CN102579342A - Targeting ginkgolide B solid lipid nanoparticle and preparation method thereof - Google Patents
Targeting ginkgolide B solid lipid nanoparticle and preparation method thereof Download PDFInfo
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- CN102579342A CN102579342A CN201210034507XA CN201210034507A CN102579342A CN 102579342 A CN102579342 A CN 102579342A CN 201210034507X A CN201210034507X A CN 201210034507XA CN 201210034507 A CN201210034507 A CN 201210034507A CN 102579342 A CN102579342 A CN 102579342A
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Abstract
The invention discloses a targeting ginkgolide B solid lipid nanoparticle and a preparation method thereof. The ginkgolide B solid lipid nanoparticle targeting a blood brain barrier is prepared with an oil-in-water emulsion process by taking a ginkgolide B as a treating medicament, taking a solid lipid material as a carrier, taking a folic acid-modified surfactant as a targeting material and taking a mixture obtained by mixing a surfactant with the folic acid-modified surfactant in a certain ratio as an emulsifier. The particle diameter is 80-200 nanometers, and the polydispersion coefficient is 0.30+/-0.10. According to the solid lipid nanoparticle, a brain targeting effect is achieved by using the folic acid-mediated phagocytosis on the surfaces of brain cells and the phagocytosis way of adsorption of a brain cell membrane by using the nanoparticle.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to ginkalide B solid lipid nanoparticle of a kind of targeting blood brain barrier and preparation method thereof.
Background technology
Alzheimer's disease (AD) is a kind of common senile chronic degeneration sacred disease, and neuron takes off mistake before patient's cerebral tissue atrophy, particularly Hippocampus and the substrate.The alzheimer's disease patient has two big pathological characters: having formed nucleus is the extracellular senile plaque (SP) of β-starch albumen (A β), forms Tau albumen with excessive phosphorylation and be fibre matting (NFTs) in the pathological changes neuron of main component.The pathologist infers that two kinds of pathological characters finally cause neuron/aixs cylinder obstacle or aixs cylinder death, thereby causes apoptosis amount finally to produce dementia symptom.The medicine that is used to treat AD by the approval of FDA and EMEA at present has only 5 kinds.Wherein 4 kinds is acetylcholinesterase inhibitor (AChEI), and the effect of this type medicine is can remedy to lose the functional consequence that cholinergic neuron causes in AD patient's brain.
Bilobalide is the one type of terpenoid lactone reactive compound that from Semen Ginkgo, extracts, and main component comprises ginkalide A, B, C, J, M, K, L, bilobalide etc., and wherein the activity with ginkalide B (GB) is the strongest.Ginkalide B is through improving Acetylcholinesterase (AChE) thereby the active acetylcholine that promotes is synthetic; And acetyl choline content in the raising brain; Remedy and lose the functional consequence that cholinergic neuron causes in AD patient's brain; Reach the effect of opposing AD, bilobalide also has following effect: the one, have the effect that is similar to BDNF, and can promote that the forebrain cholinergic neuron is grown at the bottom of the blastema.The 2nd, have the effect that is similar to nerve growth factor, can effectively suppress basal forebrain cholinergic neuron apoptosis and reach protective effect the cortical neuron apoptosis.
The present invention imagines the medicine of use ginkalide B as the treatment alzheimer's disease; But will GB effectively be transported to following two big obstacles are arranged in the brain cell: at first ginkalide B is a fat-soluble medicine; Water-fast characteristic limitations absorb distribution character in its body; And the GB half-life in vivo has only 2～3 hours, if merely with oral or solution drug administration by injection mode, and the arrival that medicine can't mass efficient and be accumulated in cerebral tissue.Secondly blood brain barrier (BBB) is the natural cover for defense of brain, and the distinctive tight connection of its iuntercellular has effectively stoped exogenous material to get into brain cell, comprises medicine or has wrapped up the drug delivery system of medicine.And material permeance BBB is mainly through approach in following 5: (1) hydrophilic micromolecule is through close-connected passive transport; (2) dysuria with lower abdominal colic of striding of lipophilic substance is transported; (3) micromolecule nutrient substance such as transport protein mediation transhipment glucose, aminoacid, choline; (4) macromole polypeptide such as receptor-mediated transport protein matter; (5) go into brain through endocytosis behind the electrostatic force absorption cationic substance.
For solving above-mentioned described problem; This patent is invented ginkalide B solid lipid nanoparticle of a kind of targeting BBB and preparation method thereof; Advantage is: the skeleton kernel of solid lipid nanoparticle is a matrix material; Can be effectively and ginkalide B merge, and biocompatibility is good, solves drug absorption difference problem.The solid lipid nanoparticle shell is selected poloxamer surfactants such as (Pluronic) for use; Contain polyoxyethylene group in the Pluronic long-chain; Its flexible water-wet behavior can avoid the medicine carrying solid lipid nanoparticle by reticuloendothelial system phagocytic in the body; Prolong its time in the body circulation, solve medicine short problem of the time of staying in vivo.Have on the blood brain barrier mediation folic acid with and the receptor of activity in vivo form tetrahydrofolic acid exist; Select folic acid to modify the poloxamer two ends as target ligand; Utilize its with brain endothelial cell on the affinity of folacin receptor, whole solid lipid nanoparticle can be led to by the folacin receptor mediated effect endocytosis in brain cell surface goes into brain.
Summary of the invention
The present invention is directed to owing to blood brain barrier acts on the medicine that causes to resisting of exogenous material and can't get into cerebral tissue; Thereby the problem that the remorse disease of brain can't effectively be treated; Designed the medicine carrying solid lipid nanoparticle that a kind of folic acid targeting material is modified; Utilize the folacin receptor specific recognition folic acid aglucon and the receptor-mediated phagocytosis on brain endothelial cell surface; And the nanoparticle material of fat property and brain cell film affinity are strong engulfs the permeable membrane approach with nanoparticle, help the medicine carrying solid lipid nanoparticle effectively to get into and bring into play drug effect in the brain.
The invention provides emulsifying agent with modified with folic acid as targeting material (or targeting emulsifying agent), matrix material is as solid lipid nanoparticle of a kind of year ginkalide B of carrier and preparation method thereof, and specifically preparation process is:
(1) with matrix material and targeting emulsifier, heating in water bath to 50～80 are ℃ to fusion.
(2) medicine is dissolved in the organic solvent of one of amount of methanol, dichloromethane, acetone, chloroform or combination in any fully.
(3) drug solution is poured in (1), insulated and stirred, complete until solvent evaporates, this moment, medicine well merged in liquid lipid.
(4) water-soluble substances (like common emulsifying agent) is dissolved in the water for injection, is heated to 50～80 ℃
(5) (4) are poured in the isothermal (3), stirred 2～4 hours under 50～80 ℃ of conditions, form colostrum.
(6) colostrum that (5) is formed carries out high speed dispersion, obtains fused solid lipid nanoparticle, rapidly fused solid lipid nanoparticle is cooled off with ice-water bath, continues to stir 5～50min until full solidification.
(7) solid lipid nanoparticle with (6) is pressed through 0.8 μ m microporous filter membrane 5 times, gets the targeting ginkalide B solid lipid nanoparticle solution of particle diameter 80～200nm.
Medicine is a ginkalide B, but is not limited to this, and medicine can also be ginkalide A, C, J, M, K, L and bilobalide and their compositions.
The targeting emulsifying agent is synthetic folic acid-poloxamer (FA-Pluronic), folic acid-phospholipid or other modified with folic acid have a surface-active emulsifying agent.
Matrix material can be single replacement, two replacement, trisubstituted fatty acid (stearic acid, Palmic acid, mountain Yu acid, lauric acid etc.) glyceride, one or more mixture in fatty acid or other lipids.
The mass ratio of medicine and matrix material between 1: 10～1: 50, preferred 1: 20; The mass ratio of targeting emulsifying agent and common emulsifying agent between 1: 2～1: 5, preferred 2: 3; Matrix material and all the mass ratio of emulsifying agents between 1: 2～2: 1, preferred 2: 1; The mass volume ratio of the consumption of medicine and water for injection is 1: 2～2: 1, preferred 1: 2.
The rotating speed of high speed dispersion can be between 5000～100000 rev/mins, the time between 4～10 minutes, preferred 7500 rev/mins, 4～6 minutes time.
The invention provides ginkalide B solid lipid nanoparticle of a kind of targeting blood brain barrier and preparation method thereof; Wherein use the emulsifying agent of synthetic modified with folic acid to be the targeting emulsifying agent; The targeting solid lipid nanoparticle that makes records particle diameter between 80～200nm with the light scattering particle size analyzer, with atomic force microscope observation result type of being shown as spherical or oval (seeing accompanying drawing 1).This solid lipid nanoparticle is contained the poloxamer parcel of polyoxyethylene segment, can avoid by reticuloendothelial system phagocytic, and effective prolong drug is circulation time in vivo.The folic acid aglucon in the nanoparticle outside can be by the epithelial folacin receptor identification of brain; The fat property material and the cell membrane affinity of packaging medicine are strong; Group's drug-carrying nanometer particle is engulfed in the approach permeable membrane entering cell through receptor-mediated engulfing with nanoparticle, thereby reaches the purpose of treatment brain diseases.
Description of drawings
Fig. 1 is a kind of targeting ginkalide B solid lipid nanoparticle AFM figure.
Fig. 2 is the nuclear-magnetism of the poloxamer of modified with folic acid
1The H collection of illustrative plates
Fig. 3 be among Fig. 1 chemical shift at the local peak position enlarged drawing of 4.5ppm-8.5ppm
The specific embodiment
Through following embodiment the specific embodiment of the present invention is described, but protection scope of the present invention is not limited to this.
FA-PluronicF68's is synthetic: (1) 1.15g paratoluensulfonyl chloride (TsCl) and 800 μ l triethylamines place three-neck flask, add an amount of anhydrous methylene chloride dissolving.The dichloromethane solution that is dissolved with 5.00gPluronicF68 is dropwise added wherein room temperature nitrogen protection condition lower magnetic force stirring reaction 12 hours.Product is deposited in an amount of ice ether after concentrating, and sucking filtration gets precipitate.Redissolve deposition twice, precipitate vacuum drying 24 hours obtains F68-OTs.(2) get potassium phthalimide (PI) 0.91g and place there-necked flask, add an amount of anhydrous N, dinethylformamide (DMF), 120 ℃, dispersed with stirring dissolving; To wherein being added dropwise to the DMF solution that is dissolved with 4.00gF68-OTs, 120 ℃, nitrogen protection was reacted 6 hours down.Product revolves to steam to be removed after the DMF, adds an amount of anhydrous methylene chloride ultrasonic dissolution, the centrifugal insoluble matter of removing wherein, and triplicate merges supernatant.Be deposited in an amount of ice ether after concentrating, sucking filtration gets precipitate.Redissolve-deposition twice, vacuum drying obtained F68-PI in 24 hours under the precipitate room temperature.(3) get 250 μ l hydrazine hydrates and place three-neck flask, use an amount of anhydrous alcohol solution, to wherein dripping the alcoholic solution be dissolved with 2.61gF68-PI gradually, the reaction 12 hours down of 80 ℃, nitrogen protection.Enriched product is deposited in it in an amount of no water-ice ether, and sucking filtration gets precipitate.Repeat dissolve with ethanol-ether sedimentation twice, vacuum drying obtained F68-NH in 24 hours under the precipitate room temperature
2(4) get folic acid 0.30g, N-hydroxy-succinamide (NHS) 0.115g, dicyclohexylcarbodiimide (DCC) 0.15g places three-neck flask, uses an amount of dmso solution, nitrogen protection lucifuge condition, reaction was carried out activation to folic acid in 2 hours under the room temperature.Add 2.00gF68-NH
2, lucifuge reaction 12 hours.Product was dialysed 1 day with the bag filter of interception molecular weight 3500Da, changed water once in initial 1 hour, changed 3 hours into after 3 times and changed water once.After 1 day that dialysis solution is centrifugal, give up precipitate (comprising the folic acid and the dicyclohexylurea that are not appeared), get supernatant and dialysed again one day, changed water once in 4 hours.Directly lyophilization promptly gets, through nuclear-magnetism
1It is FA-PluronicF68 (seeing accompanying drawing 2, accompanying drawing 3) that H characterizes product.
The preparation of targeting ginkalide B solid lipid nanoparticle: get 150mg glyceryl monostearate, 30mgFA-PluronicF68 heating in water bath to 60 ℃ to fusion; The methanol solution that is dissolved with the 7.5mg ginkalide B is dripped into gradually; Keep 60 ℃; Magnetic agitation 2h makes medicine and matrix material mix homogeneously, waves to the greatest extent up to methanol.Adding 15ml is heated to 60 ℃ the aqueous solution that is dissolved with 45mgPluronicF68; Magnetic agitation 2h obtains colostrum; 60 ℃, 7500r/min high speed dispersion colostrum 6min is placed into immediately and solidifies the 5min molding in 4 ℃ the ice-water bath; Push 0.8 μ m filter membrane 5 times, obtained targeting ginkalide B solid lipid nanoparticle solution.Size is 125.8nm, polydispersity coefficient 0.380.
Embodiment 3
The preparation of targeting ginkalide B solid lipid nanoparticle: get 150mg glyceryl monostearate, 30mgFA-PluronicF68 heating in water bath to 80 degree centigrade to fusion; The methanol solution that is dissolved with the 7.5mg ginkalide B is dripped into gradually; Keep 80 ℃; Magnetic agitation 2h makes medicine and matrix material mix homogeneously, waves to the greatest extent up to methanol.Adding 15ml is heated to 80 ℃ the aqueous solution that is dissolved with 45mgPluronicF68; Magnetic agitation 2h obtains colostrum; 80 ℃, 7500r/min high speed dispersion colostrum 6min is placed into immediately and solidifies the 5min molding in 4 ℃ the ice-water bath; Push 0.8 μ m filter membrane 5 times, obtained targeting ginkalide B solid lipid nanoparticle solution.Size is 125.4nm, polydispersity coefficient 0.319.
The preparation of targeting ginkalide B solid lipid nanoparticle: get 150mg glyceryl monostearate, 30mgFA-PluronicF68 heating in water bath to 80 degree centigrade to fusion; The methanol solution that is dissolved with the 5.0mg ginkalide B is dripped into gradually; Keep 80 ℃; Magnetic agitation 2h makes medicine and matrix material mix homogeneously, waves to the greatest extent up to methanol.Adding 10ml is heated to 80 ℃ the aqueous solution that is dissolved with 40mgPluronicF68; Magnetic agitation 2h obtains colostrum; 80 ℃, 10000r/min high speed dispersion colostrum 4min is placed into immediately and solidifies the 5min molding in 4 ℃ the ice-water bath; Push 0.8 μ m filter membrane 5 times, obtained targeting ginkalide B solid lipid nanoparticle solution.Size is 146.5nm, polydispersity coefficient 0.279.
Claims (8)
1. targeting ginkalide B solid lipid nanoparticle and preparation method thereof is characterized in that: this targeting lipid nanoparticle prescription comprises the emulsifying agent (targeting emulsifying agent) and the water for injection of medicine, matrix material, common emulsifying agent, modified with folic acid; 1. preparation technology comprises matrix material and targeting emulsifying agent is heated with stirring to 50～80 ℃ of fusions, under the insulated and stirred condition, adds the drug solution that is dissolved in a small amount of organic solvent; Complete until solvent evaporates, form the uniform drug lipid soln, 2. with common emulsifiers dissolve in water for injection; Be heated to 50～80 ℃, 3. will 2. pour into isothermal 1. in, continue to stir under 50～80 ℃ of conditions 2～4 hours; Form colostrum, carry out high speed dispersion again, obtain fused solid lipid nanoparticle; 4. rapidly above-mentioned fused solid lipid nanoparticle is under agitation cooled off 5～50min with ice-water bath; Until full solidification, 5. solidified lipid nanoparticle was pushed 0.8 μ m filter membrane 5 times, obtain targeting ginkalide B solid lipid nanoparticle solution.
2. according to said a kind of targeting ginkalide B solid lipid nanoparticle of claim 1 and preparation method thereof; It is characterized in that: medicine is a ginkalide B; But be not limited to this, medicine can also be ginkalide A, C, J, M, K, L and bilobalide and their compositions.
3. according to said a kind of targeting ginkalide B solid lipid nanoparticle of claim 1 and preparation method thereof; It is characterized in that: matrix material can be single replacement, two replacement, trisubstituted fatty acid (stearic acid, Palmic acid, mountain Yu acid, lauric acid etc.) glyceride, one or more mixture in fatty acid or other lipids (like cholesterol).
4. according to said a kind of ginkalide B targeting solid lipid nanoparticle of claim 1 and preparation method thereof; It is characterized in that: common emulsifying agent can be various model poloxamers, and phospholipid has the one or more combination thing in the surface-active emulsifying agent (like tween, sodium cholate) with other.
5. according to said a kind of targeting ginkalide B solid lipid nanoparticle of claim 1 and preparation method thereof; It is characterized in that: the emulsifying agent of modified with folic acid is the targeting material, is specially the surface-active emulsifying agent that has of synthetic folic acid-poloxamer (FA-Pluronic), folic acid-phospholipid or other modified with folic acid.
6. according to said a kind of targeting ginkalide B solid lipid nanoparticle of claim 1 and preparation method thereof, it is characterized in that: the mass ratio of prescription Chinese medicine and matrix material between 1: 10～1: 50, preferred 1: 20; The mass ratio of targeting emulsifying agent and common emulsifying agent between 1: 2～1: 5, preferred 2: 3; Matrix material and all the mass ratio of emulsifying agents between 1: 2～2: 1, preferred 2: 1; The mass volume ratio of the consumption of medicine and water for injection is 1: 2～2: 1, preferred 1: 2.
7. a kind of targeting ginkalide B solid lipid nanoparticle according to claim 1 and preparation method thereof is characterized in that: the organic solvent of preparation technology in 1. can be one of methanol, dichloromethane, acetone, chloroform or combination in any.
8. the method for preparing of a kind of targeting ginkalide B solid lipid nanoparticle according to claim 1; It is characterized in that: the preparation technology 3. dispersive rotating speed of high speed can be between 5000～100000 rev/mins; Time is between 4～10 minutes; Preferred 7500 rev/mins, 4～6 minutes time.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102813653A (en) * | 2012-08-22 | 2012-12-12 | 郭涛 | Medicine used for treating cerebral ischemic dementia and preparation method for medicine |
| CN104356141A (en) * | 2014-11-27 | 2015-02-18 | 中国药科大学 | Preparation method of ginkgolide L |
| CN105641714A (en) * | 2015-12-28 | 2016-06-08 | 四川大学 | Folic acid modified VEGFR2/Tie2 double gene composition |
| CN106361727A (en) * | 2016-11-25 | 2017-02-01 | 遵义医学院 | Bilobalide-PVA nanoparticle and preparation method thereof |
| CN106377517A (en) * | 2016-11-25 | 2017-02-08 | 遵义医学院 | Bilobalide-PVP (Polyvinyl Pyrrolidone) nano particles and preparation method thereof |
| CN106420387A (en) * | 2016-11-03 | 2017-02-22 | 浙江大学 | Traditional-Chinese-medicine-compound-targeting lipid nanosphere composite and preparing method thereof |
| CN106822920A (en) * | 2016-08-15 | 2017-06-13 | 四川大学 | The PEDF gene composites of tumour cell folacin receptor targeting |
| CN107530285A (en) * | 2015-04-29 | 2018-01-02 | 加利福尼亚大学董事会 | Detoxified using nano-particle |
| CN108815134A (en) * | 2018-07-10 | 2018-11-16 | 中国药科大学 | A kind of preparation and its application of the biology camouflage targeted nano delivery system for cerebral arterial thrombosis treatment |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102813653A (en) * | 2012-08-22 | 2012-12-12 | 郭涛 | Medicine used for treating cerebral ischemic dementia and preparation method for medicine |
| CN102813653B (en) * | 2012-08-22 | 2015-12-16 | 郭涛 | A kind ofly treat medicine of cerebral ischemia dementia and preparation method thereof |
| CN104356141A (en) * | 2014-11-27 | 2015-02-18 | 中国药科大学 | Preparation method of ginkgolide L |
| CN107530285A (en) * | 2015-04-29 | 2018-01-02 | 加利福尼亚大学董事会 | Detoxified using nano-particle |
| CN105641714A (en) * | 2015-12-28 | 2016-06-08 | 四川大学 | Folic acid modified VEGFR2/Tie2 double gene composition |
| CN106822920A (en) * | 2016-08-15 | 2017-06-13 | 四川大学 | The PEDF gene composites of tumour cell folacin receptor targeting |
| CN106420387A (en) * | 2016-11-03 | 2017-02-22 | 浙江大学 | Traditional-Chinese-medicine-compound-targeting lipid nanosphere composite and preparing method thereof |
| CN106361727A (en) * | 2016-11-25 | 2017-02-01 | 遵义医学院 | Bilobalide-PVA nanoparticle and preparation method thereof |
| CN106377517A (en) * | 2016-11-25 | 2017-02-08 | 遵义医学院 | Bilobalide-PVP (Polyvinyl Pyrrolidone) nano particles and preparation method thereof |
| CN108815134A (en) * | 2018-07-10 | 2018-11-16 | 中国药科大学 | A kind of preparation and its application of the biology camouflage targeted nano delivery system for cerebral arterial thrombosis treatment |
| CN108815134B (en) * | 2018-07-10 | 2021-07-13 | 中国药科大学 | Preparation and application of biological camouflage targeted nano drug delivery system for treating ischemic stroke |
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Application publication date: 20120718 |