CN105534955B - A kind of bilayer slow release nanoparticle and preparation method thereof - Google Patents
A kind of bilayer slow release nanoparticle and preparation method thereof Download PDFInfo
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- 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
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- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
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- 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
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Abstract
The present invention relates to a kind of double-deck slow release nanoparticles and preparation method thereof.Related nanoparticle include kernel and by kernel coat shell；Load has drug one on the kernel.In one of embodiment, load has drug two on shell.In an alternate embodiment, sheathing material is that chain is connected to acid-sensitive key, and drug three is connected on acid-sensitive key, bilayer slow release nanoparticle of the invention, it is not removed before drug can be made to reach site of action simultaneously, and drug can be discharged with the degradation of carrier material, play slow releasing function.The present invention also provides the preparation methods of the double-deck slow release nanoparticle, this method comprises: dissolution drug one and inner nuclear material, prepare kernel object using solvent evaporation method；Kernel object and sheathing material are dissolved, the double-deck slow release nanoparticle is prepared using Ionic gelation method.
Description
Technical field
The present invention relates to nano-medicament carrier field, the system of the chitosan-polylactic acid nanoparticle of specially a kind of acid-sensitive
Preparation Method.
Background technique
The micro-nano grain of rice, which can orient, conducts drugs to site of action, and is able to maintain that the control release of drug, extends
The half-life period of drug, and reduce toxic side effect etc., it is the hot spot of biomedicine field research.Current slow release nano-particle mainly has
Nanoparticle, micella, liposome etc., the either other functional groups of drug can be carried in organism by they, still
How the substep release of two or more drugs (or other function group) is realized, it is also necessary to better resolution policy.
Summary of the invention
It for the defects or inadequacies for existing technologies, should the purpose of the present invention is to provide a kind of double-deck slow release nanoparticle
Nanoparticle include kernel and by kernel coat shell；Load has drug one on the kernel.
In a kind of embodiment, load has drug two on shell of the invention.
In a kind of embodiment, inner nuclear material of the invention select polylactic acid (PLA), polyglycolic acid (PGA), lactic acid/
Co-glycolic acid (PLGA), polycaprolactone (PCL) or Poly-β-hydroxybutyric acid (PHB).PLA and PLGA further may be selected,
The molecular weight of selected PLA carrier is between 1~100kDa.
In a kind of embodiment, sheathing material of the invention is chitosan (CS), chitosan derivatives, glucan, Portugal are poly-
Sugar derivatives, pulullan polysaccharide, Radix Angelicae Sinensis polysaccharide or ganoderma lucidum polysaccharide.Chitosan and its derivative further may be selected, selected CS's
Molecular weight is between 1~100kDa.
In a kind of embodiment, sheathing material of the invention is that chain is connected to the chitosan of acid-sensitive key, chain is connected to acid-sensitive key
Chitosan derivatives, chain are connected to the glucan of acid-sensitive key, chain is connected to the glucan derivative of acid-sensitive key, chain is connected to the general of acid-sensitive key
Shandong orchid polysaccharide, chain are connected to the Radix Angelicae Sinensis polysaccharide of acid-sensitive key, chain is connected to the ganoderma lucidum polysaccharide of acid-sensitive key；Drug is connected on the acid-sensitive key
Three；The acid-sensitive key is one of following chemical bond:
R1-R31Respectively indicate different chemical groups.
In a kind of embodiment, the particle size range of nanoparticle of the invention is 0.1~1 μm.
The present invention also provides the preparation methods of the double-deck slow release nanoparticle, this method comprises:
Drug one and inner nuclear material are dissolved, kernel object is prepared using solvent evaporation method；Kernel object and sheathing material are dissolved,
The double-deck slow release nanoparticle is prepared using Ionic gelation method.
The present invention provides the preparation methods of another double-deck slow release nanoparticle, this method comprises:
Drug one and inner nuclear material are dissolved, kernel object is prepared using solvent evaporation method；Dissolve the kernel object, two and of drug
Sheathing material prepares the double-deck slow release nanoparticle using Ionic gelation method.
The double-deck slow release nanoparticle preparation method of of the invention another includes:
Drug one and inner nuclear material are dissolved, kernel object is prepared using solvent evaporation method；Dissolution is connected with the shell of acid-sensitive key
Drug three is connected on acid-sensitive key by material and drug three using dehydrating condensation method, and shell object is made；Dissolve kernel object, shell
Object and drug two prepare the double-deck slow release nanoparticle using Ionic gelation method.
Compared with the prior art, the advantages of the present invention are as follows:
It can be improved the delivery efficiency of drug when kernel entrapped drug of the present invention, while drug can be made to reach site of action
It is not removed before, and drug can be discharged with the degradation of carrier material, play slow releasing function.
Inside and outside two layers of polymers is successively degraded when two kinds of drugs of the present invention while encapsulating, can release two kinds of medicines step by step
Object, successively/collaboration play a role.Compared to a kind of independent drug, better effect can be played.
Drug or functional group are connected on sheathing material by the present invention using the chemical bond of acid-sensitive, and it is disconnected to be able to respond pH
It splits, provides support as acid-sensitive delivery system for the nanoparticle.
Detailed description of the invention
Fig. 1 is the SEM figure of the PLA nanoparticle for containing BMP-2 prepared by embodiment 1；
Fig. 2 is that composite nano-granule NLS method prepared by embodiment 1 measures nanometer particle size (531nm)；
Fig. 3 is the TEM figure of composite nano-granule prepared by embodiment 1；
Fig. 4 is the release profiles of the BMP-2 and SDF-1 of composite nano-granule prepared by embodiment 2；
Fig. 5 is the experimental result that the CCK-8 of embodiment 3 is tested；As shown, at the 5th day, between same concentration each group
And there was no significant difference (P < 0.05), illustrates the nanoparticle to cell without overt toxicity；
Fig. 6 is the experimental result that the Transwell of embodiment 3 is tested, as shown, at the 24th hour, blank nanometer
Grain group and free BMP-2 group no significant difference (P < 0.05), the every visual field cell number of SDF-1 group increase with SDF-1 concentration and are increased
And it is higher than blank nanoparticle group and free BMP-2 group, and the double-deck drug-carrying nanometer particle group is between SDF-1 group and control group, it is former
SDF-1 in cause mainly nanoparticle is just gradually released, but effective concentration illustrates bilayer lower than completely free SDF-1
Drug-carrying nanometer particle has the promotion effect of going back to the nest really to BMSC and improves and enhance with the SDF-1 concentration of release.
Fig. 7 is the release profiles of composite nano-granule OPG in different pH prepared by embodiment 3；
Fig. 8 is the TEM figure of acid-sensitive PLA-CS double-layer nanometer grain prepared by embodiment 4；
Fig. 9 is depression effect of the OPG in composite nano-granule prepared by embodiment 4 to osteoclast；A: blank control；B:
Free OPG, 10 μ g/L；C: acid-sensitive PLA-CS double-layer nanometer grain, pH 7.4；C: acid-sensitive PLA-CS double-layer nanometer grain, pH
6.8；E: acid-sensitive PLA-CS double-layer nanometer grain, its result of pH 5.6. are consistent with tablets in vitro data in embodiment 3.
Specific embodiment
Drug one of the invention can be connected on polymeric materials by chemical bond, can also pass through the side of physical encapsulation
Formula contains in the polymeric material.
Drug two of the invention can be connected on polymeric materials by chemical bond, can also pass through the side of physical encapsulation
Formula contains in the polymeric material.
Drug three of the invention is the group (antibody either other ligands) with target function, passes through the change of acid-sensitive
Learn key connection on polymer.
The system comprising three kinds of drugs can be designed in technical solution of the present invention, also be can according to need design and contained one
The micro-nano grain of rice of kind or two kinds of drugs.On specific drug, for example, drug one can choose functional protein or anti-tumor drug,
Such as bone morphogenetic protein 2 (BMP-2), camptothecine, taxol etc..Drug two can choose function factor or drug, such as
Stromal cell derived factor-1 (SDF-1), cis-platinum etc., drug two, which can combine or cooperate with drug one, has an effect.Drug three can
To select that there is the antibody or ligand, such as transferrins, osteoprotegerin (OPG) etc. of target function.
Below with reference to the example more specific description contents of the present invention.
Embodiment 1:
(1) PLA nanoparticle is prepared using oil/water type ultrasound (or emulsification) solvent evaporation method: weighs 0.1gPLA, 50 μ g
BMP-2 is dissolved in 5mL methylene chloride, as oily phase；0.8g polyvinyl alcohol (PVA) is weighed to be dissolved in 40mL distilled water as water
Phase；At 25 DEG C, mutually it is added drop-wise to oily in water phase dropwise, ultrasonic disperse (or emulsification instrument dispersion), the oil hydrosol 500r/ that will be obtained
Min magnetic agitation for 24 hours, to eliminate methylene chloride；It is collected by centrifugation after nanoparticle is cured, freeze-drying is contained after washing
The PLA nanoparticle powder of BMP-2.As shown in Figure 1.
(2) the 0.1g PLA nanoparticle powder for containing BMP-2 is dissolved in 20mL distilled water, after the CS dissolution of 0.1g is added,
Sodium tripolyphosphate (TPP) solution 4mL that mass concentration is 15% (W/V) is added dropwise, stirring makes CS in PLA nanoparticle at room temperature
Surface enrichment obtains mixed liquor, obtains composite nano-granule powder after being freeze-dried after centrifuge washing.Use dynamic light scattering method
(NLS) composite nano-granule granularity is measured, as shown in Figure 2；Composite nano-granule configuration of surface, figure are observed using projection Electronic Speculum (TEM)
3。
Embodiment 2:
The nanoparticle powder for containing BMP-2 prepared by 0.1g embodiment 1 is dissolved in 20mL distilled water, and the CS of 0.1g is added
With 10 μ g stromal cell derived factor-1s (SDF-1), TPP solution is added dropwise after dissolution, CS is made to contain SDF-1 in PLA nanoparticle
Surface enrichment, obtains that internal layer contains BMP-2, outer layer contains the PLA-CS double-layer nanometer grain of SDF-1.
It takes 10mg to be added in bag filter in freeze-drying nanoparticle powder, pipettes 5ml PBS solution in bag filter, be then placed in
In the conical flask for filling 7.4 buffer of pH, it is placed in oscillation in constant temperature oscillator (37 DEG C, 50rpm/min), timing is sustained, according to
Setting time takes 500 μ l of bag filter external solution, and supplements the PBS buffer solution of equal volume, SDF- in ELISA method detection supernatant
The amount of 1 and rhBMP-2 calculates accumulative release percentage.Release profiles are as shown in Figure 4
CCK-8 experiment: by the Marrow Mesenchymal Stem Cells kind of logarithmic growth phase into 96 orifice plates, every hole 2.0 × 103
It is a, 37 DEG C, 5% CO2Incubator culture.After cell climbs full 80%, original culture medium is absorbed, pastille culture medium is sequentially added
(blank nanoparticle group, free SDF-1 group, free rhBMP-2 group, double-layer nanometer grain group, every group of concentration is respectively 4.0,
2.0l, 1.0,0.5,0.25,0.125mg/mL), it takes out after cultivating 5 days in 37 DEG C of constant temperature incubators, is gently cleaned repeatedly with PBS
Afterwards, and in every hole 100 complete culture solutions of the μ l containing 10%CCK-8 are added, continue to be incubated in incubator after 2h under microplate reader
The absorbance value for measuring every hole, is compared to each other.As a result as shown in Figure 5.
Transwell experiment: by the Marrow Mesenchymal Stem Cells kind of logarithmic growth phase into 96 orifice plates, every hole 5.0
×103It is a, 37 DEG C, 5% CO2Incubator culture.After cell climbs full 80%, original culture medium is absorbed, different trainings are sequentially added
Support base (white nanoparticle group, free SDF-1 group, free rhBMP-2 group, double-layer nanometer grain group, every group of concentration is respectively 4.0,
1.0,0.25mg/mL), it cultivates in 37 DEG C of constant temperature incubators and takes out afterwards for 24 hours, first the culture solution in exhaustion upper chamber, be then placed in
30min is fixed in 95% ethyl alcohol, then places into 1% crystal violet dye liquor and dyes 15min, gently cleans upper chamber with major part cotton balls
Cell is placed in microscopically observation (eyepiece × 10, object lens × 20) by residual cell after dry, and 9 differences are chosen in each cell
The visual field carries out cell count, calculates its average value and variance.As a result as shown in Figure 6.
Embodiment 3:
The 0- carboxymethyl chitosan of 0.1g parts of quality is dissolved in 20mL distilled water, 0.38g1- ethyl-(3- diformazan is added
Base aminopropyl) carbodiimide (EDC), after 37 DEG C of reactions 6,40 μ L, mono- hydrazine hydrate is added, dialyses after 6~12h of reaction, freezing is dry
The dry CS for obtaining hydrazine.
The CS for weighing the hydrazine of the preparation of 0.1g embodiment 1, is dissolved in 20mL distilled water, and 10 μ g osteoprotegerins (OPG) are added.
It is protected from light 6h at room temperature, is centrifuged, washs, freeze-drying obtains chitosan-hydrazone bond-osteoprotegerin (CS-Hz-OPG)；
The nanoparticle kernel powder for containing BMP-2 is dissolved in 20mL distilled water, 0.1g CS-Hz-OPG dissolution is added, keeps away
Light, it is 15% (W/V) TPP solution 4mL that mass concentration, which is added dropwise, makes CS-Hz-OPG in PLA nanoparticle surface enrichment, obtains
Acid-sensitive PLA-CS double-layer nanometer grain.
It takes three parts of freeze-drying nanoparticle powder (every part of 10mg) to be added in bag filter, pipettes 5ml PBS solution respectively in dialysis
Bag in, be then respectively put into the conical flask of the buffer of pH 7.4,6.8,5.6, be placed in constant temperature oscillator (37 DEG C, 50rpm/
Min oscillation in), timing sustained release, takes upper 500 μ l of bag filter external solution according to setting time, and supplements the PBS buffering of equal volume
Liquid, the amount of OPG in ELISA method detection supernatant calculate accumulative release percentage, and release profiles are as shown in Figure 7.
Embodiment 4:
The nanoparticle nanoparticle powder for containing BMP-2 prepared by 0.1g embodiment 1 is dissolved in 20mL distilled water, is added
The SDF-1 of 0.1g CS-Hz-OPG and 10 μ g dissolution, are protected from light, and it is 15% (W/V) TPP solution 4mL that mass concentration, which is added dropwise, make
CS-Hz-OPG obtains acid-sensitive PLA-CS double-layer nanometer grain in PLA nanoparticle surface enrichment.Electron microscope is shown in Fig. 8.
OPG is able to suppress the differentiation of osteoclast and functions, and acid-sensitive chemistry bond energy enough responds the pH of inflammation part
OPG is released, the function of its osteoclastic effect always is played.The osteoclast of inductive formation is divided into 6 groups, is inoculated into the training of 24 holes
Feeding plate, 37 DEG C, 5% CO2Incubator culture.After cell climbs full 80%, original culture medium is absorbed, different cultures are sequentially added
Base (blank nanoparticle group, 10 μ g/L free OPG group, the acid-sensitive double-layer nanometer grain group of pH 7.4, the acid-sensitive double-layer nanometer grain of pH 6.8
Group, the acid-sensitive double-layer nanometer grain group of pH 5.6), it is taken out after cultivating 3d in 37 DEG C of constant temperature incubators, again with anti-tartaic acid phosphorus
Sour enzyme dyeing is observed and counts the number for being dyed to the osteoclast of claret.As a result as shown in Figure 9.
Claims (3)
1. it is a kind of bilayer slow release nanoparticle, the nanoparticle include kernel and by kernel coat shell；It is loaded on the kernel
There is drug one, the inner nuclear material is polylactic acid PLA；The drug one is bone morphogenetic protein 2 BMP-2；
The sheathing material is the chitosan that chain is connected to hydrazone bond, and the hydrazone bond cochain is connected to drug three, and the drug three is bone guarantor
Protect element OPG；
Load has drug two on the shell, and the drug two is stromal cell derived factor-1 SDF-1.
2. bilayer slow release nanoparticle as described in claim 1, which is characterized in that the grain of the double-deck slow release nanoparticle
Diameter range is 0.1~1 μm.
3. the preparation method of bilayer slow release nanoparticle described in claim 1, which is characterized in that
Drug one and inner nuclear material are dissolved, kernel object is prepared using solvent evaporation method；
Dissolution is connected with the sheathing material and drug three of hydrazone bond, and drug three is connected in hydrazone bond using dehydrating condensation method, is made
Shell object；
Kernel object, shell object and drug two are dissolved, the double-deck slow release nanoparticle is prepared using Ionic gelation method.
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| CN101923932A (en) * | 2009-06-09 | 2010-12-22 | 南京大学 | Multifunctional double-layer core-shell structure magnetic nano particle, preparation method and application thereof |
| CN103381146A (en) * | 2013-07-17 | 2013-11-06 | 新乡医学院 | Double-layer sustained and controlled release nanoparticle and preparation method thereof and application |
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| CN101923932A (en) * | 2009-06-09 | 2010-12-22 | 南京大学 | Multifunctional double-layer core-shell structure magnetic nano particle, preparation method and application thereof |
| CN103381146A (en) * | 2013-07-17 | 2013-11-06 | 新乡医学院 | Double-layer sustained and controlled release nanoparticle and preparation method thereof and application |
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| Title |
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| Controlled release of U-86983 from double-layer biodegradable matrices: effect of additives on release mechanism and kinetics;C.X. Song et al;《Journal of Controlled Release》;19971231;第45卷;参见全文 * |
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