Veterinary meloxicam orally dissolving film and preparation method thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a meloxicam orally dissolving film and a preparation method thereof. The orally dissolving film comprises meloxicam, sodium hydroxide, E3 type hydroxypropyl methyl cellulose, 0588 type polyvinyl alcohol, glycerol and sucralose. The orally dissolving film is suitable for oral administration of mammals, especially for the field of veterinary administration, and has the advantages of convenient administration, quick dissolving within 30 seconds 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 meloxicam 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 delivery. Background Technology

[0002] Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) of the enol class, possessing anti-inflammatory, analgesic, and antipyretic effects. Its mechanism of action is mainly related to the inhibition of cyclooxygenase and the reduction of prostaglandin synthesis. Meloxicam is used in veterinary clinical practice to treat osteoarthritis, postoperative pain, and other inflammatory diseases in companion animals such as cats and dogs.

[0003] With the increasing number of companion animals and the growing demands for higher dosages due to individual animal differences, existing tablets, capsules, and oral solutions still have room for improvement in terms of ease of administration, dosage adjustment, and palatability. Orally disintegrating films are oral formulations that disperse or dissolve drugs in a film-forming material, rapidly wetting and disintegrating them in the oral cavity. They are characterized by their portability, ability to be cut for administration, and the potential for improved palatability through flavoring agents.

[0004] However, meloxicam has low water solubility, and an alkaline pH adjuster is usually required to promote its dissolution when preparing meloxicam-containing oral films. Polyvinyl alcohol (PVA), as a film-forming material, has good water solubility and film-forming properties, but directly adding an alkaline meloxicam solution to a PVA-containing film-forming system may cause local pH changes, polymer chain conformation changes, and the precipitation of crystals or flocculent substances, thus affecting the uniformity and appearance stability of the film. Therefore, it is necessary to control the alkaline dissolution step of meloxicam and the order of compounding with the PVA film-forming system.

[0005] Chinese patent document CN120983403A discloses a meloxicam oral instant-dissolving film formulation, its preparation method, and its application. The formulation in this document comprises, by mass percentage, meloxicam, an oil phase, a surfactant, a polymeric film-forming agent, a plasticizer, a filler, and a disintegrant, and the system formed by the oil phase and the surfactant improves the solubility of meloxicam.

[0006] The preparation route described in this paper is as follows: plasticizer and flavoring agent are added to phosphate buffer solution, oil phase and surfactant are added to the resulting aqueous solution, meloxicam is added and heated and stirred to form a nanoemulsion system, and then polymeric film-forming agent, filler and disintegrant are added to obtain the film solution.

[0007] However, the film-forming system of products prepared by existing processes is prone to crystallization or flocculent precipitation, making it difficult to obtain oral films with good film uniformity and appearance stability. Summary of the Invention

[0008] The present invention aims to provide a meloxicam orally disintegrating film, its preparation method and application, in order to solve at least one technical problem existing in the actual administration of existing meloxicam oral formulations.

[0009] Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) with relatively low water solubility. In the preparation of meloxicam into orally disintegrating films, it is usually necessary to adjust the acid-base environment of the system to promote meloxicam dissolution in order to obtain a suitable drug dispersion or dissolution state. However, there are certain compatibility requirements between the dissolution state of meloxicam and the orally disintegrating film forming system. When meloxicam is in an alkaline dissolution environment and compounded with water-soluble polymeric film-forming materials, the homogeneity, viscosity, film-forming properties of the film-forming solution, as well as the mechanical and solubility properties of the resulting film, may all be affected.

[0010] On the other hand, orally dissolving films need to simultaneously meet requirements such as uniform drug content, film integrity, suitable mechanical strength, ease of peeling and cutting, minimal moisture absorption or adhesion during storage, and the ability to wet, dissolve, or disintegrate within a short time in the oral environment. Different types and models of film-forming materials, as well as different amounts of film-forming materials, can all affect the above properties.

[0011] Therefore, the purpose of this invention is to provide a meloxicam oral dissolving film with meloxicam as the active ingredient and sodium hydroxide, hydroxypropyl methylcellulose, polyvinyl alcohol and glycerin as the oral dissolving film formulation system. By selecting and optimizing the type of film-forming material, the model of film-forming material, the amount of each component and the way each component is added during the preparation process, the resulting oral dissolving film takes into account the solubility of meloxicam, the mechanical properties of the film, the integrity of the film formation and the rapid dissolution performance in the oral cavity.

[0012] The present invention also aims to provide a method for preparing the meloxicam orally disintegrating film, so as to obtain a film-forming solution with good uniformity, film-forming properties and processing properties, and to improve the stability and repeatability of the orally disintegrating film preparation process.

[0013] Furthermore, the present invention also aims to provide the application of the meloxicam orally disintegrating film in the field of oral administration to mammals, especially suitable for oral administration to animals such as dogs and cats, thereby providing meloxicam with a novel formulation that is convenient for administration, easy to administer in single doses, and suitable for oral administration to animals.

[0014] To achieve the above objectives, the present invention provides a meloxicam orally dissolving film.

[0015] The meloxicam oral dissolving film of the present invention comprises meloxicam, sodium hydroxide, hydroxypropyl methylcellulose, polyvinyl alcohol and glycerin.

[0016] Meloxicam, as the active pharmaceutical ingredient, is used to exert anti-inflammatory, analgesic, and / or antipyretic effects.

[0017] Sodium hydroxide, as an alkaline adjusting component, is used to regulate the acid-base environment of the formulation system and promote the dissolution or uniform dispersion of meloxicam in the film-forming solution. By appropriately controlling the amount of sodium hydroxide, the dissolution state of meloxicam can be improved while maintaining the resulting film-forming solution in a state suitable for subsequent film-forming processes.

[0018] Hydroxypropyl methylcellulose (HPMC) is one of the film-forming materials. HPMC can form a solution or dispersion system with a certain viscosity and film-forming ability in an aqueous system, and after drying, it forms a continuous film structure, thereby endowing the resulting oral soluble film with certain mechanical strength, integrity, and processability.

[0019] Polyvinyl alcohol (PVA) is another film-forming material. PVA possesses good water solubility, film-forming properties, and film integrity. By compounding PVA with hydroxypropyl methylcellulose, a composite film-forming system can be formed, thereby improving the potential shortcomings of single film-forming materials in terms of film strength, flexibility, peelability, and solubility.

[0020] The glycerol is used as a plasticizer. Glycerol can interact with the film-forming material and improve the flexibility of the film by changing the interaction state between polymer chains in the film structure, thereby reducing the risk of film brittleness and improving the mechanical properties and processing adaptability of the oral dissolution film.

[0021] In some embodiments, the meloxicam orally disintegrating film may also contain one or more other pharmaceutically acceptable excipients.

[0022] The other excipients may include, but are not limited to, flavoring agents, sweeteners, flavoring agents, coloring agents, fillers, humectants, stabilizers, lubricants, suspending agents, solubilizers, or other pharmaceutically acceptable excipients suitable for orally disintegrating film formulations.

[0023] In a preferred embodiment, the other excipients include flavoring agents.

[0024] In a further preferred embodiment, the flavoring agent comprises sucralose.

[0025] It should be noted that sucralose is not a necessary component of the meloxicam oral dissolving film described in this invention, but can be selectively added according to the palatability requirements of the formulation.

[0026] Selection of film-forming materials The present invention further selects film-forming materials suitable for meloxicam orally soluble films.

[0027] The film-forming material of oral dissolving films not only needs to have good film-forming ability, but also needs to form a suitable formulation system with meloxicam, alkaline adjustment components and plasticizers, so that the resulting film has both suitable mechanical properties and rapid intraoral dissolution performance.

[0028] The film-forming materials described in this invention include hydroxypropyl methylcellulose and polyvinyl alcohol.

[0029] Hydroxypropyl methylcellulose can be selected from pharmaceutical-grade hydroxypropyl methylcellulose of different viscosity grades or types.

[0030] In a preferred embodiment, the hydroxypropyl methylcellulose is type E hydroxypropyl methylcellulose.

[0031] In a further preferred embodiment, the hydroxypropyl methylcellulose is E3 type hydroxypropyl methylcellulose.

[0032] The term "E3 type" can be understood as a type of hydroxypropyl methylcellulose with corresponding viscosity grade and pharmaceutical specifications. Its specific specifications can be determined according to the pharmacopoeia standards, pharmaceutical excipient standards or supplier quality standards of the excipients used.

[0033] The polyvinyl alcohol described in this invention can be selected from pharmaceutical-grade polyvinyl alcohols with different degrees of polymerization and degree of alcoholysis.

[0034] In some embodiments, the polyvinyl alcohol may be selected from type 0588, type 1788, or other polyvinyl alcohols suitable for oral disintegrating film formulations.

[0035] In a preferred embodiment, the polyvinyl alcohol is type 0588 polyvinyl alcohol.

[0036] In a further preferred embodiment, the 0588 type polyvinyl alcohol is a polyvinyl alcohol with a degree of polymerization of about 500 and a degree of alcoholysis of about 88%.

[0037] It should be noted that the excipient designations such as "Type 0588" and "Type E3" mentioned in this invention are mainly used to characterize the material type and performance grade of the corresponding pharmaceutical excipients, and do not mean that this invention must be limited to a specific manufacturer or a specific product name. As long as the material properties are corresponding to or substantially equivalent to the above-mentioned designations and can achieve the technical effects described in this invention, they can be used in this invention.

[0038] Blend of hydroxypropyl methylcellulose and polyvinyl alcohol This invention discovers that using a single film-forming material may not necessarily meet the requirements of meloxicam oral dissolution film for both mechanical properties and rapid melting performance.

[0039] Hydroxypropyl methylcellulose exhibits good film-forming properties and water solubility, enabling the formation of continuous membrane structures; polyvinyl alcohol possesses good film-forming strength and membrane integrity. By blending these two film-forming materials, the internal polymer network structure of the membrane can be adjusted, thereby achieving a better balance between membrane mechanical properties, flexibility, peelability, and intraoral solubility.

[0040] In some embodiments of the present invention, the mass ratio of hydroxypropyl methylcellulose to polyvinyl alcohol can be adjusted according to the target membrane performance.

[0041] Preferably, the weight ratio of hydroxypropyl methylcellulose to polyvinyl alcohol is about 12:4.

[0042] Furthermore, by selecting different types of hydroxypropyl methylcellulose and polyvinyl alcohol, this invention found that the composite film-forming system composed of E3 type hydroxypropyl methylcellulose and 0588 type polyvinyl alcohol can achieve better overall performance.

[0043] Compared with other film-forming material combinations, the above-mentioned composite film-forming system can shorten the dissolution time of the orally dissolving film in the oral cavity environment while maintaining the mechanical properties of the film.

[0044] Dosage of each component In some embodiments of the present invention, the meloxicam orally dissolving film comprises, by weight: 1 dose of meloxicam Sodium hydroxide 0.13–0.17 parts, Hydroxypropyl methylcellulose 11.50–12.50 parts Polyvinyl alcohol 3.50-4.50 parts 3.50 to 4.50 parts of glycerin.

[0045] Within the above range, the specific dosage of each component can be further adjusted according to the mechanical properties, film-forming properties, peeling properties, solubility properties, and preparation process requirements of the membrane.

[0046] Preferably, the meloxicam orally dissolving film comprises, by weight: 1 dose of meloxicam Sodium hydroxide 0.15 parts 12 parts of hydroxypropyl methylcellulose 4 parts polyvinyl alcohol 4 parts glycerin.

[0047] The film-forming material system formed by the above proportions can achieve a good balance between the mechanical properties, flexibility, film integrity, and rapid dissolution performance in the oral cavity.

[0048] In some embodiments of the present invention, the oral dissolving film may also contain flavoring agents such as sucralose.

[0049] Preferably, the amount of sucralose can be adjusted according to the palatability requirements of the formulation.

[0050] Regarding the sodium hydroxide and meloxicam dissolution system Meloxicam has relatively low water solubility. Therefore, this invention improves the solubility of meloxicam by introducing sodium hydroxide into the film-forming solution to adjust the acid-base environment of the system.

[0051] In some embodiments of the present invention, sodium hydroxide is first dissolved in a portion of purified water, and then meloxicam is added to allow the meloxicam to fully dissolve in the resulting alkaline aqueous environment.

[0052] The term "dissolution" as used herein includes meloxicam existing in the system in a molecular, ionized, or other dissolved state suitable for forming a homogeneous film-forming solution.

[0053] By using the above methods, the presence of meloxicam as undissolved particles in the film-forming solution can be reduced, which helps to improve the uniformity of drug distribution in the final film.

[0054] In some embodiments, the pH of the film-forming solution can be adjusted according to the dissolution state of meloxicam, membrane stability, and oral administration requirements.

[0055] Preferably, the film-forming solution has a suitable neutral environment.

[0056] Furthermore, the pH of the film-forming solution can be approximately 6.5 to 7.5.

[0057] More preferably, the pH of the film-forming solution can be about 6.8 to 7.3.

[0058] Preparation method The present invention also provides a method for preparing meloxicam orally dissolving film.

[0059] The preparation method includes: (1) Formation of meloxicam solution Sodium hydroxide was added to some purified water and stirred until fully dissolved. Then meloxicam was added and stirred until dissolved to obtain a meloxicam solution.

[0060] (2) Add other liquid phase components Add glycerin to the resulting meloxicam solution, and add flavoring agents such as sucralose as needed, and mix well.

[0061] (3) Constructing a composite film-forming system Polyvinyl alcohol is added to the above system to fully dissolve it; then hydroxypropyl methylcellulose is added to fully disperse and / or dissolve it, thereby forming a homogeneous film-forming solution.

[0062] (4) Defoaming and film formation The obtained film-forming solution is defoamed under vacuum to reduce air bubbles in the solution; then, the solution is cast to form a wet film of a certain thickness, and dried to remove moisture, forming a film sheet; the film sheet is then cut according to the required single dose to obtain meloxicam orally disintegrating film.

[0063] Technical significance of a specific order of addition In the preparation method of the present invention, the order in which the components are added is not arbitrary.

[0064] Since meloxicam requires a suitable solubility in an alkaline environment, and the polymer system formed by polyvinyl alcohol and hydroxypropyl methylcellulose is sensitive to the solution environment, this invention preferably first establishes an alkaline solubility system for meloxicam, and then gradually introduces other components and film-forming materials.

[0065] The preferred order of addition is: Sodium hydroxide -- meloxicam -- glycerin and / or flavoring agent -- polyvinyl alcohol -- hydroxypropyl methylcellulose.

[0066] By following the above order of addition, meloxicam can first form a relatively homogeneous solution system in a suitable alkaline environment, and then combine with the composite film-forming system.

[0067] Adding polyvinyl alcohol first and dissolving it completely, followed by adding hydroxypropyl methylcellulose, helps to gradually build a composite polymer film-forming system and reduces the possibility of local agglomeration, uneven dispersion, or unstable film-forming solution caused by the concentrated addition of polymer materials.

[0068] Therefore, the preparation method described in this invention involves not only the selection of raw and auxiliary materials, but also the order of addition of different components and the process of system formation.

[0069] Vacuum defoaming Since oral dissolving films are prepared using a casting process, air bubbles in the film-forming solution may form film defects during casting and drying, such as pinholes, air bubbles, uneven thickness, or decreased mechanical properties.

[0070] Therefore, the present invention preferably performs vacuum defoaming on the film-forming solution before casting.

[0071] In some embodiments, the vacuum degree of the vacuum defoaming is ≤-0.1 MPa.

[0072] The defoaming time can be adjusted according to the viscosity of the film-forming solution, the number of bubbles, the system temperature, and the equipment conditions.

[0073] In some implementations, the film-forming solution after vacuum defoaming can be allowed to stand for a certain period of time to allow residual bubbles in the system to escape further.

[0074] Preferably, the settling time is ≥12 hours.

[0075] Vacuum defoaming and settling treatment can reduce the bubble content in the film-forming solution and improve the continuity and integrity of the cast film.

[0076] Casting and drying The oral dissolving film described in this invention can be prepared by casting.

[0077] "Casting" refers to the continuous spreading of a film-forming solution onto the surface of a carrier at a certain flow rate or speed, and the formation of a wet film with a predetermined thickness by controlling the doctor blade gap or other film-forming parameters. The solvent is then removed by drying, thereby forming a solid film.

[0078] In some embodiments of the present invention, the casting speed may be approximately 0.30 m / min.

[0079] The scraper height can be approximately 0.35 mm.

[0080] The drying temperature can be 45~50℃.

[0081] The above process parameters can be adjusted appropriately based on factors such as the film-forming equipment, the state of the film-forming solution, the ambient temperature and humidity, and the target film thickness.

[0082] Oral dissolving membrane performance The meloxicam orally dissolving membrane described in this invention has suitable membrane mechanical properties.

[0083] The “mechanical properties” mentioned here may include, but are not limited to: Membrane integrity; Flexibility; Tensile properties; Tear resistance; Film peeling performance; Cutting performance; Packaging adaptability.

[0084] The synergistic effect of hydroxypropyl methylcellulose, polyvinyl alcohol, and glycerin can give the membrane suitable strength and flexibility, thereby reducing the risk of the membrane becoming brittle or broken during peeling, cutting, packaging, and transportation.

[0085] At the same time, by controlling the type and amount of film-forming material, it is possible to avoid excessive film-forming material causing the film to become too dense, which would lead to a prolonged dissolution time in the oral cavity.

[0086] Rapid melting performance The meloxicam orally dissolving film of the present invention is suitable for rapid wetting and dissolving in the oral cavity environment.

[0087] In some embodiments of the present invention, the single-dose drug film of the orally dissolving film can dissolve within 30 seconds after oral administration.

[0088] Preferably, melting can be completed in a shorter time.

[0089] The term "dissolution" as used here refers to the process by which the oral membrane, upon contact with saliva or other oral fluids in the mouth, undergoes rapid wetting, swelling, dispersion, dissolution, and / or disintegration, causing it to essentially lose its intact membrane structure.

[0090] The dissolution time can be evaluated by measuring the time required for the membrane to transform from an intact membrane structure to a substantially disappeared state under predetermined oral conditions or simulated oral conditions.

[0091] Single-dose administration The orally dissolving film of the present invention can be prepared into single-dose film with different areas, thicknesses or weights according to the target dosage.

[0092] By cutting the film, a single-dose drug film of a predetermined dose can be obtained.

[0093] In some implementations, single-dose drug films can be packaged individually to reduce adhesion between films and the impact of environmental moisture on film performance.

[0094] The single-dose drug film is characterized by its small size, light weight, and ease of carrying and administration.

[0095] Compared to traditional solid oral dosage forms that require swallowing whole tablets, orally dissolving films can be rapidly moistened and dissolved in the oral cavity, making them particularly suitable for patients who have difficulty swallowing traditional tablets or who are not willing to cooperate with swallowing.

[0096] Veterinary oral administration The present invention also provides the use of the meloxicam orally disintegrating film in the preparation of meloxicam formulations for oral administration to mammals.

[0097] The term "mammal" as used in this invention includes, but is not limited to, humans and non-human mammals.

[0098] In some implementations, the mammal is an animal.

[0099] In a preferred embodiment, the mammal is a dog or a cat.

[0100] Therefore, the meloxicam orally disintegrating film described in this invention is particularly suitable for the field of oral administration in veterinary medicine.

[0101] For companion animals such as dogs and cats, traditional tablet administration may present problems such as refusal to eat, vomiting, difficulty swallowing, or low compliance. Orally dissolving films can be placed directly in the animal's mouth, dissolving rapidly upon contact with oral fluids, thus reducing the animal's reliance on swallowing solid dosage forms whole.

[0102] Furthermore, by preparing drugs as independent single-dose tablets, different specifications of tablets can be designed according to animal weight, disease status, and target dosage, thereby improving the convenience of administration and the flexibility of dosage management.

[0103] Therefore, the meloxicam orally disintegrating film of the present invention is particularly suitable for oral administration to companion animals such as dogs and cats.

[0104] Beneficial effects of the present invention

[0105] Compared with the prior art, the present invention has at least the following beneficial effects:

[0106] 1. A new oral formulation of meloxicam is provided. This invention prepares meloxicam into an orally disintegrating film, enabling meloxicam to be administered orally in the form of a single-dose film, providing a new formulation option in addition to traditional tablets, capsules, and oral liquids.

[0107] 2. Improve the solubility of meloxicam in the film-forming system. This invention introduces sodium hydroxide to regulate the system environment, enabling meloxicam to achieve a suitable dissolution state during the film-forming process. This facilitates the formation of a uniform film-forming solution and promotes the uniform distribution of the drug within the film.

[0108] 3. Construction of a hydroxypropyl methylcellulose / polyvinyl alcohol composite film-forming system This invention uses a blend of hydroxypropyl methylcellulose and polyvinyl alcohol as the main film-forming material, and preferably uses E3 type hydroxypropyl methylcellulose and 0588 type polyvinyl alcohol, so that the resulting film achieves a good balance between mechanical properties, film integrity and rapid melting performance.

[0109] 4. Glycerin improves the mechanical properties of membranes. This invention improves the flexibility of the film and reduces the risk of film breakage by adding an appropriate amount of glycerol as a plasticizer, thereby improving the adaptability of the film for peeling, cutting, packaging and transportation.

[0110] 5. Achieves faster oral dissolution performance By optimizing the type and amount of film-forming material, the meloxicam orally dissolving film of the present invention can be rapidly wetted and dissolved in the oral environment, preferably within 30 seconds, thereby improving the convenience of drug administration.

[0111] 6. The preparation process has good operability. This invention, through the rational setting of steps such as meloxicam dissolution, film-forming material addition, vacuum defoaming, casting, and drying, can obtain a film-forming solution with a relatively uniform state, which is suitable for continuous casting and subsequent cutting processing.

[0112] 7. Suitable for oral administration to animals such as dogs and cats. This invention further applies meloxicam orally disintegrating film to oral administration in mammals, especially suitable for oral administration in veterinary animals such as dogs and cats, providing an easy-to-use single-dose orally disintegrating film formulation for meloxicam administration in companion animals.

[0113] 8. It has the potential to further expand into products with different specifications. This invention uses a film as a drug carrier. Different single-dose specifications can be obtained by adjusting the film area, thickness, drug loading per unit area, and cutting specifications, thereby adapting to different body weights and different dosage requirements. Detailed Implementation

[0114] It should be understood that the meloxicam orally disintegrating film described in this invention is not limited to the specific components, models, proportions, and process parameters mentioned above. Without departing from the technical concept of this invention, those skilled in the art can make appropriate adjustments to the types of excipients, component proportions, film size, single-dose specifications, film-forming solution concentration, casting parameters, drying conditions, and packaging methods according to actual formulation requirements.

[0115] Unless otherwise expressly stated, the terms "comprising" and "including" in this invention should be understood as open-ended expressions, meaning that in addition to the listed components, other pharmaceutically acceptable components may be included; expressions such as "about" and "substantially" are used to cover reasonable range variations due to factors such as raw material batches, testing methods, equipment precision, and process fluctuations.

[0116] The amounts of each component described in this invention can be expressed as parts by weight, weight percentage, unit dose content, or other suitable measurement methods as needed. Unless otherwise specified, the proportions between the components can be converted according to the formulation objectives.

[0117] The "oral dissolving film" mentioned in this invention refers to a film preparation suitable for placement in the oral cavity, which can be rapidly wetted and dissolved, dispersed and / or disintegrated under the action of oral fluids.

[0118] The "single-dose drug film" mentioned in this invention refers to an independent film that has been cut and formed, contains a predetermined amount of meloxicam, and is suitable for single-dose administration.

[0119] The "oral administration for veterinary use" mentioned in this invention refers to the use of the meloxicam orally disintegrating film for oral administration to non-human mammals, including but not limited to dogs and cats.

[0120] Unless otherwise stated, the raw materials, excipients, equipment and processes used in this invention can all be conventional pharmaceutical raw materials, pharmaceutical excipients, formulation equipment and preparation methods in the art.

[0121] Without departing from the concept and technical essence of this invention, those skilled in the art can make various equivalent substitutions, simple modifications, or adjustments to this invention, and all such modifications should be included within the scope of protection of this invention. The following embodiments do not constitute a limitation on the scope of this invention.

[0122] Example 1: Standard Formulation and Preparation

[0123] 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.

[0124] Table 1

[0125] Note 1: The solvent used in the process and ultimately removed is purified water, which is removed during the drying process.

[0126] ① Weigh the raw and auxiliary materials according to the prescription amount.

[0127] ② Weigh out 95% purified water and stir to create a vortex. While stirring, slowly add sodium hydroxide, stirring until dissolved. Then add meloxicam, stirring until dissolved, then add sucralose, stirring until dissolved, then add glycerin. After stirring and dispersing evenly, slowly add polyvinyl alcohol, stirring until dissolved, then slowly add hydroxypropyl methylcellulose. After all the hydroxypropyl methylcellulose has been added, rinse the inside of the mixing tank with the remaining 5% purified water to ensure the hydroxypropyl methylcellulose is 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 7.0, which is the final solution.

[0128] ③ 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.

[0129] ④ Set an appropriate cutting speed to cut the film into single-dose films of the target weight. The theoretical cutting size is 20×15mm. Pack the film with appropriate inner packaging material, 1 film / bag.

[0130] Summary: After testing, all indicators met the quality requirements.

[0131] 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.

[0132] Table 2

[0133] The quality control of meloxicam oral disintegrating film uses meloxicam, hydroxypropyl methylcellulose, polyvinyl alcohol, glycerin, sodium hydroxide, and sucralose as raw and auxiliary materials. The analytical methods used are all derived from the Chinese Pharmacopoeia 2025 Edition, BP2021 / EP10.6, USP43-NF37, JP17 and manufacturer standards, and comply with the relevant guidelines issued by the State Drug Administration and ICH and the general requirements of the Chinese Pharmacopoeia 2025 Edition.

[0134] Example 2: Selection of film-forming agent The film-forming agents in the orally dissolving film include hydroxypropyl methylcellulose, polyvinyl alcohol, and povidone K30. To screen suitable film-forming materials for this formulation, a comparative study of the film-forming agents was conducted, and test samples were prepared. Detailed results are shown in the table below.

[0135] Table 3

[0136] Note 1: The solvent used in the process and ultimately removed is purified water, which is removed during the drying process.

[0137] ① Weigh the raw and auxiliary materials according to the prescription amount.

[0138] ② Weigh out 95% purified water and stir to create a vortex. While stirring, slowly add sodium hydroxide, stirring until dissolved. Then add meloxicam, stirring until dissolved, then add sucralose, stirring until dissolved, then add glycerin. After stirring and dispersing evenly, slowly add polyvinyl alcohol, stirring until dissolved, then slowly add hydroxypropyl methylcellulose / povidone K30. After all the hydroxypropyl methylcellulose has been added, rinse the inner wall of the mixing tank with the remaining 5% purified water to ensure that the hydroxypropyl methylcellulose is 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 value is measured to be 6.5~7.5, which is the final result.

[0139] ③ 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 carry out the casting and drying of the liquid. Check the moisture content to 4~6% and then proceed with inner packaging.

[0140] ④ Set an appropriate cutting speed to cut the film into single-dose films of the target weight. The theoretical cutting size is 20×15mm. Pack the film with appropriate inner packaging material, 1 film / bag.

[0141] Summary: Example 2-1, using hydroxypropyl methylcellulose and polyvinyl alcohol as film-forming agents, produced a good film-forming state, with mechanical properties meeting requirements and a melting time of 20 seconds, satisfying quality requirements. Example 2-2, using povidone K30 and polyvinyl alcohol, resulted in a film prone to inter-membrane adhesion and easy breakage, with mechanical properties failing to meet formulation requirements. Therefore, it is preliminarily determined that povidone K30 and polyvinyl alcohol are unsuitable for this formulation, and hydroxypropyl methylcellulose and polyvinyl alcohol will be selected for further investigation.

[0142] Example 3: Investigation of Film-Forming Agent Types Hydroxypropyl methylcellulose E3 and E5, and polyvinyl alcohol 0588 and 1788 were selected for comparative studies of different excipients to evaluate the effects of excipient type on membrane mechanical properties and solubility time, and to screen excipient types suitable for this formulation. See the table below for details.

[0143] Table 4

[0144] Note 1: The solvent used in the process and ultimately removed is purified water, which is removed during the drying process.

[0145] ① Weigh the raw and auxiliary materials according to the prescription amount.

[0146] ② Weigh out 95% purified water and stir to create a vortex. While stirring, slowly add sodium hydroxide, stirring until dissolved. Then add meloxicam, stirring until dissolved, then add sucralose, stirring until dissolved, then add glycerin. After stirring and dispersing evenly, slowly add polyvinyl alcohol, stirring until dissolved, then slowly add hydroxypropyl methylcellulose. After all the hydroxypropyl methylcellulose has been added, rinse the inside of the mixing tank with the remaining 5% purified water to ensure the hydroxypropyl methylcellulose is 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 value is measured to be 6.5~7.5, which is the final solution.

[0147] ③ 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 carry out the casting and drying of the liquid. Check the moisture content to 4~6% and then proceed with inner packaging.

[0148] ④ Set an appropriate cutting speed to cut the film into single-dose films of the target weight. The theoretical cutting size is 20×15mm. Pack the film with appropriate inner packaging material, 1 film / bag.

[0149] Summary: Examples 3-1 to 3-4 all exhibited good mechanical properties, meeting the formulation requirements. Regarding dissolution time: Example 3-1 had a dissolution time of 25 seconds, meeting the limit requirements; Examples 3-2 had dissolution times of 40 seconds, Examples 3-3 had dissolution times of 44 seconds, and Examples 3-4 had dissolution times of 54 seconds, all exceeding the limit requirements. Based on the combined mechanical properties and dissolution time results, the excipient combination corresponding to Example 3-1 was preliminarily selected, namely hydroxypropyl methylcellulose E3 and polyvinyl alcohol 0588.

[0150] Example 4: Investigation of Film-Forming Agent Dosage Hydroxypropyl methylcellulose (HMC) and polyvinyl alcohol (PVA) are used as film-forming agents. The dosage of each ingredient affects the dissolution time of the orally soluble film. The dissolution time can be optimized by adjusting the dosage of each ingredient. This experiment investigated the dosage of HMC and PVA to preliminarily determine the appropriate ratio in the formulation. Details are shown in the table below.

[0151] Table 5

[0152] Note 1: The solvent used in the process and ultimately removed is purified water, which is removed during the drying process.

[0153] ① Weigh the raw and auxiliary materials according to the prescription amount.

[0154] ② Weigh out 95% purified water and stir to create a vortex. While stirring, slowly add sodium hydroxide, stirring until dissolved. Then add meloxicam, stirring until dissolved, then add sucralose, stirring until dissolved, then add glycerin. After stirring and dispersing evenly, slowly add polyvinyl alcohol, stirring until dissolved, then slowly add hydroxypropyl methylcellulose. After all the hydroxypropyl methylcellulose has been added, rinse the inside of the mixing tank with the remaining 5% purified water to ensure the hydroxypropyl methylcellulose is 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 value is measured to be 6.5~7.5, which is the final solution.

[0155] ③ 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 carry out the casting and drying of the liquid. Check the moisture content to 4~6% and then proceed with inner packaging.

[0156] ④ Set an appropriate cutting speed to cut the film into single-dose films of the target weight. The theoretical cutting size is 20×15mm. Pack the film with appropriate inner packaging material, 1 film / bag.

[0157] Summary: Example 4-1 was prone to breakage during the peeling process, making normal peeling impossible and failing to meet formulation requirements; Examples 4-2, 4-3, and 4-4 all met the mechanical property requirements. Melting time test results: Example 4-2 had a melting time of 25 seconds, meeting the limit requirements; Example 4-3 had a melting time of 27 seconds, meeting the limit requirements; Example 4-4 had a melting time of 47 seconds, exceeding the limit requirements. Based on the combined peeling effect, mechanical properties, and melting time results, the preliminary recommended dosage of hydroxypropyl methylcellulose is 11.50~12.50g, preferably 12.00g, and the dosage of polyvinyl alcohol is 3.50~4.50g, preferably 4.00g.

[0158] Example 5: Investigation of Plasticizer Dosage Orally dissolving films are formed by the combined action of film-forming agents and plasticizers. Plasticizers improve film flexibility and reduce brittleness. This experiment selected glycerol as the plasticizer, and different dosages were used to investigate formulations and screen for suitable glycerol dosages. Details are shown in the table below.

[0159] Table 6

[0160] Note 1: The solvent used in the process and ultimately removed is purified water, which is removed during the drying process.

[0161] ① Weigh the raw and auxiliary materials according to the prescription amount.

[0162] ② Weigh out 95% purified water and stir to create a vortex. While stirring, slowly add sodium hydroxide, stirring until dissolved. Then add meloxicam, stirring until dissolved, then add sucralose, stirring until dissolved, then add glycerin. After stirring and dispersing evenly, slowly add polyvinyl alcohol, stirring until dissolved, then slowly add hydroxypropyl methylcellulose. After all the hydroxypropyl methylcellulose has been added, rinse the inside of the mixing tank with the remaining 5% purified water to ensure the hydroxypropyl methylcellulose is 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 value is measured to be 6.5~7.5, which is the final solution.

[0163] ③ 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 carry out the casting and drying of the liquid. Check the moisture content to 4~6% and then proceed with inner packaging.

[0164] ④ Set an appropriate cutting speed to cut the film into single-dose films of the target weight. The theoretical cutting size is 20×15mm. Pack the film with appropriate inner packaging material, 1 film / bag.

[0165] Summary: The membrane from Example 5-1 was brittle, and its mechanical properties did not meet the formulation requirements; the mechanical properties of Examples 5-2, 5-3, and 5-4 all met the requirements. Melting time test results: The melting time of Example 5-2 was 25 seconds, meeting the limit requirement; the melting time of Example 5-3 was 27 seconds, meeting the limit requirement; the melting time of Example 5-4 was 41 seconds, exceeding the limit and not meeting the requirements. Considering both the membrane's mechanical properties and melting time, the preliminary recommended dosage of glycerol is 3.50~4.50g, preferably 4.00g. The tentative film-forming component ratio in the formulation is hydroxypropyl methylcellulose:polyvinyl alcohol:glycerol 12:4:4.

[0166] Comparative Example 1 Meloxicam 3.0 g Polyvinyl alcohol (0588) 10.0 g Hydroxypropyl methylcellulose (E3) 35.0 g Glycerin 20.0 g 2.0 g of sucralose Sodium hydroxide (appropriate amount) Add purified water to 1000 g The preparation method is the same as in Example 1, with the main difference being: (1) 10.0 g of polyvinyl alcohol (0588); (2) 35.0 g of hydroxypropyl methylcellulose (E3); and (3) 20.0 g of glycerol.

[0167] The resulting oral dissolving film: a single-dose tablet weighs 23.33 mg and contains 1 mg of meloxicam. The dissolution time limit is 1 min 52 s. Exceeding the dissolution time limit, it cannot dissolve rapidly in the oral cavity.

Claims

1. A meloxicam orally dissolving film, characterized in that, It contains meloxicam, sodium hydroxide, hydroxypropyl methylcellulose, polyvinyl alcohol, and glycerin.

2. The meloxicam orally dissolving film according to claim 1, characterized in that, The hydroxypropyl methylcellulose is E3 type hydroxypropyl methylcellulose, and the polyvinyl alcohol is 0588 type polyvinyl alcohol.

3. The meloxicam orally dissolving film according to claim 2, characterized in that, The oral dissolving film comprises, by weight: 1 part meloxicam, 0.13-0.17 parts sodium hydroxide, 11.50-12.50 parts hydroxypropyl methylcellulose, 3.50-4.50 parts polyvinyl alcohol, and 3.50-4.50 parts glycerin.

4. The meloxicam orally dissolving film according to claim 3, characterized in that, The oral dissolving film comprises, by weight: 1 part meloxicam, 0.15 parts sodium hydroxide, 12 parts hydroxypropyl methylcellulose, 4 parts polyvinyl alcohol, and 4 parts glycerin.

5. The meloxicam orally dissolving film according to any one of claims 1 to 4, characterized in that, The single-dose film of the oral dissolving film dissolves within 30 seconds after oral administration.

6. A method for preparing a meloxicam orally disintegrating film, characterized in that, Includes the following steps: (1) Add sodium hydroxide to part of purified water, stir to dissolve, then add meloxicam and stir to dissolve; (2) Add glycerin and mix well; (3) Add polyvinyl alcohol, stir to dissolve, then add hydroxypropyl methylcellulose, mix evenly to obtain the film-forming solution; (4) The film-forming solution is defoamed under vacuum, and then cast, dried and cut to obtain the meloxicam oral soluble 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.

8. The preparation method according to claim 6 or 7, characterized in that, The casting speed is 0.30 m / min, the scraper height is 0.35 mm, and the drying temperature is 45–50℃.

9. Use of the meloxicam orally disintegrating film according to any one of claims 1 to 5 in the preparation of meloxicam 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 meloxicam orally disintegrating film is for oral administration in veterinary use.

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