An intravenous adhesive suitable for terminal sterilization and a method of making the same

Abstract

The present application relates to the field of medical devices, and more particularly to a terminal sterilization suitable intravenous adhesive and its preparation method, the preparation method comprising the following steps: step one: mixing and stirring cyanoacrylate, plasticizer, oxidizing agent and free radical polymerization inhibitor; step two: adding water absorption acid agent into the reaction container, adjusting the temperature and stirring; step three: adding poly cyanoacrylate into the reaction container and stirring; step four: continuously adding water absorption acid agent into the reaction container, adjusting the temperature and stirring to obtain the crude intravenous adhesive; step five: pressure filtration of the crude intravenous adhesive to obtain the filtrate; step six: terminal sterilization of the filtrate to obtain the intravenous adhesive product. The present application uses phosphorus pentoxide or sulfur dioxide as the water absorption acid agent, and reduces the water content of the intravenous adhesive and improves the stability of the intravenous adhesive by using the oxidizing agent, adding the water absorption acid agent in several times and adjusting the reaction temperature.

Description

Technical Field

[0001] This invention relates to the technical field of medical devices, specifically to a venous adhesive suitable for terminal sterilization and its preparation method. Background Technology

[0002] Varicose veins are a common disease, mainly caused by insufficiency of the saphenous vein valves or primary deep vein valve insufficiency of the lower extremities due to prolonged sitting or standing. Varicose veins are an irreversible disease. If left untreated, in extreme cases, blood clots may form in the veins, leading to fatal pulmonary embolism in severe cases. It may also cause rupture of the diseased vein, resulting in massive bleeding and threatening the patient's life.

[0003] The main treatments for varicose veins include conservative treatment, surgical treatment, and minimally invasive interventional treatment. In recent years, minimally invasive interventional treatment has become increasingly popular among patients due to its advantages such as minimal trauma, less bleeding, and faster recovery. Minimally invasive interventional treatments include endovenous thermal closure of the main vein, foam sclerotherapy, and intravenous adhesive injection. Among these, intravenous adhesive injection is a new method for treating varicose veins. This method does not require anesthesia; the veins are simply glued together by injecting intravenous adhesive into the main trunk of the great saphenous vein. The treatment process usually only takes a few minutes to half an hour. Compared with traditional radiofrequency and laser ablation techniques, intravenous adhesive injection has advantages such as not requiring tumescent fluid and avoiding thermal damage. Patients can walk and resume normal activities immediately after treatment without hospitalization.

[0004] Cyanopropionic acid esters are widely used as the main component of intravenous adhesives due to their excellent adhesive properties. However, their strong electron-withdrawing properties make cyanoacrylate intravenous adhesives highly susceptible to anionic polymerization and / or free radical polymerization in the presence of water, heat, or ionizing radiation. This makes it difficult to perform terminal sterilization such as dry heat sterilization or radiation sterilization, posing a risk of infection during clinical use. To improve the stability of aminoacrylate intravenous adhesives, the invention with application number 202310052072.X added acidic polymerization inhibitors such as phosphoric acid and sulfur dioxide to the adhesive. Phosphoric acid has a low pH value and can damage blood vessels. Although sulfur dioxide can inhibit polymerization after absorbing a certain amount of water, the sulfurous acid it forms after absorbing water is unstable and easily decomposes upon heating, releasing water and losing its polymerization-inhibiting effect. Summary of the Invention

[0005] To address the problem that existing intravenous adhesives are chemically unstable and difficult to terminally sterilize, this invention provides an intravenous adhesive suitable for terminal sterilization and its preparation method. Phosphorus pentoxide or sulfur dioxide is used as a water-absorbing and acid-binding agent. By using an oxidant, adding the water-absorbing and acid-binding agent in stages, and adjusting the reaction temperature, the water content of the intravenous adhesive is reduced, thereby improving its stability.

[0006] In a first aspect, the present invention provides a method for preparing an intravenous adhesive suitable for terminal sterilization, comprising the following steps: Step 1: Mix cyanoacrylate, plasticizer, oxidant and free radical polymerization inhibitor in a reaction vessel and stir until homogeneous at room temperature; Step 2: Add the water-absorbing and acid-binding agent into the reaction vessel, adjust the reaction temperature, and stir until homogeneous; Step 3: Add polycyanoacrylate to the reaction vessel and stir at room temperature until completely dissolved; Step 4: Continue adding water-absorbing and acid-binding agent into the reaction vessel, adjust the reaction temperature, and stir evenly to obtain crude intravenous adhesive; Step 5: The crude intravenous adhesive obtained in Step 4 is filtered under nitrogen pressure to obtain the filtrate; Step 6: After filling the filtrate in an anhydrous and oxygen-free environment, terminal sterilization is performed to obtain an intravenous adhesive product with a viscosity of 0-3000cp. The water-absorbing and acid-binding agents are phosphorus pentoxide or sulfur dioxide. Phosphorus pentoxide is a white powder with strong water absorption properties, which can reduce the water content in the preparation of intravenous adhesives. Under heating, it reacts with the absorbed water to form non-toxic and stable phosphoric acid. Phosphoric acid can also act as an acidic polymerization inhibitor to prevent the anionic polymerization of cyanoacrylates. Sulfur dioxide reacts with intravenous water to form sulfurous acid. Sulfurous acid has reducing properties and can react with oxidants to form stable sulfuric acid. Sulfuric acid can also act as an acidic polymerization inhibitor to prevent the anionic polymerization of cyanoacrylates.

[0007] Furthermore, in step one, by weight, there are 50-90 parts of cyanoacrylate, 5-20 parts of plasticizer, 0-0.1 parts of oxidant, and 0.01-0.1 parts of free radical polymerization inhibitor.

[0008] Furthermore, the cyanoacrylate is one or more of ethyl α-cyanoacrylate, n-butyl α-cyanoacrylate, n-octyl α-cyanoacrylate, isobutyl α-cyanoacrylate, and isooctyl α-cyanoacrylate; the plasticizer is one or more of triethyl citrate, tributyl citrate, triethyl acetyl citrate, and tributyl acetyl citrate; and the free radical polymerization inhibitor is one or more of butylated hydroxyanisole, hydroxyanisole, tert-butylcatechol, nitrobenzene, and hydroquinone.

[0009] Furthermore, the oxidizing agent is one or more of hydrogen peroxide, sodium peroxide, and dilute nitric acid. Sodium peroxide can oxidize sulfurous acid to stable sulfuric acid after absorbing water. Hydrogen peroxide and dilute nitric acid can directly oxidize sulfurous acid to stable sulfuric acid.

[0010] Furthermore, in step three, the amount of polycyanoacrylate used is 5-30 parts by weight. The weight-average molecular weight of the polycyanoacrylate is 0.5-200,000, and the viscosity is 500-3000 cp. The weight-average molecular weight of the polycyanoacrylate can be selected based on factors such as the location of the vein, the amount of blood collected, and the length of the vein. The polycyanoacrylate is one or more of poly(ethyl α-cyanoacrylate), poly(butyl α-cyanoacrylate), poly(octyl α-cyanoacrylate), poly(isobutyl α-cyanoacrylate), and poly(isooctyl α-cyanoacrylate). As a homologous polymer of cyanoacrylate, polycyanoacrylate has good compatibility with cyanoacrylate. On the one hand, it can avoid stratification during mixing, which would lead to a decrease in the viscosity of the venous adhesive. On the other hand, it can prevent polycyanoacrylate from seeping out of the venous adhesive after entering the vein and moving with the blood, thus preventing the venous adhesive from failing to seal and causing pulmonary embolism.

[0011] Furthermore, the total amount of water-absorbing and acid-binding agent used is 0.01-0.1 parts by weight.

[0012] Furthermore, in step four, a water-absorbing and acid-binding agent is added to the reaction vessel in several batches, ranging from 0 to 4 times. When the water-absorbing and acid-binding agent is phosphorus pentoxide, adding it to the reaction vessel in several batches helps to evenly disperse the phosphorus pentoxide in the intravenous adhesive, fully absorb the moisture in the intravenous adhesive, and also prevents the phosphorus pentoxide from losing its water-absorbing properties due to being coated by components with high viscosity such as polycyanoacrylate.

[0013] Furthermore, the reaction temperature is adjusted according to the type of water-absorbing and acid-binding agent. When the water-absorbing and acid-binding agent is sulfur dioxide, the reaction temperature is room temperature; when the water-absorbing and acid-binding agent is phosphorus pentoxide, the reaction temperature is 40-60℃, which is conducive to the reaction of phosphorus pentoxide with the moisture in the venous adhesive to produce phosphoric acid.

[0014] Furthermore, in step six, terminal sterilization is either dry heat sterilization or irradiation sterilization.

[0015] Secondly, the present invention also provides a venous adhesive prepared by the preparation method described above.

[0016] The beneficial effects of this invention are as follows: This invention provides an intravenous adhesive suitable for terminal sterilization and its preparation method. Phosphorus pentoxide or sulfur dioxide is used as a water-absorbing and acid-binding agent. An oxidant is added and the reaction temperature is adjusted to induce the water-absorbing and acid-binding agent to absorb water and generate a low-toxicity, stable acidic polymerization inhibitor, thus reducing the water content of the intravenous adhesive and inhibiting the anionic polymerization reaction of cyanoacrylate. The water-absorbing and acid-binding agent is added in stages to promote uniform mixing of the components in the intravenous adhesive. Polycyanoacrylate is used as a thickener, improving the compatibility between the thickener and cyanoacrylate, increasing the viscosity of the intravenous adhesive, and improving its sealing effect in venous vessels.

[0017] In summary, this invention prevents the polymerization of intravenous adhesives after heating or irradiation by improving the stability and safety of the water-absorbing acid-binding agent and reducing the water content of the intravenous adhesive, thus making it suitable for terminal sterilization. Detailed Implementation

[0018] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions in the embodiments of this invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention.

[0019] The intravenous adhesives of Examples 1-5 were prepared according to the following preparation method: Step 1: Mix butyl cyanoacrylate, triethyl citrate, dilute nitric acid and butylated hydroxyanisole in a reaction vessel and stir until homogeneous at room temperature.

[0020] Step 2: Slowly introduce sulfur dioxide gas into the reaction vessel and stir at room temperature for 1 hour until the mixture is homogeneous.

[0021] Step 3: During the stirring process, polybutyl cyanoacrylate particles with a weight average molecular weight of 0.5-100,000 are slowly added into the reaction vessel. After the polybutyl cyanoacrylate particles are added, stirring is continued at room temperature for 3 hours until the solid particles in the reaction vessel are completely dissolved, and crude intravenous adhesive is obtained.

[0022] Step 4: The crude intravenous adhesive obtained in Step 3 is subjected to nitrogen pressure filtration at a nitrogen inlet pressure of 0.1-0.3 MPa to obtain the filtrate.

[0023] Step 5: Fill the filtrate in a glove box in an anhydrous and oxygen-free environment. After filling, sterilize it with 20kGy radiation to obtain the intravenous adhesive product.

[0024] The difference between Examples 1-5 lies in the different allocation ratios of each group, as shown in Table 1.

[0025] Table 1. Distribution ratio of each group in Examples 1-5

[0026] Comparative Examples 1, 2, and 3 correspond to Examples 1, 2, and 3, respectively. The difference between Comparative Examples 1-3 and Examples 1-3 is that the oxidizing agent dilute nitric acid was not used, and the contents were filled under normal conditions.

[0027] The curing time, viscosity, oxygen content, moisture content, and sulfur atom valence state properties of Examples 1-5 and Comparative Examples 1-3 before and after radiation sterilization were tested, and the test results are shown in Table 2.

[0028] The testing methods for each performance aspect are as follows: 1. Curing time: Add 30-50 mL of 0.3 g / L NaHCO3 solution to a petri dish with a diameter of 90 mm, drop a drop of sample about 1 cm from the liquid surface, and record the curing time of the sample.

[0029] 2. Viscosity: Refer to GB / T 2794-2013 "Determination of Viscosity of Adhesives - Single-Cylinder Rotation Viscometer Method".

[0030] 3. Oxygen content: Detected using an electrochemical oxygen analyzer, model GPR-2500GB.

[0031] 4. Moisture content: Refer to Method I (Fischer method) of Moisture Determination (General Chapter 0832) in the Pharmacopoeia of the People's Republic of China (Part IV).

[0032] 5. Sulfur atom valence state: The intravenous adhesive was cured into a film, the film was removed, and X-ray photoelectron spectroscopy was used for detection.

[0033] Table 2. Performance test results of Examples 1-5 and Comparative Examples 1-3 before and after radiation sterilization.

[0034] Table 2 shows that in Examples 1-5, the viscosity of the venous adhesive increased with the increase of the polybutyl cyanoacrylate content; the moisture content decreased with the increase of sulfur dioxide and dilute nitric acid content. Under effective control of moisture and oxygen, the performance indicators before and after radiation remained relatively stable, with a viscosity difference of no more than 2%. Simultaneously, sulfur dioxide absorbed water and was oxidized into stable hexavalent sulfuric acid. In Comparative Examples 1-3, sulfur dioxide absorbed water and became unstable sulfurous acid, which further decomposed to produce sulfur dioxide and water. This resulted in ineffective control of the moisture content in the venous adhesive, leading to higher viscosity, moisture content, and oxygen content before radiation, and significant differences in performance indicators after radiation. This indicates that venous adhesives without oxidants and without controlled anhydrous and oxygen-free filling environments cannot effectively withstand the effects of radiation.

[0035] The intravenous adhesives of Examples 6-10 were prepared according to the following preparation method: Step 1: Mix 74.89 parts by weight of n-octyl cyanoacrylate, 10 parts by weight of triethyl acetyl citrate, and 0.06 parts by weight of hydroquinone in a reaction vessel and stir at room temperature for 1 hour.

[0036] Step 2: Divide the total amount of phosphorus pentoxide (0.05 parts by weight) into several equal portions, add one portion into the reaction vessel, preheat the mixture, and stir until homogeneous.

[0037] Step 3: Lower the temperature of the reaction vessel to room temperature. While stirring, slowly add 15 parts by weight of poly(n-octyl cyanoacrylate) particles with a weight average molecular weight of 100,000-200,000 into the reaction vessel. After the poly(n-octyl cyanoacrylate) particles are added, continue stirring at room temperature for 3 hours until the solid particles in the reaction vessel are completely dissolved to obtain crude intravenous adhesive.

[0038] Step 4: Continue to add the remaining amount of phosphorus pentoxide into the reaction vessel in portions, heat and preheat, then stir evenly to obtain crude intravenous adhesive.

[0039] Step 5: The crude intravenous adhesive obtained in Step 4 is subjected to nitrogen pressure filtration at a nitrogen inlet pressure of 0.1-0.3 MPa to obtain the filtrate.

[0040] Step 5: Fill the filtrate in a glove box in an anhydrous and oxygen-free environment. After filling, sterilize by dry heat to obtain the intravenous adhesive product.

[0041] The difference between Examples 6-10 lies in the different preheating conditions, number of additions, and dry heat sterilization conditions for phosphorus pentoxide. The preheating conditions, number of additions, and dry heat sterilization conditions for phosphorus pentoxide are shown in Table 3.

[0042] Table 3. Treatment conditions for phosphorus pentoxide and dry heat sterilization in Examples 6-10

[0043] The difference between Comparative Example 4 and Examples 6-10 is that phosphorus pentoxide was added to the reaction vessel in one go, and no preheating treatment was performed, and it was dispensed under normal conditions.

[0044] The curing time, viscosity, oxygen content, and moisture content of Examples 6-10 and Comparative Example 4 before and after dry heat sterilization were tested, and the test results are shown in Table 4.

[0045] Table 4. Performance test results of Examples 6-10 and Comparative Example 4 before and after dry heat sterilization.

[0046] As shown in Table 4, in Examples 6-10, the addition of phosphorus pentoxide in stages effectively controlled the moisture and oxygen in the venous adhesive, resulting in minimal changes in the various performance indicators of the venous adhesive before and after dry heat sterilization, with the viscosity increasing by less than 2%. In Comparative Example 4, the various performance indicators of the venous adhesive changed significantly after dry heat sterilization, with a marked increase in viscosity.

[0047] Mechanical properties, viscosity after accelerated aging, and cytotoxicity were tested on Examples 6 and 4 after dry heat sterilization. The test results are shown in Table 5.

[0048] The testing method is as follows: Overlap-shear tensile bearing strength: Refer to YY / T 0729.1 "Test methods for adhesive properties of tissue adhesives - Part 1: Overlap-shear tensile bearing strength".

[0049] Wound closure strength: Refer to YY / T 0729.4 "Test methods for the adhesive properties of tissue adhesives - Part 4: Wound closure strength".

[0050] Viscosity after accelerated aging: According to the Arrhenius formula, accelerated aging at 80°C for 12 days is equivalent to a shelf life of 2 years. The viscosity of the sample from Example 6 was measured after accelerated aging at 80°C for 12 days.

[0051] Cytotoxicity: After the adhesive droplets solidified into a film, they were extracted at a ratio of 6 cm² / mL. The extraction medium was MEM medium containing serum. The extraction temperature was 37±1℃ and the extraction time was 24±2h, in accordance with the extraction method specified in GB / T 16886.5-2017.

[0052] Table 5. Performance test results of Example 6 and Comparative Example 4

[0053] As shown in Table 5, in Example 6, under effective control of moisture and oxygen, the viscosity of the intravenous adhesive increased by less than 2% after 12 days of accelerated dry heat sterilization, and it could be stored at room temperature for 2 years. In Comparative Example 4, under conditions where moisture and oxygen could not be effectively controlled, the mechanical properties after dry heat sterilization were significantly lower than those of Example 6, and it was completely cured after 12 days of accelerated sterilization. Example 6, with preheating treatment of phosphorus pentoxide, showed a 100% survival rate of 79.95% for the intravenous adhesive and exhibited no cytotoxicity. Comparative Example 4, without preheating treatment, contained toxic metaphosphoric acid in its intravenous adhesive, resulting in failure to meet cytotoxicity standards.

[0054] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the present invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the present invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should also be covered within the protection scope of the present invention.

Claims

1. A method for preparing an intravenous adhesive suitable for terminal sterilization, characterized in that, Includes the following steps: Step 1: Mix cyanoacrylate, plasticizer, oxidant and free radical polymerization inhibitor in a reaction vessel and stir until homogeneous at room temperature; Step 2: Add the water-absorbing and acid-binding agent into the reaction vessel, adjust the reaction temperature, and stir until homogeneous; Step 3: Add polycyanoacrylate to the reaction vessel and stir at room temperature until completely dissolved; Step 4: Continue adding water-absorbing and acid-binding agent into the reaction vessel, adjust the reaction temperature, and stir evenly to obtain crude intravenous adhesive; Step 5: The crude intravenous adhesive obtained in Step 4 is filtered under nitrogen pressure to obtain the filtrate; Step 6: After filling the filtrate in an anhydrous and oxygen-free environment, terminal sterilization is performed to obtain an intravenous adhesive product with a viscosity of 0-3000cp. The water-absorbing and acid-binding agent is phosphorus pentoxide or sulfur dioxide; The oxidizing agent is one or more of hydrogen peroxide, sodium peroxide, and dilute nitric acid; The reaction temperature is adjusted according to the type of water-absorbing and acid-binding agent. When the water-absorbing and acid-binding agent is sulfur dioxide, the reaction temperature is room temperature; when the water-absorbing and acid-binding agent is phosphorus pentoxide, the reaction temperature is 40-60℃. In step one, by weight, there are 50-90 parts of cyanoacrylate, 5-20 parts of plasticizer, 0-0.1 parts of oxidant, and 0.01-0.1 parts of free radical polymerization inhibitor; The total amount of water-absorbing and acid-binding agent used is 0.01-0.1 parts by weight.

2. The preparation method according to claim 1, characterized in that, The cyanoacrylate is one or more of ethyl α-cyanoacrylate, n-butyl α-cyanoacrylate, n-octyl α-cyanoacrylate, isobutyl α-cyanoacrylate, and isooctyl α-cyanoacrylate; the plasticizer is one or more of triethyl citrate, tributyl citrate, and acetylated triethyl citrate; and the free radical polymerization inhibitor is one or more of butylated hydroxyanisole, hydroxyanisole, tert-butylcatechol, nitrobenzene, and hydroquinone.

3. The preparation method according to claim 1, characterized in that, In step three, the amount of polycyanoacrylate used is 5-30 parts by weight, the molecular weight of polycyanoacrylate is 0.5-200,000, and the polycyanoacrylate is one or more of poly(ethyl α-cyanoacrylate), poly(butyl α-cyanoacrylate), poly(octyl α-cyanoacrylate), poly(isobutyl α-cyanoacrylate), and poly(isooctyl α-cyanoacrylate).

4. The preparation method according to claim 1, characterized in that, In step four, a water-absorbing and acid-binding agent is added to the reaction vessel in portions.

5. The preparation method according to claim 1, characterized in that, In step six, terminal sterilization is either dry heat sterilization or irradiation sterilization.

6. A venous adhesive prepared by the preparation method according to any one of claims 1-5.

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