WO2018040407A1 - 一种血管栓塞材料、其制备方法及在药物制备中的用途 - Google Patents

一种血管栓塞材料、其制备方法及在药物制备中的用途 Download PDF

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WO2018040407A1
WO2018040407A1 PCT/CN2016/111645 CN2016111645W WO2018040407A1 WO 2018040407 A1 WO2018040407 A1 WO 2018040407A1 CN 2016111645 W CN2016111645 W CN 2016111645W WO 2018040407 A1 WO2018040407 A1 WO 2018040407A1
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isopropylacrylamide
poly
butyl methacrylate
iodine
embolization material
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PCT/CN2016/111645
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English (en)
French (fr)
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孙海霞
刘宏
李涵
曾坚
刘爽
卢欣
郭俊成
袁冰寒
李玲
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安疗生命科学（武汉）有限公司
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Priority to US16/329,287 priority Critical patent/US11291748B2/en
Publication of WO2018040407A1 publication Critical patent/WO2018040407A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0031—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/202—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with halogen atoms, e.g. triclosan, povidone-iodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/44—Radioisotopes, radionuclides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices

Definitions

  • the invention belongs to the technical field of vascular embolization materials for intervention of medical devices, in particular, the use of poly(N-isopropylacrylamide-co-butyl methacrylate) in preparing blood vessel embolization materials, and the inclusion of poly(N-iso) Vascular embolization material of propyl acrylamide-co-butyl methacrylate and dispersion medium, and preparation method thereof and use thereof in preparation of medicine.
  • Interventional therapy comes from the creative thinking and practice of angiographic diagnosis and angiography. It is based on imaging diagnosis and uses medical imaging diagnostic equipment such as DSA, CT and MRI as a guide to diagnose and treat diseases. . It has the characteristics of small trauma, accurate positioning, high curative effect, less complications, quick effect and strong repeatability. In addition to medical treatment and surgical treatment, interventional therapy has become the third largest clinical treatment.
  • TCE transcatheter arterial embolization
  • TACE transcatheter arterial chemoembolization
  • vascular embolization agent directly determines the therapeutic effect.
  • the embolization agent directly determines the therapeutic effect.
  • the vascular embolization material used for tumor treatment the following characteristics are required: 1. It has good fluidity, is easy to be injected through the catheter, does not stick to the tube, does not block the tube; 2. The gelation time is reasonable, and it is easy to diffuse and fill the tumor. In the peripheral blood vessels, the blood vessels are cast at the distal end of the tumor.
  • the embolization strength is reasonable, anti-blood flow erosion, to maintain the effect of long-term vascular embolization; 4, with good visibility, that is, X-ray shielding ability, guide the embolic agent to the correct target site; 5, anti-tumor drug length Effective release release.
  • Poly N-isopropylacrylamide temperature-sensitive polymer as a liquid embolic material has a low viscosity in the sol state, and has good thixotropy, fast gelation speed and good biocompatibility. It has become a research hotspot for vascular embolization materials for medical device intervention.
  • Chinese invention patent, CN1923303A discloses a temperature sensitive nanogel system for vascular embolization materials, including poly N-isopropyl amide polymer nanogels and dispersion medium, the vascular embolization system has in vitro fluidity Good, sol-gel phase transition speed and other characteristics, suitable for the treatment of diseases such as vascular embolism and arteriovenous malformation at the tumor site.
  • this vascular embolization system has the following disadvantages: 1. Although its fluidity is superior to that of solid embolic material, its viscosity is large, and the fluidity is still different from the currently used super-liquefied lipiodol, and the clinical time is injected. There are still some difficulties; 2, the sol-gel phase transition rate is too fast, and the clinical operation time is short, which increases the difficulty for the clinician to operate.
  • Cida patent, CN1569909A discloses a temperature-sensitive polymer and a preparation method thereof, using N-isopropyl
  • the acrylamide and N-n-propyl acrylamide form a copolymer of a monomer to obtain a temperature-sensitive polymer, the polymer is formulated into an aqueous solution, and a suitable developer is added to obtain a vascular embolization material.
  • the blood vessel embolization material provided by the invention rapidly precipitates and precipitates at body temperature, and embolizes the diseased blood vessel, thereby achieving therapeutic purposes.
  • Mainly used in the arteriovenous malformation (AVM) class for tumor embolization of liver cancer, kidney cancer and the like is not mentioned.
  • Cisoka patent, CN101690831A discloses a temperature sensitive gel-like vascular embolization material, comprising a poly(N-isopropylacrylamide) polymer nanogel and a dispersion medium, the dispersion medium is a water-soluble iodine contrast injection or Its diluent.
  • the temperature-sensitive gel vascular embolization material provided by the invention can adjust the phase transition temperature of the vascular embolization material and the embolization effect by the type and amount of the copolymer in the nanogel, the amount of the cross-linking agent, and the kind and content of the contrast agent.
  • the lowest nanogel content gives a temperature-sensitive gel vascular embolization material with low viscosity, good embolization and developability.
  • the temperature-sensitive gel-like vascular embolization material provided by the present invention still has the following problems: 1. Although the viscosity of the vascular embolization material is lowered by the type and content adjustment of the contrast agent, the fluidity is still not comparable to that of the super-liquefied lipiodol, clinical The operation is still a problem of difficulty in pushing; 2. The problem of divergence when the blood vessel embolization material is used cannot be solved, and there is a risk of being scattered by the blood flow during clinical use.
  • Ciclear invention patent, CN104130348A discloses a temperature-sensitive liquid embolic material consisting of a poly(N-isopropylacrylamide-co-butyl methacrylate) polymer, a developer and a solvent.
  • the renal embolization experiment was carried out on the pigs with a liquid embolic material with a polymer concentration of 5%.
  • the unilateral renal artery of the pigs was successfully embolized.
  • the tube was not blocked during the embolization process, and the extubation was smooth, indicating that the embolization material is easy to judge.
  • the starting point and the end point of the embolic material are easy to input into the microcatheter and have good biocompatibility.
  • the liquid embolic material provided by the present invention also has the following problems: since the poly(N-isopropylacrylamide-co-butyl methacrylate) in the vascular embolization material provided by the present invention is a linear polymer, when the concentration is low, The embolization strength is insufficient. The specific performance is in the in vitro simulation experiment. The glass beads are difficult to be plugged and easily washed away. When the concentration is high, the dispersion is not good, which is manifested in the upper end of the embedding glass beads only.
  • the vascular embolization material of the present invention has poor dispersion and is likely to be easily eroded by blood flow during clinical use, and thus does not fundamentally solve the safety problem caused by divergence of the embolic material after the microcatheter is discharged.
  • the present invention provides a vascular embolization material, which has a very low viscosity at room temperature and is a sol state with good fluidity, comparable to the fluidity of ultra-liquefied lipiodol, at body temperature. It is converted into a solid gel state, and its gelation kinetics can be regulated, and it is mainly used for vascular embolization treatment of blood-rich tumors (such as liver cancer, kidney cancer, etc.).
  • the clinical operation is highly controllable. It does not stick in the microcatheter, does not block the tube, and is easy to push.
  • the in-situ "casting" of the blood vessels from the peripheral blood vessel to the aorta is realized by means of diffusion filling.
  • the type of embolization effectively inhibits the establishment of tumor collateral circulation and improves the therapeutic effect of the tumor. It has suitable gel strength, anti-blood flow scouring, and superior performance to lipiodol, which can permanently embolize target vessels. It has ideal developing performance and avoids the safety risks caused by the operation of blending with developer for clinical use. And the problem of insufficient clarity of the development effect.
  • the vascular embolization material containing chemotherapeutic drugs, the controlled release of chemotherapeutic drugs, and the combination of chemotherapy and vascular embolization can effectively inhibit the growth of tumors.
  • poly(N-isopropylacrylamide-co-butyl methacrylate) for the preparation of a vascular embolization material, wherein poly(N-isopropylacrylamide-co-butyl methacrylate) is crosslinked Polymer, the cross-linked polymer is prepared by using N-isopropylacrylamide as a monomer, N,N'-dimethylenebisacrylamide as a crosslinking agent, and butyl methacrylate as a copolymerization
  • the poly(N-isopropylacrylamide-co-butyl methacrylate) crosslinked polymer was obtained by thermally initiated free radical polymerization using a soap-free emulsion polymerization method.
  • poly(N-isopropylacrylamide-co-butyl methacrylate) in the preparation of a vascular embolization material, poly(N-isopropylacrylamide-co-butyl methacrylate) has the following Structure:
  • Poly(N-isopropylacrylamide-co-butyl methacrylate) is spherical, optionally, poly(N-isopropylpropene)
  • the amide-co-butyl methacrylate has an intrinsic viscosity of 40 to 100 ml/g.
  • a blood vessel embolization material comprising a dispersion medium and poly(N-isopropylacrylamide-co-butyl methacrylate), wherein poly(N-isopropylacrylamide-co-butyl methacrylate) is Crosslinked polymer.
  • vascular embolization material poly(N-isopropylacrylamide-co-butyl methacrylate) has the following structural formula:
  • Poly(N-isopropylacrylamide-co-butyl methacrylate) is spherical, optionally, poly(N-isopropylpropene)
  • the amide-co-butyl methacrylate has an intrinsic viscosity of 40 to 100 ml/g.
  • a blood vessel embolization material containing an electrolyte, a developer, a pH adjuster, and water.
  • the electrolyte is at least one selected from the group consisting of sodium chloride, sodium hydroxide, calcium chloride, disodium hydrogen phosphate, sodium dihydrogen phosphate, and calcium sodium edetate.
  • the developer includes an iodine-containing polyol, and the iodine-containing polyol is at least one of iohexol, iodophor, iopamidol or iodine.
  • the pH adjusting agent includes hydrochloric acid.
  • the blood vessel embolization material has a pH of 6.5 to 8.0.
  • a blood vessel embolization material the dispersion medium further comprises an iodine-free polyol
  • the iodine-free polyol comprises a substance selected from the group consisting of tromethamine, mannitol, Tween-80, and polyethylene glycol 200. At least one of polyethylene glycol 400 and polyethylene glycol 600.
  • a blood vessel embolization material 1 ml of a blood vessel embolization material, containing 5 to 30 mg of poly(N-isopropylacrylamide-co-butyl methacrylate), 0.1 to 30 mg of electrolyte, and 100 to 350 mg of iodine Iodine-containing polyol.
  • 1 ml of the vascular embolization material contains 10 to 20 mg of poly(N-isopropylacrylamide-co-butyl methacrylate), 0.1 to 30 mg of the electrolyte, and 150 to 240 mg of the iodine-containing polyol calculated as iodine.
  • the iodine-containing polyol is calculated in terms of iodine as follows. Taking iohexol as an example, its molecular formula is C 19 H 26 I 3 N 3 O 9 , and its molecular weight is 821.1. Wherein M I is the molecular weight of iodine 126.9, M 0 is the molecular weight of iohexol 821.1, m 0 is the mass mg of iohexol; V 0 is the volume of solution ml).
  • a blood vessel embolization material 1 ml of a blood vessel embolization material, containing 5 to 30 mg of poly(N-isopropylacrylamide-co-butyl methacrylate), 0.1 to 30 mg of electrolyte, and 100 to 350 mg of iodine.
  • the iodine-containing polyol and 0.1 to 10 mg of the iodine-free polyol further preferably, 1 ml of the vascular embolization material, containing 10 to 20 mg of poly(N-isopropylacrylamide-co-butyl methacrylate), 0.1 to 30 mg of electrolyte, 150 to 240 mg of iodine-containing polyol calculated as iodine, and 0.1 to 10 mg of iodine-free polyol.
  • a vascular embolization material further comprises a chemotherapeutic drug, wherein the chemotherapeutic drug is at least one selected from the group consisting of doxorubicin hydrochloride, epirubicin hydrochloride, mitomycin C or fluorouracil.
  • a method for preparing a blood vessel embolization material the specific step is
  • the pH of the solution obtained in the step (1) is adjusted to 6.5 to 8.0 by using a pH adjuster to obtain a blood vessel embolization material.
  • vascular embolization material for the preparation of a medicament for the treatment of cancer, further wherein the medicament is for use Treat cancer by embolization chemotherapy.
  • the vascular embolization material of the present invention comprising a poly(N-isopropylacrylamide-co-butyl methacrylate) cross-linking polymer having a suitable intrinsic viscosity, and an iodine-free polyol in a dispersion medium,
  • the presence of the iodine-containing polyol developer and the electrolyte further reduces the viscosity of the composition. Therefore, the vascular embolization material has a very low viscosity at room temperature and good fluidity, and can be comparable to the ultra-liquefied lipiodol, which does not stick when used, and does not Blocking pipe, easy to push, good operability.
  • the electrolyte in the dispersion medium can promote gelation, and cooperate with the polyol in the dispersion medium, so that the gelation time of the vascular embolization material of the invention is reasonable, 40-80S, and the clinical condition is enhanced.
  • the operation controllability at the same time, the presence of the dispersion medium provides a good phase transition environment for the polymer, so that the blood vessel embolization material does not diverge from the microcatheter to the target of the blood vessel tip, and can be fully filled to the end of the blood vessel casting Type, suitable for embolization of various lesions.
  • the vascular embolization material of the invention can promote gelation, the vascular embolization material has suitable gel strength, is resistant to blood flow erosion, has low escape rate, can effectively avoid mis-plugging, and is not embolized. Completely caused recanalization of the blood vessels, while reducing the probability of establishing collateral circulation of the tumor, achieving the purpose of permanent embolization of the peripheral blood vessels of the tumor, and effectively inhibiting the growth of the tumor.
  • the vascular embolization material provided by the invention enables the vascular embolization material to be developed under fluoroscopy by selecting a suitable developer, and enters the peripheral blood vessel with a high density shadow, thereby avoiding the pre-mixing of the contrast agent before the conventional embolic agent.
  • the safety risks brought by the shortcomings such as large operation error, uneven sample mixing and long preparation time can effectively monitor the phase transition behavior of the vascular embolization material and effectively avoid the occurrence of mis-plugging and reflux.
  • the vascular embolization material of the present invention comprises a water-soluble chemotherapy drug such as doxorubicin hydrochloride, epirubicin hydrochloride, mitomycin C or fluorouracil, and achieves the purpose of releasing and releasing the chemotherapy drug by interventional chemoembolization.
  • a water-soluble chemotherapy drug such as doxorubicin hydrochloride, epirubicin hydrochloride, mitomycin C or fluorouracil
  • Example 1 is a viscosity comparison diagram of the vascular embolization material of Example 1, the vascular embolization material of Comparative Example 2, domestic iodine oil, and super liquefied lipiodol.
  • Fig. 3 is a diagram showing the effect of the word angiography (DSA) of Experimental Example 2.
  • Fig. 5 is a general histopathological photograph of four review time points of Experimental Example 3.
  • Fig. 6 is a graph showing the effect of MR before and after the interventional treatment of Experimental Example 4.
  • Poly(N-isopropylacrylamide-co-butyl methacrylate) is prepared by using N-isopropylacrylamide as a monomer and N,N'-dimethylenebisacrylamide as cross-linking
  • the butyl methacrylate is a comonomer
  • the spherical poly(N-isopropylacrylamide-co-butyl methacrylate) crosslinked polymer is obtained by thermal initiation initiation polymerization by soap-free emulsion polymerization. .
  • Step 1 Add 10.0 g of poly(N-isopropylacrylamide-co-butyl methacrylate) having an intrinsic viscosity of 68 ml/g and 259 g of developer iohexol powder to 400 ml of water at 0 to 30 degrees Celsius. Stir well to obtain a solution containing poly(N-isopropylacrylamide-co-butyl methacrylate) and a developer, and then add 1.25 g of electrolyte calcium chloride and iodine-free polyol mannitol to the above solution. 0.3 g, make up to 500 ml, and mix well.
  • Step 2 adjusting the pH of the solution obtained in the first step to 6.5-8.0 by using a pH adjuster hydrochloric acid to obtain a mass/volume concentration of poly(N-isopropylacrylamide-co-butyl methacrylate). 20 mg/ml, calcium chloride calcium mass/volume concentration 2.5 mg/ml, mannitol mass/volume concentration 0.6 mg/ml, and iohexol mass/volume concentration of 240 mg/ml vascular embolization material in terms of iodine.
  • Table 1 The poly(N-isopropylacrylamide-co-butyl methacrylate) of Examples 2 to 10 (abbreviated as polymer in the table), the mass and the intrinsic viscosity, the quality of the developer, the quality of the electrolyte, and the Iodine polyol quality table
  • doxorubicin hydrochloride is added to the vascular embolization material of Example 1.
  • the specific method is to take 5 ml of the vascular embolization material of Example 1, extract 2 ml to ml with a 10 ml syringe, and inject 50 mg of doxorubicin for injection.
  • Star Haizheng Pfizer Pharmaceutical Co., Ltd.
  • the vortex suspension was allowed to stand for half an hour, and the lower layer of the supernatant was withdrawn to obtain the vascular embolization material of Example 11.
  • vascular embolization material containing no electrolyte and no iodine-containing polyol is as follows.
  • Step 1 Add 10.0 g of poly(N-isopropylacrylamide-co-butyl methacrylate) having an intrinsic viscosity of 68 ml/g and 259 g of developer iohexol powder to 500 ml of water at 0 to 30 degrees Celsius. Stir well.
  • Step 2 adjusting the pH of the solution obtained in the first step to 6.5-8.0 by using the pH adjuster hydrochloric acid to obtain a mass/volume of poly(N-isopropylacrylamide-co-butyl methacrylate) At a concentration of 20 mg/ml, the mass/volume concentration of the developer iohexol was 240 mg/ml of vascular embolization material in terms of iodine.
  • Step 1 Take 2.263 g of N-isopropylacrylamide, 0.032 g of sodium lauryl sulfate, 0.168 ml of butyl methacrylate, stir and dissolve in 160 ml of purified water, protect with N 2 , warm to 70 ° C, add 9.5. 10 ml of a potassium persulfate aqueous solution of mg/ml was reacted for 4.5 hours, and the reaction solution was purified by dialysis and freeze-dried to obtain a poly(N-isopropylacrylamide-co-butyl methacrylate) linear polymer solid, which was used.
  • Step 2 Weigh 10.0 g of the backup solid in step 1, 259 g of developer iohexol powder, add 400 ml of water, and mix well to obtain a linear poly(N-isopropylacrylamide-co-butyl methacrylate) and A solution of the developer was then added with 1.25 g of an electrolyte calcium chloride, and then 0.3 g of an iodine-free polyol mannitol was added thereto, and the mixture was made up to 500 ml, and uniformly mixed.
  • Step 3 adjusting the pH of the solution obtained in the second step to 6.5-8.0 by using a pH adjuster hydrochloric acid to obtain a linear polymerization of poly(N-isopropylacrylamide-co-butyl methacrylate) to mass/
  • the volume concentration was 20 mg/ml
  • the calcium chloride mass/volume concentration was 2.5 mg/ml
  • the mannitol mass/volume concentration was 0.6 mg/ml
  • the mass/volume concentration of iohexol was 240 mg/ml vascular embolization material.
  • Table 2 shows the results of performance tests of the vascular embolization materials of Examples 1 to 10 and Comparative Examples 1 and 2.
  • the vascular embolization material of the invention has a reasonable gelation time, can be controlled by gelation kinetics, has suitable gel strength, is resistant to blood flow scouring, and has better performance than iodized oil, and can last for a long time. Embedding the target blood vessel has the ideal developing performance, avoiding the safety risks caused by the operation such as blending with the developer in clinical use, and the insufficient clarity of the developing effect.
  • Example 1 is a comparative diagram of shear thinning properties and viscosity of the vascular embolization material of Example 1, the vascular embolization material of Comparative Example 2, domestic iodine oil, and super liquefied lipiodol.
  • the results of the viscosity test of Table 2 and the viscosity curve of FIG. 1 show that the vascular embolic material composition of Example 1 of the present invention and the vascular embolic material composition prepared by the linear polymer of Comparative Example 2 have shear thinning. Performance, but under the same conditions, the viscosity of the vascular embolization material of the present invention is significantly lower than that of the vascular embolic material composition formulated by the linear polymer. In addition, the composition of the present invention has a significantly lower viscosity than domestically produced lipiodol and is comparable to ultra-liquefied lipiodol.
  • Example 11 The in vitro release of the vascular embolization material of Example 11 was experimentally simulated using a drug eluting device that was able to mimic the release and release of drug release in vivo by interventional chemoembolization (TACE).
  • TACE interventional chemoembolization
  • the drug eluting device includes a glass release tank, a peristaltic pump, an oil bath, a thermometer, a conical flask, a beaker, and a connecting tube.
  • the glass release tank is a customized glass cell with a diameter of 2 cm and a height of 2 cm. The upper part is closed by a glass stopper, and the two ends of the glass release tank can be respectively connected with the connecting pipe.
  • the conical flask is placed in an oil bath, and then the conical flask, the peristaltic pump, the glass release tank, and the beaker are sequentially connected through a connecting pipe.
  • the vascular embolization material of the spirulina is injected into the glass release tank and spread over the bottom of the release tank, and then the glass stopper is placed on the glass release tank; then the peristaltic pump is turned on to provide power for the liquid to flow in.
  • the peristaltic pump is turned on to provide power for the liquid to flow in.
  • n is the nth hour
  • V n is the volume released in the nth hour
  • C n is the concentration of doxorubicin hydrochloride in the release liquid in the nth hour.
  • M Dox is the content of doxorubicin hydrochloride in doxorubicin hydrochloride
  • V gel is the volume of doxorubicin hydrochloride in the release tank.
  • ⁇ Dox is the concentration of doxorubicin hydrochloride in doxorubicin hydrochloride.
  • FIG. 2 is a graph showing the in vitro release effect of Experimental Example 1 within 7 days. The results show that the vascular embolization material of the present invention can be used in combination with a chemotherapeutic drug and has the ability to slowly release the drug.
  • the vascular embolization material of Example 1 was subjected to interventional embolization of the renal artery in normal rabbits.
  • Fig. 3 is a diagram showing the effect of digital angiography (DSA) of the vascular embolization material of Experimental Example 2 on renal artery interventional embolization in normal rabbits.
  • DSA digital angiography
  • Figures 3-A1 to 3-A3 are angiographic DSA images of rabbit renal artery before interventional embolization.
  • 3-B1 to 3-B3 correspond to the re-examination of the contrast after interventional embolization.
  • the amount of vascular embolization material of 3-B1 was 0.5 ml
  • the amount of vascular embolization material of 3-B2 was 1.0 ml
  • the amount of vascular embolization material of 3-B3 was 2.0 ml.
  • a shows the renal peripheral blood vessels
  • b and c show small arterial blood vessels
  • d and e show large arterial blood vessels.
  • FIG. 4-A to FIG. 4-D are DSA images of 1 week, 1 month, 2 months, and 3 months, respectively.
  • the material can effectively and long-term embolization of targeted blood tube.
  • Fig. 5 is a general histopathological photograph of four time points of Experimental Example 3, and Figs. 5-A to 5-D are gross histopathological photographs of one week, one month, two months, and three months, respectively.
  • VX2 tumor rabbits were treated with the vascular material composition of Example 1, an equal amount of lipiodol + gelatin sponge, and the same amount of physiological saline, respectively. After the successful intubation of the femoral artery, the hepatic artery was intubated and pulled. Postoperative management was performed postoperatively, and MRI was performed one week after surgery.
  • Figure 6 is an MR diagram before and after interventional therapy.
  • 6A to 6-C correspond to the vascular embolization material of Example 1, the lipiodol + gelatin sponge, and the physiological saline before and after the interventional treatment.
  • liver tumors in each treatment group showed an increasing trend, accompanied by regional and peripheral irregular regional necrosis, in which the vascular embolization material of Example 1 and the same amount of lipiodol + gelatin sponge embolization treatment
  • the tumor necrosis is more obvious, and most of them show flaky necrosis in the central region of the tumor. It is shown that the composition of the present invention has a good embolization effect on liver tumors.

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Abstract

聚（N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯）在制备血管栓塞材料中的用途、一种血管栓塞材料及其在制备药物中的用途。血管栓塞材料包括聚（N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯）和由电解质、显影剂、pH值调节剂和水组成分散介质，聚合物、电解质和显影剂以碘计，浓度分别为5～30mg/ml、0.1～30mg/ml及100～350mg/ml。适用于富血管性实质脏器肿瘤的栓塞治疗。

Description

一种血管栓塞材料、其制备方法及在药物制备中的用途 技术领域
本发明属于医疗器械介入用血管栓塞材料技术领域，具体为聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)在制备血管栓塞材料中的用途、一种包含聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)和分散介质的血管栓塞材料及其制备方法以及其在药物制备中的用途。
背景技术
介入治疗来自于血管造影诊断和血管造影学的创造性思维和实践，是以影像诊断作为基础，应用医学影像诊断设备如DSA、CT和MRI等作为指导，对疾病做出诊断和治疗的一项技术。它具有创伤小、定位准确、疗效高、并发症少、见效快、可重复性强等特点。除内科治疗、外科治疗外，介入治疗已成为第三大临床治疗手段。
目前临床上应用最广的介入治疗是经导管动脉栓塞术(TCE)和经导管动脉化疗栓塞术(TACE)，主要用于晚期肿瘤的治疗。这种方法能准确地将药物注入病变部位，同时对肿瘤的供血动脉进行栓塞，有效阻断其供血，导致肿瘤缺血坏死亡，但对其它部位的组织细胞毒副作用很小，治疗效果明显。
介入栓塞治疗的一个重要因素是血管栓塞剂的选择，栓塞剂直接决定了治疗效果的好坏。对于用于肿瘤治疗的血管栓塞材料，要求有如下的特点：1、具有良好的流动性，容易经导管注射，不粘管、不堵管；2、凝胶化时间合理，容易弥散填充到肿瘤末梢血管中，在肿瘤末梢血管铸型。3、栓塞强度合理，抗血流冲刷，维持长期血管栓塞的效果；4、具有良好的可视性，即X-射线屏蔽能力，引导栓塞剂递送到正确的靶标部位；5、对抗肿瘤药物长效缓控释放。然而就以上标准而言，目前市场上尚无一种栓塞剂能“打天下”，需要开发各种不同的栓塞剂以适应临床需求。
聚N-异丙基丙烯酰胺类温度敏感型聚合物作为一种液体栓塞材料，在溶胶状态具有较低的粘度，同时具有较好的触变性、快的凝胶化速度和良好的生物相容性而成为医疗器械介入用血管栓塞材料的研究热点。
中国发明专利，CN1923303A，公开了一种用于血管栓塞材料的温敏纳米凝胶体系，包括聚N-异丙基酰胺类聚合物纳米凝胶和分散介质，这种血管栓塞体系具有体外流动性好，溶胶-凝胶相变速度快等特性，适用于肿瘤部位的血管栓塞和动静脉畸形等疾病的治疗。但是，这种血管栓塞体系具有以下缺点：1、其流动性虽然优于固体栓塞材料，但其粘度大，流动性相对于目前临床常用的超液化碘油还有一定的差距，临床时推注仍有一定难度；2、溶胶-凝胶相变速率过快，临床使用时，可操作时间短，增加了临床医生的操作难度。
中国发明专利，CN1569909A，公开了一种温度敏感型聚合物及其制备方法，以N-异丙基 丙烯酰胺与N-正丙基丙烯酰胺为单体形成共聚物，得到温度敏感型聚合物，将聚合物配制成水溶液，加入适当的显影剂，得到血管栓塞材料。本发明提供的血管栓塞材料体温时迅速沉淀析出，栓塞病变血管，从而达到治疗目的。主要应用于脑动静脉畸形(AVM)类对于肝癌，肾癌等的肿瘤栓塞没有提及。
中国发明专利，CN101690831A，公开了一种温敏凝胶类血管栓塞材料，包括聚(N-异丙基丙烯酰胺)类聚合物纳米凝胶和分散介质，分散介质为水溶性含碘造影剂注射液或其稀释液。本发明提供的温敏凝胶血管栓塞材料，可以通过纳米凝胶中共聚物的种类和用量、交联剂用量等因素以及造影剂的种类和含量调节血管栓塞材料的相转变温度和起栓塞效果所需的最低纳米凝胶含量，得到粘度低、栓塞性好、可显影的温敏凝胶血管栓塞材料。但是，本发明提供的温敏凝胶类血管栓塞材料仍然存在下述问题：1、虽然通过造影剂的种类和含量调节降低了血管栓塞材料的粘度，但是其流动性仍然不能媲美超液化碘油，临床操作是仍然存在推注困难的问题；2、未能解决血管栓塞材料使用时发散的问题，临床使用时存在被血流冲刷而分散的风险。
中国发明专利，CN104130348A公开了一种温度敏感型液体栓塞材料，由聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)聚合物、显影剂和溶剂组成。选用聚合物浓度为5％的液体栓塞材料对家猪进行肾动脉栓塞实验，对家猪的单侧肾动脉进行了成功栓塞，栓塞过程未发生堵管现象，拔管顺利，表明栓塞材料容易判断栓塞材料起点和终点，容易输入微导管，生物相容性好。但是，本发明提供的液体栓塞材料还存在以下问题：由于本发明提供的血管栓塞材料中聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)为线性聚合物，当低浓度时，栓塞强度不足，具体表现在体外模拟实验时，玻璃珠难以被栓堵，容易被冲刷；当高浓度时，弥散性也不好，表现在其仅栓塞玻璃珠的上端。因此，本发明的血管栓塞材料，弥散性差，临床时存在容易被血流冲刷而发散风险，因此也没有从根本上解决介入栓塞术中，栓塞材料出微导管后因发散引起的安全问题。
发明内容
为解决现有技术存在的问题，本发明提供一种血管栓塞材料，组合物在常温下本品黏度极低，为流动性良好的溶胶态，可媲美于超液化碘油的流动性，在体温时转变为固态的凝胶态，其凝胶化动力学可调控，主要用于富血供肿瘤(如肝癌、肾癌等)的血管栓塞治疗。临床操作可控性强，在微导管中不粘管，不堵管，易推注；进入血管后，以弥散填充的方式，实现从末梢血管到主动脉的各级脉管的原位“铸型”栓塞，有效抑制肿瘤血管侧枝循环的建立，提高肿瘤治疗效果。具有合适的凝胶强度，抗血流冲刷，性能优于碘油，可持久栓塞靶血管。具有理想的显影性能，避免了临床使用时需与显影剂临用共混等操作带来的安全风险 以及显影效果清晰度不够等问题。包含化疗药物的血管栓塞材料，化疗药物的缓控释放，实现化疗与血管栓塞的联合治疗，有效的抑制肿瘤的生长。
本发明为实现上述技术目的，采用如下的技术方案：
聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)在制备血管栓塞材料中的用途，其中，聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)是交联聚合物，该交联聚合物的制备方法为：以N-异丙基丙烯酰胺为单体，N,N’-二亚甲基双丙烯酰胺为交联剂，甲基丙烯酸丁酯为共聚单体，采用无皂乳液聚合法，通过热引发自由基聚合得到聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)交联聚合物。
进一步的，聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)在制备血管栓塞材料中的用途，聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)具有下列结构式：
Figure PCTCN2016111645-appb-000001
其中，m,n表示具有一定数量重复单元，没有具体数值范围，聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)为球形，可选的，聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)的特性黏数为40～100ml/g。
一种血管栓塞材料，含有分散介质和聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)，其中，聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)为交联聚合物。
进一步的，一种血管栓塞材料，聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)具有下列结构式：
Figure PCTCN2016111645-appb-000002
其中，m，n表示具有一定数量重复单元，没有具体数值范围，聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)为球形，可选的，聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)的特性黏数为40～100ml/g。
进一步的，一种血管栓塞材料，分散介质含有电解质，显影剂、pH值调节剂和水。其中，电解质为选自氯化钠、氢氧化钠、氯化钙、磷酸氢二钠、磷酸二氢钠、依地酸钠钙中的至少一种。显影剂包括含碘多元醇，含碘多元醇为碘海醇、碘佛醇、碘帕醇或碘比醇中的至少一种。pH值调节剂包括盐酸。优选的，血管栓塞材料的pH值为6.5～8.0。
进一步的，一种血管栓塞材料，所述分散介质进一步含有不含碘的多元醇，不含碘的多元醇包括包括选自氨丁三醇、甘露醇、吐温-80、聚乙二醇200、聚乙二醇400和聚乙二醇600的至少一种。
进一步的，一种血管栓塞材料，1毫升血管栓塞材料，含有5～30mg聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)，0.1～30mg电解质，以及100～350mg以碘计算的含碘多元醇。进一步优选的，1毫升血管栓塞材料，含有10～20mg聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)，0.1～30mg电解质，150～240mg以碘计算的含碘多元醇。
含碘多元醇以碘计，其计算方法如下。以碘海醇为例，其分子式为C19H26I3N3O9，其分子量为821.1，则以碘计算公式为
Figure PCTCN2016111645-appb-000003
其中MI为碘的分子量126.9，M0为碘海醇分子量821.1，m0为碘海醇的质量mg；V0为溶液的体积ml)。
进一步的，一种血管栓塞材料，1毫升血管栓塞材料，含有5～30mg聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)，0.1～30mg电解质，100～350mg以碘计算的含碘多元醇以及0.1～10mg不含碘的多元醇，进一步优选的，1毫升血管栓塞材料，含有10～20mg聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)，0.1～30mg电解质，150～240mg以碘计算的含碘多元醇，以及0.1～10mg不含碘的多元醇。
进一步的，一种血管栓塞材料，进一步含有化疗药物，化疗药物为选自盐酸多柔比星、盐酸表柔比星、丝裂霉素C或氟尿嘧啶的至少一种。
一种制备血管栓塞材料的方法，具体步骤为，
(1)在0～30摄氏度下，向含有聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)和显影剂的溶液中添加电解质和不含碘的多元醇，进行混合；
(2)利用pH值调节剂将步骤(1)中所得到的溶液的pH值调节至6.5～8.0，获得血管栓塞材料。
血管栓塞材料在制备药物中的用途，所述药物用于治疗癌症，进一步的，所述药物用于 通过栓塞化疗术治疗癌症。
本发明采用上述技术方案得到如下的有益效果：
1、本发明的血管栓塞材料，含有合适的特性黏数的聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)交联聚合物，分散介质中的不含碘的多元醇，含碘多元醇显影剂以及电解质的存在，进一步降低了组合物的粘度，因此，血管栓塞材料，室温下的粘度极低，流动性好，可以媲美超液化碘油，使用时不粘管，不堵管，易推注，可操作性好。
2、本发明的血管栓塞材料，分散介质中的电解质可以促进凝胶化，与分散介质中的多元醇配合，使得本发明的血管栓塞材料凝胶化时间合理，为40～80S，增强了临床时的操作可控性，同时，分散介质的存在给聚合物提供了良好的相转变环境，使得血管栓塞材料从微导管至靶向血管末梢的过程中不发散，并且能够充分填充至血管末梢铸型，适用于各种病灶的栓塞。
3、本发明的血管栓塞材料，分散介质中的电解质可以促进凝胶化，血管栓塞材料具有合适的凝胶强度，耐血流冲刷，逸散率低，能够有效避免误栓，以及因栓塞不完全而导致的血管再复通，同时降低了肿瘤侧枝循环建立的几率，实现肿瘤末梢血管的永久性栓塞的目的，有效的抑制肿瘤的生长。
4、本发明提供的血管栓塞材料通过合适的显影剂的选择，使血管栓塞材料可以在透视下显影，且呈高密度影进入末梢血管，避免了常规栓塞剂术前需与造影剂预混带来的操作误差大、样品混合不均一，准备时间长等缺点带来的安全风险，同时可以有效监测血管栓塞材料的相转变行为，有效的避免误栓及返流的发生。
5、本发明的血管栓塞材料，包含盐酸多柔比星、盐酸表柔比星、丝裂霉素C或氟尿嘧啶等水溶性化疗药物，通过介入化疗栓塞术，达到化疗药物缓控释放的目的，实现化疗与血管栓塞的联合治疗，有效的抑制肿瘤的生长。
附图说明
图1为实施例1的血管栓塞材料、对比例2的血管栓塞材料、国产碘油以及超液化碘油的黏度对比图。
图2为实验例1的体外释放曲线图。
图3为实验例2的字血管减影造影术(DSA)效果图。
图4为实验例3的四个复查时间点的DSA造影图像。
图5为实验例3的四个复查时间点的大体组织病理照片。
图6为实验例4的介入治疗前后的MR效果图。
具体实施方式
聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)的制备方法为，以N-异丙基丙烯酰胺为单体，N,N’-二亚甲基双丙烯酰胺为交联剂，甲基丙烯酸丁酯为共聚单体，采用无皂乳液聚合法，通过热引发自由基聚合得到球形的聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)交联聚合物。(参见华中科技大学硕士学位论文，《肝癌介入治疗用的高浓度聚(N-异丙基丙烯酰胺-CO-甲基丙烯酸丁酯)纳米凝胶分散体的制备、表征及相关生物学评价》，廖远霞，第12页)
实施例1
步骤一，在0～30摄氏度下，将10.0g特性粘数为68ml/g的聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)及显影剂碘海醇粉末259g加入400ml水中，搅拌均匀，得到含有聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)和显影剂的溶液，然后向上述溶液中加入电解质氯化钙1.25g及不含碘多元醇甘露醇0.3g，定容至500ml，混合均匀。
步骤二，利用pH值调节剂盐酸将步骤一中所得到的溶液的pH值调节至6.5～8.0，得到聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)质量/体积浓度为20mg/ml，氯化钙钙质量/体积浓度2.5mg/ml，甘露醇质量/体积浓度0.6mg/ml，碘海醇的质量/体积浓度以碘计为240mg/ml的血管栓塞材料。
实施例2～10的聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)的质量及特性黏数、显影剂的质量、电解质的质量、不含碘多元醇的质量如表1所示，其余制备过程与实施例1相同。
实施例2～10
表1实施例2～10的聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)(表中简称聚合物)质量及特性黏数、显影剂的质量、电解质的质量、不含碘多元醇质量表
Figure PCTCN2016111645-appb-000004
Figure PCTCN2016111645-appb-000005
实施例11
本实施例在实施例1的血管栓塞材料中加入盐酸多柔比星，具体方法为取实施例1的血管栓塞材料5ml，用10ml注射器抽取2ml～ml，并注入50mg的注射用盐酸多柔比星(海正辉瑞制药有限公司)中，常温下涡悬仪震摇5分钟后，静置半小时，抽取下层清液，即得实施例11的血管栓塞材料。
对比例1
不含电解质及不含碘的多元醇的血管栓塞材料的制备，方法如下。
步骤一，在0～30摄氏度下，将10.0g特性粘数为68ml/g的聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)及显影剂碘海醇粉末259g加入500ml水中，搅拌均匀。
步骤二，利用所述pH值调节剂盐酸将步骤一中所得到的溶液的pH值调节至6.5～8.0，得到聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)质量/体积浓度为20mg/ml，显影剂碘海醇的质量/体积浓度以碘计为240mg/ml的血管栓塞材料。
对比例2
线性聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)血管栓塞材料的制备，方法如下。
步骤一：取N-异丙基丙烯酰胺2.263g，十二烷基硫酸钠0.032g，甲基丙烯酸丁酯0.168ml，搅拌溶于160ml纯化水中，N2保护下，升温至70℃，加入9.5mg/ml的过硫酸钾水溶液10ml,反应4.5h，反应液经透析纯化、冷冻干燥，得聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)线性聚合物固体，备用。
步骤二：称取步骤一中备用固体10.0g，显影剂碘海醇粉末259g，加入400ml水中，混合均匀，得到含有线性聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)和显影剂的溶液，然后向其中加入电解质氯化钙1.25g，然后加入不含碘多元醇甘露醇0.3g，定容至500ml，混合均匀。
步骤三，利用pH值调节剂盐酸将步骤二中所得到的溶液的pH值调节至6.5～8.0，得到聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)线性聚合为质量/体积浓度为20mg/ml，氯化钙质量/体积浓度2.5mg/ml，甘露醇质量/体积浓度0.6mg/ml，碘海醇的质量/体积浓度以碘计为240mg/ml的血管栓塞材料。
表2为实施例1～10及对比例1～2的血管栓塞材料的性能测试结果。
表2实施例1～10及对比例1～2的血管栓塞材料的性能指标
Figure PCTCN2016111645-appb-000006
Figure PCTCN2016111645-appb-000007
由表2的测试结果可以证明，本发明的血管栓塞材料凝胶化时间合理，其凝胶化动力学可调控，具有合适的凝胶强度，抗血流冲刷，性能优于碘油，可持久栓塞靶血管，具有理想的显影性能，避免了临床使用时需与显影剂临用共混等操作带来的安全风险以及显影效果清晰度不够等问题。
同时，由对比例1的测试结果可以看出，血管栓塞材料中不含有电解质时，其体外凝胶化时间太长，容易发散，不能够很好的在血管末梢铸型，逸散率高，容易误栓。
同时，由对比例2的测试结果可以看出，当血管栓塞材料的聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)为线性聚合物时，在相同条件下，其黏度明显高于实施例1的黏度，其流动性相比较差。而且体外凝胶化时间太短，临床使用时，可操作时间短，增加了临床医生的操作难度，介入治疗时，没有足够的时间进入血管末梢并铸型。
图1为实施例1的血管栓塞材料、对比例2的血管栓塞材料、国产碘油以及超液化碘油的剪切变稀性以及黏度的对比图。
表2的黏度测试结果及图1的黏度曲线可以看出，本发明实施例1的血管栓塞材料组合物及对比例2中线性聚合物所配制的血管栓塞材料组合物均有剪切变稀的性能，但在相同条件下，本发明的血管栓塞材料黏度明显低于线性聚合物所配制的血管栓塞材料组合物。另外，本发明的组合物黏度明显低于国产碘油，且可媲美于超液化碘油。
实验例1
对实施例11的血管栓塞材料的体外释放使用药物洗脱装置进行实验模拟，此药物洗脱装置能够很好模拟的介入化疗栓塞(TACE)体内释放药物分布及释放。
所述药物洗脱装置包括玻璃释放池，蠕动泵、油浴锅、温度计、锥形瓶、烧杯和连接管。玻璃释放池为订制的直径2cm、高2cm的专用的玻璃池，上部用玻璃塞封闭，玻璃释放池两端可分别与连接管连接。将锥形瓶置于油浴锅中，然后将锥形瓶、蠕动泵、玻璃释放池和烧杯之间通过连接管依次连接。
将整个装置放置在避光环境中，实验时，先将油浴锅温度调节为37℃，蠕动泵流速调节为10rpm，然后打开油浴锅，将0.01M的PBS的释放液注入锥形瓶中，并放置在油浴锅内，并由温度计监控温度以保证释放液的温度为37℃；然后将玻璃释放池上的玻璃塞取出，用移液枪用移液枪吸取50μL实施例11的负载多柔比星的血管栓塞材料，注入玻璃释放池，并使之铺满释放池底部，再将玻璃塞盖在玻璃释放池上；然后打开蠕动泵提供动力，待液体流入 释放池时，开始计时。定时从烧杯中取样，测定样品荧光强度。按照下述公式计算盐酸多柔比星的累积释放率。
累积释放量Sn＝C1×V1+C2×V2+…+Cn×Vn
MDox＝V凝胶×ρDox
累积释放率(％)＝Sn/MDox×100
其中，n为第n个小时，Vn为第n个小时释放的体积，Cn为第n个小时释放液中盐酸多柔比星的浓度。MDox为载盐酸多柔比星的中盐酸多柔比星的含量，V凝胶为释放池中加入载盐酸多柔比星的体积。ρDox为载盐酸多柔比星的中盐酸多柔比星的浓度。
图2为实验例1的7天内的体外释放效果图。结果显示本发明的血管栓塞材料可以与化疗药物混合使用，且具有药物缓慢控制释放的能力。
实验例2
将实施例1的血管栓塞材料对正常家兔进行肾动脉行介入栓塞。
图3为实验例2的血管栓塞材料对正常家兔进行肾动脉行介入栓塞的数字血管减影造影术(DSA)效果图。
其中，图3-A1至3-A3为家兔肾动脉行介入栓塞术前的血管造影DSA图。3-B1到3-B3分别对应介入栓塞术后的复查造影图。其中3-B1的血管栓塞材料用量为0.5ml，3-B2的血管栓塞材料用量为1.0ml，3-B3的血管栓塞材料用量为2.0ml。图中a所示为肾末梢血管，b和c所示为小动脉血管，d和e所示为大动脉血管。
图3所示结果表明，可以通过控制血管栓塞材料的用量实现不同水平的肾动脉栓塞，临床时医生可以根据肿瘤部位选择血管栓塞材料的用量，进一步增强了血管栓塞材料临床时的可操作性。
实验例3
使用实施例1的血管栓塞材料对正常家兔右侧后肾动脉进行栓塞实验。
取实验前禁食禁水12小时的健康日本大耳白兔30只，进行股动脉插管，插管成功后，进行肾动脉插管，后进行肾动脉栓塞术(RAE)，术毕拔管，然后进行股动脉拔管及术后管理，并于肾动脉栓塞术后一周、一个月、两个月及三个月共四个时间点，每个时间点随机取5只栓塞术后兔进行复查造影，并在四个复查造影后，进行病理学观察。
图4为实验例3四个复查时间点的复查DSA造影图像，图4-A至图4-D分别为1周，1个月，2个月和3个月的复查DSA造影图像。
结果显示在1周、1个月、2个月和3个月四个设定复查时间点时复查，均未见右侧肾动脉复通，亦未见侧枝循环形成，表明本发明的血管栓塞材料可以有效且长期的栓塞住靶向血 管。
图5为实验例3的四个时间点的大体组织病理照片，图5-A至5-D分别为1周，1个月，2个月和3个月的复查的大体组织病理照片。
结果显示，随着复查时间点的延长，栓塞侧肾脏逐渐缩小，而对侧肾脏不同程度代偿性增大。表明本发明的血管栓塞材料对靶向血管的有效栓塞性。
实验例4
使用实施例1的血管材料组合物、等量的碘油+明胶海绵、等量的生理盐水分别对VX2肿瘤兔进行介入治疗，方法为，股动脉插管成功后，进行肝动脉插管，拔管后进行术后管理，并在术后一周进行核磁共振MRI检查。
图6为介入治疗前后的MR图。其中，图6-A至6-C分别对应实施例1的血管栓塞材料，碘油+明胶海绵，以及生理盐水进行介入治疗前后的MR图。
结果显示，各治疗组中肝脏肿瘤均呈增大趋势，伴随有中央及周边不规则的区域性坏死，其中，经实施例1的血管栓塞材料以及经等量的碘油+敏胶海绵栓塞治疗的肿瘤坏死较为明显，多数表现为肿瘤中央区片状坏死。表明本发明组合物对肝脏肿瘤有很好的栓塞效果。

Claims (11)

  1. 聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)在制备血管栓塞材料中的用途，其特征在于：所述聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)是交联聚合物，该交联聚合物的制备方法为：以N-异丙基丙烯酰胺为单体，N,N’-二亚甲基双丙烯酰胺为交联剂，甲基丙烯酸丁酯为共聚单体，采用无皂乳液聚合法，通过热引发自由基聚合得到聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)交联聚合物。
  2. 根据权利要求1所述的聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)在制备血管栓塞材料中的用途，其特征在于：所述聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)具有下列结构式：
    Figure PCTCN2016111645-appb-100001
    其中，m,n表示具有数量重复单元；
    所述聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)的特性黏数为40～100ml/g。
  3. 一种血管栓塞材料，其特征在于，含有：分散介质和聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)，所述聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)为交联聚合物。
  4. 根据权利要求3所述的血管栓塞材料，其特征在于：所述聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)具有下列结构式：
    Figure PCTCN2016111645-appb-100002
    其中，m,n表示具有数量重复单元；
    所述聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)的特性黏数为40～100ml/g。
  5. 根据权利要求3所述的血管栓塞材料，其特征在于，所述分散介质含有：
    电解质，所述电解质为选自氯化钠、氢氧化钠、氯化钙、磷酸氢二钠、磷酸二氢钠、依地酸钠钙中的至少一种；
    显影剂，所述显影剂包括含碘多元醇，所述含碘多元醇为碘海醇、碘佛醇、碘帕醇或碘比醇中的至少一种；
    pH值调节剂，所述pH值调节剂包括盐酸；
    以及水；
    所述血管栓塞材料的pH值为6.5～8.0。
  6. 根据权利要求5所述的血管栓塞材料，其特征在于：所述分散介质还含有不含碘的多元醇。
  7. 根据权利要求6所述的血管栓塞材料，其特征在于：所述不含碘的多元醇包括选自氨丁三醇、甘露醇、吐温-80、聚乙二醇200、聚乙二醇400和聚乙二醇600的至少一种。
  8. 根据权利要求5所述的血管栓塞材料，其特征在于，1毫升所述血管栓塞材料含有：
    5～30mg所述聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)；
    0.1～30mg所述电解质；
    100～350mg以碘计算的所述含碘多元醇；
    以及可选的，0.1～10mg所述不含碘的多元醇。
  9. 根据权利要求8所述的血管栓塞材料，其特征在于，1毫升所述血管栓塞材料含有：
    10～20mg所述聚(N-异丙基丙烯酰胺-co-甲基丙烯酸丁酯)；
    0.1～30mg所述电解质；
    150～240mg以碘计算的所述含碘多元醇；
    以及可选的，0.1～10mg所述不含碘的多元醇。
  10. 根据权利要求3～9任一项所述的血管栓塞材料，其特征在于：还含有化疗药物，所述化疗药物为选自盐酸多柔比星、盐酸表柔比星、丝裂霉素C或氟尿嘧啶的至少一种。
  11. 权利要求3～10任一项所述的血管栓塞材料在制备药物中的用途，所述药物用于通过栓塞化疗术治疗癌症。
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