CN103301073B - Methotrexate targeted nanoparticle sustained-release preparation and preparation method thereof - Google Patents
Methotrexate targeted nanoparticle sustained-release preparation and preparation method thereof Download PDFInfo
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- CN103301073B CN103301073B CN201310239345.8A CN201310239345A CN103301073B CN 103301073 B CN103301073 B CN 103301073B CN 201310239345 A CN201310239345 A CN 201310239345A CN 103301073 B CN103301073 B CN 103301073B
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Abstract
The invention relates to the field of medical antineoplastic medicine preparations, and particularly relates to a methotrexate targeted nanoparticle sustained-release preparation and a preparation method thereof. The MTX (Methotrexate) targeted nanoparticle sustained-release preparation comprises MTX and a carrier material, wherein the carrier material is mPEG-PLA (Methoxy Polyethylene Glycol-Poly Lactic Acid). According to another technical scheme, the invention provides the preparation method of the MTX targeted nanoparticle sustained-release preparation. The preparation method comprises the following steps of: mixing and cross-linking an mPEG-PLA solution and an MTX solution to prepare a solution C; dialyzing the solution C, and then freeze-drying to obtain a freeze-dried product; and dissolving the freeze-dried product by using an organic solvent, dialyzing, and then filtering and freeze-drying to obtain MTX-PLA-mPEG targeted sustained-release nanoparticles. The MTX targeted nanoparticle sustained-release preparation disclosed by the invention has the characteristics of good stability, higher medicine-loading rate, less in-vivo toxic side effect, high tumor suppression effect, stability in drug release, long drug release time and the like and has the advantages of simple preparation method and convenience for use.
Description
Technical field
The present invention relates to pharmaceutical anti-tumor medicinal preparation field, particularly relate to a kind of methotrexate (MTX) targeted nano granule slow releasing preparation preventing malignant growth and recurrence and preparation method thereof.
Background technology
Methotrexate (MTX) is a kind of folic acid class antimetabolic medicament, combination can be carried out with the folacin receptor of tumor cell surface and play good targeting, be usually used in various treating malignant tumor, also be conventional antirheumatic, MTX pharmaceutically also has many disadvantages, seldom measure by blood brain barrier during treatment brain tumor, this product can increase hepatic and renal function toxicity, because drug mechanism is reached the synthesis hindering DNA of tumor cell, so also have drug effect to normal biological cell, toxic reaction is larger.
Nanoparticle through modifying enters in body as pharmaceutical carrier, can effectively reduce engulfing of human body reticuloendothelial system (RES) macrophage, intercellular substance can be passed through as nano level particle, the blood capillary minimum by human body and blood brain barrier (BBB), and absorbed by cell tissue, nanoparticle pharmaceutical carrier can control medicine at targeting moiety Co ntrolled release, reduce drug dose, medicament curative effect enhancement reduce drug toxicity.Meanwhile, particIe system can avoid pharmaceutically active to lose, and is conducive to storage and the transport of medicine.Because the plurality of advantages of nanoparticle, become a kind of up-and-coming novel pharmaceutical formulation.
The self assembly undertaken by dialysis is at present mainly used in being applied to the nano spherical particle that hydrophobic drug is prepared into nucleocapsid structure, and the nano particle diameter prepared due to dialysis is even, and impurity is less, and preparation method is simple, applies more and more extensive; But for the good MTX of hydrophilic, be difficult to utilize dialysis and carrier to form the particle of medicine carrying, be not loaded with the pertinent literature record of the PLA slow release nanometer particle of MTX at present by dialysis preparation.
Summary of the invention
The object of the present invention is to provide a kind of dialysis process target slow-release nanometer formulation preparing water-soluble anti-tumor medicine methotrexate and preparation method thereof.
Technical scheme of the present invention is for providing a kind of methotrexate targeted nano granule slow releasing preparation; comprise crude drug MTX and carrier material; described carrier material is mPEG-PLA; described carrier material is the amphiphilic block polymer that poly glycol monomethyl ether and polylactic acid synthesize, and described MTX and mPEG-PLA mass ratio is 1:5-1:10.
Preferably, in MT reconnaissance X targeted nano granule slow releasing preparation, the molecular weight of described mPEG-PLA is 5000-50000 dalton.
Another technical scheme of the present invention, for providing a kind of preparation method of MT reconnaissance X targeted nano granule slow releasing preparation, comprises the steps:
1) mPEG-PLA is dissolved in organic solvent, obtains solution A; Then take MTX to be dissolved in DMSO aqueous solution, obtain solution B; Described MTX and mPEG-PLA mass ratio is 1:5-1:10, in solution B, add cross-linking agent, and described cross-linking agent is EDC and NHS, by solution A, B mixing, reacts 12h under nitrogen protection, obtains solution C;
2) impurity is removed in solution C dialysis, lyophilizing obtains MTX-PLA-mPEG complex dried frozen aquatic products;
3) by MTX-PLA-mPEG complex dried frozen aquatic products organic solvent dissolution, dialysis 8h, dialysate filter lyophilizing, obtains MTX-PLA-mPEG target slow-release preparation.
Preferably, in the preparation method of above-mentioned MTX targeted nano granule slow releasing preparation, described mPEG-PLA is the polylactic acid of poly glycol monomethyl ether grafting, and its molecular weight is 5000-50000 dalton.
Preferably, in the preparation method of above-mentioned MTX targeted nano granule slow releasing preparation, described step 1) and 3) in organic solvent be dimethyl sulfoxide, dichloromethane, acetone or DMF.
Preferably, in the preparation method of above-mentioned MTX targeted nano granule slow releasing preparation, described step 3) is: by MTX-PLA-mPEG complex dried frozen aquatic products acetone solution; dialysis 8h; dialysate filter lyophilizing, cobalt radiation sterilization, obtains MTX-PLA-mPEG target slow-release preparation.
Preferably, the preparation method of above-mentioned MTX targeted nano granule slow releasing preparation comprises the steps:
1) weighing molecular weight is 10000 daltonian mPEG-PLA400mg, dissolves to obtain solution with 10ml dichloromethane; Weigh MTX crude drug 40mg, EDC10mg and NHS5mg is dissolved in DMSO and obtains solution B; By solution A and B mixing, react 12h under nitrogen protection and obtain solution C;
2) C solution transferred in minimum penetrating 8000 daltonian bag filters, put in deionized water and carry out dialysis and obtain suspension, the lyophilizing of gained suspension obtains MTX-PLA-mPEG complex dried frozen aquatic products;
3) by MTX-PLA-mPEG complex dried frozen aquatic products acetone solution, dialysis 8h, dialysate filter lyophilizing, obtains MTX targeted nano granule slow releasing preparation.
Beneficial effect of the present invention: MTX and the mPEG-PLA carrier in MTX targeted nano granule slow releasing preparation of the present invention forms medicine carrying particle, has the hypotoxicity not available for naked medicine; The PLA fraction self assembly of medicine carrying particles hydrophobic forms core, hydrophilic medicament MTX and mPEG is in the interface of PLA core, hydrophobic PLA makes medicine more easily be loaded into, and hydrophilic mPEG make medicine carrying particle in vivo circulation time greatly extend, more easily reach tumor tissues play drug effect.
MTX targeted nano granule slow releasing preparation of the present invention has good stability, and drug loading is higher; The features such as in body, toxic and side effects is little, and tumor-inhibiting action is strong, and drug release is stablized, and drug release time is long, MTX targeted nano granule slow releasing preparation preparation method of the present invention is simple, easy to use.
Detailed description of the invention
By describing technology contents of the present invention, structural feature in detail, being realized object and effect, be explained in detail below in conjunction with embodiment.
The nomenclature of drug that the present invention uses illustrates as table 1:
Table 1
Example 1: weigh polylactic acid (mPEG-PLA) 400mg that molecular weight is 5000 daltonian poly glycol monomethyl ether grafting, put in beaker and dissolve to obtain A liquid with 10ml chloroform; In addition, weigh MTX crude drug 40mg, EDC10mg and NHS5mg is dissolved in appropriate DMSO and obtains B liquid; Both A and B liquid is mixed; and reaction 12h obtains C liquid under nitrogen protection; C liquid is transferred in minimum penetrating 8000 daltonian bag filters; put in deionized water and dialyse; suspension lyophilizing obtains MTX-PLA-mPEG complex dried frozen aquatic products; by it with the 8h that dialyses after acetone solution, by lyophilizing after gained suspension filtered, both obtained MTX targeted nano granule slow releasing preparation.
The shape of particle utilizing this law to prepare for paramecium shape or class spherical, mean diameter is 230nm, drug loading 7.1%, and the time of drug release 80% is 7 days.
Example 2: weigh polylactic acid (mPEG-PLA) 400mg that molecular weight is 20000 dalton's poly glycol monomethyl ether grafting, put in beaker and dissolve to obtain A liquid with 10ml DMF (DMF); In addition, weigh MTX crude drug 50mg, EDC12mg and NHS5mg is dissolved in appropriate DMSO and obtains B liquid; Both A and B liquid is mixed; and reaction 12h must contain the C liquid of MTX-PLA-mPEG complex under nitrogen protection; C liquid is transferred in minimum penetrating 8000 daltonian bag filters; put in deionized water and dialyse; suspension lyophilizing obtains MTX-PLA-mPEG complex dried frozen aquatic products; by it with the 8h that dialyses after acetone solution, by lyophilizing after gained suspension filtered, both obtained MTX targeted nano granule slow releasing preparation.
The shape of particle utilizing this law to prepare for paramecium shape or class spherical, mean diameter is 270nm, drug loading 8.2%, and the time of drug release 80% is 7 days.
Example 3: weigh polylactic acid (mPEG-PLA) 400mg that molecular weight is 35000 dalton's poly glycol monomethyl ether grafting, put in beaker and dissolve to obtain A liquid with 10ml DCM; Weigh MTX crude drug 60mg, EDC15mg and NHS6mg is dissolved in appropriate DMSO and obtains B liquid; Both A and B liquid is mixed; and reaction 12h obtains C liquid under nitrogen protection; C liquid is transferred in minimum penetrating 8000 daltonian bag filters; put in deionized water and dialyse; suspension lyophilizing obtains MTX-PLA-mPEG complex dried frozen aquatic products; by it with the 8h that dialyses after acetone solution, by lyophilizing after gained suspension filtered, both obtained MTX targeted nano granule slow releasing preparation.
The shape of particle utilizing this law to prepare for paramecium shape or class spherical, mean diameter is 320nm, drug loading 9.3%, and extracorporeal simulating experiment learns that the time of drug release 80% is 8 days.
Example 4: weighing with molecular weight is polylactic acid (mPEG-PLA) 400mg of 50000 dalton's poly glycol monomethyl ether grafting, puts in beaker and dissolves to obtain A liquid with 10ml DCM; In addition, weigh MTX crude drug 80mg, EDC20mg and NHS10mg is dissolved in appropriate DMSO and obtains B liquid; Both A and B liquid is mixed; and reaction 12h obtains C liquid under nitrogen protection; C liquid is transferred in minimum penetrating 8000 daltonian bag filters; put in deionized water and dialyse; suspension lyophilizing obtains MTX-PLA-mPEG complex dried frozen aquatic products, by it with the 8h that dialyses after acetone solution, by lyophilizing after gained suspension filtered; cobalt radiation sterilization, both obtained MTX targeted nano granule slow releasing preparation.
The shape of particle utilizing this law to prepare for paramecium shape or class spherical, mean diameter is 360nm, drug loading 10.4%, and extracorporeal simulating experiment learns that the time of drug release 80% is 8 days.
Medicine carrying particle in MTC targeted nano granule preparation of the present invention is that paramecium shape or class are spherical, and particle diameter distributes between 100-500nm, and MTC targeted nano granule preparation current potential is 0, and product leaves standstill and do not precipitate, and good stability, has good targeting and slow release characteristic; Cell toxicity test shows that MTX-PLA-mPEG nanoparticle has stronger tumor-inhibiting action, and tumor killing effect is better than MTX aqueous injection.Product of the present invention is mainly used in injection and local injection in body, and object is Tumor suppression growth and recurrence.
The foregoing is only embodiments of the invention; not thereby the scope of the claims of the present invention is limited; every utilize description of the present invention to do equivalent structure or equivalent flow process conversion; or be directly or indirectly used in other relevant technical fields, be all in like manner included in scope of patent protection of the present invention.
Claims (5)
1. a preparation method for methotrexate targeted nano granule slow releasing preparation, is characterized in that, comprises the steps:
1) mPEG-PLA is dissolved in organic solvent, obtains solution A; MTX is dissolved in DMSO, obtains solution B; Described MTX and mPEG-PLA mass ratio is 1:5-1:10, in solution B, add cross-linking agent, and described cross-linking agent is EDC and NHS, by solution A, B mixing, reacts 12 h under nitrogen protection, obtains solution C; Described mPEG-PLA is the polylactic acid of poly glycol monomethyl ether grafting;
2) impurity is removed in solution C dialysis, lyophilizing obtains MTX-PLA-mPEG complex dried frozen aquatic products;
3) by MTX-PLA-mPEG complex dried frozen aquatic products organic solvent dissolution, dialyse 8 h, and dialysate filter lyophilizing obtains MTX-PLA-mPEG target slow-release preparation.
2. the preparation method of methotrexate targeted nano granule slow releasing preparation according to claim 1, is characterized in that, described mPEG-PLA is the polylactic acid of poly glycol monomethyl ether grafting, and its molecular weight is 5000-50000 dalton.
3. the preparation method of methotrexate targeted nano granule slow releasing preparation according to claim 1, is characterized in that, described step 1) and 3) in organic solvent be dimethyl sulfoxide, dichloromethane, acetone or DMF.
4. the preparation method of methotrexate targeted nano granule slow releasing preparation as claimed in claim 1; it is characterized in that; described step 3) is: by MTX-PLA-mPEG complex dried frozen aquatic products acetone solution; dialyse 8 h; dialysate filter lyophilizing; cobalt radiation sterilization, obtains MTX-PLA-mPEG target slow-release preparation.
5. the preparation method of methotrexate targeted nano granule slow releasing preparation as claimed in claim 1, is characterized in that, comprise the steps:
1) weighing molecular weight is 10000 daltonian mPEG-PLA 400 mg, dissolves to obtain solution with 10 ml dichloromethane; Weigh MTX crude drug 40 mg, EDC 10mg and NHS 5mg is dissolved in DMSO and obtains solution B; By solution A and B mixing, react 12 h under nitrogen protection and obtain solution C;
2) C solution transferred in minimum penetrating 8000 daltonian bag filters, put in deionized water and carry out dialysis and obtain suspension, the lyophilizing of gained suspension obtains MTX-PLA-mPEG complex dried frozen aquatic products;
3) by MTX-PLA-mPEG complex dried frozen aquatic products acetone solution, dialyse 8 h, and dialysate filter lyophilizing obtains MTX targeted nano granule slow releasing preparation.
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| CN109045272A (en) * | 2018-08-01 | 2018-12-21 | 厦门市壳聚糖生物科技有限公司 | A kind of bortezomib phosphatide complexes and the preparation method and application thereof |
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| 5-氟尿嘧啶的聚乙二醇-聚乳酸的胶束制备及其体外释药研究;庞国棉等;《广东药学院学报》;20110430;第27卷(第2期);第116-120页 * |
| Methotrexate-loaded biodegradable polymeric micelles: Preparation, physicochemical properties and in vitro drug release;Ying Zhang etal;《Colloids and Surfaces B: Biointerfaces》;20051231;第44卷;第104-109页 * |
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