctigenin 100mg, make it dissolving with the about 5mL heating of acetone; Take by weighing hydroxypropyl-alpha-cyclodextrin 2.0g, add stirring and dissolving under the water 5mL room temperature.Drip arctigenin solution.Add solution, continue to stir, be thick until solution, drying under reduced pressure, promptly.
Embodiment 5:
Get arctigenin 100mg, make it dissolving with the about 15mL heating of dehydrated alcohol; Take by weighing hydroxypropyl-gamma-cyclodextrin 1.3g, add stirring and dissolving under the water 5mL room temperature.Drip arctigenin solution.Add solution, continue to stir, be thick until solution, drying under reduced pressure, promptly.
Embodiment 6:
Get arctigenin 100mg, make it dissolving with the about 15mL heating of methanol; Take by weighing sulfobutyl ether-beta-cyclodextrin 3.0g, add stirring and dissolving under the water 20mL room temperature.Drip arctigenin solution.Add solution, continue to stir, be thick until solution, drying under reduced pressure, promptly.
Embodiment 7:
Take by weighing embodiment 3 preparation arctigenin hydroxypropyl-beta-cyclodextrin inclusion 1000g, cross 80 mesh sieves, add microcrystalline Cellulose 1000g and form pharmaceutical formulation as diluent, mixing, add binding agent system soft material, granulate with 24 mesh sieves, dry back granulate adds the moderate lubrication agent, tabletting, coating, that is, content of dispersion is the 100mg/ sheet.
Embodiment 8:
Take by weighing embodiment 3 preparation arctigenin hydroxypropyl-beta-cyclodextrin inclusion 100g, add the injection water and make 1000ml, cross 0.2 μ m film, packing 10ml/ bottle rolls lid, sterilizes 15 minutes, and promptly gets 10mg/ml for 121 ℃.
The 1 arctigenin cyclodextrin clathrate solubility test of test example
Precision takes by weighing and is ground into fine powder arctigenin 5mg and arctigenin hydroxypropyl-beta-cyclodextrin inclusion 500mg (pressing embodiment 3 preparations) respectively, places 25 ± 2 ℃ of 50ml distilled water, 30 seconds of powerful jolting every 5 minutes; Observe the dissolving situation in 30 minutes.Arctigenin still has visible particles of solute, and its water solubility belongs to almost insoluble matter of water less than 0.1mg/ml; The arctigenin HP-is dissolving fully then.
In addition precision takes by weighing and is ground into fine powder arctigenin hydroxypropyl-beta-cyclodextrin inclusion 3000mg (press embodiment 3 prepares), places 25 ℃ ± 2 ℃ 30ml distilled water, 30 seconds of powerful jolting every 5 minutes; Observe the dissolving situation in 30 minutes, the arctigenin HP-is dissolved fully.Therefore arctigenin HP-water solubility belongs to water-soluble material greater than 100mg/ml.
Test example 2 arctigenin hydroxypropyl-beta-cyclodextrin inclusions and arctigenin oral administration biaavailability are relatively.
1. medicinal liquid preparation
It is an amount of to take by weighing arctigenin hydroxypropyl-beta-cyclodextrin inclusion (pressing embodiment 2 preparations), adds deionized water dissolving, is made into concentration for containing arctigenin 5mg/mL solution, is sample A; It is an amount of to take by weighing arctigenin, adds 1% carboxymethylcellulose sodium solution suspendible, makes the 5mg/mL suspension, is sample B.
2. gastric infusion scheme rat fasting 16h freely drinks water, difference gastric infusion sample A and sample B, and dosage is respectively 50mg/kg.Respectively at 15min, 30min after 5min before the administration and the administration, 45min, 60min, 90min, 120min, 180min, 240min, 300min,, 360min, 480min get blood, separation of serum.
3. sample treatment
The accurate just sample 0.2mL of blood plasma that draws of the processing of plasma sample, accurate 10% trichloroacetic acid, the 40 μ L that add cold preservation, vortex 3min, the centrifugal 10min of 12000r/min draws the about 120 μ L of supernatant and places point end sample introduction bottle, HPLC auto injection.
The mensuration of 4 samples
4.1 instrument
1100 series of high efficiency chromatograph of liquid (U.S. Agilent company); Comprise the G1312A binary pump, the G1313A automatic sampler,
4.2 the chromatographic condition chromatographic column that plasma sample is measured: discover ODS post (250mm * 4mm, 5 μ m); Mobile phase: methanol: water (60: 50); Flow velocity 1mL/min detects wavelength: 280nm.
4.3 result
The bioavailability of table 1 arctigenin clathrate and arctigenin relatively
| Parameter | Arctigenin | The arctigenin clathrate |
| Tmax/h | 0.65 | 1.8 |
| Cmax/μg/ml | 6.2 | 39.4 |
| T 1/2/h | 1.4 | 3.2 |
| AUC 0-∞/μg.h/ml | 182.63 | 1394.64 |
The above results shows: oral arctigenin hydroxypropyl-beta-cyclodextrin inclusion blood drug level (Cmax) shows that far above oral arctigenin blood drug level (Cmax) arctigenin clathrate bioavailability improves a lot.
The influence of test example 3 arctigenin clathrate xylol induced mice auricle edemas
1. material and animal
Arctigenin clathrate: respectively by being used to irritate stomach and injection after embodiment 7,8 preparations.
Dexamethasone: lot number 0601146, Zhengzhou Lingrui Pharmaceutical Co., Ltd. produces.
Dimethylbenzene: Hangzhou Zhong Shan chemistry company limited production.
Kunming mouse, unming Medical College's Experimental Animal Center provides.
2. divide into groups and method
Get 80 of Kunming kind white mice, be divided into 8 groups at random.Model group (HP-), arctigenin clathrate high dose group (ip, 100mg/kg), middle dosage group (ip, 50mg/kg), low dose group (ip, 25mg/kg), arctigenin clathrate high dose group (ig, 100mg/kg), middle dosage group (ig, 50mg/kg), low dose group (ig, 25mg/kg), the dexamethasone positive controls (ip, 2mg/kg).40min after the administration is applied to the wide two sides of mouse right ear with 50 μ l dimethylbenzene and causes inflammation, and left ear in contrast, cause the disconnected neck of scorching back 1h and put to death power, cut two ears, lay auricle at same position respectively with the card punch of diameter 9mm along the auricle baseline, immediately weigh, calculate and respectively organize swelling degree and suppression ratio.
Heavy (the mg)-auris dextra auricle of swelling degree (mg)=left ear auricle heavy (mg)
Suppression ratio (%)=(the average auricle of the average auricle weight-administration of model group group is heavy)/average auricle of model group heavy * 100%
3. result
No matter oral still lumbar injection all can significantly suppress the auricle edema that dimethylbenzene causes to arctigenin clathrate (25mg/kg, 50mg/kg, 100mg/kg), but the injection effect is better than oral.See table 1 for details.
Table 1 arctigenin clathrate xylol cause mice auricle swelling influence (x ± s, n=10)
| Group | Dosage (mg/kg) | Swelling degree (mg) | Suppression ratio (%) |
| Model group Dexamethasone group arctigenin inclusion compound (ig) arctigenin inclusion compound (ip) | - - 25 50 100 25 50 100 | 23.52±2.81 4.34±2.69 *** 14.17±2.39 * 11.33±2.85 ** 9.81±2.11 *** 13.82±2.74 * 8.73±2.49 ** 6.20±1.09 *** | - 81.5 39.8 51.8 58.3 41.2 62.9 73.6 |
Annotate: compare * P＜0.05, * * P＜0.01, * * * P＜0.001 with model group.
Claims (6)
1, a kind of pharmaceutical composition that contains arctigenin and cyclodextrin derivative is characterized in that arctigenin is comprised in the cyclodextrin derivative, and the two proportioning is: arctigenin 1g, cyclodextrin derivative 3g～30g.
2, the described pharmaceutical composition of claim 1 is characterized in that arctigenin is comprised in the cyclodextrin derivative, and the two proportioning is: arctigenin 1g, cyclodextrin derivative 3g～10g.
3, the pharmaceutical composition of claim 1 is characterized in that: cyclodextrin derivative can be selected from: the alpha-cyclodextrin derivant of various substitution values, beta-cyclodextrin derivative, gamma-cyclodextrin derivant and sulfobutyl ether-beta-cyclodextrin derivant.
4, the pharmaceutical composition of claim 1 is characterized in that: cyclodextrin derivative is preferably the HP-derivant.
5, the preparation of drug combination method of claim 1 is characterized in that: get the arctigenin of 1 weight portion, dissolve with appropriate solvent; Get the cyclodextrin derivative of 3-30 weight portion, add an amount of water stirring and dissolving, under the high-speed stirred situation, the arctigenin drips of solution is added in the cyclodextrin derivative solution, continue agitating solution,, obtain the arctigenin cyclodextrin mixt until being thick.
6, the Pharmaceutical composition of claim 1 adds one or more pharmaceutic adjuvants and makes dosage form on any pharmaceutics.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20120029070A1 (en) * | 2009-03-27 | 2012-02-02 | Kracie Pharma, Ltd. | Burdock fruit extract containing arctigenin at high content and process for producing same |
| CN102342928A (en) * | 2010-07-23 | 2012-02-08 | 山东新时代药业有限公司 | Medicinal application of arctigenin |
| CN102863485A (en) * | 2012-10-16 | 2013-01-09 | 南京农业大学 | Process for purifying arctiin crude product |
| CN102885781A (en) * | 2011-07-23 | 2013-01-23 | 鲁南贝特制药有限公司 | Solid dispersion of arctigenin and oral solid preparation |
| EP2832355A1 (en) * | 2012-03-26 | 2015-02-04 | Kracie Pharma, Ltd. | Anticancer agent |
| CN109602724A (en) * | 2019-02-21 | 2019-04-12 | 江苏省中医药研究院 | A kind of arctigenin oral administration nanometer preparation and preparation method thereof |
| CN109718210A (en) * | 2017-10-31 | 2019-05-07 | 鲁南制药集团股份有限公司 | A kind of arctigenin preparation |
| CN114366710A (en) * | 2022-01-20 | 2022-04-19 | 苏州大学附属第一医院 | Application of injectable burdock microcarrier in treating advanced osteoarthritis |
-
2007
- 2007-03-07 CN CN 200710135648 patent/CN101036644A/en active Pending
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9586921B2 (en) | 2009-03-27 | 2017-03-07 | Kracie Pharma, Ltd. | Burdock fruit extract containing arctigenin at high content and process for producing same |
| US20120029070A1 (en) * | 2009-03-27 | 2012-02-02 | Kracie Pharma, Ltd. | Burdock fruit extract containing arctigenin at high content and process for producing same |
| CN102365092B (en) * | 2009-03-27 | 2016-05-11 | 客乐谐制药株式会社 | The burdock extract that arctigenin content is high and manufacture method thereof |
| CN102342928A (en) * | 2010-07-23 | 2012-02-08 | 山东新时代药业有限公司 | Medicinal application of arctigenin |
| CN102885781B (en) * | 2011-07-23 | 2015-12-09 | 鲁南贝特制药有限公司 | A kind of solid dispersion of aretigenin and oral solid formulation |
| CN102885781A (en) * | 2011-07-23 | 2013-01-23 | 鲁南贝特制药有限公司 | Solid dispersion of arctigenin and oral solid preparation |
| EP2832355A1 (en) * | 2012-03-26 | 2015-02-04 | Kracie Pharma, Ltd. | Anticancer agent |
| EP2832355A4 (en) * | 2012-03-26 | 2015-12-23 | Kracie Pharma Ltd | Anticancer agent |
| US9700572B2 (en) | 2012-03-26 | 2017-07-11 | National Cancer Center | Anti-cancer agent |
| CN102863485B (en) * | 2012-10-16 | 2015-03-11 | 南京农业大学 | Process for purifying arctiin crude product |
| CN102863485A (en) * | 2012-10-16 | 2013-01-09 | 南京农业大学 | Process for purifying arctiin crude product |
| CN109718210A (en) * | 2017-10-31 | 2019-05-07 | 鲁南制药集团股份有限公司 | A kind of arctigenin preparation |
| CN109602724A (en) * | 2019-02-21 | 2019-04-12 | 江苏省中医药研究院 | A kind of arctigenin oral administration nanometer preparation and preparation method thereof |
| CN109602724B (en) * | 2019-02-21 | 2022-02-11 | 江苏省中医药研究院 | Oral nanometer preparation of arctigenin and preparation method thereof |
| CN114366710A (en) * | 2022-01-20 | 2022-04-19 | 苏州大学附属第一医院 | Application of injectable burdock microcarrier in treating advanced osteoarthritis |
| CN114366710B (en) * | 2022-01-20 | 2023-11-17 | 苏州大学附属第一医院 | Application of injectable burdock microcarrier in treating advanced osteoarthritis |
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