CN101167719B - Gallo catechin and gallate microcapsule granule and preparation technique thereof - Google Patents
Gallo catechin and gallate microcapsule granule and preparation technique thereof Download PDFInfo
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- CN101167719B CN101167719B CN2007101652708A CN200710165270A CN101167719B CN 101167719 B CN101167719 B CN 101167719B CN 2007101652708 A CN2007101652708 A CN 2007101652708A CN 200710165270 A CN200710165270 A CN 200710165270A CN 101167719 B CN101167719 B CN 101167719B
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Abstract
The invention relates to pigallocatechin gallate (EGCG) microcapsule granules and a process for preparation. The microcapsule granules take pigallocatechin gallate as the capsule core, cellulose ethyl ether (EC) and or carbowax (PEG) as the capsule body, and sodium carboxymethylstarch (CMS-Na) as the accelerating agent. The microcapsule granules have the advantages of good stability, excellent effect, and stable dissolution rate, and resolve the problems of absorbent quality and flowability of pigallocatechin gallate. The invention is applicable for the development of medicament, food, feed stuff and the like.
Description
Technical field
The present invention relates to epigallocatechin gallate (EGCG) (EGCG) is the hydrophobicity microcapsule and the preparation technology thereof of capsule-core.
Background technology
Epigallocatechin gallate (EGCG) (EGCG) is the main component in the tea polyphenols, extensively be distributed in the medicinal plants, it is as a kind of Natural antioxidant and free radical scavenger, food, medicine (comprising veterinary drug), feedstuff and a plurality of fields of chemical industry have been widely used in, modern pharmacological research shows that EGCG has the effect of antitumor, antithrombotic, antioxidation, defying age, antibacterium virus.
But, because the phenolic hydroxyl group in the EGCG molecule is very active, the moisture absorption, oxidation, polymerization or condensation or the like easily, thus degrade out multiple material, less stable.Owing to the mobile relatively poor sub-dose packaging that also is unfavorable for pharmaceutical dosage form of EGCG, make it in storage and application process, to be subjected to certain limitation in addition.
At home, also do not find the report of relevant EGCG oral solid formulation at present.Prepare the technology of oral dosage form according to routine, all will make crude drug have flowability through raw material and certain adjuvant being made the process of intermediate, hydrophobicity and compressibility or the like be so that make granular preparation, capsule, tablet again.We once attempted to prepare the EGCG granule with the particulate method of traditional preparation process; the starch slurry of employing variable concentrations or ethanol are as adhesive; under the effect of granulator, make the particle diameter homogeneous granules; but employed starch slurry in this process (containing big water gaging) and ethanol can make the EGCG dissolving; find in the practice that preparing the EGCG granule with traditional method is easy to become brownish red, stability decreases in dry run.Simultaneously we find that also the high-temperature spray process to the stability of EGCG all is and disadvantageous.
Summary of the invention
Be unsuitable for the problem of commercial Application at epigallocatechin gallate (EGCG) (EGCG) easily oxidizable, hygroscopicity, flowability etc., the present invention develops a kind of EGCG microcapsule, solved the hygroscopicity problem of EGCG powder, stability, good fluidity, the dissolution height, slow release, controlled release purpose have been reached, simultaneously the drug loading height.
The present invention is by selecting specific adjuvant, and the proportioning of strict simultaneously control EGCG and adjuvant makes EGCG be in non-dissolved state all the time, by the rate of release of adjuvant adjusting EGCG from the hydrophobicity microcapsule, thereby makes the microcapsule of making reach goal of the invention.
An object of the present invention is to provide a kind of epigallocatechin gallate (EGCG) microcapsule granule.
Another object of the present invention provides a kind of preparation method of epigallocatechin gallate (EGCG) microcapsule granule.
The objective of the invention is to be achieved through the following technical solutions:
A kind of epigallocatechin gallate (EGCG) microcapsule granule, it is made up of following components by weight ratio:
Epigallocatechin gallate (EGCG) 1-4,
Ethyl cellulose 0.5-1.5,
Polyethylene Glycol 0-0.2,
Carboxymethyl starch sodium 0.2-3.
The preparation method of epigallocatechin gallate (EGCG) microcapsule granule of the present invention is as follows:
Method one:
(1) ethyl cellulose with the 0.5-1.5 weight portion is dissolved in the dichloromethane, the preparation obtain ethyl cellulose solution concentration at 4.5-7% (g/v),
(2) epigallocatechin gallate (EGCG), the Polyethylene Glycol of 0-0.2 weight portion and the carboxymethyl starch sodium of 0.1-3 weight portion of adding 1-4 weight portion in above-mentioned ethyl cellulose solution, stirring makes its abundant suspendible, slowly drip petroleum ether, the control mixing speed, complete to the system precipitation, with sedimentary microcapsule and separated from solvent, obtain encystation thing and solvent mixture A, the encystation thing is dried up in exsiccator, promptly.
Method two:
(1) ethyl cellulose of 0.5-1.5 weight portion is dissolved under the normal pressure of said method one isolated solvent mixture A＜45 ℃ fraction in, the concentration that preparation obtains ethyl cellulose solution is at 4.5-7% (g/v),
(2) epigallocatechin gallate (EGCG), the Polyethylene Glycol of 0-0.2 weight portion and the carboxymethyl starch sodium of 0.1-3 weight portion of adding 1-4 weight portion in above-mentioned ethyl cellulose solution, stirring makes its abundant suspendible, slowly drip under the normal pressure of said method one isolated solvent mixture A＞60 ℃ fraction, the control mixing speed, complete to the system precipitation, with sedimentary microcapsule and separated from solvent, will obtain the encystation thing and in exsiccator, dry up, promptly.
In microcapsule granule of the present invention, be active component with the epigallocatechin gallate (EGCG), as capsule-core, its weight proportion is the 1-4 weight portion, preferred 2-3 weight portion.With ethyl cellulose and Polyethylene Glycol is the capsule material, and the weight proportion of described ethyl cellulose is the 0.5-1.5 weight portion, is preferably 1 weight portion, and the weight proportion of Polyethylene Glycol is the 0-0.2 weight portion, is preferably the 0.05-0.1 weight portion.Find in the practice, when the weight proportion of epigallocatechin gallate (EGCG) active component and capsule material is controlled in the framework of the present definition, the microcapsule good dispersion that makes, the microcapsule size is even, attractive in appearance.As short releasing agent, its weight proportion is 0.2-3 with sodium carboxymethyl cellulose in the present invention, is preferably the 0.2-2 weight portion.Find also in the practice that the selection of capsule material and short releasing agent has very big influence to the dissolution of EGCG microcapsule, the present invention is by a large amount of screenings, and selecting ethyl cellulose and Polyethylene Glycol is that capsule material, sodium carboxymethyl cellulose have reached good effect as short releasing agent.
In preparation technology of the present invention, owing to select specific adjuvant for use and adopt dichloromethane and petroleum ether as solvent, make epigallocatechin gallate (EGCG) be in non-dissolved solid crystal state all the time, overcome existing technology and made EGCG be in the unsettled defective that dissolved state causes as solvent because of containing water and ethanol.The microcapsule granule good stability that makes, encapsulation is effective, and good fluidity has good dissolution, and the productive rate height can reach more than 90%, and drug loading＞50%, microcapsule are similar round, particle diameter is between the 60-80 order.
Description of drawings:
High temperature that accompanying drawing 1:EGCG microencapsulated sample exposes and the HPLC under the high humidity situation.
Further specify the present invention by the following examples:
The specific embodiment
1. 1 kinds of epigallocatechin gallate (EGCG) microcapsule granules of embodiment, it is made up of following components by weight ratio:
Epigallocatechin gallate (EGCG) 2,
Ethyl cellulose 1
Polyethylene Glycol 0.1,
Carboxymethyl starch sodium 1.8.
Its preparation technology is:
(1) ethyl cellulose with 1 weight portion is dissolved in the dichloromethane, the preparation obtain ethyl cellulose solution concentration at 5% (g/v),
(2) epigallocatechin gallate (EGCG), the Polyethylene Glycol of 0.1 weight portion and the carboxymethyl starch sodium of 1.8 weight portions of adding 2 weight portions in above-mentioned ethyl cellulose solution, stirring makes its abundant suspendible, mixing speed is controlled at 1500 rev/mins, slowly drip petroleum ether, complete to the system precipitation, with sedimentary microcapsule and separated from solvent, obtain encystation thing and solvent mixture A, the encystation thing is dried up in exsiccator, promptly.
2. 1 kinds of epigallocatechin gallate (EGCG) microcapsule granules of embodiment, it is made up of following components by weight ratio:
Epigallocatechin gallate (EGCG) 3,
Ethyl cellulose 1
Polyethylene Glycol 0.2
Carboxymethyl starch sodium 0.5.
Its preparation technology is:
(1) ethyl cellulose with 1 weight portion is dissolved in the dichloromethane, the preparation obtain ethyl cellulose solution concentration at 6% (g/v),
(2) epigallocatechin gallate (EGCG), the Polyethylene Glycol of 0.2 weight portion and the carboxymethyl starch sodium of 0.5 weight portion of adding 3 weight portions in above-mentioned ethyl cellulose solution, stirring makes its abundant suspendible, mixing speed is controlled at 1500 rev/mins, slowly drip petroleum ether, complete to the system precipitation, with sedimentary microcapsule and separated from solvent, obtain encystation thing and solvent mixture A, the encystation thing is dried up in exsiccator, promptly.
3. 1 kinds of epigallocatechin gallate (EGCG) microcapsule granules of embodiment, it is made up of following components by weight ratio:
Epigallocatechin gallate (EGCG) 2,
Ethyl cellulose 1.5
Polyethylene Glycol 0.05,
Carboxymethyl starch sodium 1.
Its preparation technology is:
(1) ethyl cellulose of 1.5 weight portions is dissolved under the normal pressure of said method one isolated solvent mixture A＜45 ℃ fraction in, in, the concentration that preparation obtains ethyl cellulose solution is at 7% (g/v),
(2) epigallocatechin gallate (EGCG), the Polyethylene Glycol of 0.05 weight portion and the carboxymethyl starch sodium of 1 weight portion of adding 2 weight portions in above-mentioned ethyl cellulose solution, stirring makes its abundant suspendible, mixing speed is controlled at 1500 rev/mins, slowly drip under the normal pressure of said method one isolated solvent mixture A＞60 ℃ fraction, complete to the system precipitation, with sedimentary microcapsule and separated from solvent, obtain the encystation thing and in exsiccator, dry up, promptly.
Below further specify effect of the present invention by experiment:
Experiment 1: the dissolution determination of EGCG microcapsule of the present invention:
Adopt the slurry method of Chinese Pharmacopoeia (2005 editions) regulation
[4]Precision takes by weighing the EGCG microcapsule 500mg of the embodiment of the invention 1, pack in the 100 mesh sieve mesh bags, with the 0.05%SDS aqueous solution is dissolution medium, and it is 4～5 that acetic acid is regulated pH, 37.0 ± 0.5 ℃ of temperature, rotating speed is 70 commentaries on classics/min, get the release medium that release solution 5ml replenishes equivalent simultaneously 10,20,30,45,60,90,120 respectively, 0.45 μ m microporous filter membrane filters, and measures according to following chromatographic condition:
Instrument:
HPLC1100 highly effective liquid phase chromatographic system (U.S. aglient company),
UV--3101PC (day island proper Tianjin),
KQ3200DB type numerical control supersonic washer (city of Kunshan's ultrasonic instrument company limited),
Ten thousand/analytical balance FA2104S (going up Nereid section).
Found that microcapsule can stripping in 1h more than 80%, the complete stripping of 2h (n=2), find simultaneously the EGCG aqueous solution with this understanding 2 hours stable, do not see that new chromatographic peak occurs.
Experiment 2: the fluidity determining of EGCG microcapsule of the present invention:
According to micromeritis
[6]Principle, adopt and decide the angle of repose (θ) that end method is measured the EGCG microcapsule of the embodiment of the invention 2:
Get a piece of paper, draw radius (R) with compasses and be the garden of 2.5cm, granule is loaded in placed in-line three little funnels; aim at the center of circle, allow granule slowly from funnel, flow out, treat that granuloplastic taper heap bottom overlaps with circular boundary; stop rapidly, measure the height (H) of cone.Triplicate H is respectively 1.5,1.3,1.4cm; Tg θ=H/R=0.6,0.52,0.56; θ=31.0 °, 27.5 °, 29.2 °
Angle of repose θ=29.2 °＜30 °, good fluidity
Experiment 3: the stability of EGCG microcapsule of the present invention is measured:
1 instrument and reagent
1.1 reagent
EGCG microcapsule (embodiment of the invention 1) and blank capsule,
EGCG reference substance (U.S. sigma company, purity＞95%),
Acetonitrile chromatographically pure, water are redistilled water, and other reagent is commercially available analytical pure.
1.2 key instrument
HPLC1100 highly effective liquid phase chromatographic system (U.S. aglient company),
KQ3200DB type numerical control supersonic washer (city of Kunshan's ultrasonic instrument company limited),
Electric heating constant temperature air dry oven 101-1 (Shanghai make a leapleap forward medical apparatus and instruments factory)
Ten thousand/analytical balance FA2104S (going up Nereid section).
Other instruments are the simple glass instrument
2 methods and result
2.1 reagent is prepared:
In 60 ℃, 40 ℃ drying baker, place respectively and fill KNO
3The exsiccator of saturated solution is measured inner humiture with Hygrothermograph, is respectively 1#60 ℃, 86%, 2#40 ℃, 88%.
In 60 ℃, 40 ℃ drying baker, place the exsiccator that fills the NaCl saturated solution respectively and measure inner humiture, be respectively 3#60 ℃, 76%, 4#40 ℃, 76% with Hygrothermograph.
Experiment:
2.2 influence factor's experiment
Require the EGCG microcapsule is carried out violent influence factor's experiment with reference to pharmacopeia.Take by weighing 4 parts of EGCG microcapsules respectively, opening places weighing botle to place above-mentioned environment respectively, investigates 10 days, the results are shown in Table 1.Chromatogram is seen accompanying drawing 1 after 10 days.
Table 1:EGCG microcapsule is placed on the result under high temperature and the high humidity:
The EGCG microcapsule shows more stable characteristic under high temperature, high humidity interaction factor environment as can be seen from the chart, and content does not have too big variation, does not observe new material and occur from chromatogram.
3. brief summary
The EGCG microcapsule was placed 10 days under high temperature, super-humid conditions, and the microcapsule character does not almost change, and HPLC carries out assay, did not have new degradation peak to occur, and content does not change, and illustrates highly stable.
Experimental example 4: organic solvent residual is measured
According to 26 editions pharmacopeia requirements of the U.S., be the gas chromatogram external standard method.Detect the organic solvent residual of the embodiment of the invention 1 microcapsule
Chromatographic condition adopts SE-54 (30m * 0.32mm * 1 μ m) chromatographic column, flame ionic detector, carrier gas H
2, flow velocity 1.8ml/min, 200 ℃ of sample introduction temperature, 250 ℃ of detected temperatures.
Dichloromethane goes out the peak at 2.92min as a result, and content＜600 μ g/g meet standards of pharmacopoeia, and are qualified.
Claims (3)
1. epigallocatechin gallate (EGCG) microcapsule granule, it is made up of following components by weight ratio:
Epigallocatechin gallate (EGCG) 1-4,
Ethyl cellulose 0.5-1.5,
Polyethylene Glycol 0-0.2,
Carboxymethyl starch sodium 0.2-3.
2. a kind of epigallocatechin gallate (EGCG) microcapsule granule according to claim 1, it is made up of following components by weight ratio:
Epigallocatechin gallate (EGCG) 2-3,
Ethyl cellulose 1,
Polyethylene Glycol 0.05-0.1,
Carboxymethyl starch sodium 0.2-2.
3. the preparation method of a kind of epigallocatechin gallate (EGCG) microcapsule granule according to claim 1 and 2,
Method one:
1) ethyl cellulose is dissolved in the dichloromethane, the preparation obtain ethyl cellulose solution concentration at 4.5-7% (g/v),
2) in above-mentioned ethyl cellulose solution, add epigallocatechin gallate (EGCG), Polyethylene Glycol and carboxymethyl starch sodium, stirring makes its abundant suspendible, slowly drip petroleum ether, the control mixing speed, complete to the system precipitation, with sedimentary microcapsule and separated from solvent, obtain encystation thing and solvent mixture A, the encystation thing is dried up in exsiccator, promptly;
Method two
1) ethyl cellulose of 0.5-1.5 weight portion is dissolved under the normal pressure of said method one isolated solvent mixture A＜45 ℃ fraction in, the concentration that preparation obtains ethyl cellulose solution is at 4.5-7% (g/v),
2) epigallocatechin gallate (EGCG), the Polyethylene Glycol of 0-0.2 weight portion and the carboxymethyl starch sodium of 0.1-3 weight portion of adding 1-4 weight portion in above-mentioned ethyl cellulose solution, stirring makes its abundant suspendible, slowly drip under the normal pressure of said method one isolated solvent mixture A＞60 ℃ fraction, the control mixing speed, complete to the system precipitation, with sedimentary microcapsule and separated from solvent, will obtain the encystation thing and in exsiccator, dry up, promptly.
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| CN102600302B (en) * | 2012-04-19 | 2013-08-07 | 中国计量学院 | Preparation method of bioavailability-enhanced catechin oral solution |
| CN102885177A (en) * | 2012-10-25 | 2013-01-23 | 安吉依思味食品有限公司 | An Ji white tea micro-capsule and preparation method thereof |
| CN104306352A (en) * | 2014-09-22 | 2015-01-28 | 江苏天晟药业有限公司 | Glabridin microcapsule and preparation method thereof |
| CN104920868B (en) * | 2015-06-10 | 2018-05-01 | 华南农业大学 | Epigallo-catechin gallate (EGCG)（EGCG）Application in terms of pig feed additive is prepared |
| CN106201614A (en) * | 2016-07-11 | 2016-12-07 | 天津中兴智联科技有限公司 | A kind of universal method and system that multiple similar software can be carried out chain type upgrading |
| CN107173458B (en) * | 2017-05-23 | 2021-04-27 | 三河汇福生物科技有限公司 | Microencapsulated composite antioxidant for edible oil and fat and preparation method thereof |
| CN107049992A (en) * | 2017-05-31 | 2017-08-18 | 盛林 | A kind of EGCG micro pill capsules and preparation method thereof |
| CN109864982A (en) * | 2019-03-22 | 2019-06-11 | 大连医诺生物股份有限公司 | Epigallo-catechin gallate (EGCG) microcapsule powder and preparation method thereof |
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