CN102871966A - Nano drug carrier particles for improving bioavailability of rapamycin and preparation method thereof - Google Patents
Nano drug carrier particles for improving bioavailability of rapamycin and preparation method thereof Download PDFInfo
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- CN102871966A CN102871966A CN2012104014343A CN201210401434A CN102871966A CN 102871966 A CN102871966 A CN 102871966A CN 2012104014343 A CN2012104014343 A CN 2012104014343A CN 201210401434 A CN201210401434 A CN 201210401434A CN 102871966 A CN102871966 A CN 102871966A
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Abstract
The invention discloses nano drug carrier particles for improving the bioavailability of rapamycin and a preparation method thereof, so as to carry out a drug effect optimization. The nano drug carrier particles are prepared in the following steps that according to the principle of an emulsion solvent evaporation method, a determined amount of PEG-PLGA and rapamycin are respectively dissolved in acetone; after being mixed uniformly, the PEG-PLGA, the rapamycin and the acetone are slowly added into water to be stirred by magnetic force; after a certain period of time, the obtained liquid is ultrasonically homogenated, and organic phase is removed in a vacuum dryer; the obtained water phase removes free medicine in a centrifugal tube; and then an ultrafiltration tube is used for concentration, and nano particles are obtained after freezing and drying. The method has the advantages of convenience in operation, simplicity and feasibility, good repeatability and the like. The prepared nano drug carrier particles can improve the utilization rate of the medicine by improving the absorptivity of the medicine and prolonging the cycling time in a human body. Meanwhile, the nano particles which are prepared through the method have good biocompatibility, and surface active groups can further modify ligands or targeted groups.
Description
Technical field
The present invention relates to biomaterial and field of nanometer technology, be specifically related to a kind of have suitable envelop rate and drug loading, high biological safety, and can slowly discharge nanoscopic drug carriers of drug rapamycin and preparation method thereof.
Background technology
Rapamycin (Rapamycin) is the strong immunosuppressive drug with low nephrotoxicity, is widely used in the transplant operation.Simultaneously it again can the establishment blood vessel injury after propagation and the transfer ability of vascular smooth muscle cell, thereby reduce the generation of vascular restenosis, and it can also promote myocardium damaged place cardiomyocyte proliferation, thereby very large application prospect is arranged aspect treating cardiovascular disease.But owing to the low-solubility of himself and the administering mode of present stage, greatly limited performance and the range of application of its drug effect.
Nano medicament carrying system has become the study hotspot in pharmaceutics and modern biomedical field as a kind of effective means of optimizing drug effect.Study more nano medicament carrying system and comprise nanometer liposome, nanosphere, nanocapsule, solid lipid nanoparticle and polymer capsule etc.At present, the study hotspot of nano medicament carrying system mainly concentrates on the exploitation for the diagnosis of cancer and targeted therapy preparation, and the part preparation has been arranged, and the stage enters clinical trial or comes into the market by experiment.Cardiovascular disease is the same with cancer, human health in serious threat, but because part disease pathomechanism is explained imperfection, lack the reasons such as efficient targeting effect group, drug-loading system research for the cardiovascular disease diagnosis medicine lags far behind cancer, and many medicines are because poorly water-soluble, absorbance is low, bioavailability is low, the factors such as oral administration difficulty are not yet well used, at present, the research of rapamycin nano-carrier still is in the starting stage both at home and abroad, domestic do not have a listing of effective rapamycin sustained-release oral preparation, in view of the good therapeutic effect of this medicine in many diseases field, develop a kind of suitable nano-carrier for this medicine and accord with the demands of the market and clinical needs.
This patent uses emulsion-solvent evaporation method to prepare the PEG-PLGA Nano microsphere and carries rapamycin, and similarly research has no report.PLGA and PEG are the high molecular polymer that possesses biological safety of FDA approval, and the two synthetic block polymer vivo degradation product has no side effect to body.Nanoparticle with the emulsion-solvent evaporation method preparation, internal layer is the core that is formed by physical action by hydrophobicity PLGA block and medicine, skin is hydrophilic PEG hydrated sheath, this hydrated sheath not only can solve the water solublity problem of insoluble drug rapamycin, can also help nano-particle to hide engulfing of reticuloendothelial system, reduce the adhesive attraction of serum albumin, thereby the time of staying of prolong drug in blood circulation, be conducive to the exploitation of oral slow-releasing preparation, avoided the high request of intravenous drug preparation Surfactant and dissolvent residual, potential biological safety risk and the inconvenience on the administering mode.Because the PEG end can be active group, can further modify aglucon or other targeting group at nano grain surface by simple chemical reaction, reach the purpose of targeting pathological tissues, organ, thereby improve the drug level of lesions position, reduce medicine to the toxic and side effects of other histoorgan.In addition, PLGA is as a kind of biodegradable polymer, can in cyclic process, slow degradation be the small-molecule substance of inanimate object toxicity, in degradation process, discharge simultaneously the medicine of parcel, realize the slow release of medicine, can also control the rate of release of medicine by the ratio of lactic acid and hydroxyacetic acid among the change PLGA, in the hope of satisfying the administration requirements of different pharmaceutical, improve absorbance and the bioavailability of medicine, reach the maximization of drug effect.
Summary of the invention
Technical problem: the objective of the invention is by the nanometer synthetic technology, make up the nano medicament carrying system for drug rapamycin, optimize existing drug administration mode, solve the problem of rapamycin water solublity, absorbability, targeting, bioavailability existence.The advantages such as another object of the present invention provides a kind of method for preparing above-mentioned rapamycin nano medicament carrying system, makes it have good reproducibility, and is easy to operate, simple, with low cost.
Technical scheme: in order to realize the foregoing invention purpose, the nanoparticle be used to improving the rapamycin bioavailability of the present invention is:
Use polyethylene glycol-polylactic acid hydroxyl ethanol acid copolymer PEG-PLGA as carrier, wherein the PEG end is methoxyl group, amino or carboxyl active group, form the internal package rapamycin with nucleocapsid structure by emulsion-solvent evaporation method, outside hydrophilic particle diameter is the nanoparticle of 100～120nm.
The preparation method of the nanoparticle be used to improving the rapamycin bioavailability of the present invention may further comprise the steps:
1) takes by weighing described copolymer p EG-PLGA and rapamycin, fully be dissolved in the acetone respectively;
2) behind the acetone soln mix homogeneously of magnetic agitation with the acetone soln of described copolymer p EG-PLGA and rapamycin, obtain organic liquid mixture, this organic liquid mixture is splashed in the water under the magnetic agitation, keep continuing to stir 30～60min, obtain the mixing material of organic facies and water;
3) with step 2) gained mixing material ultrasonic emulsification instrument supersound process 1～2min;
4) vacuum drying 3～6h removes acetone;
5) with step 4) remove acetone after remaining liq be transferred to the centrifugal free drug of removing in the centrifuge tube;
6) shift supernatant ultrafiltration and concentration nano-particle to the super filter tube, residual acetone is removed in the ultra-pure water washing;
7) the gained concentrated solution uses the freezer dryer lyophilizing.
Wherein:
Step 1) copolymer p EG-PLGA and the rapamycin concentration ratio that feeds intake is 9-11 in: 1, and use acetone as solvent, the volume ratio of dissolving PEG-PLGA and the used acetone of rapamycin is 2: 1.
Step 2) volume of water is 2: 1 with the ratio of organic liquid mixture volume in, and the speed that organic facies splashes into water is 0.5mL/min.
Beneficial effect: the invention has the advantages that: adopt simple emulsion-solvent evaporation method to prepare nanoparticle, the method is with low cost, do not need super clean experimental situation, favorable repeatability, and can prepare in enormous quantities, have the advantages such as easy row convenient and simple for operation, with low cost and favorable repeatability, these advantages can be widely used in the nanoparticle preparation of various hydrophobic medicine.The nanoparticle good water solubility of preparation has good biocompatibility and biological safety, and can be active group effectively prolong drug release time, and PEG end, is conducive to followingly realize target administration and prepare diagnosis and treatment one body preparation.
The specific embodiment
The present invention is described further below in conjunction with specific embodiment.
The preparation of rapamycin medicament-carried nano granule (RAPA-NPs): precision takes by weighing 100mg PEG-PLGA and 5mg rapamycin, fully is dissolved in respectively in 4mL and the 2mL acetone.Magnetic agitation with the organic facies mix homogeneously after, with the speed of 0.5mL/min, the organic facies mixed liquor is splashed into 12mL aqueous phase under the magnetic agitation, keep middling speed to continue to stir 30min.Gained liquid is removed organic facies with the dry 3h of the ultrasonic 1min of ultrasonic emulsification instrument (3s opens for instrument parameters: Φ 3 gear levers, 20%, 20 ℃ of power, and 1s closes) final vacuum.Liquid rotating is moved to centrifugal free drug (parameter: 3000rpm, 25 ℃, the 15min of removing in the centrifuge tube, * 2), shift supernatant ultrafiltration and concentration nano-particle (parameter: 4000rpm, 35 ℃ to the super filter tube, 15min, * 2), residual organic solvent is removed in the ultra-pure water washing.Concentrated solution remain in 4 ℃ for subsequent use, get part and add 5% (w/v) sucrose as the freeze drying protectant mix homogeneously, lyophilizing in freezer dryer, weighing quality.
Nanoparticle size characterizes: use Particle Size Analyzer and dynamic light scattering to measure particle size and dispersibility, acquired results coincide, and the mean diameter that records is 112.25 ± 5.56nm, and the coefficient of dispersion is 0.248.
Vitro drug release: configure certain density RAPA-NPs solution 2mL, solvent is PBS: ethanol=9: 1, and put into 37 ℃ of calorstats and hatch, respectively at 4h, 7h, 20h, 30h, 42h, 52h, 70h takes out centrifugal (10000rpm, 25 ℃, 30min), draw supernatant 1.5mL and be stored in 4 ℃ of concentration to be measured, in nanoparticle precipitate, add the 1.5mL solvent and continue to hatch.Use ultraviolet spectrophotometer to measure to hatch that rapamycin goes out concentration at the light absorption value at 277nm place by the linear fit Equation for Calculating in the supernatant that different time obtains, drafting drug release curve, and carry out match, determine drug release model and equation thereof.Experimental result shows that release amount of medicine arrives 40% within the 20h, and slow release duration＞90h shows and can play good medicament slow release effect afterwards, and pharmaceutical release time-concentration relationship meets Higuchi and discharge model, meets the experiment expected results.
The cytotoxicity test: use CCK-8 test kit and schwann cell to carry out the cytotoxicity test, administration concentration is respectively 0.002,0.02,0.2,2,20 μ g/mL, and the continuous culture observation of cell is active.Test result shows, the rapamycin nanoparticle can suppress cell-proliferation activity to a certain extent, and inhibition strengthens with concentration in certain concentration range, but do not observe the reduction of cell quantity, show that this nano-particle does not have cell killing toxicity, has good biological safety.
Claims (4)
1. nanoparticle that is used for improving the rapamycin bioavailability, it is characterized by: use polyethylene glycol-polylactic acid hydroxyl ethanol acid copolymer PEG-PLGA as carrier, wherein the PEG end is methoxyl group, amino or carboxyl active group, form the internal package rapamycin with nucleocapsid structure by emulsion-solvent evaporation method, outside hydrophilic particle diameter is the nanoparticle of 100 ~ 120nm.
2. the preparation method of the nanoparticle be used to improving the rapamycin bioavailability as claimed in claim 1 is characterized in that the method may further comprise the steps:
1) takes by weighing described copolymer p EG-PLGA and rapamycin, fully be dissolved in the acetone respectively;
2) behind the acetone soln mix homogeneously of magnetic agitation with the acetone soln of described copolymer p EG-PLGA and rapamycin, obtain organic liquid mixture, this organic liquid mixture is splashed in the water under the magnetic agitation, keep continuing to stir 30 ~ 60min, obtain the mixing material of organic facies and water;
3) with step 2) gained mixing material ultrasonic emulsification instrument supersound process 1 ~ 2min;
4) vacuum drying 3 ~ 6h removes acetone;
5) step 4) is removed acetone after remaining liq be transferred to the centrifugal free drug of removing in the centrifuge tube;
6) shift supernatant ultrafiltration and concentration nano-particle to the super filter tube, residual acetone is removed in the ultra-pure water washing;
7) the gained concentrated solution uses the freezer dryer lyophilizing.
3. the preparation method of the nanoparticle be used to improving the rapamycin bioavailability according to claim 2, it is characterized in that: copolymer p EG-PLGA and the rapamycin concentration ratio that feeds intake is 9-11:1 in the step 1), use acetone as solvent, the volume ratio of dissolving PEG-PLGA and the used acetone of rapamycin is 2:1.
4. the preparation method of the nanoparticle be used to improving the rapamycin bioavailability according to claim 2 is characterized in that step 2) in the ratio of volume and organic liquid mixture volume of water be 2:1, the speed that organic facies splashes into water is 0.5mL/min.
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107049963A (en) * | 2017-06-23 | 2017-08-18 | 北京化工大学 | A kind of sirolimus Nano medication composition and preparation method thereof |
| CN107072965A (en) * | 2014-11-05 | 2017-08-18 | 西莱克塔生物科技公司 | The method and composition related to the synthesis nano particle with the rapamycin in stable over-saturation state |
| WO2018129268A1 (en) * | 2017-01-07 | 2018-07-12 | Selecta Biosciences, Inc. | Patterned dosing of immunosuppressants coupled to synthetic nanocarriers |
| US10335395B2 (en) | 2013-05-03 | 2019-07-02 | Selecta Biosciences, Inc. | Methods of administering immunosuppressants having a specified pharmacodynamic effective life and therapeutic macromolecules for the induction of immune tolerance |
| US10420835B2 (en) | 2011-04-29 | 2019-09-24 | Selecta Biosciences, Inc. | Tolerogenic synthetic nanocarriers for antigen-specific deletion of T effector cells |
| CN110693883A (en) * | 2019-11-21 | 2020-01-17 | 安徽医科大学第一附属医院 | Preparation method and application of rapamycin-entrapped zinc-organic framework drug delivery system |
| CN112236459A (en) * | 2018-04-23 | 2021-01-15 | 灰色视觉公司 | Improved continuous microparticle production |
| WO2021057007A1 (en) * | 2019-09-26 | 2021-04-01 | 严鹏科 | Rapamycin nanoscale sustained-release agent and preparation method thereof |
| CN114767659A (en) * | 2022-04-27 | 2022-07-22 | 中山大学孙逸仙纪念医院 | Medicinal preparation targeting PITPNM3 and preparation method and application thereof |
| US11426451B2 (en) | 2017-03-11 | 2022-08-30 | Selecta Biosciences, Inc. | Methods and compositions related to combined treatment with antiinflammatories and synthetic nanocarriers comprising an immunosuppressant |
| US11633422B2 (en) | 2014-09-07 | 2023-04-25 | Selecta Biosciences, Inc. | Methods and compositions for attenuating anti-viral transfer vector immune responses |
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| US10420835B2 (en) | 2011-04-29 | 2019-09-24 | Selecta Biosciences, Inc. | Tolerogenic synthetic nanocarriers for antigen-specific deletion of T effector cells |
| US11235057B2 (en) | 2011-04-29 | 2022-02-01 | Selecta Biosciences, Inc. | Methods for providing polymeric synthetic nanocarriers for generating antigen-specific tolerance immune responses |
| US11717569B2 (en) | 2011-04-29 | 2023-08-08 | Selecta Biosciences, Inc. | Tolerogenic synthetic nanocarriers |
| US10441651B2 (en) | 2011-04-29 | 2019-10-15 | Selecta Biosciences, Inc. | Tolerogenic synthetic nanocarriers for generating CD8+ regulatory T cells |
| US10357482B2 (en) | 2013-05-03 | 2019-07-23 | Selecta Biosciences, Inc. | Methods providing a therapeutic macromolecule and synthetic nanocarriers comprising immunosuppressant locally and concomitantly to reduce both type I and type IV hypersensitivity |
| US10357483B2 (en) | 2013-05-03 | 2019-07-23 | Selecta Biosciences, Inc. | Methods comprising dosing combinations for reducing undesired humoral immune responses |
| US10434088B2 (en) | 2013-05-03 | 2019-10-08 | Selecta Biosciences, Inc. | Methods related to administering immunosuppressants and therapeutic macromolecules at a reduced pharmacodynamically effective dose |
| US10335395B2 (en) | 2013-05-03 | 2019-07-02 | Selecta Biosciences, Inc. | Methods of administering immunosuppressants having a specified pharmacodynamic effective life and therapeutic macromolecules for the induction of immune tolerance |
| US11298342B2 (en) | 2013-05-03 | 2022-04-12 | Selecta Biosciences, Inc. | Methods providing a therapeutic macromolecule and synthetic nanocarriers comprising immunosuppressant locally and concomitantly to reduce both type I and type IV hypersensitivity |
| CN111068061A (en) * | 2013-05-03 | 2020-04-28 | 西莱克塔生物科技公司 | Administration combination for reducing undesired humoral immune responses |
| US10668053B2 (en) | 2013-05-03 | 2020-06-02 | Selecta Biosciences, Inc. | Tolerogenic synthetic nanocarriers to reduce or prevent anaphylaxis in response to a non-allergenic antigen |
| US11633422B2 (en) | 2014-09-07 | 2023-04-25 | Selecta Biosciences, Inc. | Methods and compositions for attenuating anti-viral transfer vector immune responses |
| CN107072965B (en) * | 2014-11-05 | 2021-05-11 | 西莱克塔生物科技公司 | Methods and compositions related to synthetic nanoparticles with rapamycin in a stable supersaturated state |
| CN107072965A (en) * | 2014-11-05 | 2017-08-18 | 西莱克塔生物科技公司 | The method and composition related to the synthesis nano particle with the rapamycin in stable over-saturation state |
| CN110325203A (en) * | 2017-01-07 | 2019-10-11 | 西莱克塔生物科技公司 | Medelling with the immunosuppressor of synthesis nano-carrier coupling is administered |
| WO2018129268A1 (en) * | 2017-01-07 | 2018-07-12 | Selecta Biosciences, Inc. | Patterned dosing of immunosuppressants coupled to synthetic nanocarriers |
| US11426451B2 (en) | 2017-03-11 | 2022-08-30 | Selecta Biosciences, Inc. | Methods and compositions related to combined treatment with antiinflammatories and synthetic nanocarriers comprising an immunosuppressant |
| CN107049963A (en) * | 2017-06-23 | 2017-08-18 | 北京化工大学 | A kind of sirolimus Nano medication composition and preparation method thereof |
| CN107049963B (en) * | 2017-06-23 | 2020-11-03 | 北京化工大学 | Sirolimus nano-drug composition and preparation method thereof |
| CN112236459A (en) * | 2018-04-23 | 2021-01-15 | 灰色视觉公司 | Improved continuous microparticle production |
| WO2021057007A1 (en) * | 2019-09-26 | 2021-04-01 | 严鹏科 | Rapamycin nanoscale sustained-release agent and preparation method thereof |
| CN110693883A (en) * | 2019-11-21 | 2020-01-17 | 安徽医科大学第一附属医院 | Preparation method and application of rapamycin-entrapped zinc-organic framework drug delivery system |
| CN114767659A (en) * | 2022-04-27 | 2022-07-22 | 中山大学孙逸仙纪念医院 | Medicinal preparation targeting PITPNM3 and preparation method and application thereof |
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