Medical adhesive and preparation method thereof

Abstract

The invention relates to a medical adhesive and a preparation method thereof. The medical adhesive is prepared from the following raw materials in parts by mass: 60 to 90 parts of cyanoacrylate, 5 to 30 parts of plasticizer, 0 to 7 parts of acrylate rubber, 0.05 to 0.08 part of polyoxyethylene hydrogenated castor oil and 0.02 to 0.04 part of hydroquinone. The medical adhesive has proper viscosity after being sterilized at high temperature, is proper in adhesive strength and hardness after being cured, can have flexibility on the premise of ensuring the blood vessel closing effect, does not have obvious foreign body sensation even under the conditions that limbs act and the blood vessel form is changed, and can be used for preparing the medical adhesive. And even blood vessels are punctured.

Description

Technical Field

[0001] This invention relates to the field of medical materials, and in particular to a medical adhesive and its preparation method. Background Technology

[0002] Varicose veins, especially those in the lower extremities, are the most important disease of the venous system and one of the most common vascular diseases of the limbs. Symptoms vary in severity. Mild cases often present with symptoms such as heaviness, swelling, fatigue, and weakness, which usually occur when standing at rest and disappear quickly after walking or lying down. As the symptoms worsen, the superficial veins in the lower extremities become prominent, dilated, and even tortuous or clumped, becoming more noticeable when standing. Furthermore, it can lead to nutritional changes in the skin, such as thinning, desquamation, pigmentation, eczematous dermatitis, liposcleroderma, and white atrophy. Itching can cause scratching, leading to secondary infections and venous ulcers. Additionally, it can cause thrombophlebitis and acute bleeding. Therefore, varicose veins not only alter the appearance of the lower extremities, affecting aesthetics, but also pose a serious challenge to the patient's health.

[0003] The core principle of varicose vein treatment is to block blood flow in the varicose veins, preventing them from affecting normal blood vessels or further developing and worsening symptoms. Tissue-based medical adhesives can quickly and effectively close wounds, especially non-absent wounds on the skin surface, and their safety has been proven through years of clinical application. The main component of this adhesive is cyanoacrylate, with α-cyanoacrylate being the most commonly used. After thorough wound cleaning, a polymerization reaction is initiated by air, a small amount of water or anions in the wound, forming a film within tens of seconds that evenly covers the wound surface. This film inhibits bacterial growth, promotes rapid wound healing, and eliminates the need for suture removal. Applying tissue-based medical adhesives to varicose veins will make venous closure even easier.

[0004] Traditional cyanoacrylate medical adhesives are mostly used on the skin surface. Only adhesives used for embolization in the treatment of gastric varicose veins are implanted into the human body. Currently, there are no commercially available medical adhesives for treating varicose veins in the lower extremities, with only a few in clinical trials. However, these medical adhesives suffer from problems such as high hardness after curing, strong foreign body sensation, and a tendency to cause adverse reactions like phlebitis. Furthermore, the traditional preparation process for medical adhesives involves only mixing at room temperature or low temperature, without high-temperature sterilization, thus failing to meet the requirements for medical dry heat sterilization. Summary of the Invention

[0005] Therefore, it is necessary to provide a medical adhesive and its preparation method, which can have a suitable viscosity after high-temperature sterilization, and has appropriate adhesion and hardness after curing, so as to not only ensure the closure effect of blood vessels, but also take into account a certain degree of flexibility.

[0006] A medical adhesive, wherein the raw materials for preparing the medical adhesive, by weight, include: 60-90 parts of cyanoacrylate, 5-30 parts of plasticizer, 0-7 parts of acrylate rubber, 0.05-0.08 parts of polyoxyethylene hydrogenated castor oil, and 0.02-0.04 parts of hydroquinone.

[0007] In some embodiments, the cyanoacrylate includes one or both of α-butyl cyanoacrylate and α-octyl cyanoacrylate.

[0008] In some embodiments, the cyanoacrylate comprises α-butyl cyanoacrylate and α-octyl cyanoacrylate in a mass ratio of (5~6):(2~3).

[0009] In some embodiments, the plasticizer includes a citrate plasticizer, which includes one or more of triethyl citrate, tributyl citrate, acetylated triethyl citrate, and acetylated tributyl citrate.

[0010] In some embodiments, the raw materials for preparing the medical adhesive, by weight, include: 50 to 60 parts of n-butyl α-cyanoacrylate, 20 to 30 parts of n-octyl α-cyanoacrylate, 10 to 30 parts of plasticizer, 5 to 7 parts of acrylate rubber, 0.05 to 0.08 parts of polyoxyethylene hydrogenated castor oil, and 0.02 to 0.04 parts of hydroquinone.

[0011] In some embodiments, the medical adhesive satisfies one or more of the following conditions:

[0012] (1) The viscosity of the medical adhesive at 25°C is 1200 mPa·s to 1400 mPa·s;

[0013] (2) The T-peel strength of the medical adhesive is 1N~4N;

[0014] (3) The curing time of the medical adhesive is 10s~120s.

[0015] A method for preparing a medical adhesive includes the following steps:

[0016] The raw materials are mixed and stirred, and then sterilized by dry heat to prepare the medical adhesive;

[0017] The raw materials, by weight, include: 60-90 parts of cyanoacrylate, 5-30 parts of plasticizer, 0-7 parts of acrylate rubber, 0.05-0.08 parts of polyoxyethylene hydrogenated castor oil, and 0.02-0.04 parts of hydroquinone.

[0018] In some embodiments, the temperature for mixing and stirring the raw materials is 60°C to 65°C, and the time is 10 min to 60 min.

[0019] In some embodiments, the step of mixing and stirring the raw materials includes:

[0020] The polyoxyethylene hydrogenated castor oil is kept at 60℃~65℃ for 10min~15min, and 0.05 part~0.08 part is added to the reaction vessel. The temperature is kept at 60℃~65℃ for another 10min~30min. The mixture is then cooled to allow the polyoxyethylene hydrogenated castor oil to spread at the bottom of the reaction vessel.

[0021] Add 60-90 parts of cyanoacrylate, 5-30 parts of plasticizer, 0-7 parts of acrylate rubber, and 0.02-0.04 parts of hydroquinone to the reaction vessel, and stir at 60-65°C for 10-60 minutes.

[0022] In some embodiments, the dry heat sterilization step is performed at a temperature of 160°C to 165°C for 2 hours to 4 hours.

[0023] The inventors discovered in their experiments that, due to the high reactivity of cyanoacrylate, traditional medical adhesives are typically mixed only at room temperature or low temperature to achieve a suitable viscosity, but this often fails to meet sterility requirements. The aforementioned medical adhesive, however, achieves synergy among its components through adjustments to their proportions. This allows for sterilization via dry heat, maintaining the adhesive viscosity within a suitable range while simultaneously meeting sterility requirements. Furthermore, the synergistic effect of the components ensures effective vascular closure while maintaining flexibility after curing. Even during limb movement and changes in blood vessel morphology, there is no noticeable foreign body sensation or risk of blood vessel puncture. Attached Figure Description

[0024] To more clearly illustrate the technical solutions in the embodiments of this application, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0025] Figure 1 This is a process flow diagram of the preparation method of medical adhesive in some embodiments. Detailed Implementation

[0026] To facilitate understanding of the present invention, a more comprehensive description of the invention will be provided below in conjunction with specific embodiments. Preferred embodiments of the invention are given in the specific embodiments. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0028] Unless otherwise stated or in case of contradiction, the terms or phrases used in this invention shall have the following meanings:

[0029] In this invention, "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined with "first" and "second" may explicitly or implicitly include at least one of those features.

[0030] In the description of this invention, "a plurality of" means at least two, such as two, three, etc., unless otherwise explicitly specified.

[0031] In this invention, "one or several" refers to any one, any two, or any two or more of the listed items. "Several" refers to any two or more.

[0032] In this invention, unless otherwise specified, all percentage concentrations refer to the final concentration. The final concentration refers to the proportion of the added component in the system after the addition of that component.

[0033] The terms "preferred," "more preferably," etc., used in this invention refer to embodiments of the invention that provide certain beneficial effects under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the description of one or more preferred embodiments does not imply that other embodiments are unavailable, nor is it intended to exclude other embodiments from the scope of this invention.

[0034] When a numerical range is disclosed in this invention, the range is considered continuous and includes the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Further, when the range refers to an integer, it includes every integer between the minimum and maximum values ​​of the range. Moreover, when multiple ranges are provided to describe a feature or characteristic, the ranges may be combined. In other words, unless otherwise specified, all ranges disclosed in this invention should be understood to include any and all subranges to which they are incorporated.

[0035] In this invention, the technical features described in an open-ended manner include both closed-ended technical solutions composed of the listed features and open-ended technical solutions that include the listed features.

[0036] The terms "comprising" and "having," and any variations thereof, used in embodiments of this invention are intended to cover non-exclusive inclusion. For example, a process, method, system, product, or device that includes a series of steps or units is not limited to the steps or units listed, but may optionally include steps or units not listed, or may optionally include other steps or components inherent to such processes, methods, products, or devices.

[0037] In this invention, the reference to "embodiment" means that a specific feature, structure, or characteristic described in connection with an embodiment may be included in at least one embodiment of this application. The appearance of this phrase in various places in the specification does not necessarily refer to the same embodiment, nor is it a mutually exclusive, independent, or alternative embodiment. It will be explicitly and implicitly understood by those skilled in the art that the embodiments described in this invention can be combined with other embodiments.

[0038] Currently, the treatment of varicose veins is mainly divided into four categories: (1) conservative treatment, namely wearing elastic stockings for pressure treatment or taking medication; (2) sclerotherapy, using sclerosing agents such as polidocanol to occlude blood vessels to achieve the therapeutic effect; (3) surgical treatment, selecting a suitable location to ligate the veins and stripping the varicose veins; (4) minimally invasive treatment, including electrocoagulation, laser (EVLT), radiofrequency ablation (RFA), and transillumination varicose vein peeling (TIPP).

[0039] Each treatment method has its own limitations or shortcomings. For example, conservative treatment is simple to perform but requires long-term treatment, which tests the patient's compliance; sclerotherapy is less painful and less expensive, but it is prone to recurrence and requires a high level of skill from the surgeon; surgical treatment can completely solve the problem of varicose veins, but it is more invasive to patients, requires a longer hospital stay, and is relatively more expensive; minimally invasive treatment can treat varicose veins in a targeted manner while reducing patient trauma, but it requires high-level treatment equipment and skilled surgeons, and no single treatment method is suitable for all types of varicose veins.

[0040] As described in the background section, applying tissue adhesives to varicose veins would make venous closure easier. Therefore, researching a medical adhesive suitable for treating varicose veins in the lower extremities has excellent application prospects. However, traditional medical adhesives have poor flexibility, and their preparation process involves only room temperature or low-temperature mixing, without high-temperature dry heat sterilization, thus failing to meet the requirements for medical dry heat sterilization (160°C for more than 2 hours, or 170°C for more than 1 hour, or 180°C for more than half an hour).

[0041] Based on this, the first aspect of the present invention provides a medical adhesive, wherein the raw materials for preparing the medical adhesive, by weight, include: 60 to 90 parts of cyanoacrylate, 5 to 30 parts of plasticizer, 0 to 7 parts of acrylate rubber, 0.05 to 0.08 parts of polyoxyethylene hydrogenated castor oil, and 0.02 to 0.04 parts of hydroquinone.

[0042] In some embodiments, the cyanoacrylate includes one or both of butyl α-cyanoacrylate (NBCA) and octyl α-cyanoacrylate (NOCA). Preferably, the cyanoacrylate includes both NBCA and NOCA. Experiments have shown that using NOCA in combination with NBCA can reduce the curing speed while maintaining the adhesive strength of medical adhesives, and at the same time improve the toughness of the cured film.

[0043] Furthermore, the mass ratio of NBCA to NOCA is (5~6):(2~3). Specifically, in the raw materials for preparing medical adhesives, the mass fraction of α-cyanoacrylate n-butyl ester is 50 parts to 60 parts, and the mass fraction of α-cyanoacrylate n-octyl ester is 20 parts to 30 parts.

[0044] In some embodiments, the raw materials for preparing the medical adhesive, by weight, include: 50 to 60 parts of n-butyl α-cyanoacrylate, 20 to 30 parts of n-octyl α-cyanoacrylate, 5 to 30 parts of plasticizer, 0 to 7 parts of acrylate rubber, 0.05 to 0.08 parts of polyoxyethylene hydrogenated castor oil, and 0.02 to 0.04 parts of hydroquinone.

[0045] Optionally, the mass fractions of cyanoacrylate may be, but are not limited to, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90 parts or any combination of these values.

[0046] By selecting and adjusting the dosage of polyoxyethylene hydrogenated castor oil, the viscosity of the raw material can be gradually increased under heating conditions through magnetic stirring. Dry heat sterilization then controls the viscosity of the medical adhesive within a suitable range, while also meeting sterility requirements. Furthermore, if the dosage of polyoxyethylene hydrogenated castor oil is too high, the viscosity of the medical adhesive increases too rapidly, curing before sterilization and rendering it unusable. If the dosage of polyoxyethylene hydrogenated castor oil is too low, the curing time is too short, and the flexibility is significantly reduced.

[0047] In some embodiments, the polyoxyethylene hydrogenated castor oil may be, but is not limited to, PEG-60; for example, the polyoxyethylene hydrogenated castor oil may also be PEG-40, etc.

[0048] Optionally, in some embodiments, the mass fraction of polyoxyethylene hydrogenated castor oil in the raw materials for preparing the medical adhesive is 0.05 to 0.08 parts. For example, the mass fraction of polyoxyethylene hydrogenated castor oil in the raw materials for preparing the medical adhesive may be, but is not limited to, 0.05 parts, 0.055 parts, 0.06 parts, 0.065 parts, 0.07 parts, 0.075 parts, 0.08 parts, or any combination of these values.

[0049] By incorporating acrylate rubber (ACM) into other components, the flexibility of the cured medical adhesive is further improved while ensuring effective vascular closure. Even during limb movement and changes in blood vessel morphology, there is no noticeable foreign body sensation, and there is no risk of blood vessel puncture. However, if too much acrylate rubber is used, the cured medical adhesive will have excellent toughness but insufficient adhesive strength and an excessively long curing time, which is detrimental to practical applications. Therefore, it is understood that in some embodiments, acrylate rubber may not be added.

[0050] In a specific example, the mass fraction of acrylate rubber in the raw materials for preparing the medical adhesive can be, but is not limited to, 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, or any combination of these values. Preferably, the mass fraction of acrylate rubber in the raw materials for preparing the medical adhesive is 5 to 7 parts. At these mass fractions, both curing speed and post-curing flexibility can be further balanced.

[0051] By adding hydroquinone and adjusting its dosage, and combining it with other components, the viscosity of the medical adhesive can be controlled within a suitable range. This prevents the injected medical adhesive from being diluted by blood or washed away to unintended sites and solidifying, thus extending the shelf life of the medical adhesive. Too much hydroquinone will prolong the thickening time, while too little will result in poor product stability and easy solidification into a film under sterile conditions.

[0052] Optionally, the mass fraction of hydroquinone in the raw materials for preparing medical adhesives is 0.02 to 0.04 parts. For example, the mass fraction of hydroquinone in the raw materials for preparing medical adhesives may be, but is not limited to, 0.02 parts, 0.025 parts, 0.03 parts, 0.035 parts, 0.04 parts, or any combination of these values.

[0053] In some embodiments, the plasticizer includes a citrate plasticizer. For example, in a specific example, the plasticizer includes triethyl citrate (TEC). It is understood that the plasticizer may also be tributyl citrate, acetylated triethyl citrate, acetylated tributyl citrate, etc. Specifically, the citrate plasticizer includes one or more of triethyl citrate, tributyl citrate, acetylated triethyl citrate, and acetylated tributyl citrate.

[0054] Optionally, in the raw materials for preparing medical adhesives, the mass fraction of the plasticizer can be, but is not limited to, 5 parts, 6 parts, 8 parts, 10 parts, 12 parts, 14 parts, 16 parts, 18 parts, 20 parts, 22 parts, 24 parts, 26 parts, 28 parts, 30 parts, or any combination of these values. In a specific example, the mass fraction of the plasticizer is 10 to 30 parts. If the mass fraction of the plasticizer is less than 5 parts, the prepared medical adhesive has poor performance, similar to pure cyanoacrylate. If the mass fraction of the plasticizer exceeds 30 parts, the bonding effect is poor. When the mass fraction of the plasticizer is between 5 and 30 parts, it has a certain bonding effect. Preferably, the effect is significant when the mass fraction of the plasticizer is between 10 and 30 parts. Therefore, in some embodiments, the mass fraction of the plasticizer is 5 to 30 parts, and preferably, it is 10 to 30 parts.

[0055] In some embodiments, the raw materials for preparing the medical adhesive, by weight, include: 50 to 60 parts of n-butyl α-cyanoacrylate, 20 to 30 parts of n-octyl α-cyanoacrylate, 10 to 30 parts of plasticizer, 5 to 7 parts of acrylate rubber, 0.05 to 0.08 parts of polyoxyethylene hydrogenated castor oil, and 0.02 to 0.04 parts of hydroquinone.

[0056] Furthermore, by weight, the raw materials for preparing the medical adhesive include: 55 parts of n-butyl α-cyanoacrylate, 30 parts of n-octyl α-cyanoacrylate, 10 parts of plasticizer, 5 parts of acrylate rubber, 0.05 parts of polyoxyethylene hydrogenated castor oil, and 0.02 parts of hydroquinone.

[0057] In some embodiments, the viscosity of the medical adhesive at 25°C is 1200 mPa·s to 1400 mPa·s. This viscosity is suitable for injection and storage. For example, the viscosity of the medical adhesive at 25°C may be, but is not limited to, 1200 mPa·s, 1220 mPa·s, 1240 mPa·s, 1260 mPa·s, 1280 mPa·s, 1300 mPa·s, 1320 mPa·s, 1340 mPa·s, 1360 mPa·s, 1380 mPa·s, 1400 mPa·s, or any range of these values. Further, the viscosity of the medical adhesive at 25°C is 1200 mPa·s to 1300 mPa·s.

[0058] In some embodiments, the T-peel strength of the medical adhesive is 1N to 4N. For example, the T-peel strength of the medical adhesive may be, but is not limited to, 1N, 1.5N, 2N, 2.5N, 3N, 3.5N, 4N, or any combination of these values.

[0059] In some embodiments, the curing time of the medical adhesive is 10s to 120s. For example, the curing time of the medical adhesive may be, but is not limited to, 10s, 20s, 30s, 40s, 50s, 60s, 70s, 80s, 90s, 100s, 110s, 120s, or any combination of these values. Optionally, the curing time of the medical adhesive is 60s to 120s.

[0060] In some embodiments, the cured medical adhesive film can withstand five 180° bends without breaking. Furthermore, the cured medical adhesive film can withstand ten 180° bends without breaking.

[0061] Furthermore, in some embodiments, the medical adhesive has a viscosity of 1200 mPa·s to 1400 mPa·s at 25°C, a T-peel strength of 1 N to 4 N, and a curing time of 10 s to 120 s. The cured adhesive film can be bent back and forth 5 times at 180° without breaking. Even further, the medical adhesive has a viscosity of 1200 mPa·s to 1300 mPa·s at 25°C, a T-peel strength of 1 N to 4 N, and a curing time of 60 s to 120 s. The cured adhesive film can be bent back and forth 180° 10 times without breaking. The above-mentioned medical adhesives, after curing, have suitable adhesive strength and hardness, ensuring not only the closure effect of blood vessels but also a certain degree of flexibility, allowing them to conform to the deformation of blood vessels or limbs without causing a noticeable foreign body sensation.

[0062] The aforementioned medical adhesives have at least the following advantages:

[0063] The aforementioned medical adhesive, through adjustments to its components and proportions, achieves synergy among the components, enabling sterilization via dry heat sterilization. This allows the viscosity of the medical adhesive to be controlled within a suitable range while also meeting sterility requirements. Furthermore, the aforementioned medical adhesive, while ensuring vascular closure, also maintains flexibility after curing, so that even when the limb moves and the vascular morphology changes, there will be no obvious foreign body sensation or even puncture of the blood vessel.

[0064] A second aspect of the present invention provides a method for preparing a medical adhesive, comprising the following steps:

[0065] The raw materials are mixed and stirred, and then sterilized by dry heat to prepare the medical adhesive;

[0066] The raw materials, by weight, include: 60-90 parts of cyanoacrylate, 5-30 parts of plasticizer, 0-7 parts of acrylate rubber, 0.05-0.08 parts of polyoxyethylene hydrogenated castor oil, and 0.02-0.04 parts of hydroquinone.

[0067] In some embodiments, during the step of mixing and stirring the raw materials, the temperature is 60°C to 65°C and the time is 10 min to 60 min.

[0068] In some embodiments, the stirring speed in the step of mixing the raw materials is 500 rpm. If the stirring speed is too low, such as 100 rpm, the mixing intensity is insufficient and the mixing time is prolonged; if the stirring speed exceeds 600 rpm, the solution will splash inside the flask and adhere to the mouth of the flask; choosing 500 rpm can achieve the maximum mixing intensity without splashing the solution and shorten the mixing time.

[0069] Furthermore, the step of mixing and stirring the raw materials includes:

[0070] First, keep the polyoxyethylene hydrogenated castor oil at 60℃~65℃ for 10min~15min, then add it to the reaction vessel, continue to keep it at 60℃~65℃ for 10min~15min, and then cool it to spread the polyoxyethylene hydrogenated castor oil at the bottom of the reaction vessel.

[0071] Add 60-90 parts of cyanoacrylate, 5-30 parts of plasticizer, 0-7 parts of acrylate rubber, and 0.02-0.04 parts of hydroquinone to the reaction vessel, and stir at 60℃-65℃ for 10-60 minutes.

[0072] By adding polyoxyethylene hydrogenated castor oil first, ensuring it spreads evenly at the bottom of the reaction vessel, and then adding the remaining raw materials, the materials can be thoroughly and uniformly mixed, reducing the risk of uncontrollable polymerization due to uneven mixing. Furthermore, polyoxyethylene hydrogenated castor oil is solid at room temperature but becomes liquid upon heating, making it easier to weigh and control the amount added.

[0073] In a specific example, the reaction vessel is a flat-bottomed flask; however, it is understood that the reaction vessel is not limited to this.

[0074] In a specific example, the mixing time may be, but is not limited to, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min, or any combination of these values. Preferably, the mixing temperature is 60°C and the mixing time is 60 min.

[0075] In some embodiments, the dry heat sterilization step is performed at a temperature of 160°C to 165°C for a time of 2 hours to 4 hours. For example, the dry heat sterilization time may be, but is not limited to, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, or any combination of these values. Preferably, the dry heat sterilization temperature is 160°C and the time is 2 hours.

[0076] Please see Figure 1 In some embodiments, the preparation steps of the medical adhesive include:

[0077] Step S110: Keep the polyoxyethylene hydrogenated castor oil at 60℃~65℃ for 10min~15min, then take 0.05 part~0.08 part and add it to the reaction vessel, continue to keep it at 60℃~65℃ for 10min~15min, and then cool it to spread the polyoxyethylene hydrogenated castor oil at the bottom of the reaction vessel.

[0078] Step S120: Add 60 to 90 parts of cyanoacrylate, 5 to 30 parts of plasticizer, 0 to 7 parts of acrylate rubber and 0.02 to 0.04 parts of hydroquinone to the reaction vessel, and stir at 60°C to 65°C for 10 to 60 minutes.

[0079] Step S130: Seal the mixed raw materials and perform dry heat sterilization at 160℃~165℃ for 2h~4h to prepare medical adhesive.

[0080] The preparation method of the above-mentioned medical adhesive is simple and the reaction conditions are mild. By selecting appropriate raw materials and proportions, the materials are mixed by stirring, and then the viscosity is controlled by dry heat sterilization to meet aseptic requirements. At the same time, the viscosity of the medical adhesive is suitable, which facilitates the injection and storage of the medical adhesive. In addition, the adhesive has suitable bonding strength and hardness after curing, which not only ensures the closure effect of blood vessels, but also provides a certain degree of flexibility, allowing it to conform to the deformation of blood vessels or limbs without obvious foreign body sensation.

[0081] To make the objectives and advantages of the present invention clearer, the medical adhesive of the present invention and its effects are further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are only for explaining the present invention and should not be used to limit the present invention. Unless otherwise specified, the following embodiments do not include components other than unavoidable impurities. Unless otherwise specified, the drugs and instruments used in the embodiments are conventional choices in the art. Experimental methods in the embodiments that do not specify specific conditions are implemented according to conventional conditions, such as those described in literature, books, or methods recommended by the manufacturer.

[0082] Example 1

[0083] This embodiment provides a medical adhesive, the preparation steps of which are as follows:

[0084] (1) The following raw materials were obtained by mass: 90 parts of α-cyanoacrylate n-butyl ester, 10 parts of triethyl citrate, 0.05 parts of polyoxyethylene hydrogenated castor oil and 0.02 parts of hydroquinone.

[0085] (2) Keep the polyoxyethylene hydrogenated castor oil in a 60℃ oven for 10 min, drop it into a 250mL flat-bottomed flask, transfer the flat-bottomed flask to a 60℃ oven, keep it in the oven for 10 min, and then take it out to cool to room temperature so that the polyoxyethylene hydrogenated castor oil can be fully spread on the bottom of the flask.

[0086] (3) Add 90 parts of α-cyanoacrylate, 10 parts of triethyl citrate and 0.02 parts of hydroquinone through a funnel, stir in an oil bath at 60°C for 30 min at a stirring rate of 500 r / min, and then cool to room temperature.

[0087] (4) Dispense the sample obtained in (3) into 5 mL vials, seal them, and transfer them to a dry heat sterilizer for high-temperature sterilization at 160°C for 2 hours. After cooling to room temperature, the medical adhesive of this embodiment can be obtained.

[0088] Examples 2-3

[0089] Examples 2 and 3 respectively provide a medical adhesive. The preparation process is similar to that of Example 1, except that the composition of the medical adhesive is different and the oil bath time at 60°C is different, as shown in Table 1 below.

[0090] Example 4

[0091] This embodiment provides a medical adhesive, the preparation process of which is similar to that of Embodiment 1, except that the temperature is 100°C during the mixing and stirring process in step (3).

[0092] Comparative Example 1

[0093] Comparative Example 1 provides a medical adhesive, the preparation process of which is similar to that of Example 1, except that the thickener PEG-60 is not used.

[0094] Comparative Example 2

[0095] Comparative Example 2 provides a medical adhesive, the preparation process of which is similar to that of Example 1, except that an excessive amount of thickener PEG-60 is used.

[0096] Comparative Example 3

[0097] Comparative Example 3 provides a medical adhesive, the preparation process of which is similar to that of Example 3, except that an excessive amount of toughening agent ACM is used.

[0098] Comparative Example 4

[0099] Comparative Example 4 provides a medical adhesive, the preparation process of which is similar to that of Example 1, except that the polymerization inhibitor hydroquinone is not used.

[0100] Comparative Example 5

[0101] Comparative Example 5 provides a medical adhesive, the preparation process of which is similar to that of Example 1, except that an excessive amount of the polymerization inhibitor hydroquinone is used.

[0102] Comparative Example 6

[0103] Comparative Example 6 provides a medical adhesive, the preparation process of which is similar to that of Example 1, except that the thickener is different. In Comparative Example 6, methyl methacrylate (PMMA) is used instead of PEG-60 in Example 1.

[0104] Comparative Example 7

[0105] Comparative Example 7 provides a medical adhesive, the preparation process of which is similar to that of Example 3, except that the toughening agent is different. In Comparative Example 7, cellulose acetate butyrate (CAB) is used instead of ACM in Example 3.

[0106] Comparative Example 8

[0107] Comparative Example 8 provides a medical adhesive, the preparation process of which is similar to that of Example 1. The difference is that no polymerization inhibitor is used. In Comparative Example 8, sulfur dioxide is used to replace hydroquinone in Example 1. However, since sulfur dioxide is gaseous, it is introduced into the reaction system through the gas path during the oil bath stirring process. The gas intake is controllable, but the exhaust cannot be monitored. The final amount added into the reaction system is difficult to accurately quantify, reproducibility is difficult to guarantee, and the complexity of operation is significantly increased. Therefore, no subsequent performance tests were conducted.

[0108] The raw material composition and process parameters for preparing the medical adhesives in the above embodiments and comparative examples are shown in Tables 1 and 2 below.

[0109] Table 1. Raw material composition for the preparation of medical adhesives in each embodiment and comparative example.

[0110]

[0111] Table 2. Raw material composition for the preparation of medical adhesives in each embodiment and comparative example.

[0112]

[0113] The following is the test section:

[0114] 1. Viscosity: Measured using a rotating cone-plate viscometer, each measurement requires only 0.5mL~1.0mL of sample, while other viscosity testing methods require at least 16mL of sample, greatly saving sample usage. The temperature is 25℃.

[0115] 2. Adhesion Strength: Based on the intended use, after the blood vessel is closed using medical adhesive, the pressure exerted on the vessel by venous return in the short term is mainly similar to the peeling force. Therefore, YY / T 0729.2-2009 Test Method for Tissue Adhesive Properties Part 2: T-Peel Tensile Bearing Strength was selected as the main evaluation index for adhesion strength. A 25mm wide pigskin strip was used as the substrate. Medical adhesive was applied to the pigskin strip using a dropper of a specific size. Another pigskin strip was placed parallel to the adhesive strip, and a weight of a certain mass was pressed onto the area coated with medical adhesive. The T-peel test was performed after 3 minutes.

[0116] 3. Curing time: Add 10mL of simulated serum to a 90mm diameter petri dish, use a dropper of a certain specification to draw up the medical adhesive, and drop a drop at a height of 5cm. Record the time from the edge of the medical adhesive to complete curing into a film, and record it as the curing time.

[0117] 4. Flexibility: Lift the cured film and bend it 180°, then bend it back and forth a certain number of times. Visually inspect for any cracks or hard objects.

[0118] The test results of the medical adhesives in the above embodiments and comparative examples are shown in Tables 3 and 4 below:

[0119] Table 3 Test results of medical adhesives in each embodiment and comparative example

[0120]

[0121] Table 4 Test results of medical adhesives in each embodiment and comparative example

[0122]

[0123] As can be seen from the comparison between Example 1 and Comparative Example 1, using PEG-60 as a thickener can rapidly increase the viscosity of medical adhesives, appropriately reduce the bonding strength, prolong the curing time, and improve the toughness of the cured film.

[0124] As can be seen from the comparison between Example 1 and Comparative Example 2, excessive use of PEG-60 causes the viscosity of the medical adhesive to increase too quickly, and it solidifies before sterilization, making it unusable.

[0125] As can be seen from the comparison between Example 1 and Example 2, using NOCA to partially replace NBCA can reduce the curing speed and improve the toughness of the cured film while ensuring the bonding strength of the medical adhesive.

[0126] As can be seen from the comparison between Example 1 and Example 3, using ACM as a toughening agent can reduce the curing speed while ensuring the bonding strength of medical adhesives, and the toughness of the cured film is significantly improved.

[0127] As can be seen from the comparison between Examples 1 and 4, increasing the oil bath temperature has no significant effect on the curing speed and toughness, but it will increase the viscosity of the medical adhesive. Therefore, the oil bath temperature can be adjusted to meet different viscosity requirements.

[0128] As can be seen from the comparison between Example 1 and Comparative Examples 1 and 2, the viscosity of the medical adhesive is too low without the use of thickener PEG-60, while the medical adhesive is unusable after the oil bath process is cured due to the excessive use of thickener PEG-60. Therefore, it is necessary to use an appropriate amount of thickener PEG-60 to maintain the appropriate viscosity of the medical adhesive.

[0129] As can be seen from the comparison of Examples 2, 3 and Comparative Example 3, excessive use of ACM results in good toughness of the cured medical adhesive, but the bonding strength is too low and the curing time is too long.

[0130] As can be seen from the comparison between Example 1 and Comparative Examples 4 and 5, without the polymerization inhibitor hydroquinone, the medical adhesive is unusable because it has already cured during the process. However, with excessive amounts of the polymerization inhibitor hydroquinone, the viscosity of the medical adhesive is too low, and the color after sterilization is brownish-yellow. Therefore, it is necessary to use an appropriate amount of the polymerization inhibitor hydroquinone to maintain the appropriate viscosity and appearance of the medical adhesive.

[0131] As can be seen from the comparison between Example 1 and Comparative Example 6, replacing PEG-60 with PMMA will significantly prolong the thickening time of medical adhesives, and the thickening efficiency of PMMA is much lower than that of PEG-60.

[0132] As can be seen from the comparison between Example 3 and Comparative Example 7, replacing ACM with CAB does not significantly improve toughness.

[0133] As can be seen from the comparison between Example 1 and Comparative Example 8, replacing hydroquinone with SO2 significantly increases the operational difficulty.

[0134] As can be seen from the above experimental data, the medical adhesive prepared in the above embodiments has the following advantages:

[0135] (1) Due to the high reactivity of the main raw materials, the inventors, through a lot of creative work, selected polyoxyethylene hydrogenated castor oil as a thickener, acrylate rubber as a toughening agent, and hydroquinone as a polymerization inhibitor. The combination of these components, compared with other thickeners, toughening agents, polymerization inhibitors, etc., makes the medical adhesive have a suitable viscosity and a suitable curing speed, and the cured film has a certain degree of flexibility.

[0136] (2) During the reaction process, the viscosity and curing speed of medical adhesives can be adjusted by controlling the oil bath temperature and time, as well as the sterilization temperature and time.

[0137] (3) By optimizing the formula and process, the one-pot synthesis of medical adhesives can be achieved. While meeting clinical needs, it also has the following advantages: the viscosity of the medical adhesive is moderate, avoiding the occurrence of ectopic bonding; the medical adhesive is soft after curing, reducing patient discomfort and stimulation to blood vessels and tissues; a balance between bonding strength and toughness is achieved, that is, high toughness is maintained while ensuring bonding strength; and the concentrated release of heat during the curing process of the medical adhesive avoids thermal stimulation to patients.

[0138] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0139] The above-described embodiments are merely illustrative of several implementation methods of the present invention, facilitating a detailed understanding of the technical solutions of the present invention, but should not be construed as limiting the scope of protection of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. It should be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided by the present invention through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the appended claims. Therefore, the scope of protection of this invention patent should be determined by the content of the appended claims, and the specification and drawings can be used to interpret the content of the claims.

Claims

1. A medical adhesive characterized by, The raw materials for preparing the medical adhesive include, in parts by mass, a cyanoacrylate 60-90 parts, a plasticizer 5-30 parts, an acrylate rubber 0-7 parts, polyoxyethylene hydrogenated castor oil 0.05-0.08 parts, and hydroquinone 0.02-0.04 parts.

2. The medical adhesive of claim 1, wherein The cyanoacrylate includes one or both of n-butyl alpha-cyanoacrylate and n-octyl alpha-cyanoacrylate.

3. The medical adhesive of claim 2, wherein The cyanoacrylate includes n-butyl alpha-cyanoacrylate and n-octyl alpha-cyanoacrylate in a mass ratio of (5-6):(2-3).

4. The medical adhesive of claim 1 wherein, The plasticizer includes a citrate plasticizer, which includes one or more than two kinds of mixture of triethyl citrate, tributyl citrate, acetyl triethyl citrate, and acetyl tributyl citrate.

5. The medical adhesive of claim 1 wherein, The raw materials for preparing the medical adhesive include, in parts by mass, n-butyl alpha-cyanoacrylate 50-60 parts, n-octyl alpha-cyanoacrylate 20-30 parts, a plasticizer 10-30 parts, an acrylate rubber 5-7 parts, polyoxyethylene hydrogenated castor oil 0.05-0.08 parts, and hydroquinone 0.02-0.04 parts.

6. The medical adhesive according to any one of claims 1 to 5, wherein The medical adhesive satisfies one or more of the following conditions: (1) The viscosity of the medical adhesive at 25°C is 1200 mPa·s-1400 mPa·s; (2) The T-peel strength of the medical adhesive is 1 N-4 N; (3) The curing time of the medical adhesive is 10 s-120 s.

7. A method for preparing a medical adhesive characterized by, The method includes the following steps: Mixing and stirring the raw materials, and dry heat sterilization, to prepare the medical adhesive; The raw materials include, in parts by mass, a cyanoacrylate 60-90 parts, a plasticizer 5-30 parts, an acrylate rubber 0-7 parts, polyoxyethylene hydrogenated castor oil 0.05-0.08 parts, and hydroquinone 0.02-0.04 parts.

8. The method of preparing a medical adhesive according to claim 7, wherein In the step of mixing and stirring the raw materials, the temperature is 60-65°C, and the time is 10-60 min.

9. The method of preparing a medical adhesive according to claim 8, wherein The step of mixing and stirring the raw materials includes: The polyoxyethylene hydrogenated castor oil is incubated at 60-65°C for 10-15 min, 0.05-0.08 parts of which is added to a reaction container, which is further incubated at 60-65°C for 10-15 min, and then cooled to spread the polyoxyethylene hydrogenated castor oil on the bottom of the reaction container; The cyanoacrylate 60-90 parts, the plasticizer 5-30 parts, the acrylate rubber 0-7 parts, and the hydroquinone 0.02-0.04 parts are added to the reaction container, which is stirred at 60-65°C for 10-60 min.

10. The method of claim 7, 8 or 9, wherein the medical adhesive is prepared by the steps of: In the step of dry heat sterilization, the temperature is 160-165°C, and the time is 2-4 h.

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