CN105796529B - A kind of preparation method and applications of gambogicacid self-assembling polymers nanoparticle - Google Patents
A kind of preparation method and applications of gambogicacid self-assembling polymers nanoparticle Download PDFInfo
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- CN105796529B CN105796529B CN201610330456.3A CN201610330456A CN105796529B CN 105796529 B CN105796529 B CN 105796529B CN 201610330456 A CN201610330456 A CN 201610330456A CN 105796529 B CN105796529 B CN 105796529B
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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
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
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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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
Abstract
The present invention relates to a kind of preparation method and applications of gambogicacid self-assembling polymers nanoparticle.Polyethylene glycol, ε caprolactones, stannous octoate and toluene are added in three-necked bottle, in stirring and N2Under protection, 12h is reacted in 130 DEG C of oil baths；After reaction, toluene is screwed out；Dichloromethane lysate, is slowly dropped into a large amount of cold petroleum ethers and is precipitated, and repetitive operation filters, obtains polymer material；It takes gambogicacid to be placed in eggplant-shape bottle, after acetonitrile dissolving is added, adds polymer material, it dissolves again, screws out acetonitrile, form one layer of pharmaceutical film after acetonitrile screws out in bottle wall, it is put into vacuum drying chamber, removes trace acetonitrile, pure water is added, hydration process is carried out at 65 DEG C, then solution is placed in ice-water bath, ultrasound 2 times, each 2min under 315W power, ultrasound terminates, and crosses 0.45 μm of filter membrane.Nanoparticle encapsulation rate prepared by the present invention is high, drugloading rate is high, stability is good.
Description
Technical field
The present invention relates to gambogicacid self-assembling polymers nanoparticles of a kind of high encapsulation rate and its preparation method and application, belong to
In pharmaceutical chemistry technical field.
Background technology
Gambogicacid (gambogic acid, GA) is the main active of gamboge, can selectively induce tumour cell
Apoptosis has all shown extensive stronger antitumor action in vivo and in vitro, has stronger inhibition to make kinds of tumor cells
With, and to normal hemopoietic system and immune function without apparent inhibition.The antitumor mechanism of gambogicacid may be that retardance is thin
Born of the same parents' period, inducing cell apoptosis inhibit angiogenesis, related gene and albumen are combined and influenced with TfR (TfR)
Expression etc. it is related.Since solubility is minimum (being less than 0.5 μ g/mL) in water for gambogicacid, plasma clearance is fast, and distribution is wide in vivo
General, the bioavilability for resulting in gambogicacid is very low, significantly limits its Clinical practice.Therefore, developing anti-tumor medicaments rattan
The novel form of yellow acid is one of the critical issue solved needed for tumor research and development.
Self-assembling polymers nanoparticle is a kind of novel nano carrier that fast development is got up in recent years.It is by amphiphilic
Property polymer reach be self-assembly of after critical aggregation concentration (CMC) in water, there is hydrophobic cores and hydrophily shell
Nucleus-shell structure, also known as polymer micelle.Self-assembling polymers nanoparticle had both provided a hydrophobic kernel as drug
Storage cavern, and a hydrophilic shell is provided to maintain the stability in water environment.Just because of its special structure, from group
Dress polymer nanoparticle can increase the stability of drug in vivo and in vitro, increase the dissolubility of hydrophobic drug, and improve drug
The transfer performance of molecule.As novel drug delivery system, self-assembled nanometer grain is also equipped with other tempting properties, such as
Active targeting can be realized through modification, there is good biocompatibility, increase bioavilability etc..Since it has smaller grain
Diameter, therefore it is easy to be gathered in tumor tissues by " infiltration and reservation " (EPR) effect, plays targeting, while can also
Mitigate the toxic side effect of normal tissue.
Currently, gambogicacid has in preparation, solubilizer or cosolvent are commonly incorporated into solve the problems, such as that its solubility is small.But
It is the long-time service of these solubilizer and cosolvent, renal toxicity, allergy, neurotoxicity and Cardiovascular Toxicity etc. can be caused a series of
Adverse reaction.Also some researchers have studied the novel forms of gambogicacid, scarce but that there are stability is poor, drugloading rate is low mostly etc.
It falls into, so it is extremely urgent to solve the defects such as its solubility is small, bioavilability is low to study a kind of novel formulation of gambogicacid.
Invention content
The purpose of the present invention is overcome that the preparation stability of existing gambogicacid is poor, encapsulation rate is low and drugloading rate is low etc. to lack
Point, provide a kind of high encapsulation rate, high drug load, stabilization gambogicacid self-assembling polymers nanoparticle preparation method and its answer
With.
The technical solution adopted by the present invention is：A kind of preparation method of gambogicacid self-assembling polymers nanoparticle, including such as
Lower step：
1) prepared by polymer material：Polyethylene glycol, 6-caprolactone, stannous octoate and toluene are added in three-necked bottle,
Mechanical agitation and N2Under protection, 10-14h is reacted in 120-140 DEG C of oil bath；After reaction, reaction product naturally cools to room temperature,
Screw out toluene；With dichloromethane lysate, product all after dissolving, it is slowly instilled in petroleum ether and is precipitated, taken out
Filter, precipitation is dissolved with dichloromethane again, and in being slowly dropped into petroleum ether, repetitive operation, filtering obtains white product, and vacuum is dry
It is dry, obtain polymer material；
2) it takes gambogicacid to be placed in eggplant-shape bottle, after acetonitrile dissolving is added, adds polymer material, dissolve again, utilize
Rotary Evaporators screw out acetonitrile, form one layer of pharmaceutical film after acetonitrile screws out in bottle wall, are put into 40 DEG C of vacuum in vacuum drying chamber
Overnight, trace acetonitrile is removed, pure water is added, hydration process 2-8h is carried out at 60-70 DEG C, solution is then placed in ice-water bath
In, ultrasound 2-6 times under 135-315W power, each 2min, ultrasound terminates, and crosses 0.45 μm of filter membrane to get gambogicacid self assembly
Polymer nanoparticle.
A kind of preparation method of above-mentioned gambogicacid self-assembling polymers nanoparticle, the polyethylene glycol are selected from poly- second two
Alcohol 2000, Macrogol 4000, Macrogol 6000 and PEG 8000.Preferably, the polyethylene glycol is poly- second two
Alcohol 6000.
A kind of preparation method of above-mentioned gambogicacid self-assembling polymers nanoparticle, in molar ratio, 6-caprolactone:Poly- second two
Alcohol=2:0.1~9:0.1.Preferably, 6-caprolactone:Polyethylene glycol=4:0.1.
A kind of preparation method of above-mentioned gambogicacid self-assembling polymers nanoparticle, in mass ratio, gambogicacid:Polymeric material
Material=1:5~1:1.25.Preferably, gambogicacid:Polymer material=1:1.25.
A kind of preparation method of above-mentioned gambogicacid self-assembling polymers nanoparticle, it is preferred that ultrasonic power 315W.
The preparation method of above-mentioned a kind of gambogicacid self-assembling polymers nanoparticle, it is preferred that ultrasound 2 times, each 2min.
The gambogicacid self-assembling polymers nanoparticle prepared according to above-mentioned method is in preparing anti-tumor medicinal preparation
Using.
The present invention, in the catalysis of stannous octoate, causes 6-caprolactone (ε-using polyethylene glycol as the hydrophilic block of polymer
CL) ring-opening polymerisation, synthesis equation are as follows：
The beneficial effects of the invention are as follows：The present invention selects polyethylene glycol for hydrophilic block, and polycaprolactone is hydrophobic block, and two
The equal biological nontoxic of person, bio-compatible synthesize the polymer polycaprolactone-polyethylene glycol-polycaprolactone with biocompatibility.
In aqueous solution, polymer self assembles are " sun flower pattern " nanoparticle, wherein by gambogicacid package, are transmitted, its hardly possible is solved
Dissolubility problem extends its action time in vivo, improves bioavilability.Gambogicacid self-assembling polymers prepared by the present invention
Nanoparticle has good long circulating, good effect, stability, small toxicity, good biocompatibility, the spy that encapsulation rate is high and drugloading rate is high
Point, encapsulation rate are up to 99%, and drugloading rate is up to 40%.
Description of the drawings
Fig. 1 is the grain size distribution of gambogicacid self-assembling polymers nanoparticle prepared by embodiment 2.
Fig. 2 is the transmission electron microscope observing aspect graph of gambogicacid self-assembling polymers nanoparticle prepared by embodiment 2；
In figure, a:200nm is observed under the visual field；b：600nm is observed under the visual field.
Fig. 3 is the nanoparticle external release profile of gambogicacid self-assembling polymers nanoparticle prepared by embodiment 2.
Fig. 4 be gambogicacid and gambogicacid self-assembling polymers nanoparticle when for 24 hours to the inhibiting effect of BGC-823 cells.
Fig. 5 be gambogicacid and gambogicacid self-assembling polymers nanoparticle in 36h to the inhibiting effect of BGC-823 cells.
Fig. 6 be gambogicacid and gambogicacid self-assembling polymers nanoparticle in 48h to the inhibiting effect of BGC-823 cells.
Fig. 7 is mean blood plasma concentration-time after rat vein administration gambogicacid and gambogicacid self-assembling polymers nanoparticle
Curve.
Specific implementation mode
The preparation method of 1 gambogicacid self-assembling polymers nanoparticle of embodiment
Preparation method is as follows：
1) prepared by polymer material：0.04mol Macrogol 6000s, 0.001mol 6-caprolactones, 0.0001mol is pungent
Sour stannous and 5ml toluene are added in three-necked bottle, in mechanical agitation and N2Under protection, 12h is reacted in 130 DEG C of oil baths；Reaction terminates
Afterwards, reaction product naturally cools to room temperature, screws out toluene；It is after product all dissolves, it is slow with dichloromethane lysate
The a large amount of cold petroleum ethers of instillation in precipitated, filter, precipitation is dissolved with dichloromethane again, in being slowly dropped into petroleum ether,
Repetitive operation, filtering obtain white product, and 40 DEG C of vacuum drying obtain polymer material.
2) it takes 40mg gambogicacids to be placed in eggplant type bottle respectively, after the dissolving of 10ml acetonitriles is added, adds 50mg polymeric materials
Material, dissolves again, screws out acetonitrile using Rotary Evaporators, forms one layer of pharmaceutical film after acetonitrile screws out in bottle wall, be put into vacuum
40 DEG C of vacuum are stayed overnight in drying box, remove trace acetonitrile, and 20ml pure water is added, and hydration process 4h are carried out at 65 DEG C, then
Solution is placed in ice-water bath, ultrasound 2 times under 45W, 135W, 225W, 315W power respectively, each 2min, ultrasound terminates, mistake
0.45 μm of filter membrane is to get gambogicacid self-assembling polymers nanoparticle.As a result such as table 1.
Table 1
It is ultrasonic at 45W and 135W, there is a large amount of precipitation to generate, illustrates that the nanoparticle to be formed is less, most of drug is not
It is wrapped to settle.By table 1 as it can be seen that nanoparticle solution made from 225W power, grain size and PDI are than made from 315W power
Nanoparticle is big, considers that nanoparticle dispersion is evenly made from 315W power.For encapsulation rate and drugloading rate, ultrasonic power 315W
When encapsulation rate highest, be 99.12%, drugloading rate 41.20%.It is preferred, therefore, that ultrasonic power is 315W.
The preparation of 2 gambogicacid self-assembling polymers nanoparticle of embodiment
For method with embodiment 1, ultrasonic power selects 315W, only change ultrasonic number be respectively 1 time, 2 times, 3 times, 4 times,
5 times, 6 times, each 2min, measure grain size, PDI, encapsulation rate, the drugloading rate such as table 2 of gambogicacid self-assembling polymers nanoparticle.
Table 2
As can be seen from Table 2, when ultrasonic time increases 4min by 2min, encapsulation rate and drugloading rate highest.When continuing growing ultrasound
Between, encapsulation rate declines instead.And ultrasonic time is long, and polymer backbone is caused to be broken, and particle rupture, solution is unstable, hair
Some raw coagulations.It is preferred, therefore, that the time is 4min.
The preparation of 3 gambogicacid self-assembling polymers nanoparticle of embodiment
Method selects 315W with embodiment 1, ultrasonic power, and it is respectively 2h, 4h, 6h, 8h only to change hydration time, is measured
Grain size, PDI, encapsulation rate, the drugloading rate such as table 3 of gambogicacid self-assembling polymers nanoparticle.
Table 3
As seen in Table 3, hydration time increases to 8h by 2h, and in 4h, encapsulation rate and drugloading rate reach highest, select aquation
Time 4h.
The preparation of 4 gambogicacid self-assembling polymers nanoparticle of embodiment
Method only changes rate of charge with embodiment 1, and the mass ratio of gambogicacid and polymer material is respectively 1:10、1:
5、1:2、1:1.25、1:1, measure the grain size of gambogicacid self-assembling polymers nanoparticle, PDI, encapsulation rate, drugloading rate such as the following table 4.
Table 4
By table 4 as it can be seen that the ratio of drug and material is by 1:10 increase to 1:1.25, encapsulation rate gradually increases, in ratio 1:
Reach maximum when 1.25.The amount of drug is continued growing to ratio to 1:1, encapsulation rate declines instead.Meanwhile with the amount of drug
Increase higher encapsulation rate.
The preparation of 5 gambogicacid self-assembling polymers nanoparticle of embodiment
Method only changes polyethylene glycol with embodiment 1, measure gambogicacid self-assembling polymers nanoparticle grain size,
PDI, encapsulation rate, drugloading rate such as the following table 5.
Table 5
The preparation method of 6 gambogicacid self-assembling polymers nanoparticle of embodiment
(1) preparation method is as follows：
1) prepared by polymer material：0.04mol Macrogol 6000s, 0.001mol 6-caprolactones, 0.0001mol is pungent
Sour stannous and 5ml toluene are added in three-necked bottle, in mechanical agitation and N2Under protection, 12h is reacted in 130 DEG C of oil baths；Reaction terminates
Afterwards, reaction product naturally cools to room temperature, screws out toluene；It is after product all dissolves, it is slow with dichloromethane lysate
The a large amount of cold petroleum ethers of instillation in precipitated, filter, precipitation is dissolved with dichloromethane again, in being slowly dropped into petroleum ether,
Repetitive operation, filtering obtain white product, and 40 DEG C of vacuum drying obtain polymer material.
2) it takes 40mg gambogicacids to be placed in eggplant type bottle, after the dissolving of 10ml acetonitriles is added, adds 50mg polymer materials, then
Secondary dissolving screws out acetonitrile using Rotary Evaporators, forms one layer of pharmaceutical film after acetonitrile screws out in bottle wall, be put into vacuum drying chamber
In 40 DEG C of vacuum stay overnight, remove trace acetonitrile, 20ml pure water be added, hydration process 4h is carried out at 65 DEG C, then by solution
It is placed in ice-water bath, ultrasound 2 times under 315W power, each 2min, ultrasound terminates, and crosses 0.45 μm of filter membrane to get gambogicacid from group
Fill polymer nanoparticle.
Particle diameter distribution is as shown in Figure 1, as seen from Figure 1, and nanoparticle grain size is 217.7nm, and 0.138 grain size of the positions PDI is suitable, divides
It dissipates uniform and stable.
Nanoparticle form is observed as shown in Fig. 2, from Figure 2 it can be seen that nanoparticle is at spherical shape, form is uniform.
(2) it applies
In-vitro release curves such as Fig. 3 of the gambogicacid self-assembling polymers nanoparticle of acquisition, as seen from Figure 3, release slowly,
Persistently, gambogicacid needs to enter back into surrounding medium from diffusing out in hydrophobic core.
The gambogicacid self-assembling polymers nanoparticle of acquisition carries out anti tumor activity in vitro research.Study gambogicacid and its from
Assemble extracorporeal anti-tumor function of the polymer nanoparticle to human gastric cancer cells BGC-823 cell.The cell of nanoparticle when for 24 hours
Inhibiting rate is less than gambogicacid bulk pharmaceutical chemicals (such as Fig. 4), but as incubation time extends to 36h, 48h (such as Fig. 5-6), nanoparticle it is thin
Born of the same parents' inhibiting rate is higher than gambogicacid bulk pharmaceutical chemicals.As it can be seen that gambogicacid self-assembled nanometer grain has preferable extracorporeal anti-tumor function, and have
There is certain slow release effect.
The gambogicacid self-assembling polymers nanoparticle of acquisition carries out rat Internal pharmacokinetics research.It is quiet that big rat-tail is given respectively
Arteries and veins injects the gambogicacid and gambogicacid self-assembling polymers nanoparticle of doses, investigates its characteristics of pharmacokinetics, blood concentration with
The change curve of time such as Fig. 7 is compared with gambogicacid bulk pharmaceutical chemicals, gambogicacid self-assembled nanometer grain mean residence time and half-life period
Increasing, clearance rate reduces, and highest blood concentration improves, and has long circulating effect, illustrates gambogicacid self-assembled nanometer grain is made,
Its metabolic process in rat body can be changed.
Claims (5)
1. a kind of preparation method of gambogicacid self-assembling polymers nanoparticle, it is characterised in that preparation method is as follows：
1）It is prepared by polymer material：Macrogol 6000,6-caprolactone, stannous octoate and toluene are added in three-necked bottle,
Stirring and N2Under protection, 120-140 DEG C of oil bath reaction 10-14 h；After reaction, reaction product naturally cools to room temperature, rotation
Go out toluene；With dichloromethane lysate, product all after dissolving, is slowly dropped into petroleum ether and is precipitated, and is filtered, and is sunk
Shallow lake is dissolved with dichloromethane again, and in being slowly dropped into petroleum ether, repetitive operation, filtering obtains white product, is dried in vacuo, obtains
Polymer material；
2）It takes gambogicacid to be placed in eggplant-shape bottle, after acetonitrile dissolving is added, adds polymer material, dissolve again, utilize rotation
Evaporimeter screws out acetonitrile, forms one layer of pharmaceutical film after acetonitrile screws out in bottle wall, is put into 40 DEG C of vacuum in vacuum drying chamber and stays overnight,
Trace acetonitrile is removed, pure water is added, hydration process 2-8 h are carried out at 60-70 DEG C, then solution is placed in ice-water bath,
Ultrasound 2 times under 315 W power, each 2min, ultrasound terminates, and crosses 0.45 μm of filter membrane and is received to get gambogicacid self-assembling polymers
The grain of rice；In mass ratio, gambogicacid:Polymer material=1:2~1: 1.25.
2. a kind of preparation method of gambogicacid self-assembling polymers nanoparticle according to claim 1, it is characterised in that：It presses
Molar ratio, 6-caprolactone:Macrogol 6000=2: 0.1~9 : 0.1.
3. a kind of preparation method of gambogicacid self-assembling polymers nanoparticle according to claim 2, it is characterised in that：It presses
Molar ratio, 6-caprolactone:Macrogol 6000=4: 0.1.
4. a kind of preparation method of gambogicacid self-assembling polymers nanoparticle according to claim 1, it is characterised in that：It presses
Mass ratio, gambogicacid:Polymer material=1: 1.25.
5. the gambogicacid self-assembling polymers nanoparticle prepared according to claim 1-4 any one of them methods is preparing anti-swell
Application in tumor medicine preparation.
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| CN108478804B (en) * | 2018-05-08 | 2020-09-22 | 辽宁大学 | Polyacrylic acid-S-S-drug copolymer and preparation method thereof |
| CN114767620B (en) * | 2022-03-16 | 2023-06-27 | 四川省医学科学院·四川省人民医院 | Gambogic acid-loaded multistage response injectable hydrogel and application thereof |
| CN116172961B (en) * | 2023-02-17 | 2023-08-25 | 中国中医科学院中药研究所 | Gambogic acid dimer self-assembled nanoparticle and preparation method and application thereof |
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