CN116509916A - Erigeron breviscapus active site liposome, and preparation method and application thereof - Google Patents
Erigeron breviscapus active site liposome, and preparation method and application thereof Download PDFInfo
- Publication number
- CN116509916A CN116509916A CN202310714108.6A CN202310714108A CN116509916A CN 116509916 A CN116509916 A CN 116509916A CN 202310714108 A CN202310714108 A CN 202310714108A CN 116509916 A CN116509916 A CN 116509916A
- Authority
- CN
- China
- Prior art keywords
- active site
- liposome
- erigeron breviscapus
- dicaffeoyl quinic
- quinic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- UFCLZKMFXSILNL-PSEXTPKNSA-N Isochlorogenic acid b Chemical compound O([C@@H]1C[C@@](O)(C[C@H]([C@H]1OC(=O)\C=C\C=1C=C(O)C(O)=CC=1)O)C(O)=O)C(=O)\C=C\C1=CC=C(O)C(O)=C1 UFCLZKMFXSILNL-PSEXTPKNSA-N 0.000 claims abstract description 57
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
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Abstract
The invention discloses erigeron breviscapus active site liposome, which consists of 80-95 parts of flavonoids compounds and 105-120 parts of caffeic acid ester compounds, wherein the flavonoids compounds are extracted and converted from erigeron breviscapus according to parts by weight, and the flavonoids compounds are prepared from the following components in parts by weight: the flavonoid compound contains 50-65% of high baicalein by mass, the caffeic acid ester compound contains 10-20% of 4, 5-dicaffeoyl quinic acid by mass, and 5-20% of 3, 4-dicaffeoyl quinic acid by mass, and the drug loading rate of the erigeron breviscapus active site in the liposome is 0.8-1.2mg/ml. The active site liposome has the biological activities of improving hypoxia tolerance, reducing vascular resistance, inhibiting platelet aggregation, inhibiting thrombosis, reducing lipid peroxidation caused by hypoxia reoxygenation and the like, has a therapeutic effect on whole brain ischemia and local brain ischemia, and is used in medicines, special foods and daily chemicals.
Description
Technical Field
The invention relates to the technical field of preparation of traditional Chinese medicine liposome, in particular to erigeron breviscapus active site liposome and a preparation method and application thereof.
Background
Erigeron breviscapus is a dried whole herb of erigeron breviscapus Erigeron breviscapus (vant.) Hand-Mazz of Compositae, and is collected in early flowering phase, and is distributed in regions such as Yunnan, sichuan, guizhou, guangxi, hunan, tibet, etc., wherein 95% of erigeron breviscapus is produced in Yunnan province, and is mainly distributed in regions such as red river, wen mountain, chuxiong, marble, yuxi, etc. of Yunnan. Erigeron breviscapus contains various active ingredients such as flavonoid, caffeic acid esters, aromatic acids, coumarin, pyrones and the like, has various physiological activities and functions such as free radical removal, antioxidation, thrombosis inhibition, platelet aggregation inhibition, cerebral ischemia reperfusion resistance and the like, and is widely applied to the clinic treatment of various diseases such as cardiovascular and cerebrovascular diseases, diabetes, renal lesions, low-oxygen pulmonary arterial hypertension, chronic pulmonary heart disease, rheumatoid arthritis, liver function damage and the like.
For a long time, the main substance foundation/active site around the development and application of erigeron breviscapus is flavonoid compounds represented by scutellarin/scutellarin. Modern pharmacological, pharmacodynamic and pharmacokinetic studies have shown that: scun itself has no pharmacological activity or low activity, can exert drug effect after entering organism, and has low absorption and bioavailability by oral administration. In view of obvious race, sex, age and administration route differences of organisms on scutellarin metabolic transformation, products on the market are developed around scutellarin/scutellarin active sites, the curative effects of the products have obvious individual differences, the development and application values are limited, and the maximum development and utilization can not be realized.
Modern phytochemistry and pharmacological studies have shown that: the caffeic acid esters compound derived from herba Erigerontis has the same/similar pharmacological activity as scutellarin/scutellarin, and part of the compounds have pharmacological activity obviously superior to that of scutellarin/scutellarin, and the content of the compounds in herba Erigerontis is far higher than that of flavonoid parts, and the compounds are also main active parts of herba Erigerontis. With the intensive research, it was found that there was in vitro interconversion between the individual isomers of the dicaffeoate compounds. Modern kinetic studies have shown that: after the dicaffeoate compound is absorbed into blood by the body, the blood concentration of the 3, 5-dicaffeoylquinic acid is rapidly depleted and disappears, the prototype compound detected in the blood plasma is mainly 4, 5-dicaffeoylquinic acid and 3, 4-dicaffeoylquinic acid, and the blood concentration of the 3, 5-dicaffeoylquinic acid and the blood concentration of the 4, 5-dicaffeoylquinic acid have obvious conditions of the depletion. The following is demonstrated: the caffeic acid ester compounds are converted by isomers after being absorbed into blood by organisms, and the compounds which exert the drug effect are 4, 5-dicaffeoyl quinic acid and 3, 4-dicaffeoyl quinic acid, and the two have definite development and application advantages. However, the caffeic acid ester compounds are not absorbed by oral administration, and have the problems of interconversion in vivo and in vitro, and the technical bottlenecks of unclear components, unknown mechanism, uncontrollable quality and the like exist in development and application.
In conclusion, the erigeron breviscapus flavonoid and caffeic acid esters have the problems of poor quality stability and controllability, low oral absorption, longer in-vivo conversion and metabolism processes, long effective time, large individual difference of curative effects and the like of main active sites, and the development and application of the erigeron breviscapus are greatly limited.
Disclosure of Invention
In order to solve the problems and the bottlenecks existing in the prior art, the invention provides erigeron breviscapus active site liposome and a preparation method thereof; also provides the application and the application of the active site liposome.
The invention provides erigeron breviscapus active site liposome which is realized by adopting the following technical scheme:
first, the invention provides erigeron breviscapus active site liposome. The erigeron breviscapus active site consists of 80-95 parts by weight of flavonoid compounds extracted and converted from erigeron breviscapus and 105-120 parts by weight of caffeic acid ester compounds; the flavonoid compound is high baicalein, scutellarin and scutellarin, and the caffeic acid ester compound is 4, 5-dicaffeoyl quinic acid, 3, 4-dicaffeoyl quinic acid, 3, 5-dicaffeoyl quinic acid and 1, 5-dicaffeoyl quinic acid; the weight percentage of high baicalein in the flavonoid compound is 50-65%, the weight percentage of 4, 5-dicaffeoyl quinic acid in the caffeic acid ester compound is 10-20%, and the weight percentage of 3, 4-dicaffeoyl quinic acid is 5-20%; the drug loading rate of the active site of the liposome erigeron breviscapus is 0.8-1.2mg/ml.
Preferably, the erigeron breviscapus active site consists of 84-92 parts of flavonoid compounds and 108-116 parts of caffeic acid ester compounds, wherein the flavonoid compounds are extracted and converted from erigeron breviscapus in parts by weight; the flavonoid compound is high baicalein, scutellarin, and the caffeic acid ester compound is 4, 5-dicaffeoyl quinic acid, 3, 4-dicaffeoyl quinic acid, and 3, 5-dicaffeoyl quinic acid; the flavonoid compound contains 55-62% of high baicalein by mass, the caffeic acid ester compound contains 12-17% of 4, 5-dicaffeoyl quinic acid by mass and 9-18% of 3, 4-dicaffeoyl quinic acid by mass; the drug loading rate of the active site of the liposome erigeron breviscapus is 0.9-1.1mg/ml.
The erigeron breviscapus active site liposome is prepared according to the following steps:
(1) Extracting and separating erigeron breviscapus: pulverizing herba Erigerontis, percolating with 40-70% ethanol, collecting percolate, concentrating at 60deg.C under reduced pressure to 25deg.C to obtain a relative density of 0.92-1.10, purifying with macroporous resin, eluting with 65 deg.C hot water, eluting with 50% ethanol, collecting ethanol eluate, concentrating at 60deg.C under reduced pressure to 25deg.C to obtain a relative density of 0.92-1.10, extracting with ethyl acetate for 3 times, and collecting ethyl acetate extract and mother liquor after extraction;
(2) Preparation of erigeron breviscapus active site: concentrating the ethyl acetate extract collected in the step (1) to one fifth of the original volume at 60 ℃ under reduced pressure, adding ethanol with the concentration of 40-70% of the same volume, refluxing for 1.5-2.0 hours under heat, concentrating under reduced pressure, and drying to obtain caffeic acid ester compounds; adding hydrochloric acid into the extracted mother solution collected in the step (1) to adjust the pH to 1-2, standing for 24 hours, preparing a solution of 20mg/ml by using 95% ethanol for precipitation, adjusting the pH to be neutral by using 20% NaOH, and adding concentrated hydrochloric acid according to the mass ratio: ethylene glycol: reacting the water=1:10:10 solution at 90-120deg.C for 4-6 hr, filtering, and drying to obtain flavonoids; pulverizing the above materials at a certain proportion, mixing, and sieving with 100 sieve to obtain herba Erigerontis active site;
(3) Blank liposome preparation: hydrogenated soybean lecithin in molar ratio: cholesterol: polyethylene glycol=20-60:5-40:5 is lipid, adding hydration medium after fully dissolving with ethanol, stirring at 65deg.C for 45min, sequentially passing through 400nm, 200nm, 100nm, 50nm microporous filter membrane, and dialyzing with dialysis medium at 4deg.C overnight to obtain the final product;
(4) Preparation of erigeron breviscapus active site liposome: adding solubilization buffer solution into the erigeron breviscapus active site prepared in the step (2), preparing into 1.6-1.9mg/ml saturated solution by ultrasonic at 50 ℃, adding the preheated blank liposome prepared in the step (3) into the solution to prepare medicine carrying concentration, incubating for 45min at 60 ℃ under heat preservation and stirring, pre-freezing for 12h at-20 ℃, and freeze-drying to obtain the erigeron breviscapus.
Preferably, the hydration medium adopted in the blank liposome preparation in the step (3) is a mixed solution of calcium acetate with the molar concentration of 300 mmol/L and the pH of 7.3-7.5 and hydroxypropyl-beta-cyclodextrin with the mass concentration of 20%; the dialysis medium is one of sucrose with 1% -10% and 4-hydroxyethyl piperazine ethane sulfonic acid with pH of 7.5.
Preferably, the solubilization buffer used in the step (4) is a mixed solution of 4-hydroxyethyl piperazine ethane sulfonic acid with a molar concentration of 300-500 mmol/l and a pH of 6.0-7.5 and hydroxypropyl-beta-cyclodextrin with a mass concentration of 15% -45%.
The invention also provides application and application of the erigeron breviscapus active site liposome, which is realized by the following technical scheme:
firstly, the erigeron breviscapus active site liposome provided by the invention has the biological activities of improving hypoxia tolerance, reducing vascular resistance, inhibiting platelet aggregation, inhibiting thrombosis and reducing brain tissue lipid peroxidation caused by hypoxia reoxygenation, has a therapeutic effect on whole brain ischemia and local brain ischemia, and is used in medicines, special foods and daily chemicals.
And then, the erigeron breviscapus active part provided by the invention is further prepared into tablets, capsules, granules, powder, soft capsules, dripping pills, oral liquid, injection, patches, cream and facial masks by adding or not adding auxiliary materials acceptable by medicines, special foods and daily chemicals.
Compared with the prior art, the erigeron breviscapus active site liposome has the following beneficial technical effects:
(1) The erigeron breviscapus active site liposome prepared by the invention has the advantages that through the complete technical scheme, the flavonoid compound mainly containing erigeron breviscapus is converted into the flavonoid compound mainly containing erigeron breviscapus, the dicaffeate isomer mainly containing 3, 5-dicaffeoylquinic acid is converted into the caffeic acid ester compound mainly containing 4, 5-dicaffeoylquinic acid and 3, 4-dicaffeoylquinic acid, and after administration, the efficacy is directly exerted without the need of metabolic conversion of the organism, so that the effective time is obviously shortened, and the individual difference caused by different metabolism of the organism is avoided;
(2) The erigeron breviscapus active site liposome prepared by the invention combines the converted flavonoid and caffeic acid ester specific composition substances according to a specific proportion by a specific technical scheme, and further prepares the liposome with specific drug loading capacity, thus blocking the in vitro conversion of each compound (particularly dicaffeoyl quinic acid isomer) at the active site, realizing stable and efficient absorption by oral administration, and having the characteristics of clear ingredients, clear mechanism, stable and controllable quality, safe and effective use and the like;
(3) The erigeron breviscapus active site liposome prepared by the invention has the advantages of obviously improving pharmacological activity, shortening effective time and having extremely important significance for acute and serious diseases such as stroke (brain collateral stasis) and the like by synergism of multiple components (mainly comprising the biologically active compounds such as high baicalein, 4, 5-dicaffeoyl quinic acid and 3, 4-dicaffeoyl quinic acid which directly exert the drug effect are confirmed by modern pharmacokinetics researches), multiple targets (different acting targets of flavonoids and caffeoyl esters) and multiple mechanisms (obvious difference of pharmacological action mechanisms of the compounds).
Detailed Description
The invention is further illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are for illustration only and are not intended to limit the scope of the invention in any way, and that any changes or substitutions made thereto are intended to be within the scope of the invention.
Example 1 erigeron breviscapus extraction separation
Taking erigeron breviscapus dried whole herb, crushing and sieving with a 20-mesh sieve, and detecting: the total flavone content is 2.2% and the total caffeic acid ester content is 3.8%.
Pulverizing herba Erigerontis, percolating with 70% ethanol, collecting percolate, concentrating at 60deg.C under reduced pressure to 25deg.C to obtain a relative density of 1.10, purifying the concentrate with macroporous resin, eluting with 65deg.C hot water, eluting with 50% ethanol, collecting ethanol eluate, concentrating at 60deg.C under reduced pressure to 25deg.C to obtain a relative density of 1.10, extracting with ethyl acetate for 3 times, collecting ethyl acetate extract and mother liquor after extraction;
example 2 preparation of caffeic acid esters
1 liter of ethyl acetate extract liquid collected in the example 1 is taken, concentrated and dried to prepare caffeic acid ester compound I;
the remaining ethyl acetate extract of example 1 was concentrated to one fifth of the original volume at 60℃under reduced pressure, and then an equal volume of 40% ethanol was added thereto and heated to reflux for 2.0 hours, and concentrated under reduced pressure and dried to obtain caffeic acid ester compound II. And (3) detecting: the mass percent of the 4, 5-dicaffeoylquinic acid is 14.43 percent, and the mass percent of the 3, 4-dicaffeoylquinic acid is 17.53 percent.
EXAMPLE 3 preparation of flavonoid
1 liter of extracted mother liquor collected in the example 1 is taken, concentrated and dried to prepare the flavonoid compound I;
example 1 the mother liquor after the residual extraction was adjusted to pH 1.5 by adding hydrochloric acid, standing for 24 hours, precipitating with 95% ethanol to give a 20mg/ml solution, adjusting pH to neutral with 20% NaOH, and concentrating hydrochloric acid in mass ratio: ethylene glycol: the water=1:10:10 solution reacts for 5 hours at the temperature of 105 ℃, and the flavonoid compound II is obtained after filtering and drying. And (3) detecting: the mass percentage of the high baicalein is 59.29 percent.
EXAMPLE 4 preparation of active site I
105g of the caffeoyl ester compound II prepared in example 2 and 95g of the flavonoid compound II prepared in example 3 are respectively taken, crushed, mixed and sieved by a 100-mesh sieve to prepare an active site I.
EXAMPLE 5 preparation of active site II
107.5g of the caffeoyl ester compound II prepared in example 2 and 87.5g of the flavonoid compound II prepared in example 3 are respectively taken, and the active site II is prepared by crushing, mixing and sieving with a 100-mesh sieve.
EXAMPLE 6 preparation of active site III
117g of the caffeoyl ester compound II prepared in example 2 and 83g of the flavonoid compound II prepared in example 3 are respectively taken, crushed, mixed and sieved by a 100-mesh sieve to prepare an active site III.
EXAMPLE 7 preparation of active site IV
139.5g of the caffeoyl ester compound II prepared in example 2 and 160.5g of the flavonoid compound II prepared in example 3 are respectively taken, crushed, mixed and sieved by a 100-mesh sieve to prepare an active site IV.
EXAMPLE 8 blank Liposome I preparation
Hydrogenated soybean lecithin in molar ratio: cholesterol: polyethylene glycol=54:35:5 is lipid, after being fully dissolved by ethanol, 300mM calcium acetate with pH=7.4 and 20% hydroxypropyl-beta-cyclodextrin mixed solution are added, the mixture is stirred for 45min at 65 ℃, and then sequentially passes through 400nm, 200nm, 100nm and 50nm microporous filter membranes, and 4-hydroxyethyl piperazine ethane sulfonic acid with pH=7.5 is used as a dialysis medium for dialysis at 4 ℃ for overnight, thus obtaining the product.
EXAMPLE 9 blank Liposome II preparation
Hydrogenated soybean lecithin in molar ratio: cholesterol: polyethylene glycol=60:21:5 is lipid, after being fully dissolved by ethanol, 300mM calcium acetate with pH=7.5 and 20% hydroxypropyl-beta-cyclodextrin mixed solution are added, stirred for 45min at 65 ℃, sequentially pass through 400nm, 200nm, 100nm and 50nm microporous filter membranes, and are dialyzed overnight at 4 ℃ by using 10% sucrose as a dialysis medium, thus obtaining the product.
EXAMPLE 10 preparation of active site Liposome I
Taking erigeron breviscapus active site II prepared in example 5, adding 400mM of mixed solution of 4-hydroxyethyl piperazine ethane sulfonic acid with pH=6.0 and 30% hydroxypropyl-beta-cyclodextrin, preparing into 1.8mg/ml saturated solution by ultrasonic at 50 ℃, adding the preheated blank liposome I prepared in example 8 to prepare medicine carrying concentration, preserving heat, stirring and incubating for 45min at 60 ℃, pre-freezing for 12h at-20 ℃, and freeze-drying to obtain the erigeron breviscapus active site II. And (3) detecting: the drug loading rate of the liposome erigeron breviscapus active site is 0.95mg/ml.
EXAMPLE 11 preparation of active site Liposome II
Taking erigeron breviscapus active site III prepared in example 6, adding 300mM of mixed solution of 4-hydroxyethyl piperazine ethane sulfonic acid with pH=6.5 and 20% hydroxypropyl-beta-cyclodextrin, preparing into 1.6mg/ml saturated solution by ultrasonic at 50 ℃, adding the preheated blank liposome II prepared in example 9 to prepare medicine carrying concentration, preserving heat at 60 ℃, stirring and incubating for 45min, pre-freezing for 12h at-20 ℃, and freeze-drying to obtain the erigeron breviscapus active site III. And (3) detecting: the drug loading rate of the liposome erigeron breviscapus active site is 0.9mg/ml.
EXAMPLE 12 preparation of active site Liposome III
Taking erigeron breviscapus active site IV prepared in example 7, adding 400mM of mixed solution of 4-hydroxyethyl piperazine ethane sulfonic acid with pH=6.0 and 30% hydroxypropyl-beta-cyclodextrin, preparing into saturated solution by ultrasonic at 50 ℃, adding preheated blank liposome I in example 8, incubating for 45min at 60 ℃ with heat preservation and stirring, pre-freezing for 12h at-20 ℃, and freeze-drying to obtain the erigeron breviscapus active site IV. And (3) detecting: the drug loading rate of the liposome erigeron breviscapus active site is 0.76mg/ml.
Example 13 preparation of granules
50g of the active site liposome I prepared in example 10 is weighed, a proper amount of lactose and pregelatinized starch are added, and the granules are prepared by granulating, drying and finishing.
Example 14 tablet preparation
50g of the active site liposome I prepared in example 10 was weighed, and a proper amount of pregelatinized starch, dextrin and microcrystalline cellulose was added, followed by mixing, granulating, drying and tabletting to prepare tablets.
EXAMPLE 15 hard capsule preparation
100g of active site II prepared in example 11 is weighed, a proper amount of lactose, microcrystalline cellulose, silicon dioxide and magnesium stearate are added, and the mixture is mixed, granulated and filled to prepare the hard capsule.
EXAMPLE 16 preparation of lyophilized powder for injection
150g of the active site II prepared in example 11 is weighed, sodium bicarbonate, sodium chloride, mannitol and water for injection are added, and the freeze-dried powder injection is prepared through dissolution, filtration, encapsulation, sterilization and freeze-drying.
For further explanation of the present invention, caffeic acid ester compound i prepared in example 2, caffeic acid ester compound ii prepared in example 2, flavonoid compound i prepared in example 3, flavonoid compound ii prepared in example 3, active site ii prepared in example 5, active site iv prepared in example 7, active site liposome i prepared in example 10, and active site liposome iii prepared in example 12 were selected as test samples, numbered (1), (2), (3), (4), (5), (6), (7), and (8). Carrying out the isomer conversion investigation, flavonoid scutellarin conversion investigation, active site stability test, active site liposome bioavailability test and brain ischemia influence test of active site and liposome on caffeic acid ester compounds, and comparing the results, wherein the specific steps are as follows:
1. conversion investigation of caffeic acid ester compound isomer
And (2) selecting the samples as test samples, and respectively detecting the content of 3, 5-dicaffeoyl quinic acid, 4, 5-dicaffeoyl quinic acid and 3, 4-dicaffeoyl quinic acid, wherein the results are shown in table 1.
TABLE 1 results of investigation of the conversion of isomers of caffeic acid esters
Table 1 shows: compared with the sample group (1), the content of the 3, 5-dicaffeoyl quinic acid, the content of the 4, 5-dicaffeoyl quinic acid and the content of the 3, 4-dicaffeoyl quinic acid in the sample group (2) prepared by the specific technical scheme of the invention are obviously changed. Wherein: the 3, 5-dicaffeoylquinic acid content is reduced by 41.5%, the 4, 5-dicaffeoylquinic acid content is increased by 4.78 times, and the 3, 4-dicaffeoylquinic acid content is increased by 1.19 times.
It is hereby assumed that: the special technical scheme of the invention can obviously promote the conversion between isomers of the dicaffeate compounds derived from erigeron breviscapus medicinal materials, and convert 3, 5-dicaffeoylquinic acid into 4, 5-dicaffeoylquinic acid and 3, 4-dicaffeoylquinic acid.
2. Conversion investigation of flavonoids scutellarin
Samples (3) and (4) are selected as test samples, and the scutellarin and high baicalein contents are detected respectively, and the results are shown in Table 2.
TABLE 2 results of flavonoid scutellarin conversion investigation
Table 2 shows: compared with the sample group (3), the content of scutellarin and high baicalein in the sample group (4) prepared by the specific technical scheme of the invention is obviously changed. Wherein: the scutellarin content is reduced by 90.08%, while the high baicalein content is increased by 35.93 times.
It is hereby assumed that: the preparation of the specific technical scheme of the invention can obviously promote the scutellarin from erigeron breviscapus medicinal materials to be greatly converted into high baicalein.
3. Active site stability test
Samples (5) and (6) are selected as test samples, a proper amount of the test samples are weighed and placed in clean and airtight transparent glass bottles respectively, and the test samples are placed in a stability investigation box with the temperature of (40+/-2) ℃ and the relative humidity of (75+/-5) percent according to the principle of guiding stability test of bulk drugs and preparations (four parts 9001 of the 2020 edition of Chinese pharmacopoeia), and the content detection of the high baicalein, scutellarin, 3, 4-dicaffeoyl quinic acid, 4, 5-dicaffeoyl quinic acid and 3, 5-dicaffeoyl quinic acid is carried out in 0 days, 30 days, 60 days and 90 days, and the results are shown in table 3.
TABLE 3 examination of active site stability
Table 3 shows: in the 90-day stability study, the index component contents of both sample groups were varied to different extents. Wherein: the content of each compound in sample group (5) was not significantly changed. The content of the flavonoid compound high baicalein in the sample group (6) is obviously reduced, and the content of scutellarin is obviously increased; the content of the caffeic acid ester compound 3, 5-dicaffeoyl quinic acid is obviously increased, and the content of 3, 4-dicaffeoyl quinic acid and 4, 5-dicaffeoyl quinic acid is obviously reduced.
It is hereby assumed that: the active site (sample (5)) prepared by the specific technical scheme of the invention blocks the mutual conversion between flavonoid and caffeic acid ester compounds, and realizes the technical effects of clear components and stable and controllable quality. The flavonoid compounds and caffeic acid ester compounds prepared by the technical scheme of the invention are combined with the active part (sample group (6)) by the technical scheme of the invention, and the possibility of mutual conversion still exists.
4. Active site liposome stability assay
Samples (7) and (8) were selected as test samples, the free drugs were removed, and the samples were stored at 4℃and the encapsulation efficiency was measured by sampling for 0, 30, 60 and 90 days, respectively, and the results are shown in Table 4.
TABLE 4 results of active site liposome stability (encapsulation efficiency) investigation
Table 4 shows: in the 90-day stability study, the encapsulation efficiency was reduced to a different extent for both groups of samples, wherein: sample (7) had only 7.6% drug leakage in the 90 day study test, while sample (8) had 20.7% drug leakage. The invention shows that the stability of the erigeron breviscapus active site liposome prepared by the complete technical scheme is obviously improved.
5. Active site liposome bioavailability assay
Sample and grouping: commercial high baicalein, 3, 4-dicaffeoylquinic acid and 4, 5-dicaffeoylquinic acid standard substances are used as reference substances, and samples (5) and (7) are selected as test samples.
Animals: the test animals were randomly divided into 2 groups of 24 healthy rabbits weighing about 3kg, each group of 12 animals, and marked. Fasted 12 hours before and during the test, and only drunk freely.
Dose design:
the oral clinical recommended dose of the active site liposome of the invention is 120mg (calculated by active site), wherein: contains 40mg of high baicalein, 12mg of 3, 4-dicaffeoylquinic acid and 11.6mg of 4, 5-dicaffeoylquinic acid. Calculated according to the weight of a 60kg adult, the dosage is 2 mg/(kg.d), the dosage of the converted rabbit is 2.8 mg/(kg.d), namely, the dosage of the rabbit high baicalein is 0.93 mg/(kg.d), the dosage of the 3, 4-dicaffeoylquinic acid is 0.28 mg/(kg.d), and the dosage of the 4, 5-dicaffeoylquinic acid is 0.27 mg/(kg.d).
According to the principle of equal dose comparison, the administration dose of the sample group (5) is 2.8 mg/(kg.d), and the administration dose of the sample group (7) is 0.74 g/(kg.d).
The design of a test scheme is as follows:
the rabbits were fasted for 12 hours in advance before the test, only were free to drink water, then the above samples were dissolved and respectively subjected to gastric lavage and sample feeding, and after the sample feeding, the content of high baicalein, 3, 4-dicaffeoylquinic acid and 4, 5-dicaffeoylquinic acid in the blood plasma was densely measured, and half an hour after the time to peak plasma concentration was reached, the maximum plasma concentration (C max )。
After the test sample is filled into the stomach, stopping the medicine for one week until the sample in the animal body is completely metabolized. The standard substance solutions of high baicalein, 3, 4-dicaffeoylquinic acid and 4, 5-dicaffeoylquinic acid were then given in equal doses by intravenous injection, and the content (ng/mL) of each standard substance in plasma was determined, which was used as reference data to calculate the bioavailability, and the results are shown in table 5 in detail.
TABLE 5 bioavailability test results (mean)
Table 5 shows: the blood concentration of the sample (7) of the high baicalein, the 3, 4-dicaffeoylquinic acid and the 4, 5-dicaffeoylquinic acid in the blood plasma of the rabbit is obviously higher than that of the sample (5), and compared with the sample (5), the bioavailability of the high baicalein of the sample (7) is improved by 2.06 times, the bioavailability of the 3, 4-dicaffeoylquinic acid is improved by 2.56 times, and the bioavailability of the 4, 5-dicaffeoylquinic acid is improved by 2.70 times.
It is hereby assumed that: the active site liposome (sample (7)) prepared according to the complete technical scheme of the invention obviously improves the oral absorption bioavailability of the active site.
6. Test of influence of active site and Liposome on cerebral ischemia
Test animals: male gerbils provided by Shanghai pharmaceutical research laboratory of the national institute of sciences had a body weight of 79.+ -.10 g and a total of 50.
Grouping: the test consisted of 5 groups of 10 animals each. Wherein: one group was given normal saline as a blank control group by lavage, and samples (5), (6), (7) and (8) were selected as test groups.
Dose setting: the active site liposome of the invention is about to recommend clinical dose of 120mg (calculated by active site), calculated by 60kg body weight of adult, the dosage is 2 mg/(kg.d); the corresponding dose is 8.64 mg/(kg.d) according to the conversion of the body surface area of the gerbil. According to the principle of equal dose comparison, the dosage of the sample group (5) is 8.64 mg/(kg.d), the dosage of the sample group (6) is 8.64 mg/(kg.d), the dosage of the sample group (7) is 2.27 g/(kg.d), and the dosage of the sample group (8) is 2.84 g/(kg.d).
Sample liquid preparation: and respectively taking each group of samples, dissolving the samples by using 0.1% sodium carbonate solution, and preparing a test solution for later use.
The experimental method comprises the following steps: the mice were placed on a hot plate to maintain the body temperature at 37 ℃, anesthetized with diethyl ether, the skin of the central carotid line was incised, the common carotid arteries on both sides were isolated, and after ligation for 30min, reperfusion was performed. And after the molding is successful, the gastric lavage and the administration of the test liquid are carried out according to the dosage of each group of samples, and the administration frequency is single administration. The ischemia reperfusion behavior scoring criteria for the mice were as follows:
data and statistics: the animals were each observed for behavioural score and cumulative mortality after dosing for 2,4,6, 24 hours after ischemia reperfusion. Behavioural score data is expressed as x±sd and cumulative mortality is expressed as%. The results are shown in tables 6 and 7.
TABLE 6 influence on behavioral scoring after ischemia reperfusion of gerbils (x+ -SD)
Table 6 shows: following administration, the behavioural scores of each group of animals increased to varying degrees over time. The behavioral scores of the test animals in the sample groups (5), (6), (7) and (8) after ischemia reperfusion are obviously lower than that of the blank control group (P < 0.05) in 2h, 4h, 6h and 24 h; the behavioural scores of the test animals in sample group (7) after ischemia reperfusion were significantly lower than those in sample groups (5), (6) and (8) at 2h, 4h, 6h and 24h (P < 0.05).
TABLE 7 effect on cumulative mortality after ischemia reperfusion in gerbils
Table 7 shows: with increasing time after administration, the cumulative mortality of each group of animals increased to a different extent. Wherein: the cumulative mortality of the tested animals after 24 hours of administration of the blank control group is obviously higher than that of the other groups; the cumulative mortality of the tested animals after 24 hours of administration of the sample group (7) is obviously lower than that of the sample groups (5), (6) and (8).
Conclusion of the test: the erigeron breviscapus active site liposome (sample (7)) prepared according to the complete technical scheme of the invention has a protective effect on the whole brain ischemia injury caused by the cerebral ischemia reperfusion of the sargassum horneri, and can obviously reduce the behavioural score and the death rate of cerebral ischemia after the cerebral ischemia reperfusion.
In conclusion, the erigeron breviscapus active site liposome prepared by the complete technical scheme of the invention realizes the conversion of erigeron breviscapus from erigeron breviscapus medicinal materials into high baicalein, the conversion of 3, 5-dicaffeoyl quinic acid into 4, 5-dicaffeoyl quinic acid and 3, 4-dicaffeoyl quinic acid, and the blocking of the further conversion among various compounds, and has the characteristics of clear components, clear mechanism, stable and controllable quality, obviously improved oral absorption and bioavailability, obviously reduced behavioural score and mortality after cerebral ischemia reperfusion and the like.
Claims (6)
1. A erigeron breviscapus active site liposome, which is characterized in that: the erigeron breviscapus active site consists of 80-95 parts by weight of flavonoid compounds extracted and converted from erigeron breviscapus and 105-120 parts by weight of caffeic acid ester compounds; the flavonoid compound is high baicalein, scutellarin and scutellarin, and the caffeic acid ester compound is 4, 5-dicaffeoyl quinic acid, 3, 4-dicaffeoyl quinic acid, 3, 5-dicaffeoyl quinic acid and 1, 5-dicaffeoyl quinic acid; the weight percentage of high baicalein in the flavonoid compound is 50-65%, the weight percentage of 4, 5-dicaffeoyl quinic acid in the caffeic acid ester compound is 10-20%, and the weight percentage of 3, 4-dicaffeoyl quinic acid is 5-20%; the drug loading rate of the active site of the liposome erigeron breviscapus is 0.8-1.2mg/ml; the active site liposome is prepared by the following steps:
(1) Extracting and separating erigeron breviscapus: pulverizing herba Erigerontis, percolating with 40-70% ethanol, collecting percolate, concentrating at 60deg.C under reduced pressure to 25deg.C to obtain a relative density of 0.92-1.10, purifying with macroporous resin, eluting with 65 deg.C hot water, eluting with 50% ethanol, collecting ethanol eluate, concentrating at 60deg.C under reduced pressure to 25deg.C to obtain a relative density of 0.92-1.10, extracting with ethyl acetate for 3 times, and collecting ethyl acetate extract and mother liquor after extraction;
(2) Preparation of erigeron breviscapus active site: concentrating the ethyl acetate extract collected in the step (1) to one fifth of the original volume at 60 ℃ under reduced pressure, adding ethanol with the concentration of 40-70% of the same volume, refluxing for 1.5-2.0 hours under heat, concentrating under reduced pressure, and drying to obtain caffeic acid ester compounds; adding hydrochloric acid into the extracted mother solution collected in the step (1) to adjust the pH to 1-2, standing for 24 hours, preparing a solution of 20mg/ml by using 95% ethanol for precipitation, adjusting the pH to be neutral by using 20% NaOH, and adding concentrated hydrochloric acid according to the mass ratio: ethylene glycol: reacting the water=1:10:10 solution at 90-120deg.C for 4-6 hr, filtering, and drying to obtain flavonoids; pulverizing the above materials at a certain proportion, mixing, and sieving with 100 sieve to obtain herba Erigerontis active site;
(3) Blank liposome preparation: hydrogenated soybean lecithin in molar ratio: cholesterol: polyethylene glycol=20-60:5-40:5 is lipid, adding hydration medium after fully dissolving with ethanol, stirring at 65deg.C for 45min, sequentially passing through 400nm, 200nm, 100nm, 50nm microporous filter membrane, and dialyzing with dialysis medium at 4deg.C overnight to obtain the final product;
(4) Preparation of erigeron breviscapus active site liposome: adding solubilization buffer solution into the erigeron breviscapus active site prepared in the step (2), preparing into 1.6-1.9mg/ml saturated solution by ultrasonic at 50 ℃, adding the preheated blank liposome prepared in the step (3) into the required drug carrying concentration, incubating for 45min at 60 ℃ under heat preservation and stirring, pre-freezing for 12h at-20 ℃, and freeze-drying to obtain the erigeron breviscapus active site.
2. A erigeron breviscapus active site liposome according to claim 1, wherein: the erigeron breviscapus active site consists of 84-92 parts of flavonoids compounds and 108-116 parts of caffeic acid ester compounds, wherein the flavonoids compounds are extracted and converted from erigeron breviscapus, and the flavonoids compounds are extracted and converted from erigeron breviscapus; the flavonoid compound is high baicalein, scutellarin, and the caffeic acid ester compound is 4, 5-dicaffeoyl quinic acid, 3, 4-dicaffeoyl quinic acid, and 3, 5-dicaffeoyl quinic acid; the flavonoid compound contains 55-62% of high baicalein by mass, the caffeic acid ester compound contains 12-17% of 4, 5-dicaffeoyl quinic acid by mass and 9-18% of 3, 4-dicaffeoyl quinic acid by mass; the drug loading rate of the active site of the liposome erigeron breviscapus is 0.9-1.1mg/ml.
3. A erigeron breviscapus active site liposome according to any one of claims 1-2, wherein: the hydration medium adopted in the preparation of the blank liposome in the step (3) is a mixed solution of calcium acetate with the molar concentration of 300 mmol/L and the pH of 7.3-7.5 and hydroxypropyl-beta-cyclodextrin with the mass concentration of 20%; the dialysis medium is one of sucrose with 1% -10% and 4-hydroxyethyl piperazine ethane sulfonic acid with pH of 7.5.
4. A erigeron breviscapus active site liposome according to any one of claims 1-2, wherein: the solubilising buffer used in the step (4) is a mixed solution of 4-hydroxyethyl piperazine ethane sulfonic acid with the molar concentration of 300-500 mmol/L and the pH value of 6.0-7.5 and hydroxypropyl-beta-cyclodextrin with the mass concentration of 15-45%.
5. A erigeron breviscapus active site liposome according to any one of claims 1-2, wherein: the active site liposome has the biological activities of improving hypoxia tolerance, reducing vascular resistance, inhibiting platelet aggregation, inhibiting thrombosis, and reducing lipid peroxidation of brain tissue caused by hypoxia reoxygenation, and has therapeutic effects on whole brain ischemia and local brain ischemia, and can be used in medicines, special foods, and daily chemicals.
6. A erigeron breviscapus active site liposome according to claim 5, wherein: the active site liposome can be further prepared into tablets, capsules, granules, powder, soft capsules, dripping pills, oral liquid, injection, freeze-dried powder injection, patches, cream and facial masks by adding or not adding auxiliary materials acceptable by medicines, special foods and daily chemicals.
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