Semaglutide oral film preparation and preparation method thereof

Abstract

The invention relates to the field of pharmacy, in particular to a semaglutide oral film preparation and a preparation method thereof. The semaglutide oral film preparation comprises a penetration enhancer, wherein the penetration enhancer is selected from diethylene glycol monoethyl ether, lauryl sodium sulfate, polysorbate 80 or propylene glycol. The oral film preparation is good in stability, in-vivo absorption is obviously increased, and bioavailability is remarkably improved.

Description

Technical Field

[0001] The present invention relates to the pharmaceutical field, and in particular to a semaglutide oral thin film and a preparation method thereof. Background Art

[0002] Semaglutide is a new long-acting glucagon-like peptide-1 (GLP-1) analog. As a GLP-1 receptor agonist, it can selectively bind to and activate the GLP-1 receptor, which is the target of natural GLP-1. GLP-1 is a physiological hormone that has multiple effects on glucose metabolism mediated by the GLP-1 receptor. Semaglutide lowers blood sugar by stimulating insulin secretion and reducing glucagon secretion, both of which are glucose-dependent. Therefore, when blood sugar rises, insulin secretion is stimulated and glucagon secretion is inhibited. The mechanism by which semaglutide lowers blood sugar also involves a slight delay in early postprandial gastric emptying. In addition, semaglutide can also have a significant weight loss effect by reducing appetite and reducing food intake.

[0003] Semaglutide was developed by Novo Nordisk. Currently, there are two drug formulations of Semaglutide, namely injection and oral preparation. In December 2017, the FDA approved the marketing of Semaglutide injection (trade name: Ozempic); in September 2019, the FDA formally approved the marketing application of oral Semaglutide (trade name Rybelsus). As an injection, the marketed Semaglutide is taken once a week, with each injection of 0.25-1.0 mg (0.25 mg each time for the first 4 weeks, and then increased to 0.5-1.0 mg / time). There are still the shortcomings of pain, irritation, cross infection, and poor compliance of the percutaneous injection route. At present, Novo Nordisk's oral Semaglutide products avoid injection, greatly improve patient compliance, and increase the administration rate. Because peptide drugs have large molecular weight and hydrophilic properties, especially macromolecules with a molecular weight greater than 1,000 Da, they have poor gastrointestinal mucosal penetration and are easily affected by gastrointestinal pH and enzymatic degradation, resulting in extremely low bioavailability of their oral preparations. The small molecule absorption enhancer 8-(2-hydroxybenzamido) sodium octanoate (SNAC) is added to the oral semaglutide excipients. SNAC can form a relatively high pH environment near the corrosion site of the tablet in the stomach, thereby reducing the degradation of pepsin. The surrounding of the hydrophobic molecule SNAC increases the lipophilicity of the semaglutide tablets and promotes the absorption of the drug in the gastric mucosa. The degree of absorption of semaglutide depends on the amount of SNAC co-formulated with it. Despite this, the oral absorption rate (bioavailability) of semaglutide is still low, about 0.5-1%. Compared with subcutaneous injections, the bioavailability of oral semaglutide is lower. In addition, there may be individual absorption differences in oral semaglutide. Oral semaglutide compensates for these problems by giving a higher dose, and can also achieve the same clinical effect as subcutaneous injections. At present, the product is taken orally as one tablet a day, each tablet is 7mg or 14mg, and the oral absorption rate (bioavailability) is 0.5-1%. The dose of active ingredients required for the oral dosage form of semaglutide is much higher than that of subcutaneous injections. In addition, Novo Nordisk prices oral semaglutide at US$26 per day, or US$772 per 30 tablets, making treatment costs high for patients.

[0004] Oralthin films (OTF) are polymer films used for local or systemic absorption and treatment. They can enter the blood circulation through the dense capillaries under the oral mucosa or through the sublingual absorption. The oral mucosa is easy for drugs to penetrate and absorb, and the effect is fast. The drug administration method will not damage normal tissues. It can also prevent the drug from being exposed to the acid and enzyme environment of the digestive tract to cause drug degradation. The advantages of oral thin films include: 1. Oral fast-dissolving films do not require injection (injection also requires attention to the administration site), which is convenient for administration and increases patient compliance; according to the information of marketed drugs, oral dosage forms have fewer adverse reactions than injection solutions. 2: When administering oral tablets, the amount of water needs to be controlled. When administering oral fast-dissolving films, water is not required. It is convenient for administration and easy to carry. 3. Improve bioavailability: The buccal mucosa and sublingual mucosa in the oral cavity are non-keratinized mucosa, which is an ideal administration site for biomacromolecules. The mucosa is highly vascularized. After passing through the mucosa, the drug can directly return to the systemic circulation through the capillaries and veins, avoiding the first-pass effect of the liver and improving the bioavailability of the drug.

[0005] CN110354106A discloses a film that dissolves quickly in the oral cavity and a preparation method thereof. The film contains glycerin in its formulation and has the problems of being easy to absorb moisture and having poor stability, and the absorption of the film is poor.

[0006] Therefore, it is still necessary to develop semaglutide oral thin films with better stability and absorption. Summary of the invention

[0007] In view of the above technical status, the present invention provides an improved semaglutide oral thin film, wherein the semaglutide oral thin film comprises a penetration enhancer, wherein the penetration enhancer is selected from diethylene glycol monoethyl ether, sodium lauryl sulfate, polysorbate 80 or propylene glycol;

[0008] In the present invention, as one of the embodiments, the penetration enhancer is diethylene glycol monoethyl ether.

[0009] In the present invention, as one of the embodiments, the content of the penetration enhancer in the semaglutide oral film is 5-13%, preferably 7-13%, and more preferably 10-13%, based on the mass of the oral film.

[0010] In the present invention, as one of the embodiments, the content of semaglutide in the semaglutide oral film is 1 to 30% by weight of the oral film, preferably 5 to 25%, and more preferably 10 to 20%.

[0011] In the present invention, as one of the embodiments, the semaglutide oral thin film further comprises a film-forming material, a plasticizer and a pH regulator.

[0012] In the present invention, as one of the embodiments, the semaglutide oral film further comprises a colorant, a flavoring agent or a combination of the two.

[0013] In the present invention, as one of the embodiments, the semaglutide oral film further comprises a solvent.

[0014] In the present invention, as one embodiment, the content of the film-forming material is 30 to 90%, preferably 40 to 70%, and more preferably 40 to 60%.

[0015] In the present invention, as one embodiment, the content of the plasticizer is 5 to 25%, and more preferably 10 to 20%.

[0016] In the present invention, as one embodiment, the content of the colorant is 0 to 5%, preferably in the range of 0.5 to 3.0%, and more preferably in the range of 0.5 to 2.5%.

[0017] In the present invention, as one embodiment, the content of the flavoring agent is 0 to 5%, preferably in the range of 1.0 to 4.0%, and more preferably in the range of 1.5 to 3.5%.

[0018] In the present invention, as one of the embodiments, the pH adjuster is selected from disodium hydrogen phosphate; the pH adjuster adjusts the pH value to 7.0 to 7.8, and the further preferred range is 7.2 to 7.6.

[0019] In the present invention, as one embodiment, the content of the solvent is 0 to 30%, more preferably 10 to 20%.

[0020] In the present invention, as one of the embodiments, the film-forming material is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxyethyl cellulose or any combination thereof; in the present invention, as one of the embodiments, the polymer film-forming material is a combination of hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

[0021] In the present invention, as one of the embodiments, the plasticizer is selected from one of polyethylene glycol 400, glycerol, sorbitol, propylene glycol or any combination thereof. In the present invention, as one of the embodiments, the plasticizer is polyethylene glycol.

[0022] In the present invention, as one of the embodiments, the colorant can be one of a pigment and a FD&C dye or a mixture thereof.

[0023] In the present invention, as one of the embodiments, the flavoring agent is selected from sucralose, aspartame, stevioside, sorbitol, mannitol, xylitol, aspartame or edible flavors.

[0024] In the present invention, as one of the embodiments, the solvent is water for injection, anhydrous ethanol or a combination thereof.

[0025] The present invention also provides a method for preparing an oral thin film, which comprises: dispersing a film-forming material in an inorganic solvent at 60 to 80° C., stirring evenly, then adding a plasticizer, a permeation enhancer and a pH adjuster, and optionally adding a flavoring agent and / or a colorant to dissolve evenly, cooling to room temperature, then adding semaglutide and an organic solvent, stirring to obtain a uniform viscous liquid, degassing, and then coating and drying to obtain the product.

[0026] In the present invention, as one of the embodiments, the room temperature is 25°C to 30°C.

[0027] In the present invention, as one of the embodiments, the temperature during the coating process is 40-60° C. In the present invention, too high a temperature will affect the stability of the semaglutide API, and too low a temperature will not completely evaporate the solvent.

[0028] In the present invention, as one of the embodiments, the method includes degassing which can be a degassing method commonly used in the art, such as static degassing, heating degassing or vacuum degassing; as one of the preferred embodiments, static degassing is used.

[0029] In the present invention, as one of the embodiments, the inorganic solvent is water for injection.

[0030] In the present invention, as one of the embodiments, the organic solvent is anhydrous ethanol.

[0031] In the present invention, the preparation of the drug solution is usually to disperse the water-soluble polymer material in a solvent to prepare a uniform polymer liquid, then add a plasticizer, a flavoring agent, etc. to dissolve, and then disperse the drug in the polymer solution and stir to obtain a uniform viscous drug solution. The viscosity of the drug solution is appropriate to prevent uneven coating or inability to remove bubbles.

[0032] The drug solution needs to be stirred continuously during the preparation process, which will inevitably produce a large number of bubbles. Common degassing methods include static degassing, heating degassing and vacuum degassing. The static degassing method is not suitable for drug solutions that have been placed for too long to produce stratification or precipitation. The heating degassing method is not suitable for drugs that are unstable to heat. The vacuum degassing method requires a vacuum degassing machine.

[0033] The laboratory uses static degassing for 4 to 8 hours, and coating can be carried out when no obvious bubbles are generated by gently stirring with a glass rod. The storage time of this product is tested: the prepared glue solution will not be separated or precipitated after being placed for 24 hours.

[0034] In laboratories, smooth glass plates are often used for coating and then dried in an oven. The drying temperature should not be too high, generally not exceeding 60°C. It can also be dried at room temperature, or gradually raised from low temperature to a higher temperature. If necessary, a flat backing material can be laid on the glass plate to enhance the demoulding performance of the film. In large-scale production, a coating machine can be used for coating, which can better control the thickness and uniformity of the coating, thereby obtaining a film with accurate dosage.

[0035] Compared with the prior art, the orodispersible film prepared by the present invention not only has good stability, but also the drug is absorbed through the oral mucosa, and with the help of a penetration enhancer, the in vivo absorption is significantly increased, and the bioavailability is increased. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 : Blood drug concentration data of semaglutide orodispersible film in Experimental Example 2. DETAILED DESCRIPTION

[0037] The following examples are used to further illustrate the present invention, but are not intended to limit the effective scope of the present invention in any way.

[0038] Example 1 Screening of oral dissolving film formulation composition

[0039] 1.1 Investigation of film-forming material model and dosage:

[0040] By investigating different film-forming material models and dosages, the film-forming material models and dosages of the present invention are finally determined as follows:

[0041] The film-forming material is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxyethyl cellulose or any combination thereof. Preferably, the polymer film-forming material is a combination of hydroxypropyl cellulose and hydroxypropyl methyl cellulose. The content of the film-forming material of the present invention is 30-90%, preferably 40-70%, and more preferably 40-60%.

[0042] The semaglutide oral thin film preparation was prepared according to the film-forming material model and dosage prescription composition in Table 1.

[0043] 1.1.1 Preparation method: Add film-forming material, plasticizer, colorant, flavoring agent, penetration enhancer and pH adjuster to water for injection and dissolve them at 70°C. After the solution is cooled to room temperature, add semaglutide and stir to dissolve. Let stand to defoam. Use a small laboratory coating machine for coating. Place the coated sample in an electric constant temperature forced air drying oven (temperature 60°C) to dry and remove the solvent water for injection.

[0044] 1.1.2 Test method: The properties, breaking force, and melting time of the sublingual and buccal mucosa of the preparation were recorded.

[0045] Table 1 Film-forming material model and dosage formulation composition

[0046]

[0047]

[0048] Result analysis: From the above evaluation index results, it can be seen that the films prepared by each component have good flatness and foldability, plasticity and toughness, the film surface is smooth and flat, and the tensile strength meets the requirements of cutting, packaging, transportation and clinical use. The dissolution time in different parts of the oral cavity (sublingual and buccal mucosa) is appropriate and the taste is good.

[0049] 1.2 Investigation of plasticizer types, models and dosage:

[0050] By investigating different types, models and dosages of plasticizers, the types, models and dosages of the plasticizers of the present invention are finally determined as follows:

[0051] The plasticizer selected in the present invention includes polyethylene glycol 400, glycerol, sorbitol, propylene glycol or any combination thereof, preferably polyethylene glycol. The content of the plasticizer is 5-25%, more preferably 10-20%.

[0052] Semaglutide oral film preparations were prepared according to the type, model and amount of plasticizers in Table 2.

[0053] 1.2.1 Preparation method: Dissolve and disperse the film-forming material, plasticizer, colorant, flavoring agent, penetration enhancer and pH adjuster in water for injection at 70°C, add semaglutide and stir to dissolve the solution after the solution is cooled to room temperature; let stand to defoam; use a small laboratory coating machine for coating, and place the coated sample in an electric constant temperature forced air drying oven (temperature 60°C) to remove the solvent water for injection.

[0054] 1.2.2 Test method: The properties, breaking force, and melting time of the sublingual and buccal mucosa of the preparation were recorded.

[0055] Table 2 Plasticizer types, models and dosages Investigation of prescription composition

[0056]

[0057]

[0058] Result analysis: Different types and models of plasticizers were investigated. Although glycerol can increase the toughness of the film, it has a certain hygroscopicity. If too much glycerol is added, the humidity requirement for the preparation process of the orally soluble film is high. The humidity needs to be controlled within the range of ≤25% RH. The humidity of the sample prepared with polyethylene glycol was controlled within the range of ≤40% RH.

[0059] The film prepared by the above components has good flatness, foldability, plasticity and toughness, a smooth and flat surface, and a tensile strength that meets the requirements of cutting, packaging, transportation and clinical use. The dissolving time in different parts of the oral cavity (sublingual and buccal mucosa) is appropriate and the taste is good.

[0060] 1.3 Solvent: Anhydrous ethanol concentration investigation:

[0061] By investigating different solvent types and concentrations, the concentration of anhydrous ethanol of the present invention was finally determined as follows:

[0062] The content of the anhydrous ethanol selected in the present invention is 0 to 30%, and more preferably 10 to 20%.

[0063] The semaglutide oral thin film preparation was prepared according to the anhydrous ethanol concentration in Table 3.

[0064] 1.3.1 Preparation method: Dissolve and disperse the film-forming material, plasticizer, colorant, flavoring agent, penetration enhancer and pH adjuster in water for injection at 70°C, add semaglutide and stir to dissolve the solution after the solution is cooled to room temperature; let stand to defoam; use a small laboratory coater for coating, and dry the coated sample in an electric constant temperature forced air drying oven (temperature 60°C) to remove the solvent water for injection.

[0065] 1.3.2 Test method: The properties, breaking force, and melting time of the sublingual and buccal mucosa of the preparation were recorded.

[0066] Table 3 Anhydrous ethanol concentration investigation formula composition

[0067]

[0068] Analysis of results: Semaglutide has poor thermal stability. The addition of anhydrous ethanol as solvent can shorten the coating and drying time and ensure stability. However, excessive addition may affect the solubility of the raw materials and film-forming materials in the preparation process. In addition, ethanol is closely related to the surface tension of the film material during the coating process, which directly affects whether the orodispersible film can be peeled off from the film material intact.

[0069] When the ethanol concentration is 10-20%, the film prepared by the above components has good flatness, foldability, plasticity and toughness, is easy to peel, has a smooth and flat surface, and the breaking force meets the requirements of cutting, packaging, transportation and clinical use. The dissolution time in different parts of the oral cavity (sublingual and buccal mucosa) is appropriate and the taste is good.

[0070] 1.4 Investigation of the types and dosage of penetration enhancers:

[0071] By investigating different types and dosages of penetration enhancers, the types and dosages of penetration enhancers of the present invention are finally determined as follows:

[0072] The penetration enhancer is one of diethylene glycol monoethyl ether, sodium lauryl sulfate, polysorbate 80 and propylene glycol. Preferably, the penetration enhancer is diethylene glycol monoethyl ether. The penetration enhancer dosage of the present invention is 5-13%, more preferably 7-13%.

[0073] The semaglutide oral thin film preparation was prepared according to the type and dosage of the penetration enhancer in Table 4.

[0074] 1.4.1 Preparation method: Dissolve and disperse the film-forming material, plasticizer, colorant, flavoring agent, penetration enhancer and pH adjuster in water for injection at 70°C, add semaglutide and stir to dissolve the solution after the solution is cooled to room temperature; let stand to defoam; use a small laboratory coating machine for coating, and dry the coated sample in an electric constant temperature forced air drying oven (temperature 60°C) to remove the solvent water for injection.

[0075] 1.4.2 Test method: The properties, breaking force, and melting time of the sublingual and buccal mucosa of the preparation were recorded.

[0076] Table 4 Types and dosages of penetration enhancers for formula composition

[0077]

[0078]

[0079] Result analysis: Semaglutide is a large molecule with a high molecular weight. In order to improve its permeability in the oral cavity, the type and type of penetration enhancer were screened.

[0080] Different types of penetration enhancers have a great influence on the preparation process. The samples prepared with caprylic acid capric acid polyethylene glycol glyceride directly destroyed the toughness of the film-forming material. The samples prepared with different amounts of diethylene glycol monoethyl ether had good flatness, foldability, plasticity and toughness, and were easy to peel off. The surface of the film was smooth and flat, and the tensile strength was within 10-17N, which met the requirements of cutting, packaging, transportation and clinical use. The dissolution time in different parts of the oral cavity (sublingual and buccal mucosa) was appropriate, and the taste was good.

[0081] 1.5 Selection of flavoring agents and coloring agents

[0082] By investigating the types and dosages of different flavoring agents and coloring agents, both coloring agents and flavoring agents are used to enhance the taste of the orodispersible film. During the experiment, sucralose was selected as the flavoring agent and titanium dioxide was selected as the coloring agent. The above coloring agents and flavoring agents can be replaced by taste, properties, etc. as evaluation indicators. Finally, the types and dosages of the flavoring agents and coloring agents of the present invention are determined as follows:

[0083] The flavoring agent can be sucralose, aspartame, stevioside, sorbitol, mannitol, xylitol, aspartame and edible flavors, among which sucralose has a higher sweetness and does not increase blood sugar concentration. The coloring agent can be one of a pigment and FD&C dye or a mixture thereof. The flavoring agent or coloring agent used in the present invention is preferably used in an amount of 0 to 5%.

[0084] Test Example 1: In vitro study of semaglutide orodispersible thin film

[0085] Experimental materials: The semaglutide orosoluble film prepared by prescription 16 was used for the experiment.

[0086] Methods: In vitro stimulation experiments were conducted using blank membranes without drugs. The experimental scheme and results are as follows:

[0087] Experimental protocol:

[0088] The in vitro irritation test was conducted using a blank membrane. The test protocol is as follows:

[0089]

[0090] Record the irritation of different parts of the body after taking the medicine, mainly including whether there is damage at the medication site. If there is damage, record the repair time, and record whether there is irritation within 1 day after taking the medicine.

[0091] Survey results: See Table 5

[0092] Table 5 In vitro irritation results of semaglutide (blank membrane)

[0093]

[0094] Conclusion: The results of the in vitro irritation test showed that the blank film of semaglutide had no irritation after being taken on different parts of the body. The raw materials and excipients used in the orodispersible film were non-irritating.

[0095] Test Example 2: In vivo study of semaglutide orodispersible thin film

[0096] Animals, samples and reagents: SD rats, 12, Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0097] Experimental method: 12 rats were divided into groups of 6, and prescription 14 and prescription 16 were administered respectively. A patch of about 0.5*0.5 cm containing 0.9 mg of drug was applied on the tongue of each rat. Blood was collected at 1h, 2h, 3h, 4h, 5h, and 6h to detect the drug concentration of semaglutide in plasma.

[0098] Test results: see Figure 1 And Table 6

[0099] Table 6 In vivo evaluation results of semaglutide

[0100]

[0101] Results and discussion: Prescriptions 14 and 16 were evaluated in animals. The results showed that the dosage of the penetration enhancer directly affected the absorption of the drug in vivo. When the dosage of the penetration enhancer was increased to 10%, semaglutide was significantly absorbed in animals.

Claims

1. A semaglutide oral thin film, characterized in that: The oral film comprises a penetration enhancer, and the penetration enhancer is selected from diethylene glycol monoethyl ether, sodium lauryl sulfate, polysorbate 80 or propylene glycol.

2. The oral thin film according to claim 1, characterized in that: The penetration enhancer is diethylene glycol monoethyl ether.

3. The oral film according to claim 1, characterized in that: In the oral film, the content of the penetration enhancer is 5-13%, preferably 7-13%, and more preferably 10-13%, based on the mass of the oral film.

4. The oral film according to claim 1, characterized in that In the oral film, the content of semaglutide is 1 to 30%, preferably 5 to 25%, and more preferably 10 to 20%, based on the mass of the oral film.

5. The oral film according to claim 1, characterized in that: The oral film further comprises a film-forming material, a plasticizer and a pH adjuster.

6. The oral film according to claim 1, characterized in that The oral film may also include a colorant, a flavorant, or a combination of both.

7. The oral film according to claim 1, characterized in that The oral film also includes a solvent.

8. The oral film according to claim 5, characterized in that: In the oral thin film, the content of the film-forming material is 30 to 90%, preferably 40 to 70%, and more preferably 40 to 60%, based on the mass of the oral thin film.

9. The oral film according to claim 5, characterized in that: In the oral film, the content of the plasticizer is 5 to 25%, preferably 10 to 20%, based on the mass of the oral film.

10. The oral film according to claim 6, characterized in that In the oral film, the content of the colorant is 0 to 5%, preferably 0.5 to 3.0%, and more preferably 0.5 to 2.5%, based on the mass of the oral film.

11. The oral film according to claim 6, characterized in that: In the oral film, the content of the flavoring agent is 0 to 5%, preferably 1.0 to 4.0%, and more preferably 1.5 to 3.5%, based on the mass of the oral film.

12. The oral film according to claim 5, characterized in that: The pH adjuster is selected from disodium hydrogen phosphate; the pH value is adjusted to 7.0-7.8, preferably 7.2-7.

6.

13. The oral film according to claim 7, characterized in that: In the oral film, the content of the solvent is 0 to 30% by weight, and more preferably 10 to 20% by weight.

14. The oral film according to claim 5, characterized in that The film-forming material is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxyethyl cellulose or any combination thereof; preferably, the polymer film-forming material is a combination of hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

15. The oral film according to claim 5, characterized in that The plasticizer is selected from one of polyethylene glycol 400, glycerol, sorbitol, propylene glycol or any combination thereof. Preferably, the plasticizer is polyethylene glycol.

16. The oral film according to claim 6, characterized in that The colorant is selected from pigments, FD&C dyes or mixtures thereof.

17. The oral film according to claim 6, characterized in that: The flavoring agent is selected from sucralose, aspartame, stevioside, sorbitol, mannitol, xylitol, aspartame and edible flavors.

18. The oral film according to claim 7, characterized in that: The solvent is an organic solvent, an inorganic solvent or a combination of the two. Preferably, the inorganic solvent is water for injection and the organic solvent is anhydrous ethanol.

19. The method for preparing the semaglutide oral thin film according to any one of claims 1 to 18, characterized in that: The method comprises: The film-forming material is dispersed in an inorganic solvent at 60-80°C, stirred evenly, and then a plasticizer, a penetration enhancer and a pH adjuster are added, and a flavoring agent and / or a colorant are optionally added to dissolve evenly, cooled to room temperature, and then semaglutide and an organic solvent are added, stirred to obtain a uniform viscous liquid, degassed, and then coated and dried.

20. The method according to claim 19, characterized in that The room temperature is 25°C to 30°C; the temperature during the coating process is 40°C to 60°C.

21. The method according to claim 19, characterized in that The method includes degassing by static degassing.

22. The method according to claim 19, characterized in that The inorganic solvent is water for injection.

23. The method according to claim 19, characterized in that The organic solvent is anhydrous ethanol.

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