CN106137958A - A kind of compound apigenin nanoemulsion antihypertensive drug - Google Patents

A kind of compound apigenin nanoemulsion antihypertensive drug Download PDF

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CN106137958A
CN106137958A CN201610503132.5A CN201610503132A CN106137958A CN 106137958 A CN106137958 A CN 106137958A CN 201610503132 A CN201610503132 A CN 201610503132A CN 106137958 A CN106137958 A CN 106137958A
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apigenin
nanoemulsion
emulsion
antihypertensive drug
compound
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张鸿利
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Abstract

The invention discloses a kind of compound apigenin nanoemulsion antihypertensive drug, its raw material and mass percent thereof be: apigenin 1%～15%, surfactant 5%～35%, cosurfactant 1%～20%, oil 1%～20%, Fructus Leonuri water extract 0.5%～10%, cassia seed water extract 0.5%～10%, remaining composition is distilled water, and the mass percent sum of above-mentioned raw materials is 100%.This nano-emulsion emulsion droplet granule is little, be evenly distributed, viscosity is little, good fluidity.After apigenin is prepared as nano-emulsion dosage form, hence it is evident that add the ability through blood brain barrier, significantly improve the bioavailability of former medicine, extend the half-life of medicine, reduce administration number of times；Nano-emulsion improves medicine dissolution and the penetrating power of apigenin, increases the stability of apigenin；And after compounding with the water extract of Fructus Leonuri and Semen Cassiae, there is obvious synergism, curative effect of medication plays more abundant.

Description

A kind of compound apigenin nanoemulsion antihypertensive drug
Technical field
The invention belongs to field of medicaments, relate to the novel form of a kind of antihypertensive drug apigenin, multiple particularly to one Side's apigenin nanoemulsion antihypertensive drug.
Technical background
The chemical constitution of apigenin is 4,5,7-trihydroxyflavones, three hydroxyls of its 4,5,7 position and C2C3Double bond determines The pharmacological effect of its uniqueness and biological characteristics.Apigenin source samphire Herba Apii graveolentis (Apium graveolens Var.dulce) leaf；Selaginaceae Herba Selaginellae (Selaginella tamariscina) herb；Cupressaceae Chinese juniper (Sabina Chinensis) leaf.
Zhang etc. find, apigenin concentration more than 1 time to by high K cause remove endotheliocyte mouse aorta ring Contraction has obvious relexation [IC50For (12.0 ± 1.1) μM].Phyenlephrinium to no matter with or without endotheliocyte in vitro actively Circulus venosus has stable contraction, and apigenin is with dosage (1～12.5 μM) the dependence mode master to being caused by phyenlephrinium Aortic ring contraction produces relexation, the IC of the aortic annulus relexation that Human Umbilical Vein Endothelial Cells is complete50For (3.7 ± 0.5), to going IC except the aortic annulus relexation of endotheliocyte50For (8.2+0.9) 0M, the receipts that after removing apigenin, phyenlephrinium causes Contracting effect can recover completely.Apigenin suppresses by 12 the most in a dose-dependent manner, and 13-bis-butanoic acid phorbol causes removal endothelium Contraction of Aortic ring [the IC of cell50For (34.6 ± 1.2)].After adding apigenin 30min, acetylcholine the blood vessel caused [IC5o of 5 μMs of apigenins is (0.12 ± 0.07) μM, the IC of 2.5 μMs of apigenins in lax substantially reinforcement50For (0.68 ± 0.24)]. Further study show that, apigenin suppresses the vasoconstriction caused by phyenlephrinium and high K, and causes blood vessel to receive phorbol The diastole effect of contracting is more weak.Apigenin may not affect Protein kinase C mediation vasoconstrictor effects, but inductive formation certain The endotheliocyte source sexual stimulus factor, thus produce the papaverine effect that endotheliocyte relies on.
After deliberation, the protected action of the heart of apigenin and effect for the treatment of Parkinson's disease.Modern Herba Apii graveolentis kind is Wild species domestication from original Mediterranean swampy area.The stem of wild Herba Apii graveolentis, leaf contains protein component, exceeds well over cultivation product The Herba Apii graveolentis planted.
First wild Herba Apii graveolentis is used in medically, carries first in B.C. nineth century Homeric epic<<Odyssey>> Arrive.Chinese are in seventh century of Christian era, have obtained this plant of Herba Apii graveolentis from the gift that Nepal ruler sends here.But, directly To Middle Ages, Herba Apii graveolentis just extensively eats as vegetable.About start to be used as raw vegetable in 18th century in Europe to eat, 19 Beginning of the century guides to the U.S..
The Herba Apii graveolentis of China's the earth is divided into Herba Apii graveolentis and Herba Oenanthes Javanicae.Herba Apii graveolentis is born in nonirrigated farmland；Herba Oenanthes Javanicae is nutritious, and A sweety scent assails the nostrils.Herba Apii graveolentis Mouthfeel is poor, but medicinal function is relatively strong, such as weakness of the spleen and stomach.
Herba Apii graveolentis should eat leaf as far as possible, because the content of leaf mineral, vitamin, it will be apparent that in relatively petiole Content is to be enriched many.Petiole water content is high, heat low (17 kilocalories/100g)；Seed containing protein, fat, vitamin, calcium, Phosphorus, magnesium, potassium, ferrum and zinc, heat is high (392 kilocalories/100 grams).
Possibly together with Herba Apii graveolentis unit, majudin, saccharide, organic acid etc. in Herba Apii graveolentis, the volatile oil contained has a kind of α-celery Sub-alkene, has stable and spasmolytic effect to human brain nervus centralis；In volatile oil, another kind is butyl benzoic acid is the special gas of Apium petroselimum The source of taste.Containing multiple free amino acid, aromatic oil, mannose and multivitamin in Herba Oenanthes Javanicae, normal food not only can promote food It is intended to, also blood circulation promoting and brain strengthening function.Herba Apii graveolentis is America and Europe, it is believed that can eliminate edema, has diuresis to make because having eaten Herba Apii graveolentis With.
Herba Apii graveolentis has important component Herba Apii graveolentis unit, is again apigenin, can blood pressure lowering with affect nervus centralis.About Hypotensive Mechanism, It was initially believed that it is to cause through cephalic artery body and the reflection of the chemoreceptor of aortic arch.Blood vessel inculcates test, Proving that Herba Apii graveolentis unit also has the effect of certain expansion peripheral vessel, this also has certain relation with hypotensive effect.
Gavage Herba Apii graveolentis unit 700mg/kg can substantially reduce degree and the number of times of EEG of epileptic rats, extends incubation period.Brain shape State is studied, and there is certain protective effect in Herba Apii graveolentis unit to quader cortical cell, glial cell, and cerebellar cell.Herba Apii graveolentis unit The mouse peritoneal injection central that causes of tremorine can be resisted tremble.It is emerging that anti-***e can be caused by Oral Administration in Rats Herba Apii graveolentis unit Put forth energy.
Existing such as the antihypertensive drugs of apigenin suspendible liquor currently on the market, although after Kou Fu can from gastrointestinal absorption, but Infiltration rate is slow, absorb not exclusively, and additionally the dissolution rate of tablet Chinese traditional medicine is slow, poor bioavailability, adds apigenin originally Body effect is slow so that the drug effect of apigenin cannot rapidly be utilization.
Summary of the invention
For shortcomings and deficiencies present in prior art, it is an object of the invention to provide one and be evenly distributed, stable Property good, bioavailability is high, compound apigenin nanoemulsion antihypertensive drug evident in efficacy.
The technical scheme realizing foregoing invention purpose is: a kind of compound apigenin nanoemulsion antihypertensive drug, its particle diameter Between 20.1～59.7nm, mean diameter is 42.7nm.Each raw material and mass percent thereof be:
Remaining composition is distilled water, and the mass percent sum of above-mentioned raw materials is 100%.
With normal rat rear blood pressure situation before administration, observe the hypotensive effect of Fructus Leonuri.Blank group gives The distilled water of respective amount, positive controls gives nifedipine 0.003g/kg；Experimental group give Fructus Leonuri alcohol extract ether, Ethyl acetate, n-butyl alcohol and water extract, dosage is 0.216g/mL；Gastric infusion, continuous 10d；Use carotid artery intubation, Observe respectively and record last 1 time be administered after 10,20,30,45,60min time blood pressure.Result: Fructus Leonuri water layer aligns Often rat has obvious hypotensive effect (P ＜ 0.05), and n-butanol layer, ethyl acetate layer, ether layer all can make normal rat shrink pressure Reduce (P ＞ 0.05), diastolic pressure is had no significant effect, but has certain reduction trend.Conclusion: Fructus Leonuri water soluble ingredient is to normally Rat hypotensive effect is obvious, and the main composition Han alkaloids in water layer, alkaloid is probably mainization of Fructus Leonuri hypotensive effect Study point.
Semen Cassiae is pulse family annual herb plant Semen Cassiae or the dry mature seed of little Semen Cassiae.Hypotensive effect: Semen Cassiae Infusion, alcohol-infusion, alcohol immersion all have hypotensive effect to anesthetized dog, cat, rabbit etc..In chronic experiment, decoct 2g every day (crude drug)/kg, without hypotensive effect.Semen Cassiae injection 0.05g/100g body weight is injected intravenously and spontaneous genetic hypertension can be made big Mus shrinks pressure and substantially reduces, and also makes diastolic pressure significantly reduce simultaneously, and its antihypertensive effect, Amplitude of Hypotensive, action time are superior to quiet Arteries and veins injection reserpine 0.3mg/kg group rat.Impact on hyperlipemia: mice 2 star fed by the high fat beverage containing 7% Semen Cassiae Phase, Semen Cassiae can not affect serum total cholesterol (TC) level, but can significantly raised Serum High-Density Lipoprotein-Cholesterol (HDL-C) content and improve HDL-C/TC ratio, is i.e. obviously improved the distribution situation of internal cholesterol, and beneficially prevention of arterial Atherosis.Semen Cassiae dissipates reduction experimental atherosclerosis rats total plasma cholesterol and the work of triacylglycerol (triglyceride) With, it is allowed to reduce by 29% and 73% than model group respectively, moreover it is possible to reduce triacylglycerol and the effect of suppression platelet aggregation in liver, Its value reduces by 49% and 59% than model group respectively.There are data to show anthraquinone analog compound in Semen Cassiae and there is effect for reducing blood fat.
Surfactant described in this compound nanometer emulsion non-ionic surfactant polyoxyethylene ether-40 castor oil hydrogenated (Cremophor RH 40), in castor oil polyoxyethylene ether 40 (EL40), Tween 80 or PLURONICS F87 any one or Any one mixture with span80.These surfactants are to human body low toxicity, safe, non-stimulated.
Described oil is soybean oil, Oleum Brassicae campestris, glyceryl triacetate, iso-octyl palmitate, oleic acid, ethyl oleate, lima bean Any one or a few mixture of the edible oil apoplexy due to endogenous wind such as cool isopropyl propionate (IPM) or ethyl acetate.Safe and nontoxic.
In order to reach more preferable effect, the present invention add in above-mentioned surfactant cosurfactant dehydrated alcohol, 1,2-PD, glycerol, polyethylene glycol 200 (PEG200), PEG400 (PEG400) or Macrogol 600 (PEG600) any one in, or several mixture.
In the present invention, cosurfactant is good medicine cosolvent in the structure of compound apigenin nanoemulsion equally, The present invention adds in medicine and bland helps surface such as ethanol, 1,2-PD, glycerol or polyethylene glycol 200, poly-second Glycol 400, Macrogol 600, in addition to hydrotropy effect, cosurfactant is primarily to adjust the hydrophilic of surfactant Lipophilic balance value (HLB) so that oil water interfacial tension reduces further, increases profit and the rigidity of limitans.Help surface activity Agent is incorporated in interfacial film, promotes the formation of radius of curvature very membranelle, expands the newborn district area of compound apigenin nanoemulsion.
The compound apigenin nanoemulsion of the present invention, on the one hand greatly improves the dissolubility of apigenin, decreases medicine First pass effect in vivo, promotes the gastrointestinal absorption of medicine.Apigenin is extremely difficult dissolving in water, makes transhipment and the absorption of medicine Becoming difficulty, nano-emulsion substrate is that apigenin provides good dissolving environment.First mistake can be overcome to imitate through Lymphatic time oral Should be with molecule by barrier during gastrointestinal tract；On the other hand by compounding Fructus Leonuri water extract and cassia seed water extract so that this Medicine blood pressure lowering is more steady, and effect is more longlasting.
The compound apigenin nanoemulsion of the present invention compared with prior art, has the advantage that
1. the diameter of aspirin particle of the apigenin resisting hypertension nano-emulsion of the present invention is between 20.1～59.7nm, and mean diameter is 42.7nm, is that apigenin is dissolved in oil phase, adds surfactant and cosurfactant, with dissolving Fructus Leonuri water extract and determining The distilled water of pine torch water extract is titrated to uniform, transparent nano-emulsion system.The compound apigenin nanoemulsion formed is containing apigenin Reach 6.1%.
2. the apigenin resisting hypertension nano-emulsion of the present invention is evenly distributed, and system is transparent, good stability, has relatively low surface Tension force, water-in-oil type nanoemulsion has good mobility.
3. the apigenin resisting hypertension nano-emulsion of the present invention is swallowed by reticuloendothelial cell rapidly after being administered, and makes medicine rapid Onset, and maintain constant blood drug level and pharmacodynamics effect, improve the bioavailability of medicine, reduce consumption and the use of medicine Number of times.
4. the apigenin resisting hypertension nano-emulsion of the present invention passes through Integrated TCM, plays both advantage, on the one hand blood pressure lowerings Rapidly, rapid-action, another firm face efficacy stability, persistent, meet the treatment standard of highly effective and safe.
5. the apigenin resisting hypertension nano-emulsion efficacy stability of the present invention, raw power consumption is low.
6. can be made into oral liquid after the present invention makes nano-emulsion directly to take, also can encapsulate or lyophilised powder technology through capsule Deng process.
Detailed description of the invention
Inventor provides concrete preparation method embodiment and uses the test of pesticide effectiveness to further illustrate the effect of medicine of the present invention Really.
Test example 1 compound apigenin nanoemulsion antihypertensive drug of the present invention size is analyzed
The optimal proportion of the present invention detects through transmission electron microscope, and drop is that class is spherical, and good dispersion, without adhesion；Warp Malvern Particle Size Analyzer detects its diameter Distribution between 20.1～59.7nm, and mean diameter is 42.7nm.
Test example 2 compound apigenin nanoemulsion antihypertensive drug of the present invention stability analysis
Observe compound apigenin of the present invention by following centrifugal test, photo-stability testing, temperature stability test etc. to receive The stability of rice breast antihypertensive drug, observes whether the present invention has the wild effects such as layering, muddiness or crystal precipitation.
1. high speed centrifugation test
Take the compound apigenin nanoemulsion antihypertensive drug of the present invention prepared in right amount in centrifuge tube, with 10 000r/ The rotating speed of min is centrifuged 15min, and after centrifugal test, compound apigenin nanoemulsion antihypertensive drug of the present invention still keeps centrifugal Front clear, has no the wild effects such as layering, muddiness or crystal precipitation.
2. photo-stability testing
The compound apigenin nanoemulsion antihypertensive drug prepared in right amount is loaded transparent good colourless, Clear glass bottles and jars In, seal, be positioned over 10d under normal lighting conditions, observe respectively at 1d, 2d, 4d, 6d, 8d, 10d sampling.Result shows compound recipe Every part of sample of apigenin nanoemulsion antihypertensive drug all keeps clear, has no the shakinesses such as layering, muddiness or crystal precipitation Determine phenomenon.
3. temperature stability test
The compound apigenin nanoemulsion antihypertensive drug prepared in right amount is loaded transparent good colourless, Clear glass bottles and jars In, seal, be positioned in 4 DEG C, room temperature (25 DEG C) and 40 DEG C three each 30d of investigation that keeps sample under temperature conditions, observe every 5d sampling. Result shows, compound apigenin nanoemulsion antihypertensive drug all keeps clear under these three kinds of temperature conditionss, has no point The wild effects such as layer, muddiness or crystal precipitation.
4. long-term stable experiment
3 batches of nano-emulsions are sealed in Brown Glass Brown glass bottles and jars only, are placed under the conditions of (25 ± 2) DEG C, relative humidity (60 ± 5) % 12 Individual month, sample when 0,3,6,9 and 12 months, investigate character and the changes of contents of nano-emulsion, and list of references statistical Analysis method, calculates the effect duration of compound apigenin nanoemulsion antihypertensive drug.Result of the test shows under the conditions of long term test, The outward appearance of compound apigenin nanoemulsion antihypertensive drug is always maintained at clear and bright, homogeneous, has no layering, complexion changed, flocculation and breakdown of emulsion Etc. phenomenon；Quantitative Determination of Apigenin in system extends in time and is gradually lowered, and what its content-time changing curve provided linearly returns Returning equation, the effect duration calculating compound apigenin nanoemulsion antihypertensive drug is 34.14 months.
Test example 3 rat tails manometry measures the drug effect of compound apigenin nanoemulsion antihypertensive drug (with commercially available celery Dish element suspension contrasts)
SHR rat 3 is only randomly divided into 3 groups, often group 10, be set to SHR positive controls, apigenin suspension group, Compound apigenin nanoemulsion group gives apigenin suspension, compound apigenin nanoemulsion each 20mg/kg d respectively, is dissolved in drinking-water In, all it is administered from drinking-water, 1 time/d, continuous 14 weeks.WKY6 is only Normal group, matched group not drug, and drinking-water does not limits.
Measure each group of rat tail artery blood pressure.(before medication) pressure measurement 1 time when Mus age is 6 weeks, 7 weeks ages of Mus are (after medication 1 Week) pressure measurement 1 time, surveying 1 blood pressure every two weeks later, terminating until testing.The results are shown in Table 1.
The comparison (x ± s, n=6) of rat SBP respectively organized by table 1
Result shows, compound apigenin nanoemulsion compares with positive controls and apigenin suspension, and difference is the most notable, Show that apigenin not only can significantly reduce the blood pressure of positive rats, and antihypertensive effect effect is more compared with apigenin suspension Good.
Test example 4 toxicity test
1. toxicological study project and conclusion:
Product of the present invention in strict accordance with new drug nonphosphorylated neurofilament H method and commercially available apigenin suspendible liquor contrast into Gone acute toxicity test, repeated dose toxicity test, genetic toxicity test (include the test of Salmonella reversion test, Micronuclei In The Mouse Bone Marrow, In vitro culture mammalian cell chromosome mutation test), reproductive toxicity test (General Reproductiv e Toxicity Assessment, sensitive period to teratogenic agent Toxicity test, perinatal toxicity test), carcinogenic test, immunotoxicity test and Local irritation study, result of the test is as follows.
This product is to Mouse Acute Toxicity experiment conclusion: contrast with commercially available apigenin suspendible liquor, compound apigenin nanoemulsion Untoward reaction and death in dosage does not occurs.
The genetoxic examinations such as the Salmonella reversion test of product of the present invention, mouse inbred strain and testis chromosomal aberration test The result tested is feminine gender.
Rat 30d feeds the result of product of the present invention and shows: contrast with commercially available apigenin suspendible liquor, within experimental period, In compound apigenin nanoemulsion dosage, each test group of animals growth promoter is good, body weight, food ration, routine blood test, blood biochemistry, internal organs The indexs such as coefficient all within normal range, histopathologic examination's also no abnormality seen.
This product long term toxicity test conclusion: contrasting with commercially available apigenin suspendible liquor, within experimental period, compound apigenin is received In rice Emulsion amount, this medicine has no rat untoward reaction for three months at continuous gastric infusion, and every Index for examination is all at normal model In enclosing, its main organs of pathologic finding and target organ are showed no the toxic pathological change that this guiding drug rises.
Embodiment 1
Accurately weighing EL40 24g, ethyl acetate 10g, apigenin 6.1g, 1,2-PD 12g are in room temperature (25 DEG C) condition Under stir, be slowly dropped into solubilized solution Fructus Leonuri extract and the distilled water of Semen Cassiae extract the most wherein.Along with steaming The increase of distilled water amount, system stickiness increases, when distilling the water yield and making system be become oil-in-water type nano-emulsion from Water-In-Oil, body Being that viscosity is thinning from the state of thickness, now produce is water white compound apigenin nanoemulsion, and Fructus Leonuri water carries Thing 4.2g, cassia seed water extract 4.8g, distilled water 38.9g.This embodiment is the optimum proportioning of compound apigenin nanoemulsion.
Following example step is with embodiment 1:
Embodiment 2
Apigenin 7g, Tween 80 28g, isopropyl myristate 12g, ethanol 12g, Fructus Leonuri water extract 4g, Semen Cassiae water Extract 4g, distilled water 33g.
Embodiment 3
Apigenin 6g, RH40 28g, oleic acid 10g, PEG400 3g, Fructus Leonuri water extract 5g, cassia seed water extract 7g, steam Distilled water 41g.
Embodiment 4
Apigenin 6g, EL40 castor oil hydrogenated 28g, ethyl oleate 7g, glycerol 5g, Fructus Leonuri water extract 3.5g, Semen Cassiae Sub-water extract 6.5g, distilled water 44g.
Embodiment 5
Apigenin 8g, PLURONICS F87 24g, isopropyl myristate 10g, PEG200 12g, Fructus Leonuri water extract 6g, Cassia seed water extract 4g, distilled water 34g.
Embodiment 6
Apigenin 8g, RH40 21g, soybean oil 10g, Macrogol 600 14g, Fructus Leonuri water extract 5g, Semen Cassiae water carries Thing 4g, distilled water 38g.
Embodiment 7
Apigenin 1g, Tween 80 5g, isopropyl myristate 1g, ethanol 1g, Fructus Leonuri water extract 10g, Semen Cassiae water carries Thing 10g, distilled water 72g.
Embodiment 8
Apigenin 3g, RH40 10g, oleic acid 3g, PEG400 3g, Fructus Leonuri water extract 5g, cassia seed water extract 7g, distillation Water 69g.

Claims (2)

1. a compound apigenin nanoemulsion antihypertensive drug, it is characterised in that its raw material and mass percent thereof be:
Remaining composition is distilled water, and the mass percent sum of above-mentioned raw materials is 100%；
Described surfactant is polyoxyethylene ether-40 castor oil hydrogenated, castor oil polyoxyethylene ether 40, Tween 80 or pool Lip river In husky nurse 188 any one or any one with the mixture of span80；
Described oil is soybean oil, Oleum Brassicae campestris, glyceryl triacetate, iso-octyl palmitate, oleic acid, ethyl oleate, myristic acid Any one or a few mixture of the edible oil apoplexy due to endogenous wind such as isopropyl ester or ethyl acetate；
Described cosurfactant be dehydrated alcohol, 1,2-PD, glycerol, polyethylene glycol 200, PEG400 or Any one in Macrogol 600, or several mixture.
Compound apigenin nanoemulsion antihypertensive drug the most according to claim 1, it is characterised in that the particle diameter of this medicine is situated between Between 20.1～59.7nm.
CN201610503132.5A 2016-06-23 2016-06-23 A kind of compound apigenin nanoemulsion antihypertensive drug Pending CN106137958A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107096034A (en) * 2017-04-27 2017-08-29 重庆医科大学 One kind carries apiolin hyaluronic acid targeted nano assembly and preparation method thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107096034A (en) * 2017-04-27 2017-08-29 重庆医科大学 One kind carries apiolin hyaluronic acid targeted nano assembly and preparation method thereof
CN107096034B (en) * 2017-04-27 2020-03-31 重庆医科大学 Apigenin-loaded hyaluronic acid targeted nano-assembly and preparation method thereof

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