A sterilization method for a venous embolism adhesive

Abstract

The present invention belongs to the technical field of sterilization treatment of adhesives, and particularly relates to a sterilization method for venous embolization adhesives. The sterilization method for venous embolization adhesives provided by the present invention is mainly achieved through the following means: (1) The adhesive is sub-packaged, and it is ensured that the oxygen content is less than 1% and the moisture content is less than 1% during the sub-packaging process; (2) The sub-packaged adhesive is pre-treated by freezing; (3) The adhesive after the freezing treatment in step (2) is sterilized by low-temperature radiation. The beneficial effects of the present invention are that the adhesive undergoes three steps of sub-packaging to control water and oxygen, pre-freezing treatment before sterilization, and low-temperature radiation sterilization. This not only avoids the generation of more anion free radicals by radiation of water and oxygen in the product, resulting in anionic polymerization of cyanoacrylate, but also avoids the influence of traditional high-temperature radiation sterilization on the formaldehyde release and viscosity of the adhesive. Finally, an adhesive with controllable viscosity, low formaldehyde content, and safe and effective for clinical use can be prepared.

Description

Technical Field

[0001] The present invention belongs to the technical field of sterilization treatment of adhesives, and particularly relates to a sterilization method for venous embolization adhesives. Background Art

[0002] Adhesive injection closure is a non-thermal closure treatment for great saphenous varicose veins that has emerged in recent years. It can avoid the thermal damage and pain that may be caused by thermal closure treatment, and at the same time effectively close the main vein.

[0003] However, such adhesives are extremely sensitive to moisture and require aseptic operation during the preparation process. The radiation sterilization by ray irradiation will cause more anion free radicals to be generated from the moisture and oxygen in the adhesive. Since cyanoacrylate has a strong electron-withdrawing group, it is very easy to undergo anionic polymerization, resulting in an increase in the viscosity of the adhesive or even curing.

[0004] If adhesives with different viscosities are not cryogenically treated before sterilization, it is very likely that the adhesives will cure during sterilization.

[0005] In addition, the ray energy of radiation sterilization is relatively high, and the temperature of the adhesive will increase during the sterilization process, causing polymerization of the adhesive and release of formaldehyde. Low-temperature radiation can avoid these problems.

[0006] Therefore, through sub-packaging to control water and oxygen, cryogenic treatment before sterilization, and low-temperature sterilization control, the influence of radiation sterilization on the adhesive is avoided, and an adhesive with controllable viscosity, low formaldehyde, and safe and effective for clinical use can be prepared.

[0007] In order to further ensure the quality of venous embolization adhesive products, it is very necessary to provide an efficient sterilization method that can neither affect the stability of the adhesive products nor further improve their shelf life. Summary of the Invention

[0008] To solve the above technical problems, the present invention provides a sterilization method for venous embolization adhesives.

[0009] Regarding the sterilization method for venous embolization adhesives provided by the present invention, on the one hand, the present invention strictly controls the water and oxygen conditions during the adhesive treatment process, avoiding the generation of more free radicals from the moisture and oxygen in the product, which causes the polymerization reaction of cyanoacrylate monomers to accelerate; on the other hand, cryogenic treatment is carried out before sterilization, which helps to passivate the adhesive, increase the reaction activation energy of the adhesive, make the adhesive not easily polymerize, improve the stability of the adhesive performance, and at the same time further avoid the influence of radiation sterilization on the adhesive.

[0010] The sterilization method for venous embolization adhesives provided by the present invention includes the following steps:

[0011] (1) Subpackage the adhesive;

[0012] (2) Freeze the subpackaged adhesive obtained in step (1);

[0013] (3) Perform low-temperature radiation sterilization on the frozen adhesive obtained in step (2) above.

[0014] In the above step (1), during the process of subpackaging the adhesive, ensure that the oxygen content in the subpackage is less than 1% and the moisture content is less than 1%.

[0015] In the above step (1), perform water and oxygen control operations when subpackaging the adhesive.

[0016] In the above step (2), for the said freezing treatment, the freezing temperature is -30 to -10 °C and the freezing time is 24 - 72 h.

[0017] For the low-temperature radiation sterilization described in step (3), the sterilization method used is any one of: E-beam, γ-ray, and microwave sterilization.

[0018] For the low-temperature radiation sterilization described in step (3), the sterilization conditions are: in the small-dose accumulation mode, the accumulation times are 3 - 6 times, the total sterilization dose is 10 - 30 kGy, and the radiation temperature is controlled at 0 - 35 °C.

[0019] The molecular weight of the venous embolization adhesive described in the present invention is below 200,000.

[0020] The venous embolization adhesive described in the present invention is prepared from the following raw materials in the following weight ratios:

[0021] Cyanoacrylates 50 - 90%, thickener 5 - 30%, plasticizer 5 - 30%, inhibitor 0.01 - 0.5%, antioxidant 0.01 - 0.5%.

[0022] Preferably, the cyanoacrylates in the above raw materials are any one of n-octyl cyanoacrylate and n-butyl cyanoacrylate;

[0023] The thickener is any one of poly(n-butyl cyanoacrylate) powder and n-octyl cyanoacrylate powder;

[0024] The plasticizer is any one of triethyl citrate and triethyl acetylcitrate; the inhibitor is any one of sulfur dioxide and phosphoric acid;

[0025] The antioxidant is any one of butylated hydroxyanisole and hydroquinone.

[0026] Preferably, the venous embolism adhesive is prepared from the following raw materials in the following weight ratios: n-butyl cyanoacrylate 89.98%, poly(n-butyl cyanoacrylate) powder 5%, triethyl citrate 5%, sulfur dioxide 0.01%, butylated hydroxyanisole 0.01%.

[0027] Or it is prepared from the following raw materials in the following weight ratios:

[0028] n-octyl cyanoacrylate 60%, acetyltriethyl citrate 19.8%, phosphoric acid 0.1%, hydroquinone 0.1%, poly(n-octyl cyanoacrylate) powder 20%.

[0029] The venous embolism adhesive described in the present invention is prepared in the following manner:

[0030] Add n-butyl cyanoacrylate, triethyl citrate, sulfur dioxide, and butylated hydroxyanisole into a container, stir for 0.5 - 1.5 h, then slowly add poly(n-butyl cyanoacrylate) powder, and continue stirring and reacting for 2 - 4 h until the solid powder is completely dissolved, then filter to obtain it;

[0031] Or:

[0032] Add n-octyl cyanoacrylate, acetyltriethyl citrate, phosphoric acid, and hydroquinone into a container, stir for 0.5 - 1.5 h, then slowly add poly(n-octyl cyanoacrylate) powder, and continue stirring for 2 - 4 h until the solid powder is completely dissolved, then filter to obtain it.

[0033] Preferably, for the adhesive prepared above for treating venous embolism, after filtration treatment, it further includes operations such as sub-packaging the adhesive using a glove box, freeze-treating the sub-packaged adhesive, and performing low-temperature radiation sterilization on the freeze-treated adhesive.

[0034] The beneficial effects of the present invention are as follows:

[0035] (1) The present invention provides a sterilization method for an adhesive for treating venous embolism, that is, through sub-packaging to control water and oxygen, pre-freeze treatment before sterilization, and low-temperature sterilization control, which avoids the influence of radiation sterilization on the adhesive, makes the adhesive not easily polymerize, and greatly improves the stability. An adhesive with controllable viscosity, low formaldehyde content, and safe and effective for clinical use can be prepared.

[0036] (2) The sterilization method of the present invention needs to be combined with special sub-packaging treatment operations for the adhesive, that is, strictly controlling water and oxygen during the treatment process of the adhesive to ensure that the oxygen content in the adhesive during sub-packaging is less than 1% and the water content is less than 1%. It avoids the generation of more anion free radicals due to the radiation of moisture and oxygen in the product, and cyanoacrylate has a strong electron-withdrawing group and is very easy to undergo anionic polymerization, resulting in an increase in the viscosity of the adhesive or even curing.

[0037] (3) The sterilization method of the present invention also requires a freezing treatment before sterilization. The freezing temperature is -30 to -10 °C, and the freezing time is 24 - 72 h. This inactivates the activity of the adhesive, making it require a greater reaction activation energy for curing. Therefore, the adhesive is not prone to polymerization.

[0038] (4) In the low-temperature sterilization method of the present invention, the sterilization method is any one of E-beam, γ-ray, or microwave sterilization. The conditions for radiation sterilization are as follows: in a small-dose accumulation mode, the accumulation times are 3 - 6 times, the total sterilization dose is 10 - 30 kGy, the radiation temperature is controlled at 0 - 35 °C. Since the radiation energy of radiation sterilization is relatively high, the temperature of the adhesive will rise during the sterilization process, which may cause the polymerization of the adhesive and the release of formaldehyde. Low-temperature radiation can avoid these problems. Description of the Drawings

[0039] Figure 1 It is a temperature indication label diagram for the sterilization process of the product in Example 1;

[0040] Figure 2 It is a diagram showing the moisture content and oxygen content during the product sub-packaging process in Example 2;

[0041] Figure 3 It is a diagram showing the relationship between the viscosity and aging time of the products in Example 6 and Comparative Examples 1 - 2;

[0042] Figure 4 It is a diagram showing the relationship between the curing time and aging time of the products in Example 6 and Comparative Examples 1 - 2. Detailed Embodiments

[0043] In order to enable those skilled in the art to better understand the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0044] Examples 1 - 5

[0045] Add 89.98% of n-butyl cyanoacrylate, 5% of triethyl citrate, 0.01% of sulfur dioxide, and 0.01% of butylated hydroxyanisole into a container, and stir at room temperature for 1 h; then slowly add 5% of poly(n-butyl cyanoacrylate) powder. After all the raw materials are added, continue to stir for 3 h until the solid powder is completely dissolved, and then filter;

[0046] Sub-package the obtained adhesive product in a glove box, and during the sub-packaging process, control the oxygen content to be less than 1% and the water content to be less than 1%.

[0047] After sub-packaging, put it into an ultra-low temperature refrigerator and perform a freezing treatment at a temperature of -30 to -10 °C.

[0048] Finally, radiation sterilization is adopted, and the sterilization conditions are as follows: E-beam sterilization, and the radiation sterilization conditions are in the form of small-dose accumulation. The accumulation times are 3 - 6 times, the total sterilization dose is 10 - 30 kGy, and the radiation temperature is controlled at 0 - 35°C.

[0049] In Examples 1 - 5, the sterilization doses, freezing conditions, and sterilization accumulation times are different, only the component types are the same. The reaction activation energies before and after freezing are detected, and the specific parameters of each example are shown in Table 1.

[0050] Table 1 Parameter settings of Examples 1 - 5

[0051]

[0052] For the adhesive products finally obtained in Examples 1 - 5, performance tests are carried out on sterilization temperature, curing time, viscosity, formaldehyde residue, oxygen content, water content, and reaction activation energy.

[0053] The performance evaluation is carried out according to the following criteria:

[0054] (1) Sterilization temperature: The temperature after sterilization is detected using an irreversible temperature indicating label.

[0055] (2) Curing time: In a petri dish with a diameter of 90 mm, add 30 - 50 mL of 0.3 g / L NaHCO3 solution. Drop a drop of the sample about 1 cm above the liquid surface, and record the curing time of the sample.

[0056] (3) Viscosity: Refer to GB / T 2794 - 2013 "Determination of Viscosity of Adhesives - Single Cylinder Rotational Viscometer Method".

[0057] (4) Formaldehyde residue: Detected using an ultraviolet spectrophotometer.

[0058] (5) Oxygen content test method: Detected using an oxygen analyzer.

[0059] (6) Water content test method: Refer to the first method (Karl Fischer method) of the moisture determination method (General Rules 0832) in the "Pharmacopoeia of the People's Republic of China" (Part IV).

[0060] (7) Reaction activation energy: Detected using a differential scanning calorimeter.

[0061] Among them, Figure 1 is the temperature indicating label diagram of the adhesive product in Example 1 after sterilization;

[0062] Figure 2 is the water content and oxygen content indicating diagram during the product sub-packaging process of Example 2;

[0063] The performance evaluation results of the products in Examples 1 - 5 are shown in Table 2.

[0064] Table 2 Performance Evaluation of Products in Examples 1 - 5

[0065]

[0066] The reaction activation energy is the energy required for the curing of the reaction adhesive. The higher the activation energy, the more difficult the curing, and the less likely the adhesive is to cure. The reaction activation energy of the adhesive increases with the decrease of the freezing temperature, that is, the freezing treatment can passivate the activity of the adhesive.

[0067] It can be seen from the data in the above table that for the adhesive products obtained in Examples 1 - 5, when the moisture, oxygen and temperature before radiation are effectively controlled, the reaction activation energy slightly decreases after radiation, and the change is not significant, indicating that the low-temperature radiation sterilization control has little effect on the curing of the adhesive;

[0068] At the same time, although the performance indexes such as the curing time, viscosity, formaldehyde residue, oxygen content and water content before and after radiation increase slightly, the change is not significant, and the impact on the overall performance of the adhesive is also not significant, ensuring the safety and effectiveness of the adhesive in clinical use.

[0069] Examples 6 - 10

[0070] Add 60% n-octyl cyanoacrylate, 19.8% triethyl acetylcitrate, 0.1% phosphoric acid, and 0.1% hydroquinone into a container, and stir at room temperature for 1 h; then slowly add 20% poly(n-octyl cyanoacrylate) powder. After all the raw materials are added, continue to stir for 3 h until the solid powder is completely dissolved, and then filter;

[0071] Dispense the obtained adhesive product in a glove box, and during the dispensing process, control the oxygen content in the dispensing to be less than 1% and the water content to be less than 1%.

[0072] After dispensing, put it into an ultra-low temperature refrigerator and perform freezing treatment at a temperature of -30 to -10 °C.

[0073] Finally, perform radiation sterilization. The sterilization conditions are: E electron beam sterilization. The radiation sterilization conditions are in the form of small-dose accumulation, the accumulation times are 3 - 6 times, the total sterilization dose is 10 - 30 kGy, and the radiation temperature is controlled at 0 - 35 °C.

[0074] The sterilization doses, freezing conditions, and sterilization accumulation times of each component in Examples 6 - 10 are different, but only the component types are the same, and the reaction activation energy is detected before and after freezing.

[0075] See Table 3 for the specific parameter settings of Examples 6 - 10.

[0076] Table 3 Parameter Settings of Each Component in Examples 6 - 10

[0077]

[0078] For Examples 6 - 10, performance tests were conducted on sterilization temperature, curing time, viscosity, formaldehyde residue, oxygen content, water content, and reaction activation energy. The performance evaluation results of the products are shown in Table 4.

[0079] Table 4 Performance Evaluation of Products in Examples 6 - 10

[0080]

[0081] From the above data, it can be seen that in Examples 6 - 10, under the condition of high viscosity, the moisture, oxygen content, and temperature before radiation were effectively controlled. The performance indicators of curing time, viscosity, formaldehyde residue, oxygen content, and water content before and after radiation changed slightly more than those of the low - viscosity adhesive, and the viscosity index was more obvious. This is because the polyester content in the high - viscosity adhesive is high, and polymerization is more likely to occur. Therefore, the viscosity change range is slightly larger. However, under the sterilization method of the present invention, the viscosity change is not more than 5%. Although the reaction activation energy decreased slightly after sterilization, the change was not significant. Therefore, the impact on the overall performance of the adhesive is not great, and it also ensures the safety and effectiveness of the adhesive in clinical use.

[0082] Comparative Examples 1 - 2

[0083] Based on the fact that the viscosity change of the adhesive before and after sterilization in high viscosity is slightly larger, and the reaction activation energy after sterilization is generally lower than that of the low - viscosity adhesive, considering whether it affects the later product quality of the adhesive, a stability experiment was therefore carried out.

[0084] The material compositions and ratios of Comparative Examples 1 - 2 are the same as those of Example 6.

[0085] In Comparative Example 1, glove - box dispensing and low - temperature freezing were not used, and direct radiation sterilization was carried out under the same sterilization conditions as Example 6.

[0086] In Comparative Example 2, glove - box dispensing and low - temperature freezing were used, but dry - heat sterilization was adopted, with a sterilization temperature of 140 °C and a sterilization time of 3 - 4 h.

[0087] Stability: The products were placed in a constant - temperature and constant - humidity box at a temperature of 35 °C and a humidity of 28%, and the viscosity and curing time were detected at regular intervals.

[0088] The performance evaluation of the products in Example 6 and Comparative Examples 1 - 2 is shown in Table 5.

[0089] For the sake of more clear and accurate understanding, the changes in viscosity and curing time of the products in Example 6 and Comparative Examples 1 - 2 with aging time are presented in the form of a line chart, as shown in Figure 3 、 Figure 4 。

[0090] Table 5 Performance Evaluation of Products in Example 6 and Comparative Examples 1 - 2

[0091]

[0092] It can be seen from the above table data that in Example 6, with the extension of the aging time, the viscosity and curing time performance of the adhesive hardly change, the performance is stable, and it can be stored for a long time under the condition of effectively controlling the moisture, oxygen and temperature before radiation.

[0093] In Comparative Example 1, since the moisture, oxygen and temperature before radiation were not controlled, it can be seen that with the extension of the aging time, the viscosity of the adhesive increased significantly and the curing time was further extended.

[0094] The specific principle is as follows: on the one hand, the ray energy of radiation sterilization will cause the temperature of the adhesive to rise to 62.5 - 65 °C. At the same time, the reaction activation energy of the adhesive is relatively low, and the monomers in the adhesive undergo a polymerization reaction under this condition to generate oligomers, resulting in an increase in viscosity; on the other hand, the residual moisture and oxygen in the adhesive generate more free radicals through radiation, accelerating the polymerization reaction.

[0095] For the adhesive prepared in Comparative Example 2, with the extension of the aging time, the viscosity increased sharply, and the fluidity was very poor and close to curing at the 6th month; at the same time, the curing time was also extended. The reason for this phenomenon is that the dry heat sterilization temperature is high and the time is long, and the adhesive is very easy to undergo a polymerization reaction at this high temperature, generating a large amount of polymers, resulting in a relatively large increase in viscosity and instability.

Claims

1. A sterilization method for a venous embolism adhesive, characterized in that, Including the following steps: (1) Sub-packaging the adhesive product in a glove box, wherein during the sub-packaging process, the oxygen content of the sub-packaging is controlled to be less than 1% and the water content is less than 1%; The adhesive product is prepared by the following method: Add 89.98% of n-butyl cyanoacrylate, 5% of triethyl citrate, 0.01% of sulfur dioxide, and 0.01% of butylated hydroxyanisole into a container, stir at room temperature for 1 h, then slowly add 5% of poly(n-butyl cyanoacrylate) powder. After all the raw materials are added, continue to stir for 3 h until the solid powder is completely dissolved, and then filter; (2) After the sub-packaging is completed, put the adhesive product sub-packaged in (1) into an ultra-low temperature refrigerator and freeze it at a temperature of -30°C for 72 h; (3) Sterilize the adhesive product in (2) by radiation sterilization. The sterilization condition is E-beam sterilization. The radiation sterilization condition is in a small-dose accumulation mode, the accumulation times is 6 times, the total sterilization dose is 30 kGy, and the radiation temperature is controlled to be less than 27.5°C.

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