Microbubble film agent as an alternative to titanium dioxide and method for producing the same

Abstract

This application relates to a microbubble film agent that replaces titanium dioxide and a method for producing the same. Expressed by mass percentage, the microbubble film agent is mainly manufactured from raw materials containing 0.01% to 40% of an active ingredient, 20% to 80% of a polymer film-forming material, 0.1% to 20% of a surfactant, and 2.5% to 30% of a thickener. The polymer film-forming material includes pullulan polysaccharide as the main film-forming material and an auxiliary film-forming material, with the mass ratio of pullulan polysaccharide as the main film-forming material to the auxiliary film-forming material being 1:3 to 3:1. This application provides a microbubble film agent that utilizes the physical effects of light scattering by microbubbles to produce a white, opaque coloring effect on the film, and realizes a new concept and solution as an alternative to titanium dioxide by adjusting the raw material blending ratio between pullulan polysaccharide as the main film-forming material and the auxiliary film-forming material.

Description

Technical Field

[0001] (Cross - reference to related applications) This application claims the priority of a Chinese patent application with an application number of 2024105885289 and an invention title of "Micro - bubble Film Agent Substituting Titanium Dioxide and Its Manufacturing Method", which was filed on May 13, 2024, and all of its contents are incorporated herein by reference.

[0002] (Technical Field) This application relates to the technical field of film agents, specifically to a micro - bubble film agent substituting titanium dioxide and its manufacturing method.

Background Art

[0003] Film agents have been attracting attention and being emphasized in recent years because they have characteristics such as being convenient to take, having a simple process, and good compliance. Generally, in order to ensure distinctiveness and a good appearance, film agents need to be subjected to opacifying and coloring treatments. By blocking light, unstable components in the film agent against light can be protected, and the quality of the drug can be improved. The most commonly used opaque colorant is titanium dioxide. Titanium dioxide is a white pigment with excellent whiteness, opacity, coloring power, and extremely high chemical stability. It has been widely used in fields such as food, medicine, health foods, and cosmetics for many years, and an ideal coloring effect can be obtained even with a small amount of use. Titanium dioxide can be used alone or in combination with other dyes and pigments such as iron oxide, and bright colors can be obtained, further enhancing distinctiveness and aesthetics.

[0004] However, questions have been raised about the safety of titanium dioxide use. In 2016, the French regulatory body submitted a proposal to the European Chemicals Agency (ECHA) to classify titanium dioxide as a carcinogen. Subsequently, the Evaluation Committee (RAC) passed a resolution the following year classifying titanium dioxide as a Class II carcinogen, which included the hazard designation "H351 (inhalation)". On February 18, 2020, the European Commission adopted Regulation 2020 / 217, based on the RAC's resolution, establishing a unified classification and labeling for titanium dioxide. This regulation confirmed that titanium dioxide, when present in powder form and containing 1% or more of particles with a diameter of 10 μm or less, is carcinogenic to humans after inhalation. On November 8, 2021, EU member states approved the European Commission's proposal to ban the use of titanium dioxide (E171) as a food additive from 2022. On January 14, 2022, the European Commission formally adopted a ban on the use of titanium dioxide as a food additive, stipulating a six-month transition period. This ban officially came into full effect on August 7, 2022. As a result, researchers are actively searching for alternatives to titanium dioxide in the manufacture of film-forming agents.

[0005] This application was proposed in light of these circumstances. [Overview of the project] [Problems that the invention aims to solve]

[0006] The first objective of this application is to provide a microbubble film agent that replaces titanium dioxide, which utilizes the physical effect of light scattering by microbubbles to produce a white opaque coloring effect on the film, and generates uniform microbubbles in the film agent by a specific raw material mixing ratio between the main film-forming material pullulan and the auxiliary film-forming material, thereby producing a white opaque coloring effect on the film, avoiding the addition of any colorants and opacifiers, and reducing the impact on the active ingredients due to the introduction of new auxiliary agents.

[0007] The second object of this application is to provide a method for producing a microbubble film agent that can replace titanium dioxide, the method being easy to operate, having mild operating conditions, and generating small, uniform microbubbles in the film agent by using different stirring speeds and stirring times during the manufacturing process. [Means for solving the problem]

[0008] To achieve the above-mentioned objectives of this application, the following technical means are employed.

[0009] This application, when expressed as a mass percentage, mainly, Active ingredients 0.01%~40%, Polymer film forming material 20%~80%, Surfactants 0.1% to 20%, and Made with raw materials containing 2.5% to 30% thickeners. The polymer film-forming material includes pullulan as the main film-forming material and an auxiliary film-forming material. The present invention provides a microbubble film agent that can replace titanium dioxide, wherein the mass ratio of the main film-forming material (pullulan polysaccharide) to the auxiliary film-forming material is 1:3 to 3:1.

[0010] As a more specific example, the auxiliary film-forming material includes one or more of the following: hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinyl alcohol, hydroxypropyl cellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol-polyethylene glycol graft copolymer, maltodextrin, polyethylene oxide, sodium alginate, hydroxypropyl starch, and carbomer.

[0011] As a more specific example, the auxiliary film-forming material includes one or more of the following: hydroxypropyl methylcellulose, polyvinyl alcohol, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol-polyethylene glycol graft copolymer, maltodextrin, sodium alginate, and hydroxypropyl starch.

[0012] As a more specific example, the auxiliary film-forming material is hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinyl alcohol.

[0013] As a more specific example, the mass ratio of the pullulan polysaccharide to the auxiliary film-forming material is 2:1 to 1:3.

[0014] As a more specific example, the mass ratio of the pullulan polysaccharide to the auxiliary film-forming material is 2:3.

[0015] As a more specific example, the mass ratio of hydroxypropyl methylcellulose:hydroxypropyl cellulose:polyvinyl alcohol is 1:1:1.

[0016] As a more specific example, the thickening agent is one or more of the low molecular weight thickening agent and the high molecular weight suspension aid. The low molecular weight thickener is one or more of the following: sucrose, maltose, fructose, mannitol, glucose, lactose, trehalose, xylitol, maltitol, erythritol, sorbitol, lactitol, cetyl palmitate, and stearic acid. The aforementioned polymeric suspension aid is one or more of the following: gum arabic, agar, carrageenan, dextrin, gellan gum, guar gum, pectin, propylene glycol alginate, sodium carboxymethylcellulose, starch, gelatin, tragacanth gum, xanthan gum, and gum.

[0017] As a more specific example, the mass ratio of the polymer film-forming material to the thickener is 20:1 to 1:1.

[0018] As a more specific example, the low molecular weight thickener is one or more of the following: maltose, mannitol, glucose, lactose, trehalose, xylitol, maltitol, and erythritol. The polymer suspension aid may be one or more of carrageenan, dextrin, gellan gum, guar gum, pectin, propylene glycol alginate, sodium carboxymethyl cellulose, xanthan gum, and rubber.

[0019] More specifically, as an example of implementation, the thickener is a mixture of maltose, a low molecular weight thickener, and dextrin, a polymer suspension aid.

[0020] More specifically, as an example of implementation, the mass ratio of the maltose to the dextrin is 2:3.

[0021] More specifically, as an example of implementation, the mass ratio of the polymer film-forming material to the thickener is 10:1 to 1.2:1.

[0022] [[ID=十六]]More specifically, as an example of implementation, the surfactant is one or more of sodium lauryl sulfate, polysorbate, poloxamer, lecithin, and fatty acid glyceride.

[0023] More specifically, as an example of implementation, the surfactant is sodium lauryl sulfate and polysorbate 80.

[0024] More specifically, as an example of implementation, the mass ratio of the sodium lauryl sulfate to the polysorbate 80 is 2:3.

[0025] More specifically, as an example of implementation, it further contains 0 to 35% of other auxiliary agents, and the other auxiliary agents include one or more of a disintegrant, a plasticizer, a stabilizer, a colorant, and a flavoring agent.

[0026] More specifically, as an example of implementation, the disintegrant may be one or more of crospovidone, sodium carboxymethyl cellulose, and corn starch.

[0027] More specifically, as an example of implementation, the plasticizer is one or more of glycerin, PEG, and glyceryl triacetate.

[0028] As a more specific example, the stabilizer is one or more of the following: hydroxypropyl-β-cyclodextrin, hydroxybutyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, BHT, EDTA, BHA, sodium bisulfite, and sodium pyrosulfite.

[0029] The coloring agent is one or more of the following: ferric oxide, tartrazine, amaranth, and brilliant blue. The aforementioned flavoring agent is one or more of the following: sucralose, aspartame, stevioside, mint flavor, strawberry flavor, and orange flavor.

[0030] In the above raw materials, the active ingredient is any drug that can be dissolved or dispersed in water, such as diazepam, dexmedetomidine, riluzole, clobazam, fentanyl, buprenorphine, naloxone, voglibose, rizatriptan benzoate, zolmitriptan, zolpidem tartrate, apomorphine hydrochloride, loratadine, desloratadine, rupatadine fumarate, caliprazine hydrochloride, nitroglycerin, calcitriol, alfacalcidol, paricalcitol, vitamin D, vitamin A, sildenafil citrate, tadalafil, vardenafil, racecadotril, ondansetron hydrochloride, ondansetron, granisetron hydrochloride, donepezil hydrochloride, and This includes, but is not limited to, one or more drugs such as lipiprazole, asenapine maleate, selegiline hydrochloride, rasagiline mesylate, memantine hydrochloride, olanzapine, montelukast sodium, perampanel, brexpiprazole, vaccines, or polypeptides; one or more health food functional factors such as probiotics, melatonin, vitamins and vitamin analogs, minerals and trace elements, active sugars, active polypeptides, active proteins, and functional oils; and one or more food ingredients such as menthol, cineole, methyl salicylate, mogroside, musk deer extracts, and oral hygiene products.

[0031] This invention provides a microbubble film agent having microbubbles of 1 to 100 μm, obtained by stirring the main film-forming material pullulan and an auxiliary film-forming material to generate bubbles, then adding a surfactant and a thickener and stirring at high speed. The generation of these microbubbles allows the final produced film to exhibit a white, opaque effect, effectively replacing the coloration of titanium dioxide. As a result, the produced film agent has a white, opaque appearance, providing a feasible solution to replace titanium dioxide in the film agent's composition, improving safety, and reducing the impact on the active ingredient due to the introduction of new auxiliary agents. Furthermore, the microbubble film agent of this invention can be designed to be thicker than conventional film agents, providing room for improvement in drug load capacity, and the film produced with the microbubble film agent of this invention has faster solubility and a superior feel compared to films of the prior art. Therefore, this invention found that by selecting auxiliary film-forming materials, specifically hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinyl alcohol as auxiliary film-forming materials, and setting the mass ratio of pullulan:hydroxypropyl methylcellulose:hydroxypropyl cellulose:polyvinyl alcohol to 2:1:1:1, a large amount of bubbles can be generated by slowly stirring the main film-forming material pullulan polysaccharide and the auxiliary film-forming materials. The foaming ability is clearly superior to that of mixtures of other pullulan polysaccharides and other auxiliary film-forming materials. Furthermore, when maltose and dextrin are selected as thickeners, and sodium lauryl sulfate and polysorbate 80 are selected as surfactants, the microbubbles generated by high-speed stirring after adding the surfactants and thickeners are the most stable and uniform.

[0032] In the above raw materials, the inventors, through creative work, discovered that by blending the main film-forming material, pullulan polysaccharide, and the auxiliary film-forming material in a specific mass ratio, good foaming ability can be obtained. This allows for the generation of a large amount of bubbles by low-speed stirring at a specific rate, and then the generation of microbubbles of 1 to 100 μm by high-speed stirring at a specific rate. Normally, pullulan and the auxiliary film-forming material cannot be completely mixed, so a two-phase system is formed in the mixed aqueous solution. A miscibility interface exists between the two phases, and because the interaction between the different phases is weak, the stability of the miscibility interface is generally low, making it susceptible to external disturbances such as mechanical vibrations and shear forces. As a result, changes in the phase surface and rearrangement of material molecules occur, leading to the generation of a large amount of bubbles. Therefore, when the mass ratio of the main film-forming material pullulan to the auxiliary film-forming material is set to 3:1 to 1:3, preferably 2:1 to 1:3, uniform microbubbles can be generated in the manufactured film agent. If the proportion of pullulan polysaccharide is too high, the physical performance of the film formation deteriorates, and if the proportion of pullulan is too low, it becomes difficult to form a two-phase mixed interface, and a large number of bubbles are not generated. After the generation of microbubbles, the microbubbles themselves have a certain degree of instability. Therefore, in this application, the stability of the microbubbles is improved by adding a surfactant and a thickener, and the mass ratio of the added thickener to the polymer film-forming material is limited to a specific range, with the most stable microbubbles being obtained only when the mass ratio of the polymer film-forming material to the thickener is 20:1 to 1:1, preferably 10:1 to 1.2:1. This is because, in this application, by adding a surfactant and a thickener and stirring at high speed, the surfactant reduces the surface tension of the gas-liquid interface, allowing for the formation of a further thin film, which is advantageous for the generation of more abundant bubbles. On the other hand, thickeners can improve bubble stability by absorbing a large amount of water in the mixture, thereby increasing the viscosity of the mixture, improving the mechanical strength of the bubble film, and suppressing bubble contraction and liquid penetration. This is because if the proportion of thickener is too high, the mixture becomes excessively viscous, which is unfavorable for subsequent high-speed stirring, resulting in a shortage of the corresponding film-forming material and making film formation difficult. Conversely, if the proportion of thickener is too low, the viscosity of the mixture is low, the bubble stabilization time is short, and this affects the size and uniformity of microbubbles in the film manufacturing process.

[0033] This application further provides a method for producing a microbubble film agent that replaces the above-mentioned titanium dioxide, and the production method is as follows: The process involves sequentially adding pullulan polysaccharide and polymer film-forming material, and stirring at a low speed of 100-800 r / min for 2-30 minutes to obtain a mixture. The process includes the steps of sequentially adding an active ingredient, a surfactant, and a thickener to a mixture, stirring at a high speed of 2000 to 12000 r / min for 2 to 20 minutes, and then coating and drying.

[0034] As a more specific example, a mixture is obtained by low-speed stirring at a stirring speed of 200-600 r / min for 5-20 minutes.

[0035] As a more specific example, high-speed stirring is performed at a stirring speed of 3000-8000 r / min for 3-15 minutes.

[0036] In the method for producing the microbubble film agent described above, the stirring speed and stirring time in the two stages are extremely important to this invention. This is because existing research on substitutes for titanium dioxide mainly uses white materials based on calcium carbonate, zinc oxide, talc, and starch-based products as substitute materials. However, the whiteness and shielding properties that these substitute materials can provide are weaker than those of titanium dioxide, and high doses are required to achieve the same effect as titanium dioxide, which may affect the physicochemical performance of the formulation. Furthermore, some materials proposed as substitutes for titanium dioxide require a particle size range of 1 to 100 μm, and similarly, there is a risk of carcinogenicity associated with the inhalation of nano-order particles. For this reason, there is a strong need for a reliable alternative to titanium dioxide in orally soluble film agents. Meanwhile, the inventors, through creative work, accidentally discovered that when a transparent slurry without titanium dioxide is stirred at high speed, it changes into a white, opaque foam. The film agent obtained by coating and drying this slurry exhibits an opaque white appearance and has the potential to replace titanium dioxide.

[0037] Therefore, in this application, a microbubble film agent is manufactured by selecting a specific film-forming material and using a stepwise stirring method. After adding the main film-forming material, pullulan polysaccharide, and the auxiliary film-forming material, the stirring speed is set to a range of 100 to 800 r / min, preferably 200 to 600 r / min, and the mixture is stirred at a low speed for 2 to 30 minutes, preferably 5 to 20 minutes. If the stirring speed is too low or the stirring time is too short, it is unfavorable for sufficient mixing between the pullulan polysaccharide and the auxiliary film-forming material and will affect subsequent stirring. If the stirring speed is too high, many uneven bubbles of varying sizes will be generated at the moment of stirring, affecting the uniformity of the microbubbles and the effectiveness of the film agent. [Effects of the Invention]

[0038] Compared to the prior art, the beneficial effects of this invention are as follows:

[0039] (1) The present invention provides a microbubble film agent that replaces titanium dioxide, which utilizes the physical effect of light scattering by microbubbles to produce a white opaque coloring effect on the film, and generates uniform microbubbles in the film agent by a specific raw material mixing ratio between the main film-forming material pullulan and the auxiliary film-forming material, thereby producing a white opaque coloring effect on the film, providing a feasible solution to replace titanium dioxide in the components of the film agent, and reducing the safety risks of the auxiliary agent. (2) The method for producing the microbubble film agent according to the present invention is easy to operate, the operating conditions are mild, and by using different stirring speeds and stirring times during the manufacturing process, small and uniform microbubbles are generated in the film agent. (3) The microbubble film agent relating to this application has a faster dissolution rate than ordinary film agents. [Modes for carrying out the invention]

[0040] The technical solutions in this application will be described clearly and completely below, with reference to the embodiments of this application. Clearly, the embodiments described are some, but not all, embodiments of this application. All other embodiments that a person skilled in the art could obtain without creative work based on the embodiments of this application are all within the scope of protection of this application.

[0041] To more clearly explain the technical means in this application, specific examples will be provided below.

[0042] Example 1 The manufacturing process for the microbubble film agent is as follows:

[0043] Ingredients: The active ingredient is calcitriol 0.01g. 40g of pullulan polysaccharide as the main film-forming material. As an auxiliary film-forming material, 40g of hydroxypropyl methylcellulose, As a surfactant, 0.1g of sodium lauryl sulfate, Sucrose 8g as a thickening agent, Other supplements: 11.89g. 40 g of pullulan polysaccharide, the main film-forming material, and 40 g of hydroxypropyl methylcellulose, the auxiliary film-forming material, were placed in a reaction vessel. The stirring rod was activated, the rotation speed was adjusted to 100 r / min, and the mixture was stirred at low speed for 30 minutes to obtain the mixture. Subsequently, 0.01 g of the active ingredient calcitriol, 0.1 g of the surfactant sodium lauryl sulfate, 8 g of the thickener sucrose, and 11.89 g of other auxiliary agents were added to the reaction vessel containing the mixture. The mixture was then stirred at high speed for 30 minutes at a rotation speed of 2000 r / min to obtain a slurry, which was then applied and dried to obtain a microbubble film agent.

[0044] Example 2 The manufacturing process for the microbubble film agent is as follows:

[0045] Ingredients: The active ingredient is desloratadine 40g. 10g of pullulan polysaccharide as the main film-forming material. 10g of hydroxypropyl methylcellulose as an auxiliary film-forming material. 20g of poloxamer as a surfactant, Sucrose 20g as a thickening agent. 10 g of pullulan polysaccharide, the main film-forming material, and 10 g of hydroxypropyl methylcellulose, the auxiliary film-forming material, were placed in a reaction vessel. The stirring rod was activated, the rotation speed was adjusted to 800 r / min, and the mixture was stirred at low speed for 2 minutes to obtain the mixture. Subsequently, 40 g of the active ingredient desloratadine, 20 g of the surfactant sodium lauryl sulfate, and 20 g of the thickener sucrose were added to the reaction vessel containing the mixture. The rotation speed was adjusted to 12,000 r / min and the mixture was stirred at high speed for 2 minutes to obtain a slurry, which was then applied and dried to obtain a microbubble film agent.

[0046] Example 3 The manufacturing process for the microbubble film agent is as follows:

[0047] Ingredients: The active ingredient is brexpiprazole 1g. 20g of pullulan polysaccharide as the main film-forming material, 30g of hydroxypropyl methylcellulose as an auxiliary film-forming material. As a surfactant, 15g of sodium lauryl sulfate, Sucrose 30g as a thickening agent, Other supplements: 4g. 20 g of pullulan polysaccharide, the main film-forming material, and 30 g of hydroxypropyl methylcellulose, the auxiliary film-forming material, were placed in a reaction vessel. The stirring rod was activated, the rotation speed was adjusted to 600 r / min, and the mixture was stirred at low speed for 20 minutes to obtain the mixture. Subsequently, 1 g of the active ingredient brexpiprazole, 15 g of the surfactant sodium lauryl sulfate, 30 g of the thickening agent sucrose, and 4 g of other auxiliary agents were added to the reaction vessel containing the mixture. The rotation speed was adjusted to 8000 r / min and the mixture was stirred at high speed for 20 minutes to obtain a slurry, which was then applied and dried to obtain a microbubble film agent.

[0048] Example 4 The manufacturing process for the microbubble film agent is as follows:

[0049] Ingredients: Vitamin D3 1g, Pullulan polysaccharide 43.5g, Polyvinyl alcohol 7.25g, Hydroxypropyl methylcellulose 7.25g, Sodium lauryl sulfate 1g, Maltose 15g, Sulfobutyl-β-cyclodextrin 25g. 43.5 g of pullulan polysaccharide, the main film-forming material, and 7.25 g of hydroxypropyl methylcellulose and 7.25 g of polyvinyl alcohol, the auxiliary film-forming materials, were placed in a reaction vessel. A stirring rod was activated, and the rotation speed was adjusted to 100 r / min. The mixture was stirred at low speed for 30 minutes to obtain the mixture. Subsequently, 1 g of the active ingredient vitamin D3, 1 g of the surfactant sodium lauryl sulfate, 15 g of the thickener maltose, and 25 g of sulfobutyl-β-cyclodextrin were added to the reaction vessel containing the mixture. The rotation speed was adjusted to 12,000 r / min and the mixture was stirred at high speed for 2 minutes to obtain a slurry, which was then applied and dried to obtain a microbubble film agent.

[0050] Example 5 The manufacturing process for the microbubble film agent is as follows:

[0051] Ingredients: Vitamin D 0.01g, Vitamin A 0.03g, Pullulan polysaccharide 16g, Hydroxypropylcellulose 16g, Hydroxypropyl methylcellulose 16g, Polysorbate 80 0.99g, 20g of dextrin, Hydroxypropyl-β-cyclodextrin 30g, EDTA 0.97g. 16 g of pullulan, the main film-forming material, and 16 g each of hydroxypropyl methylcellulose and hydroxypropyl cellulose, the auxiliary film-forming materials, were placed in a reaction vessel. The stirring rod was activated, the rotation speed was adjusted to 300 r / min, and the mixture was stirred at low speed for 20 minutes to obtain the mixture. Subsequently, 0.01 g of the active ingredients vitamin D and 0.03 g of vitamin A, 20 g of the thickener dextrin, 0.99 g of the surfactant polysorbate 80 (Tween 80), and other auxiliary agents (30 g of the stabilizers hydroxypropyl-β-cyclodextrin and 0.97 g of EDTA) were added to the reaction vessel containing the mixture. The mixture was then stirred at high speed for 3 minutes at a rotation speed of 10,000 r / min to obtain a slurry, which was then applied and dried to obtain a microbubble film agent.

[0052] Example 6 The manufacturing process for the microbubble film agent is as follows:

[0053] Ingredients: Tadalafil 40g, Pullulan polysaccharide 25g, Sodium alginate 8.3g, Hydroxypropyl methylcellulose 16.7g, Polysorbate 80 1g, Xanthan gum 2.5g, Crospovidone 3.3g, Strawberry flavor 2g, Sucralose 1g, Brilliant Blue 0.2g. 25 g of pullulan polysaccharide, the main film-forming material, and 16.7 g of hydroxypropyl methylcellulose and 8.3 g of sodium alginate, the auxiliary film-forming materials, were placed in a reaction vessel. The stirring rod was activated, the rotation speed was adjusted to 800 r / min, and the mixture was stirred at low speed for 2 minutes to obtain the mixture. Subsequently, 40 g of tadalafil, 1 g of polysorbate 80, 2.5 g of xanthan gum, 3.3 g of crospovidone, 2 g of strawberry flavor, 1 g of sucralose, and 0.2 g of brilliant blue were added to the reaction vessel containing the mixture. The mixture was then stirred at high speed for 20 minutes at a rotation speed of 2000 r / min to obtain a slurry, which was then applied and dried to obtain a microbubble film agent.

[0054] Example 7 The manufacturing process for the microbubble film agent is as follows:

[0055] Ingredients: Melatonin 10g, Pullulan polysaccharide 32.4g, Hydroxypropylcellulose 16.25g, Hydroxypropyl methylcellulose 16.25g, Sodium lauryl sulfate 1g, Propylene glycol alginate 10g, Crospovidone 10g, Strawberry flavor 2g, Sucralose 2g, Brilliant Blue 0.1. 32.4 g of pullulan, the main film-forming material, and 16.25 g of hydroxypropyl cellulose and 16.25 g of hydroxypropyl methylcellulose, the auxiliary film-forming materials, were placed in a reaction vessel. The stirring rod was activated, the rotation speed was adjusted to 600 r / min, and the mixture was stirred at low speed for 5 minutes to obtain the mixture. Subsequently, 10g of melatonin, 1g of sodium lauryl sulfate, 10g of propylene glycol alginate, 10g of crospovidone, 2g of strawberry flavor, 2g of sucralose, and 0.1g of brilliant blue were added to the reaction vessel containing the mixture. The mixture was then stirred at high speed for 15 minutes at a rotation speed of 4000 r / min to obtain a slurry, which was then applied and dried to obtain a microbubble film agent.

[0056] Example 8 The manufacturing process for the microbubble film agent is as follows:

[0057] Ingredients: Menthol 5g, Cineole 5g, Methyl salicylate 5g, Pullulan polysaccharide 30g, Sodium alginate 10g, Maltodextrin 10g, Poloxamer 3g, 10g of pectin, Crospovidone 15g, Strawberry flavor 3g, Stevioside 4g. 30 g of pullulan polysaccharide, the main film-forming material, and 10 g of sodium alginate and 10 g of maltodextrin, the auxiliary film-forming materials, were placed in a reaction vessel. The stirring rod was activated, the rotation speed was adjusted to 600 r / min, and the mixture was stirred at low speed for 5 minutes to obtain the mixture. Subsequently, 5g of menthol, 5g of cineole, 5g of methyl salicylate, 1g of poloxamer, 10g of pectin, 15g of crospovidone, 3g of strawberry flavor, and 4g of stevioside were added to the reaction vessel containing the mixture. The mixture was then stirred at high speed for 12 minutes at a rotation speed of 8000 r / min to obtain a slurry, which was then applied and dried to obtain a microbubble film agent.

[0058] Example 9 The manufacturing process for the microbubble film agent is as follows:

[0059] Ingredients: Sodium hyaluronate 10g, Pullulan polysaccharide 20g, Hydroxypropyl ethylcellulose 10g, Hydroxypropylcellulose 10g, Lecithin 5g, Trehalose 30g, Glycerin 5g, Mint flavor 5g, Sucralose 4g, Tartrazine 1g. 20 g of pullulan polysaccharide, the main film-forming material, and 10 g each of hydroxypropyl ethyl cellulose and hydroxypropyl cellulose, the auxiliary film-forming materials, were placed in a reaction vessel. The stirring rod was activated, the rotation speed was adjusted to 500 r / min, and the mixture was stirred at low speed for 6 minutes to obtain the mixture. Subsequently, 10g of sodium hyaluronate, 5g of lecithin, 30g of trehalose, 5g of glycerin, 5g of mint flavor, 4g of sucralose, and 1g of tartrazine were added to the reaction vessel containing the mixture. The mixture was then stirred at high speed for 10 minutes at a rotation speed of 6000 r / min to obtain a slurry, which was then applied and dried to obtain a microbubble film agent.

[0060] Example 10 The manufacturing process for the microbubble film agent is as follows:

[0061] Ingredients: Rupatadine fumarate 10g, Pullulan polysaccharide 17.4g, Hydroxypropyl methylcellulose 17.5g, Sodium lauryl sulfate 0.1g, Maltitol 25g, HP-β-cyclodextrin 30g. 17.4 g of pullulan polysaccharide, the main film-forming material, and 17.4 g of hydroxypropyl methylcellulose, the auxiliary film-forming material, were placed in a reaction vessel. The stirring rod was activated, the rotation speed was adjusted to 600 r / min, and the mixture was stirred at low speed for 5 minutes to obtain the mixture. Subsequently, 10 g of rupatadine fumarate, 0.1 g of sodium lauryl sulfate, 25 g of maltitol, and 30 g of HP-β-cyclodextrin were added to the reaction vessel containing the mixture. The mixture was then stirred at high speed for 10 minutes at a rotation speed of 5000 r / min to obtain a slurry, which was then applied and dried to obtain a microbubble film agent.

[0062] Example 11 The manufacturing process for the microbubble film agent is as follows:

[0063] Ingredients: Caliprazine hydrochloride 15g, Pullulan polysaccharide 25.8g, Polyvinyl alcohol 25.3g, Polyvinylpyrrolidone 12.7g, Poloxamer 0.1g, Gum arabic 10g, Glyceryl triacetate 10g, BHT 0.1g, Aspartame 1g. 25.8 g of pullulan polysaccharide, the main film-forming material, and 25.3 g of polyvinyl alcohol and 12.7 g of polyvinylpyrrolidone, the auxiliary film-forming materials, were placed in a reaction vessel. The stirring rod was activated, the rotation speed was adjusted to 500 r / min, and the mixture was stirred at low speed for 6 minutes to obtain the mixture. Subsequently, 15 g of the active ingredients, caliprazine hydrochloride, 0.1 g of poloxamer, 10 g of acacia gum, 10 g of glyceryl triacetate, 0.1 g of BHT, and 1 g of aspartame were added to the reaction vessel containing the mixture. The mixture was stirred at high speed for 12 minutes at a rotation speed of 8000 r / min to obtain a slurry, which was then applied and dried to obtain a microbubble film agent.

[0064] Example 12 The manufacturing process for the microbubble film agent is as follows:

[0065] Ingredients: Nitroglycerin 3g, Pullulan polysaccharide 33g, Polyvinyl alcohol 24.75g, Hydroxypropyl starch 8.25g, Fatty acid glycerides 5g, Sucrose 20g, Sodium bisulfite 2g, Sucralose 2g, Mint flavor 2g, 33 g of pullulan polysaccharide, the main film-forming material, and 24.75 g of polyvinyl alcohol and 8.25 g of hydroxypropyl starch, the auxiliary film-forming materials, were placed in a reaction vessel. The stirring rod was activated, the rotation speed was adjusted to 500 r / min, and the mixture was stirred at low speed for 6 minutes to obtain the mixture. Subsequently, 3g of nitroglycerin, 20g of sucrose, 2g of sodium bisulfite, 2g of sucralose, and 2g of mint flavor were added to the reaction vessel containing the mixture. The mixture was then stirred at high speed for 15 minutes at a rotation speed of 5000 r / min to obtain a slurry, which was then applied and dried to obtain a microbubble film agent.

[0066] Example 13 The manufacturing process for the microbubble film agent is as follows:

[0067] Ingredients: Selegiline hydrochloride 5g, Pullulan polysaccharide 40g, Carbomer 4.43g, Hydroxypropyl methylcellulose 35.47g, Poloxamer 5g, Gellan gum 5g, Stevioside 5g, Brilliant Blue 0.1g. 40 g of pullulan polysaccharide, the main film-forming material, and 4.43 g of carbomer and 35.47 g of hydroxypropyl methylcellulose, the auxiliary film-forming materials, were placed in a reaction vessel. The stirring rod was activated, the rotation speed was adjusted to 700 r / min, and the mixture was stirred at low speed for 5 minutes to obtain the mixture. Subsequently, 5 g of the active ingredients selegiline hydrochloride, 5 g of poloxamer, 5 g of gellan gum, 5 g of stevioside, and 0.1 g of brilliant blue were added to the reaction vessel containing the mixture. The mixture was then stirred at high speed for 18 minutes at a rotation speed of 6000 r / min to obtain a slurry, which was then applied and dried to obtain a microbubble film agent.

[0068] Example 14 The specific manufacturing steps for the microbubble film agent are the same as in Example 3, except that the auxiliary film-forming material is replaced with hydroxypropyl ethyl cellulose, and the gram amount of the auxiliary film-forming material itself is not changed.

[0069] Example 15 The specific manufacturing steps for the microbubble film agent are the same as in Example 3, except that the auxiliary film-forming material is replaced with hydroxyethyl cellulose, and the gram amount of the auxiliary film-forming material itself is not changed.

[0070] Example 16 The specific manufacturing steps for the microbubble film agent are the same as in Example 3, except that the auxiliary film-forming material is replaced with polyvinyl alcohol, and the gram amount of the auxiliary film-forming material itself is not changed.

[0071] Example 17 The specific manufacturing steps for the microbubble film agent are the same as in Example 3, except that the auxiliary film-forming material is replaced with polyvinyl alcohol-polyethylene glycol graft copolymer, and the gram amount of the auxiliary film-forming material itself is not changed.

[0072] Example 18 The specific manufacturing steps for the microbubble film agent are the same as in Example 3, except that the auxiliary film-forming materials are replaced with hydroxypropyl ethylcellulose and carbomer, and the gram amount of the auxiliary film-forming materials themselves remains unchanged, with 15g of hydroxypropyl ethylcellulose and 15g of carbomer.

[0073] Example 19 The specific manufacturing steps for the microbubble film agent are the same as in Example 3, except that the auxiliary film-forming materials are replaced with hydroxypropyl ethylcellulose, carbomer, and hydroxypropyl starch, and the gram amount of the auxiliary film-forming materials themselves remains unchanged, with 10 g of hydroxypropyl ethylcellulose, 10 g of carbomer, and 10 g of hydroxypropyl starch.

[0074] Example 20 The specific manufacturing steps for the microbubble film agent are the same as in Example 3, except that the auxiliary film-forming materials are replaced with polyvinyl alcohol and sodium alginate, and the gram amount of the auxiliary film-forming materials themselves remains unchanged, with 15 g of polyvinyl alcohol and 15 g of sodium alginate.

[0075] Example 21 The specific manufacturing steps for the microbubble film agent are the same as in Example 3, except that the auxiliary film-forming materials are replaced with polyvinyl alcohol, sodium alginate, and hydroxypropyl starch, and the gram amounts of the auxiliary film-forming materials themselves remain unchanged, with 10 g of polyvinyl alcohol, 10 g of sodium alginate, and 10 g of hydroxypropyl starch.

[0076] Example 22 The specific manufacturing steps for the microbubble film agent are the same as in Example 3, except that the auxiliary film-forming materials are replaced with hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinyl alcohol, the mass ratio of hydroxypropyl methylcellulose:hydroxypropyl cellulose:polyvinyl alcohol is 1:1:1, the gram amount of the auxiliary film-forming materials themselves is not changed, and the amounts are 10g of hydroxypropyl methylcellulose, 10g of hydroxypropyl cellulose, and 10g of polyvinyl alcohol.

[0077] Example 23 The specific manufacturing steps for the microbubble film agent are the same as in Example 22, except that the mass ratio of hydroxypropyl methylcellulose:hydroxypropyl cellulose:polyvinyl alcohol is adjusted to 2:1:1, the gram amount of the auxiliary film-forming material itself is not changed, and the amount of hydroxypropyl methylcellulose is 15 g, hydroxypropyl cellulose is 7.5 g, and polyvinyl alcohol is 7.5 g.

[0078] Example 24 The specific manufacturing steps for the microbubble film agent are the same as in Example 22, except that the mass ratio of hydroxypropyl methylcellulose:hydroxypropyl cellulose:polyvinyl alcohol is adjusted to 3:1:1, and the gram amount of the auxiliary film-forming material itself is not changed, with 18 g of hydroxypropyl methylcellulose, 6 g of hydroxypropyl cellulose, and 6 g of polyvinyl alcohol.

[0079] Example 25 The specific manufacturing steps for the microbubble film agent are the same as in Example 22, except that the thickener is adjusted to maltose and the amount of the thickener itself is not changed.

[0080] Example 26 The specific manufacturing steps for the microbubble film agent are the same as in Example 22, except that the thickener is adjusted to sorbitol and the amount of the thickener itself is not changed.

[0081] Example 27 The specific manufacturing steps for the microbubble film agent are the same as in Example 22, except that the thickener is adjusted to carrageenan and the gram amount of the thickener itself is not changed.

[0082] Example 28 The specific manufacturing steps for the microbubble film agent are the same as in Example 22, except that the thickeners are adjusted to maltose, mannitol, glucose, dextrin, and gum arabic, and the gram amounts of the thickeners themselves are not changed, with maltose being 6g, mannitol 6g, glucose 6g, dextrin 6g, and gum arabic 6g.

[0083] Example 29 The specific manufacturing steps for the microbubble film agent are the same as in Example 22, except that the thickeners are adjusted to maltose and dextrin, the mass ratio of maltose to dextrin is 2:3, the amount of maltose is not changed, and the amount of dextrin is 12 g.

[0084] Example 30 The specific manufacturing steps for the microbubble film agent are the same as in Example 29, except that the mass ratio of maltose to dextrin is adjusted to 1:3, the amount of the thickener itself remains unchanged, and the amount of maltose is 7.5 g and the amount of dextrin is 22.5 g.

[0085] Example 31 The specific manufacturing steps for the microbubble film agent are the same as in Example 29, except that the surfactant is adjusted to a polysorbate and the gram amount of the surfactant itself is not changed.

[0086] Example 32 The specific manufacturing steps for the microbubble film agent are the same as in Example 29, except that the surfactants are adjusted to poloxamer and lecithin, and the gram amounts of the surfactants themselves are not changed, with 7.5g of poloxamer and 7.5g of lecithin.

[0087] Example 33 The specific manufacturing steps for the microbubble film agent are the same as in Example 29, except that the surfactants are adjusted to sodium lauryl sulfate and polysorbate 80, and the gram amounts of the surfactants themselves are not changed, with 6 g of sodium lauryl sulfate and 9 g of polysorbate 80.

[0088] Example 34 The specific manufacturing steps for the microbubble film agent are the same as in Example 33, except that the surfactants are adjusted to sodium lauryl sulfate and polysorbate 80, and the gram amounts of the surfactants themselves are not changed, with 10 g of sodium lauryl sulfate and 5 g of polysorbate 80.

[0089] Comparative Example 1 The specific manufacturing steps for the microbubble film agent are the same as in Example 33, except that pullulan polysaccharide is not used as the main film-forming material.

[0090] Comparative Example 2 The specific manufacturing steps for the microbubble film agent are the same as in Example 33, except that no auxiliary film-forming materials are used.

[0091] Comparative Example 3 The specific manufacturing steps for the microbubble film agent are the same as in Example 33, except that a surfactant is not used.

[0092] Comparative Example 4 The specific manufacturing steps for the microbubble film agent are the same as in Example 33, except that a thickening agent is not used.

[0093] Comparative Example 5 The specific manufacturing steps for the microbubble film agent are the same as in Example 33, except that after adding the main film-forming material pullulan polysaccharide and the auxiliary film-forming material, the stirring speed is adjusted to 10,000 r / min.

[0094] Comparative Example 6 The specific manufacturing steps for the microbubble film agent are the same as in Example 33, except that after adding the main film-forming material pullulan polysaccharide and the auxiliary film-forming material, the stirring speed is adjusted to 50 r / min.

[0095] Comparative Example 7 The specific manufacturing steps for the microbubble film agent are the same as in Example 33, except that the stirring speed is adjusted to 600 r / min after adding the active ingredients, surfactant, and thickener.

[0096] Comparative Example 8 The specific manufacturing steps for the microbubble film agent are the same as in Example 33, except that the stirring speed is adjusted to 15,000 r / min after adding the active ingredients, surfactant, and thickener.

[0097] Comparative Example 9 In comparison with Example 33, by simply degassing the slurry by vacuum stirring, applying it, and drying it, a film agent free of conventional microbubbles is obtained without performing the two subsequent stirring steps.

[0098] Experimental Example 1 The microbubble film agents obtained in Examples 1-24 and Comparative Examples 1-9 were applied and dried, then sliced. The resulting films were detected, and the detection data is shown in Table 1 below. The dissolution time was detected using the Chinese Pharmacopoeia disintegration time test (General Rule 0921).

[0099] [Table 1] JPEG2026521557000002.jpg231157JPEG2026521557000003.jpg231157JPEG2026521557000004.jpg130157

[0100] Based on the above data, we can draw the following conclusions.

[0101] As can be seen from the data in the table, the effects of the microbubble film agents produced by the solution of the present invention in Examples 1 to 34 are all superior to those of the microbubble film agents produced in Comparative Examples 1 to 9. The microbubble film agent produced according to the solution of Example 33 has the best performance. A specific mass ratio between pullulan polysaccharide and auxiliary polymer material provides good foaming ability, generating a large amount of bubbles by low-speed stirring. Subsequently, by adding a surfactant and a thickener and further high-speed stirring, microbubbles with a diameter of 1 to 100 μm can be formed. As a result, the produced film can exhibit an opaque white appearance even without the addition of titanium dioxide, and can replace titanium dioxide in oral-soluble film agents. The present invention provides a feasible solution to replace titanium dioxide in the formulation of film agents by utilizing the physical phenomenon of light scattering by microbubbles, thereby imparting a white opaque appearance to the film agent, avoiding the addition of any colorants and opacifiers, reducing the impact on active ingredients due to the introduction of new auxiliary agents, and further allowing for a thicker design than ordinary films, providing room for improving drug carrying capacity. Furthermore, the microbubble film agent of this invention dissolves faster than the film agent produced by dry coating of the control group after degassing, but is thicker than conventional film agents, has a better feel, and can further improve discriminability.

[0102] As can be seen by comparing the microbubble film agents of Examples 14-24 and Comparative Examples 1-2, the main film-forming material and auxiliary film-forming material selected in this application have a certain influence on the effect of the final produced microbubble film agent. As can be seen from the experimental data of Example 22, compared to Examples 14-21, the microbubble film agent produced in Example 22 exhibits an opaque white appearance, and the mixing of the main film-forming material pullulan polysaccharide with the auxiliary film-forming materials hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinyl alcohol results in excellent foaming properties, allowing for the generation of smaller microbubbles during subsequent stirring. Therefore, in Example 22, the microbubble film agent produced by mixing the main film-forming material pullulan polysaccharide with the auxiliary film-forming materials hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinyl alcohol has a formed bubble diameter of 55 μm, which is clearly superior to Examples 14-21. Furthermore, because the bubble diameter is smaller, the dissolution time after film formation is also shortened, and as a result, Example 22 shows superior performance in terms of film dissolution time compared to Examples 14-21. As can be seen by comparing Example 22 with Examples 23-24, when pullulan polysaccharide is selected as the main film-forming material and hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinyl alcohol are selected as auxiliary film-forming materials, the mass ratio between the auxiliary film-forming materials also affects the effect of the microbubble film agent. As can be seen from the experimental data, when the mass ratio between the auxiliary film-forming materials is 1:1:1, the manufactured microbubble film agent has excellent foaming properties, so a large amount of bubbles can be generated during stirring, and a second high-speed stirring forms uniform and dense microbubbles, resulting in the manufactured film exhibiting an opaque white color. This is because, through the creative work of the present invention, appropriate auxiliary film-forming materials are selected and the pullulan polysaccharide and auxiliary film-forming materials satisfy the appropriate mass ratio, after the two are uniformly mixed, good foaming properties can be obtained by low-speed stirring, and as a result, a large amount of uniform microbubbles can be generated during subsequent high-speed stirring.As can be seen from the experimental data of Examples 14 to 24, when hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinyl alcohol are selected as auxiliary film-forming materials, and the mass ratio of pullulan polysaccharide:hydroxypropyl methylcellulose:hydroxypropyl cellulose:polyvinyl alcohol is 2:1:1:1, uniform microbubbles can be generated in the produced film. This is because if the proportion of pullulan polysaccharide is too high, the physical performance of the film formation deteriorates, and if the proportion of pullulan polysaccharide is too low, it becomes difficult to form a two-phase mixed interface, and a large number of bubbles are not generated.

[0103] As can be seen by comparing Examples 24-30 with Comparative Example 4, the selection of a thickening agent is extremely important for this invention. As can be seen from the experimental data of Examples 24-30, when maltose and dextrin are selected as thickening agents, the manufactured microbubble film agent is clearly superior in terms of bubble diameter and film dissolution time compared to other options. In Example 29, the bubble diameter was 55 μm and the film dissolution time was 26 s, which is superior to Examples 24-28. Therefore, it can be seen that the manufactured microbubble film agent has the optimal effect only when a mixture of maltose and dextrin is selected as the thickening agent. On the other hand, as can be seen by comparing Examples 29 to 30, the mass ratio of maltose to dextrin is also very important for this invention. As can be seen from the experimental data, when the mass ratio of maltose to dextrin in Example 30 is 1:3, the bubble diameter of the produced microbubble film agent is inferior to the bubble diameter when the mass ratio of maltose to dextrin in Example 29 is 2:3, and after the microbubbles are generated, the microbubbles themselves have a certain degree of instability. In this invention, the stability of microbubbles is improved by adding a thickening agent, and the mass ratio of the added thickening agent to the total mass of the main film-forming material pullulan and the auxiliary film-forming material is limited to a specific range, and the most stable microbubbles are obtained only when the mass ratio of the total mass of the main film-forming material pullulan and the auxiliary film-forming material to the thickening agent is 20:1 to 1:1, preferably 10:1 to 1.2:1. This is because the thickening agent absorbs a large amount of water in the mixture, improving the viscosity of the mixture, improving the mechanical strength of the bubble film, and suppressing bubble contraction and liquid penetration, thereby improving bubble stability. This is because if the proportion of the thickening agent is too high, the mixture becomes excessively viscous, which is unfavorable for subsequent high-speed stirring, and the corresponding film-forming material is insufficient, making film formation unfavorable. If the proportion of the thickening agent is too low, the viscosity of the mixture is low, the bubble stabilization time is short, and this affects the size and uniformity of microbubbles in the film manufacturing process.

[0104] As can be seen by comparing Examples 31-34 with Comparative Example 3, the selection of surfactants is extremely important for this invention. As can be seen from Example 33, when sodium lauryl sulfate and polysorbate 80 are selected as surfactants, the resulting microbubble film agent has a clearly superior bubble diameter compared to the other examples and comparative examples. This is because, in this invention, adding surfactants and stirring at high speed reduces the surface tension at the gas-liquid interface, allowing for the formation of a thinner film, which is advantageous for generating richer bubbles.

[0105] As can be seen by comparing Example 33 with Comparative Examples 5-8, in this invention, the stirring speed performed after adding the main film-forming material pullulan and the auxiliary film-forming material has a certain effect on the effect of the microbubble film agent. As can be seen from the experimental data of Example 33, when the stirring speed is within an appropriate range, the bubble diameter of the formed microbubbles is clearly superior to that of Comparative Examples 6-9. Therefore, only when the pullulan and the auxiliary film-forming material are mixed and stirred at a low speed in the range of 100-800 r / min can both generate a large amount of uniform bubbles, and then microbubbles can be formed by high-speed stirring at 2000-12000 r / min. The stirring speed is very important in this invention because if the stirring speed is too low, it is unfavorable for sufficient mixing between the pullulan polysaccharide and the auxiliary film-forming material and affects subsequent stirring, and if the stirring speed is too high, many non-uniform bubbles of varying sizes are generated at the moment of stirring, affecting the uniformity of the microbubbles and the effect of the film agent.

[0106] As can be seen by comparing Example 33 with Comparative Examples 1-9, in this application, the diameter of the microbubbles affects the appearance of the film, and it is very important for this application that the size of the microbubbles is uniform and the diameter is less than 100 μm. This is because the opaque white color is due to the light scattering effect of the microbubbles, and the smaller the diameter of the bubbles, the more scattered light there is, making the film appear more opaque, while if the diameter of the bubbles is too large, the more transmitted light there is, making it appear more transparent.

[0107] The technical features of the embodiments described above can be combined in any way, and for the sake of brevity, not all possible combinations of the technical features in the embodiments described above have been described. However, as long as these combinations of technical features are inconsistent, they should be considered to fall within the scope described herein.

[0108] The above examples describe only a few embodiments of the present application, and although these descriptions are specific and detailed, they should not be interpreted as limiting the scope of the patent of this application. Furthermore, a person skilled in the art may make various modifications and improvements as long as they do not deviate from the spirit of this application, and both such modifications and improvements fall within the scope of protection of this application. Therefore, the scope of protection of the patent of this application should be based on the attached claims.

Claims

1. A microbubble film agent that replaces titanium dioxide, and when expressed by mass percentage, mainly, Active ingredients 0.01% to 40%, Polymer film forming material 20% to 80%, Surfactants 0.1% to 20%, and Made from raw materials containing 2.5% to 30% thickeners. The polymer film-forming material comprises pullulan polysaccharide as the main film-forming material and an auxiliary film-forming material, wherein the mass ratio of pullulan as the main film-forming material to the auxiliary film-forming material is 1:3 to 3:1, and is a microbubble film agent that replaces titanium dioxide.

2. The microbubble film agent according to claim 1, wherein the auxiliary film-forming material comprises one or more of the following: hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinyl alcohol, hydroxypropyl cellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol-polyethylene glycol graft copolymer, maltodextrin, polyethylene oxide, sodium alginate, hydroxypropyl starch, and carbomer.

3. The microbubble film agent according to claim 2, wherein the auxiliary film-forming material comprises one or more of the following: hydroxypropyl methylcellulose, polyvinyl alcohol, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol-polyethylene glycol graft copolymer, maltodextrin, sodium alginate, and hydroxypropyl starch.

4. The microbubble film agent according to any one of claims 2 to 3, wherein the auxiliary film-forming material is hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinyl alcohol.

5. The microbubble film agent according to claim 4, wherein the mass ratio of the pullulan polysaccharide to the auxiliary film-forming material is 2:1 to 1:

3.

6. The microbubble film agent according to any one of claims 4 to 5, wherein the mass ratio of the pullulan polysaccharide to the auxiliary film-forming material is 2:

3.

7. The microbubble film agent according to claim 4, wherein the mass ratio of hydroxypropyl methylcellulose:hydroxypropyl cellulose:polyvinyl alcohol is 1:1:

1.

8. The aforementioned thickening agent is one or more of the following: low molecular weight thickening agents and high molecular weight suspension aids. The low molecular weight thickener is one or more of the following: sucrose, maltose, fructose, mannitol, glucose, lactose, trehalose, xylitol, maltitol, erythritol, sorbitol, lactitol, cetyl palmitate, and stearic acid. The microbubble film agent according to any one of claims 1 to 7, wherein the polymer suspension aid is one or more of the following: gum arabic, agar, carrageenan, dextrin, gellan gum, guar gum, pectin, propylene glycol alginate, sodium carboxymethylcellulose, starch, gelatin, tragacanth gum, xanthan gum, and gum.

9. The microbubble film agent according to claim 8, wherein the mass ratio of the polymer film-forming material to the thickener is 20:1 to 1:

1.

10. The low molecular weight thickener is one or more of the following: maltose, mannitol, glucose, lactose, trehalose, xylitol, maltitol, and erythritol. The microbubble film agent according to any one of claims 8 to 9, wherein the polymer suspension aid may be one or more of carrageenan, dextrin, gellan gum, guar gum, pectin, propylene glycol alginate, sodium carboxymethylcellulose, xanthan gum, and rubber.

11. The microbubble film agent according to claim 10, wherein the thickening agent is a mixture of the low molecular weight thickening agent maltose and the high molecular weight suspension aid dextrin.

12. The microbubble film agent according to any one of claims 10 to 11, wherein the mass ratio of maltose to dextrin is 2:

3.

13. The microbubble film agent according to any one of claims 10 to 12, wherein the mass ratio of the polymer film-forming material to the thickening agent is 10:1 to 1.2:

1.

14. The microbubble film agent according to any one of claims 1 to 13, wherein the surfactant is one or more of sodium lauryl sulfate, polysorbate, poloxamer, lecithin, and fatty acid glycerides.

15. The microbubble film agent according to claim 14, wherein the surfactant is sodium lauryl sulfate and polysorbate 80.

16. The microbubble film agent according to any one of claims 14 to 15, wherein the mass ratio of sodium lauryl sulfate to polysorbate 80 is 2:

3.

17. The microbubble film agent according to any one of claims 1 to 16, further comprising 0 to 35% of other auxiliary agents, wherein the other auxiliary agents comprise one or more of disintegrants, plasticizers, stabilizers, colorants, and flavoring agents.

18. The microbubble film agent according to claim 17, wherein the disintegrant may be one or more of crospovidone, sodium carboxymethylcellulose, and corn starch.

19. The microbubble film agent according to any one of claims 17 to 18, wherein the plasticizer is one or more of glycerin, PEG, and glyceryl triacetate.

20. The stabilizer is one or more of the following: hydroxypropyl-β-cyclodextrin, hydroxybutyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, BHT, EDTA, BHA, sodium bisulfite, and sodium pyrosulfite. The aforementioned coloring agent is one or more of the following: ferric oxide, tartrazine, amaranth, and brilliant blue. The microbubble film agent according to any one of claims 17 to 19, wherein the flavoring agent is one or more of sucralose, aspartame, stevioside, mint flavor, strawberry flavor, and orange flavor.

21. A method for producing a microbubble film agent according to any one of claims 1 to 20, The process involves sequentially adding pullulan polysaccharide and polymer film-forming material, and stirring at a low speed of 100 to 800 r / min for 2 to 30 min to obtain a mixture. A manufacturing method comprising the steps of sequentially adding an active ingredient, a surfactant, and a thickener to a mixture, stirring at high speed for 2 to 20 minutes at a stirring speed of 2,000 to 12,000 r / min, and then coating and drying.

22. The manufacturing method according to claim 21, wherein the mixture is obtained by low-speed stirring at a stirring speed of 200 to 600 r / min for 5 to 20 min.

23. The manufacturing method according to any one of claims 21 to 22, wherein high-speed stirring is performed for 3 to 15 minutes at a stirring speed of 3,000 to 8,000 r / min.

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