Medical adhesive with excellent mechanical properties and method for preparing the same

Abstract

The present application relates to the field of medical adhesive, especially to a medical adhesive with excellent mechanical properties and a preparation method thereof. The medical adhesive is an acid ester gel containing at least 10-25 wt% of citrate plasticizer. The medical adhesive provided in the present application has suitable viscosity and good body compatibility, and does not have the problem of poor viscosity during use. It can also help to reduce the discomfort and inflammation of the body. At the same time, under the premise of maintaining excellent hemostatic performance, the use of polymerization speed is maintained, the viscosity is moderate, and the microcatheter is not easy to be blocked and ectopic embolism during use, and the mechanical properties are excellent.

Description

Technical Field

[0001] This invention relates to the field of medical adhesives, and more particularly to a medical adhesive with excellent mechanical properties and its preparation method. Background Technology

[0002] Since their introduction, cyanoacrylate-based medical adhesives have revolutionized surgical procedures, moving from sutures to direct bonding. Existing cyanoacrylate-based medical adhesives have achieved widespread application in clinical medicine due to their advantages such as safety, non-toxicity, reliability, antibacterial properties, and rapid bonding at room temperature. However, these adhesives still suffer from problems such as poor mechanical properties, excessively rapid polymerization, low viscosity, and a tendency to cause microcatheter blockage and ectopic embolism.

[0003] Chinese patent CN112295013B provides a fast-acting hemostatic medical adhesive material, which mainly prepares the medical adhesive matrix by compounding a mixture of n-butyl cyanoacrylate and n-octyl cyanoacrylate with carboxymethyl chitosan. However, in actual operation, the performance of the matrix is ​​greatly affected by carboxymethyl chitosan, and the mechanical properties, strength and storage performance of the medical adhesive cannot be fully taken into account.

[0004] Therefore, in order to solve the above problems, the present invention provides a medical adhesive with excellent mechanical properties and its preparation method. The prepared medical adhesive not only has excellent mechanical properties and strength when used, but can also be stored normally, avoiding rapid polymerization before use. Summary of the Invention

[0005] To address the aforementioned problems, the first aspect of this invention provides a medical adhesive with excellent mechanical properties, wherein the adhesive is an acid ester gel comprising at least 10-25 wt% of a citrate ester plasticizer.

[0006] As a preferred embodiment, the citrate plasticizer is at least one selected from triethyl citrate, tri-n-butyl citrate, acetyl tributyl citrate, dimethyl citrate, and trimethyl citrate.

[0007] As a preferred embodiment, the citrate plasticizer is at least one of triethyl citrate, tri-n-butyl citrate, and acetyltributyl citrate.

[0008] As a preferred embodiment, the citrate plasticizer is triethyl citrate and acetyl tributyl citrate, with a mass ratio of 2-3:1-1.5.

[0009] As a preferred embodiment, the mass ratio of triethyl citrate to acetyltributyl citrate is 2:1.2.

[0010] As a preferred embodiment, the ester gel includes at least monoester gels and polymeric ester gels.

[0011] As a preferred embodiment, the mass ratio of the monoester gel to the polymeric ester gel is 16–22:60–80.

[0012] As a preferred embodiment, the mass ratio of the monoester gel to the polymeric ester gel is 16-18:60-66.

[0013] As a preferred embodiment, the monoester gel is at least one selected from α-butyl cyanoacrylate, α-octyl cyanoacrylate, α-isobutyl cyanoacrylate, α-methyl cyanoacrylate, and α-ethyl cyanoacrylate.

[0014] As a preferred embodiment, the monoester gel is α-butyl cyanoacrylate.

[0015] As a preferred embodiment, the polymeric ester gel is at least one of poly(n-butyl α-cyanoacrylate), poly(n-octyl α-cyanoacrylate), poly(isobutyl α-cyanoacrylate), poly(methyl α-cyanoacrylate), and poly(ethyl α-cyanoacrylate).

[0016] As a preferred embodiment, the polymeric ester gel is poly(α-cyanoacrylate) n-butyl ester.

[0017] As a preferred embodiment, the polymeric ester gel is a polymeric ester gel polymerized by high-temperature heating or a polymeric ester gel polymerized by irradiation.

[0018] As a preferred embodiment, the polymeric ester gel is poly(n-butyl α-cyanoacrylate) polymerized by irradiation.

[0019] As a preferred embodiment, the irradiation dose of the irradiated polymeric ester gel is 5–15 kGy / h.

[0020] As a preferred embodiment, the irradiation dose of the irradiated polymeric ester gel is 8–12 kGy / h.

[0021] As a preferred embodiment, the irradiation dose of the irradiated polymeric ester gel is 10 kGy / h.

[0022] As a preferred embodiment, the mass ratio of the citrate ester plasticizer to the ester gel is 16-22:78-84.

[0023] As a preferred embodiment, the mass ratio of the citrate ester plasticizer to the ester gel is 17.5–22:78–82.5.

[0024] In this invention, the compounded triethyl citrate and acetyl tributyl citrate not only effectively improve the mechanical strength of the adhesive during use, but also maintain the good morphology of the adhesive during storage, avoiding premature polymerization before use and rapid polymerization during use. The inventors believe that when the mass ratio of triethyl citrate to acetyl tributyl citrate is 2:1.2, and the mass ratio of monoester gel to polymeric ester gel is 16-18:60-66, the compounded triethyl citrate and acetyl tributyl citrate can help the intermolecular forces of irradiated poly(n-butyl α-cyanoacrylate) within α-butyl α-cyanoacrylate, thereby accelerating and enhancing the intercalation ability of the long-chain molecules of α-butyl α-cyanoacrylate, thus completely dissolving the α-butyl α-cyanoacrylate molecules. Furthermore, during use, in addition to their thickening effect, triethyl citrate and acetyl tributyl citrate can further accelerate the formation density of the polymer molecular network chain, thereby improving the mechanical strength.

[0025] The second aspect of the present invention provides a method for preparing the above-mentioned medical adhesive with excellent mechanical properties, the preparation steps being: dissolving a polymeric ester gel containing a citrate ester plasticizer into a monoester gel, mixing and dissolving evenly to obtain the adhesive.

[0026] As a preferred embodiment, the preparation steps of the medical adhesive with excellent mechanical properties are as follows: (1) mixing a citrate plasticizer with a corresponding amount of monoester gel, and then irradiating the mixture to polymerize it to obtain a polymeric ester gel containing citrate plasticizer; (2) mixing the gel obtained in step (1) with the monoester gel and dissolving it evenly to obtain the final product.

[0027] Beneficial effects:

[0028] 1. The medical adhesive provided in this invention has suitable viscosity and good human affinity, and will not cause the phenomenon of poor viscosity that makes it unusable during use. It also helps to reduce discomfort and inflammation at the site of application.

[0029] 2. The medical adhesive provided in this invention has a simple mixing and preparation method, excellent solubility of the polymeric acid ester, convenient operation, and relatively fast process, which can easily realize industrial scale-up production and has a very good market prospect.

[0030] 3. The medical adhesive provided in this invention can maintain good polymerization speed and moderate viscosity while maintaining excellent hemostatic performance, and is not likely to cause microcatheter blockage and ectopic embolism during use.

[0031] 4. The medical adhesive provided in this invention can be applied to various medical hemostasis and suture bonding applications, including slow and rapid bleeding, massive bleeding, and oozing. It can quickly absorb moisture and concentrate clotting factors to form a surface gel network with good mechanical strength. Moreover, it does not require preparation and use immediately, which greatly facilitates clinical use.

[0032] 5. The medical adhesive provided in this invention, through the compounding of triethyl citrate and acetyltributyl citrate, not only effectively improves the mechanical strength of the adhesive during use, but also maintains the good shape of the adhesive during storage. When the mass ratio of triethyl citrate to acetyltributyl citrate is 2:1.2, the compounded triethyl citrate and acetyltributyl citrate can help the intermolecular forces of irradiated poly(n-butyl cyanoacrylate) in α-butyl cyanoacrylate, thereby accelerating and enhancing the intercalation ability of the long-chain molecules of poly(n-butyl cyanoacrylate), thus completely dissolving the poly(n-butyl cyanoacrylate) molecules. Furthermore, during use, it further accelerates the formation density of the polymer molecular network chain, thereby improving the mechanical strength. Detailed Implementation

[0033] Example 1

[0034] Example 1: A first aspect provides a medical adhesive comprising, by weight percentage: 17.9% citrate plasticizer, 16.6% monoester gel, and the balance being a polymeric ester gel.

[0035] The citrate plasticizers are triethyl citrate and acetyl tributyl citrate, with a mass ratio of 2:1.2.

[0036] The monoester gel is α-cyanoacrylate n-butyl ester.

[0037] The polymeric ester gel is poly(α-cyanoacrylate) n-butyl ester.

[0038] The poly(α-cyanoacrylate) n-butyl ester is a poly(α-cyanoacrylate) n-butyl ester polymerized by irradiation, with an irradiation dose of 10 kGy / h.

[0039] The second aspect of this embodiment provides a method for preparing the above-mentioned medical adhesive, the steps of which include: (1) mixing a citrate plasticizer with a corresponding amount of monoester gel for preparing a polymeric ester gel, and then irradiating the mixture to polymerize it to obtain a polymeric ester gel containing citrate plasticizer; (2) mixing the gel obtained in step (1) with the monoester gel and dissolving it evenly to obtain the final product.

[0040] In this embodiment, α-cyanoacrylate n-butyl ester was purchased from Beijing Fuaile Company, model number 504.

[0041] In this embodiment, triethyl citrate and acetylated tributyl citrate were purchased from Shandong Kexing Chemical Co., Ltd. as pharmaceutical excipient grade products.

[0042] Example 2

[0043] The specific implementation method of this embodiment is the same as that of Embodiment 1, except that: the medical adhesive, by mass percentage, comprises: 20.4% citrate plasticizer, 16.8% monoester gel and the balance being polymeric ester gel.

[0044] Example 3

[0045] The specific implementation method of this embodiment is the same as that of Embodiment 1, except that: the medical adhesive, by mass percentage, comprises: 21.9% citrate plasticizer, 17.5% monoester gel and the balance being polymeric ester gel.

[0046] Comparative Example 1

[0047] The specific implementation method of this comparative example is the same as that of Example 1, except that the mass ratio of triethyl citrate to acetyl tributyl citrate is 2:0.5.

[0048] Comparative Example 2

[0049] The specific implementation method of this comparative example is the same as that of Example 1, except that the irradiation dose of the irradiated polymeric ester gel is 7.5 kGy / h.

[0050] Performance Evaluation

[0051] Tensile strength: The tensile strength of the medical adhesives prepared in the examples and comparative examples was tested in accordance with the product requirements of "Medical Adhesives" YY / T 0729.1-2009. Ten samples were tested for each example and comparative example, and the average value of the measured values ​​was recorded in Table 1.

[0052] T-peel tensile strength: According to the product requirements of "Medical Adhesives" YY / T 0729.1-2009, the T-peel tensile strength of the medical adhesives prepared in the examples and comparative examples was tested. Ten samples were tested for each example and comparative example, and the average value of the measured values ​​was recorded in Table 1.

[0053] Table 1

[0054] Example Tensile strength (MPa) T - Peel tensile strength (N / cm) Example 1 0.52 3.5 Example 2 0.49 3.4 Example 3 0.51 3.2 Comparative Example 1 0.28 1.9 Comparative Example 2 0.31 2.1

Claims

1. A medical adhesive characterized by: The adhesive is an acid ester gel containing at least 10-25 wt% of citrate plasticizer; The acid ester gel contains at least a monoacid ester gel and a polymeric acid ester gel; The citrate plasticizer is triethyl citrate and acetyl tributyl citrate, with a mass ratio of 2:1.2; The mass ratio of the monoacid ester gel and the polymeric acid ester gel is 16-18:60-66; The monoacid ester gel is n-butyl alpha-cyanoacrylate; the polymeric acid ester gel is poly-n-butyl alpha-cyanoacrylate; The poly-n-butyl alpha-cyanoacrylate is poly-n-butyl alpha-cyanoacrylate polymerized by irradiation, with an irradiation dose of 10 kGy / h.

2. The medical adhesive of claim 1, wherein: The mass ratio of the citrate plasticizer and the acid ester gel is 16-22:78-84.

3. A process for the preparation of a medical adhesive according to any one of claims 1-2, characterized in that: The preparation procedure is to dissolve the polymeric acid ester gel containing citrate plasticizer into the monoacid ester gel, and mix and dissolve uniformly.