WO2024149292A1 - Blood vessel closing adhesive, preparation method therefor and use thereof - Google Patents

Blood vessel closing adhesive, preparation method therefor and use thereof Download PDF

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Publication number
WO2024149292A1
WO2024149292A1 PCT/CN2024/071580 CN2024071580W WO2024149292A1 WO 2024149292 A1 WO2024149292 A1 WO 2024149292A1 CN 2024071580 W CN2024071580 W CN 2024071580W WO 2024149292 A1 WO2024149292 A1 WO 2024149292A1
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Prior art keywords
parts
sealing glue
vascular sealing
weight
cyanoacrylate
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PCT/CN2024/071580
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French (fr)
Chinese (zh)
Inventor
刘文菁
张娟凤
李慧
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苏州美创医疗科技有限公司
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Publication of WO2024149292A1 publication Critical patent/WO2024149292A1/en

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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
    • 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
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular 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
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02W—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO WASTEWATER TREATMENT OR WASTE MANAGEMENT
    • Y02W90/00—Enabling technologies or technologies with a potential or indirect contribution to greenhouse gas [GHG] emissions mitigation
    • Y02W90/10—Bio-packaging, e.g. packing containers made from renewable resources or bio-plastics

Definitions

  • the present invention belongs to the technical field of medical devices, and in particular relates to a blood vessel sealing glue and a preparation method and application thereof.
  • Varicose veins of the lower extremities are caused by blood congestion, venous tortuosity and dilatation of the superficial veins of the lower extremities. In the late stage, they may also be complicated by chronic ulcers of the lower legs. It is a common vascular surgical disease. According to relevant domestic reports, the total number of patients with varicose veins of the lower extremities in my country has exceeded 100 million, and the incidence rate is about 15%. Without treatment, patients with varicose veins are prone to heaviness, pain, itching and skin changes in the lower extremities, and develop diseases such as spider veins, hemosiderin deposition, inflammation, fat skin sclerosis and ulcers.
  • the clinical treatment methods for varicose veins of the lower extremities include traditional conservative treatment (such as elastic stockings, drug therapy, etc.), surgical treatment (such as vein stripping, ligation, etc.) and minimally invasive interventional treatment (such as foam sclerosing agent, laser, radiofrequency ablation, etc.), but these methods have more or less some defects.
  • conservative treatment such as elastic stockings, drug therapy, etc.
  • surgical treatment such as vein stripping, ligation, etc.
  • minimally invasive interventional treatment such as foam sclerosing agent, laser, radiofrequency ablation, etc.
  • the surgical adhesive is generally used for wound closure or hemostasis. If it is used for venous embolism treatment, its initial viscosity is 89mPa ⁇ s, and it can only be delivered to the lesion site through catheter intervention technology; and the surgical adhesive usually cures quickly, which on the one hand will lead to a large polymerization heat and the risk of burning blood vessels and other organs, while this risk does not need to be considered when used for wound closure or hemostasis.
  • the adhesive will begin to cure in the catheter, making the surgical operation more difficult and even making the operation difficult to continue.
  • the ⁇ -cyanoacrylate compounds used for venous embolism treatment have the following shortcomings: (1) poor toughness after curing, and there will be obvious hard lumps and foreign bodies in the clinic; (2) poor storage stability, and some monomers are prone to polymerization and failure after being placed for a period of time.
  • vascular closure glue - vena cava closure.
  • vascular closure glue is injected into the venous cavity to completely close the incomplete venous lumen, achieve the purpose of eliminating venous blood reflux, and achieve permanent closure of venous blood vessels to treat varicose veins.
  • the US FDA approved VenaSeal for marketing, and ⁇ -cyanoacrylate began to be officially used for the treatment of varicose veins of the lower extremities.
  • the primary technical problem to be solved by the present invention is to overcome the defect that the existing vascular sealing glue cannot be used to treat superficial varicose veins because it cannot be injected with a needle smaller than 30G, and then, by optimizing the type and amount of each component, a vascular sealing glue with high bonding strength, good flexibility and stability, moderate viscosity and curing speed, and direct injection with a needle smaller than 30G is provided.
  • the use of the vascular sealing glue can significantly simplify surgical operations and effectively treat varicose veins of the lower limbs, and is particularly suitable for the treatment of superficial varicose veins.
  • vascular sealing glue is easy to damage blood vessels due to its large polymerization heat.
  • a vascular sealing glue with high bonding strength, good flexibility and stability, low polymerization heat, moderate viscosity and curing speed is provided, which can be directly injected with a needle less than 30G.
  • the present invention provides the following technical solutions:
  • the present invention provides a vascular occlusive glue, wherein the raw material composition of the vascular occlusive glue is, in parts by weight:
  • the thickener is at least one of cellulose acetate butyrate, polylactic acid, and polymethyl methacrylate;
  • the weight average molecular weight of the cellulose acetate butyrate is 30,000 to 60,000;
  • the weight average molecular weight of the polylactic acid is 60,000 to 80,000;
  • the weight average molecular weight of the polymethyl methacrylate is 350,000 to 500,000.
  • the raw material composition of the vascular sealing glue is: 95-99.9 parts of n-butyl ⁇ -cyanoacrylate, 2-3.5 parts of thickener, 1.4-2.1*10 -4 parts of inhibitor and 0.5-2.5*10 -4 parts of dye.
  • the purity of the n-butyl ⁇ -cyanoacrylate is >98%.
  • the polymerization inhibitor comprises 1 to 2*10 -4 parts of free radical polymerization inhibitor and 0.1 to 0.46*10 -4 parts of acidic polymerization inhibitor.
  • the acidic polymerization inhibitor is at least one of boron trifluoride, boron trifluoride ethyl ether, sulfur dioxide, phosphoric acid, phytic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • the free radical inhibitor is at least one of butylated hydroxyanisole, tert-butylhydroquinone, hydroquinone, and resorcinol.
  • the dye is solvent blue and/or solvent violet.
  • the present invention provides a method for preparing the above-mentioned vascular sealing glue, comprising the following steps:
  • the stirring speed is 100-500 rpm.
  • the first time is 3 to 12 hours.
  • the present invention further provides use of the above-mentioned vascular occlusive glue or the vascular occlusive glue prepared according to the above-mentioned preparation method in the preparation of a drug for treating varicose veins of the lower limbs.
  • the raw material composition of the vascular sealing glue provided by the present invention includes 93 to 99.9 parts by weight of n-butyl ⁇ -cyanoacrylate, 0.1 to 4.5 parts by weight of a thickener, 1.1 to 2.46*10 -4 parts by weight of an inhibitor, and 0 to 3*10 -4 parts of a dye, wherein the thickener is at least one of cellulose acetate butyrate with a weight average molecular weight of 30,000 to 60,000, polylactic acid with a weight average molecular weight of 60,000 to 80,000, and polymethyl methacrylate with a weight average molecular weight of 350,000 to 500,000.
  • the inventors have found that the above-mentioned specific thickener not only has a thickening effect, but also has a good plasticizing effect, which can improve the viscosity of the blood vessel closure glue and enhance its flexibility after film formation; by increasing the content of n-butyl ⁇ -cyanoacrylate and adding an appropriate amount of thickener, the product can have a greater adhesive strength and can be directly injected with a needle less than 30G while ensuring the viscosity and curing speed of the product, thereby solving the defect that the current marketed product (n-butyl ⁇ -cyanoacrylate) cannot be used for superficial veins.
  • the superficial vein is short and has a large diameter.
  • the vascular closure glue is tortuous and has a small diameter. Once varicose veins occur, they will appear as earthworm-like masses. It is impossible to use catheter intervention technology to treat earthworm-like masses in superficial veins.
  • the action environment of vascular closure glue is different from that of surgical adhesives acting on the wound surface, the vascular closure glue will be affected by hemodynamics after entering the target position in the blood vessel. If the viscosity is too low or the curing is too slow, it may cause the adhesive to migrate and cause ectopic embolism.
  • the vascular closure glue provided by the present invention comprehensively considers the application environment, mode of action, operation method and other characteristics of the vascular closure glue, and can balance the product's closing effect, tissue thermal damage, mobility, and ease of operation.
  • an appropriate amount of inhibitor is added to give the product a suitable curing speed and shelf life.
  • the above three components work together to make the vascular closure glue of the present invention have both high adhesion strength and low viscosity. It has good strength and flexibility, and at the same time has suitable viscosity, curing speed and stability. It can be directly injected with a needle smaller than 30G to achieve the purpose of treating varicose veins of the lower limbs (great saphenous vein, superficial vein) with simple and quick surgery.
  • the vascular sealing glue of the present invention can be directly injected using a needle of less than 30G, which meets the clinical demand for the treatment of superficial varicose veins, and can also be applied to the treatment of varicose veins of the great saphenous vein, that is, the minimally invasive catheter intervention treatment of varicose veins of the lower limbs by non-intravascular thermal ablation; direct injection treatment greatly simplifies the surgical operation and can also significantly reduce the cost of surgery.
  • the vascular sealing glue of the present invention is particularly suitable for the treatment of superficial varicose veins because of its moderate viscosity and curing speed and the convenience of direct needle injection.
  • the vascular sealing glue provided by the present invention uses ⁇ -cyanoacrylate n-butyl ester with a purity of >98%, which is beneficial to reducing the polymerization heat of the vascular sealing glue and avoiding damage to the blood vessels due to large heat release during polymerization and curing of the vascular sealing glue.
  • the polymerization inhibitor in the vascular sealing glue provided by the present invention comprises 1 to 2*10 -4 parts by weight of a free radical polymerization inhibitor and 0.1 to 0.46*10 -4 parts by weight of an acidic polymerization inhibitor.
  • the dye in the vascular sealing glue provided by the present invention is preferably solvent blue and/or solvent violet.
  • the prior art has proposed to introduce developing groups such as triiodobenzoic acid units into the molecular structure of cyanoacrylate compounds to facilitate observation of surgical conditions, but such developing groups can only be seen under X-rays or CT, which places high demands on surgical conditions.
  • the inventors also considered that in current catheter interventional surgeries, it is necessary to pre-inject the sealing glue to the proximal or front end of the catheter. Because the catheter is transparent, it is difficult to observe and control the injection position when the colorless liquid is injected into the catheter, and it is easy to push out the front end of the catheter.
  • the sealing glue retained at the front end will solidify rapidly, causing tube blockage and operation failure.
  • the drugs required during the operation are all colorless, and doctors need to spend time distinguishing and identifying them, which poses a risk of misuse. Therefore, the vascular sealing glue of the present invention adds a dye visible to the naked eye. On the one hand, it is convenient for doctors to observe the surgical conditions, and on the other hand, it can also It can prevent doctors from misusing it, improve the convenience of surgery, and reduce the risk of confusion with drugs or contrast agents during operation.
  • the blood vessel sealing glue provided by the present invention is packed in a vial and sealed with an aluminum-plastic composite cover, which has good sealing performance, improves the storage validity period of the product, and has the advantage of being convenient for aspiration using a syringe.
  • the preparation method of the vascular sealing glue provided by the present invention comprises mixing ⁇ -cyanoacrylate n-butyl with an inhibitor and a dye, stirring to dissolve, and then slowly adding a thickener, stirring to dissolve, so as to obtain a vascular sealing glue with uniform quality.
  • the preparation method of the present invention has simple process steps, is easy to operate, and is suitable for large-scale production of medical implant-grade materials.
  • ⁇ -Butyl cyanoacrylate CAS#6606-65-1, purity>98%, the rest are impurities such as inhibitor, formaldehyde, n-butanol, ⁇ -butyl cyanoacetate, moisture, etc., and the types and contents of these impurities have negligible effects on the present invention.
  • ⁇ -Butyl cyanoacrylate CAS#6606-65-1, purity 95%, the rest are impurities such as inhibitor, formaldehyde, n-butanol, ⁇ -butyl cyanoacetate, moisture, etc., and the types and contents of these impurities have negligible effects on the present invention.
  • Cellulose acetate butyrate CAS#9004-36-8, weight average molecular weight 30,000-60,000, purchased from Shanghai MacLean Biochemical Technology Co., Ltd.
  • Polylactic acid CAS#51056-13-9, weight average molecular weight 60,000-80,000, particle size 3 mm, purchased from Shanghai MacLean Biochemical Technology Co., Ltd.
  • Polymethyl methacrylate CAS#9011-14-7, weight average molecular weight 350,000-500,000, purchased from Shanghai McLean Biochemical Technology Co., Ltd., Rohm Chemical (Shanghai) Co., Ltd.
  • n-butyl ⁇ -cyanoacrylate purity>98%), 3 g of cellulose acetate butyrate, 0.15 mg of tert-butylhydroquinone, 0.02 mg of boron trifluoride, and 0.05 mg of solvent blue 67.
  • n-butyl ⁇ -cyanoacrylate was added to the reactor, tert-butyl hydroquinone and solvent blue 67 were added under constant stirring, and dissolved by stirring at a speed of 300 rpm, then boron trifluoride was quantitatively extracted and injected into the above reactor, and stirring was continued until the mixture was uniform, and then cellulose acetate butyrate was slowly and portionedly added to avoid agglomeration, and stirring was continued for 3 hours after the addition was completed.
  • the viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, the mixture was placed in a vial and sealed for storage.
  • n-butyl ⁇ -cyanoacrylate purity>98%), 2 g of cellulose acetate butyrate, 0.13 mg of butylated hydroxyanisole, 0.01 mg of boron trifluoride, and 0.2 mg of solvent blue 67.
  • n-butyl ⁇ -cyanoacrylate was added to the reactor, butyl hydroxyanisole and solvent blue 67 were added under constant stirring, and dissolved by stirring at a speed of 200 rpm, then boron trifluoride was quantitatively extracted and injected into the above reactor, and stirring was continued until the mixture was uniform, and then cellulose acetate butyrate was slowly and portionwise added to avoid agglomeration, and stirring was continued for 5 hours after the addition was completed.
  • the viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, the mixture was placed in a vial and sealed for storage.
  • ⁇ -Butyl cyanoacrylate (purity> 98%) 97g, polymethyl methacrylate 3.5g, terephthalate Phenol 0.18 mg, phosphoric acid 0.03 mg, and solvent blue 97 0.1 mg.
  • ⁇ -cyanoacrylate n-butyl ester was added to the reactor, and hydroquinone, phosphoric acid and solvent blue 97 were added under constant stirring, and dissolved by stirring at a speed of 100 rpm, and then polymethyl methacrylate was slowly and added in portions to avoid agglomeration. After the addition was completed, stirring was continued for 6 hours. The viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, it was placed in a vial and sealed for storage.
  • n-butyl ⁇ -cyanoacrylate was added to the reactor, and resorcinol, p-toluenesulfonic acid and solvent blue 97 were added under constant stirring, and dissolved by stirring at a speed of 400 rpm, and then cellulose acetate butyrate was added slowly and in portions to avoid agglomeration, and stirring was continued for 10 hours after the addition was completed.
  • the viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, it was placed in a vial and sealed for storage.
  • n-butyl ⁇ -cyanoacrylate was added to the reactor, butyl hydroxyanisole, phytic acid and solvent violet were added under constant stirring, and dissolved by stirring at a speed of 500 rpm, and then cellulose acetate butyrate was added slowly and in portions to avoid agglomeration, and stirring was continued for 12 hours after the addition was completed.
  • the viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, it was placed in a vial and sealed for storage.
  • n-butyl ⁇ -cyanoacrylate purity >98%), 2g of polymethyl methacrylate, 0.1mg of hydroquinone, 0.046mg of benzenesulfonic acid, and 0.25mg of solvent violet D&C VIOLET NO.2.
  • ⁇ -cyanoacrylate n-butyl ester was added to the reactor, and hydroquinone, benzenesulfonic acid and solvent violet were added under constant stirring, and dissolved by stirring at a speed of 300 rpm, and then polymethyl methacrylate was slowly and added in portions to avoid agglomeration, and stirring was continued for 8 hours after the addition was completed.
  • the viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, it was put into a vial and sealed for storage.
  • n-butyl ⁇ -cyanoacrylate purity>98%), 2.5 g of polymethyl methacrylate, 0.14 mg of hydroquinone, 0.01 mg of boron trifluoride, and 0.1 mg of solvent blue 97.
  • n-butyl ⁇ -cyanoacrylate was added to the reactor, and hydroquinone and solvent blue 97 were added under constant stirring, and dissolved by stirring at a speed of 250 rpm. Then, boron trifluoride was quantitatively extracted and injected into the above reactor, and stirring was continued until the mixture was uniform, and then polymethyl methacrylate was slowly and added in portions to avoid agglomeration. After the addition was completed, stirring was continued for 5 hours. The viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, the mixture was placed in a vial and sealed for storage.
  • n-butyl ⁇ -cyanoacrylate purity>98%), 4.5g of polylactic acid, 0.17mg of resorcinol, 0.035mg of phosphoric acid, and 0.2mg of solvent violet D&C VIOLET NO.2.
  • ⁇ -cyanoacrylate n-butyl ester was added to the reactor, and resorcinol, phosphoric acid and solvent violet were added under constant stirring, and dissolved by stirring at a speed of 350 rpm, and then polylactic acid was slowly added in portions to avoid agglomeration, and stirring was continued for 6 hours after the addition was completed.
  • the viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, it was put into a vial and sealed for storage.
  • Example 3 The n-butyl ⁇ -cyanoacrylate in Example 3 was replaced by n-butyl ⁇ -cyanoacrylate of the same mass and purity of 95%.
  • the raw material composition of the vascular sealing glue provided in this embodiment is: 93g of n-butyl ⁇ -cyanoacrylate (purity>98%), 4.5g of polymethyl methacrylate, 0.18mg of hydroquinone, 0.03mg of phosphoric acid, and 0.1mg of solvent blue 97.
  • the preparation method is the same as Example 3.
  • the raw material composition of the vascular sealing glue provided in this embodiment is: 95g of n-butyl ⁇ -cyanoacrylate (purity>98%), 1.5g of polymethyl methacrylate, 0.18mg of hydroquinone, 0.03mg of phosphoric acid, and 0.1mg of solvent blue 97.
  • the preparation method is the same as Example 3.
  • the raw material composition of the vascular sealing glue provided in this embodiment is: 94g of n-butyl ⁇ -cyanoacrylate (purity>98%), 0.1g of polymethyl methacrylate, 0.18mg of hydroquinone, 0.03mg of phosphoric acid, and 0.1mg of solvent blue 97.
  • the preparation method is the same as Example 3.
  • gum arabic is used as the thickener instead of polymethyl methacrylate.
  • the raw material composition of the vascular sealing glue provided in this comparative example is: 92g of n-butyl ⁇ -cyanoacrylate (purity>98%), 4.5g of polymethyl methacrylate, 0.18mg of hydroquinone, 0.03mg of phosphoric acid, and 0.1mg of solvent blue 97.
  • the preparation method is the same as Example 3.
  • the raw material composition of the vascular sealing glue provided in this comparative example is: 94.5g of n-butyl ⁇ -cyanoacrylate (purity>98%), 6g of polymethyl methacrylate, 0.18mg of hydroquinone, 0.03mg of phosphoric acid, and 0.1mg of solvent blue 97.
  • the preparation method is the same as Example 3.
  • the test is carried out in combination with the curing time. After completing the sample preparation for the curing time, use a glass rod to pick up the cured membrane from any position in the water. If the membrane can be picked up and there is no breakage after being bent after being picked up, it is rated as excellent; if the membrane can be picked up and there are cracks after being bent after being picked up, it is rated as relatively good; if the membrane can be picked up and breaks after being bent after being picked up, it is rated as medium; if the membrane breaks after being picked up, it is rated as poor.
  • vascular sealing glue (Examples 1 to 14) provided by the present invention has the advantages of moderate viscosity, controllable curing speed, good flexibility, low polymerization heat, excellent mechanical properties and high biocompatibility, as follows:
  • the viscosity is in the range of 10-25mPa ⁇ s, which is suitable for bonding the great saphenous vein and the superficial vein. Direct injection with a syringe through a needle smaller than 30G is simple to operate and greatly saves surgical time;
  • the solidification time is within 25 seconds, which reduces the pressing time during surgery and facilitates operation;
  • the polymerization exotherm is low, and the polymerization heat is basically between 160 and 200 J/g, which minimizes the damage to the patient;
  • Comparative Example 1 uses gum arabic as a thickener, which cannot ensure the flexibility after curing into a film; Compared with Example 13, Comparative Example 2 reduces the content of n-butyl ⁇ -cyanoacrylate, which reduces the bonding strength of the vascular sealing glue, and at the same time causes the proportion of the thickener in the product to increase, and the viscosity of the product increases accordingly, and it cannot be injected through a 30G needle; Compared with Example 3, Comparative Example 3 increases the content of the thickener, which reduces the bonding strength of the vascular sealing glue, significantly increases the viscosity, and significantly prolongs the curing time, and it cannot be injected through a 30G needle, and it also thickens significantly after aging; The molecular weight of the thickener used in Comparative Examples 4 to Comparative Examples 6 is large or small, and all cannot take into account the above-mentioned properties of the vascular sealing glue; Comparative Example 7 is VenaSeal, a

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Abstract

The present invention relates to the field of medical instruments, and relates to a blood vessel closing adhesive, a preparation method therefor and a use thereof. The blood vessel closing adhesive comprises 93-99.9 parts by weight of n-butyl α-cyanoacrylate, 0.1-4.5 parts by weight of a thickening agent, 1.1-2.46*10-4 parts by weight of a polymerization inhibitor, and 0-3*10-4 parts by weight of a dye, wherein the thickening agent is at least one of cellulose acetate butyrate having a weight-average molecular weight of 30,000-60,000, polylactic acid having a weight-average molecular weight of 60,000-80,000, and polymethyl methacrylate having a weight-average molecular weight of 350,000-500,000. The described specific type of the thickening agent simultaneously has thickening and plasticizing effects, and can improve the flexibility after film formation while improving the viscosity. The synergistic effect of three components enables the blood vessel closing adhesive of the present invention to have high bonding strength and good flexibility, and also have suitable viscosity, curing speed, and stability. The blood vessel closing adhesive can be directly injected by using a 30G syringe needle, thereby achieving the purposes of treatment of lower limb varicose veins, especially superficial varicose veins, and simple and rapid operation.

Description

一种血管闭合胶及其制备方法与应用A kind of blood vessel sealing glue and its preparation method and application
相关申请的交叉引用CROSS-REFERENCE TO RELATED APPLICATIONS
本申请要求在2023年1月10日提交中国专利局、申请号为202310030312.6、发明名称为“一种血管闭合胶及其制备方法与应用”的中国专利申请的优先权，其全部内容通过引用的方式并入本文中。This application claims the priority of the Chinese patent application filed with the Chinese Patent Office on January 10, 2023, with application number 202310030312.6 and invention name “A vascular closing glue and its preparation method and application”, the entire contents of which are incorporated herein by reference.
技术领域Technical Field
本发明属于医疗器械技术领域，具体涉及一种血管闭合胶及其制备方法与应用。The present invention belongs to the technical field of medical devices, and in particular relates to a blood vessel sealing glue and a preparation method and application thereof.
背景技术Background technique
下肢静脉曲张，俗称“蚯蚓腿”或“美腿杀手”，是由于下肢浅表静脉因血液淤积、静脉迂曲和扩张所引起的，晚期还会合并小腿慢性溃疡，是一种常见的血管外科疾病。据国内相关报道，我国下肢静脉曲张的患者总数已超过1亿，发病率约为15％。在未经治疗的情况下，静脉曲张的患者容易出现下肢沉重、疼痛、瘙痒和皮肤变化等情况，并产生蜘蛛静脉、含铁血黄素沉积、炎症、脂肪皮肤硬化和溃疡等疾病。Varicose veins of the lower extremities, commonly known as "earthworm legs" or "beautiful legs killer", are caused by blood congestion, venous tortuosity and dilatation of the superficial veins of the lower extremities. In the late stage, they may also be complicated by chronic ulcers of the lower legs. It is a common vascular surgical disease. According to relevant domestic reports, the total number of patients with varicose veins of the lower extremities in my country has exceeded 100 million, and the incidence rate is about 15%. Without treatment, patients with varicose veins are prone to heaviness, pain, itching and skin changes in the lower extremities, and develop diseases such as spider veins, hemosiderin deposition, inflammation, fat skin sclerosis and ulcers.
目前，临床治疗下肢静脉曲张的方法有传统的保守治疗(如弹力袜、药物治疗等)、外科手术治疗(如静脉剥脱、结扎等)以及微创介入治疗(如泡沫硬化剂、激光、射频消融等)，但这些方法都或多或少存在着一些缺陷。随着医用高分子材料学科的迅速发展，1949年美国BFGoodrich公司的Ardis等首次合成了α-氰基丙烯酸酯类化合物，其具有优异的粘合能力，尤其是粘合人体组织的能力受到医学界的青睐，从上世纪70年代开始用于临床，目前主要用于止血和胃底静脉曲张的栓塞治疗，其作用机理是，α-氰基丙烯酸酯遇到阴离子(如血液)会很快发生聚合而粘合人体组织。 At present, the clinical treatment methods for varicose veins of the lower extremities include traditional conservative treatment (such as elastic stockings, drug therapy, etc.), surgical treatment (such as vein stripping, ligation, etc.) and minimally invasive interventional treatment (such as foam sclerosing agent, laser, radiofrequency ablation, etc.), but these methods have more or less some defects. With the rapid development of medical polymer materials, Ardis et al. of BFGoodrich Company in the United States synthesized α-cyanoacrylate compounds for the first time in 1949. Its excellent adhesion ability, especially the ability to adhere to human tissue, has been favored by the medical community. It has been used in clinical practice since the 1970s. It is currently mainly used for hemostasis and embolization treatment of gastric fundus varicose veins. Its mechanism of action is that α-cyanoacrylate will quickly polymerize and adhere to human tissue when it encounters anions (such as blood).
美国专利文献US3527841A公开了一种外科粘合剂，其是通过将0.5g聚乳酸(特性粘度I.V.＝2.04)溶解在10g 2-氰基丙烯酸正丁酯中，并在70℃下搅拌3小时制备而成。该外科粘合剂一般用于伤口闭合或止血，若用于静脉栓塞治疗，其初始粘度为89mPa·s，只能通过导管介入技术定向输送至病灶部位；并且外科粘合剂通常固化速度较快，这样一方面会导致其聚合热较大，存在灼伤血管等器官的风险，而用于伤口闭合或止血时无需考虑该风险，另一方面还会使粘合剂在导管中已经开始固化，造成手术操作难度增大，甚至会使手术难以为继。除此之外，用于静脉栓塞治疗的α-氰基丙烯酸酯类化合物还存在以下不足：(1)固化后韧性较差，临床中会有明显硬块异物感；(2)储存稳定性较差，放置一段时间后部分单体易发生聚合而失效。U.S. Patent Document US3527841A discloses a surgical adhesive, which is prepared by dissolving 0.5g of polylactic acid (intrinsic viscosity I.V. = 2.04) in 10g of 2-butyl cyanoacrylate and stirring at 70°C for 3 hours. The surgical adhesive is generally used for wound closure or hemostasis. If it is used for venous embolism treatment, its initial viscosity is 89mPa·s, and it can only be delivered to the lesion site through catheter intervention technology; and the surgical adhesive usually cures quickly, which on the one hand will lead to a large polymerization heat and the risk of burning blood vessels and other organs, while this risk does not need to be considered when used for wound closure or hemostasis. On the other hand, the adhesive will begin to cure in the catheter, making the surgical operation more difficult and even making the operation difficult to continue. In addition, the α-cyanoacrylate compounds used for venous embolism treatment have the following shortcomings: (1) poor toughness after curing, and there will be obvious hard lumps and foreign bodies in the clinic; (2) poor storage stability, and some monomers are prone to polymerization and failure after being placed for a period of time.
近年来，现有技术提出了一种利用血管闭合胶治疗下肢静脉曲张的新疗法—腔静脉闭合术，通过导管介入技术向静脉腔内注射血管闭合胶，完全闭合功能不全的静脉管腔，达到消除静脉血液反流的目的，实现永久性地闭合静脉血管来治疗静脉曲张。2015年美国FDA批准VenaSeal上市，α-氰基丙烯酸酯(血管闭合胶的主要成分)开始正式用于下肢静脉曲张的治疗，但由于其产品粘度较大，导致无法使用小于30G针头直接注射；其呈无色液体，预推注时不易观察，且价格昂贵。另外VenaSeal采用螺口瓶包装，使用时需拧开旋盖，操作繁琐、耗时，对于活性强的α-氰基丙烯酸正丁酯是不利的。并且目前国内尚无相关产品获批。In recent years, the existing technology has proposed a new treatment method for varicose veins of the lower extremities using vascular closure glue - vena cava closure. Through catheter intervention technology, vascular closure glue is injected into the venous cavity to completely close the incomplete venous lumen, achieve the purpose of eliminating venous blood reflux, and achieve permanent closure of venous blood vessels to treat varicose veins. In 2015, the US FDA approved VenaSeal for marketing, and α-cyanoacrylate (the main component of vascular closure glue) began to be officially used for the treatment of varicose veins of the lower extremities. However, due to its high viscosity, it cannot be directly injected with a needle less than 30G; it is a colorless liquid, which is not easy to observe during pre-injection, and it is expensive. In addition, VenaSeal is packaged in a screw-mouth bottle, and the cap needs to be unscrewed when used. The operation is cumbersome and time-consuming, which is not conducive to the highly active α-cyanoacrylate. And currently no related products have been approved in China.
发明内容Summary of the invention
鉴于此，本发明首要解决的技术问题是克服现有的血管闭合胶因无法用小于30G针头推注而不能用于治疗浅表静脉曲张的缺陷，进而通过优化各组分的种类和用量，提供一种粘合强度高、柔韧性和稳定性好、且粘度和固化速度适中、可由小于30G针头直接注射的血管闭合胶，使用该血管闭合胶能够显著简化手术操作，有效治疗下肢静脉曲张，特别适用于浅表静脉曲张的治疗。 In view of this, the primary technical problem to be solved by the present invention is to overcome the defect that the existing vascular sealing glue cannot be used to treat superficial varicose veins because it cannot be injected with a needle smaller than 30G, and then, by optimizing the type and amount of each component, a vascular sealing glue with high bonding strength, good flexibility and stability, moderate viscosity and curing speed, and direct injection with a needle smaller than 30G is provided. The use of the vascular sealing glue can significantly simplify surgical operations and effectively treat varicose veins of the lower limbs, and is particularly suitable for the treatment of superficial varicose veins.
本发明要解决的另一技术问题是现有的血管闭合胶因聚合热较大而易于损伤血管，进而通过优化各组分的种类和用量，提供一种粘合强度高、柔韧性和稳定性好、聚合热小且粘度和固化速度适中、可由小于30G针头直接注射的血管闭合胶。Another technical problem to be solved by the present invention is that the existing vascular sealing glue is easy to damage blood vessels due to its large polymerization heat. By optimizing the type and amount of each component, a vascular sealing glue with high bonding strength, good flexibility and stability, low polymerization heat, moderate viscosity and curing speed is provided, which can be directly injected with a needle less than 30G.
为实现上述目的，本发明提供了以下技术方案：To achieve the above object, the present invention provides the following technical solutions:
根据本发明的实施例，第一方面，本发明提供了一种血管闭合胶，以重量份数计，所述血管闭合胶的原料组成为：According to an embodiment of the present invention, in a first aspect, the present invention provides a vascular occlusive glue, wherein the raw material composition of the vascular occlusive glue is, in parts by weight:
α-氰基丙烯酸正丁酯93～99.9份，增稠剂0.1～4.5份，阻聚剂1.1～2.46*10-4份以及染料0～3*10-4份；93-99.9 parts of n-butyl α-cyanoacrylate, 0.1-4.5 parts of thickener, 1.1-2.46*10 -4 parts of inhibitor and 0-3*10 -4 parts of dye;
所述增稠剂为醋酸丁酸纤维素、聚乳酸、聚甲基丙烯酸甲酯中的至少一种；The thickener is at least one of cellulose acetate butyrate, polylactic acid, and polymethyl methacrylate;
所述醋酸丁酸纤维素的重均分子量为3万～6万；The weight average molecular weight of the cellulose acetate butyrate is 30,000 to 60,000;
所述聚乳酸的重均分子量为6万～8万；The weight average molecular weight of the polylactic acid is 60,000 to 80,000;
所述聚甲基丙烯酸甲酯的重均分子量为35万～50万。The weight average molecular weight of the polymethyl methacrylate is 350,000 to 500,000.
在本发明的实施例中，所述血管闭合胶的原料组成为：α-氰基丙烯酸正丁酯95～99.9份，增稠剂2～3.5份，阻聚剂1.4～2.1*10-4份以及染料0.5～2.5*10-4份。In an embodiment of the present invention, the raw material composition of the vascular sealing glue is: 95-99.9 parts of n-butyl α-cyanoacrylate, 2-3.5 parts of thickener, 1.4-2.1*10 -4 parts of inhibitor and 0.5-2.5*10 -4 parts of dye.
在本发明的实施例中，所述α-氰基丙烯酸正丁酯的纯度>98％。In an embodiment of the present invention, the purity of the n-butyl α-cyanoacrylate is >98%.
在本发明的实施例中，所述阻聚剂包括自由基阻聚剂1～2*10-4份和酸性阻聚剂0.1～0.46*10-4份。In an embodiment of the present invention, the polymerization inhibitor comprises 1 to 2*10 -4 parts of free radical polymerization inhibitor and 0.1 to 0.46*10 -4 parts of acidic polymerization inhibitor.
在本发明的实施例中，所述酸性阻聚剂为三氟化硼、三氟化硼乙醚、二氧化硫、磷酸、植酸、甲磺酸、对甲苯磺酸中的至少一种。In an embodiment of the present invention, the acidic polymerization inhibitor is at least one of boron trifluoride, boron trifluoride ethyl ether, sulfur dioxide, phosphoric acid, phytic acid, methanesulfonic acid, and p-toluenesulfonic acid.
在本发明的实施例中，所述自由基阻聚剂为丁基羟基茴香醚、叔丁基对苯二酚、对苯二酚、间苯二酚中的至少一种。In an embodiment of the present invention, the free radical inhibitor is at least one of butylated hydroxyanisole, tert-butylhydroquinone, hydroquinone, and resorcinol.
在本发明的实施例中，所述染料为溶剂蓝和/或溶剂紫。In an embodiment of the present invention, the dye is solvent blue and/or solvent violet.
根据本发明的实施例，第二方面，本发明提供了上述血管闭合胶的制备方法，包括如下步骤： According to an embodiment of the present invention, in a second aspect, the present invention provides a method for preparing the above-mentioned vascular sealing glue, comprising the following steps:
将α-氰基丙烯酸正丁酯与阻聚剂、染料混合，搅拌溶解，再缓慢加入增稠剂，持续搅拌第一时间。Mix α-cyanoacrylate n-butyl ester with the inhibitor and dye, stir to dissolve, then slowly add the thickener, and continue stirring for the first time.
在本发明的实施例中，所述搅拌的速度为100～500rpm。In an embodiment of the present invention, the stirring speed is 100-500 rpm.
在本发明的实施例中，所述第一时间为3～12h。In an embodiment of the present invention, the first time is 3 to 12 hours.
根据本发明的实施例，第三方面，本发明还提供了上述血管闭合胶或者根据上述制备方法制得的血管闭合胶在制备治疗下肢静脉曲张的药物中的应用。According to an embodiment of the present invention, in a third aspect, the present invention further provides use of the above-mentioned vascular occlusive glue or the vascular occlusive glue prepared according to the above-mentioned preparation method in the preparation of a drug for treating varicose veins of the lower limbs.
与现有技术相比，本发明的技术方案具有如下优点：Compared with the prior art, the technical solution of the present invention has the following advantages:
1.本发明提供的血管闭合胶的原料组成包括α-氰基丙烯酸正丁酯93～99.9重量份，增稠剂0.1～4.5重量份，阻聚剂1.1～2.46*10-4重量份以及染料0～3*10-4份，其中增稠剂为重均分子量为3万～6万的醋酸丁酸纤维素、重均分子量为6万～8万的聚乳酸、重均分子量为35万～50万的聚甲基丙烯酸甲酯中的至少一种。发明人发现，上述特定增稠剂不仅具有增稠作用，同时还具有较好的增塑效果，可以在改善血管闭合胶粘度的同时，提升其成膜后的柔韧性；通过增大α-氰基丙烯酸正丁酯的含量，并添加适量增稠剂，能够在保证产品粘度和固化速度的同时，使产品具有较大的粘合强度及可使用小于30G针头直接注射的特点，解决目前上市产品(α-氰基丙烯酸正丁酯)不能用于浅表静脉的缺陷，这是因为，不同于大隐静脉血管直又长且管径大，适于导管介入的特性，浅表静脉血管短、迂曲且管径小，一旦发生曲张会呈现出蚯蚓状团块，无法采用导管介入技术进行浅表静脉蚯蚓状团块的治疗；并且，由于血管闭合胶的作用环境与外科粘合剂作用于伤口表面不同，血管闭合胶进入血管内目标位置后会受到血流动力学影响，若粘度过低或固化过慢有可能造成粘合剂迁移而发生异位栓塞，因此，本发明提供的血管闭合胶综合考虑血管闭合胶的应用环境、作用方式、操作方法等特点，能够平衡产品的闭合效果、组织热损伤、迁移率以及操作便捷性等多方面性能。另外，为保证产品有效性、安全性、稳定性，添加适量阻聚剂，使产品具有适宜的固化速度、货架有效期。上述三种组分协同配合，使得本发明的血管闭合胶既具有较高的粘合强 度和较好的柔韧性，又同时具备适宜的粘度、固化速度及稳定性，可由小于30G针头直接注射，达到治疗下肢静脉曲张(大隐静脉、浅表静脉)且手术简便快捷的目的。1. The raw material composition of the vascular sealing glue provided by the present invention includes 93 to 99.9 parts by weight of n-butyl α-cyanoacrylate, 0.1 to 4.5 parts by weight of a thickener, 1.1 to 2.46*10 -4 parts by weight of an inhibitor, and 0 to 3*10 -4 parts of a dye, wherein the thickener is at least one of cellulose acetate butyrate with a weight average molecular weight of 30,000 to 60,000, polylactic acid with a weight average molecular weight of 60,000 to 80,000, and polymethyl methacrylate with a weight average molecular weight of 350,000 to 500,000. The inventors have found that the above-mentioned specific thickener not only has a thickening effect, but also has a good plasticizing effect, which can improve the viscosity of the blood vessel closure glue and enhance its flexibility after film formation; by increasing the content of n-butyl α-cyanoacrylate and adding an appropriate amount of thickener, the product can have a greater adhesive strength and can be directly injected with a needle less than 30G while ensuring the viscosity and curing speed of the product, thereby solving the defect that the current marketed product (n-butyl α-cyanoacrylate) cannot be used for superficial veins. This is because, unlike the great saphenous vein, which is straight, long and large in diameter and suitable for catheter intervention, the superficial vein is short and has a large diameter. The vascular closure glue is tortuous and has a small diameter. Once varicose veins occur, they will appear as earthworm-like masses. It is impossible to use catheter intervention technology to treat earthworm-like masses in superficial veins. In addition, because the action environment of vascular closure glue is different from that of surgical adhesives acting on the wound surface, the vascular closure glue will be affected by hemodynamics after entering the target position in the blood vessel. If the viscosity is too low or the curing is too slow, it may cause the adhesive to migrate and cause ectopic embolism. Therefore, the vascular closure glue provided by the present invention comprehensively considers the application environment, mode of action, operation method and other characteristics of the vascular closure glue, and can balance the product's closing effect, tissue thermal damage, mobility, and ease of operation. In addition, in order to ensure the effectiveness, safety, and stability of the product, an appropriate amount of inhibitor is added to give the product a suitable curing speed and shelf life. The above three components work together to make the vascular closure glue of the present invention have both high adhesion strength and low viscosity. It has good strength and flexibility, and at the same time has suitable viscosity, curing speed and stability. It can be directly injected with a needle smaller than 30G to achieve the purpose of treating varicose veins of the lower limbs (great saphenous vein, superficial vein) with simple and quick surgery.
本发明的血管闭合胶可以直接使用小于30G针头注射，满足了临床对浅表静脉曲张的治疗的需求，亦可适用于大隐静脉静脉曲张的治疗，即通过非血管腔内热消融的微创导管介入治疗下肢大隐静脉曲张；直接注射治疗，极大地简化了手术操作，同时也能显著降低手术费用，并且对于不适合使用导管输送血管闭合胶的浅表静脉而言，本发明的血管闭合胶因粘度和固化速度适中、便于针头直接注射而特别适于浅表静脉曲张的治疗。The vascular sealing glue of the present invention can be directly injected using a needle of less than 30G, which meets the clinical demand for the treatment of superficial varicose veins, and can also be applied to the treatment of varicose veins of the great saphenous vein, that is, the minimally invasive catheter intervention treatment of varicose veins of the lower limbs by non-intravascular thermal ablation; direct injection treatment greatly simplifies the surgical operation and can also significantly reduce the cost of surgery. Moreover, for superficial veins that are not suitable for the use of catheters to deliver vascular sealing glue, the vascular sealing glue of the present invention is particularly suitable for the treatment of superficial varicose veins because of its moderate viscosity and curing speed and the convenience of direct needle injection.
2.本发明提供的血管闭合胶，采用纯度>98％的α-氰基丙烯酸正丁酯，有利于降低血管闭合胶的聚合热，避免血管闭合胶在聚合固化时因放热量大而对血管带来损伤。2. The vascular sealing glue provided by the present invention uses α-cyanoacrylate n-butyl ester with a purity of >98%, which is beneficial to reducing the polymerization heat of the vascular sealing glue and avoiding damage to the blood vessels due to large heat release during polymerization and curing of the vascular sealing glue.
3.本发明提供的血管闭合胶中的阻聚剂，包括自由基阻聚剂1～2*10-4重量份和酸性阻聚剂0.1～0.46*10-4重量份。通过添加阻聚剂，可以有效防止血管闭合胶在货架期内发生聚合，以提高血管闭合胶的储存稳定性，确保血管闭合胶主体在施用到人体之前一直处于液体状态。发明人发现，将自由基阻聚剂和酸性阻聚剂按照上述特定比例复配，能够在保证产品有效性的前提下，使得本发明的血管闭合胶具有很好的生物相容性，保证临床使用的安全性。3. The polymerization inhibitor in the vascular sealing glue provided by the present invention comprises 1 to 2*10 -4 parts by weight of a free radical polymerization inhibitor and 0.1 to 0.46*10 -4 parts by weight of an acidic polymerization inhibitor. By adding the polymerization inhibitor, the polymerization of the vascular sealing glue during the shelf life can be effectively prevented to improve the storage stability of the vascular sealing glue and ensure that the main body of the vascular sealing glue is in a liquid state before being applied to the human body. The inventors have found that compounding the free radical polymerization inhibitor and the acidic polymerization inhibitor in the above-mentioned specific ratio can ensure the effectiveness of the product, so that the vascular sealing glue of the present invention has good biocompatibility and ensures the safety of clinical use.
4.本发明提供的血管闭合胶中的染料优选为溶剂蓝和/或溶剂紫。现有技术曾提出向氰基丙烯酸酯类化合物的分子结构中引入显影基团如三碘苯甲酸单元，以便于观察手术情况，但此类显影基团只能在X光或CT下可见，这就对手术条件有较高要求。同时，发明人还考虑到在目前的导管介入手术中，需要预注闭合胶至导管近端或前端，因导管透明，无色液体在导管内推注时，不易观察及控制推注位置，易推注出导管前端，这样在导管进入血管时，前端留置闭合胶迅速凝固，引起堵管，操作失败，其次，术中所需药品都是无色，医生需要花时间区分辨认，存在误用的风险，故而本发明的血管闭合胶中添加的是肉眼可见的染料，一方面可便于医生观察手术情况，另一方面还 可以防止医生误用，提高手术的便利性，且降低操作时与药物或显影剂混淆的风险。4. The dye in the vascular sealing glue provided by the present invention is preferably solvent blue and/or solvent violet. The prior art has proposed to introduce developing groups such as triiodobenzoic acid units into the molecular structure of cyanoacrylate compounds to facilitate observation of surgical conditions, but such developing groups can only be seen under X-rays or CT, which places high demands on surgical conditions. At the same time, the inventors also considered that in current catheter interventional surgeries, it is necessary to pre-inject the sealing glue to the proximal or front end of the catheter. Because the catheter is transparent, it is difficult to observe and control the injection position when the colorless liquid is injected into the catheter, and it is easy to push out the front end of the catheter. In this way, when the catheter enters the blood vessel, the sealing glue retained at the front end will solidify rapidly, causing tube blockage and operation failure. Secondly, the drugs required during the operation are all colorless, and doctors need to spend time distinguishing and identifying them, which poses a risk of misuse. Therefore, the vascular sealing glue of the present invention adds a dye visible to the naked eye. On the one hand, it is convenient for doctors to observe the surgical conditions, and on the other hand, it can also It can prevent doctors from misusing it, improve the convenience of surgery, and reduce the risk of confusion with drugs or contrast agents during operation.
另外，本发明提供的血管闭合胶装于西林瓶内，外加铝塑组合盖密封，其密封性好，提高产品的储存有效期，且具有使用注射器进行抽吸的便利优点。In addition, the blood vessel sealing glue provided by the present invention is packed in a vial and sealed with an aluminum-plastic composite cover, which has good sealing performance, improves the storage validity period of the product, and has the advantage of being convenient for aspiration using a syringe.
5.本发明提供的血管闭合胶的制备方法，通过将α-氰基丙烯酸正丁酯与阻聚剂和染料混合，搅拌溶解，再缓慢加入增稠剂，搅拌溶解，即可制得质量均一的血管闭合胶。本发明的制备方法工艺步骤简单，便于操作，适于医用植入级材料的大规模生产。5. The preparation method of the vascular sealing glue provided by the present invention comprises mixing α-cyanoacrylate n-butyl with an inhibitor and a dye, stirring to dissolve, and then slowly adding a thickener, stirring to dissolve, so as to obtain a vascular sealing glue with uniform quality. The preparation method of the present invention has simple process steps, is easy to operate, and is suitable for large-scale production of medical implant-grade materials.
具体实施方式Detailed ways
提供下述实施例是为了更好地进一步理解本发明，并不局限于所述最佳实施方式，不对本发明的内容和保护范围构成限制，任何人在本发明的启示下或是将本发明与其他现有技术的特征进行组合而得出的任何与本发明相同或相近似的产品，均落在本发明的保护范围之内。The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.
在本发明的实施例中所用的试剂如下：The reagents used in the embodiments of the present invention are as follows:
α-氰基丙烯酸正丁酯：CAS#6606-65-1，纯度>98％，其余为阻聚剂、甲醛、正丁醇、α-氰乙酸正丁酯、水分等杂质，这些杂质的种类和含量对本发明的影响可忽略不计。α-Butyl cyanoacrylate: CAS#6606-65-1, purity>98%, the rest are impurities such as inhibitor, formaldehyde, n-butanol, α-butyl cyanoacetate, moisture, etc., and the types and contents of these impurities have negligible effects on the present invention.
α-氰基丙烯酸正丁酯：CAS#6606-65-1，纯度95％，其余为阻聚剂、甲醛、正丁醇、α-氰乙酸正丁酯、水分等杂质，这些杂质的种类和含量对本发明的影响可忽略不计。α-Butyl cyanoacrylate: CAS#6606-65-1, purity 95%, the rest are impurities such as inhibitor, formaldehyde, n-butanol, α-butyl cyanoacetate, moisture, etc., and the types and contents of these impurities have negligible effects on the present invention.
醋酸丁酸纤维素：CAS#9004-36-8，重均分子量3万～6万，购于上海麦克林生化科技股份有限公司。Cellulose acetate butyrate: CAS#9004-36-8, weight average molecular weight 30,000-60,000, purchased from Shanghai MacLean Biochemical Technology Co., Ltd.
聚乳酸：CAS#51056-13-9，重均分子量6万～8万，粒径3mm，购于上海麦克林生化科技股份有限公司。Polylactic acid: CAS#51056-13-9, weight average molecular weight 60,000-80,000, particle size 3 mm, purchased from Shanghai MacLean Biochemical Technology Co., Ltd.
聚甲基丙烯酸甲酯：CAS#9011-14-7，重均分子量35万～50万，购于上海 麦克林生化科技股份有限公司、罗姆化学(上海)有限公司。Polymethyl methacrylate: CAS#9011-14-7, weight average molecular weight 350,000-500,000, purchased from Shanghai McLean Biochemical Technology Co., Ltd., Rohm Chemical (Shanghai) Co., Ltd.
实施例中未注明具体实验步骤或条件者，按照本领域内的文献所描述的常规实验步骤的操作或条件即可进行。所用试剂或仪器未注明生产厂商者，均为常规试剂，可通过市售获得。If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the art can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagents and can be obtained commercially.
实施例1Example 1
本实施例提供的血管闭合胶的原料组成为：The raw material composition of the vascular sealing glue provided in this embodiment is:
α-氰基丙烯酸正丁酯(纯度>98％)95g，醋酸丁酸纤维素3g，叔丁基对苯二酚0.15mg，三氟化硼0.02mg，以及0.05mg溶剂蓝67。95 g of n-butyl α-cyanoacrylate (purity>98%), 3 g of cellulose acetate butyrate, 0.15 mg of tert-butylhydroquinone, 0.02 mg of boron trifluoride, and 0.05 mg of solvent blue 67.
本实施例提供的血管闭合胶的制备方法，包括如下步骤：The method for preparing the vascular sealing glue provided in this embodiment comprises the following steps:
按上述用量，将α-氰基丙烯酸正丁酯加入到反应器中，在不断搅拌下加入叔丁基对苯二酚和溶剂蓝67，以300rpm的速度搅拌溶解，然后，定量抽取三氟化硼，注入上述反应器中，继续搅拌至混合均匀，而后缓慢并分次加入醋酸丁酸纤维素，以避免结块，添加完毕后持续搅拌3h。检测粘度及固化时间等指标，结果如表1所示，满足要求后装入西林瓶中，密封储存。According to the above dosage, n-butyl α-cyanoacrylate was added to the reactor, tert-butyl hydroquinone and solvent blue 67 were added under constant stirring, and dissolved by stirring at a speed of 300 rpm, then boron trifluoride was quantitatively extracted and injected into the above reactor, and stirring was continued until the mixture was uniform, and then cellulose acetate butyrate was slowly and portionedly added to avoid agglomeration, and stirring was continued for 3 hours after the addition was completed. The viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, the mixture was placed in a vial and sealed for storage.
实施例2Example 2
本实施例提供的血管闭合胶的原料组成为：The raw material composition of the vascular sealing glue provided in this embodiment is:
α-氰基丙烯酸正丁酯(纯度>98％)96g，醋酸丁酸纤维素2g，丁基羟基茴香醚0.13mg，三氟化硼0.01mg，以及0.2mg溶剂蓝67。96 g of n-butyl α-cyanoacrylate (purity>98%), 2 g of cellulose acetate butyrate, 0.13 mg of butylated hydroxyanisole, 0.01 mg of boron trifluoride, and 0.2 mg of solvent blue 67.
本实施例提供的血管闭合胶的制备方法，包括如下步骤：The method for preparing the vascular sealing glue provided in this embodiment comprises the following steps:
按上述用量，将α-氰基丙烯酸正丁酯加入到反应器中，在不断搅拌下加入丁基羟基茴香醚和溶剂蓝67，以200rpm的速度搅拌溶解，然后，定量抽取三氟化硼，注入上述反应器中，继续搅拌至混合均匀，而后缓慢并分次加入醋酸丁酸纤维素，以避免结块，添加完毕后持续搅拌5h。检测粘度及固化时间等指标，结果如表1所示，满足要求后装入西林瓶中，密封储存。According to the above dosage, n-butyl α-cyanoacrylate was added to the reactor, butyl hydroxyanisole and solvent blue 67 were added under constant stirring, and dissolved by stirring at a speed of 200 rpm, then boron trifluoride was quantitatively extracted and injected into the above reactor, and stirring was continued until the mixture was uniform, and then cellulose acetate butyrate was slowly and portionwise added to avoid agglomeration, and stirring was continued for 5 hours after the addition was completed. The viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, the mixture was placed in a vial and sealed for storage.
实施例3Example 3
本实施例提供的血管闭合胶的原料组成为：The raw material composition of the vascular sealing glue provided in this embodiment is:
α-氰基丙烯酸正丁酯(纯度>98％)97g，聚甲基丙烯酸甲酯3.5g，对苯二 酚0.18mg，磷酸0.03mg，以及0.1mg溶剂蓝97。α-Butyl cyanoacrylate (purity> 98%) 97g, polymethyl methacrylate 3.5g, terephthalate Phenol 0.18 mg, phosphoric acid 0.03 mg, and solvent blue 97 0.1 mg.
本实施例提供的血管闭合胶的制备方法，包括如下步骤：The method for preparing the vascular sealing glue provided in this embodiment comprises the following steps:
按上述用量，将α-氰基丙烯酸正丁酯加入到反应器中，在不断搅拌下加入对苯二酚、磷酸和溶剂蓝97，以100rpm的速度搅拌溶解，而后缓慢并分次加入聚甲基丙烯酸甲酯，以避免结块，添加完毕后持续搅拌6h。检测粘度及固化时间等指标，结果如表1所示，满足要求后装入西林瓶中，密封储存。According to the above dosage, α-cyanoacrylate n-butyl ester was added to the reactor, and hydroquinone, phosphoric acid and solvent blue 97 were added under constant stirring, and dissolved by stirring at a speed of 100 rpm, and then polymethyl methacrylate was slowly and added in portions to avoid agglomeration. After the addition was completed, stirring was continued for 6 hours. The viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, it was placed in a vial and sealed for storage.
实施例4Example 4
本实施例提供的血管闭合胶的原料组成为：The raw material composition of the vascular sealing glue provided in this embodiment is:
α-氰基丙烯酸正丁酯(纯度>98％)98g，醋酸丁酸纤维素4g，间苯二酚0.16mg，对甲苯磺酸0.04mg，以及0.3mg溶剂蓝97。98 g of n-butyl α-cyanoacrylate (purity>98%), 4 g of cellulose acetate butyrate, 0.16 mg of resorcinol, 0.04 mg of p-toluenesulfonic acid, and 0.3 mg of solvent blue 97.
本实施例提供的血管闭合胶的制备方法，包括如下步骤：The method for preparing the vascular sealing glue provided in this embodiment comprises the following steps:
按上述用量，将α-氰基丙烯酸正丁酯加入到反应器中，在不断搅拌下加入间苯二酚、对甲苯磺酸和溶剂蓝97，以400rpm的速度搅拌溶解，而后缓慢并分次加入醋酸丁酸纤维素，以避免结块，添加完毕后持续搅拌10h。检测粘度及固化时间等指标，结果如表1所示，满足要求后装入西林瓶中，密封储存。According to the above dosage, n-butyl α-cyanoacrylate was added to the reactor, and resorcinol, p-toluenesulfonic acid and solvent blue 97 were added under constant stirring, and dissolved by stirring at a speed of 400 rpm, and then cellulose acetate butyrate was added slowly and in portions to avoid agglomeration, and stirring was continued for 10 hours after the addition was completed. The viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, it was placed in a vial and sealed for storage.
实施例5Example 5
本实施例提供的血管闭合胶的原料组成为：The raw material composition of the vascular sealing glue provided in this embodiment is:
α-氰基丙烯酸正丁酯(纯度>98％)96.5g，醋酸丁酸纤维素4.5g，丁基羟基茴香醚0.2mg，植酸0.025mg，以及0.15mg溶剂紫D&C VIOLET NO.2。96.5g of n-butyl α-cyanoacrylate (purity >98%), 4.5g of cellulose acetate butyrate, 0.2mg of butyl hydroxyanisole, 0.025mg of phytic acid, and 0.15mg of solvent violet D&C VIOLET NO.2.
本实施例提供的血管闭合胶的制备方法，包括如下步骤：The method for preparing the vascular sealing glue provided in this embodiment comprises the following steps:
按上述用量，将α-氰基丙烯酸正丁酯加入到反应器中，在不断搅拌下加入丁基羟基茴香醚、植酸和溶剂紫，以500rpm的速度搅拌溶解，而后缓慢并分次加入醋酸丁酸纤维素，以避免结块，添加完毕后持续搅拌12h。检测粘度及固化时间等指标，结果如表1所示，满足要求后装入西林瓶中，密封储存。According to the above dosage, n-butyl α-cyanoacrylate was added to the reactor, butyl hydroxyanisole, phytic acid and solvent violet were added under constant stirring, and dissolved by stirring at a speed of 500 rpm, and then cellulose acetate butyrate was added slowly and in portions to avoid agglomeration, and stirring was continued for 12 hours after the addition was completed. The viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, it was placed in a vial and sealed for storage.
实施例6Example 6
本实施例提供的血管闭合胶的原料组成为： The raw material composition of the vascular sealing glue provided in this embodiment is:
α-氰基丙烯酸正丁酯(纯度>98％)97g，聚甲基丙烯酸甲酯2g，对苯二酚0.1mg，苯磺酸0.046mg，以及0.25mg溶剂紫D&C VIOLET NO.2。97g of n-butyl α-cyanoacrylate (purity >98%), 2g of polymethyl methacrylate, 0.1mg of hydroquinone, 0.046mg of benzenesulfonic acid, and 0.25mg of solvent violet D&C VIOLET NO.2.
本实施例提供的血管闭合胶的制备方法，包括如下步骤：The method for preparing the vascular sealing glue provided in this embodiment comprises the following steps:
按上述用量，将α-氰基丙烯酸正丁酯加入到反应器中，在不断搅拌下加入对苯二酚、苯磺酸和溶剂紫，以300rpm的速度搅拌溶解，而后缓慢并分次加入聚甲基丙烯酸甲酯，以避免结块，添加完毕后持续搅拌8h。检测粘度及固化时间等指标，结果如表1所示，满足要求后装入西林瓶中，密封储存。According to the above dosage, α-cyanoacrylate n-butyl ester was added to the reactor, and hydroquinone, benzenesulfonic acid and solvent violet were added under constant stirring, and dissolved by stirring at a speed of 300 rpm, and then polymethyl methacrylate was slowly and added in portions to avoid agglomeration, and stirring was continued for 8 hours after the addition was completed. The viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, it was put into a vial and sealed for storage.
实施例7Example 7
本实施例提供的血管闭合胶的原料组成为：The raw material composition of the vascular sealing glue provided in this embodiment is:
α-氰基丙烯酸正丁酯(纯度>98％)99.9g，聚甲基丙烯酸甲酯2.5g，对苯二酚0.14mg，三氟化硼0.01mg，以及0.1mg溶剂蓝97。99.9 g of n-butyl α-cyanoacrylate (purity>98%), 2.5 g of polymethyl methacrylate, 0.14 mg of hydroquinone, 0.01 mg of boron trifluoride, and 0.1 mg of solvent blue 97.
本实施例提供的血管闭合胶的制备方法，包括如下步骤：The method for preparing the vascular sealing glue provided in this embodiment comprises the following steps:
按上述用量，将α-氰基丙烯酸正丁酯加入到反应器中，在不断搅拌下加入对苯二酚和溶剂蓝97，以250rpm的速度搅拌溶解，然后，定量抽取三氟化硼，注入上述反应器中，继续搅拌至混合均匀，而后缓慢并分次加入聚甲基丙烯酸甲酯，以避免结块，添加完毕后持续搅拌5h。检测粘度及固化时间等指标，结果如表1所示，满足要求后装入西林瓶中，密封储存。According to the above dosage, n-butyl α-cyanoacrylate was added to the reactor, and hydroquinone and solvent blue 97 were added under constant stirring, and dissolved by stirring at a speed of 250 rpm. Then, boron trifluoride was quantitatively extracted and injected into the above reactor, and stirring was continued until the mixture was uniform, and then polymethyl methacrylate was slowly and added in portions to avoid agglomeration. After the addition was completed, stirring was continued for 5 hours. The viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, the mixture was placed in a vial and sealed for storage.
实施例8Example 8
本实施例提供的血管闭合胶的原料组成为：The raw material composition of the vascular sealing glue provided in this embodiment is:
α-氰基丙烯酸正丁酯(纯度>98％)95g，聚乳酸4.5g，间苯二酚0.17mg，磷酸0.035mg，以及0.2mg溶剂紫D&C VIOLET NO.2。95g of n-butyl α-cyanoacrylate (purity>98%), 4.5g of polylactic acid, 0.17mg of resorcinol, 0.035mg of phosphoric acid, and 0.2mg of solvent violet D&C VIOLET NO.2.
本实施例提供的血管闭合胶的制备方法，包括如下步骤：The method for preparing the vascular sealing glue provided in this embodiment comprises the following steps:
按上述用量，将α-氰基丙烯酸正丁酯加入到反应器中，在不断搅拌下加入间苯二酚、磷酸和溶剂紫，以350rpm的速度搅拌溶解，而后缓慢并分次加入聚乳酸，以避免结块，添加完毕后持续搅拌6h。检测粘度及固化时间等指标，结果如表1所示，满足要求后装入西林瓶中，密封储存。According to the above dosage, α-cyanoacrylate n-butyl ester was added to the reactor, and resorcinol, phosphoric acid and solvent violet were added under constant stirring, and dissolved by stirring at a speed of 350 rpm, and then polylactic acid was slowly added in portions to avoid agglomeration, and stirring was continued for 6 hours after the addition was completed. The viscosity and curing time and other indicators were tested, and the results are shown in Table 1. After meeting the requirements, it was put into a vial and sealed for storage.
实施例9 Example 9
除以下内容外，其余内容与实施例3相同。Except for the following contents, the rest is the same as Example 3.
采用等质量的纯度为95％的α-氰基丙烯酸正丁酯代替实施例3中的α-氰基丙烯酸正丁酯。The n-butyl α-cyanoacrylate in Example 3 was replaced by n-butyl α-cyanoacrylate of the same mass and purity of 95%.
实施例10Example 10
除以下内容外，其余内容与实施例3相同。Except for the following contents, the rest is the same as Example 3.
采用对苯二酚0.21mg代替实施例3中的对苯二酚0.18mg和磷酸0.03mg。0.21 mg of hydroquinone was used to replace 0.18 mg of hydroquinone and 0.03 mg of phosphoric acid in Example 3.
实施例11Embodiment 11
除以下内容外，其余内容与实施例3相同。Except for the following contents, the rest is the same as Example 3.
采用磷酸0.21mg代替实施例3中的对苯二酚0.18mg和磷酸0.03mg。0.21 mg of phosphoric acid was used to replace 0.18 mg of hydroquinone and 0.03 mg of phosphoric acid in Example 3.
实施例12Example 12
本实施例提供的血管闭合胶的原料组成为：α-氰基丙烯酸正丁酯(纯度>98％)93g，聚甲基丙烯酸甲酯4.5g，对苯二酚0.18mg，磷酸0.03mg，以及0.1mg溶剂蓝97。The raw material composition of the vascular sealing glue provided in this embodiment is: 93g of n-butyl α-cyanoacrylate (purity>98%), 4.5g of polymethyl methacrylate, 0.18mg of hydroquinone, 0.03mg of phosphoric acid, and 0.1mg of solvent blue 97.
制备方法同实施例3。The preparation method is the same as Example 3.
实施例13Example 13
本实施例提供的血管闭合胶的原料组成为：α-氰基丙烯酸正丁酯(纯度>98％)95g，聚甲基丙烯酸甲酯1.5g，对苯二酚0.18mg，磷酸0.03mg，以及0.1mg溶剂蓝97。The raw material composition of the vascular sealing glue provided in this embodiment is: 95g of n-butyl α-cyanoacrylate (purity>98%), 1.5g of polymethyl methacrylate, 0.18mg of hydroquinone, 0.03mg of phosphoric acid, and 0.1mg of solvent blue 97.
制备方法同实施例3。The preparation method is the same as Example 3.
实施例14Embodiment 14
本实施例提供的血管闭合胶的原料组成为：α-氰基丙烯酸正丁酯(纯度>98％)94g，聚甲基丙烯酸甲酯0.1g，对苯二酚0.18mg，磷酸0.03mg，以及0.1mg溶剂蓝97。The raw material composition of the vascular sealing glue provided in this embodiment is: 94g of n-butyl α-cyanoacrylate (purity>98%), 0.1g of polymethyl methacrylate, 0.18mg of hydroquinone, 0.03mg of phosphoric acid, and 0.1mg of solvent blue 97.
制备方法同实施例3。The preparation method is the same as Example 3.
对比例1Comparative Example 1
除以下内容外，其余内容与实施例3相同。Except for the following contents, the rest is the same as Example 3.
采用等质量的阿拉伯胶代替聚甲基丙烯酸甲酯作为增稠剂。 An equal amount of gum arabic is used as the thickener instead of polymethyl methacrylate.
对比例2Comparative Example 2
本对比例提供的血管闭合胶的原料组成为：α-氰基丙烯酸正丁酯(纯度>98％)92g，聚甲基丙烯酸甲酯4.5g，对苯二酚0.18mg，磷酸0.03mg，以及0.1mg溶剂蓝97。The raw material composition of the vascular sealing glue provided in this comparative example is: 92g of n-butyl α-cyanoacrylate (purity>98%), 4.5g of polymethyl methacrylate, 0.18mg of hydroquinone, 0.03mg of phosphoric acid, and 0.1mg of solvent blue 97.
制备方法同实施例3。The preparation method is the same as Example 3.
对比例3Comparative Example 3
本对比例提供的血管闭合胶的原料组成为：α-氰基丙烯酸正丁酯(纯度>98％)94.5g，聚甲基丙烯酸甲酯6g，对苯二酚0.18mg，磷酸0.03mg，以及0.1mg溶剂蓝97。The raw material composition of the vascular sealing glue provided in this comparative example is: 94.5g of n-butyl α-cyanoacrylate (purity>98%), 6g of polymethyl methacrylate, 0.18mg of hydroquinone, 0.03mg of phosphoric acid, and 0.1mg of solvent blue 97.
制备方法同实施例3。The preparation method is the same as Example 3.
对比例4Comparative Example 4
除以下内容外，其余内容与实施例3相同。Except for the following contents, the rest is the same as Example 3.
采用等质量的重均分子量为30～33万的聚甲基丙烯酸甲酯(购自罗姆化学有限公司)代替实施例3中的聚甲基丙烯酸甲酯作为增稠剂。An equal amount of polymethyl methacrylate with a weight average molecular weight of 300,000 to 330,000 (purchased from Rohm Chemical Co., Ltd.) was used as a thickener instead of the polymethyl methacrylate in Example 3.
对比例5Comparative Example 5
除以下内容外，其余内容与实施例2相同。Except for the following contents, the rest is the same as Example 2.
采用等质量的重均分子量为7～10万的醋酸丁酸纤维素(购自上海麦克林生化科技股份有限公司)代替实施例2中的醋酸丁酸纤维素作为增稠剂。An equal amount of cellulose acetate butyrate with a weight average molecular weight of 70,000 to 100,000 (purchased from Shanghai MacLean Biochemical Technology Co., Ltd.) was used as a thickener instead of the cellulose acetate butyrate in Example 2.
对比例6Comparative Example 6
除以下内容外，其余内容与实施例8相同。Except for the following contents, the rest is the same as Example 8.
采用等质量的重均分子量为2～5万的聚乳酸(购自上海麦克林生化科技股份有限公司)代替实施例8中的聚乳酸作为增稠剂。An equal amount of polylactic acid with a weight average molecular weight of 20,000 to 50,000 (purchased from Shanghai MacLean Biochemical Technology Co., Ltd.) was used as a thickener instead of the polylactic acid in Example 8.
对比例7Comparative Example 7
美敦力公司的VenaSeal静脉闭合胶。Medtronic's VenaSeal venous closure sealant.
实验例Experimental example
分别采用下述方法，对本发明实施例1～14及对比例1～7提供的血管闭合胶进行性能测试，结果如表1所示。 The following methods were used to test the performance of the vascular sealing adhesives provided in Examples 1 to 14 of the present invention and Comparative Examples 1 to 7. The results are shown in Table 1.
(1)粘度(1) Viscosity
参考2020版《中华人民共和国药典》四部通则0633黏度测定法(第三法旋转黏度计测定法)的试验方法进行。Refer to the test method of Viscosity Determination Method (Method 3 Rotational Viscometer Determination Method) in Part IV General Chapter 0633 of the 2020 edition of the Pharmacopoeia of the People's Republic of China.
(2)固化时间(2) Curing time
在直径为90mm的平皿中，加入0.3g/L的NaHCO3溶液50mL(现配制)，吸取一滴血管闭合胶，并在距液面1cm处滴下一滴，记录从边缘开始至完全固化成膜的时间，即为固化时间。In a 90 mm diameter dish, add 50 mL of 0.3 g/L NaHCO 3 solution (prepared freshly), draw a drop of vascular sealing glue, and drop a drop 1 cm from the liquid surface. Record the time from the edge to the complete solidification of the film, which is the solidification time.
(3)柔韧性(3) Flexibility
与固化时间合并开展试验，在完成固化时间的样品制备后，用玻璃棒从水中任意位置挑起固化膜片，若膜片能挑起，且挑起弯折后无断裂，评为优；若膜片能挑起，且挑起后弯折后有裂纹，评为较优；若膜片能挑起，且挑起后弯折后断裂，评为中；若膜片挑起后破裂，评为差。The test is carried out in combination with the curing time. After completing the sample preparation for the curing time, use a glass rod to pick up the cured membrane from any position in the water. If the membrane can be picked up and there is no breakage after being bent after being picked up, it is rated as excellent; if the membrane can be picked up and there are cracks after being bent after being picked up, it is rated as relatively good; if the membrane can be picked up and breaks after being bent after being picked up, it is rated as medium; if the membrane breaks after being picked up, it is rated as poor.
(4)聚合热(4) Heat of polymerization
按照GB/T 19466.1-2004的试验方法进行。Carry out according to the test method of GB/T 19466.1-2004.
(5)拉伸强度(5) Tensile strength
参考标准YY/T 0729.3-2009组织血管闭合胶粘接性能试验方法第3部分：拉伸强度。Reference standard YY/T 0729.3-2009 Test method for adhesive properties of tissue vascular sealing adhesives Part 3: Tensile strength.
(6)闭合强度(6) Closure strength
参考标准YY/T 0729.4-2009组织血管闭合胶粘接性能试验方法第4部分：闭合强度。Reference standard YY/T 0729.4-2009 Test method for adhesive properties of tissue vascular closure adhesives Part 4: Closure strength.
(7)细胞毒性(7) Cytotoxicity
参考标准GB/T 16886.5-2017方法进行。Refer to the standard GB/T 16886.5-2017 method.
(8)稳定性(8) Stability
将血管闭合胶产品于82℃下加速老化7天后，观察血管闭合胶有无明显增稠现象。After the vascular sealing glue product was aged at 82°C for 7 days, the vascular sealing glue was observed to see if there was any obvious thickening.
(9)推注(9) Push injection
使用1mL注射器吸取一定量的血管闭合胶，若通过30G针头正常推出， 无明显阻力，且推出液体呈线状，判定为可推注；否则判定为不可推注。Use a 1mL syringe to draw a certain amount of vascular sealing glue. If it is pushed out normally through a 30G needle, If there is no obvious resistance and the liquid is pushed out in a linear shape, it is judged to be injectable; otherwise, it is judged to be not injectable.
在使用1mL注射器和30G针头时，过大的推注力仍无法使推出的液体呈线状，还存在导致针头脱落的风险。When using a 1mL syringe and a 30G needle, excessive injection force still cannot make the pushed liquid into a linear shape, and there is also a risk of causing the needle to fall off.
表1血管闭合胶的性能测试结果
Table 1 Performance test results of vascular sealing glue
说明：表1中“/”表示未测试。Note: “/” in Table 1 means not tested.
由此可见，本发明提供的血管闭合胶(实施例1～14)具有粘度适中、固化速度可控、柔韧性好、聚合热低、力学性能优异且生物相容性高等优点，具体如下：It can be seen that the vascular sealing glue (Examples 1 to 14) provided by the present invention has the advantages of moderate viscosity, controllable curing speed, good flexibility, low polymerization heat, excellent mechanical properties and high biocompatibility, as follows:
(1)粘度在10-25mPa·s范围内，适用于大隐静脉与浅静脉的粘合，可 用注射器通过小于30G针头直接注射，操作简单，大大节约手术时间；(1) The viscosity is in the range of 10-25mPa·s, which is suitable for bonding the great saphenous vein and the superficial vein. Direct injection with a syringe through a needle smaller than 30G is simple to operate and greatly saves surgical time;
(2)固化时间在25s以内，减少手术中的按压时间，便于操作；(2) The solidification time is within 25 seconds, which reduces the pressing time during surgery and facilitates operation;
(3)柔韧性好，无异物感，无触感；(3) Good flexibility, no foreign body sensation, no tactile sensation;
(4)聚合放热低，聚合热基本在160～200J/g之间，最大限度降低对患者的损伤；(4) The polymerization exotherm is low, and the polymerization heat is basically between 160 and 200 J/g, which minimizes the damage to the patient;
(5)力学性能优异，粘合强度高，闭合强度达到31N以上；(5) Excellent mechanical properties, high bonding strength, and closing strength of more than 31N;
(6)合适的配方以及比例的调配使最终产品的毒性较小，通过MTT测试，无潜在细胞毒性；(6) The appropriate formulation and proportion make the final product less toxic and has no potential cytotoxicity as tested by MTT;
(7)稳定性好，经一段时间老化后无明显增稠现象。(7) Good stability, no obvious thickening after aging for a period of time.
与实施例1～14相比，对比例1采用阿拉伯胶作为增稠剂，无法保证固化成膜后的柔韧性；与实施例13相比，对比例2减少了α-氰基丙烯酸正丁酯的含量，使得血管闭合胶的粘合强度下降，同时导致增稠剂在产品中的占比变大，相应地产品粘度变大，无法通过30G针头推注；与实施例3相比，对比例3增大了增稠剂的含量，使得血管闭合胶的粘合强度下降、粘度明显增大，固化时间明显延长，不能通过30G针头推注，老化后还明显增稠；对比例4～对比例6采用的增稠剂的分子量或大或小，均不能兼顾血管闭合胶的上述性能；对比例7即目前用于临床的静脉闭合胶VenaSeal，固化时间通常为2～3分钟，且其粘度远大于本发明的血管闭合胶，无法使用针头推注。Compared with Examples 1 to 14, Comparative Example 1 uses gum arabic as a thickener, which cannot ensure the flexibility after curing into a film; Compared with Example 13, Comparative Example 2 reduces the content of n-butyl α-cyanoacrylate, which reduces the bonding strength of the vascular sealing glue, and at the same time causes the proportion of the thickener in the product to increase, and the viscosity of the product increases accordingly, and it cannot be injected through a 30G needle; Compared with Example 3, Comparative Example 3 increases the content of the thickener, which reduces the bonding strength of the vascular sealing glue, significantly increases the viscosity, and significantly prolongs the curing time, and it cannot be injected through a 30G needle, and it also thickens significantly after aging; The molecular weight of the thickener used in Comparative Examples 4 to Comparative Examples 6 is large or small, and all cannot take into account the above-mentioned properties of the vascular sealing glue; Comparative Example 7 is VenaSeal, a venous sealing glue currently used in clinical practice, which usually has a curing time of 2 to 3 minutes, and its viscosity is much greater than that of the vascular sealing glue of the present invention, and it cannot be injected using a needle.
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。 Obviously, the above embodiments are merely examples for clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims (10)

  1. 一种血管闭合胶，其特征在于，以重量份数计，所述血管闭合胶的原料组成为：A vascular sealing glue, characterized in that, in parts by weight, the raw materials of the vascular sealing glue are composed of:
    α-氰基丙烯酸正丁酯93～99.9份，增稠剂0.1～4.5份，阻聚剂1.1～2.46*10-4份以及染料0～3*10-4份；93-99.9 parts of n-butyl α-cyanoacrylate, 0.1-4.5 parts of thickener, 1.1-2.46*10 -4 parts of inhibitor and 0-3*10 -4 parts of dye;
    所述增稠剂为醋酸丁酸纤维素、聚乳酸、聚甲基丙烯酸甲酯中的至少一种；所述醋酸丁酸纤维素的重均分子量为3万～6万；The thickener is at least one of cellulose acetate butyrate, polylactic acid, and polymethyl methacrylate; the weight average molecular weight of the cellulose acetate butyrate is 30,000 to 60,000;
    所述聚乳酸的重均分子量为6万～8万；The weight average molecular weight of the polylactic acid is 60,000 to 80,000;
    所述聚甲基丙烯酸甲酯的重均分子量为35万～50万。The weight average molecular weight of the polymethyl methacrylate is 350,000 to 500,000.
  2. 根据权利要求1所述的血管闭合胶，其特征在于，α-氰基丙烯酸正丁酯95～99.9份，增稠剂2～3.5份，阻聚剂1.4～2.1*10-4份以及染料0.5～2.5*10-4份。The vascular sealing glue according to claim 1, characterized in that it comprises 95 to 99.9 parts of n-butyl α-cyanoacrylate, 2 to 3.5 parts of a thickener, 1.4 to 2.1*10 -4 parts of an inhibitor, and 0.5 to 2.5*10 -4 parts of a dye.
  3. 根据权利要求1或2所述的血管闭合胶，其特征在于，所述α-氰基丙烯酸正丁酯的纯度>98％。The vascular sealing glue according to claim 1 or 2, characterized in that the purity of the α-cyanoacrylate is >98%.
  4. 根据权利要求1或2所述的血管闭合胶，其特征在于，所述阻聚剂包括自由基阻聚剂1～2*10-4份和酸性阻聚剂0.1～0.46*10-4份。The vascular sealing glue according to claim 1 or 2, characterized in that the inhibitor comprises 1 to 2*10 -4 parts of free radical inhibitor and 0.1 to 0.46*10 -4 parts of acidic inhibitor.
  5. 根据权利要求4所述的血管闭合胶，其特征在于，所述酸性阻聚剂为三氟化硼、三氟化硼乙醚、二氧化硫、磷酸、植酸、甲磺酸、对甲苯磺酸中的至少一种；和/或，The vascular sealing glue according to claim 4, characterized in that the acidic inhibitor is at least one of boron trifluoride, boron trifluoride ethyl ether, sulfur dioxide, phosphoric acid, phytic acid, methanesulfonic acid, and p-toluenesulfonic acid; and/or,
    所述自由基阻聚剂为丁基羟基茴香醚、叔丁基对苯二酚、对苯二酚、间苯二酚中的至少一种。The free radical inhibitor is at least one of butylated hydroxyanisole, tert-butylhydroquinone, hydroquinone and resorcinol.
  6. 根据权利要求1或2所述的血管闭合胶，其特征在于，所述染料为溶剂蓝和/或溶剂紫。The vascular sealing glue according to claim 1 or 2, characterized in that the dye is solvent blue and/or solvent violet.
  7. 权利要求1～6任一项所述的血管闭合胶的制备方法，其特征在于，包括如下步骤：The method for preparing the vascular sealing glue according to any one of claims 1 to 6, characterized in that it comprises the following steps:
    将α-氰基丙烯酸正丁酯与阻聚剂、染料混合，搅拌溶解，再缓慢加入增稠剂，持续搅拌第一时间。Mix α-cyanoacrylate n-butyl ester with the inhibitor and dye, stir to dissolve, then slowly add the thickener, and continue stirring for the first time.
  8. 根据权利要求7所述的制备方法，其特征在于，所述搅拌的速度为 100～500rpm。The preparation method according to claim 7, characterized in that the stirring speed is 100～500rpm.
  9. 根据权利要求7或8所述的制备方法，其特征在于，所述第一时间为3～12h。The preparation method according to claim 7 or 8, characterized in that the first time is 3 to 12 hours.
  10. 权利要求1～6任一项所述的血管闭合胶或者根据权利要求7～9任一项所述的制备方法制得的血管闭合胶在制备治疗下肢静脉曲张的药物中的应用。 Use of the vascular sealing glue according to any one of claims 1 to 6 or the vascular sealing glue prepared according to the preparation method according to any one of claims 7 to 9 in the preparation of a drug for treating varicose veins of the lower limbs.
PCT/CN2024/071580 2023-01-10 2024-01-10 Blood vessel closing adhesive, preparation method therefor and use thereof WO2024149292A1 (en)

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