CN102429877A - Double-targeting-function medicament sustained-release system prepared by supercritical fluid technique - Google Patents
Double-targeting-function medicament sustained-release system prepared by supercritical fluid technique Download PDFInfo
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- CN102429877A CN102429877A CN2011104569605A CN201110456960A CN102429877A CN 102429877 A CN102429877 A CN 102429877A CN 2011104569605 A CN2011104569605 A CN 2011104569605A CN 201110456960 A CN201110456960 A CN 201110456960A CN 102429877 A CN102429877 A CN 102429877A
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Abstract
In the invention, based on a tumor cell surface folic acid acceptor and tumor blood vessel endotheliocyte acceptor double-targeting mechanism, supercritical CO2 solvent-resistant technique is utilized to encapsulate directed treating peptide and anti-tumor medicament amycin in a folic acid-coupled polylactic acid-polyethylene glycol carrier so as to prepare a medicament sustained-release microsphere with ovarian cancer double-targeting and treating functions, and the prepared microsphere has smooth surface, average particle diameter of 2.56-5.88 mu m, maximal medicament loading amount of 20.57% and encapsulation rate of 76.01%.
Description
Technical field
The invention belongs to pharmaceutical dosage form novel preparation method and applied technical field, relate to and adopt dual-target to reduce existing anticancer drugs, doxorubicin body endogenous toxin side-effect problem, comprise the structure of dual-target carrier and the parcel of medicine.
Background technology
Amycin is a kind of broad-spectrum anti-cancer drug, can suppress the synthetic of RNA and DNA, and the strongest to the inhibitory action of RNA, antitumor spectra is wider, and kinds of tumors is all had effect, belongs to cell cycle nonspecific agent (CCNSA), and the tumor cell of various growth cycles is all had killing action.Be used to treat acute lymphoblastic leukemia, acute myeloblastic leukemia, He Jiejin and non Hodgkin lymphoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, chorionic epithelioma, carcinoma of prostate, carcinoma of testis, gastric cancer, hepatocarcinoma etc. clinically.Its effect is obvious, often is used as the second line medicine, promptly when the choice drug drug resistance, can consider to use this medicine.
Use amycin clinically and mostly be intravenous injection type doxorubicin hydrochloride, directly get final product with the water for injection dissolving.But amycin can produce biochemical effect widely to body, has intensive cytotoxic effect, and its mechanism is its intercalation of DNA and suppress the synthetic of DAN and RNA.Common side effect is for influencing hemopoietic function of bone marrow; Show as platelet and leukopenia; Cardiac toxicity; Heart failure can occur when serious, can see nauseating, vomiting, stomatitis, alopecia, hyperpyrexia, phlebitis and cutaneous pigmentation etc., small number of patients has heating, hemorrhagic erythema and liver function injury.
Exploitation amycin novel form mainly contains microemulsion, micelle, prodrug, liposome, gel, implant and medicine slow release stent etc. at present.Strengthening adriablastina target and prolonging slow-release time is the focus of studying at present.Though the targeted drug preparation of research can play certain targeting at present, the efficient of targeting is not high, and is so medicine is obvious inadequately in the gathering of focal zone, still very big to the injury of normal histoorgan.
The method for preparing of traditional medicament slow-release microsphere mainly contains self assembly, spray drying method, emulsifying volatility process, phase detachment technique etc.These technical methods without exception relate to organic solvent, high temperature, acid-base reagent etc., in the medicine carrying microballoons for preparing organic reagent residual, protein drug is all had certain infringement.Supercritical fluid technology prepares the polymer support microsphere and enjoys people's attention in recent years, mainly have benefited from remedying the shortcoming of above method for preparing, and the preparation process is simple, with low cost.Ultimate principle is to utilize supercritical fluid as anti-solvent, absorbs organic solvent, reduces polypeptide, drug solubility in the organic solvent in the solution, makes its supersaturation and precipitates and separate out the formation microsphere particle.The supercritical fluid that on supercritical anti-solvent method basis, grows up is forced dispersion soln technology (Solution-enhanced dispersion by supercritical fluids; SEDS); With coaxial two streaming nozzle application and SAS process so that solution fully atomize; Increase mass transfer effect, thereby obtain higher solution supersaturation speed and crystalline deposit speed to prepare more tiny granule.The triple channel supercritical fine particle device that adopts laboratory to design voluntarily; Being about to the polymer organic solution line separates with albumen, polypeptide and pharmaceutical aqueous solution pipeline; Adopt coaxial three streaming nozzles; Reduce organic solvent and polypeptide class bioactive molecule time of contact greatly, kept having the active function of bioactive molecule to greatest extent.
The objective of the invention is in the triple channel supercritical fine particle device of design voluntarily, to adopt supercritical CO
2Force the two targeting peptide-doxorubicin medicament slow-release microspheres of dispersion soln technology preparation; Adopt dual-target mode (promptly utilize can with the folic acid and the polypeptide of tumor cell and tumor vascular endothelial cell surface specific receptors bind); Amycin is assembled at focal zone as much as possible, improved the drug effect of amycin and can reduce toxic and side effects in this medicine body.
Summary of the invention
The objective of the invention is to make up a kind of new target medicament slow release microsphere, solve medicine in the traditional method can not effectively be gathered in focal zone, to shortcomings such as body toxic and side effects, organic reagent are residual.
The present invention seeks to realize through following technical scheme:
The step of concrete grammar is following:
Folic acid graft polymers process can be described below: lactic acid monomer and the ring-opening polymerisation under stannous octoate catalysis of glycolic monomer; And under the catalysis of triethylamine, dicyclohexylcarbodiimide with folic acid (folic acid; FA) form the active fat (NHS-folate) of FA with N-maloyl imines (NHS) esterification, the latter can form the PLLA-PEG-FA conjugate with the PLLA-PEG coupling.
The continous way anti-dissolving agent process can be described below: the CO2 in the steel cylinder liquefies through refrigeration system; By high-pressure plunger pump pressurization, after the water bath with thermostatic control in the pipeline heats up, pump in the autoclave by the outside pipeline of coaxial nozzle; Treat to meet the requirements of in the still pressure; Keep CO2 and pump into speed, open the venting air valve with certain speed venting, to keep the still internal pressure constant; After reaching experimental temperature; The organic solution that is dissolved with polymer pumps in the autoclave through HPLC (HPLC) pump pipeline in the nozzle of still top, regulates outside drying baker of autoclave and pipeline bath temperature, the control temperature in the kettle; Regulate vent valve, keep the still internal pressure.The organic solution that is dissolved with polymer pumps in the autoclave through HPLC (HPLC) pump pipeline in the nozzle of still top; The nozzle interior conduit pumps in the autoclave through the still top via another HPLC (HPLC) pump to be dissolved with the aqueous solution of protein and peptide.After finishing pump appearance, it is constant to keep pressure and temperature, continues with behind CO2 and the dry certain hour of ethanol, and slowly release when treating that the still internal pressure is reduced to normal pressure, is taken out sample.In this SEDS process; Add modifier in the pipeline of CO2; To change the nonpolar of CO2; Be beneficial to the intermiscibility of CO2 to aqueous solution, make the supersaturation fast of bioactive molecule medicine, therefore on the carbon dioxide conveyance conduit, also will add a HPLC (HPLC) pump is used to carry dehydrated alcohol.
Purposes of the present invention: the present invention is mainly used in preparation dual-target medicine carrying microballoons; At general medicine carrying microballoons surface grafting folic acid (tumor cell surface receptor-folacin receptor) and internal package tumor vascular endothelial cell specific receptor polypeptide (WSGPGVWAGSVK), to reach dual-target, make the medicine amycin concentrate on the focal zone slow release efficiently and to reduce purpose to normal histoorgan toxic and side effects.
The invention has the advantages that the preparation process is gentle, environmentally safe has solved traditional unconspicuous problem of medicine carrying microballoons targeting property specific aim, can design more multiple target drug-carrying microsphere with this design concept, has expanded the range of application of medicine carrying microballoons.
Description of drawings
Fig. 1. preparation dual-target carried medicine sustained-release microsphere flow chart;
Fig. 2. polylactic acid-polyglycol (PEG-PLLA) medicine carrying microballoons (a), targeted peptide-amycin-folic acid-polylactic acid-polyglycol (HP-DOX-FA-PEG-PLLA) medicine carrying microballoons (b).
The specific embodiment
(1) amycin, polypeptid solution
In reaction bulb 1, add 50-60mg amycin and 30mg polypeptide WSG, add quantitative aqueous acetic acid (33%, v/v), under room temperature, dissolve.
(2) polymer organic solution
In reaction bulb 2, add the PEG-PLLA macromolecular material of 100-120mg grafting folic acid, add quantitative organic solvent, under room temperature, dissolve.
(3) modulation of system process parameter
Reach after the temperature and pressure of test requirements document; Supercritical CO 2 passes through the coaxial three streaming nozzle outer passage in autoclave top by high-pressure plunger pump; Also to add a HPLC (HPLC) pump on the carbon dioxide conveyance conduit and be used to carry dehydrated alcohol; Organic solution is through HPLC (HPLC) pump pipeline in the nozzle of still top, the aqueous solution of protein and peptide via another HPLC (HPLC) pump through the still top nozzle interior conduit, pump in the autoclave simultaneously.Supercritical CO 2 is forced organic solution to disperse as disperse medium, simultaneously also as anti-solvent, and the organic solvent in the absorbent solution; Ethanol changes the nonpolar of supercritical CO 2 as a kind of modifier, is beneficial to the intermiscibility of CO2 to aqueous solution, makes the supersaturation fast of bioactive molecule medicine.
Claims (1)
1. dual-target novel drugs sustained-release micro-spheres is characterized in that:
(1) the described dual-target novel drugs sustained-release micro-spheres polymer support polyethylene glycol-lactic acid (FA-PEG-PLLA) that is grafting folic acid (FA);
(2) described dual-target novel drugs sustained-release micro-spheres is to adopt supercritical CO
2Anti-solvent method is embedded in anticarcinogen amycin and tumor vessel specificity targeted therapy peptide (WSGPGVWAGSVK) and prepares among the FA-PEG-PLLA;
(3) described dual-target novel drugs sustained-release micro-spheres, the folic acid percent grafting is 15-22%, the concentration 10%wt-20%wt of medicine amycin, the concentration 5%wt-10%wt of polypeptide, the concentration of polymer organic solution is at 1%wt/v-2.5% wt/v.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105395491A (en) * | 2015-12-30 | 2016-03-16 | 东华大学 | Method for preparing porous microspheres containing adriamycin heptapeptides |
| CN109589414A (en) * | 2018-12-27 | 2019-04-09 | 佳木斯大学 | A method of use supercritical carbon dioxide extraction apparatus to carry out drug loading by carrier of GO or CNTs |
-
2011
- 2011-12-31 CN CN2011104569605A patent/CN102429877A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105395491A (en) * | 2015-12-30 | 2016-03-16 | 东华大学 | Method for preparing porous microspheres containing adriamycin heptapeptides |
| CN105395491B (en) * | 2015-12-30 | 2018-04-10 | 东华大学 | A kind of preparation method of the porous microsphere of heptapeptide containing adriamycin |
| CN109589414A (en) * | 2018-12-27 | 2019-04-09 | 佳木斯大学 | A method of use supercritical carbon dioxide extraction apparatus to carry out drug loading by carrier of GO or CNTs |
| CN109589414B (en) * | 2018-12-27 | 2022-02-15 | 佳木斯大学 | Method for carrying out drug loading by using GO or CNTs as carrier through supercritical carbon dioxide extraction device |
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Application publication date: 20120502 |