CN106581647A - PH response insulin slow release nanoparticle, and preparation method and application thereof - Google Patents
PH response insulin slow release nanoparticle, and preparation method and application thereof Download PDFInfo
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
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- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
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Abstract
The invention relates to a pH response insulin slow release nanoparticle, and a preparation method and an application thereof, and concretely discloses a triblock copolymer. The triblock copolymer is an A-B-C block copolymer, wherein the A block is biodegradable polyethylene glycol monomethyl ether, and the molecular weight is 4000-6000; the B block is polycaprolactone, and the molecular weight is 8000-15000; and the C block is N,N-diethylaminoethyl polybasic polymethacrylate, and the molecular weight is 8000-12000. The pH response insulin slow release nanoparticle is formed by a nanocapsule formed by self-assembling the triblock polymer and insulin loaded on the nanocapsule. The nanoparticle can accurately deliver drugs according to different pH values, and can simultaneously reach sustained and controlled release effects.
Description
Technical field
The invention belongs to pharmaceutical dosage form and Nano medication preparing technical field, more particularly to a kind of triblock polymer is born
Carry the medicine of insulin.
Background technology
Insulin (INS) is the choice drug for treating type i diabetes.But, INS bodies intracellular metabolite eliminates fast, easily quilt
Stomach enteral strong acid, alkali, digestive ferment destruction degraded, the low defect of bioavilability, therefore clinical often hypodermic injection and need long term frequent
Administration, this is easy for causing internal blood concentration fluctuation excessive, and to patient life danger is brought.In recent years, INS is increased to reach
Intestines and stomach stability, improve bioavilability, extend internal hypoglycemic time, the purposes such as administration number of times are reduced, with good raw
The natural biodegradable macromolecular material of thing compatibility such as alginate, sodium hyaluronate, Chitosan-phospholipid complex etc. and people
Work synthesising biological degradable high polymer material such as polycaprolactone (PCL), polyacrylic acid and its copolymer, polylactide and its copolymer
Deng the nanoparticle delivery system for being applied to INS.
Huynh etc. forms the INS of cation and junction belt electronegativity using poly- amino ester under low pH and low temperature, in high pH
With the characteristic that volatile deprotonation under high temperature forms insoluble block, it is prepared for pH sensitive temperature control sustained-release injected gel, should
Carry medicinal gel can long-acting slow-release 15 days in vitro, single injection can make rat blood sugar that normal level, but its bag were maintained in one week
Envelope rate is relatively low and injection process easily causes blocking.
The content of the invention
In order to solve the above problems, one aspect of the invention provides a kind of triblock polymer, the three block polymerization
Thing is A-B-C shape block copolymers, and wherein A blocks are biodegradable poly glycol monomethyl ether (mPEG), and molecular weight is
4000-6000 (preferably 5000)；B block is polycaprolactone (ε-PCL), and molecular weight is 8000-15000 (preferably 10000-
13000)；C blocks be polybases polymethylacrylic acid-N, N- lignocaine ethyl esters, molecular weight be 8000-12000 (preferably
10000)。
Another aspect of the invention provides a kind of preparation method of aforesaid triblock copolymer, and it includes following step
Suddenly：
1) mPEG-PCL-OH is synthesized；
2) synthetic macromolecule initiator mPEG-PCL-Br；
3) triblock polymer mPEG-PCL-PDEAEMA is synthesized；
Wherein, step 1) with mPEG and ε-CL as raw material, the Sn (oct) of 1% ε-CL molal weights2For catalyst, pass through
Ring-opening polymerization method synthesizes mPEG-PCL-OH；
Step 2) TEA and BiBB (w is added in mPEG-PCL-OH:w:W, mPEG-PCL-OH:TEA:BiBB=1:3-6:
1-3, preferably 1:4:2) reaction obtains macromole evocating agent mPEG-PCL-Br；
Step 3) mPEG-PCL- is generated under CuBr and Bpy catalysis with macromole evocating agent mPEG-PCL-Br and DEAEMA
PDEAEMA(w:w:w,mPEG-PCL-Br:Bpy:CuBr=1:3-6:1-3, preferably 1:4:2) triblock polymer.
There is provided a kind of pH response insulin slow release nanoparticles, it is gathered another aspect of the present invention by the three block of the present invention
The insulin loaded on nanocapsule that compound is self-assembly of and nanocapsule is constituted.
In the inventive solutions, in pH responses insulin slow release nanoparticle between insulin and triblock polymer
Mass ratio be 2～9.9:10, preferably 8.5～9.5:10, further, it is preferable to be 9:10.
In the inventive solutions, polymer shared by hydrophilic segment volume point in pH responses insulin slow release nanoparticle
The percentage coefficient f of subpopulation producteoFor 0.5-0.6.
There is provided the preparation method of pH response insulin slow release nanoparticles, it includes following step to another aspect of the present invention
Suddenly：
1) with acid leach solution insulin, and pH value is adjusted to 5.5-6.5, preferably 6；
2) triblock polymer mPEG-PCL-PDEAEMA is dissolved with organic solvent, and drops to step 1) resulting solution
In；
3) remove after organic solvent and precipitation is collected by centrifugation, pH response insulin slow release nanoparticles are obtained after freezing.
Another aspect of the present invention is preparing the use as drug carrier system there is provided the triblock polymer of the present invention
On the way, it is preferable that the drug carrier system is nanoparticle, micella, sustained and controlled release medicament carrier, pH sensitive medicaments carriers.
The present invention another aspect provide the present invention pH response insulin slow release nanoparticle prepare treatment diabetes,
Use in hyperglycemia, prediabetes, glucose tolerance reduction, type i diabetes, type ii diabetes, the medicine of syndrome X
On the way.
Another aspect of the invention provides a kind of pharmaceutical composition, and its pH responses insulin slow release of the present invention is received
The grain of rice.
In the inventive solutions, the preparation of pharmaceutical composition is injection.
The present invention is with pH response type polybases polymethylacrylic acid-N, N- lignocaine ethyl esters (PDEAEMA) grafting biofacies
Capacitive is good, biodegradable poly glycol monomethyl ether (mPEG) and PCL segments, and it is higher to be prepared for envelop rate, internal hypoglycemic
Curative effect is preferably and injection is without the INS slow release nano-particles for blocking.
The present invention obtains controllable three of molecular weight stabilizers initially with the method synthesis that ROP reactions and ATRP reactions combine
Block polymer mPEG-PCL-PDEAEMA；With the polymer as pharmaceutical carrier, pH value of solution is adjusted, made positively charged
PDEAEMA forms ion complex with the INS of oppositely charged, obtains being wrapped up the load INS nanoparticle of winding by hydrophilic segment,
And the physicochemical property of the nanoparticle, release in vitro and internal hypoglycemic curative effect are further investigated, it is the sustained release preparation exploitation of INS
Reference is provided.
The cationic polymers such as existing document report, PDEAEMA, PDMAEMA, can be biological frequently as non-viral gene vector
Degradation-type polyester is usually used in the embedding of dewatering medicament, therefore the polymer support obtained with polyester block grafted cation polymer exists
Gene and drug delivery aspect have huge application potential.At present, by the related block copolymerization of PDEAEMA and grafting PDEAEMA
The research that thing is used for embedding protein medicaments is less, therefore selects segment based on mPEG-PCL, is grafted PDEAEMA, obtains to egg
White class medicine has the high embedding ability triblock copolymer with outstanding slow release effect again.It is polymer drug-carried with this, can not only
The stability of the medicine that is embedded is improved, can also be by adjusting the factor such as solution ph and hydrophobic segment length come regulating medicine release
Behavior, and then burst drug release amount is reduced, delay insoluble drug release.
Self assembly behavior of the polymer in water is affected by solution ph.This is due to both existing on PDEAEMA segments
, there is hydrophobic alkyl in hydrophilic tertiary amine groups, tertiary amine groups can be protonated and deprotonation in different pH environment again.
Strong acid environment be pH be 1.2 and 2.5 when, tertiary amine groups protonation, make a large amount of positive charges, one side positive electricity on PDEAEMA segment bands
Repulsive interaction between lotus makes PDEAEMA segments show as extended conformation, so as in the form of molecule in the aqueous solution
In, the positive electric field around another aspect segment has attracted the anion in the aqueous solution, and these negative electrical charges prevent PDEAEMA segments
Further stretching, extension, the two collective effect causes polymer nanoparticle to be mutually agglomerated into bulk.And at pH6～7.4, with pH
The increase of value, tertiary amine groups protonation gradually weakens, and PDEAEMA segments hydrophobicity strengthens and causes itself segment to shrink winding
Or there is random winding with PCL segments, and nanoparticle kernel is formed, prevent copolymer to be collected as bigger particulate, ultimately result in
Nanoparticle particle diameter is presented the trend for reducing.
Nanoparticle discharges polypeptide can be divided into three-phase with the typical curve of protein drug：Initial burst release phase, diffusion controlled release
Mutually with degraded controlled release phase, when controlled release phase is spread and degraded controlled release overlaps, medicine can continuously discharge.Therefore drug release in vitro
In experiment, tablets in vitro curve of the different polymer supported INS nanoparticles in two kinds of pH dissolution mediums present the quick release phase and
Gentle acquisition time.At the release initial stage, particle surface INS is larger with the concentration difference of INS in dissolution medium so that by hydrogen bond or its
His adhesion sticks to the INS of nanoparticle hydrophilic surface and is fast released, and forms burst effect.As surface combines INS's
Release, nanoparticle starts disintegration and forms space, and the INS of inside particles embedding is continuously released by.But due to particle surface Jing aquations
Swelling to have gradually formed hydration shell, inside particles INS reduces with INS concentration differences in dissolution medium, and inside and outside osmotic pressure is reduced, and makes grain
Sub internal INS is to dissolution medium diffusion hindered.And with the prolongation of drug release time, the mPEG-PCL segment Jing in nanoparticle are external
Ester linkage hydrolyzing, slowly degrade without processes such as enzyme ammonolysis, further hinder the release of the INS of inside particles embedding, therefore gently release
Put the phase rate of releasing drug is slow and relative constancy.
The release in vitro of polymer drug-carried nanoparticle has certain pH sensitiveness, this cation with PDEAEMA segments
Characteristic is relevant.INS is mainly written into nanoparticle by there is electrostatic interaction with amino positively charged on PDEAEMA segments
In.Under acid condition, easily there is the shell that protonation is swelling, with PEG forms nanoparticle in PDEAEMA segments, be exposed to INS and release
In putting medium, the electric charge in dissolution medium can disturb the electrical function of PDEAEMA and INS so that INS releases are accelerated, and in
In property or alkaline environment, the contraction nucleation of PDEAEMA segments, medicine is wrapped in hydrophobic inner core, has completely cut off connecing for dissolution medium
Touch, cause INS releases to slow down.In two kinds of dissolution mediums, mPEG5k-PCL13k-PDEAEMA10k carries the prominent of INS nanoparticles and releases
Amount and drug release rate carry INS nanoparticles significantly lower than mPEG5k-PCL10k-PDEAEMA10k, are on the one hand probably hydrophobic chain
The stability for enhancing nanoparticle structure of section.Studies have reported that, amphipathic nature polyalcohol self assembly form in the solution
It is relevant with the hydrophobe segment of polymer, the percentage coefficient f of polymer molecule cumulative volume shared by hydrophilic segment volume can be passed througheo
It is determined that, as 0.2 ＜ feo≤ 0.4 can form imitated vesicle structure, and polymeric bladder bubble structure has good stability, and structural strength is big, resists dilute
Ability is released strong, the advantages of Drug loading capacity is big.The present invention is preparing pKs of pH when carrying INS nanoparticles less than PDEAEMA segmentsa
(7.3), PDEAEMA segments are hydrophilic segment, and mPEG5k-PCL10k-PDEAEMA10k carries the f of INS nanoparticleseoIt is worth for 0.6, and
MPEG5k-PCL13k-PDEAEMA10k carries the f of INS nanoparticleseoIt is worth for 0.53.Speculate the nanoparticle structure of formation of the latter more
Close to vesica, therefore its CAC value is less, and structure is more stable, and envelop rate and carrying drug ratio are also higher.On the other hand, PCL segments
Increase can also increase nanoparticle kernel hydrophobicity, the interaction of medicine and carrier be enhanced indirectly, while can also slow down nanometer
The disintegration rate of grain, makes dissolution medium be not easily accessible inside particles, so as to delay drug releasing rate.
Carry polypeptide mainly has emulsion process, dialysis, membrane process, solvent volatilization with the preparation method of pharmaceutical grade protein nanoparticle
Method, precipitation method etc..The present invention is prepared with nanoprecipitation technology and carries INS nanoparticles, and preparation method is simple, and mild condition only passes through
Adjusting pH value of solution makes polymer and medicine form ion complex, and it is spontaneous in self assembling process wrapped up by hydrophilic segment, make
Obtain particle diameter less, the higher drug-carrying nanometer particle of envelop rate, carrying drug ratio.The polymer supported INS nanometers plastochondria has in vitro obvious
Sustained release and prominent drug release amount is less, can reach in vivo continual and steady hypoglycemic effect, it is to avoid vivo medicine concentration fluctuation is excessive,
Drug administration by injection number of times is reduced, therefore has certain application prospect.But it is molten with organic due to cannot be avoided medicine in its preparation process
The contact of agent, and still need to drug administration by injection, thus change preparation method, polymer architecture is carried out modifying transformation to obtain other to
The sustained release preparation of prescription formula is still under study for action.
Beneficial effect
The nanoparticle of the present invention can carry out the accurate delivery of medicine according to different pH value, while slow controlled release can be reached
Effect.
Description of the drawings
Fig. 1 is the synthetic route chart of triblock polymer mPEG-PCL-PDMAEMA.
Fig. 2 is FT-IR result spectrograms, and all spectrograms are in 1109cm in Fig. 2-1Place there are stretching for mPEG segment C-O keys
Contracting vibration peak, in 1724cm-1Place there are the stretching vibration peak of PCL segment C=O keys, in 2878cm-1Place there are mPEG chains
Section and PCL segment-CH2- stretching vibration peak, show that mPEG and PCL synthesize successfully.Due in mPEG5k-PCL10k-Br
- C-Br- proportion very littles, therefore Fig. 2-A and Fig. 2-B difference be not obvious.In 2776cm in Fig. 2-C-1And 2834cm-1Place
It can clearly be seen that the flexible peak of the distinctive methyl of PDEAEMA and methylene, show PDEAEMA and mPEG5k-PCL10k-Br into
Work(is polymerized, and infared spectrum result is consistent with the expected structure of polymer.In the same manner, mPEG5k-PCL13k-PDEAEMA10k is pressed
Same method carries out infrared analysis, and also confirmation has obtained corresponding triblock polymer.
Fig. 3 is 1H-NMR result collection of illustrative plates, and all spectrograms have the methyl proton characteristic peak (H of mPEG in Fig. 3a, δ=
3.4ppm) with methene proton characteristic peak (Hb, δ=3.66ppm).In Fig. 3-A, δ=4.07ppm (Hg), δ=2.33ppm
(Hc), δ=1.65ppm (HdAnd Hf) and δ=1.39ppm (He) belong to the methene proton characteristic peak of PCL, show mPEG and ε-
CL is successfully polymerized.Compared with Fig. 3-A, there is bromomethyl proton characteristic peak (H in Fig. 3-Bh, δ=1.94ppm).In Fig. 3-C,
In δ=2.73ppm (Hl), δ=2.59ppm (Hm), δ=1.84ppm (Hi), δ=1.07ppm (Hn) and δ=0.9ppm (HjWith
Hh) signal peak be DEAEMA characteristic peak, show that DEAEMA is polymerized with macromole evocating agent mPEG-PCL-Br.
Fig. 4 is pyrene fluorescence intensity ratio I338/I333 and nanoparticle log concentration graph of a relation.
Fig. 5 is grain diameter influence's result figure of the nanoparticle that pH value is formed to polymer.
Fig. 6 is the transmission electron microscope picture of the grain diameter influence of the nanoparticle that pH value is formed to polymer.
Fig. 7 is the transmission electron microscope picture for loading nanoparticle particle diameter after INS, and wherein A is mPEG5k-PCL10k-PDEAEMA10k
Blank nanoparticle, B is that mPEG5k-PCL10k-PDEAEMA10k carries INS nanoparticles, and C is mPEG5k-PCL13k-PDEAEMA10k
Blank nanoparticle, D is that mPEG5k-PCL13k-PDEAEMA10k carries INS nanoparticles.
Fig. 8 is the release in vitro result figure for carrying INS nanoparticles.
Fig. 9 is the internal pharmacodynamic results figure for carrying INS nanoparticles, and wherein A is internal blood concentration figure, and B is blood sugar concentration change
Change figure.
Specific embodiment
Agents useful for same of the present invention and instrument
Diethylaminoethyl base ethyl ester (DEAEMA, 99%), 6-caprolactone (ε-CL, purity 99%), polyethylene glycol
Monomethyl ether (mPEG5000), stannous octoate (Sn (oct)2, 95%), and 2- bromine isobutyl acylbromides (BiBB, 98%), 2,2'- bipyridyls
(Bpy, 99.0%), (CuBr, 99.0%), (98%) STZ is purchased from Shanghai Aladdin biochemistry section to Streptozotocin to cuprous bromide
Skill limited company, insulin bulk drug (INS, Xuzhou Wanbang Jinqiao Pharmaceutical Co., Ltd., lot number 1601A09), BCA albumen
Concentration measuring kit (green skies Bioisystech Co., Ltd), pork insulin ELISA detection kit, bag filter (8000～
14000, Ke Hao bioengineering Co., Ltds), other reagents such as dichloromethane (DCM), tetrahydrofuran (THF), triethylamine (TEA)
It is analysis pure.
Malvern-3000Hs type photon correlation spectrometers (Malvern company of Britain), the type nuclear magnetic resonance ripples of Avance II 40
General instrument (German Brooker company), the type Fourier infrared spectrographs of Nicolet 6700 (match Mo Feishier companies of the U.S.), H-
7650 type transmission electron microscopes (Japanese Hitachi companies), RF-5301PC type fluorescence detectors (Japanese Shimadzu Corporation),
IMark type ELIASAs (BIO-RAD companies), refrigerated centrifuge (German Eppenddorf companies), the type centrifuges of Pico 21 are (beautiful
Match Mo Feishier companies of state)
Sprague-Dawley (SD) rat, male, is provided, the quality certification by Nanfang Medical Univ's animal experimental center：
SCXK (Guangdong) 2011-0015.
The synthesis of the triblock polymer mPEG-PCL-PDEAEMA of embodiment 1
The synthesis of 1.mPEG-PCL-OH
Using ring-opening polymerisation method.Precision weighs appropriate mPEG5000 and ε-CL (w:w,1:2-2.6), it is placed in 50ml and is dried circle
In the flask of bottom, with the Sn (oct) of 1% ε-CL molal weights2For catalyst, 24h. reactions are reacted in nitrogen environment at 130 DEG C
Add appropriate DCM dilutions after end, precipitate in excessive ice ether, suction filtration, collect precipitation, the appropriate DCM of addition dissolves again.Repeat
Aforesaid operations 2 times, obtain white powder product, and at 40 DEG C constant weight is dried under vacuum to.
2. the synthesis of macromole evocating agent mPEG-PCL-Br
Precision weighs appropriate above-mentioned product mPEG-PCL-OH and is dried round-bottomed flask in 50ml, adds appropriate DCM dissolvings, in
TEA and BiBB (w is proportionally added in ice-water bath:w:w,mPEG-PCL-OH:TEA:BiBB=1:4:2), nitrogen environment under room temperature
Middle reaction 48h.After reaction terminates, filter, 35 DEG C of revolvings remove a large amount of organic solvents, precipitate in excessive ice methyl alcohol, suction filtration, receive
Collection precipitation, adds appropriate DCM to dissolve again, repeats aforesaid operations 2 times, obtains white powder product, is vacuum dried at 30 DEG C
To constant weight.
3. triblock polymer mPEG-PCL-PDEAEMA synthesis
By atomic radicals polymerisation, macromole evocating agent and DEAEMA (w:w,1.5-1.8:1) in CuBr and Bpy
Catalysis is lower to generate mPEG-PCL-PDEAEMA triblock polymers.Precision weighs appropriate macromole evocating agent and is placed in 50ml and is dried justifies
In the flask of bottom, appropriate dry THF dissolving is added, be proportionally added into Bpy, DEAEMA and CuBr (w successively under nitrogen environment:w:
W, macromole evocating agent:Bpy:CuBr=1:4:2), 24h is reacted in nitrogen environment at 60 DEG C.After reaction terminates, add appropriate
THF dilute, copper complex is removed in neutral alumina column, with the bag filter that intercepting molecular weight is 8000～14000 go from
Dialysis 24h (changing a deionized water per 8h) in sub- water, the unreacted monomer of removing and small molecular weight impurity, freeze-drying, finally
Obtain triblock polymer mPEG-PCL-PDMAEMA.Synthetic route is as shown in Figure 1.
The sign of the polymer of embodiment 2
1 FTIR spectrum (FT-IR) is characterized
KBr after appropriate product to be measured and drying is milled into at room temperature powder, taking appropriate powder is carried out at compressing tablet
Reason, scans 400～4 000cm-1Wave number absorption spectrum.
FT-IR spectrogram interpretations of result
All spectrograms are in 1109cm in Fig. 2-1Place there are the stretching vibration peak of mPEG segment C-O keys, in 1724cm-1
Place there are the stretching vibration peak of PCL segment C=O keys, in 2878cm-1Place there are mPEG segments and PCL segment-CH2- stretch
Contracting vibration peak, shows that mPEG and PCL synthesize successfully.Due to-C-Br- proportion the very littles in mPEG5k-PCL10k-Br,
Therefore Fig. 2-A and Fig. 2-B difference be not obvious.In 2776cm in Fig. 2-C-1And 2834cm-1Place is it can clearly be seen that PDEAEMA is special
The flexible peak of some methyl and methylene, shows that PDEAEMA is successfully polymerized with mPEG5k-PCL10k-Br, infared spectrum
As a result it is consistent with the expected structure of polymer.In the same manner, mPEG5k-PCL13k-PDEAEMA10k carries out in the same way infrared
Analysis, also confirms and has obtained corresponding triblock polymer.
2 proton nmr spectras (1H-NMR) characterize
Deuterochloroform (CDCl3) it is solvent, tetramethylsilane (TMS) is internal standard, and the nuclear-magnetism light of testing sample is determined at 25 DEG C
Spectrum.Position and area according to relevant peaks in spectrogram, determines that polymer architecture is constituted and the degree of polymerization.
1H-NMR profiling results are analyzed
In Fig. 3 there is the methyl proton characteristic peak (H of mPEG in all spectrogramsa, δ=3.4ppm) and methene proton feature
Peak (Hb, δ=3.66ppm).In Fig. 3-A, δ=4.07ppm (Hg), δ=2.33ppm (Hc), δ=1.65ppm (HdAnd Hf) and δ=
1.39ppm(He) belong to the methene proton characteristic peak of PCL, show that mPEG and ε-CL are successfully polymerized.Compared with Fig. 3-A,
There is bromomethyl proton characteristic peak (H in Fig. 3-Bh, δ=1.94ppm).In Fig. 3-C, in δ=2.73ppm (Hl), δ=2.59ppm
(Hm), δ=1.84ppm (Hi), δ=1.07ppm (Hn) and δ=0.9ppm (HjAnd Hh) signal peak be DEAEMA characteristic peak,
Show that DEAEMA is polymerized with macromole evocating agent mPEG-PCL-Br.The number that can calculate polymer by nuclear magnetic spectrogram is homogeneous
To molecular mass, according to δ=3.66ppm (Hb) peak area and δ=2.33ppm (Hc) ratio of peak area can calculate the poly- of PCL sections
It is right, according to δ=2.67ppm (Hl) peak area and δ=4.07ppm (HgAnd Hk) ratio of peak area can calculate DEAEMA sections
The degree of polymerization, is shown in Table 1.
The sign of the polymer of table 1 and polymer nanoparticle
The measure of 3 critical aggregation concentrations
The critical aggregation concentration that triblock polymer is determined using fluorescence probe method is CAC values.CAC values are to characterize polymerization
The important parameter of thing nano particle structure stability and anti-dilution capacity, CAC values are less, and anti-dilution capacity is stronger, particle structure
It is more stable.As shown in Figure 4, mPEG5k-PCL10k-PDEAEMA10k carries INS nanoparticles and mPEG5k-PCL13k-
PDEAEMA10k carries the critical aggregation concentration of INS nanoparticles and is respectively 6.4 × 10-4g·L-1With 2.8 × 10-4g·L-1。
The sign of 4 polymer nanoparticle particle diameters and form
Table is carried out to the granularity of polymer drug-carried nanoparticle using dynamic light scattering laser particle size and Zeta potential analyzer
Levy, take nanoparticle solution to be measured in right amount, fully dilution detects particle diameter and zeta current potentials after being allowed to be uniformly dispersed；Using transmitted electron
Microscope (TEM) observes the size and form of polymer supported INS nanoparticles.Appropriate nanoparticle solution to be measured is taken, fully after dilution,
Drip on carbon film copper mesh, stop 3min, with filter paper unnecessary solution is sucked, 0.1% Salkowski's solution dyeing 3min, room is added dropwise
The lower drying of temperature, transmission electron microscope observing shoots particle shape.Result of the test is referring to the result of embodiment 5.
The preparation of the polymer supported INS nanoparticles of embodiment 3
Polymer nanoparticle is prepared using nanoprecipitation technology.Precision weighs appropriate INS and is dissolved in 6ml, 0.01mol/L's
HCl solution, under pH meter detection, its pH value is adjusted to 6.0 with 1mol/L NaOH solutions.6mg polymer is substantially soluble in
In 0.6ml tetrahydrofurans, during above-mentioned solution is slowly dropped under stirring condition, being stirred overnight in fume hood under room temperature makes tetrahydrochysene furan
Mutter and wave to the greatest extent.4 DEG C, 30min is centrifuged under the conditions of 14000rpm, collects precipitation, deionized water is washed 3 times, and freeze-drying obtains final product polymerization
Thing carries INS nanoparticles.Polymer blank nanoparticle is prepared with method.
The measure of the envelop rate of embodiment 4 and carrying drug ratio
Respectively by the 6ml blank polymer nanoparticle solution and polymer supported INS nanoparticles solution of different dispensing ratios 4
DEG C, it is centrifuged under the conditions of 14000rpm after 0.5h and collects supernatant.INS contents in supernatant are determined using BCA methods, further according to following formula meter
Calculate the envelop rate and drugloading rate of polymer drug-carried nanoparticle.
Envelop rate (EE%)=(quality of the gross mass of INS-supernatant INS)/dispensing gross mass × 100%
Carrying drug ratio (DL%)=(quality of the gross mass of INS-supernatant INS)/nanometer formulation gross mass × 100%.
The envelop rate of polymer supported INS nanoparticles and drugloading rate interpretation of result
Investigate two by carrier of mPEG5k-PCL10k-PDEAEMA10k and mPEG5k-PCL13k-PDEAEMA10k respectively
The polymer supported INS performances of different molecular weight are planted, rate of charge is as shown in table 2.Envelop rate is evaluation carrier quality of materials quality
Important indicator, envelop rate is higher, and free drug is fewer, i.e., sustained drug release effect is better, and drugloading rate is evaluation carrier material load
One important indicator of property of medicine energy, the higher drug carrying ability of drugloading rate is better.Therefore selection envelop rate and drugloading rate are examined for overall target
Optimum rate of charge is examined, weight coefficient is 0.5, the rate of charge with highest comprehensive grading group is optimal.2 are the results are shown in Table, wherein,
It is higher than 20%wt (P that mPEG5k-PCL10k-PDEAEMA10k carries the comprehensive grading conspicuousness of INS nanoparticle 90%wt rate of charge groups
<0.001), 50%wt (P<0.001) with 70%wt (P<0.001) comprehensive grading of rate of charge group, mPEG5k-PCL13k-
The comprehensive grading conspicuousness of PDEAEMA10k drug-carrying nanometer particle 90%wt rate of charge groups is higher than 20%wt (P<0.001), 50%wt
(P<0.001) with 70%wt (P<0.001) comprehensive grading of rate of charge group, therefore two kinds of final choice 90%wt rate of charge preparation gathers
Compound nanoparticle carries out follow-up test.
The envelop rate of the polymer supported INS nanoparticles of table 2 and drugloading rate (n=3)
The solution ph of embodiment 5 is investigated to polymer self assembles behavior
Method is with embodiment 1 the 4th.Take 6 parts of 6ml deionized waters, under pH meter detection, with 0.01mol/L HCl and
1mol/L NaOH are adjusted to different pH (1.2,2.5,6,6.4,7.2,7.4), separately take 6 parts of 6mg triblock polymers, and difference is molten
In 0.6ml THF, fully after dissolving, under 200rpm stirrings, slowly (10s/ in above-mentioned deionized water is dropwise instilled respectively
D), it is stirred overnight in fume hood under room temperature and waves THF to the greatest extent.The particle diameter and form of polymer nanoparticle are detected.
Polymer nanoparticle particle diameter and morphological analysis
MPEG5k-PCL10k-PDEAEMA10k polymer is selected to observe solution ph to polymer self assembles behavior
Affect.From Fig. 5 and 6, when pH value of solution is 1.2 and 2.5, nanoparticle there occurs reunion, and particle diameter is larger, be 6- in pH value of solution
When 7.4, as solution ph increases, nanoparticle particle diameter is gradually presented reduction trend, and form is also presented spherical or spherical shape.
DLS results be displayed in pH value of solution for 6 when, polymer mPEG5k-PCL10k-PDEAEMA10k and mPEG5k-
The particle diameter of PCL13k-PDEAEMA10k blank nanoparticles is respectively 78.5 ± 2.5nm and 81.8 ± 2nm, carries the nanoparticle of INS
Particle diameter is respectively 169 ± 7.1nm and 181.9 ± 6.67nm, it is seen that nanoparticle particle diameter is significantly increased after load INS, this size
The change of size can directly be observed by TEM, see Fig. 7.TEM results are displayed in above-mentioned environment, blank nanoparticle and carry medicine
Nanoparticle state spherical in shape, and dispersion ratio is more uniform.Both are 60 rans by blank particle diameter, carry the grain of INS nanoparticles
Footpath is respectively 150 and 170 rans.Because DLS test be nanoparticle hydrated diameter, and TEM test be nanoparticle
Dry state size, therefore the two test result slightly has difference.
Embodiment 6 carries the release in vitro behavior of INS nanoparticles and investigates
Precision weighing INS bulk drugs and each 5mg of polymer supported INS nano-granule freeze-dried powders, are respectively placed in the centrifuge tube of 50mL,
Add 5ml PBS (0.01mol/L, pH=6.4,7.2), in 37 ± 1 DEG C of waters bath with thermostatic control, 80rpm is at the uniform velocity stirred, and
Keep sink conditions.According to set time point samples 0.5ml, while supplementing the fresh medium of equivalent isothermal.Sample Jing
After 14000rpm centrifugation 30min, take out supernatant and determine INS contents, the medicine in the computational rules time adds up release rate.Each
Sample operation repetitive 3 times, vitro cumulative release profiles are drawn with the mean value of preparation to the time.
Carry the tablets in vitro result of INS nanoparticles
In order to verify the pH sensitivity characteristics of hydrophobic segment length and PDEAEMA segments to polymer nanoparticle drug release behavior
Affect, have selected the polymer nanoparticle with difference PCL segments is carried out respectively in vitro in the dissolution medium of pH6.4 and 7.2
Release behavior is investigated.As shown in Figure 8, INS bulk drugs discharge quickly in pH6.4 and pH7.2, are respectively in 24h cumulative releases
63.68% and 59.94%, and different polymer supported INS nanoparticles are in the quick release phase in front 6h, subsequent rate of releasing drug by
Step tends towards stability.In pH6.4, mPEG5k-PCL10k-PDEAEMA10k carries INS nanoparticles and mPEG5k-PCL13k-
PDEAEMA10k carries the Cumulative release amount point that INS nanoparticles are respectively 24.31% and 21.60%, 120h in the prominent amount of releasing of front 6h
Wei 53.24% and 45.09%.And in pH7.2, both drug release rates are below the drug release rate in pH6.4, and soon
The drug release amount of fast acquisition time is significantly reduced.MPEG5k-PCL10k-PDEAEMA10k carries INS nanoparticles and mPEG5k-PCL13k-
It is only respectively 14.53% and the cumulative release after 13.36%, 120h that PDEAEMA10k carries INS nanoparticles in the prominent amount of releasing of front 6h
Amount is only 44.48% and 32.66%.Dynamics fitting result shows, the two release in vitro behavior in two kinds of dissolution mediums
It is best with the fitting effect of Weibull models, point out said preparation to there is the hangover.As can be seen from Figure 8, two kinds of pH releases are situated between
In matter, mPEG5k-PCL13k-PDEAEMA10k carries the burst drug release amount of INS nanoparticles and is below mPEG5k-PCL10k-
PDEAEMA10k carries INS nanoparticles and the former releases the drug more slowly in the gentle phase, and slow-release time is longer.
Effect tests in the body of embodiment 7
Male SD rat is selected to set up the diabetes rat model of STZ inductions.Overnight fasting before modeling, second day empty stomach abdomen
Chamber injection streptozotocin (STZ) (60mg/kg, citrate buffer, pH4.2), starts to monitor blood sugar after one week.Choose blood sugar
Value continues one week higher than 16.7mmol/L, and body weight is the rat 24 of 200 ± 20g, rat is randomly divided into into four groups of (mPEG5k-
PCL13k-PDEAEMA10k blank nanoparticle groups, INS groups, mPEG5k-PCL10k-PDEAEMA10k carry INS nanoparticles group and
MPEG5k-PCL13k-PDEAEMA10k carries INS nanoparticle groups), 6 per group, it is administered to the dose subcutaneous of 5IU/kg respectively
Medicine, puts according to set time eye socket and takes blood 0.5ml, takes a small amount of whole blood for determining blood glucose value, draws internal blood sugar concentration curve,
Remainder whole blood is centrifuged 30min in 4 DEG C, under the conditions of 3000rpm, takes supernatant blood plasma, is examined with insulin ELISA detection kit
Internal blood medicine content is surveyed, internal Drug-time curve is drawn, is utilized according to the Relative biological that following formula calculates polymer supported INS nanoparticles
Degree.
Statistical analysis
Statistical analysis are carried out using SPSS20.0 softwares, data mean ± standard deviation is represented, using single factor test variance
Analysis (One-Way Anova) two-sided test, P<0.05(*P<0.05；**P<0.01；***P<0.001) to there is conspicuousness poor
It is different.
Internal pharmacodynamic results
From Fig. 9-A, diabetes rat hypodermic injection blank nanoparticle, INS bulk drugs are received with different polymer supported INS
After the grain of rice, the internal blood concentration of the drug-carrying nanometer particle group and INS groups peaking after 2h, and the peak value of INS groups is higher than carrying medicine
Nanoparticle group, subsequent INS groups decline rapidly in 2～12h blood concentrations, and 48h is less than 0.5mIU/L after administration, and AUC is only
For 75.072.And the drug elimination rate of drug-carrying nanometer particle group is slow compared with INS groups.Wherein, mPEG5k-PCL10k-
PDEAEMA10k carries the peak plasma concentrations of INS nanoparticle groups and carries INS nanoparticles higher than mPEG5k-PCL13k-PDEAEMA10k
Group, faster, blood concentration 48h after administration is less than 1.5mIU/L, relative bioavailability (153.7%) to drug elimination rate
Also it is low compared with the latter's (155.23%).The blood sugar level curve of Fig. 9-B can prove above-mentioned change.From Fig. 9-B, after administration,
Blank nanoparticle group blood sugar maintains level before administration, and fluctuating range is less；INS groups blood sugar after 2h is minimized, subsequent blood
It is sugared substantially to rise, and it is gradually restored to the blood sugar level before being administered；And the blood sugar of different polymer supported INS nanoparticles groups is also obvious
Decline, blood sugar is minimized in 2～4h.Wherein, mPEG5k-PCL10k-PDEAEMA10k carries INS nanoparticle group blood sugar after 4h
Gradually rise, and go up to 13.3mmol/L after 48h, and mPEG5k-PCL13k-PDEAEMA10k carries INS nanoparticle groups 4
Less, blood sugar is maintained between 5.1～7.5mmol/L the blood sugar level total ripple of～48h.With reference to the normal blood of SD rat limosis
Sugar value, it is known that the blood sugar reducing function time of INS groups is only 4h；MPEG5k-PCL10k-PDEAEMA10k carries the drop of INS nanoparticle groups
Sugared action time is 12h, and the action time that mPEG5k-PCL13k-PDEAEMA10k carries INS nanoparticles is 48h.With
INS is compared, and the internal hypoglycemic time of polymer drug-carried nanoparticle is obviously prolonged.
Claims (10)
1. a kind of triblock polymer, the triblock polymer is A-B-C shape block copolymers, and wherein A blocks are for can be biological
The poly glycol monomethyl ether (mPEG) of degraded, molecular weight is 4000-6000 (preferably 5000)；B block be polycaprolactone (ε-
PCL), molecular weight is 8000-15000 (preferably 10000-13000)；C blocks be polybases polymethylacrylic acid-N, N- diethylaminos
Base ethyl ester, molecular weight is 8000-12000 (preferably 10000).
2. the preparation method of the triblock copolymer described in a kind of claim 1, it comprises the steps：
1) mPEG-PCL-OH is synthesized；
2) synthetic macromolecule initiator mPEG-PCL-Br；
3) triblock polymer mPEG-PCL-PDEAEMA is synthesized；
Wherein, step 1) with mPEG and ε-CL as raw material, the Sn (oct) of 1% ε-CL molal weights2For catalyst, gathered by open loop
Conjunction method synthesizes mPEG-PCL-OH；
Step 2) TEA and BiBB (w is added in mPEG-PCL-OH:w:W, mPEG-PCL-OH:TEA:BiBB=1:3-6:1-3,
Preferably 1:4:2) reaction obtains macromole evocating agent mPEG-PCL-Br；
Step 3) mPEG-PCL- is generated under CuBr and Bpy catalysis with macromole evocating agent mPEG-PCL-Br and DEAEMA
PDEAEMA(w:w:w,mPEG-PCL-Br:Bpy:CuBr=1:3-6:1-3, preferably 1:4:2) triblock polymer.
3. a kind of pH responds insulin slow release nanoparticle, and it is self-assembly of by the triblock polymer described in claim 1
The insulin loaded on nanocapsule and nanocapsule is constituted.
4. pH according to claim 3 responds insulin slow release nanoparticle, wherein between insulin and triblock polymer
Mass ratio be 2～9.9:10, preferably 8.5～9.5:10, further, it is preferable to be 9:10.
5. the pH according to any one of claim 3-4 responds insulin slow release nanoparticle, the shared polymerization of hydrophilic segment volume
The percentage coefficient f of thing molecule cumulative volumeeoFor 0.5-0.6.
6. the pH described in any one of claim 3-5 responds the preparation method of insulin slow release nanoparticle, and it is comprised the following steps：
1) with acid leach solution insulin, and pH value is adjusted to 5.5-6.5, preferably 6；
2) triblock polymer mPEG-PCL-PDEAEMA is dissolved with organic solvent, and drops to step 1) in resulting solution；
3) remove after organic solvent and precipitation is collected by centrifugation, pH response insulin slow release nanoparticles are obtained after freezing.
7. the triblock polymer described in claim 1 is preparing the purposes as drug carrier system, it is preferable that the medicine
Transmission carrier is nanoparticle, micella, sustained and controlled release medicament carrier, pH sensitive medicaments carriers.
8. described in any one of claim 3-5 pH response insulin slow release nanoparticle prepare treatment diabetes, hyperglycemia,
Purposes in prediabetes, glucose tolerance reduction, type i diabetes, type ii diabetes, the medicine of syndrome X.
9. a kind of pharmaceutical composition, it includes the pH response insulin slow release nanoparticles described in any one of claim 3-5.
10. medicine according to claim 9, its preparation is injection.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107519484A (en) * | 2017-09-18 | 2017-12-29 | 湘潭大学 | A kind of oral preparation method for carrying insulin nano micella |
| CN108478785A (en) * | 2018-04-23 | 2018-09-04 | 湘潭大学 | A kind of oral insulin micelle nano grain and preparation method thereof |
| CN109464657A (en) * | 2018-11-26 | 2019-03-15 | 常州工程职业技术学院 | A kind of method that block copolymer carries insulin control release |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101792516A (en) * | 2009-12-28 | 2010-08-04 | 苏州大学 | Biodegradable polymer vesicles and preparation and application thereof |
| CN104758247A (en) * | 2015-04-22 | 2015-07-08 | 广东工业大学 | pH responsive polymer mixed micelle and application thereof |
| CN104922694A (en) * | 2015-07-20 | 2015-09-23 | 南方医科大学 | Insulin controlled-release nanometer particle and preparing method thereof |
-
2016
- 2016-12-22 CN CN201611196325.7A patent/CN106581647B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101792516A (en) * | 2009-12-28 | 2010-08-04 | 苏州大学 | Biodegradable polymer vesicles and preparation and application thereof |
| CN104758247A (en) * | 2015-04-22 | 2015-07-08 | 广东工业大学 | pH responsive polymer mixed micelle and application thereof |
| CN104922694A (en) * | 2015-07-20 | 2015-09-23 | 南方医科大学 | Insulin controlled-release nanometer particle and preparing method thereof |
Non-Patent Citations (4)
| Title |
|---|
| GUIJING LIU等: "The highly efficient delivery of exogenous proteins into cells mediated by biodegradable chimaeric polymersomes", 《BIOMATERIALS》 * |
| 孙琳等: "多重敏感性共聚物的制备及其自组装行为研究", 《化学研究与应用》 * |
| 朱亚明等: "MePEG-b-PCL-b-PDMAEMA 的可控合成及性能研究", 《化学学报》 * |
| 李伟炜等: "mPEG-PCL 聚合物囊泡的制备及INS-mPEG114-PCL152囊泡体外释放特性考察", 《中国实验方剂学杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107519484A (en) * | 2017-09-18 | 2017-12-29 | 湘潭大学 | A kind of oral preparation method for carrying insulin nano micella |
| CN108478785A (en) * | 2018-04-23 | 2018-09-04 | 湘潭大学 | A kind of oral insulin micelle nano grain and preparation method thereof |
| CN109464657A (en) * | 2018-11-26 | 2019-03-15 | 常州工程职业技术学院 | A kind of method that block copolymer carries insulin control release |
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