An adhesive for treating varicose great saphenous vein and its preparation method

Abstract

The application belongs to the technical field of medical devices, and particularly relates to an adhesive for treating varicose great saphenous vein and a preparation method thereof. The adhesive is obtained by the following steps: (1) preparation of poly cyanoacrylate powder; (2) preparation of the adhesive: 50-85 parts of cyanoacrylate, 5-30 parts of plasticizer, 0.01-0.5 parts of polymerization inhibitor and 0.01-0.5 parts of antioxidant are uniformly stirred, 10-30 parts of poly cyanoacrylate powder is slowly added, and stirring is continued until complete dissolution and filtration, and the adhesive is obtained. The prepared adhesive has a weight average molecular weight of 0.5-10 million, a viscosity of 500-3000 cp, low formaldehyde content, is not diluted by blood when implanted into a blood vessel, does not flow with blood, reduces the risk of ectopic embolism, reduces the risk of allergy and inflammation, and the adhesive has a curing time of less than 20 s, can quickly polymerize and form a clot to block the blood vessel when implanted into the target vein position.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medical devices, and particularly relates to an adhesive for treating varicose great saphenous vein and a preparation method thereof. BACKGROUND

[0002] The great saphenous vein is a superficial vein located on the inner side of the lower limb, extending from the foot to the root of the thigh, and then to the deep vein of the lower limb. Generally speaking, the poor elastic performance of the vein wall and the excessively high pressure in the vein are the direct causes of varicose great saphenous vein. The diseased superficial vein is elongated, dilated and tortuously curved, and is mostly found in people who are engaged in standing work and physical labor, such as teachers, salespersons, surgeons, etc.

[0003] Adhesive injection closure is a non-thermal closure method for treating varicose great saphenous vein that has emerged in recent years. This method can avoid the heat damage and pain caused by thermal closure treatment, and can effectively close the main vein.

[0004] Among them, the cyanoacrylate adhesive develops the most rapidly. Compared with other adhesives, the cyanoacrylate adhesive has many advantages, such as single component, no solvent, good flowability, rapid curing at room temperature, stable chemical properties, no degradation of harmful substances, low viscosity and high adhesive strength.

[0005] However, the great saphenous vein is thick, and the adhesive needs to have a certain viscosity, so the viscosity of the adhesive needs to be high and the gelation speed needs to be fast. Therefore, the adhesive required for treating the great saphenous vein needs to have a certain viscosity. If the viscosity is too high, it is not easy to implant in the applicable part of the great saphenous vein, otherwise, if the viscosity is too low, it is easy to be washed away by blood to the non-treatment site, causing ectopic embolism, and even death in severe cases. A common way to increase viscosity is to introduce other thickening agents, but the biological safety cannot be guaranteed.

[0006] In addition, the cyanoacrylate adhesive also has certain clinical risks when used for vein embolization, mainly in two aspects: first, allergic reaction / inflammatory reaction; second, pulmonary embolism / cerebral infarction / thrombosis risk.

[0007] Among them, the allergic reaction / inflammatory reaction is caused by the reaction of formaldehyde released after the solidification of the medical adhesive with the amine group in the human body tissue; the pulmonary embolism / cerebral infarction / thrombosis is caused by the size of the clot formed by the solidification of the adhesive in the blood vessel not matching the inner diameter of the blocked target blood vessel. There are many reports of such adverse events for commercially available products used for great saphenous vein embolization, and the preparation process of the currently reported adhesives still has these problems.

[0008] As disclosed in patent US 20150314022A1, dry heat sterilization is used for the adhesive, the temperature range is 110-120℃, and the time is 1-2h. With the increase of sterilization temperature, the movement between gas molecules is strengthened, and the formaldehyde in cyanoacrylate can be quickly released into the adhesive. When treating the great saphenous vein, the probability of inflammation is greatly increased.

[0009] In CN113679876A, butyl acetate cellulose is used as a thickening agent. Although the viscosity of the medical tissue adhesive is improved, the introduction of other materials affects the balance of biological safety and physical and chemical properties, causing irritation and other adverse reactions in patients.

[0010] In CN114796590A, a self-adhesion type medical glue is obtained by thermal initiation radical polymerization. The viscosity of the medical glue is effectively controlled (600-3000cp) by controlling the time of thermal initiation curing. Although no other substances are introduced during the preparation process, with the increase of temperature during the polymerization reaction, the residual formaldehyde in cyanoacrylate is quickly released into the medical glue and is not easy to volatilize, thereby increasing the incidence of inflammation and irritation and causing discomfort in patients.

[0011] Based on the above analysis, the adhesive for treating great saphenous vein embolism should have three characteristics: first, low formaldehyde content, which can effectively reduce the risk of allergic reaction / inflammation; second, controllable viscosity, which can effectively embolize the applicable site and avoid ectopic embolization; and third, rapid curing, which can quickly embolize the great saphenous vein and avoid ectopic embolization. SUMMARY

[0012] In order to solve the above technical problems, the present application provides a kind of adhesive for treating varicose great saphenous vein and its preparation method.

[0013] The adhesive for treating varicose great saphenous vein of the present application is prepared by the method of precipitation. The main basis is that the solubility of poly cyanoacrylate powder in different solvents is significantly different. The first poor solvent contains trace amounts of hydroxyl ions, and cyanoacrylate undergoes weak polymerization reaction to form small particle size emulsion, obtaining low molecular weight polymer. In the second poor solution, there are more amounts of hydroxyl ions, which quickly polymerize, terminate the reaction, precipitate, and separate into layers to obtain uniform crystal form of poly cyanoacrylate powder.

[0014] The preparation method of the adhesive for treating varicose great saphenous vein of the present application is realized according to the following steps:

[0015] (1) Preparation of poly cyanoacrylate powder

[0016] The cyan acrylate is slowly added into the first poor solvent under mechanical stirring at room temperature, polymerized, then the second poor solvent is added, polymerized and precipitated, filtered and dried to obtain the cyan acrylate powder;

[0017] (2) Preparation of the adhesive

[0018] The cyan acrylate, the plasticizer, the polymerization inhibitor and the antioxidant are stirred uniformly at room temperature, and the cyan acrylate powder prepared in step (1) is slowly added, and the stirring is continued until the solid powder is completely dissolved, and then filtered to obtain the adhesive for treating varicose great saphenous vein.

[0019] In the above steps, the cyan acrylate monomer is at least one of cyan acrylate α-cyan acrylate ethyl ester, α-cyan acrylate n-butyl ester, α-cyan acrylate n-octyl ester, α-cyan acrylate isobutyl ester and α-cyan acrylate isooctyl ester.

[0020] Preferably, the cyan acrylate monomer is at least one of α-cyan acrylate n-butyl ester and α-cyan acrylate n-octyl ester.

[0021] The cyan acrylate is slowly added into the first poor solvent under mechanical stirring at room temperature, polymerized, then the second poor solvent is added, polymerized and precipitated, filtered and dried to obtain the cyan acrylate powder;

[0022] Preferably, the cyan acrylate is at least one of poly α-cyan acrylate n-butyl ester and poly α-cyan acrylate n-octyl ester.

[0023] The plasticizer is at least one of triethyl citrate, tributyl citrate, acetyl triethyl citrate and acetyl tributyl citrate.

[0024] Preferably, the plasticizer is at least one of triethyl citrate and acetyl triethyl citrate.

[0025] The polymerization inhibitor is at least one of phosphoric acid, sulfuric acid, hydrochloric acid, acetic acid, p-toluene sulfonic acid and sulfur dioxide.

[0026] Preferably, the polymerization inhibitor is at least one of phosphoric acid and sulfur dioxide.

[0027] The antioxidant is at least one of butylated hydroxyanisole, hydroxyanisole, tert-butyl catechol, nitrobenzene and hydroquinone.

[0028] Preferably, the antioxidant is at least one of butylated hydroxyanisole and hydroquinone.

[0029] In the step (1), the first poor solvent is at least one of weakly acidic water, methanol, ethanol, isopropanol, ethylene glycol, benzyl alcohol, and isoamyl alcohol.

[0030] Preferably, the first poor solvent is at least one of methanol, ethanol, and isopropanol.

[0031] In the step (1), the second poor solvent is at least one of purified water, sodium carbonate solution, sodium bicarbonate solution, sodium acetate solution, and potassium acetate.

[0032] Preferably, the second poor solvent is at least one of water and sodium bicarbonate solution.

[0033] The mass of the first poor solvent is 5-20 times the mass of the cyanoacrylate, and the mass of the second poor solvent is 10-50 times the mass of the cyanoacrylate.

[0034] In addition, the weight parts of the ingredients of the adhesive of the present application are as follows: cyanoacrylate monomer 50-85 parts, polycyanoacrylate 10-30 parts, plasticizer 5-30 parts, polymerization inhibitor 0.01-0.5 parts, and antioxidant 0.01-0.5 parts.

[0035] In addition, the adhesive for treating varicose great saphenous vein and the use thereof prepared according to the above steps are also within the protection scope of the present application.

[0036] The present application has the following advantages:

[0037] (1) The present application provides an adhesive for treating varicose great saphenous vein, which has controllable viscosity (500-3000 cp), low formaldehyde content, and can be quickly cured (curing time < 20 s), and a preparation method thereof.

[0038] (2) The present application uses self-polymerized polycyanoacrylate as a thickening agent of the adhesive, and by controlling the addition amount of the thickening agent, the viscosity of the adhesive can be controlled, which can effectively embolize in the applicable site and will not cause ectopic embolization due to blood dilution.

[0039] (3) The polycyanoacrylate powder of the present application is washed for multiple times in the preparation process, which effectively removes the formaldehyde in the polymerization process, so that the adhesive has low formaldehyde residue, and the molecular weight is effectively controlled to be in the range of 50,000-1,000,000. The polycyanoacrylate with low molecular weight still has certain polymerization characteristics, and promotes the curing together with the monomer, so as to achieve the effects of quick curing and closing the blood vessels.

[0040] (4) The adhesive of the present application does not introduce other substances, has good biocompatibility, reduces the incidence of inflammation and allergic adverse reactions, and the patient will not feel obvious foreign body implantation. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 Molecular weight detection chart for the poly cyano acrylate powder of Example 5;

[0042] Figure 2 Particle size range chart for the poly cyano acrylate powder of Example 5;

[0043] Figure 3 Particle size picture for the poly cyano acrylate powder of Example 5;

[0044] Figure 4 Formaldehyde residue detection chart for the poly cyano acrylate powder of Example 5;

[0045] Figure 5 Placement position chart of the adhesive of Comparative Example 4 inside the oven;

[0046] Figure 6 Curing chart of the adhesive of Comparative Example 4. DETAILED DESCRIPTION

[0047] In order to enable a person skilled in the art to better understand the present application, the present application will be further described in conjunction with specific embodiments.

[0048] Examples 1-5

[0049] At room temperature, n-butyl cyano acrylate was slowly added into isopropyl alcohol under mechanical stirring, after 1 h of reaction, purified water was added and stirring was continued for 30 min, the mixed solution was transferred to a Buchner funnel, a circulating water vacuum pump was connected for filtration, and then vacuum drying was performed for 6 h, the powder was collected, weighed, and the yield was calculated.

[0050] The component types of each example were the same, only the component proportions were different, and the specific component proportioning conditions are shown in Table 1.

[0051] Table 1 Component proportioning conditions of Examples 1-5

[0052] Example Example 1 Example 2 Example 3 Example 4 Example 5 n-butyl α-cyanoacrylate (g) 10 10 10 10 10 isopropanol (g) 50 80 100 200 200 purified water (g) 100 200 300 400 500

[0053] Examples 6-10

[0054] At room temperature, n-butyl cyano acrylate was slowly added into isopropyl alcohol under mechanical stirring, after 1 h of reaction, purified water was added and stirring was continued for 30 min, the mixed solution was transferred to a Buchner funnel, a circulating water vacuum pump was connected for filtration, and then vacuum drying was performed for 6 h, the powder was collected, weighed, and the yield was calculated.

[0055] The component types of each example were the same, only the component proportions were different, and the specific component proportioning conditions are shown in Table 2.

[0056] Table 2: The ratio of each component of Examples 6-10

[0057]

[0058] Examples 11-16

[0059] In a glass bottle, n-butyl α-cyanoacrylate, plasticizer triethyl citrate, polymerization inhibitor sulfur dioxide, antioxidant butylated hydroxyanisole were added, stirred at room temperature for 1 h, and thickening agent poly-n-butyl α-cyanoacrylate powder (prepared in Example 5) was slowly added;

[0060] After all the raw materials were added, stirring was continued for 3 h until the solid powder was completely dissolved, and finally filtered with a 0.65 μm filter screen.

[0061] The types of components of each example were the same, only the ratio of components was different, and the specific ratio of components is shown in Table 3.

[0062] Table 3: The ratio of each component of Examples 11-16

[0063]

[0064]

[0065] Comparative Examples 1-3

[0066] At room temperature, n-butyl cyanoacrylate was slowly added to isopropyl alcohol under mechanical stirring, after 1 h of reaction, the mixed solution was directly transferred to a Buchner funnel, connected to a circulating water vacuum pump for filtration, and then vacuum dried for 6 h. The powder was collected, weighed, and the yield was calculated.

[0067] The types of components of each comparative example were the same, only the ratio of components was different, and the specific ratio of components is shown in Table 4.

[0068] Table 4: The ratio of components of Comparative Examples 1-3

[0069] Example Comparative Example 1 Comparative Example 2 Comparative Example 3 n-butyl α-cyanoacrylate (g) 10 10 10 isopropanol (g) 10 20 30 purified water (g) 20 40 80

[0070] Comparative Example 4

[0071] A high viscosity adhesive was prepared using the thermal polymerization method reported in the literature, and the specific steps were as follows:

[0072] In a container, n-butyl cyanoacrylate 75 g, triethyl citrate 25 g, sulfur dioxide 50 mg, butylated hydroxyanisole 60 mg were added, after all the raw materials were added, stirring was continued at room temperature for 1 h, until the solid powder was completely dissolved, then placed in an electric heating air drying oven for heating, the heating temperature was 140 °C, and the time was 3 h. The ratio of each component was the same, only the placement position in the drying oven was different, such as Figure 5As shown, respectively, placed in the oven inside four corners and the center position.

[0073]

[0074]

[0075] The above data shows that the adhesive process prepared by the thermal polymerization method is very unstable, the viscosity difference is large at different positions of the drying oven, even the curing phenomenon appears, and the residual formaldehyde is high, and the wound closure strength is low.

[0076] Example 17

[0077] The yield, molecular weight, and formaldehyde content of the poly cyano acrylate powder prepared in Examples 1-5 and Comparative Examples 1-3 were tested.

[0078] Among them, the molecular weight is detected by gel permeation chromatography; the residual formaldehyde is detected by ultraviolet spectrophotometer, and the detection results are shown in Table 5.

[0079] Table 5 Properties of poly cyano acrylate powder of Examples 1-5 and Comparative Examples 1-3

[0080] Test item Yield (%) Weight average molecular weight Molecular weight dispersion coefficient Formaldehyde content (ppm) Example 1 93 5001 1.27 13 Example 2 92 18231 1.23 15 Example 3 95 98596 1.13 37 Example 4 96 50016 1.17 6 Example 5 94 10023 1.00 5 Example 6 95 15000 1.07 17 Example 7 93 27931 1.12 18 Example 8 94 68879 1.23 19 Example 9 95 100006 1.14 51 Example 10 96 9078 1.05 17 Comparative Example 1 75 203001 2.38 584 Comparative Example 2 72 204897 2.49 449 Comparative Example 3 77 203475 2.35 365

[0081] The poly cyano acrylate powder prepared in the present application is prepared by a two-step precipitation method due to the difference in solubility of the cyano acrylate in different solvents. The specific mechanism is that the first poor solvent contains a trace amount of hydroxyl ions, and the cyano acrylate undergoes a polymerization reaction to generate a low molecular weight polymer, which is terminated in the second poor solution to precipitate, so that the crystal form of the poly cyano acrylate powder is uniform.

[0082] In addition, the cyano acrylate is washed in the poor solvent for multiple times, which effectively reduces the residual formaldehyde content of the poly cyano acrylate powder.

[0083] And from the data in the above table, it can also be seen that the weight average molecular weight of the poly cyano acrylate powder of Examples 1-5 is concentrated in 0.5-10 million, and the dispersion coefficient is in the range of 1.0-1.27, which is small, and the formaldehyde content is low.

[0084] In Examples 6-10, especially in Example 3 and Example 9, since the weight average molecular weight of the prepared cyano acrylate powder is large, the formaldehyde content is also high, so it is necessary to control the molecular weight of the cyano acrylate powder.

[0085] Comparative Examples 1-3, the formaldehyde content increased significantly, the weight average molecular weight also became large, and the dispersity coefficient was also high; this was because the poly cyanoacrylate powder was difficult to precipitate in the first poor solvent, the yield was low, and the poly cyanoacrylate powder was prone to agglomeration, and the poly cyanoacrylate powder was not washed sufficiently by the second poor solvent, so the formaldehyde content of the poly cyanoacrylate powder increased significantly.

[0086] Example 18

[0087] The curing time, flexibility, viscosity, formaldehyde residue, lap-shear tensile load strength, wound closure strength and other properties of the adhesives obtained in Examples 11-16 were tested.

[0088] Performance evaluation method and standard

[0089] (1) Curing time: 0.3 g / L NaHCO3 solution 30-50 mL was added in a flat dish with a diameter of 90 mm, and a drop of sample was dropped at a distance of about 1 cm from the liquid surface, and the curing time of the sample was recorded.

[0090] (2) Flexibility: after the adhesive was cured to form a film, a glass rod with a diameter of 0.3 cm was used to pick up the film from any position and bend it by 180 degrees without breaking the film.

[0091] (3) Viscosity: refer to GB / T 2794-2013 “Determination of viscosity of adhesives - Single cylinder rotational viscometer method”.

[0092] (4) Formaldehyde residue: detected by ultraviolet spectrophotometer.

[0093] (5) Lap-shear tensile load strength: refer to YY / T 0729.1 “Test methods for adhesive-bonded properties of tissue adhesives - Part 1: lap-shear tensile load strength”.

[0094] (6) Wound closure strength: refer to YY / T 0729.4 “Test methods for adhesive-bonded properties of tissue adhesives - Part 4: wound closure strength”.

[0095] The test results of various properties are shown in Table 6.

[0096] Table 6 Performance of adhesives of Examples 11-16

[0097]

[0098] From the above data, it can be seen that as the content of the thickening agent increases, the viscosity of the adhesive shows an upward trend, and the formaldehyde residue shows a downward trend.

[0099] In addition, the formaldehyde residue of the same product currently sold on the market for great saphenous vein embolization therapy is 689 ppm, which is much higher than the formaldehyde residue content in the adhesives prepared by the present application.

[0100] Example 19

[0101] Biological evaluation: According to GBT 16886.12-2005 Medical devices-Biological evaluation of medical devices-Part 12: Sample preparation and reference to statistical area and volume of leaching liquid, simulate clinical use, the adhesive seals the blood vessel to solidify into irregular solid, therefore, a strict leaching ratio of 0.2 g / mL is adopted.

[0102]

[0103] The adhesive droplet prepared in Example 13 is solidified and soaked at 37°C for 24 h according to a leaching ratio of 0.2 g / mL to obtain a test liquid, and the cytotoxicity is tested according to GB / T 16886.5 (the leaching liquid medium is MEM medium); the test liquid is obtained by soaking at 37°C for 72 h, and the intracutaneous irritation and sensitization are tested according to GB / T 16886.10 (the leaching liquid medium is physiological saline and cottonseed oil), and it is found that the cytotoxicity (cell proliferation rate 83.42%), intracutaneous irritation and sensitization are qualified, and the clinical use is safe.

[0104] Compared with the prior art, the biological evaluation of the adhesive is usually carried out by leaching according to the area after solidification into a film, although the cytotoxicity, intracutaneous irritation and sensitization are qualified, for example, a leaching ratio of 1.25 cm 2 / mL is adopted, the leaching time is 24 h, under this condition, the dilution ratio of the adhesive is larger than that of the present application, the dissolution of the cyanoacrylate monomer is less, the toxicity is correspondingly small, and the result is more likely to be qualified.

Claims

1. A method for preparing an adhesive for treating varicose veins of the great saphenous vein, comprising the following steps: (1) Preparation of polycyanoacrylate powder At room temperature, cyanoacrylate monomers are slowly added to a first undesirable solvent under mechanical stirring for polymerization. Then, a second undesirable solvent is added, and polymerization and precipitation are carried out. The mixture is filtered and dried to obtain polycyanoacrylate powder. The weight-average molecular weight of the polycyanoacrylate powder is concentrated in the range of 0.5 million to 100,000, and the dispersion index is in the range of 1.0 to 1.

27. The cyanoacrylate monomer is α-cyanoacrylate n-butyl ester; The first undesirable solvent is at least one of ethanol and isopropanol; The second undesirable solvent is at least one of purified water and sodium bicarbonate solution; The mass of the first undesirable solvent is 5 to 20 times the mass of cyanoacrylate, and the mass of the second undesirable solvent is 10 to 50 times the mass of cyanoacrylate. (2) Preparation of adhesive The cyanoacrylate monomer, plasticizer, polymerization inhibitor and antioxidant are stirred evenly at room temperature, and the polycyanoacrylate powder prepared in step (1) is slowly added. Stirring is continued until the solid powder is completely dissolved. Filtering is then performed to obtain the adhesive. The weight proportions of each raw material are as follows: 50-85 parts of cyanoacrylate monomer, 10-30 parts of polycyanoacrylate powder, 5-30 parts of plasticizer, 0.01-0.5 parts of polymerization inhibitor, and 0.01-0.5 parts of antioxidant. The cyanoacrylate monomer is α-cyanoacrylate n-butyl ester, the plasticizer is triethyl citrate, the polymerization inhibitor is sulfur dioxide, and the antioxidant is selected from butylated hydroxyanisole.

2. The use of the adhesive prepared according to the method of claim 1 in the preparation of materials for treating varicose veins of the great saphenous vein.

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