CN106377517A - Bilobalide-PVP (Polyvinyl Pyrrolidone) nano particles and preparation method thereof - Google Patents
Bilobalide-PVP (Polyvinyl Pyrrolidone) nano particles and preparation method thereof Download PDFInfo
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- CN106377517A CN106377517A CN201611054480.5A CN201611054480A CN106377517A CN 106377517 A CN106377517 A CN 106377517A CN 201611054480 A CN201611054480 A CN 201611054480A CN 106377517 A CN106377517 A CN 106377517A
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
Abstract
The invention relates to the field of medicine, in particular to bilobalide-PVP (Polyvinyl Pyrrolidone) nano particles and a preparation method thereof. The bilobalide-PVP nano particles are of a core-shell structure, a core of the bilobalide-PVP nano particles is bilobalide, and a shell of the bilobalide-PVP nano particles is PVP. The preparation method of the bilobalide-PVP nano particles comprises the following steps: adding the bilobalide in an organic solvent, and filtering after full dissolving; adding a bilobalide solution in a PVP solution, and carrying out ultrasonic emulsification treatment after uniform mixing; collecting a mixed solution after the ultrasonic emulsification treatment is ended, and evaporating the organic solvent; centrifuging a sample, washing by using purified water, precipitating, centrifuging again, carrying out the operation repeatedly, and washing nano particles clearly, thus obtaining the bilobalide-PVP nano particles. According to the bilobalide-PVP nano particles disclosed by the invention, a carrier is not required to be used, the bilobalide is prevented from being in contact with body fluid of blood and the like during an in-vivo delivery process after being coated by the PVP, and the stability can be increased; due to a flexible hydrophilic feature of the PVP, the bilobalide-PVP nano particles can be prevented from being swallowed by an in-vivo reticuloendothelial system, the time of the bilobalide-PVP nano particles in general circulation is prolonged, and the problem of short retention time of medicine in a body is solved.
Description
Technical field
The invention belongs to field of medicaments is and in particular to a kind of bilobalide nanoparticle and preparation method thereof.
Background technology
Bilobalide is the fat-soluble physiologically active ingredient in Semen Ginkgo, is the platelet activating factor with height specificity
Receptor antagonist, has expansion coronary vasodilator, improves the effects such as cerebral circulation, suppression platelet aggregation, atherosclerosis,
It is the first-selected natural drug of Current therapeutic cardiovascular and cerebrovascular disease, occupy world pharmaceutical market natural drug umber one position for a long time, and
Increased year by year with the speed more than 10%.
But, bilobalide is fat-soluble medicine, and water-fast characteristic limits its body absorption distribution character, and
Half-life in vivo only has 2～3 hours, blood concentration fluctuation big, if simple with capsule, oral or solution is administered to
Prescription formula, medicine cannot the reaching and be accumulated in site of action of mass efficient, while bringing greatly inconvenience to patient
It is added significantly to medical expense；Meanwhile, need using organic solvent and surfactant, easily produce toxic and side effects anti-with bad
Should wait.
Modern nanosecond science and technology provide new Scientific Methodology for field of medicaments.With nanotechnology and material, in nanometer
On yardstick, micronized processing and substance modification are carried out to medicine, using its " small size " effect, insoluble drug can be improved
Dissolubility, dispersibility, significantly strengthen biological activity and target utilization rate；The usage amount of organic solvent can be reduced, reduce poison secondary
Effect and untoward reaction.
Using modern nanotechnology, bilobalide is prepared into nanoparticle becomes and improve bilobalide solubility property, raising
Utilization ratio of drug and drug effect, reduce the important channel of toxic and side effects.
Research report currently, with respect to bilobalide nanoparticle is simultaneously few, and the patent of application has " in a kind of targeting Semen Ginkgo
Ester B solid lipid nanoparticle and preparation method thereof (application number：201210034507.X) ", " a kind of cerebral ischemia for the treatment of is dull-witted
Medicine and preparation method thereof（The patent No.：ZL201210301233.6）”；The paper of report has " ginkalide B flexible nano fat
The preparation of plastid and transdermal test in vitro research（Liu Ting etc.）", " research of bilobalide PELGE nanoparticle（Fu Yan etc.）", " in Semen Ginkgo
Ester nanoparticles Study of cytotoxicity（Jiang Qingfeng etc.）", " HPLC-ELSD method measures the PEG-PLGA nanoparticle carrying ginkalide B
Envelop rate and drug loading（Zhang Lin etc.）”.These patents and nanoparticle described in paper are will be after bilobalide is combined with carrier, warp
Nanorize obtains nanoparticle after processing.The carrier being adopted is liposome, PBCA, polylactic acid-glycolic base second
Acid and Polyethylene Glycol triblock copolymer（PELGE）, polyethylene glycol-polylactic acid-co-glycolic acid (PEG-PLGA) etc..On
State carrier price used by preparation method, preparation process complicated, and the bilobalide nanoparticle dissolubility of gained is poor, the half-life
Short, the time of staying is also short in vivo for medicine.
Content of the invention
The present invention is poor for bilobalide dissolubility, half-life short, and the time of staying is also short in vivo for medicine, designs and prepares
A kind of bilobalide-PVP nanoparticle, to improve the dissolubility of bilobalide, extends the half-life, improves bioavailability and medicine
Effect.
Bilobalide-PVP the nanoparticle of the present invention, this nanoparticle is nucleocapsid structure, and its kernel is bilobalide, and shell is
PVP.
PVP is polyvinyl alcohol resin, product system white solid, and external form divides cotton-shaped, graininess, three kinds of powdery；Nonpoisonous and tasteless,
Pollution-free, can dissolve in 80--90 DEG C of water.Its aqueous solution has good cementability and film property；Be resistant to oils, lubricant and
Most of organic solvent such as hydro carbons；There is long-chain polyhydric alcohol esterification, the chemical property such as etherificate, acetalation.
Wherein, the bilobalide-PVP nanoparticle particle diameter distribution of the present invention is between 30 ~ 1000nm.
It is preferably 30 ~ 500nm, more preferably 30 ~ 300nm.
Described bilobalide is ginkalide A, ginkalide B, ginkalide C, bilobalide J, bilobalide M, silver
One or more of Fructus Pruni lactone K, bilobalide L and bilobalide.Bilobalide is ginkalide A, ginkalide B, Semen Ginkgo
Lactone C, bilobalide J, bilobalide M, the general name of bilobalide K, bilobalide L and this big class mixture of bilobalide, its
In, ginkalide A (ginkgolideA;GA), ginkalide B (ginkgolideB;GB), ginkalide C (ginkgolideC;
GC), Semen Ginkgo lactone M (ginkgolideM;GM), Semen Ginkgo lactone J (ginkgolideJ;GJ), Semen Ginkgo lactone K
(ginkgolideK;GK), Semen Ginkgo lactone K (ginkgolideL;GL) be diterpene-kind compound, its difference be containing hydroxyl
The position that number connects with hydroxyl is different.
For reaching above-mentioned purpose, the preparation method of employing is：
Step one, bilobalide is added in organic solvent, after fully dissolving, filters；
Step 2, bilobalide solution is added in PVP solution, after mixing, carries out ultrasonic emulsification process；
After step 3, ultrasonic end, collect mixed solution, evaporate organic solvent；
Step 4, sample is centrifuged, purification water washing precipitates, recentrifuge, nanoparticle is cleaned up by repeatable operation, you can
Obtain bilobalide-PVP nanoparticle.
Wherein, the organic solvent in step one be one of methanol, ethanol, dichloromethane, acetoneand ethyl acetate or
Combination in any.
Between 0.1% ~ 10%, bilobalide solution is existed the concentration of the PVP solution in step 2 with the volume ratio of PVP solution
2:1~1:Between 20.
It is furthermore preferred that the concentration of the PVP solution in step 2 is between 2% ~ 8%, the body of bilobalide solution and PVP solution
Amass and compare 1:3~1：9.
Beneficial effects of the present invention：The present invention is with the bilobalide nanoparticle difference of prior art, the silver of the present invention
The kernel of Fructus Pruni lactone-PVP nanoparticle is bilobalide, and shell is PVP it is not necessary to use carrier；Meanwhile, after PVP parcel,
Avoid the contact of bilobalide and the body fluid such as blood in internal course of conveying, stability can be improved.Additionally, the flexibility of PVP
Water-wet behavior, is avoided that nanoparticle, by internal reticuloendothelial system phagocytic, extends its time in body circulation, solves medicine and exists
Short problem of the internal time of staying.
Brief description
Fig. 1 is the grain size distribution of bilobalide-PVP nanoparticle.
Specific embodiment
Below by specific embodiment, the present invention is further detailed explanation：
The specific embodiment of the present invention is described by example below, but protection scope of the present invention, it is not limited to this.
Fig. 1 is the grain size distribution of bilobalide-PVP nanoparticle, is found out by Fig. 1, in the Semen Ginkgo prepared by the present embodiment
Ester-PVP nanoparticle, between 100 ~ 500nm, mean diameter is 238.27nm to particle diameter distribution, and particle has good dispersibility,
Its particle coefficient of dispersion is 0.256.
Embodiment 1
1.5g bilobalide is added in 30ml ethyl acetate, after fully dissolving, filters, collect filtrate, standby.Measure
0.5ml bilobalide solution is added in 2.5ml0.1%PVP solution, after mixing, carries out ultrasonic emulsification process.After ultrasonic end,
Collect mixed solution, rotation under room temperature evaporates organic solvent.Then sample is centrifuged 30min（4 DEG C, 10000rpm）, collect
Precipitation, adds deionized water to suspend again, recentrifuge.Repeatable operation 5 times, nanoparticle is cleaned up, obtains bilobalide
Nanoparticle-PVP solution.Size is 632.68nm, and polydispersity coefficient is 0.436.
Embodiment 2
1.5g bilobalide is added in 30ml ethanol, after fully dissolving, filters, collect filtrate, standby.Measure 0.5ml silver
Fructus Pruni lactone solution is added in 2.5ml2%PVP solution, after mixing, carries out ultrasonic emulsification process.After ultrasonic end, collect mixing
Solution, rotation under room temperature evaporates organic solvent.Then sample is centrifuged 30min（4℃,10000rpm）, collect precipitation, add
Deionized water suspends again, recentrifuge.Repeatable operation 5 times, nanoparticle is cleaned up, and obtains bilobalide nanoparticle-PVP
Solution.Average hydrodynamic diameter is 398.41nm, and polydispersity coefficient is 0.265.
Embodiment 3
1.5g bilobalide is added in 30ml acetone, after fully dissolving, filters, collect filtrate, standby.Measure 0.5ml silver
Fructus Pruni lactone solution is added in 2.5ml6%PVP solution, after mixing, carries out ultrasonic emulsification process.After ultrasonic end, collect mixing
Solution, rotation under room temperature evaporates organic solvent.Then sample is centrifuged 30min（4℃,10000rpm）, collect precipitation, add
Deionized water suspends again, recentrifuge.Repeatable operation 5 times, nanoparticle is cleaned up, and obtains bilobalide nanoparticle-PVP
Solution.Average hydrodynamic diameter is 305.04nm, and polydispersity coefficient is 0.280.
Embodiment 4
1.5g bilobalide is added in 30ml dichloromethane/ethyl acetate/acetone mixture (volume ratio is 1:1:1) in,
After fully dissolving, filter, collect filtrate, standby.Measure 0.5ml bilobalide dichloromethane/ethyl acetate/acetone mixed solution
It is added in 2.5ml8%PVP solution, after mixing, carry out ultrasonic emulsification process.After ultrasonic end, collect mixed solution, under room temperature
Rotary evaporation falls organic solvent.Then sample is centrifuged 30min（4℃,10000rpm）, collect precipitation, add deionized water again
Secondary suspension, recentrifuge.Repeatable operation 5 times, nanoparticle is cleaned up, and obtains bilobalide nanoparticle-PVP solution.Averagely
Hydrodynamic diameter is 395.70nm, and polydispersity coefficient is 0.268.
Embodiment 5
1.5g bilobalide is added in 30ml dichloromethane/ethyl acetate/alcohol mixed solution (volume ratio is 1:1:1),
After fully dissolving, filter, collect filtrate, standby.Measure 0.5ml bilobalide/dichloromethane/ethyl acetate/ethanol mixing molten
Liquid is added in 2.5ml10%PVP solution, after mixing, carries out ultrasonic emulsification process.After ultrasonic end, collect mixed solution, often
The lower rotation of temperature evaporates organic solvent.Then sample is centrifuged 30min（4℃,10000rpm）, collect precipitation, add deionization
Water suspends again, recentrifuge.Repeatable operation 5 times, nanoparticle is cleaned up, and obtains bilobalide nanoparticle-PVP solution.
Average hydrodynamic diameter is 308.13nm, and polydispersity coefficient is 0.222.
Embodiment 6
1.5g bilobalide is added in 30ml dichloromethane/ethyl acetate/acetone mixed solution (volume ratio is 1:2:3),
After fully dissolving, filter, collect filtrate, standby.Measure 2.0ml bilobalide/dichloromethane/ethyl acetate/acetone mixing molten
Liquid is added in 1.0ml6%PVP solution, after mixing, carries out ultrasonic emulsification process.After ultrasonic end, collect mixed solution, room temperature
Lower rotation evaporates organic solvent.Then sample is centrifuged 30min（4℃,10000rpm）, collect precipitation, add deionized water
Suspend again, recentrifuge.Repeatable operation 5 times, nanoparticle is cleaned up, and obtains bilobalide nanoparticle-PVP solution.Grain
Footpath size is 635.62nm, and polydispersity coefficient is 0.635.
Embodiment 7
1.5g bilobalide is added in 30ml dichloromethane/ethyl acetate/acetone mixed solution (volume ratio is 1:1:1),
After fully dissolving, filter, collect filtrate, standby.Measure 0.75ml bilobalide/dichloromethane/ethyl acetate/acetone mixing molten
Liquid is added in 2.25ml6%PVP solution, after mixing, carries out ultrasonic emulsification process.After ultrasonic end, collect mixed solution, often
The lower rotation of temperature evaporates organic solvent.Then sample is centrifuged 30min（4℃,10000rpm）, collect precipitation, add deionization
Water suspends again, recentrifuge.Repeatable operation 5 times, nanoparticle is cleaned up, and obtains bilobalide nanoparticle-PVP solution.
Size is 244.42nm, and polydispersity coefficient is 0.282.
Embodiment 8
1.5g bilobalide is added in 30ml dichloromethane/ethyl acetate/acetone mixed solution (volume ratio is 1:1:1),
After fully dissolving, filter, collect filtrate, standby.Measure 0.30ml bilobalide/dichloromethane/ethyl acetate/acetone mixing molten
Liquid is added in 2.70ml5%PVP solution, after mixing, carries out ultrasonic emulsification process.After ultrasonic end, collect mixed solution, often
The lower rotation of temperature evaporates organic solvent.Then sample is centrifuged 30min（4℃,10000rpm）, collect precipitation, add deionization
Water suspends again, recentrifuge.Repeatable operation 5 times, nanoparticle is cleaned up, and obtains bilobalide nanoparticle-PVP solution.
Size is 238.27nm, and polydispersity coefficient is 0.256.
Embodiment 9
1.5g bilobalide is added in 30ml dichloromethane/ethyl acetate/acetone mixed solution (volume ratio is 1:1:1),
After fully dissolving, filter, collect filtrate, standby.Measure 0.15ml bilobalide/dichloromethane/ethyl acetate/acetone mixing molten
Liquid is added in 3.0ml5%PVP solution, after mixing, carries out ultrasonic emulsification process.After ultrasonic end, collect mixed solution, room temperature
Lower rotation evaporates organic solvent.Then sample is centrifuged 30min（4℃,10000rpm）, collect precipitation, add deionized water
Suspend again, recentrifuge.Repeatable operation 5 times, nanoparticle is cleaned up, and obtains bilobalide nanoparticle-PVP solution.Grain
Footpath size is 251.46nm, and polydispersity coefficient is 0.398.
Above-described is only embodiments of the invention, and in scheme, the general knowledge here such as known concrete structure and characteristic is not made
Excessive description.It should be pointed out that for a person skilled in the art, on the premise of without departing from present configuration, acceptable
Make some deformation and improve, these also should be considered as protection scope of the present invention, these are implemented all without the impact present invention
Effect and practical applicability.This application claims protection domain should be defined by the content of its claim, in description
Specific embodiment etc. records the content that can be used for explaining claim.
Claims (9)
1. it is characterised in that including shell and kernel, described kernel is bilobalide to bilobalide-PVP nanoparticle, and shell is
PVP.
2. bilobalide-PVP nanoparticle according to claim 1 it is characterised in that described shell external diameter be 30 ~
Between 1000nm.
3. bilobalide-PVP nanoparticle according to claim 2 it is characterised in that described shell external diameter be 30 ~
Between 500nm.
4. bilobalide-PVP nanoparticle according to claim 3 it is characterised in that described shell external diameter be 30 ~
Between 300nm.
5. according to described bilobalide-PVP nanoparticle arbitrary in claim 1 ~ 4 it is characterised in that：Described bilobalide
For ginkalide A, ginkalide B, ginkalide C, bilobalide J, bilobalide M, bilobalide K, bilobalide L and Semen Ginkgo
One or more of lactone.
6. bilobalide-PVP nanoparticle according to claim 5 preparation method it is characterised in that：Prepare including following
Method,
Step one, bilobalide is added in organic solvent, after fully dissolving, filters；
Step 2, bilobalide solution is added in PVP solution, after mixing, carries out ultrasonic emulsification process；
After step 3, ultrasonic end, collect mixed solution, evaporate organic solvent；
Step 4, sample is centrifuged, purification water washing precipitates, recentrifuge, nanoparticle is cleaned up by repeatable operation, you can
Obtain bilobalide-PVP nanoparticle.
7. the preparation method of bilobalide-PVP nanoparticle according to claim 6 is it is characterised in that having in step one
Machine solvent is one of methanol, ethanol, dichloromethane, acetoneand ethyl acetate or combination in any.
8. bilobalide-PVP nanoparticle according to claim 7 preparation method it is characterised in that：In step 2
, between 0.1% ~ 10%, the volume ratio of bilobalide solution and PVP solution is 2 for the concentration of PVP solution:1~1:Between 20.
9. bilobalide-PVP nanoparticle according to claim 8 preparation method it is characterised in that：In step 2
, between 2% ~ 8%, the volume ratio of bilobalide solution and PVP solution is 1 for the concentration of PVP solution:3~1：9.
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Cited By (1)
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| CN107929283A (en) * | 2017-12-29 | 2018-04-20 | 江苏康缘药业股份有限公司 | Ginkgo diterpenoid-lactone composition |
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Cited By (3)
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| CN107929283A (en) * | 2017-12-29 | 2018-04-20 | 江苏康缘药业股份有限公司 | Ginkgo diterpenoid-lactone composition |
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Application publication date: 20170208 |