CN1762332A - Temperature-controllable thermotherapeutic embolize micro-sphere and preparation method thereof - Google Patents
Temperature-controllable thermotherapeutic embolize micro-sphere and preparation method thereof Download PDFInfo
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- CN1762332A CN1762332A CN 200510050061 CN200510050061A CN1762332A CN 1762332 A CN1762332 A CN 1762332A CN 200510050061 CN200510050061 CN 200510050061 CN 200510050061 A CN200510050061 A CN 200510050061A CN 1762332 A CN1762332 A CN 1762332A
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- embolize
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Abstract
The invention relates to a temperature controllable thermotherapy plug micro-sphere, magnetic response micro-sphere is scattered in the cross linked net formed by high polymer material; the grain size of the thermotherapy plug is between 50-2000 mum, the weight proportion of the magnetic response micro-sphere in the whole plug micro-sphere is 0.5-45%. The preparing method I this invention comprises the following steps: a: adding the metal material into the solution of high polymer material, mixing uniformly to form the solution containing magnetic high polymer material; b: adding the solution containing magnetic high polymer material into the discontinuous phase with stirring; c: preparing the magnetic response polymer micro-sphere; d: filtering, washing and preparing the turbid liquor of the magnetic response micro-sphere; e: preparing dry magnetic response polymer micro-sphere. The good effect of the invention is as follows: adding the low Curie temperature metal material with automatic temperature control into the high polymer material to form the thermotherapy plug micro-sphere with two functions of thermotheraphy and plug, the temperature of the thermotherapy plug micro-sphere will increase in the alternating magnetic field to realize the thermotheraphy to the tumor; the temperature can be controlled automatically.
Description
Technical field
The present invention relates to the thermotherapy microsphere embolization agent, particularly a kind of temperature-controllable thermotherapeutic embolize micro-sphere and preparation method thereof.
Background technology
Statistics according to " 2003 the special rate of part cities and counties top ten disease death and the cause of death constitute " in " Chinese health statistics summary in 2004 ", Chinese malignant tumor mortality was 134.54/10 ten thousand in 2003, was significantly higher than the cerebrovascular (105.40/10 ten thousand) that comes second mortality rate.Malignant tumor has become the maximum killer who threatens China's people's life health.General conventional therapy: excision, systemic chemotherapy, radiotherapy etc., therapeutic effect is relatively poor, and recurrence easily.
The discovery of arterial thrombosis art and application make tumor treatment produce once big leap.This kind method be with vascular occlusive agent by injecting therapentic part by conduit, the effect of physics thromboembolism, the supply of blocking-up tumor blood makes cancerous cell because ischemia and anoxia and death, thereby the realization therapeutic purposes.Prove that by a large amount of clinical practices the arterial thrombosis art is to treat carcinoid first-selected therapies such as malignant tumor, hysteromyoma such as hepatocarcinoma at present; The arterial thrombosis art has tempting application prospect aspect auxiliary treatment, the various hemorrhage treatment of diseases such as treatment before treatment hemangioma, arteriovenous malformotion, hyperthyroidism, art in addition.But the absorbable gelatin sponge particle of many clinically at present employing iodized oils, hammer-shears system, stainless steel coil etc. are as suppository.And the oil droplet of the spontaneous formation of iodized oil is very little, enters pulmonary circulation by sinus hepaticus easily, causes acute pulmonary embolism, and simultaneously the consumption of iodized oil is restricted, cause easily thromboembolism not exclusively and thromboembolism not lasting, can not realize effective embolotherapy; Stainless steel coil can only the bigger blood vessel of thromboembolism, thereby causes serious thromboembolism syndrome; The absorbable gelatin sponge particle of hammer-shears system also can only the bigger blood vessel of thromboembolism, and grain diameter difference is very big, causes the thromboembolism of non-operation purpose easily, causes serious adverse.Therefore, lack ideal suppository and become the key factor that restriction cancerous protuberance disease gets involved artery embolization for treatment.
The patented product of my company, 200410017045.6) and absorbable gelatin sponge particle suppository (number of patent application: 200410017046.0) solved the shortcoming of above-mentioned suppository effectively embolism agent of granule of polyvinyl alcohol (number of patent application:, product has permanent thromboembolism effect and thromboembolism effect in mid-term, product has plurality of specifications such as 150-350 μ m, 350-560 μ m, 560-710 μ m, 710-1000 μ m, 1000-1400 μ m, 1400-2000 μ m, and the granule of product 80% has effectively prevented the generation of non-surgery side effect within the particle size range of regulation.But simple arterial thrombosis is the kill tumor cell directly, has influenced the further raising of artery embolization for treatment tumor effect.Therefore, seek the developing direction that a kind of suppository with multiple therapeutical effect has become suppository.
The existing research technology that adopt preparation medicine carrying suppository in the hope of realizing the dual function of chemotherapy and thromboembolism more.But present chemoembolization agent can't solve the technical barrier of the technical bottleneck and the long term maintenance tumor locus chemotherapeutics high concentration of drug loading.Therefore, serious restriction the therapeutic effect of chemoembolization.
The thermotherapy technology of tumor is a new technique that just grows up in recent years.The principle of tumor thermotherapy (hyperthermia) is to utilize physical method that tissue is heated to the temperature that can kill cancerous cell and keeps certain hour, thereby reaches the purpose of direct kill cancer cell.Tumor tissues is because vascular malformation when temperature raises, often causes the heat savings, and the comparable normal structure of local temperature is high 5 ℃.Tumor tissues is heated to 41 ℃～46 ℃ and the effective kill tumor cell of certain time energy.The automatic control of targeting thermotherapy and thermotherapy temperature is the innocent and malignant tumour minimally-invasive treatment technology that has potentiality at present, is clinical thermotherapy Developing Trend in Technology.
Prior art is mainly with Fe
3O
4Or reduced iron powder is magnetic material, and preparation drug loaded magnetic microsphere in the hope of be gathered in tumor locus under the guiding of externally-applied magnetic field, is realized target administration; Or the preparation implantation is used the magnetic son and is prepared the targeting thermotherapy of outer tunicary magnetic fluid in the hope of the realization tumor locus.
Said method all has tangible weak point: with Fe
3O
4Or reduced iron powder is the drug loading problem that the drug loaded magnetic microsphere of magnetic material preparation is difficult to solve chemotherapeutics, and the contained medicine of microsphere is not enough to the drug level of long term maintenance tumor locus; The gathering of externally-applied magnetic field guiding simultaneously can not realize complete thromboembolism, does not reach the dual purpose of chemoembolization.The thermotherapy method of implanting the magnetic son itself is exactly traumatic, and in order to make thermotherapy not have the blind area, the tumor of a 5cm * 5cm * 5cm need be implanted about 150 magnetic sons; And, implant the magnetic son and can't adjust its distribution along with the variation of the state of an illness.Outer tunicary magnetic fluid is to study comparatively sophisticated targeting thermotherapy preparation at present, but magnetic fluid enters the body circulation from tumor locus easily, excretes by kidney at last, is difficult to keep the effect of thermotherapy.And independent thermotherapy causes the heat tolerance of tumor tissues easily, thereby reduces the effect of thermotherapy.
Summary of the invention
The object of the present invention is to provide temperature-controllable thermotherapeutic embolize micro-sphere of a kind of function admirable that can be used for cancerous protuberance targeting thermotherapy and artery embolization for treatment and preparation method thereof.
The technical solution adopted for the present invention to solve the technical problems.The thermotherapeutic embolize micro-sphere that contains low Curie temperature (40 ℃～65 ℃) magnetic respective material, successful solution two crucial difficult problems of cancerous protuberance arterial thrombosis art and the temperature automatically controlled thermotherapy technology of targeting, realized the synergism of two kinds of tumor micro-wound technology.Simple arterial thrombosis art is kill cancer cell fast, and tumor tissues is set up collateral circulation easily, thereby influences therapeutic effect; Simple thermotherapy causes the heat tolerance of tumor tissues easily, and therapeutic effect is not obvious.And thermotherapeutic suppository has been blocked the blood supply and the oxygen supply of tumor tissues, has limited the metaboilic level and the aerobic metabolism of tumor tissues, the hot tolerance of tumor tissues is descended, cause the lactic acid of tumor tissues, improves thermotherapy effect; The direct kill tumor cell of thermotherapy suppresses DNA, RNA and proteinic synthetic, makes tumor tissues can not form collateral circulation, improves the therapeutical effect of arterial thrombosis.
This temperature control thermotherapeutic embolize micro-sphere is made up of macromolecular material and the magnetic response microgranule that comprises within it, and the magnetic response microparticulate is in the cross-linked network that macromolecular material forms; The particle diameter of thermotherapy bolt microspheres agent is between 50 μ m-2000 μ m, and the weight ratio that the magnetic response microgranule accounts for whole embolism microball is 0.5-45%.
Described macromolecular material is one or more the combination in polyvinyl alcohol, ethyl cellulose, glucosan, polylactic acid, sodium alginate, the carboxymethyl/glucosan that methylates, alkene monomer polymer or the gelatin copolymer.
Described magnetic response microgranule employing Curie temperature is that 40～65 ℃ alloy material is made, and described magnetic response microgranule is manganese-zinc ferrite, ferroplatinum or monel.
A kind of preparation method of temperature control thermotherapeutic embolize micro-sphere comprises following step:
---is that 40～65 ℃ alloy material (as manganese-zinc ferrite, ferroplatinum and monel etc.) joins in the solution that contains 5-20% (W/V) macromolecular material approximately with particle diameter less than 0.5 micron Curie temperature, and mix homogeneously forms and contains the magnetic macromolecular solution;
---decentralized photo is the solution that contains the solution of at least a surfactant or contain at least a firming agent;
---at 500-1800rmin
-1Stir down, in the water bath with thermostatic control of room temperature or 50-90 ℃, will contain the magnetic macromolecular solution and add in the decentralized photo;
---continue to stir 2-6h, filter;
Or
---emulsion is added to outer aqueous phase, continue to stir 2-6h, complete to the organic solvent volatilization, filter;
Or
---drip an amount of firming agent, continue to stir, filter;
---sucking filtration is collected thus obtained microsphere on filter, with the purified water washing for several times;
---adopt machinery or chemical method to remove the magnetic response microgranule of microsphere surface;
---with suitable solvent washing, dehydration;
---adopt methods such as oven drying at low temperature, lyophilization or airpillow-dry, prepare exsiccant magnetic response polymer microballoon;
---the two sieve methods of employing pharmacopeia prepare the product of different-grain diameter scope, packing, cobalt 60 sterilizations.
Described magnetic response microgranule is manganese-zinc ferrite, ferroplatinum or monel.
The surfactant of described decentralized photo emulsion is one or more high molecular surfactant, and the weight ratio content in decentralized photo is 0.8%-5%.The surfactant of described decentralized photo emulsion is one or more nonionic surfactants, and the weight ratio content in decentralized photo is 0.8%-5%.
Described firming agent is low-carbon (LC) aldehyde compound such as formaldehyde, or bivalence particlized compound such as Ca
2+, or ion-type macromolecular material such as chitosan, sodium alginate.
Beneficial effect of the present invention is as follows: the defective that has overcome existing pastille microsphere and magnetic microsphere method for designing and using method.
1, the low Curie temperature alloy material that will have an A.T.C adds macromolecular material and forms the thermotherapeutic embolize micro-sphere with thermotherapy and the effect of thromboembolism double treatment, and thermotherapeutic embolize micro-sphere can heat up in alternating magnetic field, the thermotherapy of realization tumor.
2, the thermotherapeutic embolize micro-sphere heating-up temperature can reach 40～65 ℃, and can A.T.C.
3, macromolecular scaffold (substrate) material selection can be in human body materials such as biodegradable polylactic acid, sodium alginate, gelatin copolymer, preparation suppository a middle or short term; Select for use polyvinyl alcohol etc. not Biodegradable material prepare permanent suppository, satisfy the requirement of different clinical treatments.
4, magnetic response material employing Curie temperature is 40～65 ℃ a alloy material, as manganese-zinc ferrite, ferroplatinum and monel etc., to realize the be heated intensification of suppository in alternating magnetic field, realizes the thermotherapy of tumor; Because 40～65 ℃ of Curie temperature of material itself lose magnetism the magnetic response material after reaching design temperature, realize temperature auto control simultaneously.
5, the preparation method of microsphere embolization agent adopts and disperses solidification method, and curing adopts: the method that directly volatilizes organic solvent or adding firming agent initiated polymerization.
The specific embodiment
Below by embodiment technical scheme of the present invention is further described:
Embodiment 1.
---is that 40～65 ℃ MnZn ferrite material add 100ml contain in the dichloromethane solution of 10% (W/V) polylactic acid with particle diameter less than 0.5 micron Curie temperature with 10g, and ultrasonic 60 seconds (100W) forms and contain the magnetic macromolecular solution;
---decentralized photo is the aqueous solution that contains 0.05% Tween 80 and 0.5%PVA.
---low whipping speed is 500-1800rmin
-1Under the condition, above-mentioned solution is added in the decentralized photo emulsifying 5min (room temperature);
---emulsion is added to outer aqueous phase, continue to stir 2h, complete to the organic solvent volatilization;
---sucking filtration is collected thus obtained microsphere on filter, with purified water washing 5-10 time;
---gained thermotherapy microsphere is put in the oscillator, shaken 24 hours;
---in alcoholic solution, cross 400 mesh sieves;
---collect microsphere, vacuum drying 72 hours;
---the two sieve methods of employing pharmacopeia prepare the product of different-grain diameter scope, packing, cobalt 60 sterilizations.
Embodiment 2.
---10 gram sodium alginates are dissolved in the 200ml distilled water in 80 ℃ of water-baths, and adding the 6g particle diameter is 40～65 ℃ MnZn ferrite material less than 0.5 micron Curie temperature, puts on the agitator fully mixing, forms to contain the magnetic macromolecular solution;
---decentralized photo is 2% (W/V) calcium chloride solution;
---stirring 500-1800rmin
-1Under the condition, will contain the magnetic macromolecular solution and splash into or pressurize and spray in the decentralized photo, and continue to stir;
---gained thermotherapy microsphere is put in the oscillator, shaken 24 hours;
---in alcoholic solution, cross 400 mesh sieves;
---collect microsphere, vacuum drying 72 hours;
---the two sieve methods of employing pharmacopeia prepare the product of different-grain diameter scope, packing, cobalt 60 sterilizations.
Embodiment 3.
---6 gram gelatin are dissolved in the 200ml distilled water in 50 ℃ of water-baths, and adding the 4g particle diameter is 40～65 ℃ MnZn ferrite material less than 0.5 micron Curie temperature, puts on the agitator fully mixing, forms to contain the magnetic macromolecular solution;
---decentralized photo is the liquid paraffin of 2% (V/V) surfactant sorbester p17, and firming agent is the formalin after diluting;
---in 50 ℃ of water-baths, will contain the magnetic macromolecular solution and splash in the decentralized photo, stir 500-1800rmin
-1, behind the following emulsifying 10min of stirring;
---emulsion is changed in the ice bath, drip the formaldehyde firming agent, continue to stir 1.5h, 270 mesh sieves filter;
---gained thermotherapy microsphere is put in the oscillator, shaken 24 hours;
---in alcoholic solution, cross 400 mesh sieves;
---collect microsphere, vacuum drying 72 hours;
---the two sieve methods of employing pharmacopeia prepare the product of different-grain diameter scope, packing, cobalt 60 sterilizations.
Claims (9)
1, a kind of temperature control thermotherapeutic embolize micro-sphere, is made up of macromolecular material and the magnetic response microgranule that comprises within it, it is characterized in that: Curie temperature is that the magnetic response microparticulate made of 40～65 ℃ alloy material is in the cross-linked network of macromolecular material formation; The particle diameter of thermotherapy bolt microspheres agent is between 50 μ m-2000 μ m, and the weight ratio that the magnetic response microgranule accounts for whole embolism microball is 0.5-45%.
2, temperature control thermotherapeutic embolize micro-sphere according to claim 1 is characterized in that: described macromolecular material is one or more the combination in polyvinyl alcohol, ethyl cellulose, glucosan, polylactic acid, sodium alginate, the carboxymethyl/glucosan that methylates, alkene monomer polymer or the gelatin copolymer.
3, temperature control thermotherapeutic embolize micro-sphere according to claim 1 is characterized in that: described magnetic response microgranule is manganese-zinc ferrite, ferroplatinum or monel.
4, a kind of method for preparing temperature control thermotherapeutic embolize micro-sphere as claimed in claim 1 is characterized in that: comprise following step:
A: is that 40～65 ℃ alloy material joins in the solution that contains 5-20% (W/V) macromolecular material approximately with particle diameter less than 0.5 micron Curie temperature, and mix homogeneously forms and contains the magnetic macromolecular solution;
B: stir down, will contain the magnetic macromolecular solution and add in the decentralized photo;
C: continue stirring and volatilize organic solvent; Or the adding firming agent, initiated polymerization makes the magnetic response polymer microballoon;
D: filter, washing is prepared into the magnetic response microsphere suspension;
E: adopt lyophilization or airpillow-dry, prepare exsiccant magnetic response polymer microballoon.
5, the preparation method of temperature control thermotherapeutic embolize micro-sphere according to claim 4 is characterized in that: described magnetic response microgranule is manganese-zinc ferrite, ferroplatinum or monel.
6, the preparation method of temperature control thermotherapeutic embolize micro-sphere according to claim 4 is characterized in that: described decentralized photo is the solution that contains the solution of at least a surfactant or contain at least a firming agent.
7, the preparation method of temperature control thermotherapeutic embolize micro-sphere according to claim 4, it is characterized in that: the surfactant of described decentralized photo emulsion is one or more high molecular surfactant, and the weight ratio content in decentralized photo is 0.8%-5%.
8, the preparation method of temperature control thermotherapeutic embolize micro-sphere according to claim 4, it is characterized in that: the surfactant of described decentralized photo emulsion is one or more nonionic surfactants, and the weight ratio content in decentralized photo is 0.8%-5%.
9, the preparation method of temperature control thermotherapeutic embolize micro-sphere according to claim 4 is characterized in that: described firming agent is the low-carbon (LC) aldehyde compound, or bivalence particlized compound, or the ion-type macromolecular material.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102905733A (en) * | 2009-10-06 | 2013-01-30 | 明尼苏达大学董事会 | Bioresorbable embolization microspheres |
| CN107661499A (en) * | 2017-11-07 | 2018-02-06 | 东南大学 | A kind of preparation method of magnetic induction thermotherapeutic embolize micro-sphere |
| CN107887099A (en) * | 2017-11-10 | 2018-04-06 | 西安交通大学医学院第附属医院 | It is a kind of to be used for minimally invasive lower identical temperature control self-fixing magnetic composite, its preparation and its anastomosis system |
| US10182979B2 (en) | 2016-03-22 | 2019-01-22 | Regents Of The University Of Minnesota | Biodegradable microspheres |
| CN110339359A (en) * | 2019-07-26 | 2019-10-18 | 佛山科学技术学院 | A kind of near infrared light thermotherapeutic embolize micro-sphere and its preparation method and application |
| CN113425887A (en) * | 2021-07-06 | 2021-09-24 | 南方科技大学 | Functionalized shape anisotropic hydrogel particle embolic agent and preparation method and application thereof |
| CN114887109A (en) * | 2022-05-23 | 2022-08-12 | 大连理工大学 | Self-temperature-controlled magnetic-response drug release embolism microsphere with CT/MR developing function and preparation method thereof |
-
2005
- 2005-06-10 CN CN 200510050061 patent/CN1762332A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102905733A (en) * | 2009-10-06 | 2013-01-30 | 明尼苏达大学董事会 | Bioresorbable embolization microspheres |
| CN102905733B (en) * | 2009-10-06 | 2014-10-15 | 明尼苏达大学董事会 | Bioresorbable embolization microspheres |
| US10179187B2 (en) | 2009-10-06 | 2019-01-15 | Regents Of The University Of Minnesota | Bioresorbable embolization microspheres |
| US11439725B2 (en) | 2009-10-06 | 2022-09-13 | Regents Of The University Of Minnesota | Bioresorbable embolization microspheres |
| US10182979B2 (en) | 2016-03-22 | 2019-01-22 | Regents Of The University Of Minnesota | Biodegradable microspheres |
| CN107661499A (en) * | 2017-11-07 | 2018-02-06 | 东南大学 | A kind of preparation method of magnetic induction thermotherapeutic embolize micro-sphere |
| CN107887099A (en) * | 2017-11-10 | 2018-04-06 | 西安交通大学医学院第附属医院 | It is a kind of to be used for minimally invasive lower identical temperature control self-fixing magnetic composite, its preparation and its anastomosis system |
| CN107887099B (en) * | 2017-11-10 | 2020-04-28 | 西安交通大学医学院第一附属医院 | Anastomosis device based on temperature-control self-adaptive magnetic composite material for micro-wound anastomosis |
| CN110339359A (en) * | 2019-07-26 | 2019-10-18 | 佛山科学技术学院 | A kind of near infrared light thermotherapeutic embolize micro-sphere and its preparation method and application |
| CN110339359B (en) * | 2019-07-26 | 2021-11-09 | 佛山科学技术学院 | Near-infrared thermotherapy embolism microsphere and preparation method and application thereof |
| CN113425887A (en) * | 2021-07-06 | 2021-09-24 | 南方科技大学 | Functionalized shape anisotropic hydrogel particle embolic agent and preparation method and application thereof |
| CN114887109A (en) * | 2022-05-23 | 2022-08-12 | 大连理工大学 | Self-temperature-controlled magnetic-response drug release embolism microsphere with CT/MR developing function and preparation method thereof |
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