Absorbable tissue bonding patch and preparation method thereof

Abstract

The invention provides an absorbable tissue bonding patch and a preparation method thereof. The absorbable tissue bonding patch comprises a supporting layer and a bonding agent layer which are in contact with each other; wherein the supporting layer comprises interwoven fibers with the diameter of 10 nm to 100 microns, and the supporting layer is of a porous structure; and the support layer is derived from a film-forming composition, the film-forming composition comprising a polyester compound, the polyester compound comprising poly (trimethylene carbonate). The absorbable tissue bonding patch is simple in structure, through combination of the supporting layer and the adhesive layer, on the premise of excellent bonding force, the absorbable tissue bonding patch further has good elasticity and high rupture strength, can better conform to tissue movement under the pressure condition, keeps tight and lasting adhesion on the tissue surface, and has the advantages that the absorbable tissue bonding patch can be used for absorbing tissues, and the absorbable tissue bonding patch has a good application prospect. And wound tearing caused by tensile deformation of tissues near the wound is effectively inhibited, and clinical use is convenient and the effect is good.

Description

Technical Field

[0001] The invention relates to an absorbable tissue adhesive patch and a preparation method thereof, and belongs to the field of medical implant materials. Background Art

[0002] Clinically, surgical sutures are used to bind tissues together after injury or surgery. However, they usually have disadvantages such as long suturing time and possible secondary damage to the tissues during the suturing process. In addition, stress concentration around the suture points can lead to serious complications such as leakage or infection at the suture points. They are not suitable for wound sealing and blockage of tissues and organs such as blood vessels and the gastrointestinal tract in the body.

[0003] Wounds of some tissues and organs in the body will be dynamically stretched or expanded under the influence of internal liquid pressure and organ movement. The sealing materials of such tissues and organs need to have good adhesion, mechanical properties and tissue compliance, be able to meet the dynamic mechanical microenvironment in the body, and have good biocompatibility and degradability. They can be hydrolyzed or enzymatically broken down into substances that can be excreted from the body through tissue metabolism, without the need for re-surgery for removal. Although the existing tissue adhesive patches have good initial adhesion, the adhesion decreases rapidly over time. For example, they may often separate from the tissue after only a few seconds or minutes. They are not elastic and have poor tissue compliance. When the tissue is deformed by pressure, pulsation, etc., they cannot conform to the tissue movement and maintain tight and lasting adhesion on the tissue surface. They cannot effectively inhibit the stretching deformation of the tissue near the wound, and the clinical use effect is poor.

[0004] CN114887122A discloses a viscous gel composite material and its preparation method and application. The viscous gel composite material includes an A region and a B region, the B region is distributed on the periphery of the A region, or the B region is distributed on both sides of the A region, and the elastic modulus of the viscous gel composite material increases from the B region to the A region; the viscous gel composite material includes a viscous gel matrix and a two-dimensional fiber network topologically entangled with the viscous gel matrix. The overall design of this scheme is relatively complicated, requiring at least one of the viscous gel matrix and the two-dimensional fiber network to have an elastic modulus in different distribution areas, so as to adjust the elastic modulus distribution of the entire composite material. In addition, the viscous gel composite material is difficult to make, the preparation method is complicated, and the two-dimensional fiber network needs to be prepared using a special electrospinning device. In addition, when in use, it is necessary to align the A region with a higher elastic modulus in the viscous gel composite material so that it is located above the wound, and the B region with a lower elastic modulus is located around the wound, which is inconvenient to use.

[0005] Therefore, researching an absorbable tissue adhesive patch with good adhesion, elasticity, excellent tissue compliance, and good clinical effect has become a technical problem that needs to be solved urgently. Summary of the invention

[0006] Problems to be Solved by the Invention

[0007] In view of the technical problems existing in the prior art, for example, the existing tissue adhesion patches do not have elasticity and have poor tissue compliance, etc., the present invention firstly provides an absorbable tissue adhesion patch. The absorbable tissue adhesion patch of the present invention has good adhesion and elasticity, excellent tissue compliance, is convenient for clinical use and has good effects.

[0008] The present invention also provides a preparation method of the absorbable tissue adhesion patch. The preparation method is simple and easy to implement, the raw materials are easy to obtain, and it is suitable for mass production.

[0009] Solutions for Solving the Problems

[0010] The present invention firstly provides an absorbable tissue adhesion patch, which comprises a support layer and an adhesive layer in contact with each other; wherein,

[0011] the support layer comprises fibrils with a diameter of 10 nm to 100 μm and intertwined with each other, and the support layer has a porous structure; and,

[0012] the support layer is derived from a film-forming composition, and the film-forming composition comprises a polyester compound, and the polyester compound comprises polytrimethylene carbonate.

[0013] Furthermore, the polyester compound further comprises one or a combination of two of polycaprolactone and glycolide-trimethylene carbonate copolymer.

[0014] Furthermore, the polyester compound comprises a combination of polytrimethylene carbonate and polycaprolactone, or comprises a combination of polytrimethylene carbonate and glycolide-trimethylene carbonate copolymer;

[0015] Preferably, the mass ratio of the polytrimethylene carbonate to the polycaprolactone or glycolide-trimethylene carbonate copolymer is (1 to 6):(1 to 5), preferably (1 to 4):(1 to 3).

[0016] Furthermore, the film-forming composition further contains a natural polymer material; preferably, the mass ratio of the polyester compound to the natural polymer material is (1 to 11):(1 to 6), preferably (1 to 7):(1 to 4).

[0017] Furthermore, the film-forming composition comprises a combination of a natural polymer material, polytrimethylene carbonate and polycaprolactone, or comprises a combination of a natural polymer material, polytrimethylene carbonate and glycolide-trimethylene carbonate copolymer;

[0018] Preferably, based on the total mass of the film-forming composition being 100%, the content of the polycaprolactone or the glycolide-trimethylene carbonate copolymer is 6% to 35%, preferably 12% to 25%.

[0019] Furthermore, the absorbable tissue adhesion patch has at least one of the following characteristics:

[0020] The tensile strength of the absorbable tissue adhesion patch is 2 Mpa to 5.5 Mpa;

[0021] The breaking tensile strain of the absorbable tissue adhesion patch is 45% to 350%, preferably 150% to 300%;

[0022] The bursting strength of the absorbable tissue adhesion patch is 30 kPa or more.

[0023] Furthermore, the adhesive layer is derived from an adhesive composition, and the adhesive composition includes an acrylic compound, a photoinitiator, and a crosslinking agent; wherein,

[0024] Based on the total mass of the adhesive composition being 100%, the content of the acrylic compound is 20% to 55%, the content of the photoinitiator is 0.1% to 0.3%, and the content of the crosslinking agent is 0.05% to 0.6%;

[0025] Preferably, at least part of the acrylic compound has an N-hydroxysuccinimide group. Preferably, based on the total mass of the adhesive composition being 100%, the content of the acrylic compound having an N-hydroxysuccinimide group is 0.5% to 5%.

[0026] Furthermore, the adhesive composition further contains a biodegradable biomaterial and a solvent; based on the total mass of the adhesive composition being 100%, the content of the biodegradable biomaterial is 0.5% to 15%, and the content of the solvent is 40% to 70%.

[0027] The present invention also provides a preparation method of the absorbable tissue adhesion patch according to the present invention, which includes the following steps:

[0028] Obtain a film-forming composition and dissolve it in a solvent to prepare a spinning dope;

[0029] Obtain an adhesive composition. Preferably, the adhesive composition includes an acrylic compound, a photoinitiator, and a crosslinking agent;

[0030] Spinning the spinning dope by a spinning process to obtain a support layer;

[0031] Use the adhesive composition to form an adhesive layer on at least one surface of the support layer and perform composite molding with the support layer;

[0032] Preferably, the composite molding includes one or a combination of two or more of laying flat, coating, casting, and spraying; More preferably, the coating includes spin coating and / or blade coating.

[0033] Furthermore, the preparation method further includes the following steps:

[0034] Make the adhesive composition present on at least one surface of the support layer, and carry out a chemical reaction under the irradiation of ultraviolet light to obtain a molded body;

[0035] Carry out post-treatment on the molded body to obtain an absorbable tissue adhesion patch;

[0036] Preferably, the wavelength of the ultraviolet light is 365 nm to 405 nm, and the irradiation time of the ultraviolet light is 30 s to 100 min.

[0037] Effects of the Invention

[0038] The absorbable tissue adhesion patch of the present invention has a simple structure. By combining the support layer and the adhesive layer, on the premise of having excellent adhesive force, it also has good elasticity and high rupture strength, can better conform to tissue movement under pressure conditions, and maintain a tight and lasting adhesion on the tissue surface, effectively inhibiting wound tearing caused by tensile deformation of the tissue near the wound, and is convenient and effective for clinical use.

[0039] The preparation method of the absorbable tissue adhesion patch of the present invention is simple, easy to mold, and suitable for large-scale industrial production.

[0040] The absorbable tissue adhesion patch of the present invention has good biocompatibility and biodegradability, and can be applied to the closed fitting of in-vivo tissues, especially suitable for the adhesion and sealing of cerebrospinal fluid leakage, lung leakage, and tissue wounds such as blood vessels, stomach, intestines, and arteries. Description of the Drawings

[0041] Figure 1 Shows a three-dimensional structural view of an absorbable tissue adhesion patch according to an embodiment of the present invention;

[0042] Figure 2 Shows an SEM image of the absorbable tissue adhesion patch of Example 1 of the present invention. Among them, the left figure is the SEM image taken from the support layer side, and the right figure is the SEM image taken from the adhesive layer side;

[0043] Figure 3 Shows an SEM image of the absorbable tissue adhesion patch of Example 2 of the present invention. Among them, the left figure is the SEM image taken from the support layer side, and the right figure is the SEM image taken from the adhesive layer side;

[0044] Figure 4 The SEM images of the absorbable tissue adhesive patch of Example 3 of the present invention are shown, where the left figure is the SEM image taken from the support layer side, and the right figure is the SEM image taken from the adhesive layer side;

[0045] Figure 5 The SEM images of the absorbable tissue adhesive patch of Example 4 of the present invention are shown, where the left figure is the SEM image taken from the support layer side, and the right figure is the SEM image taken from the adhesive layer side;

[0046] Figure 6 The SEM images of the absorbable tissue adhesive patch of Example 5 of the present invention are shown, where the left figure is the SEM image taken from the support layer side, and the right figure is the SEM image taken from the adhesive layer side;

[0047] Figure 7 The SEM images of the absorbable tissue adhesive patch of Example 6 of the present invention are shown, where the left figure is the SEM image taken from the support layer side, and the right figure is the SEM image taken from the adhesive layer side;

[0048] Figure 8 The SEM images of the absorbable tissue adhesive patch of Comparative Example 1 of the present invention are shown, where the left figure is the SEM image taken from the support layer side, and the right figure is the SEM image taken from the adhesive layer side;

[0049] Figure 9 The self-made porcine lung model of the present invention is shown;

[0050] Figure 10 The tissue compliance experiment using the absorbable tissue adhesive patch of Example 1 is shown. The left side shows the state during the simulation of lung inflation, and the right side shows the state during the simulation of lung deflation;

[0051] Figure 11 The tissue compliance experiment using the absorbable tissue adhesive patch of Example 5 is shown. The left side shows the state during the simulation of lung inflation, and the right side shows the state during the simulation of lung deflation;

[0052] Figure 12 The tissue compliance experiment using the absorbable tissue adhesive patch of Example 6 is shown. The left side shows the state during the simulation of lung inflation, and the right side shows the state during the simulation of lung deflation;

[0053] Figure 13 The tissue compliance experiment using the absorbable tissue adhesive patch of Comparative Example 1 is shown. The left side shows the state during the simulation of lung inflation, and the right side shows the state during the simulation of lung deflation;

[0054] Figure 14The tissue compliance experiment using the absorbable tissue adhesion patch of Comparative Example 2 is shown. The left side shows the state during lung inflation simulation, and the right side shows the state during lung deflation simulation;

[0055] Explanation of reference numerals:

[0056] 1: Support layer; 2: Adhesive layer. Detailed implementation manners

[0057] Various exemplary embodiments, features, and aspects of the present invention will be described in detail below. The special word "exemplary" here means "serving as an example, embodiment, or illustration". Any embodiment described as "exemplary" here does not have to be construed as superior to or better than other embodiments.

[0058] In addition, to better illustrate the present invention, numerous specific details are given in the following detailed implementation manners. Those skilled in the art should understand that the present invention can be implemented without some specific details. In other instances, methods, means, equipment, and steps well-known to those skilled in the art are not described in detail in order to highlight the gist of the present invention.

[0059] Unless otherwise stated, the units used in this specification are all international standard units, and the numerical values and numerical ranges appearing in the present invention should be understood to include the systematic errors inevitable in industrial production.

[0060] In this specification, the meaning expressed by using "can" includes both the meaning of performing a certain process and the meaning of not performing a certain process.

[0061] In this specification, the so-called "some specific / preferred implementation manners", "other specific / preferred implementation manners", "implementation manners", etc. refer to the specific elements (for example, features, structures, properties, and / or characteristics) related to the implementation manner described are included in at least one of the implementation manners described here, and may exist in other implementation manners or may not exist in other implementation manners. In addition, it should be understood that the elements can be combined in various implementation manners in any suitable way.

[0062] In this specification, the numerical range expressed by using "numerical value A to numerical value B" refers to the range including the end point numerical values A and B.

[0063] In this specification, when using "normal temperature" and "room temperature", the temperature can be 15 to 25 °C.

[0064] <First aspect>

[0065] The present invention provides an absorbable tissue adhesion patch, which includes a support layer 1 and an adhesive layer 2 in contact with each other; wherein,

[0066] The support layer 1 includes fiber filaments with diameters ranging from 10 nm to 100 μm that are intertwined with each other, and the support layer 1 has a porous structure; and,

[0067] The support layer 1 is derived from a film-forming composition, and the film-forming composition includes a polyester compound, and the polyester compound includes polytrimethylene carbonate.

[0068] The absorbable tissue adhesion patch of the present invention has at least one of the following characteristics: the tensile strength of the absorbable tissue adhesion patch is 2 Mpa to 5.5 Mpa, for example: 2.2 Mpa, 2.5 Mpa, 2.8 Mpa, 3 Mpa, 3.2 Mpa, 3.5 Mpa, 3.8 Mpa, 4 Mpa, 4.2 Mpa, 4.5 Mpa, 4.8 Mpa, 5 Mpa, 5.2 Mpa, etc.; the breaking tensile strain of the absorbable tissue adhesion patch is 45% to 350%, preferably 150% to 300%, for example: 50%, 80%, 100%, 120%, 150%, 180%, 200%, 220%, 250%, 280%, 300%, 320%, etc.; the bursting strength of the absorbable tissue adhesion patch is above 30 kPa, specifically, the bursting strength of the tissue adhesion patch can be 30 kPa to 60 kPa, for example: 32 kPa, 35 kPa, 38 kPa, 40 kPa, 42 kPa, 45 kPa, 48 kPa, 50 kPa, 52 kPa, 55 kPa, 58 kPa, etc.

[0069] The absorbable tissue adhesion patch of the present invention has a simple structure. By combining the support layer 1 and the adhesive layer 2, on the premise of having excellent persistent adhesiveness, the elasticity and bursting strength of the entire absorbable tissue adhesion patch can be improved, it can conform to tissue deformation, and it is convenient and effective for clinical use.

[0070] The absorbable tissue adhesion patch of the present invention can include a three-layer structure, that is, adhesive layers 2 are provided on both surfaces of the support layer 1. It can also include a structure with four or more layers, that is, the support layer 1 and the adhesive layer 2 are alternately adhered to form a multi-layer structure. In addition, in the present invention, the absorbable tissue adhesion patch can also include other layer structures, and the present invention does not specifically limit the other layer structures included, as long as the functions of the present invention can be achieved.

[0071] The thickness of the absorbable tissue adhesive patch of the present invention is 0.008 mm to 0.30 mm, preferably 0.10 mm to 0.25 mm, for example: 0.01 mm, 0.05 mm, 0.1 mm, 0.12 mm, 0.15 mm, 0.2 mm, 0.22 mm, 0.25 mm, 0.28 mm, etc.; when the thickness of the absorbable tissue adhesive patch is 0.008 mm to 0.30 mm, the absorbable tissue adhesive patch can simultaneously have more excellent adhesive force and mechanical properties.

[0072] In addition, in the absorbable tissue adhesive patch of the present invention, optionally, a release layer is provided on the outermost adhesive layer 2. In the present invention, the purpose of providing the release layer can be to keep the adhesive layer 2 unaffected by other substances and prevent the adhesive layer 2 from adhering to non-target tissues before intended use. The present invention does not specifically limit the material of the release layer, as long as it does not affect the function of the absorbable tissue adhesive patch of the present application.

[0073] <Support layer 1>

[0074] The support layer 1 of the present invention comprises fibrils with diameters of 10 nm to 100 μm that are intertwined with each other, and the support layer 1 has a porous structure. In the present invention, the support layer 1 can play the roles of preventing adhesion of the wound surface, providing mechanical support, and facilitating interventional surgery. The support layer 1 of the present invention is derived from a film-forming composition; the film-forming composition comprises a polyester compound, and the polyester compound comprises polytrimethylene carbonate. The inventors of the present invention have found that using polytrimethylene carbonate can obtain a support layer 1 with excellent properties, and polytrimethylene carbonate (PTMC) has good biocompatibility and degradation properties, and degrades to be alkaline, greatly reducing the possibility of inflammation occurring during the degradation of the absorbable tissue adhesive patch.

[0075] Furthermore, the polyester compound further comprises one or a combination of two of polycaprolactone (PCL) and glycolide-trimethylene carbonate copolymer (PGA-TMC).

[0076] In some specific embodiments, in order to obtain a support layer 1 with more excellent properties, the polyester compound of the present invention is preferably a combination of polytrimethylene carbonate and polycaprolactone or a combination of polytrimethylene carbonate and glycolide-trimethylene carbonate copolymer. When using a combination of polytrimethylene carbonate and polycaprolactone or a combination of polytrimethylene carbonate and glycolide-trimethylene carbonate copolymer, the shrinkage of the support layer 1 can be improved and its elasticity can be enhanced.

[0077] In order to more effectively exert the function of polycaprolactone or glycolide-trimethylenecarbonate copolymer, the mass ratio of the polytrimethylene carbonate to the polycaprolactone or glycolide-trimethylenecarbonate copolymer is (1-6):(1-5), preferably (1-4):(1-3), such as: 1:1, 1:2, 1:3, 1:4, 1:5, 2:1, 2:3, 2:5, 3:1, 3:2, 3:4, 3:5, 4:1, 4:3, 4:5, 5:1, 5:2, 5:3, 5:4, etc.

[0078] In some specific embodiments, the film-forming composition further comprises a natural polymer material; the inventors of the present invention have found that when a combination of a polyester compound and a natural polymer material is used, the shrinkage and adhesion of the fibers can be improved, the fiber morphology is obvious, the pore size becomes larger, which is beneficial to the tight combination of the adhesive layer 2 and the support layer 1, and the softness of the support layer 1 is improved.

[0079] Furthermore, in order to most effectively exert the function of the natural polymer material, in the present invention, the mass ratio of the polyester compound to the natural polymer material is (1-11):(1-6), more preferably (1-7):(1-4), such as: 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 2:1, 2:3, 2:5, 3:1, 3:2, 3:4, 3:5, 4:1, 4:3, 4:5, 5:1, 5:2, 5:3, 5:4, 5:6, 6:1, 6:5, 7:1, 7:2, 7:3, 7:7, 7:5, 7:6, etc.

[0080] Specifically, in the present invention, the natural polymer material includes one or a combination of two or more of gelatin, collagen, silk fibroin, hyaluronic acid, cellulose, and chitin.

[0081] Furthermore, when the film-forming composition includes a combination of a natural polymer material, polytrimethylene carbonate and polycaprolactone or glycolide-trimethylenecarbonate copolymer, the shrinkage and adhesion of the fibers of the support layer 1 are improved, the fiber morphology is obvious, the pore size becomes larger, which is beneficial to the adhesion of the support layer 1 and the adhesive layer 2, and the mechanical properties, rupture strength and softness of the absorbable tissue adhesive patch are improved.

[0082] Preferably, based on the total mass of the film-forming composition being 100%, the content of polycaprolactone or glycolide-trimethylenecarbonate copolymer is 6% to 35%, preferably 12% to 25%, such as: 8%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, etc. When the content of polycaprolactone or glycolide-trimethylenecarbonate copolymer is 6% to 35%, preferably 12% to 25%, the pore size of the support layer 1 is appropriate, and the obtained tissue adhesion patch has good tensile strength and elongation at break at the same time. When the content of polycaprolactone or glycolide-trimethylenecarbonate copolymer is too low, the shrinkage and adhesion of the filaments of the support layer 1 cannot be effectively improved; when the content of polycaprolactone or glycolide-trimethylenecarbonate copolymer is too high, the elongation at break performance of the tissue adhesion patch deteriorates significantly.

[0083] In addition, in order to form filaments, the film-forming composition of the present invention can be dissolved in a solvent to prepare a spinning dope for spinning. Specifically, the solvent can be an organic solvent, such as: a combination of one or more of hexafluoroisopropanol, trifluoroethanol, chloroform, dichloromethane, tetrahydrofuran, N,N'-dimethylformamide, etc.

[0084] Furthermore, in the present invention, the mass-volume ratio of the film-forming composition to the solvent can be 1% to 12%, such as: 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, etc.

[0085] Regarding the preparation method of the film-forming composition, the present invention is not particularly limited, and generally, the components of the film-forming composition can be mixed to obtain it. Regarding the mixing temperature, the present invention is not particularly limited, and generally, it can be carried out at room temperature.

[0086] <Adhesive layer 2>

[0087] The adhesive layer 2 is derived from an adhesive composition, and the adhesive composition includes an acrylic compound, a photoinitiator, and a crosslinking agent; wherein,

[0088] Based on the total mass of the adhesive composition being 100%, the content of the acrylic compound is 20% to 55%, the content of the photoinitiator is 0.1% to 0.3%, and the content of the crosslinking agent is 0.05% to 0.6%.

[0089] The adhesive composition of the present invention has strong adhesion and can be applied to the adhesion and sealing of cerebrospinal fluid leakage, lung leakage, and tissue wounds such as blood vessels, stomach, intestines, and arteries.

[0090] Acrylic compound

[0091] In the present invention, at least part of the acrylic compound has an N-hydroxysuccinimide group. Since at least part of the acrylic compound has an N-hydroxysuccinimide group, there are carboxyl groups and N-hydroxysuccinimide groups in the acrylic compound. The carboxyl group can form immediate molecular bonds (such as hydrogen bonds and electrostatic interactions) with the tissue surface, and the N-hydroxysuccinimide group can further form covalent coupling or crosslinking with the amine groups on the tissue within a few minutes, so that the absorbable tissue adhesion patch can be quickly adhered to the tissue surface to seal and prevent leakage.

[0092] In the present invention, based on the total mass of the adhesive composition being 100%, the content of the acrylic compound having an N-hydroxysuccinimide group is 0.5% to 5%, for example: 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, etc. When the content of the acrylic compound having an N-hydroxysuccinimide group is 0.5% to 5%, the obtained adhesive layer 2 has good adhesiveness.

[0093] Furthermore, when the content of the acrylic compound having an N-hydroxysuccinimide group is 0.5% to 5%, the content of other acrylic compounds is 19.5% to 50%, for example: 20%, 25%, 30%, 35%, 40%, 45%, etc. Generally, the acrylic compound having an N-hydroxysuccinimide group can be N-hydroxysuccinimide acrylate; other acrylic compounds can be acrylic acid and / or polyacrylic acid, etc. By using different acrylic compounds in the present invention, the adhesion performance of the adhesive layer 2 is made more excellent.

[0094] Photoinitiator

[0095] A photoinitiator refers to a compound that decomposes upon irradiation with active energy rays such as ultraviolet light or visible light to generate free radical species, cationic species, or anionic species. In the present invention, a photoinitiator is used so that the adhesive composition of the present invention can be cured under ultraviolet light conditions.

[0096] Based on the total mass of the adhesive composition being 100%, the content of the photoinitiator is 0.1% to 0.3%, for example: 0.12%, 0.15%, 0.18%, 0.2%, 0.22%, 0.25%, 0.28%, etc. When the content of the photoinitiator is 0.1% to 0.3%, the effects of the present invention can be most effectively exerted.

[0097] As the photoinitiator, there is no particular limitation. Specifically, the photoinitiator may include one or a combination of two or more of α-ketoglutaric acid, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (Irgacure 2959), bis(pentafluorophenyl) titanocene, fluorinated diphenyl titanocene (Irgacure 784), and lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP).

[0098] Crosslinking agent

[0099] The purpose of using the crosslinking agent in the present invention is to enable the adhesive composition to maintain its own form well while bonding and not be quickly dissolved by tissue fluid or lose its adhesiveness. By using the crosslinking agent, the crosslinking density of the hydrogel formed by the adhesive composition becomes larger, the swelling becomes smaller, and the degradation rate becomes slower.

[0100] In order to effectively exert the function of the crosslinking agent, based on the total mass of the adhesive composition being 100%, the content of the crosslinking agent is 0.05% - 0.6%, for example: 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, etc.

[0101] Specifically, in the present invention, the crosslinking agent includes one or a combination of two or more of gelatin methacrylate, hyaluronic acid methacrylate, oxidized alginate methacrylate, polycaprolactone diacrylate, N,N-bis(acryloyl)cystamine, N,N'-methylenebis(acrylamide), polyethylene glycol diacrylate, and polyethylene glycol dimethacrylate.

[0102] Other components

[0103] The adhesive composition of the present invention may further contain other components, such as biodegradable biomaterials and solvents. By using biodegradable biomaterials in the present invention, the adhesiveness of the adhesive composition can be enhanced.

[0104] In some specific embodiments, in order to most effectively exert the function of the biodegradable biomaterial, based on the total mass of the adhesive composition being 100%, the content of the biodegradable biomaterial is 0.5% - 15%, for example: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, etc.

[0105] As a biodegradable biomaterial, the present invention is not particularly limited and can be a biodegradable biomaterial commonly used in the art, preferably a water-soluble biodegradable biomaterial. Specifically, the biodegradable biomaterial can be one or a combination of two or more of gelatin, hyaluronic acid, chitosan, sodium alginate, carboxymethyl chitosan, etc.

[0106] By using a solvent, the present invention enables the support layer 1 and the adhesive layer 2 to be composite-molded. Based on the total mass of the adhesive composition being 100%, the content of the solvent is 40% - 70%, for example: 45%, 50%, 55%, 60%, 65%, etc.

[0107] For the solvent in the adhesive composition, the present invention is not particularly limited as long as it can dissolve the adhesive composition. Specifically, it can be water and / or an acetic acid solution with a mass concentration of 0.1% - 5%.

[0108] For the preparation method of the adhesive composition, the present invention is not particularly limited. Generally, the components of the adhesive composition can be mixed to obtain it. For the mixing temperature, the present invention is not particularly limited and can generally be carried out at room temperature.

[0109] <Second aspect>

[0110] The second aspect of the present invention provides a preparation method of an absorbable tissue adhesive patch according to the first aspect of the present invention, comprising the following steps:

[0111] Obtain a film-forming composition and dissolve it in a solvent to make a spinning dope;

[0112] Obtain an adhesive composition. Preferably, the adhesive composition includes an acrylic compound, a photoinitiator, and a crosslinking agent;

[0113] Spinning the spinning dope by a spinning process to obtain a support layer;

[0114] Use the adhesive composition to form an adhesive layer on at least one surface of the support layer and composite-mold it with the support layer;

[0115] Specifically, the composite molding includes: one or a combination of two or more of spreading, coating, casting, and spraying. Preferably, the coating includes spin coating and / or blade coating.

[0116] In some specific embodiments, the preparation method further includes the following steps:

[0117] After the adhesive composition is present on at least one surface of the support layer, a chemical reaction is carried out under the irradiation of ultraviolet light to obtain a molded body;

[0118] Optionally, the formed body is post-treated to obtain an absorbable tissue adhesion patch.

[0119] Specifically, the spinning process includes one or a combination of two or more of electrospinning technology, centrifugal spinning technology, hot melt spinning technology, and melt electrospinning technology.

[0120] The principle of electrospinning is that during the electrospinning process, a high voltage is applied to the polymer liquid to introduce charges into the liquid. When the charges in the liquid accumulate to a certain amount, the liquid will form a Taylor cone at the nozzle. Under the action of an external electric field force, the surface tension is overcome to form a liquid jet. Then, under the combined action of electrostatic repulsion, Coulomb force, and surface tension, the polymer jet moves along an irregular spiral trajectory. The jet is stretched and pulled in a very short time. As the solvent volatilizes or heat dissipates, the polymer jet solidifies to form micro / nano fibers. During the electrospinning process, many parameters will affect the final electrospun fibers. By controlling the process parameters, micro / nano fibers with different sizes, morphologies, and structures can be prepared.

[0121] During the electrospinning process of the present invention, the process parameters will affect the support layer obtained by electrospinning. By controlling the process parameters, support layers with different sizes, morphologies, and structures can be prepared. The present invention has no special requirements for the electrospinning method, and it can be a commonly used electrospinning method in the art. Specifically, the conditions for electrospinning of the present invention are as follows: placing the spinning stock solution in an electrospinning syringe, with the ambient temperature being 19°C to 30°C, the relative humidity of the spinning environment being 50% to 65%, adjusting the propulsion speed of the micro-injection pump to 3 mL / h to 6 mL / h, adjusting the voltage of the high-voltage generator to 24 kV to 32 kV, adjusting the receiving distance of the receiving device to 18 cm to 25 cm, and performing electrospinning to obtain a support layer.

[0122] Furthermore, when performing electrospinning, a fiber raw material can be prepared in advance, and the fiber raw material is dissolved in a solvent to prepare a spinning stock solution of the fiber raw material with a certain concentration. Among them, the fiber raw material is the film-forming composition in the first embodiment.

[0123] In some specific implementation schemes, after the support layer is prepared, it further includes: a step of washing and / or drying the support layer to remove the solvent. Specifically, the washing can include: washing the support layer with an alcohol solvent to remove the solvent, thereby obtaining a support layer. The alcohol solvent includes a mixture of alcohol and water, preferably a mixture of ethanol and water, and more preferably, the mass fraction of ethanol in the mixture of ethanol and water is above 70%, for example: 70% to 95%.

[0124] For drying, the present invention is not particularly limited, and generally drying can be carried out in an air atmosphere. For the drying temperature, the present invention is not particularly limited, as long as the function of the absorbable tissue adhesion patch is not affected.

[0125] Next, the adhesive composition is made to exist on at least one surface of the support layer to form an adhesive layer. Specifically, one or a combination of two or more of spreading, coating, casting, spraying, etc. can be adopted, so that the adhesive composition exists on at least one surface of the support layer to form an adhesive layer. More preferably, the coating includes spin coating and / or blade coating.

[0126] Then, a chemical reaction is carried out under the irradiation of ultraviolet light to obtain a molded body. The present invention is not particularly limited to the parameters of the ultraviolet light. Specifically, considering the effect of the chemical reaction, the wavelength of the ultraviolet light is 365 nm to 405 nm, and the irradiation time of the ultraviolet light is 30 s to 100 min.

[0127] For the post-treatment, the present invention is not particularly limited and can be carried out as needed. Specifically, the post-treatment includes steps of removing residual organic solvents and / or drying; preferably, the molded body is soaked in an alcohol solvent to remove residual organic solvents; more preferably, the number of soakings is 1 to 10 times.

[0128] For the alcohol solvent, the present invention is not particularly limited and can be a commonly used alcohol solvent in the art. For example: methanol, ethanol, etc. Preferably, the present invention uses ethanol with a concentration of 75% to 95%. By using ethanol with a concentration of 75% to 95% and soaking repeatedly for multiple times, residual organic solvents can be effectively removed.

[0129] For drying, the present invention is not particularly limited, and generally drying can be carried out in an air atmosphere. For the drying temperature, the present invention is not particularly limited, as long as the function of the absorbable tissue adhesion patch is not affected.

[0130] Finally, the obtained absorbable tissue adhesion patch can be cut, sealed and packaged, and then irradiated and sterilized. For example: Co-60 γ-ray irradiation sterilization treatment can be adopted.

[0131] <Third aspect>

[0132] The third aspect of the present invention provides a use of the absorbable tissue adhesion patch according to the first aspect of the present invention for preparing hard cerebrospinal membrane sealing products, blood vessel sealing products, lung sealing products, intestinal anastomosis products, cerebrospinal fluid leakage products. The absorbable tissue adhesion patch of the present invention is very convenient to use and can be directly applied to the tissue or wound site.

[0133] Examples

[0134] The embodiments of the present invention will be described in detail below in conjunction with examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the examples, the operations are carried out under conventional conditions or conditions recommended by the manufacturer. All reagents or instruments not specified by the manufacturer can be obtained as conventional products through commercial purchase.

[0135] Example 1

[0136] (1) Take 1.5 g of polytrimethylene carbonate (PTMC) and dissolve it in 30 mL of hexafluoroisopropanol, and stir evenly to prepare a spinning dope.

[0137] (2) Place the spinning dope in an electrospinning syringe, adjust the feeding speed of the micro-injection pump to 6 mL / h, the voltage of the high-voltage generator to 32 kV, the relative humidity of the spinning environment to 63%, the environmental temperature to 21 °C, and the receiving distance of the receiving device to 22 cm, and carry out electrospinning to obtain a fiber membrane.

[0138] (3) After electrospinning, soak the fiber membrane in a 95% ethanol solution, soak it repeatedly to remove the residual hexafluoroisopropanol, and then dry it to obtain a support layer.

[0139] (4) Dissolve 0.25 g of α-ketoglutaric acid, 0.1 g of gelatin methacrylate, 1 g of N-hydroxysuccinimide acrylate, and 31.5 g of acrylic acid in 67.15 g of deionized water, mix and stir evenly to prepare an adhesive composition.

[0140] (5) Fix the support layer on a doctor blade coater, then scrape the adhesive composition on the support layer, then irradiate with ultraviolet light for 30 min, the wavelength of the ultraviolet light is 365 nm, and then dry it to obtain a molded body.

[0141] (6) Soak the molded body repeatedly in a 75% ethanol solution to remove the residual acrylic acid, dry it, then carry out sealed packaging, and carry out Co-60 γ-ray irradiation sterilization treatment to obtain an absorbable tissue adhesive patch.

[0142] Example 2

[0143] (1) Take 0.75 g of gelatin and 0.75 g of polytrimethylene carbonate (PTMC) and dissolve them in 30 mL of hexafluoroisopropanol, and stir evenly to prepare a spinning dope.

[0144] (2) Place the spinning dope in an electrospinning syringe, adjust the pushing speed of the micro-injection pump to 6 mL / h, the voltage of the high-voltage generator to 32 kV, the relative humidity of the spinning environment to 63%, the ambient temperature to 21 °C, and the receiving distance of the receiving device to 22 cm, and perform electrospinning to obtain a fiber membrane.

[0145] (3) After electrospinning is completed, soak the fiber membrane in a 95% ethanol solution and soak it repeatedly to remove the residual hexafluoroisopropanol, and then dry it to obtain a support layer.

[0146] (4) Dissolve 0.25 g of α-ketoglutaric acid, 0.1 g of gelatin methacrylate, 1 g of N-hydroxysuccinimide acrylate, and 31.5 g of acrylic acid in 67.15 g of deionized water, and mix and stir evenly to prepare an adhesive composition.

[0147] (5) Fix the support layer on a doctor blade coater, then scrape the adhesive composition on the support layer, then irradiate with ultraviolet light for 30 min, the ultraviolet light wavelength is 365 nm, and then dry to obtain a molded body.

[0148] (6) Soak the molded body in a 75% ethanol solution repeatedly to remove the residual acrylic acid, dry it, then perform sealed packaging, and perform Co-60 γ-ray irradiation sterilization treatment to obtain an absorbable tissue adhesive patch.

[0149] Example 3

[0150] (1) Take 0.12 g of polycaprolactone, 0.69 g of gelatin, and 0.69 g of poly(trimethylene carbonate) and dissolve them in 30 mL of hexafluoroisopropanol and stir evenly to prepare a spinning dope.

[0151] (2) Place the spinning dope in an electrospinning syringe, adjust the pushing speed of the micro-injection pump to 6 mL / h, the voltage of the high-voltage generator to 32 kV, the relative humidity of the spinning environment to 63%, the ambient temperature to 21 °C, and the receiving distance of the receiving device to 22 cm, and perform electrospinning to obtain a fiber membrane.

[0152] (3) After electrospinning is completed, soak the fiber membrane in a 95% ethanol solution and soak it repeatedly to remove the residual hexafluoroisopropanol, and then dry it to obtain a support layer.

[0153] (4) Dissolve 0.25 g of α-ketoglutaric acid, 0.1 g of gelatin methacrylate, 1 g of N-hydroxysuccinimide acrylate, and 31.5 g of acrylic acid in 67.15 g of deionized water, and mix and stir evenly to prepare an adhesive composition.

[0154] (5) Fix the support layer on the doctor blade coater, then scrape the adhesive composition onto the support layer, then perform ultraviolet light irradiation for 30 min with the ultraviolet light wavelength of 365 nm, and then dry to obtain a molded body.

[0155] (6) Immerse the molded body repeatedly in a 75% ethanol solution to remove the residue of acrylic acid, perform sealed packaging after drying, and perform Co-60 γ-ray irradiation sterilization treatment to obtain an absorbable tissue adhesive patch.

[0156] Example 4

[0157] (1) Take 0.5 g of polycaprolactone, 0.5 g of gelatin and 0.5 g of poly(trimethylene carbonate) and dissolve them in 30 mL of hexafluoroisopropanol, stir evenly to prepare a spinning dope.

[0158] (2) Place the spinning dope in an electrospinning syringe, adjust the propulsion speed of the micro-injection pump to 6 mL / h, the voltage of the high-voltage generator to 32 kV, the relative humidity of the spinning environment to 63%, the ambient temperature to 21 °C, and the receiving distance of the receiving device to 22 cm, and perform electrospinning to obtain a fibrous membrane.

[0159] (3) After electrospinning is completed, immerse the fibrous membrane repeatedly in a 95% ethanol solution to remove the residue of hexafluoroisopropanol, and then dry to obtain a support layer.

[0160] (4) Dissolve 0.25 g of α-ketoglutaric acid, 0.1 g of gelatin methacrylate, 1 g of N-hydroxysuccinimide acrylate, and 31.5 g of acrylic acid in 67.15 g of deionized water, mix and stir evenly to prepare an adhesive composition.

[0161] (5) Fix the support layer on the doctor blade coater, then scrape the adhesive composition onto the support layer, then perform ultraviolet light irradiation for 30 min with the ultraviolet light wavelength of 365 nm, and then dry to obtain a molded body.

[0162] (6) Immerse the molded body repeatedly in a 75% ethanol solution to remove the residue of acrylic acid, perform sealed packaging after drying, and perform Co-60 γ-ray irradiation sterilization treatment to obtain an absorbable tissue adhesive patch.

[0163] Example 5

[0164] (1) Take 0.3 g of polycaprolactone, 0.6 g of gelatin and 0.6 g of poly(trimethylene carbonate) and dissolve them in 30 mL of hexafluoroisopropanol, stir evenly to prepare a spinning dope.

[0165] (2) Place the spinning dope in an electrospinning syringe, adjust the feeding rate of the micro-injection pump to 6 mL / h, the voltage of the high-voltage generator to 32 kV, the relative humidity of the spinning environment to 63%, the ambient temperature to 21 °C, and the receiving distance of the receiving device to 22 cm, and perform electrospinning to obtain a fibrous membrane.

[0166] (3) After electrospinning is completed, soak the fibrous membrane in a 95% ethanol solution and soak it repeatedly to remove the residual hexafluoroisopropanol, and then dry it to obtain a support layer.

[0167] (4) Dissolve 0.25 g of α-ketoglutaric acid, 0.1 g of gelatin methacrylate, 1 g of N-hydroxysuccinimide acrylate, and 31.5 g of acrylic acid in 67.15 g of deionized water, and mix and stir evenly to prepare an adhesive composition.

[0168] (5) Fix the support layer on a doctor blade coater, then scrape the adhesive composition on the support layer, then irradiate with ultraviolet light for 30 min, the wavelength of the ultraviolet light is 365 nm, and then dry to obtain a molded body.

[0169] (6) Soak the molded body in a 75% ethanol solution repeatedly to remove the residual acrylic acid, dry it, then perform sealed packaging, and perform Co-60 γ-ray irradiation sterilization treatment to obtain an absorbable tissue adhesive patch.

[0170] Example 6

[0171] (1) Take 0.4 g of glycolide-trimethylene carbonate copolymer, 0.6 g of gelatin, and 0.6 g of polytrimethylene carbonate and dissolve them in 30 mL of hexafluoroisopropanol and stir evenly to prepare a spinning dope.

[0172] (2) Place the spinning dope in an electrospinning syringe, adjust the feeding rate of the micro-injection pump to 6 mL / h, the voltage of the high-voltage generator to 32 kV, the relative humidity of the spinning environment to 63%, the ambient temperature to 21 °C, and the receiving distance of the receiving device to 22 cm, and perform electrospinning to obtain a fibrous membrane.

[0173] (3) After electrospinning is completed, soak the fibrous membrane in a 95% ethanol solution and soak it repeatedly to remove the residual hexafluoroisopropanol, and then dry it to obtain a support layer.

[0174] (4) Dissolve 0.25 g of α-ketoglutaric acid, 0.1 g of gelatin methacrylate, 1 g of N-hydroxysuccinimide acrylate, and 31.5 g of acrylic acid in 67.15 g of deionized water, and mix and stir evenly to prepare an adhesive composition.

[0175] (5) Fix the support layer on the doctor blade coater, then scrape the adhesive composition onto the support layer, then perform ultraviolet light irradiation for 30 min with an ultraviolet light wavelength of 365 nm, and then dry to obtain a molded body.

[0176] (6) Soak the molded body repeatedly in a 75% ethanol solution to remove the residue of acrylic acid, perform sealed packaging after drying, and perform Co-60 γ-ray irradiation sterilization treatment to obtain an absorbable tissue adhesive patch.

[0177] Example 7

[0178] (1) Take 0.3 g of hyaluronic acid and 1.2 g of poly(trimethylene carbonate) and dissolve them in 30 mL of hexafluoroisopropanol, stir evenly to prepare a spinning dope.

[0179] (2) Place the spinning dope in an electrospinning syringe, adjust the propulsion speed of the micro-injection pump to 3 mL / h, the voltage of the high-voltage generator to 30 kV, the relative humidity of the spinning environment to 55%, the ambient temperature to 19 °C, and the receiving distance of the receiving device to 20 cm, and perform electrospinning to obtain a fibrous membrane.

[0180] (3) After electrospinning, soak the fibrous membrane repeatedly in a 70% ethanol solution to remove the residue of hexafluoroisopropanol, and then dry to obtain a support layer.

[0181] (4) Dissolve 0.15 g of bis(pentafluorophenyl)titanocene, 0.05 g of N,N-bis(acryloyl)cystamine, 0.5 g of N-hydroxysuccinimide acrylate, 21 g of acrylic acid, and 15 g of gelatin in 63.3 g of deionized water, mix and stir evenly to prepare an adhesive composition.

[0182] (5) Fix the support layer on the doctor blade coater, then scrape the adhesive composition onto the support layer, then perform ultraviolet light irradiation for 90 min with an ultraviolet light wavelength of 365 nm, and then dry to obtain a molded body.

[0183] (6) Soak the molded body repeatedly in a 75% ethanol solution to remove the solvent residue and the residue of acrylic acid, perform sealed packaging after drying, and perform Co-60 γ-ray irradiation sterilization treatment to obtain an absorbable tissue adhesive patch.

[0184] Example 8

[0185] (1) Take 0.5 g of cellulose, 0.6 g of poly(trimethylene carbonate), and 0.3 g of polycaprolactone and dissolve them in 30 mL of hexafluoroisopropanol, stir evenly to prepare a spinning dope.

[0186] (2) Place the spinning dope in an electrospinning syringe, and adjust the feeding rate of the micro-injection pump to 4 mL / h, the voltage of the high-voltage generator to 32 kV, the relative humidity of the spinning environment to 50%, the ambient temperature to 30 °C, and the receiving distance of the receiving device to 28 cm, and perform electrospinning to obtain a fiber membrane.

[0187] (3) After electrospinning is completed, soak the fiber membrane in a 90% ethanol solution and soak it repeatedly to remove the residual hexafluoroisopropanol, and then dry it to obtain a support layer.

[0188] (4) Dissolve 0.6 g of polyethylene glycol diacrylate, 0.3 g of lithium phenyl-2,4,6-trimethylbenzoylphosphinate, 5 g of N-hydroxysuccinimide acrylate, 50 g of acrylic acid, and 0.5 g of chitosan in 43.6 g of deionized water, and mix and stir evenly to prepare an adhesive composition.

[0189] (5) Fix the support layer on a doctor blade coater, then scrape the adhesive composition onto the support layer, then irradiate with ultraviolet light for 1 min, the ultraviolet light wavelength is 365 nm, and then dry to obtain a molded body.

[0190] (6) Soak the molded body in an 80% ethanol solution and soak it repeatedly to remove the residual solvent and acrylic acid, dry it, then perform sealed packaging, and perform Co-60 γ-ray irradiation sterilization treatment to obtain an absorbable tissue adhesive patch.

[0191] Example 9

[0192] (1) Take 0.8 g of polytrimethylene carbonate, 0.6 g of collagen, and 0.2 g of glycolide-trimethylene carbonate copolymer and dissolve them in 30 mL of hexafluoroisopropanol and stir evenly to prepare a spinning dope.

[0193] (2) Place the spinning dope in an electrospinning syringe, and adjust the feeding rate of the micro-injection pump to 4 mL / h, the voltage of the high-voltage generator to 32 kV, the relative humidity of the spinning environment to 50%, the ambient temperature to 30 °C, and the receiving distance of the receiving device to 28 cm, and perform electrospinning to obtain a fiber membrane.

[0194] (3) After electrospinning is completed, soak the fiber membrane in a 90% ethanol solution and soak it repeatedly to remove the residual hexafluoroisopropanol, and then dry it to obtain a support layer.

[0195] (4) Take 30 g of polyacrylic acid, 3 g of N-hydroxysuccinimide acrylate, 0.3 g of polyethylene glycol dimethacrylate, 0.2 g of lithium phenyl-2,4,6-trimethylbenzoylphosphinate, and 5 g of gelatin and dissolve them in 61.5 mL of deionized water to prepare an adhesive composition.

[0196] (5) Fix the support layer on the doctor blade coater, then scrape the adhesive composition onto the support layer and irradiate it with ultraviolet light for 5 min. The wavelength of the ultraviolet light is 365 nm, and then dry it to obtain the formed body.

[0197] (6) Soak the formed body in 90% ethanol solution repeatedly for many times to remove the solvent residue and the residue of acrylic acid. After drying, perform sealed packaging and perform Co-60 γ-ray irradiation sterilization treatment to obtain the absorbable tissue adhesive patch.

[0198] Comparative Example 1

[0199] Replace the PTMC of the support layer material in Example 1 with polylactic acid; keep other materials and preparation methods unchanged to obtain the absorbable tissue adhesive patch.

[0200] Comparative Example 2

[0201] Commercially available product: Tie Sute purchased from BD Medical.

[0202] Performance test

[0203] 1. SEM images

[0204] Soak the absorbable tissue adhesive patches of Examples 1-6 and Comparative Example 1 in PBS for 24 h, then take them out, freeze them at -80 °C, and then perform freeze-drying. Spray gold on the freeze-dried samples and take SEM images of the two surfaces of the absorbable tissue adhesive patches respectively. The results are as Figures 2 - 8 shown.

[0205] It can be Figure 2 seen that when preparing the support layer by using poly(trimethylene carbonate) alone in Example 1, the fibers will shrink and adhere significantly during electrospinning, resulting in an unclear fiber morphology. However, it can still be seen that it has a fibrous filament morphology, and the adhesive layer is a honeycomb structure.

[0206] It can be Figure 3 seen that when preparing the support layer by using a combination of poly(trimethylene carbonate) and gelatin in Example 2, compared with Example 1, the shrinkage and adhesion of the fibers are improved, the pore size of the fiber membrane becomes slightly larger, and the fiber morphology is obvious. The adhesive layer is a honeycomb structure.

[0207] It can be Figure 4 seen that when preparing the support layer by using a combination of polycaprolactone, poly(trimethylene carbonate) and gelatin in Example 3, compared with Example 2, the shrinkage and adhesion of the fibers are further reduced, and the adhesive layers are all honeycomb structures.

[0208] It can be Figure 5 and 6It can be seen that when preparing the support layer using a combination of polycaprolactone, poly(trimethylene carbonate) and gelatin in Example 4 and Example 5, compared with Example 2, the shrinkage and adhesion of the fibers are significantly improved, the fiber morphology is obvious, and the adhesive layer is a honeycomb structure.

[0209] From Figure 7 It can be seen that when preparing the support layer using a combination of glycolide-trimethylene carbonate copolymer, poly(trimethylene carbonate) and gelatin in Example 6, compared with Example 2, the shrinkage and adhesion of the fibers are significantly improved, the fiber morphology is very obvious, and the adhesive layer is a honeycomb structure.

[0210] From Figure 8 It can be seen that when using polylactic acid (PLA) to prepare the support layer in Comparative Example 1, the fiber morphology is very obvious, there is no adhesion between the fibers, and the adhesive layer is a honeycomb structure.

[0211] 2. Thickness test

[0212] The thickness of the absorbable tissue adhesive patches of Examples 1-9 and Comparative Examples 1-2 was measured using a thickness gauge. The test results are shown in Table 1.

[0213] Table 1 Thickness test results

[0214]

[0215]

[0216] 2. Testing of mechanical properties

[0217] The tensile strength and elongation at break were determined by the method of GB / T1040.3-2006. The tensile strength and elongation at break of Examples 1-9 and Comparative Examples 1-2 were obtained by testing using an electronic universal testing machine, and the results are shown in Table 2.

[0218] Table 2 Mechanical property test results

[0219]

[0220] It can be seen from Table 2 that the absorbable tissue adhesive patch of the present invention has good tensile strength and elongation at break. The tensile strength is between 2 Mpa and 5.5 Mpa, and the elongation at break is between 45% and 350%. It can be shown that the absorbable tissue adhesive patch of the present application has excellent mechanical properties and certain elasticity.

[0221] Moreover, from the results of Example 4, it can be seen that in the support layer formed by the natural polymer material, polytrimethylene carbonate, and polycaprolactone, based on the total mass of the film-forming composition being 100%, when the content of polycaprolactone is too high, although the tensile strength of the tissue adhesive patch increases, its breaking tensile strain performance deteriorates significantly.

[0222] 3. Burst Strength Test

[0223] The burst strength is an important mechanical property of the absorbable tissue adhesive patch, which represents the minimum pressure required to cause the tissue sealed by the adhesive to rupture or burst. This property becomes particularly important when the absorbable tissue adhesive patch is used to prevent leakage from tissue wounds such as the heart, lungs, or gastrointestinal tract. The test method is as follows:

[0224] (1) The detection device consists of a base (containing a water tank), a fixed hollow cover, a water delivery system, and a pressure detection system. Take a sausage casing with a diameter of not less than 4 cm and prepare a hole with a diameter of 5 mm in the middle of the sausage casing. Use an oil-based pen to draw a point on the test tabletop and place the hole at the center of the point. Take the samples prepared in the examples and comparative examples, cut out circular test specimens with a diameter of 1.5 cm using a 1.5 cm skin biopsy punch, place the samples on the sausage casing with the small hole as the center of the circle, and make them adhere to the sausage casing to form a seal. Then place it on the test base and fix it with the hollow cover, and then apply external pressure to measure the burst strength. The burst strength is the comprehensive effect of the elasticity, toughness, and adhesiveness of the adhesive patch itself.

[0225] (2) Burst strength detection: Open the water delivery system and inject PBS solution at a rate of 2 mL / min to increase the pressure, and record the maximum pressure when the sample ruptures and fails. The test results of Examples 1-9 and Comparative Examples 1-2 are shown in Table 3.

[0226] Table 3 Burst Strength Detection Results

[0227] Experimental sample Breaking strength (kPa) Sample of Example 1 32.30 Sample of Example 2 34.20 Sample of Example 3 37.25 Sample of Example 4 31.20 Sample of Example 5 43.12 Sample of Example 6 50.39 Sample of Example 7 36.23 Sample of Example 8 35.42 Sample of Example 9 37.24 Sample of Comparative Example 1 23.34 Sample of Comparative Example 2 4.23

[0228] From the results of Table 3, it can be seen that the absorbable tissue adhesive patch of the present invention has a burst strength of not less than 30 kPa and can be used for adhesion and plugging in cases of cerebrospinal fluid leakage, lung leakage, or vascular bleeding; and it is higher than the burst strength of the adhesive patches in Comparative Examples 1-2.

[0229] 4. Adhesive Performance

[0230] The adhesive plugging effect and continuous plugging time of the absorbable tissue adhesive patch are important in vitro performance evaluations, which represent the minimum pressure required to cause the tissue sealed by the adhesive patch to rupture or burst and the duration under this pressure. This property becomes particularly important when the adhesive patch is used to prevent leakage from tissue wounds such as blood vessels, lungs, or gastrointestinal tract.

[0231] Test method: The test was carried out using the gel pressure resistance test recording tooling system instrument, and the specific method is as follows:

[0232] First, take a sausage casing with a diameter of 4 cm, prepare a hole with a diameter of 5 mm in the middle of the sausage casing, and adhere the absorbable tissue adhesion patch (15 mm × 15 mm) of the example and the comparative example to the wound. When adhering, it is necessary to ensure that the midline of the adhesive patch is exactly above the incision. Keep the pressure at 4 kPa, and use a peristaltic pump to drip the PBS solution onto the hydrogel patch at a rate of 2 mL / min until the sample fails and cannot maintain the pressure, and record the time when the material breaks and fails. The experimental results of Examples 1-9 and Comparative Examples 1-2 are shown in Table 4.

[0233] Table 4 Adhesion performance test results

[0234]

[0235] From the test results in Table 4, it can be seen that the absorbable tissue adhesion patch prepared in this application can maintain the pressure for 12 days and has a relatively long-lasting adhesive force. For Comparative Example 1, the support layer is made of polylactic acid, and it loses the pressure maintaining state at 12 days. For the TieSuTai sample in Comparative Example 2, it has already lost the pressure maintaining state on the 8th day.

[0236] 5. Tissue compliance experiment

[0237] As Figure 9 shown, use a 28G syringe needle to punch holes in the pig lung, and then stick the absorbable tissue adhesion patches (20 mm × 20 mm) obtained from Examples 1, 5, 6 and Comparative Examples 1-2 to the holes. Simulate the state of the lung during expansion by inflating the lung, and simulate the state of the lung during relaxation by pumping out the air in the lung to simulate the lung breathing phenomenon. Observe the states of the absorbable tissue adhesion patches during the relaxation and expansion of the lung to test the tissue compliance of the absorbable tissue adhesion patches. The results are as Figures 10 - 14 shown.

[0238] From Figure 10 it can be seen that regardless of whether the lung is in the expanded or relaxed state, the absorbable tissue adhesion patch of Example 1 can maintain a good shape. From Figures 11 - 12 it can be seen that regardless of whether the lung is in the expanded or relaxed state, the tissue patches of Examples 5 and 6 can adhere well to the tissue and maintain a good shape.

[0239] From Figure 13 it can be seen that for the absorbable tissue adhesion patch of Comparative Example 1, the support layer is made of polylactic acid prepared by electrospinning. Since the fiber membrane has no elasticity, the adhesion performance at the edge is poor and it cannot well conform to the deformation of the tissue. From Figure 14It can be seen that the tissue patch of Comparative Example 2 has poor adhesion at the edge in the state of lung expansion, and the material shrinks and deforms in the state of lung relaxation. Moreover, due to its poor adhesion performance, the periphery of the tissue adhesive patch of Comparative Example 2 has been detached from the lung tissue.

[0240] It should be noted that although the technical solutions of the present invention are introduced by specific examples, those skilled in the art can understand that the present invention should not be limited thereto.

[0241] The various embodiments of the present invention have been described above. The above description is exemplary and not exhaustive, and is not limited to the disclosed embodiments. Many modifications and variations are obvious to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The choice of terms used herein is intended to best explain the principles of the embodiments, practical applications, or improvements to technologies in the market, or to enable other ordinary skill in the art to understand the embodiments disclosed herein.

Claims

1. An absorbable tissue adhesion patch, characterized in that, comprising a contacting support layer and an adhesive layer; wherein, the support layer comprises fibrils with a diameter of 10 nm to 100 μm that are intertwined with each other, and the support layer has a porous structure; and, the support layer is derived from a film-forming composition, the film-forming composition comprising a polyester compound, the polyester compound comprising polytrimethylene carbonate.

2. The absorbable tissue adhesion patch according to claim 1, wherein The polyester compound further comprises one or a combination of two of polycaprolactone and glycolide-trimethylene carbonate copolymer.

3. The absorbable tissue adhesion patch according to claim 2, wherein The polyester compound comprises a combination of polytrimethylene carbonate and polycaprolactone, or comprises a combination of polytrimethylene carbonate and glycolide-trimethylene carbonate copolymer; Preferably, the mass ratio of the polytrimethylene carbonate to the polycaprolactone or glycolide-trimethylene carbonate copolymer is (1 to 6):(1 to 5), preferably (1 to 4):(1 to 3).

4. The absorbable tissue adhesion patch according to any one of claims 1-3, characterized in that, The film-forming composition further comprises a natural polymer material; preferably, the mass ratio of the polyester compound to the natural polymer material is (1 to 11):(1 to 6), preferably (1 to 7):(1 to 4).

5. The absorbable tissue adhesion patch according to claim 4, wherein The film-forming composition comprises a natural polymer material, a combination of polytrimethylene carbonate and polycaprolactone, or comprises a natural polymer material, a combination of polytrimethylene carbonate and glycolide-trimethylene carbonate copolymer; Preferably, based on the total mass of the film-forming composition being 100%, the content of the polycaprolactone or the glycolide-trimethylene carbonate copolymer is 6% to 35%, preferably 12% to 25%.

6. The absorbable tissue adhesion patch according to any one of claims 1-5, characterized in that, The absorbable tissue adhesion patch has at least one of the following characteristics: The tensile strength of the absorbable tissue adhesion patch is 2 Mpa to 5.5 Mpa; The breaking tensile strain of the absorbable tissue adhesion patch is 45% to 350%, preferably 150% to 300%; The bursting strength of the absorbable tissue adhesion patch is above 30 kPa.

7. The absorbable tissue adhesion patch according to any one of claims 1-6, characterized in that, The adhesive layer is derived from an adhesive composition, the adhesive composition comprising an acrylic compound, a photoinitiator, and a crosslinking agent; wherein, Based on the total mass of the adhesive composition being 100%, the content of the acrylic compound is 20% to 55%, the content of the photoinitiator is 0.1% to 0.3%, and the content of the crosslinking agent is 0.05% to 0.6%; Preferably, at least part of the acrylic compound has an N-hydroxysuccinimide group, and preferably, based on the total mass of the adhesive composition being 100%, the content of the acrylic compound having an N-hydroxysuccinimide group is 0.5% to 5%.

8. The absorbable tissue adhesion patch according to claim 7, wherein The adhesive composition further comprises a biodegradable biomaterial and a solvent; based on the total mass of the adhesive composition being 100%, the content of the biodegradable biomaterial is 0.5% to 15%, and the content of the solvent is 40% to 70%.

9. A method for preparing an absorbable tissue adhesion patch according to any one of claims 1-8, characterized in that, Comprising the following steps: Obtain a film-forming composition and dissolve it in a solvent to make a spinning dope; Obtain an adhesive composition, preferably, the adhesive composition comprising an acrylic compound, a photoinitiator, and a crosslinking agent; Use a spinning process to spin the spinning dope to obtain a support layer; A binder layer is formed on at least one surface of the support layer using a binder composition and is integrally molded with the support layer; Preferably, the integral molding includes one or a combination of two or more of spreading, coating, casting, and spraying; More preferably, the coating includes spin coating and / or knife coating.

10. The preparation method according to claim 9, characterized in that, The preparation method further includes the following steps: The binder composition is present on at least one surface of the support layer and undergoes a chemical reaction under the irradiation of ultraviolet light to obtain a molded body; The molded body is post-treated to obtain an absorbable tissue adhesion patch; Preferably, the wavelength of the ultraviolet light is 365 nm to 405 nm, and the irradiation time of the ultraviolet light is 30 s to 100 min.

Images