CN115364272B - Vascular embolic agent with adjustable softness and preparation method thereof - Google Patents
Vascular embolic agent with adjustable softness and preparation method thereof Download PDFInfo
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- CN115364272B CN115364272B CN202211103999.3A CN202211103999A CN115364272B CN 115364272 B CN115364272 B CN 115364272B CN 202211103999 A CN202211103999 A CN 202211103999A CN 115364272 B CN115364272 B CN 115364272B
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- polyurethane
- cyanoacrylate
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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
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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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
- A61L24/001—Use of materials characterised by their function or physical properties
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Abstract
The invention relates to a vascular embolic agent with adjustable softness and a preparation method thereof, wherein the vascular embolic agent comprises polyurethane, cyanoacrylate, a plasticizer and a stabilizer, the content of the polyurethane is 1-20%, the content of the cyanoacrylate is 80-99%, the content of the plasticizer is 0-20%, and the content of the stabilizer is 0.1-5% by weight. According to the invention, the iodinated polyurethane is added into the vascular embolic agent, so that the embolic agent has a developing effect, and the position is not required to be confirmed through a mark on a catheter during operation; by adjusting the proportion of the iodinated polyurethane and selecting the matched cyanoacrylate, the closure adhesive with different elastic moduli is obtained, and the requirement of adapting surrounding tissues after vascular embolism is met; in addition, polyurethane has little influence on the injection process of medical glue, and the mechanical property of the glue after polymerization is controllable.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a vascular embolic agent with adjustable softness and a preparation method thereof.
Background
Varicose vein of lower limb is a disease with higher incidence rate, and is mainly characterized by expansion, elongation and tortuosity of great saphenous vein of lower limb, and serious complications such as leg ulcer, thrombotic superficial phlebitis and the like are accompanied. There are various treatments for varicose veins of lower limbs according to the progress of the disease, and interventional therapy is currently becoming an important treatment means instead of conventional surgery.
Interventional procedures for treatment of varicose veins include two technical routes, thermal expansion (TT) and non-thermal non-expansion (NTNT). Thermal expansion venous interventional therapy techniques, such as radio frequency and laser ablation, have been widely studied and proven to be effective and safe. Newer non-thermal non-expansion technologies, such as medical glues and mechanochemical ablation, have emerged in recent years and are becoming clinically popular because anesthesia is not required and the skin and peripheral nerves are not at any risk of heat-related damage.
At present, medical glue used for interventional operation is mainly cyanoacrylate glue, the working mechanism of the medical glue is that the medical glue enters a great saphenous vein through a catheter and is injected with glue to cause foreign body reaction, so that the problem of varicose vein induction is solved, but the currently used glue has no developing capability, the position of the glue needs to be confirmed through a mark on the catheter in the process of injecting vascular closure glue, and in addition, the softness of n-butyl cyanoacrylate used by the glue is not completely matched with a blood vessel after forming a polymer, so that a patient has foreign body feeling. The polyurethane elastomer can be prepared by selecting proper soft and hard chain segment structures and the proportion thereof, so that the material with softness and tissue adaptation can be obtained. Polyurethane and cyanoacrylate glue are mixed to prepare the vascular embolism agent, which can meet the requirement of adjustable softness.
Disclosure of Invention
The invention aims to provide a vascular embolic agent with adjustable softness and a preparation method thereof, which are used for solving the problems that glue in the prior art has no developing effect and is easy to cause foreign body sensation to patients.
The vascular embolic agent comprises polyurethane, cyanoacrylate, plasticizer and stabilizer, wherein the polyurethane accounts for 1-20% by weight, the cyanoacrylate accounts for 80-99% by weight, the plasticizer accounts for 0-20% by weight, and the stabilizer accounts for 0.1-5% by weight.
Further, the polyurethane is an iodinated polyurethane, and the molecular weight Mn is 25000-35000.
Further, the plasticizer is one or more of tributyl citrate, acetyl tributyl citrate and ethylene glycol butyl ether.
Further, the stabilizer is one or more of butyl hydroxy anisole, 1,3 propane sultone, acetic acid, p-toluenesulfonic acid and trifluoroacetic acid.
Further, the cyanoacrylate is one or more of n-butyl alpha-cyanoacrylate, n-octyl alpha-cyanoacrylate and sec-octyl alpha-cyanoacrylate.
In another aspect, the present invention provides a method for preparing a vascular embolic agent with adjustable softness, comprising the steps of:
1) Mixing polycaprolactone diol and 1, 4-butyl diisocyanate, adding tetraiodo bisphenol A and N, N-Dimethylformamide (DMF), and stirring at room temperature for reaction for 24 hours to prepare an iodine-containing polyurethane solution;
concentrating by rotary evaporation to adjust the concentration of polyurethane solution, drying overnight at 60deg.C under vacuum to remove residual solvent, and grinding to obtain iodized polyurethane powder;
the mass ratio of the polycaprolactone diol to the 1, 4-butyl diisocyanate to the tetraiodo bisphenol A is as follows: 60:84:22, wherein the mass concentration of the N, N-Dimethylformamide (DMF) solution is 10-15wt%.
2) Mixing the iodized polyurethane powder obtained in the step 1) with n-butyl cyanoacrylate, adding a plasticizer and a stabilizer, stirring and mixing uniformly at room temperature, filling into a sealed glass bottle or ampoule bottle, sterilizing and preserving.
Further, the sterilization method in the step 2) is 160-180 degrees dry heat sterilization or 25kGy Co60 ray sterilization.
The technical scheme of the invention has the beneficial effects that:
according to the invention, the iodinated polyurethane is added into the vascular embolic agent, so that the embolic agent has a developing effect, and the position is not required to be confirmed through a mark on a catheter during operation; by adjusting the proportion of the iodinated polyurethane and selecting the matched cyanoacrylate, the closure adhesive with different elastic moduli is obtained, the requirement of adapting surrounding tissues after vascular embolism is met, and foreign body sensation of a patient is avoided; in addition, the polyurethane has little influence on the injection process of the medical glue, and the mechanical property of the glue after the glue is polymerized is controllable; the preparation method of the vascular embolic agent has stable and reproducible results and can realize mass production.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described in the following in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments.
Example 1
1) 60g of polycaprolactone diol (HO-PCL-OH, molecular weight=2000) was mixed with 84g of butyl 1, 4-diisocyanate (BDI, molecular weight= 140.14), 22g of tetraiodo bisphenol A (IBPA, molecular weight 731.87, containing 60 mmol of hydroxyl groups) and 1.5L of anhydrous N, N-Dimethylformamide (DMF) were added and reacted at room temperature with stirring for 24 hours to prepare an iodine-containing polyurethane solution. Wherein tetraiodo bisphenol a is used as a developing group and a chain extender;
concentration of the polyurethane solution was adjusted using rotary evaporation concentration, residual solvent was removed by drying overnight under vacuum at 60 c, and grinding was performed to obtain an iodinated polyurethane powder having a molecular weight Mn of about 25000 to 35000 as measured by Gel Permeation Chromatography (GPC).
2) 0.1g of iodopolyurethane and 9.9g of n-butyl alpha-cyanoacrylate (NBCA) were mixed, 30mg of Butyl Hydroxy Anisole (BHA), 10mg of trifluoroacetic acid (TFA), 30mg of 1,3 propane sultone were added, stirred uniformly at room temperature, and filled into a sealed glass bottle or ampoule bottle, and sterilized by dry heat at 180℃for 30 minutes.
Example 2
1) Step 1) of example 1;
2) 1g of iodinated polyurethane and 9g of NBCA are mixed, 50mg of BHA,20mg of acetic acid and 50mg of 1,3 propane sultone are added, stirred uniformly at room temperature, filled into a sealed glass bottle or ampoule bottle and sterilized by 25kGy Co60 rays.
Example 3
1) Step 1) of example 1;
2) 2g of iodinated polyurethane and 8g of NBCA are mixed, 50mg of BHA,10mg of p-toluenesulfonic acid and 50mg of 1,3 propane sultone are added, stirred uniformly at room temperature, filled into a sealed glass bottle or ampoule bottle and sterilized by 25kGy Co60 rays.
Example 4
1) Step 1) of example 1;
2) 2g of iodinated polyurethane, 4g of NBCA, 4g of sec-octyl alpha-cyanoacrylate (2-OCA) were mixed, 0.5g of acetyl tributyl citrate was added, 0.15g of ethylene glycol butyl ether, 50mg of BHA was added, stirred uniformly at room temperature, filled into a sealed glass bottle or ampoule bottle, and sterilized by 25kGy of Co60 radiation.
Example 5
1) Step 1) of example 1;
2) 1g of iodopolyurethane and 8g of NBCA are mixed, 1g of tributyl acetylcitrate is added, 50mg of BHA,10mg of trifluoroacetic acid (TFA) and 50mg of 1,3 propane sultone are added, stirred uniformly at room temperature, filled into a sealed glass bottle or ampoule bottle and sterilized by 25kGy Co60 rays.
Example 6
1) Step 1) of example 1;
2) 2g of iodinated polyurethane and 8g of 2-OCA are mixed, 30mgBHA is added, stirred uniformly at room temperature, filled into a sealed glass bottle or ampoule bottle, and sterilized by 25kGy Co60 rays.
Example 7
1) Step 1) of example 1;
2) 2g of iodinated polyurethane, 8g of n-octyl alpha-cyanoacrylate (NOCA) were mixed, 30mgBHA was added, stirred well at room temperature, filled into a sealed glass bottle or ampoule, and sterilized by 25kGy Co60 rays.
Comparative example 1
8g of NBCA is taken, 2g of tributyl citrate and 20mg of BHA are added, stirred uniformly at room temperature, and filled into a sealed glass bottle or ampoule bottle, and sterilized by dry heat at 180 ℃ for 30 minutes. Hydroquinone and p-methoxyphenol have been added to the cyanoacrylate starting materials to promote thermal stability.
The samples of the above examples and comparative examples were tested for sample viscosity, stability before and after sterilization, and blend cure time with simulated plasma, softness after cure.
Viscosity measurement: sampling the sample with a vertebral plate viscometer or a rotary viscometer to measure viscosity; stability before and after sterilization: comparing the difference between the color and viscosity of the sample before and after sterilization, the smaller the change, the higher the stability; evaluation of cure time and softness: the simulated plasma was placed in a 37 ℃ water bath, the samples prepared in each example and comparative example were injected into the liquid using a syringe, and the time for the glue to cure (loss of clarity) was recorded using a stopwatch; the solidified glue solution can be fished out for observation, and the softness is judged according to repeated bending conditions.
The test results are shown in the following table:
| sample viscosity (cps) | Stability of | Curing time(s) | Softness on curing | |
| Example 1 | 20-40 | +++ | 120-180 | + |
| Example 2 | 200-300 | +++ | 120-180 | ++ |
| Example 3 | 800-1000 | +++ | 60-120 | +++ |
| Example 4 | 1200-1400 | +++ | 80-140 | ++++ |
| Example 5 | 1200-1400 | +++ | 80-140 | ++++ |
| Example 6 | 1500-2000 | ++ | 120-180 | +++ |
| Example 7 | 1500-2000 | ++ | 120-180 | +++ |
| Comparative example 1 | 5-10 | +++ | 40-80 | ++ |
From the detection results, the samples obtained in examples 4 and 5 have better performance, proper viscosity and stability, and better curing softness; the sample obtained in example 1 with a small amount of the iodinated polyurethane and comparative example 1 without the addition of the iodinated polyurethane had poor curing softness, resulting in a foreign body sensation to the patient; examples 6 and 7 are suitable for the case where the viscosity requirement is high.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (2)
1. The vascular embolic agent with adjustable softness is characterized by comprising polyurethane, cyanoacrylate, a plasticizer and a stabilizer, wherein the content of the polyurethane is 1-20%, the content of the cyanoacrylate is 80-99%, the content of the plasticizer is 0-20%, and the content of the stabilizer is 0.1-5% by weight; the polyurethane is iodized polyurethane polymerized by polycaprolactone diol, 1, 4-diisobutyl cyanate and tetraiodo bisphenol A, and the molecular weight Mn is 25000-35000; the plasticizer is one or more of tributyl citrate, acetyl tributyl citrate and ethylene glycol butyl ether; the stabilizer is one or more of butyl hydroxy anisole, 1, 3-propane sultone, acetic acid, p-toluenesulfonic acid and trifluoroacetic acid; the cyanoacrylate is one or more of alpha-n-butyl cyanoacrylate, alpha-n-octyl cyanoacrylate and alpha-sec-octyl cyanoacrylate.
2. The preparation method of the vascular embolic agent with adjustable softness is characterized by comprising the following steps:
1) Mixing polycaprolactone diol and 1, 4-butyl diisocyanate, adding tetraiodo bisphenol A and N, N-Dimethylformamide (DMF), and stirring at room temperature for reaction for 24 hours to prepare an iodine-containing polyurethane solution;
concentrating by rotary evaporation to adjust the concentration of polyurethane solution, drying overnight at 60deg.C under vacuum to remove residual solvent, and grinding to obtain iodized polyurethane powder;
the mass ratio of the polycaprolactone diol to the 1, 4-butyl diisocyanate to the tetraiodo bisphenol A is as follows: 60:84:22, wherein the mass concentration of the N, N-Dimethylformamide (DMF) solution is 10-15wt%;
2) Mixing the iodized polyurethane powder obtained in the step 1) with n-butyl cyanoacrylate, adding a plasticizer and a stabilizer, stirring and mixing uniformly at room temperature, filling into a sealed glass bottle or ampoule bottle for sterilization and preserving; the sterilization method in the step 2) is 160-180 DEG dry heat sterilization or 25kGy Co60 ray sterilization.
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| GB1182416A (en) * | 1966-05-17 | 1970-02-25 | Ici Ltd | Improved Coating and Adhesive Compositions |
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| US7687053B2 (en) * | 2001-08-20 | 2010-03-30 | Boston Scientific Scimed, Inc. | Embolic compositions with non-cyanoacrylate rheology modifying agents |
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| EP3873547A4 (en) * | 2019-04-03 | 2022-08-03 | Sree Chitra Tirunal Institute for Medical Sciences and Technology | A radiopaque polymeric liquid embolic system |
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| CN113827765A (en) * | 2021-09-24 | 2021-12-24 | 南通伊诺精密塑胶导管有限公司 | Implanted cyanoacrylate medical adhesive and application thereof |
| CN114773545A (en) * | 2022-03-22 | 2022-07-22 | 上海益思妙医疗器械有限公司 | Embolic polymer solution and preparation method and application thereof |
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