CN104814949B - Improve chlorogenic acid acylate and the application of chlorogenic acid bioavilability - Google Patents
Improve chlorogenic acid acylate and the application of chlorogenic acid bioavilability Download PDFInfo
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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Abstract
The invention belongs to biomedicine field, more particularly to chlorogenic acid acylate and the application of chlorogenic acid bioavilability are improved, there is the chlorogenic acid acylate of structural formula in the present invention to be applied to the medicine for preparing treatment tumour.Content of Chlorogenic Acid acylate of the present invention can improve the bioavilability of chlorogenic acid in vivo, solve the problems, such as that chlorogenic acid is subject to the influence of intestinal flora and makes absorptivity relatively low during oral administration, while considerably improve inhibition of the chlorogenic acid to tumour.
Description
Technical field
The invention belongs to biomedicine field, more particularly to improve the chlorogenic acid acylate of chlorogenic acid bioavilability and answer
With.
Background technology
Chlorogenic acid（English：Chlorogenic acid）Also known as caffeotannic acid.That is 3-caffeoylquinic acid, is Polyphenols
Compound, is widely present in high dicotyledon and pteridophyte, is primarily present in Caprifoliaceae Lonicera（Lonicera）, chrysanthemum
Section artemisia（Artemisia）In plant, wherein the higher plant of content be mainly the bark of eucommia, honeysuckle, sunflower, after wood, coffee,
Cocoa chocolate tree etc..
The effects such as chlorogenic acid has anti-inflammatory, antiviral, antitumor, raising is immune, under acid, alkali, illumination and hot conditions
Unstable, the document report such as Zhou Honghao, Olthof MR and Gonthier MP shows that chlorogenic acid belongs to unstable Polyphenols chemical combination
Thing, and it is vulnerable to the influence of the factors such as archenteric flora, the bioavilability of oral administration is relatively low.Margreet etc. is returned in rat
It further demonstrate in enterostomy experiment, the rat of oral administration, enter sanguimotor only administration in intestinal absorption
/ 3rd of dosage, the metabolism of this experimental phenomena and intestinal flora have substantial connection；Therefore chlorogenic acid is administered orally
Mode, it is difficult to give full play to its drug action.
The content of the invention
To solve the above-mentioned problems, the present inventor provides the chlorogenic acid acylate for improving chlorogenic acid bioavilability and answers
With improving the bioavilability and tumor killing effect being administered orally when antitumor.
Solve a kind of chlorogenic acid acylate of raising chlorogenic acid bioavilability of above technical problem, it is characterised in that：
With following structural formula：
Wherein：R1、R2、R3、R4、R5For RCO+Functional group or H+Ion, RCO+Functional group is in R1、R2、R3、R4、R5Work as position
In any one or several, the RCO+R is the alkyl containing 1-6 carbon atom in functional group.
The R can be methyl, ethyl, propyl group, butyl, amyl group, hexyl, isopropyl and isobutyl group etc..
R in the structural formula1、R2And R3For H+Ion, wherein R4、R5For C2H3O+。
The chlorogenic acid acylate of this spline structure can improve bioavilability, enhancing drug effect.
It by chlorogenic acid acylate is active ingredient that the medicine, which is, adds one or more pharmaceutically acceptable medicinal taxes
The oral formulations that shape agent is prepared.
Wherein, the oral formulations are tablet, capsule, granule, powder, pill, oral liquid.
Unit formulation acylate containing the chlorogenic acid 1-1000mg of the oral formulations, unit formulation contains green original in prioritization scheme
Acylating acid thing 10-200mg.
Content of Chlorogenic Acid acylate of the present invention can be as follows with preparation method：
Chlorogenic acid and solvent are stirred dissolving in a reservoir, catalyst is added dropwise, acetylizing agent reaction is added, does
It is dry, add after solvent dissolves to be washed with water and wash the other impurity of removal, chlorogenic acid acylate is obtained after drying again.
Such as by dimethylformamide（DMF）Electromagnetic agitation in a reservoir, adds chlorogenic acid, and triethylamine is added dropwise, adds
Acetic anhydride, is dried under vacuum to dry, pours into the water of high-speed stirred and precipitates after being dissolved in ethanol, obtained after filtration drying by
Acylated chlorogenic acid, i.e. chlorogenic acid acylate；Or DMF electromagnetic agitations, chlorogenic acid is added, pyridine is added dropwise, adds appropriate acetic acid
Anhydride reactant, be dried under vacuum to it is dry, in ethyl acetate dissolve after be separately added into distillation water washing three times, separating acetic acid ethyl ester is spin-dried for
The chlorogenic acid that phenolic hydroxyl group is acetylation is obtained afterwards.
Specific steps can be as follows：
By 100ml DMF electromagnetic agitations in a reservoir, 50g chlorogenic acids are added, 0.5ml triethylamines are added dropwise, add 50ml
When acetic anhydride 36 is small, 80 DEG C are dried in vacuo 12 hours to doing, and 2000ml is poured into after being dissolved in 50ml ethanol, temperature 60 C
Precipitated in the water of high-speed stirred, the chlorogenic acid that 5 hydroxyls are acylated, i.e. chlorogenic acid acylate are obtained after filtration drying.
Or 100ml DMF electromagnetic agitations, 50g chlorogenic acids are added, 10 DEG C of constant temperature, is added dropwise 0.1ml pyridines, adds 10ml second
When anhydride reaction 24 is small, 80 DEG C of vacuum drying 12 hours are to dry, after being dissolved in 100ml ethyl acetate（Room temperature）It is separately added into
Three times, separating acetic acid ethyl ester obtains the chlorogenic acid that 4,5 phenolic hydroxyl groups are acetylation to 20ml distillations water washing after being spin-dried for.
Chlorogenic acid blood concentration in blood can be improved after chlorogenic acid acylate oral administration in the present invention, can
The bioavilability of chlorogenic acid in vivo is enough improved, chlorogenic acid is subject to the influence of intestinal flora and makes suction when solving oral administration
The problem of yield is relatively low；Considerably improve inhibition of the chlorogenic acid to tumour at the same time.
Brief description of the drawings
Fig. 1 is dog serum Content of Chlorogenic Acid blood concentration-curve map in the present invention
Fig. 2 is tumor growth curve figure in the present invention
Embodiment
Embodiment 1
A kind of chlorogenic acid acylate for improving chlorogenic acid bioavilability, it is characterised in that：With following structural formula：
Wherein：R1、R2、R3、R4、R5For RCO+Functional group or H+Ion, RCO+Functional group is in R1、R2、R3、R4、R5Work as position
In any one or it is several.
The RCO+R is the alkyl containing 1-6 carbon atom in functional group.
The chlorogenic acid acylate of this spline structure can improve bioavilability, strengthen drug effect.
It by chlorogenic acid acylate is active ingredient that the medicine, which is, adds one or more pharmaceutically acceptable medicinal taxes
The oral formulations that shape agent is prepared.
Wherein, the oral formulations are tablet, capsule, granule, powder, pill, oral liquid.
Unit formulation acylate containing the chlorogenic acid 1-1000mg of the oral formulations, unit formulation contains green original in prioritization scheme
Acylating acid thing 10-200mg.
Content of Chlorogenic Acid acylate of the present invention can be as follows with preparation method：
Chlorogenic acid and solvent are stirred dissolving in a reservoir, catalyst is added dropwise, acetylizing agent reaction is added, does
It is dry, add after solvent dissolves to be washed with water and wash the other impurity of removal, chlorogenic acid acylate is obtained after drying again.
Such as by dimethylformamide（DMF）Electromagnetic agitation in a reservoir, adds chlorogenic acid, and triethylamine is added dropwise, adds
Acetic anhydride, is dried under vacuum to dry, pours into the water of high-speed stirred and precipitates after being dissolved in ethanol, obtained after filtration drying by
Acylated chlorogenic acid, i.e. chlorogenic acid acylate；Or DMF electromagnetic agitations, chlorogenic acid is added, pyridine is added dropwise, adds appropriate acetic acid
Anhydride reactant, be dried under vacuum to it is dry, in ethyl acetate dissolve after be separately added into distillation water washing three times, separating acetic acid ethyl ester is spin-dried for
The chlorogenic acid that phenolic hydroxyl group is acetylation is obtained afterwards.
By 100ml DMF electromagnetic agitations in a reservoir, 50g chlorogenic acids are added, 0.5ml triethylamines are added dropwise, add 50ml
When acetic anhydride 36 is small, 80 DEG C are dried in vacuo 12 hours to doing, and 2000ml is poured into after being dissolved in 50ml ethanol, temperature 60 C
Precipitated in the water of high-speed stirred, the chlorogenic acid that 5 hydroxyls are acylated, i.e. chlorogenic acid acylate are obtained after filtration drying.
Embodiment 2
（1）Chlorogenic acid, it is purchased in market；Chlorogenic acid acylate：R1、R2And R3For H+Ion, wherein R4、R5For C2H3O+, it is labeled as
Sample 1；R1、R2And R3For C3H5O+, wherein R4、R5For H+Ion, labeled as sample 2；R1、R4And R5For H+, wherein R2、R3For
C7H5O+Ion, labeled as sample 3.
The preparation method of sample 1 can be：100ml DMF electromagnetic agitations, add 50g chlorogenic acids, 10 DEG C of constant temperature, is added dropwise
0.1ml pyridines, add 10ml acetic anhydrides 24 it is small when, 80 DEG C of vacuum drying 12 hours are to dry, in 100ml ethyl acetate
After dissolving（Room temperature）It is separately added into 20ml distillations water washing three times, separating acetic acid ethyl ester obtains 4,5 phenolic hydroxyl groups by second after being spin-dried for
Acylated chlorogenic acid.
Sample 2 can be such as preparation method similar or close in sample 1 with 3 preparation method.
（2）Animal subject Beagle dogs, 12,8~10kg of weight, half male and half female.
（3）Method of administration and mode single dose gavage (dosage：100mg/kg)
（4）Blood specimen collection is by 12 Beagle dogs points 4 groups, every group 3, one of which as chlorogenic acid administration group, remaining
Three groups are chlorogenic acid acylate administration group；When fasting 12 is small before administration, 5 minutes venous blood samples sample 5ml before administration, prepare empty
White serum；Again respectively at 5 after administration, 10,20,30,45,60,90,120,150 and 180 minutes when, venous blood samples sample 5ml,
After being stored at room temperature 30 minutes, centrifuge (3000rpm, 15min), divide and take serum (about 2ml) cold storage (- 20 DEG C), it is to be measured.
（5）It is prepared by solution
The preparation of reference substance solution：Take chlorogenic acid reference substance appropriate, it is accurately weighed, with the phosphoric acid of methanol -0.2% (20:80)
Solution dissolves and solution of every 1ml containing about 8mg is made, as chlorogenic acid reference substance storing solution.Refrigerator cold-storage (storing solution stationary phase
For 1 month), dilute before use.
The preparation of internal standard reference substance solution：Take Puerarin reference substance appropriate, it is accurately weighed, dissolved and be made every with methanol
1ml is containing about 84Solution, as inner mark solution, refrigerator cold-storage.
The preparation of test solution：Take serum 100L, adds the phosphoric acid of methanol -0.2% (80:20) solution, inner mark solution and
Methanol each 100, vortex oscillation 3min, stands, and centrifuges (12000rpm) 10min, takes out supernatant, molten as serum test sample
Liquid.
（6）Serum Content of Chlorogenic Acid measures
Using octadecylsilane chemically bonded silica column (150mm × 4.6mm, 5) and guard column；With mobile phase A (methanol)
With Mobile phase B (0.2% phosphoric acid), gradient elution is carried out by the program of table 1；Detection wavelength is 325nm；Flow velocity is 1ml/min；Column
40 DEG C of temperature.
Precision measures serum test solution 20, liquid chromatograph is injected, records chromatogram.
（7）Computational methods
Using internal standard method, with the content for standard curve calculating serum Content of Chlorogenic Acid of accompanying.
1 Gradient program of table elutes table
（6）Result of the test
Mean blood plasma concentration in the dog serum of each experimental group different time of table 2（n=3）
（7）Data analysis
(1) by the data analysis of table 2, after gastric infusion 45min, the blood concentration average of chlorogenic acid acylate group is respectively
139.85 ± 15.23,114.70 ± 8.44 and 118.19 ± 13.27G/ml, 42.45 ± 6.93 with chlorogenic acid groupG/ml ratios
Compared with having obvious otherness.
（8）Conclusion
Experimental result is shown, by gastric infusion mode, chlorogenic acid acylate can significantly improve the dense of medicine in blood
Degree, improves the bioavilability of chlorogenic acid.
Embodiment 3
(1) animal BALB/C-nu mouse, 18~24g of weight, is provided by Sichuan University's Experimental Animal Center.
(2) medicine chlorogenic acid, it is purchased in market；Chlorogenic acid acylate：R1、R2And R3For H+Ion, wherein R4、R5For C2H3O+, mark
It is denoted as sample 1；R1、R2And R3For C3H5O+, wherein R4、R5For H+Ion, labeled as sample 2； R1、R2、R4And R5For H+Ion, its
Middle R3For C7H5O+, labeled as sample 3.
(3) cell culture SPCA-1 cells are human lung adenocarcinoma cell line, and cell is often restored to norm Soviet Union, and passage, takes two generation kind mouse
Tumour, is rinsed 3 times with Hank's liquid, removes blood stains, fat and slough, tumour is cut into 1mm × 1mm × 1mm fragments,
Hank's liquid rinses 2 times, is proportionally added into physiological saline (1g:3ml), then in glass homogenizer grind, through 80-100 mesh sieves
Single cell suspension is made in net filtration, with trypan blue staining living cell counting number.
(4) experiment in vivo by the cell suspension prepared by 0.2mlOnly-1(containing about cell number 1 × 106It is a), it is inoculated in
Under the left front armpit of BALB/C-nu mouse, and 5 groups are randomly divided into by weight, every group 5, be respectively chlorogenic acid acylate sample 1
Group, 2 groups of chlorogenic acid acylate sample, 3 groups of chlorogenic acid acylate sample, chlorogenic acid control group, negative control group (N.S physiology salts
Water).Second day gastric infusion after inoculation, dosage 50mg/kg, once a day, successive administration 12 times.In inoculation the
Start within 6th every other day measurement gross tumor volume (V=0.52 × transplantable tumor major diameter L × transplantable tumor most minor axis W2), and claim mice weights weekly
Twice.(knurl volume is about 0.5cm when the average knurl weight of feminine gender group is more than 1.0g3) stopping experiment, cervical dislocation is put to death mouse and is claimed
Weight, strips tumour, calculates：
Tumour inhibiting rate %=[1- (administration group be averaged the average knurl weight of knurl weight/feminine gender group)] × 100%；
（5）Experimental result
(1) influence of the chlorogenic acid acylate to SPCA-1 adenocarcinoma of lung BALB/C-nu mice-transplanted tumors growth volume
3 chlorogenic acid acylate of table to SPCA-1 adenocarcinoma of lung BALB/C-nu mice-transplanted tumors growth volume influence (±s)
△ p ＜ 0.05, * p ＜ 0.01 compared with negative control group；The #p ＜ 0.01 compared with chlorogenic acid control group
(2) influence of the chlorogenic acid acylate to SPCA-1 adenocarcinomas of lung BALB/C-nu mice-transplanted tumors weight and tumour inhibiting rate
4 chlorogenic acid acylate of table to SPCA-1 adenocarcinomas of lung BALB/C-nu mice-transplanted tumors weight and tumour inhibiting rate influence (
±s)
△ p ＜ 0.05, * p ＜ 0.01 compared with negative group；The #p ＜ 0.01 compared with chlorogenic acid control group
（6）Data analysis
It can be analyzed by the growth of transplanted human volume result of table 3, from the 6th day after inoculation, chlorogenic acid acylate sample
3 groups of product 1, sample 2 and sample are contrasted with negative control group, have the significance difference opposite sex（P ＜ 0.01）；Compared with chlorogenic acid control group
With the significance difference opposite sex（P ＜ 0.01）.
It can be analyzed by the transplanting tumor weight and tumour inhibiting rate result of table 4, chlorogenic acid acylate sample 1, sample 2 and sample
3 groups contrast with negative control group, have the significance difference opposite sex（P ＜ 0.01）；With the significance difference opposite sex compared with chlorogenic acid control group
（P ＜ 0.01）, tumour inhibiting rate is higher by 22.19% to 28.13% than chlorogenic acid control group.
（7）Conclusion
By gastric infusion mode, chlorogenic acid upon administration the 6th day to the 14th day to SPCA-1 lung cancer BALB/C-nu mouse
The growth curve of transplantable tumor has obvious inhibition（P ＜ 0.05）, inhibition unobvious after the 14th day after administration.It is and green
Terminate until testing to SPCA-1 lung cancer BALB/C-nu mouse within the 6th day after ortho acid acylate sample 1, sample 2 and sample 3 are administered
The growth curve of transplantable tumor has significant inhibitory action all the time, its inhibition is apparently higher than chlorogenic acid group；Illustrate to pass through filling
Stomach administering mode, chlorogenic acid acylate have more preferable antitumous effect compared to chlorogenic acid.
Chlorogenic acid acylate sample 1, sample 2 and sample 3 to SPCA-1 lung cancer BALB/C-nu mice-transplanted tumors tumour inhibiting rate compared with
Height, has significant advantage compared with chlorogenic acid control group, and antitumous effect can be improved by further illustrating chlorogenic acid acylate.
Embodiment 4：Tablet
1. chlorogenic acid acylate 1
Chlorogenic acid acylate 1：R1、R2And R3For H+Ion, wherein R4、R5For C2H3O+
2. prescription：
3. preparation method：
The present embodiment prepares chlorogenic acid acylate tablet using wet granular pressed disc method processed.（1）It is fine that hydroxypropyl first is measured by prescription
Aqueous solution is made in dimension element；（2）Chlorogenic acid acylate, starch and the lactose for taking recipe quantity after mixing, add hypromellose
Plain aqueous solution, softwood is made after stirring；（3）By the operational procedure of the wet granulation of the softwood prepared routinely,
Sizeable particle is obtained after sieving, dry and whole grain；（4）By obtained particle and magnesium stearate tabletting after mixing,
1000 tablets, the every 100mg of acylate containing chlorogenic acid are made altogether.
Embodiment 5：Capsule
1. chlorogenic acid acylate 2
Chlorogenic acid acylate 2：R4、R5For H+Ion, wherein R1、R2And R3For C2H3O+
2. prescription：
3. preparation method：
The chlorogenic acid acylate and starch of recipe quantity are taken, is uniformly mixed, 80% ethanol solution is added and softwood is made, it is dry, it is whole
After grain 2000 capsules, every capsule acylate containing chlorogenic acid 50mg are prepared according to the conventional fabrication process of capsule.
Embodiment 6：Granule
1. chlorogenic acid acylate 3
Chlorogenic acid acylate 3：R1、R2、R4、R5For H+Ion, wherein R3For C7H5O+
2. prescription：
3. preparation method：
PVP K30 is taken, solution is made with water.Chlorogenic acid acylate, mannitol and the sucrose of recipe quantity is taken to be uniformly mixed
Afterwards, PVP K30 solution is added, softwood is made.According to the conventional fabrication process of granule, sieved to softwood, is dry
After whole grain, granule is obtained.Granule is aseptically dispensed, prepares 400 bags of granules, every bag of granule contains green original
Acylating acid thing 500mg.
Embodiment 7：Powder
1. chlorogenic acid acylate 4
Chlorogenic acid acylate 4：R1、R2、R4、R5For H+Ion, wherein R3For C2H3O+
2. prescription
4 1000g of chlorogenic acid acylate
3. preparation method
Take recipe quantity chlorogenic acid acylate sieve after, according to the conventional fabrication process of powder, it is aseptic subpackaged into containing 1000 bottles/
Bag powder, per bottle/bag powder acylate containing chlorogenic acid 1000mg.
Embodiment 8：Pill
1. chlorogenic acid acylate 5
Chlorogenic acid acylate 5：R1、R4、R5For H+Ion, wherein and R2、R3For C2H3O+
2. prescription
3. preparation method：
Suitable PVP K30 is taken, solution is configured to water, then takes the chlorogenic acid acylate and starch of recipe quantity, is used
After equivalent dilution method is uniformly mixed, PVP K30 solution is added, softwood is made after being sufficiently stirred, is made green using ball method is rubbed with the hands
Ortho acid acylate pill 1000, every pill acylate containing chlorogenic acid 1mg.
Embodiment 9：Oral liquid
1. chlorogenic acid acylate 6
Chlorogenic acid acylate 6：R3、R4、R5For H+Ion, wherein R1、R2For C4H7O+
2. prescription
3. preparation method
Chlorogenic acid acylate, phosphatide, the cholesterol of recipe quantity are taken, is dissolved in ethanol, stirs evenly rear concentration and recovery ethanol,
Be then added in 10L water ultrasound it is fully dispersed after, sterile filling is into 1000 oral liquids, and every oral liquid is 10mL, containing green original
Acylating acid thing 200mg.
The present invention provides a kind of chlorogenic acid acylate, and chlorogenic acid can be improved in blood after the acylate oral administration
Blood concentration, prompts the chlorogenic acid acylate to improve the bioavilability of chlorogenic acid in vivo；At the same time by with green original
Sour tumor killing effect contrast test finds, tumor killing effect can be significantly improved by being administered orally the mode chlorogenic acid acylate, be said
The bright chlorogenic acid acylate has the function that synergy in tumor area is treated.
Claims (5)
- A kind of 1. application for the chlorogenic acid acylate for improving chlorogenic acid bioavilability, it is characterised in that：The chlorogenic acid is acylated Thing is applied to the medicine for preparing treatment tumour；Chlorogenic acid acylate has following structural formula：Wherein：R1、R2And R3For H+Ion, wherein R4、R5For C2H3O+；Specifically preparation method is：100ml DMF electromagnetic agitations, add 50g chlorogenic acids, and 10 DEG C of constant temperature, is added dropwise 0.1ml pyridines, then When addition 10ml acetic anhydrides 24 are small, 80 DEG C are dried in vacuo 12 hours to doing, and add respectively after being dissolved in 100ml ethyl acetate Enter 20ml distillations water washing three times, separating acetic acid ethyl ester obtains the chlorogenic acid that 4,5 phenolic hydroxyl groups are acetylation after being spin-dried for.
- 2. a kind of application for the chlorogenic acid acylate for improving chlorogenic acid bioavilability, its feature exist according to claim 1 In：It by chlorogenic acid acylate is active ingredient that the medicine, which is, adds one or more pharmaceutically acceptable pharmaceutical excipients The oral formulations being prepared.
- 3. a kind of application for the chlorogenic acid acylate for improving chlorogenic acid bioavilability, its feature according to claim 2 It is：The oral formulations are tablet, capsule, granule, powder, pill, oral liquid.
- 4. a kind of application for the chlorogenic acid acylate for improving chlorogenic acid bioavilability, its feature exist according to claim 2 In：Unit formulation acylate containing the chlorogenic acid 1-1000mg of the oral formulations.
- 5. a kind of application for the chlorogenic acid acylate for improving chlorogenic acid bioavilability, its feature exist according to claim 4 In：Unit formulation acylate containing the chlorogenic acid 100-200mg of the oral formulations.
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| CN201510124457.8A CN104814949B (en) | 2015-03-20 | 2015-03-20 | Improve chlorogenic acid acylate and the application of chlorogenic acid bioavilability |
| PCT/CN2016/076820 WO2016150355A1 (en) | 2015-03-20 | 2016-03-20 | Chlorogenic acid acylate capable of improving bioavailability of chlorogenic acid and use thereof |
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| CN113143903B (en) * | 2021-04-14 | 2023-01-17 | 天津中医药大学 | Application of chlorogenic acid-containing pharmaceutical composition in preparation of antiviral drugs |
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| CN101121662A (en) * | 2006-08-11 | 2008-02-13 | 四川九章生物化工科技发展有限公司 | Chlorogenic acid ester derivative, preparation method and application thereof in pharmaceutical preparation |
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| CN101121662A (en) * | 2006-08-11 | 2008-02-13 | 四川九章生物化工科技发展有限公司 | Chlorogenic acid ester derivative, preparation method and application thereof in pharmaceutical preparation |
Non-Patent Citations (1)
| Title |
|---|
| Inhibition of Activator Protein-1, NF-κB, and MAPKs and Induction of Phase 2 Detoxifying Enzyme Activity by Chlorogenic Acid;Rentian Feng et al.;《The Journal of Biological Chemistry》;20050729;第280卷(第30期);27888-27895 * |
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