Process for realizing high-drug-loading-capacity antibacterial biological patch with controllable slow release

Abstract

The invention relates to the field of medical materials, in particular to a process for realizing a controllable slow-release antibacterial biological patch with high drug loading capacity. Different from a conventional coating type structure, the effective antibacterial components of the antibacterial patch are distributed at all positions of a patch structure network, but not only distributed at a certain layer. The prepared patch has good mechanical properties and a structure which is not easy to loosen when encountering water, the process stability is enhanced, the drug loading capacity, the drug loading speed and the like can be quantitatively and controllably adjusted according to actual requirements, and the patch can be applied to various surgical scenes such as an abdominal cavity open operation and the like and has wide application prospects. The biological patch is especially suitable for being applied to instant antibiosis after a surgical operation, not only is beneficial to infection resistance, but also can guide tissue regeneration, and is degraded along with tissue repair.

Description

Technical Field

[0001] The invention relates to the field of medical materials, and in particular to a process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release. Background Art

[0002] As an implantable medical device, the patch faces the problem of infection that cannot be ignored during use. Antibacterial functional modification of the patch has become one of the research focuses. The methods of antibacterial functional modification usually include coating method and metal ion deposition method. Patent No. CN118001456A provides a new method for preparing an anti-adhesion abdominal wall patch, which removes oil from the polypropylene patch and sensitizes it, and then places it in an ion sputtering instrument to electroplate nanosilver, so that silver ions with antibacterial function are deposited on the patch, but this method is usually not suitable for biological patches. Patent No. US8911765B2 discloses a biodegradable polymer covering for breast implants. The document records that a synthetic polymer patch is immersed in a methanol / tetrahydrofuran organic solvent containing 0.0055 g / mL of rifampicin and 0.0055 g / mL of minocycline, and then oven-dried after continuous immersion to obtain an antimicrobial patch; in this method, an attached drug coating is formed on the polymer surface by immersion and oven drying. Due to the difference in the properties of the synthetic polymer patch and the biological patch, under the same conditions, the drug loading of the biological patch is much smaller than that of the synthetic polymer patch. The biological patch formed by this coating method usually shows a low drug loading in clinical practice, resulting in failure to achieve antibacterial treatment. The problem of therapeutic effect; Patent No. CN118453962A provides a method for preparing a decellularized extracellular matrix patch with antibacterial function, wherein the decellularized small intestinal submucosal tissue is immersed in a NaClO solution for 12 hours to obtain an N-Cl antibacterial coating, which is freeze-dried and hot-pressed at 60°C to prepare an antibacterial patch; although this method has superimposed an antibacterial coating, the drug loading is still very limited, and the document does not record the chlorine loading of the final product. In addition, the addition of a large amount of antibacterial chlorine is particularly cautious for medical devices, especially for patches of Class III implantable medical devices. It is clearly stipulated that chlorine, chlorine dioxide, hypochlorous acid, etc. may have adverse effects on the human body, and the addition requires strict approval. Summary of the invention

[0003] In order to overcome the above problems, a non-coated patch with antibacterial components distributed in the internal network and surface of the patch structure is obtained. The present invention provides a process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release. The process is as follows: a base layer, an intermediate layer and a top layer are laid in sequence from bottom to top with a medium, and then laminated to obtain the patch; The medium is selected from one or more of water, antibiotic solution X, and antibiotic Y solution.

[0004] The middle layer at least includes a strip insertion layer; the strip insertion layer is obtained by arranging the bio-based strips at intervals; the intervals of the bio-based strips are 0.7-2.2 cm.

[0005] Furthermore, laying the base layer with the medium specifically comprises: wetting the substrate with the medium, laying the base layer on the substrate, flattening the base layer on the substrate, and then scraping off excess medium on the surface of the base layer with a scraper.

[0006] The purpose of wetting the substrate is to exclude the air between the base layer and the substrate and to utilize the adhesion between the wetting medium and the base layer to make the base layer flatter on the substrate.

[0007] The material of the substrate is not limited. The function of the substrate is only to provide a horizontal operating plane for the base layer. It can be a commercially available glass substrate, steel plate, copper plate, etc.

[0008] Similar to laying the base layer with a medium, laying the middle layer with a medium specifically involves wetting the base layer with the medium, laying the middle layer on the base layer, flattening the middle layer on the base layer, and then scraping off excess medium on the surface of the middle layer with a scraper.

[0009] Similar to laying the base layer with a medium, laying the top layer with a medium is specifically to wet the top layer with the medium, lay the top layer on the middle layer, flatten the top layer on the middle layer, and then scrape off excess medium on the surface of the top layer with a scraper.

[0010] Preferably, the strips are inserted into a layer, with each bio-based strip arranged in parallel.

[0011] Preferably, the strip insertion layer is formed by bio-based strips arranged at intervals; the interval between the bio-based strips is 0.7-2 cm.

[0012] Further preferably, the strip insertion layer is formed by bio-based strips arranged at intervals; the interval between the bio-based strips is 0.9-1.5 cm.

[0013] More preferably, the strip insertion layer is formed by bio-based strips arranged at intervals; the interval between the bio-based strips is 1-1.5 cm.

[0014] In order to obtain an antibacterial patch in which the antibacterial components are distributed throughout the patch structure network rather than only distributed in a certain layer, the inventors, through in-depth creative thinking, use a medium (the medium is selected from one or more of water, antibiotic solution X, and antibiotic Y solution) to lay the base layer, the middle layer, and the top layer, replacing the traditional lamination process (such as the patent No. CN105102009B or the patent No. CN115054743B that only stacks the dry film layers and then presses them), which not only ensures that the obtained patch has good mechanical properties and a structure that is not easy to loosen when exposed to water, but also effectively realizes the slow release of tetracycline in the antibiotic solution X and antibiotic Y in the antibiotic Y solution while ensuring a high drug loading, and further controls and adjusts the release rate of tetracycline and antibiotic Y; in the scheme of the present invention, especially the further control of the spacing of the bio-based strips, the above-mentioned slow release effect is particularly obvious.

[0015] The angle between the length direction of the bio-based strip and the length direction of the substrate layer is 0-90°.

[0016] Preferably, the angle between the length direction of the bio-based strip and the length direction of the base layer is 15-75°.

[0017] Further preferably, the angle between the length direction of the bio-based strip and the length direction of the base layer is 30-60°.

[0018] More preferably, the angle between the length direction of the bio-based strip and the length direction of the base layer is 35-45°.

[0019] On the basis that the interval between the bio-based strips is 0.7-2.2 cm, the angle between the length direction of the bio-based strips and the length direction of the substrate layer can be further adjusted. The angle between the length direction of the bio-based strips and the length direction of the substrate layer is 15-75°, which to a certain extent improves the problem that tetracycline is unstable when in contact with water and is prone to diastereoisomerization, resulting in decreased activity of tetracycline in the antibiotic solution X and reduced therapeutic effect.

[0020] Preferably, the process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release is as follows: a base layer, an intermediate layer and a top layer are laid in sequence with a medium from bottom to top, and then laminated and pressed at 35-55° C. to obtain the patch.

[0021] More preferably, after the base layer, the middle layer and the top layer are laid in sequence from bottom to top with the medium, they are laminated and pressed at 39-50° C. to obtain the product.

[0022] More preferably, after the base layer, the middle layer and the top layer are laid in sequence from bottom to top with the medium, they are laminated and pressed at 39-48° C. to obtain the product.

[0023] As a preferred embodiment, the process of realizing a high-drug-loaded antibacterial biological patch with controlled sustained release is as follows: S1. decellularizing the matrix material A with water to obtain a basal layer; S2. placing the bio-based strip on the substrate to form a strip insertion layer covering the substrate, thereby obtaining the intermediate layer of the antibacterial biological patch with a high drug loading and controlled sustained release; S3. Laying the acellular matrix material A on the strip insert layer with water to form the top layer of the antibacterial biological patch with high drug loading and controlled sustained release; S4.Lamination.

[0024] As a preferred embodiment, the process of realizing a high-drug-loaded antibacterial biological patch with controlled sustained release is as follows: S1. Lay the decellularized matrix material A with water to obtain a base layer; the middle layer includes two strip insertion layers (respectively, the strip insertion layer 1 and Strip Insertion Layer 2 ), the middle layer is obtained by the following steps S2-S3; S2. Placing the bio-based strip on the base layer to form a strip insert layer covering the base layer 1 ; S3. Place the bio-based strips on the strip insertion layer 1 on, to form a stripe insertion layer 2 ; S4. Laying the acellular matrix material A on the middle layer with water to form the top layer of the antibacterial biological patch with high drug loading and controlled sustained release; S5.Lamination.

[0025] As a preferred embodiment, the process of realizing a high-drug-loaded antibacterial biological patch with controlled sustained release is as follows: S1. Laying the decellularized matrix material A with water to obtain a base layer; the middle layer is obtained by the following steps S2-S3; S2. Lay the decellularized matrix material B on the basal layer with antibiotic solution X to form a sandwich covering the basal layer 1 Repeat this operation until a sandwich is formed. n ; n is a positive integer, and 1≤n≤18; S3. Place the bio-based strips in the sandwich n on, to form a stripe insertion layer 1 Repeat this operation until a stripe insertion layer is formed. m ; m is a positive integer, and 1≤m≤18; S4. Laying the acellular matrix material A on the strip insert layer with water to form the top layer of the antibacterial biological patch with high drug loading and controlled sustained release; S5. Laminate using a laminator.

[0026] As a preferred embodiment, the process of realizing a high-drug-loaded antibacterial biological patch with controlled sustained release is as follows: S1. Laying the decellularized matrix material A with water to obtain a basal layer; S2. Lay the decellularized matrix material B on the basal layer with antibiotic solution X to form a sandwich covering the basal layer 1 Repeat this operation until a sandwich is formed. n ; n is a positive integer, and 1≤n≤18; S3. Place the bio-based strips in the sandwich n on, to form a stripe insertion layer 1 Repeat this operation until a stripe insertion layer is formed. m ; m is a positive integer, and 1≤m≤18; Preferably, 1≤m≤7.

[0027] The sandwich formed after steps S2-S3 1 -Mezzanine n and Strip Insertion Layer m The combination of is a unit module; the unit module is repeatedly stacked p times to obtain an intermediate layer; p is a positive integer, and 1≤p≤18; Preferably, m+n≤20.

[0028] Furthermore, m+n≤18.

[0029] Preferably, p is a positive integer, and 1≤p≤16.

[0030] Preferably, (m+n)×p≤35. That is, the total number of the intermediate layers is controlled within 35 layers.

[0031] Furthermore, (m+n)×p≤22. That is, the total number of the middle layers is controlled within 22 layers.

[0032] Furthermore, (m+n)×p≤10.

[0033] Furthermore, (m+n)×p≤9.

[0034] S4. Laying the acellular matrix material A on the middle layer with water to form the top layer of the antibacterial biological patch with high drug loading and controlled sustained release; S5. Laminate using a laminator.

[0035] In the present invention, the base layer and the interlayer n and top layer are called continuous plane layer; strip insertion layer 1 , Strip Insertion Layer 2 and Strip Insertion Layerm They are all called discontinuous surface layers.

[0036] In the technical solution of the present invention, it is necessary to ensure that both sides of the discontinuous surface layer are in contact with the continuous plane layer.

[0037] Preferably, 60% to 100% of each planar area of ​​each non-continuous surface layer is in contact with the continuous planar layer.

[0038] The setting that both sides of the discontinuous surface layer are in contact with the continuous plane layer can not only improve the interlayer bonding force, so that the final pressed product is not easy to loosen, but also is conducive to increasing the drug loading of tetracycline in the antibiotic solution X and antibiotic Y in the antibiotic Y solution, and further promotes the distribution trend of tetracycline in the antibiotic solution X and antibiotic Y in the antibiotic Y solution distributed throughout the final patch structure network (rather than the distribution trend of the drug being distributed only in a single layer). In addition, the inventors also unexpectedly found that the contact between both sides of the discontinuous surface layer and the continuous plane layer also unexpectedly reduced the drug loss of tetracycline and antibiotic Y caused by subsequent lamination, so that the drug loss can be as low as 15wt%, and the drug loss is controlled within the range of 15-50wt%, which greatly reduces the waste of drugs and reduces production costs. The inventors speculate that this may be because the basal layer, middle layer and top layer of the decellularized matrix material retain the complete triple helix structure of the collagen fibers. In addition to being partially deposited in the porous pores of each layer, the drug nuclei can also be embedded in the spiral grooves on the triple helix chains. The setting of the discontinuous surface layer of the specific strip insertion layer has a more significant effect on the deposition adsorption and embedding adsorption, accompanied by the unique toughness between the fibers formed between the structures at this time, thereby increasing the binding force.

[0039] Decellularized matrix material A and decellularized matrix material B were purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd. and were prepared from the submucosal layer or full layer of hollow organs (intestine, stomach, bladder) of mammals (human, pig, cattle, fetal bovine, horse, sheep, dog) according to the perfusion-pressure difference method disclosed in patent CN106075583B.

[0040] Preferably, in step S1 and step S6, the decellularized matrix material A is derived from porcine bladder submucosa and is purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.; that is, the decellularized matrix material A is prepared from porcine bladder submucosa according to the perfusion-pressure difference method disclosed in patent CN106075583B.

[0041] Preferably, in steps S2-S5, the decellularized matrix material B is derived from the porcine small intestinal submucosa and is purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.; that is, the decellularized matrix material B is prepared from the porcine small intestinal submucosa according to the perfusion-pressure difference method disclosed in patent CN106075583B.

[0042] As a preferred embodiment, the antibiotic liquid X is a suspension of tetracycline metal chelate, and the suspension of tetracycline metal chelate is obtained by adjusting the pH condition of an aqueous solution of a tetracycline / metal ion mixture.

[0043] As a preferred embodiment, the pH is 7.2-8.1.

[0044] Preferably, the pH is 7.2-7.9.

[0045] More preferably, the pH is 7.2-7.7.

[0046] More preferably, the pH is 7.4.

[0047] As a preferred embodiment, in the aqueous solution of the tetracycline / metal ion mixture, the molar ratio of metal ions to tetracycline is (1.2-1.9):1 or (3-6.5):1.

[0048] Preferably, in the aqueous solution of the tetracycline / metal ion mixture, the molar ratio of metal ions to tetracycline is (1.5-1.8):1 or (3.2-4.3):1.

[0049] Preferably, the tetracycline is selected from any one of minocycline, minocycline hydrochloride, doxycycline hydrochloride and chlortetracycline.

[0050] More preferably, the tetracycline is minocycline hydrochloride.

[0051] Preferably, the metal ion is selected from one or more of calcium ion, magnesium ion, aluminum ion and zinc ion.

[0052] More preferably, the metal ion is a calcium ion.

[0053] As a preferred embodiment, the preparation method of the bio-based strip is: laying the decellularized matrix material C with antibiotic Y solution, repeating this operation 1-10 times, laminating, and cutting into rectangular strips with a width of 1-20 mm.

[0054] The acellular matrix material C was purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd. and was prepared from the submucosal layer or full layer of hollow organs (intestine, stomach, bladder) of mammals (human, pig, cattle, fetal bovine, horse, sheep, dog) according to the perfusion-pressure difference method disclosed in patent CN106075583B.

[0055] Preferably, the acellular matrix material C is purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd. and is prepared from the submucosal layer of the intestine and stomach of mammals (humans, pigs, cattle, fetal bovines, horses, sheep, dogs) according to the perfusion-pressure difference method disclosed in patent CN106075583B.

[0056] Further preferably, the preparation method of the bio-based strip is: laying the decellularized matrix material C with the antibiotic Y solution to flatten the decellularized matrix material C, repeating this operation 3-7 times, laminating with a laminator, and cutting into rectangular strips with a width of 1-20 mm.

[0057] More preferably, the preparation method of the bio-based strip is as follows: laying the decellularized matrix material C with the antibiotic Y solution to flatten the decellularized matrix material C on a horizontal plane, repeating this operation 4-5 times, laminating with a laminator, and cutting into rectangular strips with a width of 1-20 mm.

[0058] Preferably, the width of the rectangular strip is 1-15 mm.

[0059] More preferably, the width of the rectangular strip is 1-8 mm.

[0060] Further preferably, the width of the rectangular strip is 2-8 mm.

[0061] For example, the width of the rectangular strip is 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, etc.

[0062] In the present invention, the number of bio-based strips is not particularly limited, and they can be laid at intervals of 0.7-2.2 cm.

[0063] As a preferred embodiment, the antibiotic Y is a rifamycin antibiotic.

[0064] Preferably, the rifamycin antibiotics are selected from one or more of rifampicin, rifapentine, rifamycin sodium and rifabutin.

[0065] More preferably, the rifamycin antibiotic is rifampicin.

[0066] As a preferred embodiment, the preparation method of the antibiotic Y solution is: adding antibiotic Y to 85wt%-95wt% ethanol aqueous solution, so that the concentration of antibiotic Y in the antibiotic Y solution is 0.01-0.07g / mL.

[0067] Preferably, the preparation method of the antibiotic Y solution is: adding the antibiotic Y to a 90wt%-95wt% ethanol aqueous solution, so that the concentration of the antibiotic Y in the antibiotic Y solution is 0.01-0.07g / mL.

[0068] Further preferably, the preparation method of the antibiotic Y solution is: adding the antibiotic Y to a 90 wt % ethanol aqueous solution, so that the concentration of the antibiotic Y in the antibiotic Y solution is 0.01-0.07 g / mL.

[0069] Preferably, in the antibiotic Y solution, the concentration of antibiotic Y is 0.01-0.04 g / mL.

[0070] Generally speaking, for synthetic polymer substrates and biological substrates, due to the characteristics of the substrates themselves such as slow degradation of synthetic polymer substrates, under the same conditions of the same substrate loading amount and release environment, except for the different types of substrates, the drug release rate of the drug-loaded biological substrate is usually much faster than that of the drug-loaded synthetic polymer substrate. If the drug is released too quickly, it will not be able to continuously exert its antibacterial effect and may not meet the needs of clinical antibacterial treatment. This requires us to control the drug release rate of the drug-loaded biological substrate. In particular, for the antibiotic Y of the rifamycin antibiotics (specifically rifampicin) in the present invention, it has a high hydrophilicity. After being used for patch loading, it will be released because it is quickly soluble in water, further accelerating the drug release rate. Therefore, it is urgent to control the drug release rate of the drug-loaded biological substrate. The inventors of the present invention have overcome the technical resistance of the aforementioned drug being released too quickly in the biological matrix on the basis of ensuring that the intermediate layer includes at least one strip insertion layer (that is, the antibacterial biological patch includes at least one non-continuous surface layer) and the spacing and angle of the bio-based strips are within a specific range, especially when the antibiotic Y is a rifamycin antibiotic and the antibiotic solution X is a suspension of a tetracycline metal chelate. This overcoming effect is particularly significant. On the basis of the above, the number of strip insertion layers and the width of the strip insertion layers, as well as the width range of the bio-based strips, can be further controlled, which can not only enhance the process stability of the sustained release effect, but also adjust the sustained release rate according to actual needs.

[0071] The antibacterial patch obtained by the process of the antibacterial biological patch with controlled sustained release and high drug loading according to the present invention can be provided with uniform small holes with a hole diameter of 0.1-3.0 mm and a distance between two adjacent holes of 4-20 mm.

[0072] Beneficial effects: Usually, the high-incidence infection period after surgery is within three days after surgery. The process of the present invention achieves high drug loading and controllable sustained release of the antibacterial biological patch. Different from the previous coating structure, the effective antibacterial components of the antibacterial patch in the present invention are distributed throughout the patch structure network, rather than only distributed in a certain layer. The process of the present invention not only ensures that the obtained patch has good mechanical properties and a structure that is not easy to loosen when exposed to water, but also enhances the process stability. In addition, the drug loading amount, drug loading speed, etc. can be quantitatively and controllably adjusted according to actual needs. It can be applied to various surgical scenarios such as open abdominal surgery, and is particularly suitable for immediate antibacterial application after surgical operations. It is not only beneficial to anti-infection, but the biological patch can also guide tissue regeneration and degrade with tissue repair. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Figure 1This is a schematic diagram of the structure of the antibacterial biological patch with high drug loading and controllable sustained release described in Example 2; Figure 1 Middle, 1-basal layer, 2-strip intercalation layer 1 , 3-strip insertion layer 2 , 4-middle layer, 5-top layer; (The layers in the figure are staggered only to clearly show the structure of each layer. The edges of each quadrilateral of the actual product are aligned.) Figure 2 This is a schematic diagram of the structure of the antibacterial biological patch with high drug loading and controllable sustained release described in Example 3; Figure 2 Middle, 8-intermediate layer', 6-strip insertion layer 1’ , 7-strip insertion layer 2’ ; (The staggered layers in the diagram are only to clearly show the structure of each layer. The edges of each quadrilateral of the actual product are aligned.) Figure 3 (a) is a schematic diagram of the cross-sectional structure of the antibacterial biological patch with high drug loading and controlled sustained release described in Example 4; in the figure, 9-middle layer''; Figure 3 (b) is a schematic diagram of the cross-sectional structure of the antibacterial biological patch with high drug loading and controllable sustained release described in Example 5; in the figure, 11 is a unit module, 10 is an intermediate layer'''; Figure 4 This is a schematic diagram of the structure of the antibacterial biological patch with high drug loading and controlled sustained release described in Comparative Example 4; (The staggered layers in the figure are only for the purpose of clearly showing the structure of each layer, and the edges of each quadrilateral of the actual product are aligned.) Figure 5 This is a SEM scanning electron microscope of the antibacterial biological patch obtained in Example 4, wherein: Figure 5 (a) is a scanning electron microscope image of the upper surface of the patch. Figure 5 (b) is a scanning electron microscope image of the lower surface of the patch. Figure 5 (c) and Figure 5 (d) is a scanning electron microscope image of a cross section on the patch. DETAILED DESCRIPTION

[0074] All materials used in the examples are commercially available.

[0075] Example 1

[0076] This example provides a process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release, and the process is as follows: S1. Use 6 ml of water to lay the acellular matrix material A (derived from the submucosal layer of the porcine bladder, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.) so that the basal layer 实施例1 Flatten on a horizontal plane to obtain the base layer; the middle layer 实施例1 The intermediate layer is obtained by the following steps S2-S5; 实施例1It includes a strip insertion layer; the strip insertion layer is formed by bio-based strips arranged at intervals; S2. Place the bio-based strip on the substrate 实施例1 The angle between the length direction of the bio-based strip and the length direction of the base layer is 45°, the interval between the bio-based strips is 1.5 cm, and each bio-based strip is arranged in parallel to form a strip insertion layer covering the base layer, that is, the middle layer of the antibacterial biological patch with high drug loading and controlled sustained release is obtained. 实施例1 .

[0077] The preparation method of the bio-based strip is as follows: 6 mL of antibiotic Y solution is used to lay the decellularized matrix material C (derived from the submucosal layer of the porcine small intestine, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.), flatten the decellularized matrix material C, repeat this operation 4 times, laminate it using a laminator, and cut it into rectangular strips with a width of 3 mm.

[0078] The antibiotic Y is a rifamycin antibiotic, and the rifamycin antibiotic is rifampicin.

[0079] The preparation method of the antibiotic Y solution is as follows: adding the antibiotic Y into a 90 wt % ethanol aqueous solution, so that the concentration of the antibiotic Y in the antibiotic Y solution is 0.01 g / mL.

[0080] S3. Use 6mL of water in the middle layer 实施例1 The decellularized matrix material A (derived from the submucosal layer of the porcine bladder, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.) was laid on the top and flattened to form the top layer of the antibacterial biological patch with high drug loading and controlled sustained release. 实施例1 ; S4.Laminate at 45℃ for 12h to obtain.

[0081] Example 2

[0082] This example provides a process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release, and the process is as follows: S1. Use 6 ml of water to lay the decellularized matrix material A (derived from the submucosal layer of the porcine bladder, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.), flatten the basal layer, and obtain basal layer 1; the middle layer 4 is obtained by the following steps S2-S5; the middle layer 4 includes two strip insertion layers, and the middle layer 4 is obtained by the following steps S2-S3; the strip insertion layer is formed by biological-based strips arranged at intervals; S2. Place the bio-based strips on the substrate layer, the angle between the length direction of the bio-based strips and the length direction of the substrate layer is 45°, the interval between the bio-based strips is 1.5 cm, and each bio-based strip is arranged in parallel to form a strip insertion layer covering the substrate layer 1 2.

[0083] The preparation method of the bio-based strip is as follows: 6 mL of antibiotic Y solution is used to lay the decellularized matrix material C (derived from the submucosal layer of the porcine small intestine, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.), flatten the decellularized matrix material C, repeat this operation 4 times, laminate it using a laminator, and cut it into rectangular strips with a width of 3 mm.

[0084] The antibiotic Y is a rifamycin antibiotic, and the rifamycin antibiotic is rifampicin.

[0085] The preparation method of the antibiotic Y solution is as follows: adding the antibiotic Y into a 90 wt % ethanol aqueous solution, so that the concentration of the antibiotic Y in the antibiotic Y solution is 0.01 g / mL.

[0086] S3. Continue placing the bio-based strips on the strip insertion layer 1 The angle between the length direction of the bio-based strip and the length direction of the base layer is 45°, the interval between the bio-based strips is 1.5 cm, and each bio-based strip is arranged in parallel to form a strip insertion layer. 2 3; Strip Insertion Layer 1 The length direction of the bio-based strip and the strip insertion layer 2 The angle between the length directions of the bio-based strips is 90°.

[0087] S4. Lay the decellularized matrix material A (derived from the submucosal layer of the porcine bladder, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.) on the middle layer 4 with 6 mL of water, and flatten it to form the top layer 5 of the antibacterial biological patch with high drug loading and controlled sustained release; S5. Lamination at 45°C for 12 hours to obtain the obtained antibacterial biological patch with high drug loading and controlled sustained release. Figure 1 .

[0088] Example 3

[0089] This example provides a process for realizing a controlled sustained-release antibacterial biological patch with a high drug loading. The difference from Example 2 is that the middle layer '8 includes two strip insertion layers. 1’ 6. The length direction of the bio-based strip and the strip insertion layer 2’ The angle between the length directions of the bio-based strips of 7 is 0°; the strip insertion layer 2’ The bio-based strip of 7 falls exactly on the strip insertion layer 1’ The structure of the obtained antibacterial biological patch with high drug loading and controlled sustained release is as follows: Figure 2 .

[0090] Example 4

[0091] This example provides a process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release, and the process is as follows: S1. Use 6 mL of water to lay the decellularized matrix material A (derived from the submucosal layer of the porcine bladder, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.), flatten the basal layer, and obtain the basal layer; the middle layer '' 9 is obtained by the following steps S2-S3; S2. Use 6 mL of antibiotic solution X to lay acellular matrix material B (derived from the submucosa of porcine small intestine, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.) on the basal layer and flatten it to form a sandwich covering the basal layer. 1 Repeat this operation until a sandwich is formed. 2 ; n = 2; The antibiotic liquid X is a suspension of a tetracycline metal chelate, which is obtained by adjusting the pH of an aqueous solution of a tetracycline / metal ion mixture to 7.4 with an aqueous sodium hydroxide solution.

[0092] In the aqueous solution of the tetracycline / metal ion mixture, the molar ratio of the metal ion to the tetracycline is 1.7:1.

[0093] The tetracycline is minocycline hydrochloride, and the metal ion is calcium ion.

[0094] The preparation method of antibiotic solution X is as follows: add 0.1 g of minocycline hydrochloride to 10 mL of water, mix well, and continue to add 0.0045 mol / mL of calcium chloride aqueous solution to make the molar ratio of calcium ions to minocycline hydrochloride in the antibiotic solution X be 1.7:1.

[0095] S3. Place the bio-based strips in the sandwich 2 The angle between the length direction of the bio-based strip and the length direction of the substrate layer is 45°, and the interval between the bio-based strips is 1.5 cm; so as to form a covering on the interlayer 2 The stripe insertion layer is provided on the upper surface; in the stripe insertion layer, each bio-based stripe is arranged in parallel; The preparation method of the bio-based strip is as follows: 6 mL of antibiotic Y solution is used to lay the decellularized matrix material C (derived from the submucosal layer of the porcine small intestine, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.), flatten the decellularized matrix material C, repeat this operation 4 times, laminate it using a laminator, and cut it into rectangular strips with a width of 3 mm.

[0096] The antibiotic Y is a rifamycin antibiotic, and the rifamycin antibiotic is rifampicin.

[0097] The preparation method of the antibiotic Y solution is as follows: adding the antibiotic Y into a 90 wt % ethanol aqueous solution, so that the concentration of the antibiotic Y in the antibiotic Y solution is 0.01 g / mL.

[0098] S4. Lay the decellularized matrix material A (derived from the submucosal layer of the porcine bladder, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.) on the middle layer '' 9 with 6 mL of water, and flatten it to form the top layer of the antibacterial biological patch with high drug loading and controlled sustained release; S5. Use a laminator to laminate at 45°C for 12 hours.

[0099] The cross-sectional structure of the obtained antibacterial biological patch with high drug loading and controlled sustained release is as follows: Figure 3 (a).

[0100] Example 5

[0101] This example provides a process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release, and the process is as follows: S1. Use 6 mL of water to lay the decellularized matrix material A (derived from the submucosal layer of the porcine bladder, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.) to flatten the basal layer to obtain the basal layer; S2. Use 6 mL of antibiotic solution X to lay acellular matrix material B (derived from the submucosa of porcine small intestine, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.) on the basal layer and flatten it to form a sandwich covering the basal layer. 1 Repeat this operation until a sandwich is formed. 2 ; n = 2; The antibiotic liquid X is a suspension of a tetracycline metal chelate, which is obtained by adjusting the pH of an aqueous solution of a tetracycline / metal ion mixture to 7.6 with an aqueous sodium hydroxide solution.

[0102] In the aqueous solution of the tetracycline / metal ion mixture, the molar ratio of the metal ion to the tetracycline is 1.6:1.

[0103] The tetracycline is minocycline hydrochloride, and the metal ion is calcium ion.

[0104] The preparation method of antibiotic solution X is as follows: add 0.1 g of minocycline hydrochloride to 10 mL of water, mix well, and continue to add 0.0045 mol / mL of calcium chloride aqueous solution to make the molar ratio of calcium ions to minocycline hydrochloride in the antibiotic solution X be 1.6:1.

[0105] S3. Place the bio-based strips in the sandwich 2 The angle between the length direction of the bio-based strip and the length direction of the substrate layer is 45°, and the interval between the bio-based strips is 1.5 cm; so as to form a covering on the interlayer 2 A strip insertion layer on the top; in the strip insertion layer, each bio-based strip is arranged in parallel; m=1.

[0106] The preparation method of the bio-based strip is as follows: 7 mL of antibiotic Y solution is used to lay the decellularized matrix material C (derived from the submucosal layer of the porcine small intestine, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.), flatten the decellularized matrix material C, repeat this operation 4 times, laminate it using a laminator, and cut it into rectangular strips with a width of 5 mm.

[0107] The antibiotic Y is a rifamycin antibiotic, and the rifamycin antibiotic is rifampicin.

[0108] The preparation method of the antibiotic Y solution is as follows: adding the antibiotic Y into a 95 wt % ethanol aqueous solution, so that the concentration of the antibiotic Y in the antibiotic Y solution is 0.04 g / mL.

[0109] The sandwich formed after steps S2-S3 1 -Mezzanine 2 and Strip Insertion Layer 1 The combination is a unit module 11; the unit module 11 is repeatedly stacked 3 times to obtain an intermediate layer ''' 10; p=3.

[0110] S4. Lay the acellular matrix material A (derived from the submucosal layer of the porcine bladder, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.) on the middle layer ''' with 6 mL of water, and flatten it to form the top layer of the antibacterial biological patch with high drug loading and controlled sustained release; S5. Use a laminator to laminate at 43°C for 12 hours.

[0111] The cross-sectional structure of the obtained antibacterial biological patch with high drug loading and controlled sustained release is as follows: Figure 3 (b).

[0112] Comparative Example 1 This example provides a process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release, and the process is as follows: A layer of decellularized matrix material A (derived from porcine bladder submucosa, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.), 4 layers of decellularized matrix material B (derived from porcine small intestine submucosa, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.), and 1 layer of decellularized matrix material A (derived from porcine bladder submucosa, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.) were stacked in order from bottom to top, laminated at 40°C for 24 hours, taken out, immersed in antibiotic solution X for 1 hour, taken out, immersed in antibiotic solution Y for 1 hour, taken out, and the above-mentioned immersion operation was repeated 2 times (equivalent to the laminated material being immersed in antibiotic solution X 3 times and antibiotic Y solution 3 times), with an interval of 1 hour between each immersion, and finally dried at room temperature for 24 hours, and placed in a 40°C oven for further drying for 24 hours.

[0113] Wherein, the antibiotic solution X and the antibiotic solution Y were prepared according to the method of Example 4.

[0114] Comparative Example 2 This example provides a process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release, and the process is as follows: One layer of decellularized matrix material A (derived from the submucosa of porcine bladder, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.), four layers of decellularized matrix material B (derived from the submucosa of porcine small intestine, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.), and one layer of decellularized matrix material A (derived from the submucosa of porcine bladder, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.) were immersed in antibiotic solution X for 2 hours, taken out, and immersed in antibiotic Y solution for 2 hours, taken out, and freeze-dried separately. The 6 layers of treated materials were stacked from bottom to top in the aforementioned order, laminated at 80°C for 18 hours using a laminator, and then taken out.

[0115] Wherein, the antibiotic solution X and the antibiotic solution Y were prepared according to the method of Example 4.

[0116] Comparative Example 3 This example provides a process for achieving a controlled sustained-release antibacterial biological patch with a high drug loading. Different from Comparative Example 2, the 6 layers of treated materials are stacked from bottom to top in the aforementioned order, laminated at 35° C. for 24 hours, and then taken out.

[0117] Comparative Example 4 This example provides a process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release. The difference from Example 2 is that: the strip insertion layer 1 The length direction of the bio-based strip and the strip insertion layer 2 The angle between the length direction of the bio-based strips is 0°, and the strips are inserted into the layer 1 and Strip Insertion Layer 2 The bio-based strips are stacked in two layers aligned with each other, such as Figure 4 .

[0118] The base layer and the top layer are both called continuous plane layers; the stripe insertion layer 1 and Strip Insertion Layer 2 In this case, the discontinuous surface layer strips are inserted into the layer 1 and Strip Insertion Layer 2 One side of each is not in contact with the continuous plane layer.

[0119] Comparative Example 5 This example provides a process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release, which is different from Example 4 in that: In steps S2 and S3, the antibiotic solution X is a suspension of tetracycline metal chelate, which is obtained by adjusting the pH of an aqueous solution of a tetracycline / metal ion mixture to 7.3 with an aqueous sodium hydroxide solution.

[0120] In the aqueous solution of the tetracycline / metal ion mixture, the molar ratio of the metal ion to the tetracycline is 1.8:1.

[0121] The tetracycline is minocycline hydrochloride, and the metal ion is calcium ion.

[0122] The preparation method of antibiotic solution X is as follows: add 0.1 g of minocycline hydrochloride to 10 mL of water, mix well, and continue to add 0.0045 mol / mL of calcium chloride aqueous solution to make the molar ratio of calcium ions to minocycline hydrochloride in the antibiotic solution X be 1.8:1.

[0123] The preparation method of the bio-based strip is as follows: 6 mL of antibiotic Y solution is used to lay the decellularized matrix material C (derived from the submucosal layer of the porcine small intestine, purchased from Zhuoruan Medical Technology (Suzhou) Co., Ltd.), flatten the decellularized matrix material C, repeat this operation 4 times, laminate it using a laminator, and cut it into rectangular strips with a width of 10 mm.

[0124] The antibiotic Y is a rifamycin antibiotic, and the rifamycin antibiotic is rifampicin.

[0125] The preparation method of the antibiotic Y solution is as follows: adding the antibiotic Y into a 94 wt % ethanol aqueous solution, so that the concentration of the antibiotic Y in the antibiotic Y solution is 0.07 g / mL.

[0126] Furthermore, in step S3, the bio-based strips of the strip insertion layer have no gaps.

[0127] Comparative Example 6 This example provides a process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release. The difference from Example 5 is that in step S2, n=8, and the interlayer formed after steps S2-S3 1 -Mezzanine 8 and Strip Insertion Layer 1 The combination of is a unit module; the unit module is repeatedly stacked 4 times to obtain the middle layer 对比例6 ; p = 4. That is, the middle layer 对比例6 The total number of layers is controlled to be greater than 35.

[0128] Test Results 1. Morphological characterization: The high-drug-loaded antibacterial biological patch with controlled sustained release obtained by the process of Example 4 was characterized by SEM scanning electron microscopy. The results are as follows: Figure 5 ,from Figure 5It can be seen that the antimicrobial drug crystals are distributed throughout the internal network and surface of the patch structure.

[0129] 2. Mechanical properties test: The antibacterial biological patches obtained in Examples 1-5 and Comparative Examples 1-6 were completely immersed in PBS buffer and placed at a temperature of 22±2°C for 6 hours. They were then taken out and tested for tensile strength according to GB / T328.8-2007 (stretched at a steady speed of 100 mm / min until fracture, and the maximum tensile force was recorded). 0729.2-2009 peel strength test, each test was carried out 5 times in parallel, and the average value was taken. The results are shown in Table 1; according to the same process, 9 parallel experiments were carried out on Examples 4-5 and Comparative Example 6 respectively, and the average deviations of the tensile strength and peel strength of the ten experiments were calculated respectively (the calculation of the average deviation is the sum of the deviations (absolute values) of the single measured values ​​and the average value, divided by the number of measurements.), the smaller the average deviation, the more stable the sample process. The results show that the average deviation of the sample in Comparative Example 6 is much larger than the average deviation of Examples 4-5, indicating that the process stability of Comparative Example 6 is poor; the average deviations of Examples 4 and 5 are close, indicating that for this solution, the increase in the number of layers does not have a negative impact on the process stability.

[0130] Table 1 Example Tensile strength (N / cm) Peel strength (N / cm) Example 1 18 1.04 Example 2 21 0.95 Example 3 20 0.95 Example 4 25 0.89 Example 5 27 0.73 Comparative Example 1 8 0.27 Comparative Example 2 5 0.18 Comparative Example 3 10 0.21 Comparative Example 4 15 0.53 Comparative Example 5 20 0.78 Comparative Example 6 29 0.46 The tensile strength of the antibacterial patches obtained in Examples 1 to 5 were all >10 N / cm, and the peel strength was >0.7 N / cm, which reflects that the patches in Examples 1 to 5 have good mechanical properties and structures that are not easily loosened when exposed to water; among them, the patch obtained in Example 5 has increased tensile properties due to the increase in the number of layers, and the increase in the number of layers also causes a slight decrease in the interlayer bonding strength (reduced peel strength).

[0131] In Comparative Examples 1 to 3, no medium was used for laying, but each layer of material was impregnated so that each layer of material was loaded with drugs. Among them, Comparative Example 1 is to impregnate the entire pressed material, but in theory, this method only loads the drug on the surface of the material, which is equivalent to the effect of a layer of drug surface coating, and it is difficult to achieve a high drug loading of the material. At the same time, it can be seen that the mechanical properties of Comparative Example 1 are very poor. In addition, in the experiments of Comparative Examples 2 and 3, the inventors also observed that the edge thickness of the obtained product was significantly greater than the middle thickness of the product. This may be due to the shrinkage or curling of the material after impregnation, especially the obvious curling of the edge of the material after impregnation, which makes the overall thickness of the material after the lamination process obviously uneven. This obvious uneven thickness phenomenon was not observed in Examples 1-5 and Comparative Examples 1, Comparative Examples 4-6.

[0132] Compared with Example 2, the stripe insertion layer of Comparative Example 4 1 and Strip Insertion Layer 2When two layers of bio-based strips are aligned and stacked, it can be seen that their mechanical properties are significantly reduced. Not only does the peel strength (bonding force between reaction layers) decrease by 44%, but the tensile strength also decreases by 29%.

[0133] Compared with Example 4, the bio-based strips of the strip insertion layer of Comparative Example 5 have no gaps, and it can be seen that their mechanical properties are similar.

[0134] Compared with Example 5, the number of intermediate layers in Comparative Example 6 is significantly increased, the increase in tensile strength is smaller (increase by 7%), and the peel strength (reflecting the interlayer bonding force) is significantly decreased (decreased by 37%).

[0135] 3. Drug loading and process drug loss test: The antibacterial patches obtained in Example 2, Examples 4-5, and Comparative Examples 1-5 were cut into 5 cm × 5 cm samples and respectively placed in methanol for extraction. h Take the extract and test it by liquid chromatography until the extract becomes colorless, then stop sampling and testing; calculate the drug loading according to the standard curve (the standard products of rifampicin and minocycline hydrochloride are respectively dissolved in methanol, diluted into a series of standard solutions of 1-500 μg / mL, and tested by liquid chromatography to obtain the standard curve), and calculate the drug loss after the patch preparation process according to the amount of raw materials added in the process, and the results are shown in Table 2; in the liquid chromatogram, under the same conditions, minocycline hydrochloride and the diastereomers of minocycline hydrochloride have different retention times and different peak positions. According to the proportion of peak area, the proportion of the diastereomers of minocycline hydrochloride in the mixture of minocycline hydrochloride and the diastereomers of minocycline hydrochloride in Examples 4-5 and Comparative Example 5 is calculated, and the results are shown in Table 3; 5 parallel experiments are performed for each test and the average value is taken.

[0136] Table 2

[0137] Table 3 Example Proportion of diastereomers of minocycline hydrochloride (%) Example 4 2.03 Example 5 2.14 Comparative Example 5 3.85 4. In vivo drug release rate: 24 rats were anesthetized with gas, and the abdominal hair was shaved. A 5 cm long incision was made in the middle of the abdomen to fully expose the abdominal cavity. The antibacterial patches obtained in Example 4 and Comparative Examples 1-5 were cut into 2 cm × 2 cm samples, and placed on both sides of the rat's abdominal cavity. The same sample was placed on the abdominal wall and fixed with sutures. After implantation, the wound was closed. Samples were collected at 4h, 1 day, 2 days, and 3 days after surgery, and CO was inhaled. 2After euthanasia, the samples were taken out and extracted with PBS buffer solution for 24 hours. The drug loading was calculated according to the drug standard curve, recorded as W (the standard samples of rifampicin and minocycline hydrochloride were dissolved in PBS buffer solution, diluted into a series of standard solutions of 1-500μg / mL, and the standard curve was obtained by liquid chromatography injection test). In vivo release rate = (drug loading of each sample in performance test 3-W) / drug loading of each sample in performance test 3 × 100%; the results are shown in Table 4: Table 4

[0138] The “ / ” in Table 4 indicates that the drug content on the sample patch is basically undetectable, which is equivalent to indicating that the drug loading of the corresponding drug on the sample patch is 0 at this time.

Claims

1. A process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release, characterized in that: The process is as follows: after laying the base layer, the middle layer and the top layer with the medium from bottom to top, laminating, the result is obtained; The medium is selected from one or more of water, antibiotic solution X, and antibiotic Y solution; The middle layer at least includes a strip insertion layer; the strip insertion layer is obtained by arranging the bio-based strips at intervals; the intervals of the bio-based strips are 0.7-2.2 cm.

2. The process for realizing controlled sustained release of high drug loading antibacterial biological patch according to claim 1, characterized in that: The process is as follows: S1. Laying the decellularized matrix material A with water to obtain a basal layer; S2. placing the bio-based strip on the substrate to form a strip insertion layer covering the substrate, thereby obtaining the intermediate layer of the antibacterial biological patch with a high drug loading and controlled sustained release; S3. Laying the acellular matrix material A on the strip insert layer with water to form the top layer of the antibacterial biological patch with high drug loading and controlled sustained release; S4.Lamination.

3. The process for realizing controlled sustained release of high-drug-loaded antibacterial biological patch according to claim 1, characterized in that: The process is as follows: S1. Laying the decellularized matrix material A with water to obtain a base layer; the middle layer includes two strip insertion layers, and the middle layer is obtained by the following steps S2-S3; S2. The bio-based strip is placed on the substrate to form a strip insertion layer 1 covering the substrate layer; S3. Placing the bio-based strip on the strip insert layer 1 to form a strip insert layer 2; S4. Laying the acellular matrix material A on the middle layer with water to form the top layer of the antibacterial biological patch with high drug loading and controlled sustained release; S5.Lamination.

4. The process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release according to claim 1, characterized in that: The process is as follows: S1. Laying the decellularized matrix material A with water to obtain a base layer; the middle layer is obtained by the following steps S2-S3; S2. Use antibiotic solution X to lay acellular matrix material B on the basal layer to form a sandwich 1 covering the basal layer, and repeat this operation until a sandwich is formed. n ; n is a positive integer, and 1≤n≤18; S3. Place the bio-based strips in the sandwich n To form a stripe insertion layer 1, repeat this operation until a stripe insertion layer is formed. m ; m is a positive integer, and 1≤m≤18; S4. Laying the acellular matrix material A on the strip insert layer with water to form the top layer of the antibacterial biological patch with high drug loading and controlled sustained release; S5. Use a laminator to laminate.

5. The process for realizing controlled sustained release of high-drug-loaded antibacterial biological patch according to claim 1, characterized in that: The process is as follows: S1. Laying the decellularized matrix material A with water to obtain a basal layer; S2. Use antibiotic solution X to lay acellular matrix material B on the basal layer to form a sandwich 1 covering the basal layer, and repeat this operation until a sandwich is formed. n ; n is a positive integer, and 1≤n≤18; S3. Place the bio-based strips in the sandwich n To form a stripe insertion layer 1, repeat this operation until a stripe insertion layer is formed. m ; m is a positive integer, and 1≤m≤18; Interlayer 1-interlayer formed after steps S2-S3 n and Strip Insertion Layer m The combination of is a unit module; the unit module is repeatedly stacked p times to obtain the middle layer; p is a positive integer, and 1≤p≤18; S4. Laying the acellular matrix material A on the middle layer with water to form the top layer of the antibacterial biological patch with high drug loading and controlled sustained release; S5. Use a laminator to laminate.

6. The process for realizing a high drug loading antibacterial biological patch with controlled sustained release according to any one of claims 1 to 5, characterized in that: The antibiotic liquid X is a suspension of a tetracycline metal chelate, which is obtained by adjusting the pH condition of an aqueous solution of a tetracycline / metal ion mixture.

7. The process for realizing controlled sustained release of high drug loading antibacterial biological patch according to claim 6, characterized in that: The pH is 7.2-8.

1.

8. The process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release according to claim 6, characterized in that: In the aqueous solution of the tetracycline / metal ion mixture, the molar ratio of metal ions to tetracycline is (1.2-1.9):1 or (3-6.5):

1.

9. The process for realizing a high drug loading antibacterial biological patch with controlled sustained release according to any one of claims 1 to 5, characterized in that: The preparation method of the bio-based strip is as follows: laying the decellularized matrix material C with an antibiotic Y solution, repeating this operation 1-10 times, laminating, and cutting into rectangular strips with a width of 1-20 mm.

10. The process for realizing a high-drug-loaded antibacterial biological patch with controlled sustained release according to claim 9, characterized in that: The preparation method of the antibiotic Y solution is: adding antibiotic Y into 85wt%-95wt% ethanol aqueous solution, so that the concentration of antibiotic Y in the antibiotic Y solution is 0.01-0.07g / mL.

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