Tulobuterol transdermal patch and method for preparing the same

Abstract

The present application relates to the technical field of pharmaceutical preparation, and discloses a tulobuterol transdermal patch and a preparation method thereof.The tulobuterol transdermal patch comprises a backing layer, a paste layer and an anti-sticking layer, the paste layer comprises tulobuterol, pressure-sensitive adhesive and a penetration enhancer, the pressure-sensitive adhesive is a copolymer of 2-ethylhexyl acrylate, butyl acrylate, tertiary octyl acrylamide and methyl methacrylate, and the penetration enhancer contains propylene glycol and ethyl oleate.The present application adopts a new pressure-sensitive adhesive matrix, solves the problem that tulobuterol is easy to crystallize out in the patch, and enhances the transdermal effect of tulobuterol by using a penetration enhancer.The present application also discloses a preparation method of the tulobuterol transdermal patch, and the preparation process is improved, so that the loss of tulobuterol in the preparation process is reduced, the quality of the medicine is improved, and the cost is reduced.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a tuloterol transdermal patch and its preparation method. Background Technology

[0002] Taloterol is a third-generation β2-adrenergic receptor agonist, first developed by Tanabe Pharmaceutical Co., Ltd. of Japan in 1981. Taloterol acts on β2-receptors in bronchial smooth muscle, activating adenylate cyclase, an enzyme closely related to β2-receptors. This leads to the conversion of intracellular adenosine triphosphate to cyclic adenosine monophosphate, resulting in bronchodilatory effects, promotion of bronchial ciliary movement, and antitussive effects. It has a relatively weak excitatory effect on the heart and a strong anti-allergic effect. Therefore, this drug is widely used clinically for the long-term maintenance treatment of asthma, asthmatic bronchitis, and chronic bronchitis.

[0003] The long-acting transdermal absorption formulation of tuloterol was jointly developed by Nitto Denko Corporation and Abbott Laboratories Japan. It was approved for marketing in Japan in 1998 (trade name Hokunalin Tape). Nitto Denko began conducting clinical trials in China in 2004 and obtained an import drug registration certificate in November 2006, registering the trade name as "Amidi". The registered formulation includes three strengths: 2mg, 1mg, and 0.5mg.

[0004] The tuloterol transdermal patch (trade name Hokunalin Tape or "Amidi"), jointly developed by Nitto Denko Corporation and Abbott Laboratories Japan, is the world's first marketed transdermal patch for treating asthma and COPD. However, its formulation process still has some defects. The original formulation matrix uses polyisobutylene, polybutene, and alicyclic saturated hydrocarbon resins. Tuloterol has limited solubility in this matrix, resulting in a supersaturated state of the drug. This causes the drug to undergo a crystallization process after coating and drying. Different temperatures and humidity levels affect the size and morphology of the crystal particles. Different sizes and morphologies of crystal particles also result in differences in release and permeation, leading to uneven transdermal absorption. This ultimately affects the efficacy of the finished product and may cause safety issues. After crystallization, the crystals cover the surface of the ointment layer, reducing the adhesion of the sample. During 24-hour application, the product is prone to falling off the skin, resulting in poor efficacy.

[0005] Furthermore, during the preparation of tuloterol transdermal patches, the active pharmaceutical ingredient undergoes varying degrees of sublimation depending on temperature changes and drying methods, leading to a decrease in its content, increased production costs, and unstable processes that affect product quality. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides a tuloterol transdermal patch and its preparation method. This invention inhibits tuloterol crystallization by screening pressure-sensitive adhesive types; uses a penetration enhancer to ensure that the tuloterol transdermal patch of this invention has the same permeation rate and efficacy as the reference formulation; enhances adhesion by adding a tackifier, making it less prone to falling off during use; and uses a stabilizer, resulting in better stability during storage. By optimizing the preparation process, losses of the active pharmaceutical ingredient during drying are reduced, lowering costs, and more importantly, making the process more stable and improving the quality of the formulation.

[0007] The specific technical solution of this invention is as follows:

[0008] A first aspect of the present invention is to provide a tuloterol transdermal patch, characterized in that: the patch comprises a backing layer, an ointment layer, and an anti-adhesive layer;

[0009] The ointment layer contains tuloterol, pressure-sensitive adhesive, and penetration enhancer;

[0010] The pressure-sensitive adhesive is a copolymer of 2-ethylhexyl acrylate, butyl acrylate, tert-octylacrylamide, and methyl methacrylate;

[0011] The penetration enhancer contains propylene glycol and ethyl oleate.

[0012] The pressure-sensitive adhesive in this invention is formed by dissolving a copolymer of 2-ethylhexyl acrylate, butyl acrylate, tert-octylacrylamide, and methyl methacrylate in ethyl acetate. By comparing pressure-sensitive adhesives using different acrylic copolymers as the adhesive matrix, this invention found that polymers with -COOH and -OH functional groups as the adhesive matrix not only cause crystallization during the preparation of the active pharmaceutical ingredient but also increase the impurity content. Ultimately, this invention found that selecting a polymer copolymerized from the aforementioned non-functionalized monomers of 2-ethylhexyl acrylate, butyl acrylate, tert-octylacrylamide, and methyl methacrylate as the adhesive matrix is ​​more suitable.

[0013] This invention optimizes the selection of penetration enhancers to ensure that the transdermal tuloterol patch of this invention achieves the same penetration amount and efficacy as the reference. Research using four penetration enhancers—propylene glycol, ethyl oleate, isopropyl palmitate, and menthol—revealed that while ethyl oleate and isopropyl palmitate are effective when used individually, they do not achieve the same efficacy as the reference. However, by using propylene glycol and ethyl oleate synergistically, propylene glycol can slowly penetrate the stratum corneum and accumulate, continuously building channels that facilitate drug molecule passage. This further enhances the transdermal effect of ethyl oleate, thus ensuring that the transdermal tuloterol patch of this invention achieves the same penetration amount and efficacy as the reference.

[0014] In one embodiment of the tuloterol transdermal patch of the present invention, the weight percentage of each monomer in the copolymer is: 30-35% 2-ethylhexyl acrylate, 30-35% butyl acrylate, 18-23% tert-octylacrylamide, and 13-17% methyl methacrylate.

[0015] In one embodiment of the tuloterol transdermal patch of the present invention, the ointment layer further comprises a thickener and / or a stabilizer.

[0016] In one embodiment of the tuloterol transdermal patch of the present invention, the patch contains, by weight percentage, 5-8% tuloterol, 70-90% pressure-sensitive adhesive, and 5-10% penetration enhancer.

[0017] In one embodiment of the tuloterol transdermal patch of the present invention, the patch contains, by weight percentage, 5-8% tuloterol, 42-62% pressure-sensitive adhesive, 5-10% penetration enhancer, 20-40% tackifier and 0.5-1% stabilizer.

[0018] This invention has found that the drug loading of tuloterol should not be too high, otherwise crystallization will occur. Ultimately, this invention found that crystallization is less likely to occur when the drug loading is in the range of 5-8 wt%.

[0019] In one embodiment of the tuloterol transdermal patch of the present invention, the mass ratio of propylene glycol and ethyl oleate in the penetration enhancer is 1:1 to 1:2.

[0020] In one embodiment of the tuloterol transdermal patch of the present invention, the tackifier is polyisobutylene and the stabilizer is butylated hydroxytoluene.

[0021] This invention enhances adhesion by adding tackifiers, making it less likely to fall off during use. Research has shown that polyisobutylene and alicyclic saturated hydrocarbon resins can enhance the adhesion of pressure-sensitive adhesives, with polyisobutylene showing better results.

[0022] This invention has found that, based on the synergistic use of propylene glycol and ethyl oleate, further controlling their ratio within the range of 1:1 to 1:2 can further ensure that the transdermal effect is consistent with the reference.

[0023] This invention uses a stabilizer to improve the stability of the sample during storage. Furthermore, butylated hydroxytoluene (BHT) is chosen as the most effective stabilizer.

[0024] In one embodiment of the tuloterol transdermal patch of the present invention, the anti-adhesive layer is one of fluorine release film, PET release film, polyethylene release film, polypropylene release film and silicone oil film.

[0025] In one embodiment of the tuloterol transdermal patch of the present invention, the backing film is a medical backing film composite nonwoven fabric.

[0026] A second aspect of the present invention is to provide a method for preparing a tarotero transdermal patch, characterized by comprising the following steps:

[0027] (1) Dissolve the pressure-sensitive adhesive and the penetration enhancer in a solvent by stirring;

[0028] (2) Add tuloterol, stir to dissolve and mix well, let stand to remove air bubbles, and form a gel;

[0029] (3) Apply the adhesive obtained in step (2) to the surface of the release layer and dry it to form a paste layer;

[0030] (4) The backing layer is laid flat on the surface of the ointment layer to obtain tuloterol transdermal patch.

[0031] In one embodiment of the preparation method of the present invention, in step (3), the drying method is to heat the bottom plate for drying, rather than to use a blower.

[0032] In one embodiment of the preparation method of the present invention, in step (3), the drying temperature is 50-60°C, and / or

[0033] In step (4), the coating speed is 8-12 mm / min and the coating thickness is 200-400 mm.

[0034] Secondly, the present invention provides a method for preparing the above-mentioned tuloterol transdermal patch, which includes the following steps:

[0035] (1) Dissolve the thickener in n-hexane.

[0036] (2) Add pressure-sensitive adhesive, penetration enhancer and stabilizer to the product obtained in step (1), stir to dissolve and form a stable adhesive solution; add teloterol, stir to dissolve and mix well, and let stand to remove bubbles.

[0037] (3) Apply the adhesive obtained in step (2) to the surface of the anti-stick layer and dry it to form a paste layer.

[0038] (4) The backing layer is laid flat on the surface of the ointment layer to obtain tuloterol transdermal patch.

[0039] This invention optimizes the preparation process, reduces the loss of raw materials during drying, lowers costs, and, more importantly, makes the process more stable and improves quality.

[0040] Compared with the prior art, the beneficial effects of the present invention are:

[0041] (1) In this invention, a polymer without functional groups -COOH and -OH (a polymer copolymerized from monomers of 2-ethylhexyl acrylate, butyl acrylate, tert-octylacrylamide, and methyl methacrylate) is selected as the pressure-sensitive adhesive matrix. This not only avoids crystallization of the active pharmaceutical ingredient during preparation but also reduces the impurity content. Based on this, the present invention further optimizes the ratio range of each monomer to achieve even better results.

[0042] (2) The present invention uses a penetration enhancer to enhance the transdermal effect of teloterol; uses an adhesive enhancer to enhance adhesion, and has high stability and is not easy to fall off during the application process; and uses a stabilizer to ensure that the quality of the finished product is stable within the shelf life.

[0043] (3) This invention reduces the loss of tuloterol raw material during the preparation process through process improvement, improves drug quality, and reduces costs. Attached Figure Description

[0044] Figure 1 Photograph of the talloterol transdermal patch prepared in Example 9 of this invention (uncrystallized).

[0045] Figure 2 Image of the crystals from the original Amedi crystals (comparative example 1).

[0046] Figure 3 These are in vitro transdermal curves of Examples 7-11, Comparative Example 1, and Amedi of the present invention. Detailed Implementation

[0047] The present invention will be further described below with reference to embodiments.

[0048] In the embodiments of the present invention, unless otherwise specified, all instruments, materials, chemical reagents, pharmaceuticals, compounds, and biological products are commercially available products well known to those skilled in the art; in the embodiments of the present invention, unless specifically specified, the technical means used are conventional means well known to those skilled in the art.

[0049] Experimental methods for which specific conditions are not specified in the embodiments of the specification are generally performed under conventional conditions in the art or under conditions recommended by the manufacturer.

[0050] In this invention, unless otherwise specified, "above," "below," and "within" indicate inclusion of the stated number. When embodiments are described herein using "containing," "comprising," "including," or "comprise," other similar embodiments described as "consisting of" and / or "substantially consisting of" are also provided. When embodiments are described herein using "substantially consisting of," other similar embodiments described as "consisting of" are also provided. The term "and / or" as used in phrases such as "A and / or B" is intended to include both A and B; A or B; A (alone); and B (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to include each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0051] In this invention, unless otherwise specified, "%", "parts", and "ratio" usually refer to weight percentage, weight parts, and weight ratio.

[0052] Examples 1-6: Selection of pressure-sensitive adhesive and content of tuloterol

[0053] Examples 1-6 used acrylic polymers containing -COOH and -OH functional groups, as well as those without any functional groups, as pressure-sensitive adhesive matrices to investigate their related substances, toluene loading (crystallization), peel viscosity, and permeability.

[0054] The tuloterol transdermal patches provided in Examples 1-6 comprise a backing layer, an ointment layer, and an anti-adhesive layer sequentially bonded together. The ointment layer contains tuloterol (5-10%) and a pressure-sensitive adhesive. The preparation process is as follows:

[0055] (1) Weigh the tolobutrol raw material and the corresponding pressure-sensitive adhesive. The pressure-sensitive adhesive is converted according to the actual solid content.

[0056] (2) Add the prescribed amount of tuloterol raw material to the corresponding pressure-sensitive adhesive solution, stir to dissolve and form a stable adhesive solution, and let stand to remove air bubbles;

[0057] (3) Lay the fluorine release film flat on the surface of the LOGAN coating machine (model: C&D360), then set the coating speed to 10mm / s and the coating thickness to 200-400mm, and then coat the sample. Then dry the sample at 60℃ (using the bottom plate heating drying method).

[0058] (4) Using a laminating machine, lay the medical backing film composite nonwoven fabric flat on the ointment layer.

[0059] Information on pressure-sensitive adhesives is shown in Table 1:

[0060] Table 1: Pressure-Sensitive Adhesive Information

[0061]

[0062] Pressure-sensitive adhesive A: 2-ethylhexyl acrylate + butyl acrylate + tert-octylacrylamide + methyl methacrylate (DURO - TAK 87-900A), obtained through commercial purchase.

[0063] Pressure-sensitive adhesive B: 2-ethylhexyl acrylate + vinyl acetate (DURO-TAK 87-4098), obtained through commercial purchase.

[0064] Pressure-sensitive adhesive C: 2-ethylhexyl acrylate + methyl acrylate + acrylic acid (DURO-TAK 87-235A), obtained through commercial purchase.

[0065] Pressure-sensitive adhesive D: 2-Ethylhexyl acrylate + vinyl acetate + 2-hydroxyethyl acrylate + glycidyl methacrylate (DURO-TAK 387-2287), obtained through commercial purchase.

[0066] The formulations of the ointment layers in Examples 1-6 are shown in Table 2:

[0067] Table 2

[0068]

[0069] The quality testing results of the samples obtained in Examples 1-6 are shown in Tables 3 and 4:

[0070] Table 3

[0071]

[0072] Table 4

[0073]

[0074] A comparison of the data in Table 3-4 shows that:

[0075] (1) By comparing Examples 1-3, it can be seen that in Example 3, due to the excessive drug loading of the active pharmaceutical ingredient, crystallization occurred. Therefore, the preferred drug loading of the active pharmaceutical ingredient is 5-8 wt%.

[0076] (2) By screening different types of pressure-sensitive adhesives (Examples 2 and 4-6), it was found that, under the same drug loading, polymers with functional groups -COOH and -OH as the pressure-sensitive adhesive matrix not only caused crystallization of the active pharmaceutical ingredient (API) but also increased the impurity content (the API and the pressure-sensitive adhesive produced impurities due to poor compatibility, which were not introduced into the pressure-sensitive adhesive). Considering all factors, pressure-sensitive adhesive A, which uses a polymer without functional groups as the pressure-sensitive adhesive matrix, was the most suitable.

[0077] Examples 7-11 and Comparative Example 1: Screening of Penetration Enhancers

[0078] The tuloterol transdermal patches provided in Examples 7-11 comprise a backing layer, an ointment layer, and an anti-adhesive layer bonded together sequentially. The ointment layer contains tuloterol (8 wt%), pressure-sensitive adhesive, and a penetration enhancer. The preparation method is based on Examples 1-6, with the addition of propylene glycol, ethyl oleate, isopropyl palmitate, and menthol according to the formulation table in step (2).

[0079] The formulations for Examples 7-11 are shown in Table 5:

[0080] Table 5

[0081]

[0082] Test comparison

[0083] (1) Crystallization test of active pharmaceutical ingredient:

[0084] Visual inspection was used to examine Examples 7-11 and the original "Amidi" tolometrol patch under a microscope to observe whether crystals precipitated from the active pharmaceutical ingredient. The results showed that no significant crystallization occurred in Examples 7-11, while significant crystallization was observed in the original "Amidi" tolometrol patch. Figure 1 Microscopic photographs of the patch from Example 9 are shown. Figure 2 This shows a microscope image of the original "Amidi" trotteroplasty.

[0085] (2) In vitro transdermal test:

[0086] Next, prescription screening will be conducted based on in vitro transdermal experiments.

[0087] Using a LOGAN dry-heated automated transdermal system (model: SYSTEM 918-12), a 0.4 mm, 2.5 cm diameter piece of Bama miniature pig skin was fixed between the supply and receiving chambers of a Franz diffusion device. A sample (circular area 1.767 cm²) was taken, the anti-adhesive layer was removed, and the sample was applied to the epidermal layer of the Bama miniature pig skin with the backing layer facing the supply chamber. A pH 7.4 buffer solution was added to the receiving chamber, ensuring the dermal side was in contact with the receiving solution. The mixture was kept at a constant temperature of (32±0.5) °C and stirred at 600 rpm. 5 ml samples were taken at 2, 4, 8, 12, 18, and 24 hours after drug administration, filtered, and the filtrate was used for analysis. A 24-hour cumulative drug release curve was plotted based on the cumulative drug release per unit area against time. Figure 3 ),Depend on Figure 3 It is evident that, among Examples 7-11, Example 9 and the original "Amidi" tuloterrot patch (Comparative Example 1) are most similar in terms of in vitro transdermal absorption.

[0088] Examples 12-15 and Comparative Example 2: Selection of Tackifier

[0089] The tuloterol transdermal patches provided in Examples 12-15 comprise a backing layer, a paste layer, and an anti-adhesive layer sequentially bonded together. The paste layer contains tuloterol, pressure-sensitive adhesive A, propylene glycol, and ethyl oleate. By selecting tackifiers such as polyisobutylene and alicyclic saturated hydrocarbon resins, the adhesion of the patch is enhanced, making it superior to the reference "Amidi" and less prone to falling off during application. It is prepared according to the formulation process described below.

[0090] (1) Weigh the tolobutrol raw material, pressure-sensitive adhesive A, propylene glycol, ethyl oleate, polyisobutylene and alicyclic saturated hydrocarbon resin according to the above prescription percentages;

[0091] (2) Add the prescribed amount of polyisobutylene or alicyclic saturated hydrocarbon resin to an appropriate amount of n-hexane and stir to dissolve;

[0092] (3) Add the prescribed amount of pressure-sensitive adhesive A, propylene glycol, ethyl oleate and tolometrol to the above adhesive solution, stir to dissolve and mix well, and let stand to remove air bubbles;

[0093] (4) Lay the fluorine release film flat on the surface of the LOGAN coating machine (model: C&D360), then set the coating speed to 10mm / s and the coating thickness to 200-400mm, and then coat the sample at 60℃.

[0094] (4) The medical backing film is laminated with non-woven fabric and then laid flat on the ointment layer using a laminating machine.

[0095] The formulations of Examples 12-15 and Comparative Example 2 are shown in Table 6:

[0096] Table 6

[0097]

[0098] Adhesion force testing:

[0099] According to the 2025 edition of the Chinese Pharmacopoeia, under item 0952, method one, before the test, the patch, along with its packaging material, should be placed at 18–25℃ and relative humidity 40–70% for at least 2 hours. Adjust the base to maintain the horizontal position of the device, and adjust the tilt plate to 30°. Two horizontal lines, 10mm apart, are drawn on the plate. The upper line marks the starting position of the steel ball, and the lower line marks the fixation point of the test sample. Wipe the surface of the tilt plate and stainless steel ball with anhydrous ethanol, and carefully dry them with a clean, lint-free cloth. Repeat the cleaning process 3 times until the surface of the tilt plate and stainless steel ball is visually inspected and found to be clean. Cut the sample into 16mm*12mm pieces, with the long side (16mm) parallel to the long side of the tilt plate. Use double-sided tape to smoothly attach the sample to the horizontal line on the tilt plate, ensuring there are no gaps between the sample and the lower edge of the paper. Remove the release film and let the steel ball fall freely from the tilt plate. A new sample is required each time the steel ball is replaced, and the test is repeated 3 times in parallel. Weigh the largest steel ball that can be adhered to, and determine the largest ball size that can be adhered to according to the table of steel ball weight and ball size correspondence. The adhesion test results are shown in Table 7.

[0100] Table 7

[0101]

[0102] Results: Adding 20%-40% polyisobutylene as a tackifier can improve the initial tack of the patch and enhance its adhesion, resulting in better performance.

[0103] Examples 16-17 and Comparative Example 3: Selection of Stabilizers

[0104] The tuloterol transdermal patch provided in Examples 16-17 comprises a backing layer, a paste layer, and an anti-adhesive layer bonded together sequentially. The paste layer contains tuloterol, pressure-sensitive adhesive A, propylene glycol, ethyl oleate, and polyisobutylene. By adding a stabilizer to ensure product quality, the preparation process is the same as in Examples 12-15, except that in step (3), the corresponding DL-tocopherol and butylated hydroxytoluene are added according to the formula.

[0105] The formulations for Examples 16-17 are shown in Table 8:

[0106] Table 8

[0107]

[0108] The tests for the relevant substances are shown in Table 9:

[0109] Table 9

[0110]

[0111] Result: In summary, butylated hydroxytoluene (BHT) is the most effective stabilizer.

[0112] Examples 18-21: Investigation of Drying Methods

[0113] Examples 18-21 provide a tuloterol transdermal patch, the process of which includes weighing, preparation, coating, drying, cutting and packaging. Since the tuloterol raw material will gradually sublimate after rising to a certain temperature, reducing the drug loading in the ointment, this experiment adopts different temperatures and drying methods to investigate the process.

[0114] Table 10: Drying Conditions

[0115]

[0116] Table 11: Drying Conditions - Content Detection

[0117]

[0118] Results: As shown in Table 10, compared with the conventional hot air drying method, the bottom plate heating method can effectively avoid the risk of raw material loss.

[0119] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications, alterations, and equivalent transformations made to the above embodiments based on the technical essence of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A tuloterol transdermal patch, characterized in that: The patch includes a backing layer, a paste layer, and an anti-adhesive layer; The ointment layer contains tuloterol, pressure-sensitive adhesive, and penetration enhancer; The pressure-sensitive adhesive is a copolymer of 2-ethylhexyl acrylate, butyl acrylate, tert-octylacrylamide, and methyl methacrylate; The penetration enhancer is propylene glycol and ethyl oleate, with a weight ratio of propylene glycol to ethyl oleate of 1:1 to 1:

2. By weight percentage, the patch contains 5-8% tuloterrol, 75-90% pressure-sensitive adhesive, and 5-18% penetration enhancer; The copolymer contains the following monomers in weight percentage: 30-35% 2-ethylhexyl acrylate, 30-35% butyl acrylate, 18-23% tert-octylacrylamide, and 13-17% methyl methacrylate.

2. The tuloterol transdermal patch as described in claim 1, wherein the ointment layer further comprises a thickener and / or a stabilizer.

3. The tuloterol transdermal patch as described in claim 2, wherein the patch contains, by weight percentage, 5-8% tuloterol, 42-62% pressure-sensitive adhesive, 5-10% penetration enhancer, 20-40% tackifier and 0.5-1% stabilizer.

4. The tuloterol transdermal patch as described in claim 2, wherein the tackifier is polyisobutylene and the stabilizer is butylated hydroxytoluene.

5. The method for preparing tuloterrol transdermal patches according to any one of claims 1-4, characterized in that, Includes the following steps: (1) Dissolve the pressure-sensitive adhesive and the penetration enhancer in a solvent by stirring; (2) Add tuloterol, stir to dissolve and mix well, let stand to remove air bubbles, and form a gel; (3) Apply the adhesive obtained in step (2) to the surface of the release layer and dry it to form a paste layer; (4) The backing layer is laid flat on the surface of the ointment layer to obtain tuloterol transdermal patch; In step (3), the drying method is to heat and dry the bottom plate.

6. The preparation method according to claim 5, characterized in that: In step (3), the drying temperature is 50-60°C, and / or In step (4), the coating speed is 8-12 mm / min and the coating thickness is 200-400 mm.

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