A veterinary torsemide orally disintegrating film and a preparation method thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a torasemide oral dissolving film and a preparation method thereof. The oral dissolving film comprises torasemide, sodium hydroxide, hydroxypropyl methyl cellulose, polyvinyl alcohol, glycerol and sucralose, wherein the polyvinyl alcohol is polyvinyl alcohol 0588 type with a degree of polymerization of 500. The oral dissolving film is suitable for oral administration of mammals, especially in the field of veterinary administration, and has the advantages of convenient administration, rapid effect and good compliance.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to an orally disintegrating film formulation, and more specifically, to an orally disintegrating film with torasemide as the active ingredient and its preparation method. The orally disintegrating film can be used for oral administration in mammals, and is particularly suitable for veterinary drug administration. Background Technology

[0002] Torasemide is a novel, long-acting loop helix diuretic approved by the US FDA in 1993. Clinically, it is widely used to treat edema caused by heart failure, kidney disease, and cirrhosis. As an upgraded product of furosemide, which was launched in 1968, torasemide has advantages such as high bioavailability (80-90%), long duration of action (half-life of approximately 3.5 hours), and weaker potassium excretion. It also possesses certain anti-aldosterone and anti-myocardial fibrosis effects.

[0003] Currently, torasemide is mainly available in oral tablets and injectable solutions. While tablets are convenient, they present challenges such as difficulty swallowing, slow onset of action, and a significant first-pass effect, leading to poor adherence, especially in elderly patients with swallowing disorders, children, and animals. Injectable solutions, while fast-acting, are limited to use in medical institutions, preventing patients from self-administering them and thus restricting their application.

[0004] Developing torasemide into an orally disintegrating film for veterinary use has significant practical implications. Orally disintegrating films disintegrate within seconds to tens of seconds in the oral cavity, allowing the drug to be absorbed through the oral mucosa, partially bypassing the first-pass effect of the liver, resulting in rapid onset of action and improved bioavailability. For pets such as dogs and cats, the film eliminates the need for oral administration or forced injection; administration is achieved simply by applying it to the oral mucosa, greatly reducing stress and administration difficulty for animals, and significantly improving the convenience and compliance of veterinary drug administration. Furthermore, orally disintegrating films offer accurate dosage, are easy to carry in divided doses, and are suitable for long-term medication management in pets.

[0005] A search revealed no literature reports on torasemide orally disintegrating films. Among existing technologies related to diuretic orally disintegrating films, Korean patent KR1020210078278A discloses an oral disintegrating film that uses ethanol to dissolve furosemide, with HPMC as the film-forming material. Another US patent application, US20230047314A1, relates to an oral film formulation, but it is not a fast-dissolving film; the time for 80% of the active agent to be released is approximately 5 to 20 minutes, which does not meet the requirement for rapid disintegration and drug release in orally disintegrating films. Therefore, the aforementioned existing technologies are difficult to directly apply to the development of torasemide orally disintegrating films.

[0006] Therefore, developing a torasemide oral instant-dissolving film suitable for veterinary use and solving key technical problems such as its stability during film formation, drug crystallization, and palatability has significant practical value and market prospects. Summary of the Invention

[0007] To address the technical problems of limited veterinary formulations of torasemide and the lack of a market for oral dissolving films in existing technologies, this invention provides an oral dissolving film for torasemide, comprising torasemide, sodium hydroxide, hydroxypropyl methylcellulose, polyvinyl alcohol, glycerin, and sucralose.

[0008] Torasemide is the active pharmaceutical ingredient in the orally disintegrating film. Torasemide is a loop helix diuretic and can be used for related diseases or pathological conditions requiring diuretic treatment. This invention does not specifically limit the source, crystal form, particle size, or specific manufacturer of the torasemide, as long as the torasemide used is suitable for preparing the orally disintegrating film described in this invention.

[0009] The term "oral dissolving film" as used herein refers to a thin-film formulation in which a drug active ingredient is dispersed or dissolved in a membrane matrix using a water-soluble or swellable film-forming material as the main film-forming carrier. Upon contact with saliva or other oral fluids in the mouth, the oral dissolving film can rapidly wet, swell, disintegrate, dissolve, or release the drug, thus making it suitable for oral administration. Unless otherwise stated, the terms "oral dissolving film," "oral fast-dissolving film," and "oral film" used in this invention can all be used to refer to film-form oral formulations having the above characteristics.

[0010] The orally dissolving film can be prepared as a single-dose film, or it can be prepared in multiple specifications according to the actual dosage. The required drug dosage can be obtained by controlling the area, thickness, drug loading per unit area, or cutting size of the film.

[0011] In this document, unless otherwise stated, the terms 'oral dissolving film', 'instant oral dissolving film', and 'oral film' are used interchangeably. Regarding sodium hydroxide The orally dissolving membrane of the present invention contains sodium hydroxide. The sodium hydroxide serves two purposes: firstly, as a pH adjuster to regulate the acidity or alkalinity of the raw material solution containing torasemide; secondly, by adjusting the pH of the formulation system, it can improve the solubility of torasemide in the film-forming solution, thereby facilitating the formation of a homogeneous film-forming solution.

[0012] The term "pH adjuster" as used herein refers to a substance capable of adjusting the acidity or alkalinity of a formulation system to achieve a suitable pH range. The pH adjuster is not limited to substances with simple buffering properties; in this invention, sodium hydroxide can also affect the solubility of torasemide by altering the acid-base environment of the system.

[0013] In some embodiments, the sodium hydroxide is 0.23 to 0.27 parts by weight; preferably 0.25 parts.

[0014] By controlling the amount of sodium hydroxide used, this invention can improve the solubility of torasemide while reducing the adverse effects that may occur due to excessively alkaline conditions, thereby facilitating the preparation of a film-forming solution suitable for subsequent film-forming processes.

[0015] Regarding hydroxypropyl methylcellulose The hydroxypropyl methylcellulose (HPMC) is a film-forming material and can be used as one of the main membrane matrices for oral dissolving membranes.

[0016] HPMC exhibits excellent water solubility, film-forming properties, and processing characteristics, enabling it to form solutions or dispersions with a certain viscosity and film-forming ability in aqueous systems. Using HPMC can provide the necessary membrane structure for film-forming agents and improve their integrity, uniformity, and processing adaptability.

[0017] In some embodiments, the hydroxypropyl methylcellulose is 12 parts by weight.

[0018] The HPMCs described herein can be selected according to actual formulation requirements, choosing the appropriate HPMC model or specification for pharmaceutical film preparation. Unless otherwise specified, this invention does not consider a specific manufacturer, brand name, or specific viscosity grade as essential technical features.

[0019] Regarding polyvinyl alcohol Polyvinyl alcohol (PVA) is another film-forming material, which together with hydroxypropyl methylcellulose forms a composite film-forming system.

[0020] Polyvinyl alcohol (PVA) possesses excellent water solubility, film-forming properties, and mechanical properties. By combining PVA with hydroxypropyl methylcellulose, the film-forming properties, flexibility, mechanical strength, and oral solubility of the film can be adjusted.

[0021] In some embodiments, the polyvinyl alcohol is 3.75 to 4.25 parts by weight; preferably 4 parts.

[0022] In some embodiments, the polyvinyl alcohol is polyvinyl alcohol 0588. The polyvinyl alcohol 0588 can be a polyvinyl alcohol with a degree of polymerization of approximately 500 and a degree of alcoholysis of approximately 88%.

[0023] The "degree of hydrolysis" of polyvinyl alcohol (PVA) as described in this article refers to the extent to which polyvinyl acetate is converted into PVA through alcoholysis; the "degree of polymerization" is used to characterize the average number of repeating structural units in the PVA molecular chain. The degree of polymerization and degree of hydrolysis affect the water solubility, viscosity, film-forming properties, flexibility, and solubility of PVA films.

[0024] Without departing from the technical concept of the present invention, the polyvinyl alcohol may be pharmaceutical grade polyvinyl alcohol that meets the film-forming requirements of the present invention.

[0025] About glycerin The glycerol is used as a plasticizer.

[0026] The term "plasticizer" as used in this article refers to substances that can reduce intermolecular forces in film-forming materials, improve the flexibility and flexural strength of film materials, and reduce the brittleness of film agents. Glycerin has good water solubility and plasticizing effects, which can improve the flexibility of oral films and give the resulting film agents suitable mechanical properties.

[0027] In some embodiments, the glycerol is 4 parts by weight.

[0028] Regarding sucralose The sucralose is used as a flavoring agent to improve the taste of torasemide orally dissolving film and increase the acceptability of oral administration.

[0029] The term "flavoring agents" as used in this article includes sweeteners, flavoring agents, or other suitable taste modifiers that can improve the taste characteristics of pharmaceutical preparations. Sucralose, as a high-sweetness sweetener, can be used to reduce or mask unpleasant tastes that may be produced by the active ingredients in a drug.

[0030] In some embodiments, the sucralose is 1 part by weight.

[0031] Preferred prescription composition In some embodiments, the torasemide orally dissolving film of the present invention comprises, by weight: Two servings of Torasemi; Sodium hydroxide 0.23–0.27 parts; 12 parts of hydroxypropyl methylcellulose; Polyvinyl alcohol 3.75–4.25 parts; 4 parts glycerin; 1 part sucralose.

[0032] In a further embodiment, the sodium hydroxide is 0.25 parts by weight, and the polyvinyl alcohol 0588 type is 4 parts.

[0033] The proportions of the above components can be adjusted according to the target dosage, film specifications, film area, film thickness, and specific target population. Without affecting the technical efficacy of this invention, those skilled in the art can adjust the specifications of the single-dose film and the absolute dosage of each component according to actual formulation requirements.

[0034] The term "parts by weight" as used in this article refers to the relative mass relationship between the components. For example, when the parts by weight of torasemide is set to 2 parts, the parts by weight of other components are determined according to their corresponding mass ratios to torasemide. Using parts by weight to express the formulation composition is beneficial for scaling up or down the formulation between different batches and different single-dose strengths.

[0035] Oral dissolving membrane performance The torasemide orally dissolving film of the present invention has rapid dissolving properties suitable for oral administration.

[0036] The term "dissolution" as used in this article refers to the process by which an oral film, upon contact with saliva or other liquids in the oral cavity, undergoes wetting, swelling, disintegration, dissolution, or structural damage, ultimately losing its complete membrane structure.

[0037] In some embodiments, the single-dose drug film of the orally dissolving film dissolves within 30 seconds after oral administration.

[0038] The dissolution time can be determined according to applicable drug quality standards, enterprise internal control standards, or corresponding formulation evaluation methods. This invention does not impose specific limitations on the testing instruments and methods, as long as they can reasonably evaluate the dissolution performance of the film under oral administration conditions.

[0039] The oral dissolving film of this invention also possesses suitable mechanical properties. These "mechanical properties" include, but are not limited to, the film's resistance to folding, flexibility, integrity, tear resistance, and its ability to maintain its structural integrity during cutting, packaging, transportation, and use.

[0040] By adjusting the composition and dosage of film-forming materials and plasticizers, oral dissolving films can maintain rapid melting performance while possessing suitable mechanical properties.

[0041] Preparation method of oral dissolving film This invention also provides a method for preparing a torasemide orally dissolved film, comprising the following steps: (1) Add polyvinyl alcohol to a portion of purified water, stir to dissolve, and obtain an excipient solution; (2) Add sodium hydroxide to part of purified water, stir to dissolve, add torasemide and stir to dissolve, then add sucralose and glycerol, mix well to obtain the raw material solution; (3) Add the raw material solution to the excipient solution, mix evenly, add hydroxypropyl methylcellulose, stir to dissolve, and obtain the film-forming solution; (4) The film-forming solution is defoamed under vacuum, and then cast, dried and cut to obtain the torasemil oral solution film.

[0042] The "film-forming solution" mentioned in this article refers to a liquid system that contains active pharmaceutical ingredients, film-forming materials, and other pharmaceutical excipients and can form a film through methods such as casting.

[0043] The term "casting" as used in this article refers to a film-forming method in which a film-forming solution is spread on the surface of a carrier in a continuous or intermittent manner, and a film with a predetermined thickness and quality is formed by controlling the doctor blade height, casting speed, and drying conditions.

[0044] By preparing excipient solutions and raw material solutions separately, the components can be fully dissolved or dispersed, which helps to improve the uniformity of the final film-forming solution.

[0045] In some embodiments, the film-forming solution is vacuum defoamed before casting to reduce air bubbles in the film-forming solution, thereby reducing the possibility of problems such as pores, uneven thickness, surface defects, or uneven mechanical properties in the film.

[0046] In some embodiments, the vacuum degree of the vacuum defoaming is ≤-0.1MPa, and the standing time is ≥12 hours.

[0047] In some embodiments, the casting speed is 0.30 m / min, the scraper height is 0.35 mm, and the drying temperature is 45–50 °C.

[0048] The process parameters described in this article can be adjusted appropriately based on the film-forming equipment, the viscosity of the film-forming solution, the film thickness, the ambient temperature and humidity, and the specifications of the target product.

[0049] pH of the membrane forming solution and moisture content of the membrane agent In some embodiments, the pH of the film-forming solution is 7.5 to 8.5.

[0050] By controlling the pH of the film-forming solution, a suitable dissolution state of torasemil can be maintained, which is beneficial for obtaining a uniform film-forming solution.

[0051] The pH values ​​described herein can be determined using appropriate pharmaceutical or formulation analysis methods. Unless otherwise specified, the pH range refers to the pH range measured after the film-forming solution has been prepared and before casting.

[0052] In some embodiments, the moisture content of the oral dissolving film is 4-6%.

[0053] An appropriate moisture content is beneficial for maintaining the physical state and mechanical properties of oral dissolving films. Too low a moisture content may increase the film's brittleness, while too high a moisture content may affect the film's storage stability, mechanical properties, and packaging suitability. Therefore, the degree of dryness can be adjusted according to the film's composition and storage requirements.

[0054] Oral administration and application The present invention also provides the use of the torasemide orally disintegrating membrane in the preparation of torasemide formulations for oral administration to mammals.

[0055] The term "mammal" as used herein includes, but is not limited to, humans and various non-human mammals. In some embodiments, the mammal is an animal.

[0056] The orally dissolving film described in this invention is particularly suitable for veterinary drug administration. Because of its small film volume, portability, elimination of the need for large amounts of liquid to aid swallowing, and rapid dissolution in the oral cavity, the orally dissolving film is suitable for animals requiring oral administration of torasemide.

[0057] In some embodiments, the animal is a dog or a cat. The torasemide orally dissolving film can be used for oral administration to animals such as dogs or cats.

[0058] This invention does not limit the application of the oral dissolving film to dogs or cats. Under appropriate dosage and administration methods, it can also be used in other mammals that require oral administration of torasemide.

[0059] The term "oral administration for veterinary use" as used in this article refers to a method of administration in which a drug preparation suitable for animal use is administered through the animal's mouth, allowing the active drug components to enter the animal's body and exert their corresponding pharmacological effects.

[0060] Beneficial effects of the present invention Compared with the prior art, the present invention has at least the following beneficial effects: This invention provides an orally disintegrating film formulation of torasemide. By preparing torasemide into an orally disintegrating film, this invention avoids the dependence on swallowing ability during administration found in traditional tablets, thus expanding the dosage form options for oral torasemide formulations.

[0061] This invention improves the solubility of torasemil in the membrane-forming system. By using sodium hydroxide to adjust the pH of the system and creating a suitable alkaline environment, the solubility of torasemil in the membrane-forming solution is enhanced, resulting in a homogeneous membrane-forming system.

[0062] A suitable composite film-forming system was constructed. This invention uses hydroxypropyl methylcellulose and polyvinyl alcohol to form a composite film, and achieves a balance between the film-forming properties, mechanical properties and rapid solubility of the film agent by selecting an appropriate type and amount of polyvinyl alcohol.

[0063] It possesses good mechanical properties of the film. By rationally combining components such as polyvinyl alcohol and glycerin, the risk of film brittleness is reduced, giving the film suitable flexibility and integrity, thereby meeting the mechanical performance requirements during cutting, packaging, transportation, and use.

[0064] It exhibits rapid dissolution properties. The orally dissolving film of the present invention can dissolve rapidly under oral administration conditions. In some embodiments, the dissolution time of a single dose film does not exceed 30 seconds, thereby improving the convenience of oral administration.

[0065] The preparation process is suitable for industrial-scale film production. This invention employs process steps such as solution preparation, vacuum defoaming, casting, drying, and cutting. The process route is clear and facilitates scale-up and continuous production using conventional film production equipment.

[0066] Wide range of applications. The torasemide orally disintegrating film of this invention can be used for oral administration in mammals, and is particularly suitable for veterinary drug delivery. In veterinary applications, the specifications of single-dose films can be designed according to different animal species, weights, and administration requirements, making it especially suitable for oral administration in animals such as dogs and cats.

[0067] It facilitates dosage standardization and portability. Orally disintegrating films can be cut to form single-dose films according to the target dosage and are individually packaged, which is beneficial for dosage control, portability and use.

[0068] In summary, this invention provides a torasemide orally soluble film with good film-forming properties, mechanical properties, and rapid solubility through a combination of torasemide, sodium hydroxide, hydroxypropyl methylcellulose, polyvinyl alcohol, glycerol, and sucralose, combined with a corresponding preparation process. This provides a new formulation for oral administration of torasemide, and is particularly suitable for the field of oral administration in veterinary medicine. Attached Figure Description

[0069] Figure 1 The image shows a comparison of the appearance of the semi-finished products after casting and drying in Examples 3-3 and 3-4. In Example 3-3, the film surface is uniform and there is no crystal precipitation, while in Example 3-4, crystals are precipitated. Detailed Implementation

[0070] To more clearly illustrate the technical solution of the present invention, the present invention will be further described below with reference to embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. The scope of protection of the present invention is defined by the claims. Experimental methods in the embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. After reading the disclosure in this specification, those skilled in the art can make reasonable combinations, substitutions, and adjustments to the specific parameters, steps, and sequences; such modifications that do not depart from the essential spirit of the present invention all fall within the scope of protection of the present invention. Example 1: Standard Formulation and Preparation

[0071] The initial excipients selected for this product are: sodium hydroxide, hydroxypropyl methylcellulose, polyvinyl alcohol, glycerin, and sucralose. Sample preparation is carried out as detailed in the table below.

[0072] Table 1

[0073] Note 1: The solvent used in the process and ultimately removed is purified water, which is removed during the drying process.

[0074] ① Weigh the raw and auxiliary materials according to the prescription amount.

[0075] ② Weigh 45% purified water at room temperature, stir to form a vortex, slowly add polyvinyl alcohol, stir to dissolve, and obtain the excipient solution for later use.

[0076] ③ Weigh 50% purified water at room temperature, stir to form a vortex, add sodium hydroxide, stir to dissolve, add torasemide, stir to dissolve, add sucralose, stir to dissolve, add glycerol, stir to disperse evenly, and obtain the raw material solution for later use.

[0077] ④ Slowly add the raw material solution to the excipient solution while maintaining a constant stirring speed. Continue stirring until a homogeneous solution is formed. Then, slowly add hydroxypropyl methylcellulose. After all the cellulose has been added, rinse the raw material container and the inner wall of the mixing tank with the remaining 5% purified water to ensure all the raw material has been transferred to the mixing tank and that the hydroxypropyl methylcellulose can be thoroughly stirred. After stirring and dissolving, perform vacuum defoaming according to the solution state (vacuum degree: ≤-0.1MPa, standing time ≥12h, until bubbles disappear). The measured pH value is 8.0, indicating the final product is ready.

[0078] ⑤ Turn on the casting machine and adjust the casting speed to a suitable 0.30 m / min and the scraper height to 0.35 mm; set the drying temperature to 45~50℃ and the winding tension of the carrier tape to 8 kg to carry out the casting and drying of the liquid material. Check the moisture content to 5% and then proceed with inner packaging.

[0079] ⑥ Set an appropriate cutting speed to cut the film into single-dose film of the target weight. The theoretical cutting size is 20×15mm. Pack it with appropriate inner packaging material, 1 tablet / bag.

[0080] Summary: After testing, all indicators met the quality requirements.

[0081] All raw and auxiliary materials for this project are registered and filed. The information on the raw and auxiliary materials is shown in the table below.

[0082] Table 2

[0083] The quality control of torasemide, hydroxypropyl methylcellulose, polyvinyl alcohol, glycerin, sodium hydroxide, and sucralose raw materials and excipients used in torasemide orally disintegrating films is carried out. The analytical methods used are all derived from the 2025 edition of the Chinese Pharmacopoeia, BP2021 / EP10.6, USP43-NF37, JP17 and the manufacturer's standards, and comply with the relevant guidelines issued by the State Drug Administration and ICH and the general requirements of the 2025 edition of the Chinese Pharmacopoeia.

[0084] Example 2: Selection of pH Adjuster Disodium hydrogen phosphate is less irritating to the oral cavity than sodium hydroxide. To screen for a more suitable pH adjuster, a comparative study was conducted on disodium hydrogen phosphate and sodium hydroxide. Sample preparation details are shown in the table below.

[0085] Table 3

[0086] Note 1: The solvent used in the process and ultimately removed is purified water, which is removed during the drying process.

[0087] ① Weigh the raw and auxiliary materials according to the prescription amount.

[0088] ② Weigh 45% purified water at room temperature, stir to form a vortex, slowly add polyvinyl alcohol, stir to dissolve, and obtain the excipient solution for later use.

[0089] ③ Weigh 50% purified water at room temperature, stir to form a vortex, add disodium hydrogen phosphate / sodium hydroxide, stir to dissolve, then add torasemide, stir to dissolve, then add sucralose, stir to dissolve, then add glycerol, stir to disperse evenly to obtain the raw material solution, for later use.

[0090] Summary: In Example 2-1, disodium hydrogen phosphate was used as a pH adjuster to prepare the raw material solution. The raw material solution was turbid and did not completely dissolve. In Example 2-2, sodium hydroxide was used as a pH adjuster to prepare the raw material solution. The raw material was completely dissolved and the solution was clear. It was initially determined that disodium hydrogen phosphate was not suitable. Sodium hydroxide was selected as the pH adjuster for further investigation. Example 3: Investigation of Sodium Hydroxide Dosage

[0091] Sodium hydroxide is a strong base. Adjusting the pH of the system can improve the solubility of the active pharmaceutical ingredient. This experiment investigated the amount of sodium hydroxide to be added and preliminarily determined the appropriate amount in the formulation, as shown in the table below.

[0092] Table 4

[0093] Note 1: The solvent used in the process and ultimately removed is purified water, which is removed during the drying process.

[0094] ① Weigh the raw and auxiliary materials according to the prescription amount.

[0095] ② Weigh 45% purified water at room temperature, stir to form a vortex, slowly add polyvinyl alcohol, stir to dissolve, and obtain the excipient solution for later use.

[0096] ③ Weigh 50% purified water at room temperature, stir to form a vortex, add sodium hydroxide, stir to dissolve, add torasemide, stir to dissolve, add sucralose, stir to dissolve, add glycerol, stir to disperse evenly, and obtain the raw material solution for later use.

[0097] ④ Slowly add the raw material solution to the excipient solution while maintaining a constant stirring speed. Continue stirring until a homogeneous solution is formed. Then, slowly add hydroxypropyl methylcellulose. After all the solution has been added, rinse the raw material container and the inner wall of the mixing tank with the remaining 5% purified water to ensure that all the raw material has been transferred to the mixing tank and that the hydroxypropyl methylcellulose can be thoroughly stirred. After stirring and dissolving, perform vacuum defoaming according to the solution state (vacuum degree: ≤-0.1MPa, standing time ≥12h, until the bubbles disappear). Measure the pH value.

[0098] Summary: In Example 3-1, the raw material solution was turbid and not completely dissolved, so no further processing was performed; the samples prepared in Examples 3-2 and 3-3 were good; in Example 3-4, crystals precipitated after casting and drying, so no further processing was performed. The preliminary result is that the amount of sodium hydroxide used is 0.23~0.27 g, preferably 0.25 g. Example 4: Investigation of Film-Forming Agent Types

[0099] Polyvinyl alcohol (PVA) is a film-forming agent, and its performance is affected by the degree of polymerization and the degree of hydrolysis. PVA 0588 (degree of polymerization 500) and PVA 1788 (degree of polymerization 1700) both have a degree of hydrolysis of 88%. A comparative study was conducted to select a suitable film-forming material, and samples were prepared. Details are shown in the table below.

[0100] Table 5

[0101] Note 1: The solvent used in the process and ultimately removed is purified water, which is removed during the drying process.

[0102] ① Weigh the raw and auxiliary materials according to the prescription amount.

[0103] ② Weigh 45% purified water at room temperature, stir to form a vortex, slowly add polyvinyl alcohol, stir to dissolve, and obtain the excipient solution for later use.

[0104] ③ Weigh 50% purified water at room temperature, stir to form a vortex, add sodium hydroxide, stir to dissolve, add torasemide, stir to dissolve, add sucralose, stir to dissolve, add glycerol, stir to disperse evenly, and obtain the raw material solution for later use.

[0105] ④ Slowly add the raw material solution to the excipient solution while maintaining a constant stirring speed. Continue stirring until a homogeneous solution is formed. Then, slowly add hydroxypropyl methylcellulose. After all the solution has been added, rinse the raw material container and the inner wall of the mixing tank with the remaining 5% purified water to ensure all the raw material has been transferred to the mixing tank and that the hydroxypropyl methylcellulose can be thoroughly stirred. After stirring and dissolving, perform vacuum defoaming according to the solution state (vacuum degree: ≤-0.1MPa, standing time ≥12h, until bubbles disappear). The pH should be measured to be 7.5~8.5, which is the optimal value.

[0106] ⑤ Turn on the casting machine, adjust the casting speed and scraper height to the same settings, and set the drying temperature to 45~50℃ to carry out the casting and drying of the liquid material. Check the moisture content to 4~6%, and then proceed with inner packaging.

[0107] ⑥ Cut the film into single-dose films of the target weight, with a theoretical cutting size of 20×15mm. Pack it with suitable inner packaging material, 1 tablet / bag.

[0108] Summary: Example 4-1 had a melting time of 20 seconds, Example 4-2 had a melting time of 50 seconds, and the melting time requirement for this product should be within 30 seconds. Based on the combined melting time results, polyvinyl alcohol type 0588 was initially selected. Example 5: Investigation of Film-Forming Agent Dosage

[0109] This product formulation contains sodium hydroxide, and the chemical stability of polyvinyl alcohol (PVA) is easily affected by alkaline environments. To evaluate the effect of alkaline conditions on PVA, an investigation was conducted on the dosage and solution stability of PVA. The state of the film-forming solution under different dosages of PVA was examined, and the stability of the film-forming solution in the alkaline system was evaluated to screen for a suitable dosage of PVA. Sample preparation was carried out, as detailed in the table below.

[0110] Table 6

[0111] Note 1: The solvent used in the process and ultimately removed is purified water, which is removed during the drying process.

[0112] ① Weigh the raw and auxiliary materials according to the prescription amount.

[0113] ② Weigh 45% purified water at room temperature, stir to form a vortex, slowly add polyvinyl alcohol, stir to dissolve, and obtain the excipient solution for later use.

[0114] ③ Weigh 50% purified water at room temperature, stir to form a vortex, add sodium hydroxide, stir to dissolve, add torasemide, stir to dissolve, add sucralose, stir to dissolve, add glycerol, stir to disperse evenly, and obtain the raw material solution for later use.

[0115] ④ Slowly add the raw material solution to the excipient solution while maintaining a constant stirring speed. Continue stirring until a homogeneous solution is formed. Then, slowly add hydroxypropyl methylcellulose. After all the solution has been added, rinse the raw material container and the inner wall of the mixing tank with the remaining 5% purified water to ensure all the raw material has been transferred to the mixing tank and that the hydroxypropyl methylcellulose can be thoroughly stirred. After stirring and dissolving, perform vacuum defoaming according to the solution state (vacuum degree: ≤-0.1MPa, standing time ≥12h, until bubbles disappear). The pH should be measured to be 7.5~8.5, which is the optimal value.

[0116] The stability of the drug solution was investigated at room temperature for 24 hours and 48 hours, and the appearance of the drug solution was observed.

[0117] ⑤ Turn on the casting machine, adjust the casting speed and scraper height to the same settings, and set the drying temperature to 45~50℃ to carry out the casting and drying of the liquid material. Check the moisture content to 4~6%, and then proceed with inner packaging.

[0118] ⑥ Cut the film into single-dose films of the target weight, with a theoretical cutting size of 20×15mm. Pack it with suitable inner packaging material, 1 tablet / bag.

[0119] Summary: After 48 hours, the solution properties of all four samples were basically consistent with those at 0 hours, preliminarily indicating that the drug solution has good stability within 48 hours. Mechanical properties were investigated after preparing orally soluble films from each group of solutions: Example 5-1 showed cracks after a 180° folding test, and its mechanical properties did not meet the usage requirements; Examples 5-2, 5-3, and 5-4 showed good mechanical properties. Disintegration time results showed that Example 5-2 had a disintegration time of 25 seconds, Example 5-3 had a disintegration time of 27 seconds, and Example 5-4 had a disintegration time of 46 seconds. The disintegration time of this product needs to be controlled within 30 seconds. Based on the overall drug solution stability, mechanical properties, and disintegration time results, the preliminary recommended dosage of polyvinyl alcohol is 3.75~4.25g, preferably 4.00g.

Claims

1. A torasemide orally dissolving film, characterized in that, It includes torasemide, sodium hydroxide, hydroxypropyl methylcellulose, polyvinyl alcohol, glycerin, and sucralose.

2. The torasemil oral dissolving membrane according to claim 1, characterized in that, The oral dissolving film comprises, by weight: 2 parts torasemide, 0.23-0.27 parts sodium hydroxide, 12 parts hydroxypropyl methylcellulose, 3.75-4.25 parts polyvinyl alcohol, and 4 parts glycerin.

3. The torasemide orally dissolving film according to claim 1 or 2, characterized in that, The polyvinyl alcohol is of type 0588, preferably polyvinyl alcohol with a degree of polymerization of 500 and a degree of alcoholysis of 88%.

4. The torasemide orally dissolving film according to any one of claims 1 to 3, characterized in that, The sodium hydroxide comprises 0.25 parts by weight, and the polyvinyl alcohol 0588 comprises 4 parts by weight.

5. The torasemide oral dissolving film according to any one of claims 1 to 4, characterized in that, The oral dissolving film dissolves in the oral cavity in no more than 30 seconds.

6. A method for preparing a torasemide orally soluble film, characterized in that, include: (1) Add polyvinyl alcohol to a portion of purified water, stir to dissolve, and obtain an excipient solution; (2) Add sodium hydroxide to part of purified water, stir to dissolve, add torasemide and stir to dissolve, then add sucralose and glycerol, mix well to obtain the raw material solution; (3) Add the raw material solution to the excipient solution, mix well, add hydroxypropyl methylcellulose, stir to dissolve, and obtain the film-forming solution; (4) The film-forming solution is defoamed under vacuum, and then cast, dried and cut to obtain the torasemil oral solution film.

7. The preparation method according to claim 6, characterized in that, The vacuum degree of the vacuum defoaming is ≤-0.1MPa, and the standing time is ≥12 hours; the casting speed is 0.30m / min, the scraper height is 0.35mm, and the drying temperature is 45~50℃.

8. The preparation method according to claim 6 or 7, characterized in that, The pH of the film-forming solution is 7.5 to 8.5, and the water content of the oral film is 4 to 6%.

9. Use of the torasemide orally disintegrating film according to any one of claims 1 to 8 in the preparation of torasemide formulations for oral administration to mammals.

10. The use according to claim 9, characterized in that, The mammal is a dog or a cat, and the torasemil orally dissolving membrane is for oral administration in veterinary use.

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