CN104130348A - Temperature-sensitive polymer, in-situ gelation temperature-sensitive liquid embolic material and preparation method thereof - Google Patents
Temperature-sensitive polymer, in-situ gelation temperature-sensitive liquid embolic material and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of a blood vessel embolic material, and especially relates to a polymer with a temperature-sensitive feature. The polymer is obtained by co-polymerization of N-isopropylacrylamide and butyl methacrylate. The in-situ gelation temperature-sensitive liquid embolic material comprises a developer and the temperature-sensitive polymer. The polymer has the temperature-sensitive feature. With the polymer, in-situ gel can be obtained at a lesion site, and embolism error caused by polymer divergence during embolism can be avoided. The solvent used in a product formula is injection water or physiological saline with no toxic or side effect. The solvent is in a solution state with low concentration and good fluidity. A sterilization method helps maintaining a development effect of the developer.
Description
technical field
The present invention relates to vascular suppository material technical field, be particularly related to a kind of polymkeric substance with temperature sensitive characteristic, the gelatinizing-in-situ responsive to temperature type liquid embolic material that also relates to the polymkeric substance that contains this temperature sensitive characteristic, also relates to the preparation method of described gelatinizing-in-situ responsive to temperature type liquid embolic material.
background technology
Clinical embolotherapy is the important technology in interventional medicine treatment, its mechanism of action is that embolism materials is controlledly injected in the supply blood vessel or lesion vessels of diseased organ, make it to occur inaccessible, interruption blood supply, with the object that reaches Bleeding control, the change of occluding vascular venereal disease, treatment tumour and eliminate pathology sexual organ.Can be used for treating vascular disease (arteriovenous malformotion, arterio venous fistula), rich courageous and upright tumour (liver cancer, kidney, hysteromyoma), organ deactivation, blood flow changes its course etc.
The key of interventional embolization is to implement the process of embolism, and it is related to success or failure, curative effect and the complication etc. for the treatment of.Embolism process has five key components: 1. first clarify a diagnosis; 2. accurate intubate; 3. select suitable suppository; 4. correct suppository release tech; 5. finally control embolism degree.Wherein, suppository is mainly comprised of embolism materials, and therefore, embolism materials plays a part very crucial to the success or not of Embolization.
At present, the liquid embolic material having used both at home and abroad mainly contains: α-cyanoacrylaten-butyl (NBCA), Onyx, Sipacril 2739OF etc.α-cyanoacrylaten-butyl is difficult to operation, has adhesivity, exists microtubular to adhere to the danger of vessel wall, and adhesion rate reaches 3%.Although Onyx etc. have non-adhesive, because it needs solvent as delivery vehicles, and solvent DMSO has blood vessel toxicity, severe corrosive and cause the character of angionecrosis, may cause serious complication.Alkylmethacrylate polymers etc. are usingd ethanol as solvent, easily cause feeding artery spasm and tunica intima infringement.Gelatinizing-in-situ responsive to temperature type liquid embolic material has overcome above-mentioned shortcoming, has non-adhesive, and easy handling does not exist " collophore " phenomenon; Without organic solvent, carry the complication of having avoided blood vessel toxicity to cause; Nontoxic, no antigen, there is good biocompatibility; Have temperature-sensing property, during normal temperature, with aqueous solution state, exist, it is convenient in conduit, to carry, and during body temperature, at target site, solidifies rapidly, realizes embolism.
The state of the art of China's interventional therapy, not second to developed country, is now just developed to small and medium-sized cities, is popularized by big and medium-sized cities, yet, embolism materials 90% used relies on import, to expend a large amount of foreign exchanges every year, because imported materials and items is expensive, to patient, bring heavy economical load.Develop excellent performance, cheap embolism materials, can meet domestic clinical needs, can improve again the level of China's interventional therapy, can alleviate patient's economical load again, save foreign exchange, set up our national industry, there is important Social benefit and economic benefit.
The applicant had once successfully prepared NIPA and N-n-propyl acrylamide with the polymkeric substance of certain proportion copolymerization gained, and and photographic developer be dissolved in solvent and obtain the suppository (patent No.: ZL200410037836.5); When this suppository is used, polymkeric substance precipitate and separate from solvent out reaches the object of embolism, photographic developer runs off with solvent, cannot retain at lesions position, be only suitable for the small lesion of AVM class, but but for picture liver cancer, lung cancer, kidney, the tumour that the entities such as arterio venous fistula are larger is just improper, and not only effect of embolization is bad, and need a large amount of suppositories, increased patient's economical load.And gelatinizing-in-situ responsive to temperature type liquid embolic material has solved problems, the gelatinizing-in-situ of embolism materials can form larger cap, fast and effectively focus is carried out to embolism, and photographic developer can be retained in to embolism position, reach the object of postoperative development, expanded the embolism scope of application of temperature sensitive liquid embolizing agent.
Current existing technical publications application number is 200610124539.3, temperature sensing nano gel system and 200910308746.8 for vascular suppository material, temperature-sensitive nano-gel vascular embolic materials and a preparation thereof, these two patents are all that to take poly N-isopropyl acrylamide (PNIPAAm) base polymer be basic temperature sensing nano gel system.Under the effect of the bisacrylamide that NIPA and hydrophobicity allylic monomers are replaced at linking agent N-, carry out copolymerization; The multipolymer obtaining is abundant swelling in dispersion medium, then through the emulsification of high-shear homogenizer, it is uniformly dispersed, and obtains temperature-sensitive nano-gel dispersion.By the sealing of above-mentioned temperature-sensitive nano-gel dispersion, 60-Co irradiation sterilization, obtains the vascular suppository material of temperature sensing nano gel system.
There are two problems in the embolism materials of preparation in this way: 1, product is to obtain with the abundant swelling of nanogel lyophilized powder and through homogenizer emulsion dispersion, so can there is a, poor fluidity, b, narrow to the range of choice of conduit, c, operator's operation technique is required high, d, the problem such as can disperse while carrying out blood vessel embolism at embolism position; 2, in system, contain Schering AG) or ioversol class contrast medium, after 60-Co irradiation sterilization, iodine monomer can decompose and dissociate out from system, does not reach the object of radiography during operation.
summary of the invention
In order to solve the poor fluidity that in above prior art, responsive to temperature type polymkeric substance exists, range of choice to conduit is narrow, to operator's operation technique, require high, while carrying out blood vessel embolism, can disperse, easily there is free problem in iodine monomer, the invention provides a kind of improvement polymer architecture, improve the cohesion of polymkeric substance, while making its embolism, can obtain situ-gel, avoid polymkeric substance to disperse and cause mistake bolt, dissolve in the water for injection that human body is had no side effect, there is the responsive to temperature type polymkeric substance of suitable mobility.
The present invention also provides the gelatinizing-in-situ responsive to temperature type liquid embolic material that responsive to temperature type polymkeric substance prepares thus.
The present invention also provides the preparation method of described gelatinizing-in-situ responsive to temperature type liquid embolic material.
The present invention is achieved by the following measures:
A responsive to temperature type polymkeric substance, is obtained by NIPA and butyl methacrylate copolymerization, and structural formula is as follows:
，
Wherein, m, n are natural number, and the polymerization degree is 110-920.
Described responsive to temperature type polymkeric substance, preferably NIPA and butyl methacrylate mass ratio are 5:0.1-0.3.
A gelatinizing-in-situ responsive to temperature type liquid embolic material, preferably includes the responsive to temperature type polymkeric substance described in photographic developer and claim 1 or 2.
Described gelatinizing-in-situ responsive to temperature type liquid embolic material, is preferably comprised of according to the ratio of weight ratio 1-10:64:100 responsive to temperature type polymkeric substance, photographic developer and solvent.
Described gelatinizing-in-situ responsive to temperature type liquid embolic material, preferably photographic developer is Schering AG).
Described gelatinizing-in-situ responsive to temperature type liquid embolic material, preferred solvent is water for injection or physiological saline.
A preparation method for gelatinizing-in-situ responsive to temperature type liquid embolic material, comprises the following steps:
(1) NIPA reacts under the effect of initiator and linking agent with butyl methacrylate, obtains responsive to temperature type polymkeric substance;
(2) responsive to temperature type polymkeric substance and developer dissolves, in water for injection or physiological saline, are prepared into gelatinizing-in-situ responsive to temperature type embolism materials.
Described preparation method, preferably the weight ratio of NIPA and butyl methacrylate is 5:0.1-0.3.
Described preparation method, preferably initiator is Diisopropyl azodicarboxylate, linking agent is dimethacrylate TEG ester.
Described preparation method, preferably NIPA carried out the dissolve-repreparation of several times before using, and carried out purifying.
Beneficial effect of the present invention:
1, polymkeric substance has temperature-sensing property, at lesions position, can obtain situ-gel, and while avoiding embolism, polymkeric substance is dispersed and the mistake bolt that causes:
Polymkeric substance has the characteristic of phase transition temperature, under room temperature state, is solution state, is easy to carry out supraconductivity by microtubular and selects targeting to reach focus, is transformed into mutually gel under body temperature, reaches the object of vascular embolization.Polymkeric substance is when being phase-changed into gel, and the optimization by structure improves, and has improved the cohesion of polymkeric substance, after phase transformation, in focus, realize gelatinizing-in-situ, form soft gel, can carry out the blood vessel embolism at kinds of tumors position, as liver cancer, kidney, the noumenal tumours such as lung cancer;
2, in formula for a product, solvent for use is water for injection or physiological saline, have no side effect, and solution state, concentration is low, good fluidity
Current liquid embolic material contains organic solvent mostly, as dehydrated alcohol, and lipiodol etc., and gelatinizing-in-situ responsive to temperature type embolism materials adopts water for injection or physiological saline to make solvent, and non-stimulated, have no side effect, there is good biological safety;
Gelatinizing-in-situ responsive to temperature type embolism materials can reach and dissolve state completely, but not collosol state, concentration is low, and good fluidity can prevent that collophore plugging from occurring;
3, sterilising method can keep the development effect of photographic developer
In documents, adopt 60-Co irradiation sterilization, this sterilization method can make the iodine decomposition in photographic developer structure free out, thereby affects the development effect of photographic developer, this patent adopts moist heat sterilization mode, reach identical sterilising effect, can avoid again the decomposition of photographic developer, keep development effect.
Accompanying drawing explanation
Fig. 1 is external embolism modeling device,
Fig. 2 is the effect of embolization figure of the embolism materials that contains different concns responsive to temperature type polymkeric substance,
Fig. 3 is the state before the phase transformation of gelatinizing-in-situ responsive to temperature type liquid embolic material and after phase transformation.
Embodiment
For a better understanding of the present invention, below in conjunction with specific embodiment, further illustrate.
embodiment 1:
Get NIPA 10g, carry out recrystallization processing; Get the NIP after processing, butyl methacrylate is reacted in dioxane 50ml, after stirring logical nitrogen 10min, add initiator Diisopropyl azodicarboxylate 0.08g, linking agent dimethacrylate TEG ester 0.1g, 60 ℃ are stirred and sealed reaction 6h, obtain responsive to temperature type multipolymer.
By responsive to temperature type multipolymer repetitive scrubbing in water, purifying, dries; Product after drying is dissolved in water for injection according to a certain percentage together with photographic developer Schering AG), and moist heat sterilization, obtains gelatinizing-in-situ responsive to temperature type liquid embolic material.
Embodiment 2-6: preparation process is identical with embodiment mono-.
In each embodiment, NIPA and butyl methacrylate or methyl methacrylate consumption see the following form 1.
Each embodiment raw material consumption of table 1
From table 1, content is found out, select butyl methacrylate and methyl methacrylate to carry out copolyreaction with NIP respectively, and methyl methacrylate cannot obtain situ-gel type polymkeric substance, although structurally difference is less for both, but in this application, but only have butyl methacrylate to be suitable for.And preferably the mass ratio of NIPA and butyl methacrylate is 5:0.1-0.3.
effect of embolization test:
1, the foundation of external model
External model simulation intratumoral vasculature group, as shown in Figure 1, the granulated glass sphere of 12g diameter 2mm is packed in the granulated glass sphere container of volume 10ml, granulated glass sphere container is placed in the Glass tubing of constant temperature, by pvc pipe and normal saline bottle, be connected, the vertical range of physiological saline and glass column outlet is 150cm; Microtubular is placed in granulated glass sphere container by breeches joint.Constant temperature water tank, for Glass tubing provides thermostatical circulating water, makes the water temperature in Glass tubing maintain 37 ℃.By the flow rate regulation of physiological saline (37 ℃), be about 0.3ml/s, below outflow end, put the beaker of a Sheng hot water.With 1ml syringe holder gelatinizing-in-situ responsive to temperature type liquid embolic material, by microtubular, inject, observe the disperse situation of suppository, have sediment-free process granulated glass sphere by exporting outflow, inject aqueous copolymers solution continuously until current stop.By this experimental installation, can inquire into its embolism usefulness as dispersivity and effect of embolization.
Select responsive to temperature type polymer concentration to be respectively 1%, 5%, 10% gelatinizing-in-situ responsive to temperature type liquid embolic material carries out external simulation test,
As shown in Figure 2.As seen from the figure, the concentration of embolism materials is little, and after embolism, dispersivity is slightly poor, and there is a small amount of gap at granulated glass sphere lower edge place, and sediment-free process granulated glass sphere is by exporting outflow; 5% embolism materials dispersivity is good, without precipitation, flows out, and model embolism is complete, and this concentration effect of embolization is best; It is large that embolism materials concentration becomes, the upper end of embolism granulated glass sphere closely, and dispersivity is poor, and sediment-free flows out; So the suppository concentration that experimentation on animals is selected is 5%.
2, experimentation on animals:
This experiment is main carries out embolism with the gelatinizing-in-situ responsive to temperature type liquid embolic material that contains 5% responsive to temperature type polymkeric substance to the Renal artery of family pig, and then the effect of embolization of definite embolism materials.
Method: select healthy family pig, body weight 25～30kg.Guiding catheter is placed on to Renal artery opening part, through guiding catheter, microtubular is inserted to the Renal artery, through microtubular injection gelatinizing-in-situ responsive to temperature type liquid embolic material, until the complete embolism of the Renal artery.After embolism at once, within 1 week, 4 weeks, 8 weeks, 12 weeks, 24 weeks, carry out follow-up observation.
The one-sided Renal artery to family pig in experiment has carried out successful embolism, in embolism and follow-up observation process, does not run into technical difficulty, and effect of embolization is comparatively satisfied, and plugging phenomenon does not occur embolism process, and tube drawing is smooth.And reconfirm that gelatinizing-in-situ responsive to temperature type liquid embolic material is good to dissimilar microtubular compatibility.After embolism, follow-up observation laboratory animal all survives well, and neural, moving situation all, less than abnormal, also occurs without deformity.After sacrifice of animal, dissect, gross specimen is observed, and cerebral tissue has no abnormal changes, and histological observation shows no obvious abnormalities, and pathology light microscopic finding: acute phase, subacute stage, chronic phase are showed no obvious inflammatory reaction has no vessel wall destruction and dysmorphology and changes.
Result shows: 1. the gelatinizing-in-situ responsive to temperature type liquid embolic material of development, as a kind of non-adhesive liquid embolic material, has easy judgement embolism starting point and terminal, easily by carrying microtubular, and can compatible various commercially available microtubulars; 2. low, the good biocompatibility of gelatinizing-in-situ responsive to temperature type liquid embolic material viscosity, no cytotoxicity, the controllability of development are good; 3. the gelatinizing-in-situ responsive to temperature type liquid embolic material effect of embolization of development is reliable and stable, therefore can be used as a kind of desirable non-adhesive liquid embolic material.
Fig. 3 is the state before the phase transformation of gelatinizing-in-situ responsive to temperature type liquid embolic material and after phase transformation.
Above-described embodiment is preferably embodiment of the present invention; but embodiments of the present invention are not subject to the restriction of embodiment; other is any does not deviate from change, modification, the combination made under spirit of the present invention and principle, substitute, simplify and all should be equivalent substitute mode, within being included in protection scope of the present invention.
Claims (10)
1. a responsive to temperature type polymkeric substance, it is characterized in that being obtained by NIPA and butyl methacrylate copolymerization, and structural formula is as follows:
，
Wherein, m, n are natural number, and the polymerization degree is 110-920.
2. responsive to temperature type polymkeric substance according to claim 1, is characterized in that NIPA and butyl methacrylate mass ratio are 5:0.1-0.3.
3. a gelatinizing-in-situ responsive to temperature type liquid embolic material, is characterized in that comprising the responsive to temperature type polymkeric substance described in photographic developer and claim 1 or 2.
4. gelatinizing-in-situ responsive to temperature type liquid embolic material according to claim 3, is characterized in that being comprised of according to the ratio of weight ratio 1-10:64:100 responsive to temperature type polymkeric substance, photographic developer and solvent.
5. gelatinizing-in-situ responsive to temperature type liquid embolic material according to claim 4, is characterized in that photographic developer is Schering AG).
6. gelatinizing-in-situ responsive to temperature type liquid embolic material according to claim 4, is characterized in that solvent is water for injection or physiological saline.
7. a preparation method for gelatinizing-in-situ responsive to temperature type liquid embolic material, is characterized in that comprising the following steps:
(1) NIPA reacts under the effect of initiator and linking agent with butyl methacrylate, obtains responsive to temperature type polymkeric substance;
(2) responsive to temperature type polymkeric substance and developer dissolves, in water for injection or physiological saline, are prepared into gelatinizing-in-situ responsive to temperature type embolism materials.
8. preparation method according to claim 7, the weight ratio that it is characterized in that NIPA and butyl methacrylate is 5:0.1-0.3.
9. preparation method according to claim 7, is characterized in that initiator is Diisopropyl azodicarboxylate, and linking agent is dimethacrylate TEG ester.
10. preparation method according to claim 7, is characterized in that NIPA carried out the dissolve-repreparation of several times before using, and carried out purifying.
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| CN104861928A (en) * | 2015-05-21 | 2015-08-26 | 长安大学 | Thermosensitive salt-releasing material as well as preparation method and application thereof |
| CN105693920A (en) * | 2016-02-03 | 2016-06-22 | 山东大学 | Preparation method of long-term-development in-situ-gelation temperature-sensitive liquid embolic material |
| CN106334213A (en) * | 2016-08-31 | 2017-01-18 | 安疗生命科学（武汉）有限公司 | Blood vessel embolism material as well as preparation method and application thereof to medicine preparation |
| CN110215542A (en) * | 2018-03-02 | 2019-09-10 | 成都远睿生物技术有限公司 | A method of forming the interim obturator of blood vessel |
| CN112876604A (en) * | 2021-01-21 | 2021-06-01 | 杨杨 | Temperature-sensitive polymer with good fluidity, embolism material and preparation method thereof |
| CN115068665A (en) * | 2022-02-09 | 2022-09-20 | 上海市第十人民医院 | Liquid embolic agent |
| WO2023163170A1 (en) * | 2022-02-28 | 2023-08-31 | 国立大学法人北海道大学 | Embolic agent and blood vessel embolization kit |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104861928A (en) * | 2015-05-21 | 2015-08-26 | 长安大学 | Thermosensitive salt-releasing material as well as preparation method and application thereof |
| CN105693920A (en) * | 2016-02-03 | 2016-06-22 | 山东大学 | Preparation method of long-term-development in-situ-gelation temperature-sensitive liquid embolic material |
| CN105693920B (en) * | 2016-02-03 | 2018-01-30 | 山东大学 | The preparation method of long-term development gelatinizing-in-situ responsive to temperature type liquid embolic material |
| CN106334213A (en) * | 2016-08-31 | 2017-01-18 | 安疗生命科学（武汉）有限公司 | Blood vessel embolism material as well as preparation method and application thereof to medicine preparation |
| CN106334213B (en) * | 2016-08-31 | 2019-07-26 | 安疗生命科学（武汉）有限公司 | A kind of vascular suppository material, preparation method and the purposes in medicine preparation |
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| CN110215542A (en) * | 2018-03-02 | 2019-09-10 | 成都远睿生物技术有限公司 | A method of forming the interim obturator of blood vessel |
| CN112876604A (en) * | 2021-01-21 | 2021-06-01 | 杨杨 | Temperature-sensitive polymer with good fluidity, embolism material and preparation method thereof |
| CN115068665A (en) * | 2022-02-09 | 2022-09-20 | 上海市第十人民医院 | Liquid embolic agent |
| WO2023163170A1 (en) * | 2022-02-28 | 2023-08-31 | 国立大学法人北海道大学 | Embolic agent and blood vessel embolization kit |
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Application publication date: 20141105 |