CN110179750A - A kind of chlorogenic acid self-emulsifying composition and application thereof - Google Patents
A kind of chlorogenic acid self-emulsifying composition and application thereof Download PDFInfo
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- CN110179750A CN110179750A CN201910523981.0A CN201910523981A CN110179750A CN 110179750 A CN110179750 A CN 110179750A CN 201910523981 A CN201910523981 A CN 201910523981A CN 110179750 A CN110179750 A CN 110179750A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
A kind of chlorogenic acid self-emulsifying composition and application thereof.The invention belongs to pharmaceutical technology fields, and in particular to a kind of self-emulsifying composition and application thereof of chlorogenic acid nanoscale drug delivery system.The self-emulsifying composition of nanoscale drug delivery system of the invention, the compound containing recombination rate > 70% that chlorogenic acid-matrix material is formed, specific oil phase, emulsifier and assistant for emulsifying agent, but not aqueous phase.Self-emulsifying composition and its preparation of the invention, can be used for antitumor, anti inflammatory immunity and antiviral treatment.
Description
Technical field
The present invention relates to a kind of chlorogenic acid self-emulsifying composition and preparation method thereof and purposes, belong to the technology of medicine preparation
Field.
Background technique
Chlorogenic acid also known as caffeotannic acid (Chlorogenic acid, abbreviation CA), are to be widely present in honeysuckle, Eucommiaceae
One of the plants such as the leaf of plant Cortex Eucommiae, sunflower seeds, oriental wormwood and blue potted flower organic acid, have anti-oxidant, antibacterial, it is antiviral,
The multiple pharmacological effects such as hypoglycemic, lipid-loweringing, blood pressure lowering and immunological regulation.In a variety of physiological activity, it is immunized possessed by chlorogenic acid
Adjustment effect makes it become one of the natural products of Recent study hot topic in terms of immunotherapy of tumors.The researchs such as Xue hair
Existing, chlorogenic acid can be changed with the M2 type in reversing tumor associated macrophages to M1 type, to play antitumor effect.
Clinically using at present is chlorogenic acid for injection ice dry powder needle, long-term intramuscular injection poor compliance.Due to green original
The pharmacological activity of acid oral administration is poor, and chlorogenic acid oral preparation that so far there are no is used for clinical treatment.
For immunological regulation class drug, it is not that drug concentration more high-drug-effect is better, therefore, improves bioavilability merely
It is different surely to obtain ideal oral medication effect.Which type of composition can break through chlorogenic acid oral administration and control for clinic
The limitation for the treatment of, it is unpredictable.
In order to develop the preparation for being suitable for oral administration, 1048566954 B of patent CN discloses a kind of chlorogenic acid micro emulsion
And its preparation process and application, core content, it is strong using chlorogenic acid hydrophily and the feature of lipophilicity difference, is prepared for by water
Water-In-Oil (W/O) micro emulsion that phase, oily phase, emulsifier and assistant for emulsifying agent are formed, its purpose is to improve bioavilability, improve
Oral medication effect, but since chlorogenic acid is Polyphenols chemical structure, easily generation chemical degradation is stored in aqueous solution, because
This, prepares the micro emulsion existing defects containing water phase.
Self-emulsified drug delivery system (SEDDS) be the uniform liquid formed by oily phase, emulsifier and assistant for emulsifying agent, semisolid or
Solid can be used for containing for drug.With microemulsion phase ratio, SEDDS composition not aqueous phase, therefore the area for having essence is formed
Not, this containing for unstable chemcial property drug, more advantage.But the preparation of SEDDS has pole to physical and chemical properties of drugs
High request, lipophilic drugs are more suitable for containing, and hydrophilic chlorogenic acid is then restricted.
It influences two big factors of load medicine SEDDS characteristic: 1) being contained the property of drug.Fat-soluble medicine is more advantageous to
SEDDS's contains, and hydrophilic medicament biggish for polarity, and it is difficult usually to carry medicine, or easily generation layering is even heavy after placement
It forms sediment.2) oily phase, the classification and composition ratio of emulsifier and assistant for emulsifying agent: three is an entirety, and any ingredient changes
Become or the composition ratio of three change, can all directly affect SEDDS appearance character (such as can be liquid, it is also possible to
Semisolid or solid), physical stability (such as can behave as uniform solution, it is also possible to layering even precipitate), chemical stability
Partial size (meet water and form nanoscale or micron order emulsion droplet) after (difference of drug degradation degree) and emulsification.The ideal medicine that carries is from cream
Change composition, should meet the following conditions: 1) the long-term storage in refrigeration or under room temperature should be the uniform clear liquid of appearance
Body should not be layered；2) the long-term storage in refrigeration or under room temperature, should be the uniform clear liquid of appearance, does not answer
Solidification or precipitating occurs, avoids the processing links using preceding " by medicinal mixture heating and melting ", convenient for taking, and reduces drug
Degradation；3) self-emulsifying is high-efficient, simulated gastrointestinal environments, after adding a certain amount of water to dilute, can quick spontaneous emulsification, form nanoscale
Emulsion droplet；4) after self-emulsifying mixtures directly take orally, the emulsion droplet that spontaneous emulsification is formed in stomach and intestine should be nanoscale (i.e. 1-
1000nm thinks that 1-1000nm belongs to a nanometer model and raises in pharmacy), (i.e. > 1 μm, recognize in pharmacy without should be micron order
Then to belong to micron order more than 1 μm).
But, there is apparent defect in the existing Research Literature about chlorogenic acid self-emulsifying drug delivery systems.
Chen Li etc., in " Formulation and in-vitro evaluation of the chlorogenic acid from micro emulsion drug delivery system " with ethyl oleate be oil
Phase, Tween 80 are emulsifier, and glycerol is to help agent, be prepared for containing chlorogenic acid from micro emulsion, drugloading rate adds up to 60mg/g
100 times of water dilutions, are stirred, the emulsifiable emulsion droplet for partial size about 16nm under the conditions of 37 degree and 50rpm.But reference literature method,
It is oily phase with ethyl oleate, Tween 80 is emulsifier, and glycerol is to help agent, according to oily phase: emulsifier: assistant for emulsifying agent=1:3:6
Mass ratio, being prepared for drugloading rate is 60mg/g from microemulsion solution, the results show that prepared chlorogenic acid is from microemulsion preconcentrate
Show apparent lamination.It is placed in room temperature and 4 DEG C, stratification state aggravates.
Patent CN104826118A discloses a kind of chlorogenic acid and its phospholipid modified object of derivative and preparation method thereof,
Phospholipid modified object is applied to the preparation of " administration nano-drug administration system or micron drug delivery system ".But the patent equally exists obvious lack
It falls into；1) for micro emulsion or/from micro emulsion drug delivery system preparation when, obtain being micron drug delivery system rather than administration nano-drug administration system；
2) for micro emulsion or/from micro emulsion drug delivery system preparation when, the emulsifier used is polyoxyethylene sorbitan monoleate, polyoxyethylene oleate, liquid
One of body lecithin and Emulsifier EL-60 or more than one mixtures, it is verified, show obtained from micro emulsion mixing
Object is obviously layered, and upper layer is the solid gel without mobility.
Summary of the invention
In view of defect existing for existing research, the invention patent discloses a kind of chlorogenic acid and receives on the basis of system research
The self-emulsifying composition and its preparation method and application of rice drug delivery system.
The present invention provides a kind of self-emulsifying compositions of chlorogenic acid administration nano-drug administration system, it is by chlorogenic acid matrix material
Compound, oily phase, emulsifier and assistant for emulsifying agent composition；The emulsifier is any one of LABRAFIL M 1944CS and its derivative
Kind is several；The chlorogenic acid matrix material compound is that chlorogenic acid is combined with matrix material.
Further, the recombination rate of the chlorogenic acid matrix material compound is greater than 70%, preferably greater than 80%, more preferably
Greater than 90%.
Further, the composition Content of Chlorogenic Acid is 5-200mg/g.
Further, the composition Content of Chlorogenic Acid is 10-150mg/g.
Further, the molar ratio of the chlorogenic acid matrix material compound Content of Chlorogenic Acid and matrix material be 1:0.25~
1:8, preferably 1:0.25~1:4.
Further, the matrix material is selected from cholesterol, phospholipid or cholic acid salt；It is preferred that phospholipid.
Further, the phospholipid is soybean lecithin, yolk phospholipid, phosphatidyl glycerol ester, distearoylphosphatidyl
Choline, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, two nutmeg phosphatidyl cholines, in ceramide
Any one or a few；It is preferred that soybean lecithin and/or yolk phospholipid.
Further, the oily phase, emulsifier and assistant for emulsifying agent mass percent, based on three's summation 100%, oil is mutually
10-50%, emulsifier 30-60%, assistant for emulsifying agent 20-60%.
Further, the LABRAFIL M 1944CS derivative is Labraso, the poly- second two of oleic acid
Alcohol glyceride or linoleic acid LABRAFIL M 1944CS.
Further, it is described oil mutually be soybean oil, corn oil, olive oil, coconut oil, peanut oil, camellia oil, castor oil,
Oleic acid sorbitol ester, olein, glyceryl linoleate, labrafil1944cs, Maisine35-1, ethyl oleate, sub- oil
Acetoacetic ester, C8/C10Monoglyceride, coconut oil C8/C10Diglyceride, coconut oil C8/C10It is triglycerides, Trivent OCG, pungent
Acid triglyceride, sad monoglyceride, capric acid monoglyceride, capric acid diglyceride, Triglyceride DDD, pungent capric acid glycerol list
Ester, Glycerin, mixed triester with caprylic acid capric acid, pungent Triglyceride DDD, isopropyl myristate, linoleic acid LABRAFIL M 1944CS, Gelucire,
Any one or a few in Capryol 90；It is preferred that ethyl oleate, oleic acid sorbitol ester, olein, linoleic acid
Ester, labrafil1944cs, Maisine35-1, ethyl linoleate, C8/C10Monoglyceride, coconut oil C8/C10Diglyceride, coconut palm
Seed oil C8/C10Triglycerides, Trivent OCG, Sunfat GDC-S, sad monoglyceride, capric acid monoglyceride, capric acid are sweet
Oily diester, Triglyceride DDD, pungent capric acid monoglyceride, Glycerin, mixed triester with caprylic acid capric acid, pungent Triglyceride DDD, myristic acid isopropyl
Ester, linoleic acid LABRAFIL M 1944CS, any one or a few in Gelucire, Capryol 90.
Further, the assistant for emulsifying agent is propylene carbonate, ethylene glycol monomethyl ether, glycerol furfural, the different mountain of dimethyl
Pear ester, diethylene glycol monoethyl ether, PEG400, glycerol, labraosol, any one or a few in benzyl alcohol；It is preferred that two
Methyl Soquad, diethylene glycol monoethyl ether, glycerol, any one or a few in labraosol.
Further, it further includes antioxidant；The antioxidant is vitamin E, vitamin-e ester analog derivative or dibutyl
Hydroxy-methylbenzene any one or a few.
The present invention also provides a kind of self-emulsifying composition methods for preparing chlorogenic acid administration nano-drug administration system, it includes as follows
Step:
(1) it prepares the compound of chlorogenic acid and matrix material: weighing chlorogenic acid and matrix material according to the ratio, be dissolved in organic molten
In agent, mix, stand 15-30min, rotary evaporation or spray drying removal organic solvent, then be dried under reduced pressure to get；
(2) it prepares blank self-emulsifying concentrate: weighing oily phase, emulsifier and assistant for emulsifying agent according to the ratio, be uniformly mixed, i.e.,
?；
(3) it prepares chlorogenic acid self-emulsifying composition: step (1) compound being added in step (2) concentrate, has been dissolved
Entirely to get；
Or:
Step (1) compound is added together with oily phase, emulsifier and assistant for emulsifying agent according to the ratio, is uniformly mixed, i.e.,
?；
Or:
First step (1) compound and any one dissolution in oily phase, emulsifier or assistant for emulsifying agent are mixed according to the ratio, then plus
Enter other two kinds of ingredients mix to get.
Further, step (1) organic solvent is low molecule alcohol；The low molecule alcohol is ethyl alcohol, anhydrous second
Any one or a few in alcohol, the tert-butyl alcohol；It is preferred that dehydrated alcohol.
Further, shaking is dissolved as described in step (3) to dissolve, shake speed 210rpm, 25 DEG C of temperature.
The present invention also provides a kind of chlorogenic acid preparations, it is by aforementioned chlorogenic acid self-emulsifying composition, in addition pharmaceutically
The preparation of acceptable carrier composition.
Further, the preparation be oral preparation, mucosa delivery preparation, percutaneous drug administration preparation, intestinal canal administration preparation or
Neulized inhalation preparation.
Further, the oral preparation is tablet, granule, capsule, oral solution, drops or spray；It is described viscous
Film drug-delivery preparation or percutaneous drug administration preparation are paint, spray or other suitable dosage forms；The intestinal canal administration preparation is liquid preparation
Or it is dissolved in oleaginous base and suppository is made.
Further, the tablet, granule or capsule are that chlorogenic acid self-emulsifying composition is dispersed in micro mist silicon
On glue or other adsorptive solid materials, along with auxiliary material acceptable on medicament is made.
Further, the Neulized inhalation is that the packing of chlorogenic acid self-emulsifying composition is made for Neulized inhalation with preparation
Concentrated solution faces used time atomising device or uses nebulization equipment after adding water, physiological saline or glucose injection dilution
Carry out Neulized inhalation.
The present invention finally provides a kind of chlorogenic acid self-emulsifying composition or chlorogenic acid preparation in preparation treatment and/or pre-
Purposes in anti-malignant tumour, immunocompromised, bacteriovirus infection and/or oxidation resistant drug.
The present invention attempts chlorogenic acid chlorogenic acid/phosphatide is made multiple on the basis of the chlorogenic acid of open report is from micro emulsion
Close after object again with its oily phase, emulsifier and/or emulsion is helped to be mixed from micro emulsion, quality condition is specific as follows:
On Chen Li etc. " chlorogenic acid from the Formulation of micro emulsion drug delivery system and in-vitro evaluation " Research foundation, first will it attempt
Chlorogenic acid/phosphatide complexes (molar ratio 1:1, mass ratio 1:2.2) is made in chlorogenic acid, to improve drug lipophilicity, and with
Compound is intermediate vector, then by same oily phase, emulsifier and helps agent prescription preparation 60mg/ml (in terms of chlorogenic acid) from micro-
Cream, but found in preparation process, obtained chlorogenic acid self-emulsifying composition still shows layering, and upper layer is solid gel, nothing
Mobility.After 37 DEG C are placed 1 day, the stratification state that upper layer is solid gel state is still presented, is not improved.Further,
Prepare from micro emulsion using " Emulsifier EL-60 " replacement " Tween 80 ", as a result, it has been found that, prepared chlorogenic acid self-emulsifying
Stratification state is still presented in the initial character of composition.Thus prompt, when use chlorogenic acid/phosphatide complexes for intermediate vector preparation from
When micro emulsion, " Tween 80 " no matter is used as emulsifier or uses " Emulsifier EL-60 " for emulsifier, can not obtain outer
See the self-emulsifying mixtures for uniform liquid.
Referring to phospholipid modified object and its preparation side of a kind of chlorogenic acid and its derivative disclosed in patent CN104826118A
Method take ethyl oleate as oily phase, and Tween 80, Emulsifier EL-60 and RH40 hydrogenation Emulsifier EL-60 are emulsifier, two
Ethylene glycol monomethyl ether, propylene glycol and polyethylene glycol are assistant for emulsifying agent, and chlorogenic acid phosphatide complexes are intermediate vector, according to oil
Phase: emulsifier: assistant for emulsifying agent mass ratio is that 2:5:3 is prepared for chlorogenic acid phosphatide complexes from micro emulsion (drugloading rate 60mg/g).Knot
Fruit shows, prepared that three layering, semigel shape and solidification states, and room temperature or the feelings of 4 DEG C of placements are presented from microemulsion system
Still above-mentioned three kinds of states are presented under condition, concrete outcome is described see table 1.
Table 1 prepares situation from micro emulsion referring to the chlorogenic acid phosphatide complexes of publication
With reference to currently used oily phase, emulsifier and assistant for emulsifying agent, and it is used for the system of chlorogenic acid self-emulsifying composition
Standby and droplet measurement.Specific steps: being oily phase with ethyl oleate, Tween 80 is emulsifier, and glycerol is assistant for emulsifying agent, proportions
(mass ratio) is mixed by 1:3:6, obtains blank from microemulsion solution；
Separately take respectively chlorogenic acid bulk pharmaceutical chemicals and chlorogenic acid phosphatide complexes (after chlorogenic acid is mixed with soybean lecithin 1:1,
It is dissolved with dehydrated alcohol, dry to be made) above-mentioned blank is added to from micro emulsion, it dissolves, chlorogenic acid is made to carry concentration 60mg/
Ml is placed one week, is seen whether to be layered；It takes two kinds of load medicines from micro emulsion, 100 times of water dilution is added, shaking swashs in 2min
Light particle size analyzer determination emulsion droplet size.
As a result such as the following table 2:
Table 2: Tween 80 is that the self-emulsifying composition of emulsifier investigates result
The result shows that ethyl oleate is oily phase, Tween 80 is emulsifier, and glycerol is assistant for emulsifying agent, obtained to contain green original
The partial size from after micro emulsion, dilution of acid is small, but refrigerates or be placed at room temperature for 3 days and lamination occur；It is obtained to contain chlorogenic acid phosphorus
The partial size from after micro emulsion, dilution of fat complexes is micron order, and solidification phenomenon occurs in refrigeration, and room temperature storage occurs apparent point
Layer.
To sum up, there is unstable state or partial size is big from micro emulsion itself and unstable in the chlorogenic acid of existing report after placement
Defect.By chlorogenic acid and matrix material it is compound after, according still further to its oily phase, emulsifier and help emulsion composition preparation from micro emulsion still
It is so unstable, from three the different degrees of presentation layering of microemulsion system, semigel shape and solidification states after placement.
And the self-emulsifying composition of chlorogenic acid administration nano-drug administration system of the present invention is intermediate carry with chlorogenic acid/lipid complex
Body, mixing of the emulsifier using LABRAFIL M 1944CS and its derivative one or more, manufactured self-emulsifying composition,
At least six moon is placed under the conditions of room temperature and 2-8 DEG C, is not in solidification or lamination, is shown as uniform fluid
Shape, after being diluted with water can quick emulsification formed nanoscale emulsion droplet, emulsion droplet size < 500nm.
Specific experiment of the present invention is as follows:
It 1, is the preparation and detection of intermediate vector about chlorogenic acid/lipid complex CHAPC
Using soybean lecithin as matrix material, chlorogenic acid and soybean lecithin are fed intake according to the medicine rouge ratio of following table,
Be added together into the round-bottomed flask of 1L, using dehydrated alcohol as solvent, make drug concentration control in 60mg/ml, to chlorogenic acid and
Soybean lecithin all after dissolution, is placed at room temperature for 15min, is then dried under reduced pressure and removes in Rotary Evaporators 100rpm, 40 DEG C of revolvings
Dehydrated alcohol is removed, after ethyl alcohol is evaporated, continues 100rpm in room temperature and is dried under reduced pressure 1h for ethyl alcohol except clean.
The serial composite powder for taking preparation measures recombination rate according to following method, the results are shown in Table 3.
(1) reference substance solution: weighing chlorogenic acid standard items 25mg into 25ml volumetric flask, accurate with ethanol solution constant volume
1ml is measured into 50ml volumetric flask, with 30% ethanol water constant volume, as reference substance solution；
(2)WAlways: 80mg chlorogenic acid compound is weighed into 25ml volumetric flask, is shaken up with dehydrated alcohol constant volume, and precision measures
1ml is shaken up, as test sample W into 50ml volumetric flask with 30% ethanol water constant volumeAlwaysSolution；
(3)WIt is compound: 80mg chlorogenic acid compound is weighed into 25ml volumetric flask, and constant volume after being dissolved with chloroform is filtered with 0.22um
Film filtering, precision measure subsequent filtrate 1ml, nitrogen is blown volatilize solvent (chloroform) after, with 30% ethanol water accurate dilutions to 50mL, as
Test sample WIt is compoundSolution.
On the basis of the above sample is made, it is measured using following HPLC condition.
Mobile phase: 0.4% phosphoric acid: acetonitrile=82:18
Detection wavelength: 328nm
Flow velocity: 1.0mL/min
Column temperature: 25 DEG C
Sample volume: 10uL
Stop Time:8min
3 dehydrated alcohol of table is solvent, and different medicine rouge are than compound (CHAPC) and recombination rate
The result shows that medicine rouge ratio (molar ratio) is 1:0.25 to 1:8, compound obtained is compound complete, and recombination rate exists
99% or more.
It feeds intake by chlorogenic acid/soybean lecithin medicine rouge ratio (molar ratio) for 1:1, prepares compound using different solvents,
And recombination rate is investigated, as a result such as the following table 4.
Influence of 4 different solvents of table to compound (CHAPC) preparation result
The result shows that when medicine rouge ratio (molar ratio) is 1:1, methanol, tetrahydrofuran, chloroform, the recombination rate in methylene chloride
Lower, the recombination rate in the tert-butyl alcohol, ethyl acetate is 70% or more, and the recombination rate of ethyl alcohol (95% concentration) is 80% or more.
Using egg yolk lecithin, phosphatidyl glycerol ester, Distearoyl Phosphatidylcholine, cholesterol, cholate as matrix material,
Dehydrated alcohol is solvent, is 1:1 by medicine rouge ratio (molar ratio), and ibid method prepares compound, number be followed successively by CHAPC 15,
CHAPC 16, CHAPC 17, CHAPC 18, CHAPC 19 measure recombination rate, the results showed that, recombination rate is 92% or more.
About the type of matrix material, natural phospholipid, synthetic phospholipid, cholesterol and cholate can be met the requirements, but excellent
Select natural phospholipid.
2, the portfolio ratio result of study of the self-emulsifying composition of the invention patent
It is oily phase with ethyl oleate, Labraso (labrasol) is emulsifier, transcutol
HP is assistant for emulsifying agent, and three's mass ratio is 2:3:5, is uniformly mixed, prepares blank self emulsifying emulsions；Separately take the phosphatide of chlorogenic acid multiple
Object CHAPC 3 is closed, is dissolved in above-mentioned blank self emulsifying emulsions, controls the drugloading rate of chlorogenic acid in 10-200mg/ml, temperature 25
DEG C, revolving speed 210rpm.The chlorogenic acid self-emulsifying composition is obtained after object dissolution completely to be composite；It takes and carries medicine self emulsifying emulsions
In right amount, add water 100 to be diluted again, investigate partial size (wherein droplet measurement method: with liquid-transfering gun essence after self-emulsifying efficiency and emulsification
It is close to pipette 20 μ L chlorogenic acid self-emulsifying compositions, it is added in the 5mlEP pipe equipped with 2ml Wahaha deionized water, gently shakes up, turn
Cuvette is moved to, its partial size is then measured using laser diffraction particle size instrument).As a result such as table 5.
Table 5: Labraso is that the self-emulsifying of emulsifier investigates result
Prompt can get good self-emulsifying and receive within the scope of 10mg/g-150mg/g (medicament/composition) drugloading rate
Rice drug delivery system.
On the basis of table 5, and carry out the research of series, comprising:
(1) using different numbers chlorogenic acid/phosphatide complexes carry out self-emulsifying composition preparation, discovery CHAPC 1 to
CHAPC 5, CHAPC 15 to CHAPC 19, can get it is good as a result, appearance be uniform solution, and emulsify after partial size exist
Secondly 200nm is hereinafter, be CHAPC 6, CHAPC 7, CHAPC 9, CHAPC 10, partial size is in 500nm or less after emulsification.Other are multiple
It is poor to close object effect, emulsification partial size is micron order.
Thus it prompts, for the self-emulsifying composition of the chlorogenic acid administration nano-drug administration system of the invention patent, " green original therein
The molar ratio of acid/lipid complex ", chlorogenic acid and matrix material can be met the requirements in 1:0.25~1:8, but it is preferred that 1:
0.25~1:4；The recombination rate of chlorogenic acid and matrix material can be met the requirements 70% or more, but preferably 90% or more.
(2) it attempts to replace Labraso using different LABRAFIL M 1944CS derivatives
(labrasol), self-emulsifying composition is prepared, discovery oleic acid LABRAFIL M 1944CS (1944cs), sub- oil
Acid polyethylene glycol glyceride (The mixing of any one or more than one arbitrary proportions M2125CS),
It meets the requirements.
(3) attempt mutually to replace ethyl oleate using different oil, prepare self-emulsifying composition, discovery soybean oil, corn oil,
Olive oil, coconut oil, peanut oil, camellia oil, castor oil, oleic acid sorbitol ester, olein, glyceryl linoleate,
Labrafil1944cs, Maisine35-1, ethyl linoleate, C8/C10 monoglyceride, coconut oil C8/C10 diglyceride, coconut palm
Seed oil C8/C10 triglycerides, Trivent OCG, Sunfat GDC-S, sad monoglyceride, capric acid monoglyceride, capric acid are sweet
Oily diester, Triglyceride DDD, pungent capric acid monoglyceride, Glycerin, mixed triester with caprylic acid capric acid, pungent Triglyceride DDD, myristic acid isopropyl
Ester, linoleic acid LABRAFIL M 1944CS (M2125CS), Gelucire, Capryol 90 is used equally for oily phase,
And substantially meet the requirement of self-emulsifying composition preparation, wherein with ethyl oleate, oleic acid sorbitol ester, olein, sub- oil
Acid glyceride, labrafil1944cs, Maisine35-1, ethyl linoleate, C8/C10 monoglyceride, coconut oil C8/C10 are sweet
Oily dibasic acid esters, coconut oil C8/C10 triglycerides, Trivent OCG, Sunfat GDC-S, sad monoglyceride, capric acid glycerol list
Ester, capric acid diglyceride, Triglyceride DDD, pungent capric acid monoglyceride, Glycerin, mixed triester with caprylic acid capric acid, pungent Triglyceride DDD, Pork and beans
Cool isopropyl propionate, linoleic acid LABRAFIL M 1944CS (M2125CS), in Gelucire, Capryol 90
The mixed effect of one or more kinds of arbitrary proportions is more preferable, the self-emulsifying composition of preparation, and the emulsion droplet size after dilution is smaller.
(4) attempted with different assistant for emulsifying agents replace diethylene glycol monoethyl ether (HP), prepare certainly
Emulsification composition, the results showed that, propylene carbonate, glycerol furfural, Dimethyl isosorbide, PEG400, glycerol, labraosol,
The mixing of one or more of benzyl alcohol arbitrary proportion, is used equally for emulsifier, wherein with Dimethyl isosorbide,
Diethylene glycol monoethyl ether (HP), one of glycerol, labraosol or more than one arbitrary proportions
Mixing, effect is more preferable, and wherein with diethylene glycol monoethyl ether (HP effect) is optimal.
(5) the composition mass ratio for adjusting oily phase, emulsifier and assistant for emulsifying agent three, carries out self-emulsifying composition preparation.It presses
Three's summation is 100% meter, when it is oily be mutually 10-50%, emulsifier 30-60%, assistant for emulsifying agent 20-60%, can get good
Self-emulsifying composition.
(6) in addition, for prevent grease-like composition from storing for a long time rancid, also repay tried to be added in self-emulsifying composition it is anti-
Oxygen agent, vitamin E and its esters, BHT can be used.
3, the preparation method of the self-emulsifying composition of the invention patent
(1) preparation of " compound of chlorogenic acid and matrix material ": chlorogenic acid and matrix material are weighed, it is moderate to be dissolved in polarity
Organic solvent in, mix, place certain time (15-30min), rotary evaporation or spray drying removal organic solvent, decompression
It is dry to get；
(2) preparation of " blank self-emulsifying concentrate ": oily phase, emulsifier and assistant for emulsifying agent are weighed in proportion, is stirred
Uniformly to get；
(3) preparation of " self-emulsifying composition of chlorogenic acid administration nano-drug administration system ": will " chlorogenic acid and matrix material it is compound
Object " is added into " blank self-emulsifying concentrate ", and places it in air bath oscillator, 25 DEG C of temperature, revolving speed 210rpm or
Suitable condition oscillation obtains the chlorogenic acid self-emulsifying group after " compound of chlorogenic acid and matrix material " dissolution completely
Close object.Character is uniform clear liquid.
3 steps of the above method are poly-, optionally, can also be by the compound and oil phase, emulsifier of chlorogenic acid and matrix material
It is added, is uniformly mixed together with assistant for emulsifying agent, self-emulsifying composition is made；Or it by compound and oily phase, emulsifier or helps
First dissolution mixes in any one of emulsifier, adds other two kinds of ingredients, mix to get.
4, the application of the self-emulsifying composition of the invention patent
A kind of self-emulsifying composition of chlorogenic acid administration nano-drug administration system, can be used for being made suitable for mouth disclosed in the invention patent
The preparation of administration is taken, such as by self-emulsifying concentrate direct packaging at soft capsule, hard capsule, oral solution, drops, spray, wherein
It is preferred that soft capsule and drops.In addition, self-emulsifying composition concentrate can be also dispersed in superfine silica gel powder or other adsorptive solids
On material, in addition common auxiliary material on medicament, is made tablet for oral use, capsule, granule or electuary etc..
Oral preparation is directly taken, without taking again after emulsification is first diluted with water.Utilize the self-emulsifying of self-emulsifying composition
Ability can quickly form nanoscale emulsion droplet under the conditions of gastro-intestinal Fluid environment and gastrointestinal peristalsis.
In addition to oral preparation, self-emulsifying composition of the invention can also dispense the concentrated solution being made for Neulized inhalation, face
Used time adds water, physiological saline or glucose injection dilution, carries out Neulized inhalation using nebulization equipment.
The self-emulsifying composition of the invention patent is successively used for lewis lung cancer and Treatment for Glioma, using gastric infusion,
Dosage shows good therapeutic effect within the scope of 20-80mg/kg, the no significant difference compared with drug administration by injection.
To sum up, the present invention is in chlorogenic acid and matrix material molar ratio 1:0.25~1:8, preferably 1:0.25~1:4；Oily phase,
Emulsifier with assistant for emulsifying agent three based on summation 100%, oily phase 10-50%, emulsifier 30-60%, assistant for emulsifying agent 20-60%,
Wherein emulsifier uses the mixing of LABRAFIL M 1944CS and its derivative one or more；Drugloading rate 10mg/g-
150mg/g (medicament/composition), the self-emulsifying composition of chlorogenic acid administration nano-drug administration system obtained, stability are good and mixed with water
Partial size is small after conjunction.Different preparations are made in the composition and are used for antitumor, anti inflammatory immunity and antiviral therapy, there is significant effect
Fruit has practical application promotional value.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Detailed description of the invention
Fig. 1: the separation detection HPLC map of chromatographic condition one in test example 1
Fig. 2: the separation detection HPLC map of chromatographic condition two in test example 1
Fig. 3: the chlorogenic acid self-emulsifying composition and chlorogenic acid of this patent are from micro emulsion to the tumor killing effect of lewis lung cancer
Fig. 4: tumor killing effect of the chlorogenic acid self-emulsifying composition to subcutaneous glioma
Fig. 5: tumor killing effect of the chlorogenic acid self-emulsifying composition to glioma in situ
Specific embodiment
Embodiment 1 is that intermediate prepares chlorogenic acid self-emulsifying composition using different emulsifiers with CHAPC 3
(1) preparation of " compound of chlorogenic acid and matrix material ": green original is weighed according to the preparation method of above-mentioned CHAPC 3
Acid and matrix material, be dissolved in dehydrated alcohol, mix, place 15min, rotary evaporation remove organic solvent, be dried under reduced pressure to get
CHAPC 3；
(2) preparation of " blank self-emulsifying concentrate ": 2:5:3 in mass ratio weighs ethyl oleate, emulsifier (according to table 6
The type of middle emulsifier is changed) and transcutol HP, be uniformly mixed to get；
(3) it the preparation of " self-emulsifying composition of chlorogenic acid administration nano-drug administration system ": is weighed according to drugloading rate calculating in table 6
CHAPC3 and blank cream, mixing are placed in air bath oscillator, and 25 DEG C of temperature, revolving speed 210rpm.It is dissolved completely to CHAPC 3
After obtain the chlorogenic acid self-emulsifying composition.And investigate partial size, 2-8 DEG C of placement after its initial character plus 100 times of water dilutions
6 months characters are placed at room temperature for 6 months characters.
The chlorogenic acid self-emulsifying composition of 6 different emulsifiers of table preparation
Embodiment 2 is that intermediate uses different oily phase: emulsifier with CHAPC 3: the chlorogenic acid of assistant for emulsifying agent preparation is certainly
Emulsification composition
(1) preparation of " compound of chlorogenic acid and matrix material ": green original is weighed according to the preparation method of above-mentioned CHAPC 3
Acid and matrix material, be dissolved in dehydrated alcohol, mix, place 15min, rotary evaporation remove organic solvent, be dried under reduced pressure to get
CHAPC 3；
(2) preparation of " blank self-emulsifying concentrate ": using ethyl oleate as oily phase, labrasol as emulsifier,
Transcutol HP is as assistant for emulsifying agent, and according to phase oily in table 7: emulsifier: the mass ratio of assistant for emulsifying agent weighs a certain amount of oil
Acetoacetic ester, labrasol and transcutol HP are uniformly mixed to get blank self-emulsifying concentrate；
(3) it the preparation of " self-emulsifying composition of chlorogenic acid administration nano-drug administration system ": is weighed according to drugloading rate calculating in table 7
CHAPC3 and blank cream, mixing are placed in air bath oscillator, and 25 DEG C of temperature, revolving speed 210rpm.It is dissolved completely to CHAPC 3
After obtain the chlorogenic acid self-emulsifying composition.And investigate partial size, 2-8 DEG C of placement after its initial character plus 100 times of water dilutions
6 months characters are placed at room temperature for 6 months characters.
The oily phase of 7 different quality ratio of table: emulsifier: the chlorogenic acid self-emulsifying composition of assistant for emulsifying agent preparation
Embodiment 3 prepares chlorogenic acid self-emulsifying composition by intermediate of different CHAPC
1) preparation of " compound of chlorogenic acid and matrix material ": chlorogenic acid is weighed according to the preparation method of above-mentioned CHAPC
It with matrix material, is dissolved in dehydrated alcohol, mixes, place 15min, rotary evaporation removes organic solvent, is dried under reduced pressure to get not
Same chlorogenic acid and phosphatide complexes CHAPC (being shown in Table 8)；
(2) preparation of " blank self-emulsifying concentrate ": using ethyl oleate as oily phase, labrasol as emulsifier,
For transcutol HP as assistant for emulsifying agent, 2:5:3 in mass ratio weighs ethyl oleate, labrasol and transcutol HP,
It is uniformly mixed to get blank self-emulsifying concentrate；
(3) it the preparation of " self-emulsifying composition of chlorogenic acid administration nano-drug administration system ": is weighed according to drugloading rate calculating in table 8
CHAPC and blank cream, mixing are placed in air bath oscillator, and 25 DEG C of temperature, revolving speed 210rpm.After CHAPC dissolution completely
Obtain the chlorogenic acid self-emulsifying composition.And investigate partial size, 2-8 DEG C of placement 6 after its initial character plus 100 times of water dilutions
A month character is placed at room temperature for 6 months characters.
8 difference CHAPC of table is the chlorogenic acid self-emulsifying composition of intermediate preparation
4 difference CHAPC of embodiment: blank prepares chlorogenic acid self-emulsifying composition from micro emulsion ratio
(1) preparation of " compound of chlorogenic acid and matrix material ": green original is weighed according to the preparation method of above-mentioned CHAPC 3
Acid and matrix material, be dissolved in dehydrated alcohol, mix, place 15min, rotary evaporation remove organic solvent, be dried under reduced pressure to get
CHAPC 3；
(2) preparation of " blank self-emulsifying concentrate ": using ethyl oleate as oily phase, labrasol as emulsifier,
Transcutol HP is as assistant for emulsifying agent, according to oily phase: emulsifier: the mass ratio of assistant for emulsifying agent weighs a certain amount of for 2:5:3
Ethyl oleate, labrasol and transcutol HP are uniformly mixed to get blank self-emulsifying concentrate is obtained；
(3) preparation of " self-emulsifying composition of chlorogenic acid administration nano-drug administration system ": newborn according to CHAPC in table 9 and blank
Mass ratio weighs CHAPC 3 and blank emulsion, and the mixture of different drugloading rates is obtained after mixing, and places it in air bath oscillation
In device, 25 DEG C of temperature, revolving speed 210rpm.The chlorogenic acid self-emulsifying composition is obtained after CHAPC 3 dissolves completely.And it examines
Examine its initial character, plus 100 times of water dilution after partial size, 6 months characters of 2-8 DEG C of placement, be placed at room temperature for 6 months characters.
9 difference CHAPC of table is the chlorogenic acid self-emulsifying composition of intermediate preparation
The study on the stability of the chlorogenic acid self-emulsifying composition of different antioxidant is added in embodiment 5
(1) preparation of " compound of chlorogenic acid and matrix material ": green original is weighed according to the preparation method of above-mentioned CHAPC 3
Acid and matrix material, be dissolved in dehydrated alcohol, mix, place 15min, rotary evaporation remove organic solvent, be dried under reduced pressure to get
CHAPC 3；
(2) preparation of " blank self-emulsifying concentrate ": using ethyl oleate as oily phase, labrasol as emulsifier,
Transcutol HP is as assistant for emulsifying agent, according to oily phase: emulsifier: the mass ratio of assistant for emulsifying agent weighs a certain amount of for 2:5:3
Ethyl oleate, labrasol and transcutol HP are uniformly mixed to get blank self-emulsifying concentrate.And resulting
Antioxidant is added in blank self-emulsifying concentrate (type is as shown in table 10)；
(3) preparation of " self-emulsifying composition of chlorogenic acid administration nano-drug administration system ": according to the mass ratio of CHAPC and blank cream
1.2:5 weighs " the compound CHAPC 3 of chlorogenic acid and matrix material " and is added into " blank self-emulsifying concentrate ", and is set
In air bath oscillator, 25 DEG C of temperature, revolving speed 210rpm.The chlorogenic acid is obtained after CHAPC 3 dissolves completely from cream
Change composition.And it investigates partial size, 2-8 DEG C of 6 months characters of placement after its initial character plus 100 times of water dilutions and is placed at room temperature for 6
Month character.
The chlorogenic acid self-emulsifying composition of different antioxidant is added in table 10
6 chlorogenic acid self-emulsifying composition of embodiment is used for soft capsule preparation for oral use or nebulizer administration
(1) preparation of " compound of chlorogenic acid and matrix material ": green original is weighed according to the preparation method of above-mentioned CHAPC 3
Acid and matrix material, be dissolved in dehydrated alcohol, mix, place 15min, rotary evaporation remove organic solvent, be dried under reduced pressure to get
CHAPC 3；
(2) preparation of " blank self-emulsifying concentrate ": using ethyl oleate as oily phase, labrasol as emulsifier,
Transcutol HP is as assistant for emulsifying agent, according to oily phase: emulsifier: the mass ratio of assistant for emulsifying agent weighs a certain amount of for 2:5:3
Ethyl oleate, labrasol and transcutol HP are uniformly mixed to get blank self-emulsifying concentrate；
(3) preparation of " self-emulsifying composition of chlorogenic acid administration nano-drug administration system ": according to the mass ratio of CHAPC and blank cream
1.2:5 weighs " the compound CHAPC 3 of chlorogenic acid and matrix material " and is added into " blank self-emulsifying concentrate ", and is set
In air bath oscillator, 25 DEG C of temperature, revolving speed 210rpm.The chlorogenic acid is obtained after CHAPC 3 dissolves completely from cream
Change composition.
(4) the chlorogenic acid self-emulsifying composition is packed into soft capsule, prepares soft capsule preparation for oral use.It can additionally incite somebody to action
The chlorogenic acid self-emulsifying composition adds water, physiological saline or glucose injection dilution, and connection nebulization equipment is atomized
Inhalation.
Beneficial effects of the present invention are further illustrated below by way of test example:
The research of test example 1:HPLC content assaying method
Chlorogenic acid is polyphenol class formation, chemical degradation easily occurs under solution state, if chromatographic condition cannot make main peak
It is efficiently separated with catabolite, then will have a direct impact on the accuracy of study on the stability result.For this purpose, accelerated the failure using high temperature
Self-emulsifying sample, is demulsified with dehydrated alcohol, is diluted with water to the test liquid that chlorogenic acid concentration is about 0.1mg/ml, investigates following two
Kind condition is measured.
Chromatographic condition one: isocratic elution, mobile phase are 0.4% phosphoric acid: acetonitrile=82:18；Flow velocity: 1mL/min；Detect wave
It is long: 328nm；Column temperature: 25 DEG C；Sampling volume: 10 μ L.
Chromatogram is shown in attached drawing 1.
Chromatographic condition two: using gradient elution, and mobile phase condition is as follows.
Column temperature: 25 DEG C；Flow velocity: 1.0mL/min；Wavelength: 328nm sampling volume: 10 μ L
Chromatogram is shown in Fig. 2.
Fig. 1 and Fig. 2 it was found that, under the measurement concentration conditions of setting, chlorogenic acid main peak that two kinds of chromatographic conditions measure
Area difference is little, but to the separation detection ability of impurity, chromatographic condition two is substantially better than chromatographic condition one.Therefore, subsequent to adopt
The study on the stability of self-emulsifying sample is carried out with chromatographic condition two.
Test example 2: the study on the stability of chlorogenic acid self-emulsifying composition
The self-emulsifying composition sample of 9 groups of differences of Example 1 and embodiment 2 number, is transferred in 4 DEG C and room temperature condition
It sets 7 months, takes out, carry out appearance character and chemical stability is investigated.
Appearance character: 9 groups of samples are placed 7 months through 4 DEG C and under room temperature, are the uniform solution of clear, nothing
Precipitating, shows that physical stability is good.
Content: taking stability sample, accurately weighed, is demulsified with dehydrated alcohol, is diluted with water to chlorogenic acid concentration and is about
The test solution of 0.1mg/ml separately takes chlorogenic acid bulk pharmaceutical chemicals, prepares the contrast solution of suitable concentration；Take test solution with compare it is molten
Each 10 μ L of liquid injects liquid chromatograph, detects in accordance with the law according to the chromatographic condition two (gradient elution) in test example 1, and external standard method calculates medicine
Object concentration, and mark content is calculated according to physical and chemical drugloading rate.
The result shows that 9 groups of self-emulsifying composition samples, place 7 months in 4 DEG C and under room temperature, mark content is steady
It is scheduled within the scope of 95-105%, with initial phase ratio, content and impurity are without significant change.
Test example 3: chlorogenic acid self-emulsifying composition examines the inhibition tumor effect of the ICR mouse of subcutaneous lotus lewis lung cancer
It examines
The tumor suppression effect of chlorogenic acid self-emulsifying composition is carried out using the C57BL/6 mouse for inoculating lewis lung cancer
Fruit evaluation.Tumor-bearing mice stomach-filling is given according to the qf oral administration dosage of 35mg/kg and 30mg/kg respectively within second day after lotus knurl
Give chlorogenic acid from micro emulsion (preparation method with document Li Chen, Chang-shun Liu, Qing-zhen Chen, SenWang,
Yong-ai Xiong,Jing Jing,Jia-jia Lv.Characterization,pharmacokinetics and
tissue distribution of chlorogenic acid-loaded self-microemulsifying drug
Delivery system.European Journal of Pharmaceutical Sciences, 2017,100:102-108,
Abbreviation chlorogenic acid is from micro emulsion) and chlorogenic acid self-emulsifying composition (sample number into spectrum 1 in embodiment), stomach-filling oral normal saline conduct
Control, continuous gavage are administered 13 days, during which observe the state and weight of animal, and second day disconnected neck puts to death mouse after administration,
It strips tumor tissues to weigh, and compared with the knurl weight of control group, as tumor suppression efficiency rating.The results are shown in attached figure 3.
The results show that all experimental animals are in good condition, and weight is not decreased obviously during entire administration.Fig. 3
The results show that chlorogenic acid self-emulsifying composition disclosed by the invention is to the inhibitory rate of lewis lung cancer to 88.57 ± 0.17%,
And chlorogenic acid only has 50.24 ± 9.07% from the tumour inhibiting rate of micro emulsion.It is green in the case where dosage is less than chlorogenic acid from micro emulsion
The tumor suppression efficiency of ortho acid self-emulsifying composition is 1.76 times from micro emulsion of chlorogenic acid.
Test example 4: chlorogenic acid self-emulsifying composition investigates the inhibition tumor effect of the ICR mouse of subcutaneous lotus glioma
Chlorogenic acid self-emulsifying composition is carried out using the ICR mouse for inoculating G422 to imitate the tumor suppression of glioma
Fruit evaluation.It is positive right to give respectively according to the qf oral administration dosage of 30mg/kg to tumor-bearing mice stomach-filling within second day after lotus knurl
According to Cytoxan (CTX, dosage) and chlorogenic acid self-emulsifying composition, (sample number into spectrum 1, dosage are respectively as follows: 20mg/ in embodiment
Kg, abbreviation CHA SME 20；40mg/kg, abbreviation CHA SME 40；60mg/kg, abbreviation CHA SME 60), stomach-filling takes orally physiology
Salt water is administered 13 days as control, continuous gavage.Chlorogenic acid raw material aqueous solution is injected intraperitoneally simultaneously, and (dosage is respectively as follows: 10mg/
Kg, abbreviation CHA 10；20mg/kg, abbreviation CHA 20；40mg/kg, abbreviation CHA 40.) as a comparison.Period observes animal
State and weight, second day disconnected neck puts to death mouse after administration, strips tumor tissues and weighs, and the knurl weight with control group
It compares, as tumor suppression efficiency rating.The results are shown in attached figure 4.
The results show that all experimental animals are in good condition, and weight is not decreased obviously during entire administration.Fig. 4
The results show that chlorogenic acid self-emulsifying composition (CHA SME 20, CHA SME 40 and CHA SME 60) disclosed by the invention is right
The inhibitory rate of the I CR mouse of G422 is inoculated to 30.71 ± 6.42%, 20.17 ± 8.94% and 33.46 ± 5.97%,
The intraperitoneal injection group of effect and chlorogenic acid raw material medicine solution quite (CHA 10:31.7 ± 8.07%；CHA 20:27.82±
9.0%；CHA 40:23.82 ± 4.92%).
Test example 5: chlorogenic acid self-emulsifying composition investigates the inhibition tumor effect of the ICR mouse of glioma in situ
Chlorogenic acid self-emulsifying composition is carried out using the ICR mouse of in-situ inoculating G422 to imitate the tumor suppression of glioma
Fruit evaluation.Positive control drug Temozolomide (TMZ, 50mg/kg) is given to tumor-bearing mice stomach-filling respectively within second day after lotus knurl
(sample number into spectrum 1, dosage are respectively 20mg/kg and 35mg/kg, abbreviation: CHA in embodiment with chlorogenic acid self-emulsifying composition
SME20mg/kg and CHA SME 35mg/kg), stomach-filling oral normal saline is administered 13 days as control, continuous gavage.In addition,
Simultaneously using intraperitoneal administration chlorogenic acid raw material medicine solution (dosage is respectively 10mg/kg and 20mg/kg, referred to as: CHA10mg/kg and
CHA 20mg/kg) as control.Period observes the state and weight of animal, and the gross tumor volume size of animal is measured after administration,
As tumor suppression efficiency rating.The results are shown in attached figure 5.
The results show that all experimental animals are in good condition, and weight is not decreased obviously during entire administration.Fig. 5
The results show that chlorogenic acid self-emulsifying composition (CHA SME 35mg/kg) disclosed by the invention is small to the ICR of in-situ inoculating G422
The inhibitory rate of mouse is to 54.8%, hence it is evident that better than chlorogenic acid bulk pharmaceutical chemicals intraperitoneal injection group (CHA 10mg/kg, 27.1%；CHA
20mg/kg, 45.6%).
To sum up, the self-emulsifying composition of chlorogenic acid administration nano-drug administration system of the present invention, is placed not under the conditions of room temperature and 2-8 DEG C
It will appear solidification or lamination, can be used for being administered orally, mucosa delivery, percutaneous dosing, intestinal canal administration or Neulized inhalation system
The preparation of agent.Gastroenteric environment after simulation oral administration, the water of 10-1000 times of volume of composition, difference pH buffer, manually
Gastric juice or simulated intestinal fluid are diluted, and are slightly shaken, and can quickly form average grain diameter in 500nm nanoscale administration below
System.Self-emulsifying composition and its preparation of the invention, can be used for antitumor, anti inflammatory immunity and antiviral treatment.
Claims (21)
1. a kind of self-emulsifying composition of chlorogenic acid administration nano-drug administration system, which is characterized in that it is by chlorogenic acid and matrix material
The compound of formation, oily phase, emulsifier and assistant for emulsifying agent composition；The emulsifier is LABRAFIL M 1944CS and its derivative
Any one or a few.
2. self-emulsifying composition according to claim 1, which is characterized in that the chlorogenic acid matrix material compound is answered
Conjunction rate is greater than 70%, preferably greater than 80%, more preferably greater than 90%.
3. self-emulsifying composition according to claim 1, which is characterized in that the composition Content of Chlorogenic Acid is 5-
200mg/g。
4. self-emulsifying composition according to claim 3, which is characterized in that the composition Content of Chlorogenic Acid is 10-
150mg/g。
5. chlorogenic acid self-emulsifying composition according to claim 1, which is characterized in that the chlorogenic acid matrix material is compound
The molar ratio of object Content of Chlorogenic Acid and matrix material is 1:0.25~1:8, preferably 1:0.25~1:4.
6. chlorogenic acid self-emulsifying composition according to claim 1 or 5, which is characterized in that the matrix material is selected from gallbladder
Sterol, phospholipid or cholic acid salt；It is preferred that phospholipid.
7. chlorogenic acid self-emulsifying composition according to claim 6, which is characterized in that the phospholipid be soybean lecithin,
Yolk phospholipid, phosphatidyl glycerol ester, Distearoyl Phosphatidylcholine, dipalmitoylphosphatidylcholine, two palmityl phosphatidyl second
Hydramine, two nutmeg phosphatidyl cholines, any one or a few in ceramide；It is preferred that soybean lecithin and/or yolk phosphorus
Rouge.
8. self-emulsifying composition according to claim 1, which is characterized in that the oil phase, emulsifier and assistant for emulsifying agent matter
Percentage is measured, based on three's summation 100%, oil is mutually 10-50%, emulsifier 30-60%, assistant for emulsifying agent 20-60%.
9. chlorogenic acid self-emulsifying composition according to claim 1, which is characterized in that the LABRAFIL M 1944CS is derivative
Object is Labraso, oleic acid LABRAFIL M 1944CS or linoleic acid LABRAFIL M 1944CS.
10. chlorogenic acid self-emulsifying composition according to claim 1 or 8, which is characterized in that it is described oil mutually be soybean oil,
Corn oil, olive oil, coconut oil, peanut oil, camellia oil, castor oil, oleic acid sorbitol ester, olein, linoleic acid
Ester, labrafil1944cs, Maisine35-1, ethyl oleate, ethyl linoleate, C8/C10Monoglyceride, coconut oil C8/C10It is sweet
Oily dibasic acid esters, coconut oil C8/C10Triglycerides, Trivent OCG, Sunfat GDC-S, sad monoglyceride, capric acid glycerol list
Ester, capric acid diglyceride, Triglyceride DDD, pungent capric acid monoglyceride, Glycerin, mixed triester with caprylic acid capric acid, pungent Triglyceride DDD, Pork and beans
Cool isopropyl propionate, linoleic acid LABRAFIL M 1944CS, any one or a few in Gelucire, Capryol90；It is preferred that oil
Acetoacetic ester, oleic acid sorbitol ester, olein, glyceryl linoleate, labrafil1944cs, Maisine35-1, linoleic acid
Ethyl ester, C8/C10Monoglyceride, coconut oil C8/C10Diglyceride, coconut oil C8/C10Triglycerides, Trivent OCG, octanoic acid
Diglyceride, sad monoglyceride, capric acid monoglyceride, capric acid diglyceride, Triglyceride DDD, pungent capric acid monoglyceride,
Glycerin, mixed triester with caprylic acid capric acid, pungent Triglyceride DDD, isopropyl myristate, linoleic acid LABRAFIL M 1944CS, Gelucire,
Any one or a few in Capryol90.
11. chlorogenic acid self-emulsifying composition according to claim 1 or 8, which is characterized in that the assistant for emulsifying agent is carbonic acid
Propylene diester, ethylene glycol monomethyl ether, glycerol furfural, Dimethyl isosorbide, diethylene glycol monoethyl ether, PEG400, glycerol,
Any one or a few in labraosol, benzyl alcohol；It is preferred that Dimethyl isosorbide, diethylene glycol monoethyl ether, glycerol,
Any one or a few in labraosol.
12. chlorogenic acid self-emulsifying composition according to claim 1, which is characterized in that it further includes antioxidant；It is described anti-
Oxygen agent be vitamin E, vitamin-e ester analog derivative or dibutyl hydroxy toluene any one or a few.
13. a kind of self-emulsifying composition method for preparing the described in any item chlorogenic acid administration nano-drug administration systems of claim 1-12,
It is characterized in that, it includes the following steps:
(1) it prepares the compound of chlorogenic acid and matrix material: weighing chlorogenic acid and matrix material according to the ratio, be dissolved in organic solvent
In, mix, stand 15-30min, rotary evaporation or spray drying removal organic solvent, then be dried under reduced pressure to get；
(2) prepare blank self-emulsifying concentrate: weigh oily phase, emulsifier and assistant for emulsifying agent according to the ratio, be uniformly mixed to get；
(3) it prepares chlorogenic acid self-emulsifying composition: step (1) compound is added in step (2) concentrate, dissolution is complete, i.e.,
?；
Or:
Step (1) compound is added together with oily phase, emulsifier and assistant for emulsifying agent according to the ratio, be uniformly mixed to get；
Or:
First step (1) compound and any one dissolution in oily phase, emulsifier or assistant for emulsifying agent are mixed according to the ratio, added another
Outer two kinds of ingredients mix to get.
14. preparation method according to claim 13, which is characterized in that step (1) organic solvent is low mass molecule alcohol
Class；The low molecule alcohol is ethyl alcohol, dehydrated alcohol, any one or a few in the tert-butyl alcohol；It is preferred that dehydrated alcohol.
15. preparation method according to claim 13, which is characterized in that step (3) is described to be dissolved as shaking dissolution, shaking
Temperature is room temperature, speed 210rpm.
16. a kind of chlorogenic acid preparation, which is characterized in that it is the chlorogenic acid self-emulsifying as described in claim 1-12 any one
Composition, in addition the preparation of pharmaceutically acceptable carrier composition.
17. preparation according to claim 16, which is characterized in that the preparation is oral preparation, mucosa delivery preparation, warp
Skin drug-delivery preparation, intestinal canal administration preparation or Neulized inhalation preparation.
18. preparation according to claim 17, which is characterized in that the oral preparation be tablet, granule, capsule,
Oral solution, drops or spray；The mucosa delivery preparation or percutaneous drug administration preparation are paint, spray or other suitable dosage forms；Institute
Intestinal canal administration preparation is stated to be liquid preparation or be dissolved in oleaginous base suppository is made.
19. preparation according to claim 18, which is characterized in that the tablet, granule or capsule are by chlorogenic acid
Self-emulsifying composition is dispersed on superfine silica gel powder or other adsorptive solid materials, along with acceptable auxiliary material system on medicament
At.
20. preparation according to claim 17, which is characterized in that the Neulized inhalation is by chlorogenic acid self-emulsifying with preparation
The concentrated solution for Neulized inhalation is made in composition packing.
21. chlorogenic acid self-emulsifying composition described in claim 1-12 any one or claim 16-20 any one
The chlorogenic acid preparation is in preparation treatment and/or prevention malignant tumour, immunocompromised, bacteriovirus infection and/or anti-oxidant
Drug in purposes.
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| CN201910523981.0A CN110179750A (en) | 2019-06-17 | 2019-06-17 | A kind of chlorogenic acid self-emulsifying composition and application thereof |
| PCT/CN2020/096427 WO2020253689A1 (en) | 2019-06-17 | 2020-06-16 | Chlorogenic acid self-emulsifying composition and use thereof |
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| WO2020253689A1 (en) * | 2019-06-17 | 2020-12-24 | 四川九章生物科技有限公司 | Chlorogenic acid self-emulsifying composition and use thereof |
| CN113143903A (en) * | 2021-04-14 | 2021-07-23 | 天津中医药大学 | Application of chlorogenic acid-containing pharmaceutical composition in preparation of antiviral drugs |
| CN113509439A (en) * | 2021-07-12 | 2021-10-19 | 博睿先锋(北京)生物科技有限公司 | Application of self-emulsifying delivery system in preparation of oral medicine for treating lymphatic metastasis tumor |
| CN113827566A (en) * | 2020-06-24 | 2021-12-24 | 中国医学科学院药物研究所 | Chlorogenic acid-lipid complex liposome and preparation method and application thereof |
| CN114504563A (en) * | 2022-02-23 | 2022-05-17 | 博睿先锋(北京)生物科技有限公司 | Chlorogenic acid self-emulsifying composition capsule and preparation method thereof |
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| CN112716898A (en) * | 2021-02-22 | 2021-04-30 | 青岛康地恩动物药业有限公司 | Tilmicosin self-emulsifying oral preparation and preparation method thereof |
| CN113041352B (en) * | 2021-03-11 | 2023-01-17 | 天津中医药大学 | Chlorogenic acid-containing pharmaceutical composition, preparation method and application thereof |
| CN114246827B (en) * | 2022-01-04 | 2023-04-11 | 中山大学 | Fish oil microemulsion preparation and preparation method thereof |
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| CN113509439A (en) * | 2021-07-12 | 2021-10-19 | 博睿先锋(北京)生物科技有限公司 | Application of self-emulsifying delivery system in preparation of oral medicine for treating lymphatic metastasis tumor |
| CN114504563A (en) * | 2022-02-23 | 2022-05-17 | 博睿先锋(北京)生物科技有限公司 | Chlorogenic acid self-emulsifying composition capsule and preparation method thereof |
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| WO2020253689A1 (en) | 2020-12-24 |
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