CN115054723A

CN115054723A - Flexible adhesive

Info

Publication number: CN115054723A
Application number: CN202210996063.1A
Authority: CN
Inventors: 刘文菁; 张娟凤; 李慧
Original assignee: Suzhou Meichuang Medical Technology Co ltd
Current assignee: Suzhou Meichuang Medical Technology Co ltd
Priority date: 2022-08-19
Filing date: 2022-08-19
Publication date: 2022-09-16
Anticipated expiration: 2042-08-19
Also published as: CN115054723B

Abstract

The invention provides a flexible adhesive, belongs to the technical field of medical instruments, and particularly relates to treatment of varicosity. The invention adopts the following formula, 50-80 parts by weight of adhesive main body, 9-15 parts by weight of first plasticizer, 5-10 parts by weight of second plasticizer, 10-20 parts by weight of thickening agent and 150-700 ppm of stabilizing agent, wherein the adhesive main body is n-butyl cyanoacrylate, isobutyl cyanoacrylate or a mixture of the two; the first plasticizer is a mixture of n-octyl cyanoacrylate and ethoxyethyl cyanoacrylate; the second plasticizer is a citrate plasticizer; solves the problem that the strength and the toughness of the medical adhesive can not be obtained simultaneously. The medical adhesive provided by the invention has the advantages of good toughness, high strength, excellent curing speed, no whitening phenomenon and high stability.

Description

Flexible adhesive

Technical Field

The invention belongs to the technical field of medical instruments, and particularly relates to the field of varicosity treatment.

Background

Varicose veins are the most common peripheral vascular disease, the pathogenesis of which is related to valve insufficiency, venous hypertension, weakness of the vein wall or inflammation, and when the vein wall becomes thinner, dilates, and the vein valve is severely damaged, the vein vessel is severely distorted and dilated. The venous valve has a check function similar to a one-way valve in a blood vessel, and when the venous valve is not good in function or is lost, blood in the vein cannot be guaranteed to flow centripetally well. In the course of the disease progression, complications such as thrombophlebitis, stasis dermatitis, inflammatory pigmentation of the skin and old rotten legs may also occur.

Thrombophlebitis usually occurs if the varicose veins are inflamed, painful, hot, and hard. If the complication is not treated in time, the range of the thrombus is enlarged, and if the thrombus is enlarged to a deep vein, the thrombus is easy to fall off to cause pulmonary embolism, so that sudden death is caused. The corollary of long-term varicose veins is skin lesions such as itching, brown and dark brown pigmentation of the skin in the legs, rashes, thickening and lightening of the skin or desquamation, which are often found on the ankle and are the hallmarks of venous stasis in the legs and increased venous pressure. This skin change results in a decrease in skin repair function, difficulty in healing after injury and susceptibility to subcutaneous steatosis, which is also a precursor to skin ulceration. The serious consequence of long-term varicose veins is venous leg ulcers, known as "rotten legs", which are skin ulcers that appear to heal poorly, and other lesions that result from severe infections and prolonged unhealing of the ulcers. If the ulcer is infected or the vein is corroded to cause vein rupture, serious bleeding complications can be caused, and serious consequences such as hemorrhagic shock can be caused if the bleeding is not found timely.

Therefore, varicose veins should be treated as early as possible once the diagnosis is clear, and currently, surgical removal, ablation or vessel closure methods are available for varicose veins. Among them, the method of sealing blood vessels is less invasive and less harmful, and is selected by many patients. Various minimally invasive techniques based on the principle of endoluminal closure have been widely used and become recommended guidelines. Compared with other minimally invasive surgery methods, the medical adhesive applied to the vascular closure surgery has the latest technology, and has the advantages of convenience in operation, improvement of life quality and definite curative effect.

The alpha-cyanoacrylate medical adhesive is a common medical adhesive at present, has the functions of embolism, hemostasis, bonding fixation, replacement of suture and a carrier and the like in clinical application, solves the problem that the traditional operation method cannot reach, and has main clinical applications of: 1. and (3) embolism: because the alpha-cyanoacrylate has the characteristic of rapid coagulation with blood and tissue fluid, the alpha-cyanoacrylate is often used as a vascular embolization agent and is mainly used for embolization treatment of cerebral surgery vascular embolization, esophageal and gastric fundus varices, lower limb varices and the like; 2. and (3) rapid hemostasis: the alpha-cyanoacrylate glue is sprayed on the tissue surface to be quickly solidified into a film, the polymerized film is very tightly embedded with the wound tissue surface, and the network structure firmly draws the wound and is clinically used for quickly stopping bleeding of spleen, liver, pancreas and the like; 3. bonding and fixing: the alpha-cyanoacrylate has higher bonding strength, and is mainly used for bonding soft and hard tissues of a human body, bonding and fixing an operation incision and a trauma incision and the like; 4. replacing surgical sutures: in trabeculectomy, after surgical suture is replaced by the medical adhesive of the n-octyl cyanoacrylate, the adhesive force is firmer than point suture of the suture in a short time, and the medical adhesive is mainly used for repairing puncture holes and treating skin wound surfaces; 5. carrying out nano medicine loading: the alpha-cyanoacrylate is a carrier with targeting property and good biocompatibility for promoting the drug to enter cells, and can be used as an excellent material for nano drug loading.

Chinese patent application CN 106552282 a discloses a medical adhesive made of cyanoacrylate, which has high adhesive strength but high hardness, and if used for sealing blood vessels, the medical adhesive can cause patients to have strong foreign body sensation and may cause mechanical damage to the blood vessels. Generally, when the strength of the adhesive is large, the flexibility tends to be poor. Some adhesives also exhibit whitening and foaming during use, and even shrink and crack, causing the adhesive to migrate through the blood vessels, reducing the reliability of the treatment. In addition, most adhesives have poor stability and cannot meet the storage period requirement of hospitals even though ampoules are used for storage.

Therefore, the problem of obtaining an adhesive suitable for varicose veins, which has good toughness and high bonding strength and stability, is still solved by the technical personnel in the field.

Disclosure of Invention

The invention aims to solve the problem that the medical adhesive in the prior art cannot have the defects of good toughness, high strength and high stability, so that the adhesive which has good toughness, high bonding strength, excellent curing time, no whitening phenomenon and good stability and is suitable for varicose vein treatment is prepared.

The above purpose of the invention is realized by the following technical scheme:

a medical adhesive comprising:

50-80 parts of adhesive main body, 9-15 parts of first plasticizer, 5-10 parts of second plasticizer, 10-20 parts of thickening agent and 150-700 ppm of stabilizing agent;

the main body of the adhesive is n-butyl cyanoacrylate, isobutyl cyanoacrylate or a mixture of the two; the first plasticizer is a mixture of n-octyl cyanoacrylate and ethoxyethyl cyanoacrylate; the second plasticizer is citrate esters.

The medical adhesive also comprises 5-10 parts by weight of a toughening agent.

The medical adhesive comprises 65-80 parts by weight of an adhesive main body; more preferably, 68 to 77 parts by weight of the adhesive body is included.

The first plasticizer contains 3-13 parts by weight of n-octyl cyanoacrylate and 2-8 parts by weight of ethoxyethyl cyanoacrylate;

preferably, the coating comprises 4 to 10 weight parts of n-octyl cyanoacrylate and 2 to 7 weight parts of ethoxyethyl cyanoacrylate;

more preferably, the composition contains 6 to 9 parts by weight of n-octyl cyanoacrylate and 4 to 6 parts by weight of ethoxyethyl cyanoacrylate.

The second plasticizer is acetyl triethyl citrate, acetyl tributyl citrate or a mixture of the acetyl triethyl citrate and the acetyl tributyl citrate;

preferably, the ratio of the second plasticizer to the first plasticizer is from 7:15 to 9: 11;

more preferably, the ratio of the second plasticizer to said first plasticizer is from 7:12 to 8: 13.

The stabilizer comprises 50-200 ppm of acidic polymerization inhibitor and 500 ppm of radical polymerization inhibitor 100-.

The acidic polymerization inhibitor is boron trifluoride; or the acidic polymerization inhibitor comprises 30-150 ppm of methanesulfonic acid, 15-100 ppm of phosphoric acid and 1-130 ppm of phytic acid; or the acidic polymerization inhibitor comprises 30-150 ppm of methanesulfonic acid, 15-100 ppm of boron trifluoride and 1-130 ppm of phytic acid.

Preferably, the acidic polymerization inhibitor comprises 40-100 ppm of methanesulfonic acid, 30-80 ppm of phosphoric acid and 35-130 ppm of phytic acid;

more preferably, the acidic polymerization inhibitor comprises 50-80 ppm of methanesulfonic acid, 40-50 ppm of phosphoric acid and 50-75 ppm of phytic acid.

The free radical polymerization inhibitor is butyl hydroxy anisol, 2, 6-di-tert-butyl-4-methylphenol or hydroquinone;

preferably, the content of the radical polymerization inhibitor is 200-400 ppm;

more preferably, the content of the radical polymerization inhibitor is 280-330 ppm.

The toughening agent is polyethylene glycol 400 or polyethylene glycol 600; preferably, the content of the toughening agent is 6 to 9 parts by weight.

The thickening agent is cellulose ester, polylactic acid or PMMA; preferably, the content of the thickener is 12 to 18 parts by weight; more preferably, the content of the thickener is 15 to 17 parts by weight.

The technical scheme of the invention has the following beneficial effects:

the medical adhesive provided by the invention is suitable for varicose vein treatment, and based on the characteristics of varicose vein treatment, the medical adhesive provided by the invention adopts the first plasticizer and the second plasticizer, and has the advantages of high strength, good toughness, excellent curing speed, no whitening phenomenon and high stability. Through the synergistic effect of the compounded stabilizer, the first plasticizer and the second plasticizer, the strength and the curing speed of the adhesive are further ensured, and meanwhile, good toughness and stability can be maintained.

The medical adhesive provided by the invention has good flexibility, the flexibility of veins in the treated area is maintained, the discomfort of a patient can be reduced, and the treatment sequelae can be effectively reduced. Meanwhile, the medical adhesive has the closing strength of not less than 20N, and can reach more than 35N at most, and the plugging effect is good. The curing time is optimized, and when the curing time is controlled to be 45-55s, the blood vessel can be quickly sealed to achieve the medical effect, and the damage to the blood vessel caused by heat release is reduced to the maximum extent. In addition, the medical adhesive has an aromatic odor which is derived from n-octyl cyanoacrylate, and the experience of patients receiving treatment is improved. Good stability also allows the adhesive to be stored for extended periods of time.

Detailed Description

The technical solutions of the present invention will be described clearly and completely below, and it should be apparent that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. In addition, the technical features involved in the different embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.

The polyethylene glycol 400, polyethylene glycol 600 and polylactic acid used in the following examples are specifically:

polyethylene glycol 400, cas: 25322-68-3, molecular weight 400, available from Mecline.

Polyethylene glycol 600, cas: 25322-68-3, molecular weight 600, available from Mecline.

Polylactic acid: and (5) cas: 26100-51-6 particle size 3 mm, molecular weight: 80000, from Michelin.

The medical adhesive provided in each example and each comparative example was obtained by accurately weighing each component, uniformly stirring and mixing, and performing a performance test by the following method.

And (3) testing the strength: section 4 of the tissue adhesive bond Performance test method by YY/T0729.4-2009: wound closure Strength the adhesive was tested for closure strength.

Specifically, an instrument meeting the requirements of the 4 instrument part is adopted, and according to the 5 test base materials, the 6 test samples and the 7 sample preparation part, fresh pigskin is adopted to prepare the test samples, wherein the length of each sample is 10cm, the width of each sample is 2.5cm, and the thickness of each sample is 5 mm. Condition conditioning was carried out according to the "8 test procedure" and the experimental work was carried out at 37 ℃.

And (3) testing the curing speed: in clinical use, if the curing speed of the medical adhesive is too fast, the medical adhesive is easy to stick and block pipes, the medical adhesive is often cured before reaching the action part, the treatment effect is influenced, even side effects are generated, and the curing speed is too slow, the blocking effect is influenced, and the curing strength is reduced. The curing rate of the adhesive obtained in each example and comparative example was measured by adding 50ml of physiological saline solution to a dish having a diameter of 90mm, sucking the adhesive with a dropper, dropping one drop at a position 5cm above the liquid surface, and recording the curing time of the adhesive solution.

Flexibility test: detecting the flexibility of the adhesive by visual observation and touch perception, dripping 1-2 drops of the adhesive into a wet plate for complete curing, picking up the cured adhesive film, repeatedly bending the adhesive film by 90 degrees and then repeatedly bending the adhesive film by 180 degrees for observation,

level 1: the membrane can be lifted, is soft and cloth-like, is continuously bent for 5 times at 90 degrees and then continuously bent for 5 times at 180 degrees, the bent part is still intact, and the membrane has no foreign body sensation.

Stage 2: the membrane can be lifted, is soft and cloth-like, is continuously bent for 5 times at 90 degrees, the bent part is still intact, and the membrane has no foreign body sensation;

and continuously bending the film for 5 times at 180 degrees, wherein the bent part has slight crease, but the film is kept intact, and the film has no foreign body sensation.

And 3, level: the membrane can be lifted, is soft and like cloth feeling or paper feeling, is continuously bent for 5 times at 90 degrees, the bent part is still intact, and the membrane has no foreign body feeling;

and continuously bending the film for 5 times at 180 degrees, wherein the film breaks when being bent, or the film presents a foreign body feeling when being bent.

4, level: the membrane can be lifted, naturally bent to have a paper-like feeling, and bent for 5 times at 90 degrees, wherein a folding line is formed at the bent position, or the membrane has a foreign body feeling, or the membrane is broken.

And 5, stage: the membrane cannot be lifted; or, after being picked up, the steel cannot be naturally bent; or, after being lifted, the steel wire is bent naturally and then broken.

According to the above evaluation criteria, ratings 1-3 meet the use criteria, grading the applicable blood vessels of different body parts according to different flexibility.

And (3) stability testing: the product is sealed and then placed at 60 ℃ for accelerated aging, and the product shape is observed after 7 days. The adhesive liquid was 5cm in length and dipped in the adhesive, and then the adhesive was lifted up vertically at a constant speed, the state of dripping was observed, and the adhesive without accelerated aging was rated according to the following criteria.

Stage 1: the same dripping phenomenon as the non-accelerated aging adhesive, the same time as the non-aged adhesive, and no obvious residue on the glass rod, from the lifting of the glass rod from the liquid surface until all liquid is dripped.

And 2, stage: the same dripping phenomenon as the adhesive without accelerated aging occurs, the time from the glass rod being lifted off the liquid surface to the completion of all liquid dripping is longer than that of the adhesive without accelerated aging, and no obvious residue is left on the glass rod.

And 3, level: the same dripping phenomena as the unaged adhesive, from the lifting of the glass rod off the liquid surface until all the liquid has dripped off, was longer than the unaged adhesive and there was visible residue on the glass rod.

4, level: the glass rod has a wire drawing phenomenon at the initial stage of lifting away from the liquid surface, the adhesive liquid drops like honey, and visible residues are left on the glass rod.

And 5, stage: the liquid is nearly free of fluidity, the viscosity is extremely high, and the dripping test cannot be carried out.

Whitening test: taking 1-2 drops of the product to cure at room temperature, observing the whitening degree of the product by eye after curing for 24 hours, and if the product is not whitened completely, judging the product to be level 1; if slightly whitened, grade 2 is evaluated; if whitening is severe, grade 3 is evaluated.

And (3) odor test: the medical adhesive provided in each of the examples and comparative examples was subjected to an odor test by 5 test persons, and was marked as having an offensive odor or a fragrant odor.

Example 1

This embodiment provides a medical adhesive, which is composed of the following components: 75 g of n-butyl cyanoacrylate, 9 g of n-octyl cyanoacrylate, 4 g of ethoxyethyl cyanoacrylate, 8 g of acetyl tributyl citrate, 16 g of polylactic acid, 7g of polyethylene glycol 400, 60 ppm of methanesulfonic acid, 45 ppm of phosphoric acid, 60 ppm of phytic acid and 300 ppm of butyl hydroxy anisole.

The preparation method of the medical adhesive provided by the embodiment comprises the following steps: accurately weighing n-butyl cyanoacrylate, n-octyl cyanoacrylate, ethoxyethyl cyanoacrylate and tributyl acetylcitrate, stirring at room temperature for 5min, adding accurately weighed polyethylene glycol 400, methanesulfonic acid, phosphoric acid, phytic acid and butyl hydroxy anisol, stirring until uniform mixing, slowly adding accurately weighed polylactic acid while stirring, continuously stirring for 2-3h until complete dissolution, bottling, sealing and storing.

Example 2

This embodiment provides a medical adhesive, which is composed of the following components: 68 g of n-butyl cyanoacrylate, 6 g of n-octyl cyanoacrylate, 6 g of ethoxyethyl cyanoacrylate, 7g of acetyl tributyl citrate, 17g of polylactic acid, 6 g of polyethylene glycol 400, 50 ppm of methanesulfonic acid, 50 ppm of phosphoric acid, 50 ppm of phytic acid and 280 ppm of butyl hydroxyanisole.

The preparation method of the medical adhesive provided in this example is substantially the same as that of example 1, and the adhesive main body, the first plasticizer and the second plasticizer are stirred for 5min at room temperature, then the other components except the thickener are added, the stirring is continued until the components are uniformly mixed, finally the thickener is added, the stirring is continued for 2-3h until the components are completely dissolved, and the mixture is bottled, sealed and stored.

Example 3

This embodiment provides a medical adhesive, which is composed of the following components: 77 g of n-butyl cyanoacrylate, 7.5 g of n-octyl cyanoacrylate, 5g of ethoxyethyl cyanoacrylate, 7.5 g of tributyl acetylcitrate, 15 g of polylactic acid, 9 g of polyethylene glycol 400, 80 ppm of methanesulfonic acid, 40 ppm of phosphoric acid, 75 ppm of phytic acid and 330 ppm of butylated hydroxyanisole.

The results of the performance tests of the medical adhesives provided in examples 1-3 are as follows:

as can be seen from the above table, the medical adhesives provided in examples 1 to 3 have adhesive strengths of 27.2N, 25.7N and 26.3N, respectively, and such high strengths ensure firm closure of blood vessels during actual treatment without the adhesive falling off. The adhesive has excellent curing speed, ensures the treatment speed, and simultaneously emits little heat in the curing process without damaging blood vessels. In addition, the cured adhesive is soft and cloth-like, is resistant to bending and has no foreign matters, so that the treated blood vessel can still keep good flexibility, and a patient has no foreign matters, and the mechanical damage of the blood vessel caused by the extrusion of muscles can be avoided even when the patient moves. Meanwhile, no whitening phenomenon was observed in the cured adhesive film, and an aromatic odor was observed.

Example 4

This embodiment provides a medical adhesive, which is composed of the following components: 75 g of n-butyl cyanoacrylate, 13 g of n-octyl cyanoacrylate, 2 g of ethoxyethyl cyanoacrylate, 7g of acetyl tributyl citrate, 16 g of polylactic acid, 7g of polyethylene glycol 400, 60 ppm of methanesulfonic acid, 45 ppm of phosphoric acid, 60 ppm of phytic acid and 300 ppm of butyl hydroxyanisole.

Example 5

This embodiment provides a medical adhesive, which is composed of the following components: 75 g of n-butyl cyanoacrylate, 3g of n-octyl cyanoacrylate, 8 g of ethoxyethyl cyanoacrylate, 9 g of acetyl tributyl citrate, 16 g of polylactic acid, 7g of polyethylene glycol 400, 60 ppm of methanesulfonic acid, 45 ppm of phosphoric acid, 60 ppm of phytic acid and 300 ppm of butyl hydroxyanisole.

Example 6

This embodiment provides a medical adhesive, which is composed of the following components: 75 g of n-butyl cyanoacrylate, 9 g of n-octyl cyanoacrylate, 4 g of ethoxyethyl cyanoacrylate, 8 g of acetyl tributyl citrate, 16 g of polylactic acid, 7g of polyethylene glycol 400, 40 ppm of methanesulfonic acid, 80 ppm of phosphoric acid, 35 ppm of phytic acid and 200 ppm of butyl hydroxyanisole.

Example 7

This embodiment provides a medical adhesive, which is composed of the following components: 75 g of n-butyl cyanoacrylate, 9 g of n-octyl cyanoacrylate, 4 g of ethoxyethyl cyanoacrylate, 8 g of acetyl tributyl citrate, 16 g of polylactic acid, 7g of polyethylene glycol 400, 100 ppm of methanesulfonic acid, 30 ppm of phosphoric acid, 130 ppm of phytic acid and 400 ppm of butyl hydroxyanisole.

The performance test results of the medical adhesive provided in the above examples are as follows:

examples 4-7 still maintain good strength, and examples 4 and 5 also satisfy the application requirements of medical adhesives, with a flexibility test result of 2. The medical adhesives provided in examples 4 to 7 were not observed in whitening phenomenon and had aromatic odor. Example 4 increased the amount of the first plasticizer and example 5 decreased the amount of the first plasticizer compared to example 1, and it can be seen that the strength of example 4 was 28.1N and the strength of example 5 was 26.9N, and it can be seen that the first plasticizer not only has an effect on the flexibility together with the second plasticizer, but also the first plasticizer has a great effect on the strength.

Example 8

This embodiment provides a medical adhesive, which is composed of the following components: 75 g of n-butyl cyanoacrylate, 9 g of n-octyl cyanoacrylate, 4 g of ethoxyethyl cyanoacrylate, 8 g of tributyl acetylcitrate, 16 g of polylactic acid, 7g of polyethylene glycol 400, 165 ppm of methanesulfonic acid and 300 ppm of butylated hydroxyanisole.

Example 9

This embodiment provides a medical adhesive, which is composed of the following components: 75 g of n-butyl cyanoacrylate, 9 g of n-octyl cyanoacrylate, 4 g of ethoxyethyl cyanoacrylate, 8 g of acetyl tributyl citrate, 16 g of polylactic acid, 7g of polyethylene glycol 400, 160 ppm of methanesulfonic acid, 145 ppm of phosphoric acid and 160 ppm of phytic acid.

Example 10

This embodiment provides a medical adhesive, which is composed of the following components: 75 g of n-butyl cyanoacrylate, 9 g of n-octyl cyanoacrylate, 4 g of ethoxyethyl cyanoacrylate, 8 g of tributyl acetylcitrate, 16 g of polylactic acid, 7g of polyethylene glycol 400 and 465 ppm of butyl hydroxy anisole.

the medical adhesives provided in examples 8-10 had slightly longer cure times, preferably in the range of 55-65 seconds. It can be seen that the selection of the stabilizer influences the curing time, the curing time of the adhesive product using only the acidic stabilizer or the free radical polymerization inhibitor is beyond the most preferable range of 45-55s, and the compounded stabilizer selected by the invention not only can ensure excellent stability of the adhesive, but also can provide the most excellent curing speed.

Example 10 provides a medical adhesive using only a radical polymerization inhibitor, which is inferior in curing time and stability to example 1. The medical adhesive provided by the example 9 only uses the compounded acidic polymerization inhibitor, and the curing time and the stability of the medical adhesive are inferior to those of the medical adhesive provided by the example 1. The use of only an acidic polymerization inhibitor prolongs the curing time and affects the stability, and when a radical polymerization inhibitor is further compounded, the curing time is optimized. The stability is affected by using only the radical polymerization inhibitor, and it can be seen that the stability of example 10 reaches grade 3, and when the acidic polymerization inhibitor is further compounded, the stability is optimized.

Example 11

This embodiment provides a medical adhesive, which is composed of the following components: 75 g of n-butyl cyanoacrylate, 9 g of n-octyl cyanoacrylate, 4 g of ethoxyethyl cyanoacrylate, 8 g of acetyl tributyl citrate, 10g of polyethylene glycol 600, 60 ppm of methanesulfonic acid, 45 ppm of phosphoric acid, 60 ppm of phytic acid and 300 ppm of butyl hydroxyanisole.

The preparation method of the medical adhesive provided in this example is basically the same as that of example 1, and the adhesive main body, the first plasticizer and the second plasticizer are stirred for 5min at room temperature, then the other components are added, and the stirring is continued until the mixture is uniformly mixed, and the mixture is bottled, sealed and stored.

Example 12

This embodiment provides a medical adhesive, which is composed of the following components: 65 g of n-butyl cyanoacrylate, 9 g of n-octyl cyanoacrylate, 4 g of ethoxyethyl cyanoacrylate, 8 g of acetyl tributyl citrate, 18 g of polylactic acid, 10g of polyethylene glycol 400, 60 ppm of methanesulfonic acid, 45 ppm of phosphoric acid, 60 ppm of phytic acid and 300 ppm of hydroquinone.

Example 13

This embodiment provides a medical adhesive, which is composed of the following components: 80g of n-butyl cyanoacrylate, 9 g of n-octyl cyanoacrylate, 4 g of ethoxyethyl cyanoacrylate, 8 g of acetyl tributyl citrate, 12 g of polylactic acid, 5g of polyethylene glycol 400, 60 ppm of methanesulfonic acid, 45 ppm of phosphoric acid, 60 ppm of phytic acid and 300 ppm of butyl hydroxyanisole.

The preparation method of the medical adhesive provided by the embodiment is basically the same as that of the embodiment 1, the adhesive main body, the first plasticizer and the second plasticizer are stirred for 5min at room temperature, then other components except the thickening agent are added, the stirring is continued until the components are uniformly mixed, finally the thickening agent is added, the stirring is continued for 2-3h until the components are completely dissolved, and the mixture is bottled, sealed and stored.

examples 11 to 13 provide medical adhesives having adhesive strength of 29 to 30N and a high curing speed, while achieving flexibility satisfactory in use, and free from whitening and having an aromatic odor. The medical adhesives provided in examples 11-13 are also suitable for the treatment of varicose veins, and after being implanted into a blood vessel, the blood vessel is well closed by applying external pressure, and the medical adhesives have extremely high closing strength, and can achieve better blocking effect on the thicker and highly elastic blood vessels. The proper curing speed also reduces the risk of the patient being burned by the exothermic heat of curing during the treatment.

Example 14

This embodiment provides a medical adhesive, which is composed of the following components: 80g of n-butyl cyanoacrylate, 1 g of n-octyl cyanoacrylate, 8 g of ethoxyethyl cyanoacrylate, 10g of triethyl citrate, 10g of polylactic acid, 7g of polyethylene glycol 600 and 700 ppm of sulfuric acid.

Example 15

This embodiment provides a medical adhesive, which is composed of the following components: 50 g of n-butyl cyanoacrylate, 5g of n-octyl cyanoacrylate, 4 g of ethoxyethyl cyanoacrylate, 5g of triethyl citrate, 10g of polylactic acid, 50 ppm of ascorbic acid and 100 pm of 2, 6-di-tert-butyl-4-methylphenol.

Example 16

This embodiment provides a medical adhesive, which is composed of the following components: 50 g of n-butyl cyanoacrylate, 5g of n-octyl cyanoacrylate, 4 g of ethoxyethyl cyanoacrylate, 10g of polylactic acid, 5g of triethyl citrate, 200 ppm of boron trifluoride and 500 pm of 2, 6-di-tert-butyl-4-methylphenol.

The preparation method of the medical adhesive provided in this example comprises the following steps of placing n-butyl cyanoacrylate, n-octyl cyanoacrylate, ethoxyethyl cyanoacrylate and triethyl citrate into a sealed flask, stirring for 5min at room temperature, adding 2, 6-di-tert-butyl-4-methylphenol, continuing to stir until the mixture is uniformly mixed, then, pumping boron trifluoride according to the amount, injecting into the liquid in the sealed flask, continuing to stir until the mixture is uniformly mixed, finally, adding polylactic acid, continuing to stir for 2-3h until the mixture is completely dissolved, bottling, sealing and storing.

Example 17

This embodiment provides a medical adhesive, which is composed of the following components: 75 g of n-butyl cyanoacrylate, 9 g of n-octyl cyanoacrylate, 4 g of ethoxyethyl cyanoacrylate, 8 g of tributyl citrate, 16 g of polylactic acid, 7g of polyethylene glycol 400, 60 ppm of methanesulfonic acid, 45 ppm of phosphoric acid, 60 ppm of phytic acid and 300 ppm of butyl hydroxyanisole.

The above examples provide the following results of the performance test of the medical adhesive:

the stability and flexibility of examples 14-16 did not stand out significantly compared to the other examples, and whitening was also observed, but the basic requirements for varicose vein treatment were still met.

Example 17, using tributyl citrate as the second plasticizer, the flexibility rating of example 17 was 2 and the flexibility rating of example 1 was 1, with tributyl acetyl citrate having a more superior flexibility contribution in the adhesive system of the present invention, as compared to example 1 using tributyl acetyl citrate.

Comparative example 1

The present comparative example provides a medical adhesive consisting of the following ingredients: 75 g of n-butyl cyanoacrylate, 5g of n-octyl cyanoacrylate, 4 g of ethoxyethyl cyanoacrylate, 20 g of polylactic acid, 7g of polyethylene glycol 400, 60 ppm of methanesulfonic acid, 45 ppm of phosphoric acid, 60 ppm of phytic acid and 300 ppm of butyl hydroxyanisole.

The preparation method of the medical adhesive provided by the comparative example is as follows: 75 g of n-butyl cyanoacrylate, 5g of n-octyl cyanoacrylate and 4 g of ethoxyethyl cyanoacrylate are uniformly mixed, then 7g of polyethylene glycol 400, 60 ppm of methanesulfonic acid, 45 ppm of phosphoric acid, 60 ppm of phytic acid and 300 ppm of butyl hydroxy anisol are added, stirring is continued until uniform mixing is achieved, finally 20 g of polylactic acid is added, stirring is carried out for 2-3h until complete dissolution is achieved, and bottling, sealing and storing are carried out.

Comparative example 2

The present comparative example provides a medical adhesive consisting of the following ingredients: 75 g of n-butyl cyanoacrylate, 10g of acetyl tributyl citrate, 16 g of polylactic acid, 7g of polyethylene glycol 400, 60 ppm of methanesulfonic acid, 45 ppm of phosphoric acid, 60 ppm of phytic acid and 300 ppm of butyl hydroxyanisole.

The preparation method of the medical adhesive provided by the comparative example is as follows: 75 g of n-butyl cyanoacrylate and 10g of acetyl tributyl citrate are uniformly mixed, then 7g of polyethylene glycol 400, 60 ppm of methanesulfonic acid, 45 ppm of phosphoric acid, 60 ppm of phytic acid and 300 ppm of butyl hydroxy anisol are added, stirring is continued until uniform mixing is achieved, finally 16 g of polylactic acid is added, stirring is carried out for 2-3h, complete dissolution is achieved, and then bottling, sealing and storage are carried out.

Comparative example 3

The present comparative example provides a medical adhesive consisting of the following ingredients: 75 g of n-butyl cyanoacrylate, 18 g of n-octyl cyanoacrylate, 8 g of acetyl tributyl citrate, 16 g of polylactic acid, 7g of polyethylene glycol 400, 60 ppm of methanesulfonic acid, 45 ppm of phosphoric acid, 60 ppm of phytic acid and 300 ppm of butyl hydroxyanisole.

The preparation method of the medical adhesive provided by the comparative example is as follows: 75 g of n-butyl cyanoacrylate, 18 g of n-octyl cyanoacrylate and 8 g of acetyl tributyl citrate are uniformly mixed, then 7g of polyethylene glycol 400, 60 ppm of methanesulfonic acid, 45 ppm of phosphoric acid, 60 ppm of phytic acid and 300 ppm of butyl hydroxy anisol are added, stirring is continued until the mixture is uniformly mixed, finally 16 g of polylactic acid is added, stirring is carried out for 2-3h until the polylactic acid is completely dissolved, and bottling, sealing and storing are carried out.

Comparative example 4

The present comparative example provides a medical adhesive consisting of the following ingredients: 75 g of n-butyl cyanoacrylate, 10g of ethoxyethyl cyanoacrylate, 8 g of acetyl tributyl citrate, 16 g of polylactic acid, 7g of polyethylene glycol 400, 60 ppm of methanesulfonic acid, 45 ppm of phosphoric acid, 60 ppm of phytic acid and 300 ppm of butyl hydroxyanisole.

The preparation method of the medical adhesive provided by the comparative example is as follows: 75 g of n-butyl cyanoacrylate, 10g of ethoxyethyl cyanoacrylate and 8 g of acetyl tributyl citrate are uniformly mixed, then 7g of polyethylene glycol 400, 60 ppm of methanesulfonic acid, 45 ppm of phosphoric acid, 60 ppm of phytic acid and 300 ppm of butyl hydroxy anisol are added, stirring is continued until uniform mixing is achieved, finally 16 g of polylactic acid is added, stirring is carried out for 2-3h until complete dissolution is achieved, and bottling, sealing and storing are carried out.

Comparative example 5

The present comparative example provides a medical adhesive consisting of the following ingredients: 75 g of n-butyl cyanoacrylate, 9 g of n-octyl cyanoacrylate, 4 g of ethoxyethyl cyanoacrylate, 8 g of tributyl acetylcitrate, 16 g of polylactic acid and 7g of polyethylene glycol 400.

The preparation method of the medical adhesive provided by the comparative example is as follows: 75 g of n-butyl cyanoacrylate, 9 g of n-octyl cyanoacrylate, 4 g of ethoxyethyl cyanoacrylate and 8 g of tributyl acetylcitrate are mixed uniformly, 7g of polyethylene glycol 400 is added, stirring is continued until the mixture is uniformly mixed, and finally 16 g of polylactic acid is added, stirred for 2-3h until the polylactic acid is completely dissolved, bottled, sealed and stored.

The performance test results of the medical adhesive provided by the above comparative examples are as follows:

as can be seen from the data of comparative examples 1 and 2, the adhesive product without the first plasticizer or without the second plasticizer had a strength reduced below 20N, a flexibility of 4 or 5 grades, and could not be used as an adhesive for varicose veins. In addition, the whitening phenomenon of comparative example 2 is severe, and thus it can be seen that the first plasticizer has an effect of improving the whitening phenomenon.

In comparative example 3, the content of n-octyl cyanoacrylate in the first plasticizer was increased, and with the first plasticizer out of the compounding ratio range of the present invention, the flexibility reached grade 4 and it was not possible to use it as an adhesive for varicose veins. Comparative example 4 the first plasticizer in the adhesive formulation did not contain N-octyl cyanoacrylate, was only ethoxyethyl cyanoacrylate, had a strength reduction below 20N, achieved a level 4 flexibility, and was not used as an adhesive for varicose veins. However, by compounding N-octyl cyanoacrylate with ethoxyethyl cyanoacrylate into the formulation of the present invention, the strength can reach more than 20N, even 27.2N of example 1, and the flexibility also meets the use requirement.

In addition, although the same stabilizer formulation was used, the stability of comparative examples 1 to 4 was weaker than that of example 1, and the stabilizer had a synergistic effect with other components in the binder system, and in particular, the acidic polymerization inhibitor of the present invention, which had a synergistic effect with the first and second plasticizers and the amounts thereof, was compounded with 40 to 100 ppm of methanesulfonic acid, 30 to 80 ppm of phosphoric acid, and 1 to 130 ppm of phytic acid.

The whitening data of comparative examples 1-4 show that n-octyl cyanoacrylate in the first plasticizer has a better whitening effect, but the first plasticizer needs to be compounded with n-octyl cyanoacrylate and ethoxyethyl cyanoacrylate for use together in consideration of the properties of flexibility, strength and the like.

In summary, from the above test data, it can be seen that the medical adhesive provided by the present invention can balance the strength and flexibility of the adhesive by compounding the mixture of n-octyl cyanoacrylate and ethoxyethyl cyanoacrylate as the first plasticizer with the second plasticizer, so as to achieve a good blocking effect and ensure good experience of patients. When the first compounded plasticizer is not adopted or only the first plasticizer or the second plasticizer is adopted, various properties of the medical adhesive cannot meet the use requirements at the same time. When the stabilizer is not added, the stability can not meet the use requirement, and the curing speed is too high, so that the heat release is too large, and the vessel is burnt.

It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications derived therefrom are intended to be within the scope of the present invention.

Claims

1. A medical adhesive, comprising:

the main body of the adhesive is n-butyl cyanoacrylate, isobutyl cyanoacrylate or a mixture of the two; the first plasticizer is a mixture of n-octyl cyanoacrylate and ethoxyethyl cyanoacrylate; the second plasticizer is a citrate plasticizer;

the stabilizer comprises 50-200 ppm of acidic polymerization inhibitor and 500 ppm of free radical polymerization inhibitor;

the acidic polymerization inhibitor comprises 30-150 ppm of methanesulfonic acid, 15-100 ppm of phosphoric acid and 1-130 ppm of phytic acid; or the acidic polymerization inhibitor comprises 30-150 ppm of methanesulfonic acid, 15-100 ppm of boron trifluoride and 1-130 ppm of phytic acid.

2. The medical adhesive according to claim 1, further comprising 5 to 10 parts by weight of a toughening agent.

3. The medical adhesive according to claim 1 or 2, comprising 65 to 80 parts by weight of the adhesive body.

4. The medical adhesive according to claim 1 or 2,

the first plasticizer contains 3-13 parts by weight of n-octyl cyanoacrylate and 2-8 parts by weight of ethoxyethyl cyanoacrylate.

5. The medical adhesive according to claim 1 or 2, wherein the second plasticizer is acetyl triethyl citrate, acetyl tributyl citrate or a mixture of both;

the ratio of the second plasticizer to the first plasticizer is 7:15 to 9: 11.

6. The medical adhesive according to claim 1 or 2, wherein the radical polymerization inhibitor is butylated hydroxyanisole, 2, 6-di-tert-butyl-4-methylphenol or hydroquinone;

the content of the free radical polymerization inhibitor is 200-400 ppm.

7. The medical adhesive according to claim 2, wherein the toughening agent is polyethylene glycol 400 or polyethylene glycol 600; the content of the toughening agent is 6-9 parts by weight.

8. The medical adhesive according to claim 1 or 2, wherein the thickener is a cellulose ester-based thickener, polylactic acid, or PMMA; the content of the thickening agent is 12-18 parts by weight.