CN103751856B - A kind of polylactic acid embolism microsphere with good dispersion - Google Patents
A kind of polylactic acid embolism microsphere with good dispersion Download PDFInfo
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- CN103751856B CN103751856B CN201410028018.2A CN201410028018A CN103751856B CN 103751856 B CN103751856 B CN 103751856B CN 201410028018 A CN201410028018 A CN 201410028018A CN 103751856 B CN103751856 B CN 103751856B
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Abstract
The invention belongs to macromolecular material and biomedical engineering field, be specifically related to a kind of polylactic acid embolism microsphere with good dispersion.The polylactic acid-based copolymer adopting part hydrophilic is to polylactic acid microsphere modifying surface; microsphere surface is made to cover the polyethylene glycol protective of one deck neutrality; thus improve polylactic acid microsphere dispersibility in an aqueous medium and stability; solve part polylactic acid microsphere when implementing arteries Embolization; easy gathering is agglomerating, the problem of blocking injection needle or embolization catheter.Polylactic acid embolism microsphere of the present invention adopts the Absorbable rod that can be used for human body and degradation material to be prepared from, and has good histocompatibility, belongs to environment-friendly material, have broad application prospects.
Description
Technical field
The invention belongs to macromolecular material and biomedical engineering field, be specifically related to a kind of polylactic acid embolism microsphere with good dispersion.
Background technology
Arterial embolization is the medical skill by insertion ductus arteriosus, embolism microball being passed to target tissue and target organ.The object of thromboembolism blocks to supply and nutrition the blood of target area.If target tissue thing is tumor, then can make the tumor cell ischemic necrosis of target area.Embolism microball is general comparatively large, and size is different depending on thromboembolism position, but is generally all micron order microsphere.Arterial thrombosis microsphere is divided into biodegradable and nonbiodegradable two large classes by material.The permanent embolism microball comprising non-degradable conventional clinically at present, as polyvinyl alcohol Contour SE microsphere, three acrylic gelatin EmBosphere microspheres etc., and degradable sodium alginate micro ball etc.; In addition the microsphere that a large amount of research is many is also had, as embolism microball prepared by the materials such as gelatin, the Pseudobulbus Bletillae (Rhizoma Bletillae), Algin, albumin, polylactic acid, starch, chitosan, glucosan.
Polylactic acid microsphere is the more concerned embolism microball of a class, because polylactic acid has good histocompatibility and biological degradability, be can be used for human body by U.S. FDA approval, and the degradation rate of polylactic acid material can be controlled by molecular structure adjustment.Such as Flandroy etc. have studied the effect of embolization of polylactic acid microsphere in rabbit kidney tremulous pulse and degraded situation, prove that polylactic acid microsphere is a kind of comparatively ideal embolism materials (J Control Release, 1997,44,153).
The embolism microball of bag medicine carrying thing can play the dual function of thromboembolism and Drug therapy, because the blood supply of the thromboembolism hindrance blocks tumor of microsphere makes tumor ischemia necrosis, thus make the chemotherapeutic of high concentration easier in tumor tissues disperse, and tumor is under the condition of ischemia, anoxia, to chemotherapeutics and internal radiation more responsive.In addition, medicine carrying microballoons is released into tumor locus with can making drug slow, thus reduces cancer therapy drug in the distribution of its hetero-organization and toxic and side effects, and thus the current research to polylactic acid embolism microsphere is mainly based on medicine carrying microballoons.Liu Zhengkun etc. have prepared the polylactic acid microsphere that bag carries cisplatin medicine, carry out embolotherapy, have studied the distribution situation (Acta Pharmaceutica Sinica, 1993,28,792) of polylactic acid microsphere each internal organs in Mice Body in the mouse model body of suffering from secondary liver cancer; Cheng Jingliang etc. have studied the 5-fluorouracil polylactic acid microsphere of 104 ~ 200 μm to the arteriorenal effect of embolization of rabbit, prove that it is a kind of degradable tip type suppository (Henan Medical Univ.'s journal, 1994,29,299); Chen Hongyu etc. have prepared tanshinone IIA-PLGA microsphere, study new zealand white rabbit Hepatic artery distal embolization effect, find that the thromboembolism time was 30 ~ 42 days (interventional radiology magazine, 2010,19,977; CN103083251A).Patent CN101011607A reports the polylactic acid microsphere of parcel developing material, can implement arterial embolization under X-ray machine guiding.
In addition, radionuclide is loaded in embolism microball, injects liver tumor arteriosomes by the method for intubation intervention, the combination of arterial embolization and tumor Inner irradiation can be realized, make the toleration of tumor cell to ischemia, anoxia lower, thus realize the effect of Synergistic.Vente etc. have prepared the polylactic acid microsphere of year radioactivity holmium-166, after injecting Hepar Sus domestica tremulous pulse, show lower toxicity in vivo generally, MRI scanning can find obvious atrophy of liver lobe phenomenon (Eur J Nucl Med Mol maging, 2008,35,1259).Smits etc. adopt the polylactic acid microsphere carrying holmium-166 unresectable secondary liver cancer to be carried out to dosage escalation experiment (clinical I phase) of embolotherapy, by to after the treatment Data acquisition and issuance of 15 patients, confirm that this treatment means is feasible and safe clinically, and image-guided treatment (Lancet Oncol can be realized, 2012,13,1025).
But because polylactic acid microsphere is prepared from by hydrophobic polylactic acid base polymer on the whole, the emulsifying agent (as PVAC polyvinylalcohol) adopted in usual preparation process can be gone by washing in end processing sequences, cause the general hydrophilic in polylactic acid microsphere surface poor, be difficult in an aqueous medium be uniformly dispersed, easily float on liquid level or reunite together.When implementing Vascular embolization for patient clinically, microsphere cannot stable dispersion in injection or iodized oil developer solution, hydrophobic microsphere is easily assembled agglomerating, blocking injection needle or embolization catheter, causes operation technique difficulty.The present invention makes improvement to existing polylactic acid microsphere and technology of preparing thereof; the hydrophilic polylactic acid-based macromolecule-ethylene glycol copolymer of part is adopted to carry out modification to microsphere surface; microsphere surface is made to cover the polyethylene glycol protective of one deck neutrality; thus improve polylactic acid microsphere dispersibility in an aqueous medium and stability; the operation easier of obvious reduction arterial embolization, has broad application prospects.
Summary of the invention
The object of the present invention is to provide a kind of polylactic acid embolism microsphere with good dispersion.
The polylactic acid embolism microsphere with good dispersion that the present invention proposes, described polylactic acid embolism microsphere has spherical or that class is spherical form, be made up of biodegradable polylactic acid-based high-molecular material A and the hydrophilic polylactic acid-based macromolecule-ethylene glycol copolymer B of part, polylactic acid-based high-molecular material A forms the main body of embolism microball, the hydrophilic polylactic acid-based macromolecule-ethylene glycol copolymer B of part covers the body surfaces of embolism microball, and form the hydrophilic protective layer of one deck, Absorbable organic halogens and be evenly dispersed in the solution based on water, the diameter range of described polylactic acid embolism microsphere is 50 ~ 100 μm, 100 ~ 300 μm, 300 ~ 500 μm, the percentage by weight of polylactic acid-based high-molecular material A and the hydrophilic polylactic acid-based macromolecule-ethylene glycol copolymer B of part is as follows:
Weight percentages of components wt%
Polylactic acid-based high-molecular material A 80 ~ 99
Polylactic acid-based macromolecule-ethylene glycol copolymer B 1 ~ 20 that part is hydrophilic
Its gross weight meets 100%.
In the present invention, described polylactic acid-based high-molecular material A is any one or several in polylactic acid, Poly(D,L-lactide-co-glycolide, polylactic acid-caprolactone copolymer, polylactic acid-caprolactone-co-glycolic acid.
The copolymer that in the present invention, the hydrophilic polylactic acid-based macromolecule-ethylene glycol copolymer B of described part is polylactic acid, Poly(D,L-lactide-co-glycolide, polylactic acid-caprolactone copolymer, any one and Polyethylene Glycol in polylactic acid-caprolactone-co-glycolic acid form.
Have the application of polylactic acid embolism microsphere in the artery embolization for treatment of tumor for good dispersion, described polylactic acid embolism microsphere inside can comprise the slow releasing pharmaceutical be used for the treatment of, or can not comprise medicine.
The invention has the advantages that: important improvement is made to current existing polylactic acid embolism microsphere, although existing polylactic acid embolism microsphere have biodegradable with Absorbable rod, the feature such as evident in efficacy, but because microsphere is prepared from by hydrophobic polylactic acid base polymer on the whole, when implementing Vascular embolization for patient clinically, hydrophobic microspheres is easily assembled agglomerating, blocking injection needle or embolization catheter, cause operation difficulty or failure.Embolism microball of the present invention, surface is covered by polylactic acid-based macromolecule-ethylene glycol copolymer, Polyethylene Glycol segment can form a very thin neutral hydrophilic layer at microsphere surface, microsphere can be stablized and be evenly dispersed in normal saline, injection, iodized oil developer solution and blood, and can increase by volume because of hydration in the blood vessel, improve the effect of thromboembolism.
Accompanying drawing explanation
Fig. 1: be the microphotograph before poly lactic-co-glycolic acid embolism microball screening prepared by embodiment 1;
Fig. 2: be the microphotograph after poly lactic-co-glycolic acid embolism microball screening prepared by embodiment 1;
Fig. 3: be the microphotograph after polylactic acid embolism microball screening prepared by embodiment 2;
Fig. 4: be the microphotograph after polylactic acid-caprolactone embolism microball screening prepared by embodiment 3.
Detailed description of the invention
Below in conjunction with specific embodiment, such scheme is described further.Should be understood that these embodiments are not limited to for illustration of the present invention limit the scope of the invention.The implementation condition adopted in embodiment can do further adjustment according to the condition of concrete producer, and not marked implementation condition is generally the condition in normal experiment.
embodiment 1:the preparation of poly lactic-co-glycolic acid embolism microball
10g Poly(D,L-lactide-co-glycolide is dissolved in methylene chloride, is mixed with the solution that concentration is 200mg/mL, as initial oil phase; 1g poly lactic-co-glycolic acid/ethylene glycol copolymer is dissolved in pure water, is mixed with the aqueous solution of 1%, as initial aqueous phase, and add and possess powerful being at the uniform velocity uniformly mixed in the reactor of function; Oil-phase solution is slowly joined in above-mentioned reactor, and keeps the rotating speed of 500 rpm at the uniform velocity to stir, emulsifying 30 minutes; Again 0.5% poly lactic-co-glycolic acid of 5 times amount/ethylene glycol copolymer aqueous solution is added in above-mentioned reactor, increase the ratio of aqueous phase, continue stirring 12 hours, make microsphere solidified forming; First filter, then sucking filtration removes a large amount of moisture content, obtains microsphere powder; After lyophilization, then microsphere is carried out fine graded process by screening machine, obtain poly lactic-co-glycolic acid embolism microball.
Through microscopic examination, prepared poly lactic-co-glycolic acid embolism microball has regular spherical design, and mean diameter is 76 μm, and microsphere is good dispersion in the aqueous mediums such as water, normal saline and iodized oil developer solution, and can stable dispersion more than 5 hours.
embodiment 2:the preparation of polylactic acid embolism microball
Pure for 15g polylactic acid is dissolved in solvent chloroform, is mixed with the solution that concentration is 220mg/mL, as initial oil phase; 1.3g polylactic acid/ethylene glycol copolymer is dissolved in pure water, is mixed with the aqueous solution of 1%, as initial aqueous phase, and add and possess powerful being at the uniform velocity uniformly mixed in the reactor of function; Oil-phase solution is slowly joined in above-mentioned reactor, and keeps the rotating speed of 400 rpm at the uniform velocity to stir, emulsifying 30 minutes; Again 0.5% polylactic acid of 5 times amount/ethylene glycol copolymer aqueous solution is added in above-mentioned reactor, increase the ratio of aqueous phase, continue stirring 12 hours, make microsphere solidified forming; First filter, then sucking filtration removes a large amount of moisture content, obtains microsphere powder; After lyophilization, then microsphere is carried out fine graded process by screening machine, obtain polylactic acid embolism microball.
Through microscopic examination, prepared polylactic acid embolism microball has regular spherical design, and mean diameter is 192 μm, and microsphere is good dispersion in the aqueous mediums such as water, normal saline and iodized oil developer solution, and can stable dispersion more than 5 hours.
embodiment 3:the preparation of polylactic acid-caprolactone embolism microball
25g polylactic acid-caprolactone copolymer is dissolved in methylene chloride, is mixed with the solution that concentration is 300mg/mL, as initial oil phase; 1.7g polylactic acid-caprolactone/ethylene glycol copolymer is dissolved in pure water, is mixed with the aqueous solution of 1%, as initial aqueous phase, and add and possess powerful being at the uniform velocity uniformly mixed in the reactor of function; Oil-phase solution is slowly joined in above-mentioned reactor, and keeps the rotating speed of 350 rpm at the uniform velocity to stir, emulsifying 30 minutes; Again 0.5% polylactic acid of 5 times amount-caprolactone/ethylene glycol copolymer aqueous solution is added in above-mentioned reactor, increase the ratio of aqueous phase, continue stirring 12 hours, make microsphere solidified forming; First filter, then sucking filtration removes a large amount of moisture content, obtains microsphere powder; After lyophilization, then microsphere is carried out fine graded process by screening machine, obtain polylactic acid-caprolactone embolism microball.
Through microscopic examination, prepared polylactic acid-caprolactone embolism microball has regular spherical design, and mean diameter is 380 μm, and microsphere is good dispersion in the aqueous mediums such as water, normal saline and iodized oil developer solution, and can stable dispersion more than 5 hours.
embodiment 4:the form observation of polylactic acid embolism microsphere measures with dispersibility
Adopt the polylactic acid embolism microsphere of optical microscope to preparation to observe, and calculate the mean diameter of microsphere.Be dispersed in respectively by polylactic acid embolism microball in the aqueous mediums such as water, normal saline and iodized oil developer solution, being mixed with weight fraction is 10% dispersion liquid, leaves standstill under 25 DEG C of environment, observes dispersibility and the stability of microsphere.Microphotograph is shown in Fig. 1-Fig. 4, and test result sees the following form:
Above-described embodiment, only for technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalent transformations of doing according to spirit of the present invention or modification, all should be encompassed within protection scope of the present invention.
Claims (3)
1. one kind has the polylactic acid embolism microsphere of good dispersion, it is characterized in that described polylactic acid embolism microsphere has spherical or that class is spherical form, be made up of biodegradable polylactic acid-based high-molecular material A and the hydrophilic polylactic acid-based macromolecule-ethylene glycol copolymer B of part, polylactic acid-based high-molecular material A forms the main body of embolism microball, the hydrophilic polylactic acid-based macromolecule-ethylene glycol copolymer B of part covers the body surfaces of embolism microball, and form the hydrophilic protective layer of one deck, Absorbable organic halogens and be evenly dispersed in the solution based on water, the diameter range of described polylactic acid embolism microsphere is 50 ~ 100 μm, 100 ~ 300 μm, 300 ~ 500 μm, the percentage by weight of polylactic acid-based high-molecular material A and the hydrophilic polylactic acid-based macromolecule-ethylene glycol copolymer B of part is as follows:
Weight percentages of components wt%
Polylactic acid-based high-molecular material A 80 ~ 99
Polylactic acid-based macromolecule-ethylene glycol copolymer B 1 ~ 20 that part is hydrophilic
Its gross weight meets 100%.
2. a kind of polylactic acid embolism microsphere with good dispersion according to claim 1, is characterized in that described polylactic acid-based high-molecular material A is any one or several in polylactic acid, Poly(D,L-lactide-co-glycolide, polylactic acid-caprolactone copolymer, polylactic acid-caprolactone-co-glycolic acid.
3. a kind of polylactic acid embolism microsphere with good dispersion according to claim 1, is characterized in that the hydrophilic polylactic acid-based macromolecule-ethylene glycol copolymer B of described part is polylactic acid, copolymer that Poly(D,L-lactide-co-glycolide, polylactic acid-caprolactone copolymer, any one and Polyethylene Glycol in polylactic acid-caprolactone-co-glycolic acid form.
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| CN105214145A (en) * | 2014-06-23 | 2016-01-06 | 李茂全 | The application of polylactic acid microsphere in hemorrhage |
| CN105193735A (en) * | 2014-06-23 | 2015-12-30 | 李茂全 | Application of polylactic acid microspheres in malignant tumors |
| CN110548173B (en) * | 2019-08-26 | 2021-10-26 | 苏州恒瑞迦俐生生物医药科技有限公司 | Preparation method of chemoembolization microsphere with microwave sensitization effect |
| CN111603575A (en) * | 2020-02-28 | 2020-09-01 | 彭盛 | Radioactive embolism microsphere with core-shell structure and preparation method and application thereof |
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| US7303575B2 (en) * | 2002-08-01 | 2007-12-04 | Lumen Biomedical, Inc. | Embolism protection devices |
| WO2006013309A1 (en) * | 2004-08-03 | 2006-02-09 | Biocompatibles Uk Limited | Drug delivery from embolic agents |
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| CN101007190A (en) * | 2007-01-12 | 2007-08-01 | 李艳芳 | Biodegradable imaging microspheres vascular embolization material |
| CN101007189A (en) * | 2007-01-12 | 2007-08-01 | 李艳芳 | Biodegradable imaging microspheres vascular embolization material containing drug |
| CN101889985A (en) * | 2010-07-08 | 2010-11-24 | 东华大学 | Medicament-carrying nano microspheres and preparation method thereof |
| CN102895197A (en) * | 2012-09-26 | 2013-01-30 | 上海交通大学 | Method for preparing microspheres through oil in nano-particle suspension-oil in oil and sustained-release microspheres |
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