An oseltamivir phosphate orally dissolving film and a preparation method thereof

Abstract

The present application relates to a kind of oseltamivir phosphate mouth dissolving film and preparation method thereof, belong to the technical field of pharmaceutical preparation.The oseltamivir phosphate mouth dissolving film of the present application includes the following weight percentage of each component:oseltamivir phosphate:50-80%, film-forming material:15-40%, filler:3-15%, plasticizer:0-10%, other excipients:0-10%.The present application also relates to the preparation method of oseltamivir phosphate mouth dissolving film.The mouth dissolving film prepared by the present application can solve the problem of taking for children, the elderly and patients with difficulty in swallowing with vomiting symptoms, the present application selects polyvinyl alcohol as the main film-forming material, greatly improves the drug loading of drug, has good stability, low cost and mature and simple process, more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, and relates to an orally disintegrating film formulation with oseltamivir phosphate as the active ingredient and its preparation method. Background Technology

[0002] Oseltamivir phosphate, chemical name: (3R,4R,5S)-4-acetamido-5-amino-3(1-ethoxy)-1-cyclohexene-1-carboxylic acid ethyl ester phosphate, structural formula as follows:

[0003]

[0004] The active metabolite of oseltamivir phosphate (oseltamivir carboxylate) is a potent and selective inhibitor of influenza virus neuraminidase, capable of inhibiting the neuraminidase activity of influenza A and B viruses, and is suitable for the treatment and prevention of influenza A and B.

[0005] Viral infections can cause a variety of diseases, seriously endangering human life and health. Children and the elderly have weaker immune systems and are more susceptible to influenza. Currently available oseltamivir phosphate preparations are mainly in the form of capsules, dry suspensions, and granules. Capsules need to be taken with water, which can be psychologically challenging for children and elderly patients with swallowing difficulties, leading to repeated unsuccessful attempts to take the medication. Patients often refuse to take the medication, vomit, or hide it. While granules address these issues to some extent, they are still not convenient to take, requiring water to dissolve. Furthermore, granules are fragile during transportation—some break into powder, potentially causing inaccurate dosages and requiring stricter requirements for production, packaging, and storage. When administering dry suspensions, the entire bottle of medication must be reconstituted first. The reconstituted solution can only be stored under specific conditions for a certain period of time. The reconstituted solution is highly sensitive to temperature and humidity, and the stability of the medication during storage directly affects its safety. Proper storage of the medication solution is crucial to ensuring patient safety. If the medication solution is not stored correctly and promptly after use, or if it is removed to an unsuitable storage environment within a short period, patients cannot assess the safety of the medication solution or determine whether it is still safe to continue taking it. In addition, patients need to use special measuring cups or applicators during administration, which can easily lead to inaccurate dosages and is inconvenient to carry, thus limiting its widespread clinical application.

[0006] Currently, there are no oral dissolving film products for oseltamivir phosphate on the market. Oral dissolving films provide accurate dosage, do not require water, dissolve rapidly in the mouth, have good compliance, are small in size and light in weight, and are easy to carry. They are especially suitable for children, the elderly, and patients with vomiting symptoms and difficulty swallowing. They dissolve immediately upon placement in the mouth, preventing children from vomiting. This solves the problems of inaccurate dosage of capsules, granules, and dry suspensions, the need for water to take them, poor compliance in children and elderly patients with vomiting difficulties, and inconvenience in carrying them. Summary of the Invention

[0007] In view of the shortcomings of existing technologies and the lack of orally disintegrating film formulations in the market, this invention provides an orally disintegrating film formulation of oseltamivir phosphate and its preparation method. The purpose is to provide an orally disintegrating film formulation of oseltamivir phosphate that is convenient to take, easy to be accepted by patients, has a simple and easy preparation process, is suitable for industrial production, is convenient to store and transport, and has good stability.

[0008] This invention provides an oseltamivir phosphate orally disintegrating film formulation, comprising the following components in weight percentage:

[0009]

[0010] In some preferred embodiments, an oseltamivir phosphate orally disintegrating film formulation of the present invention comprises the following components in weight percentages:

[0011]

[0012] In some preferred embodiments of the oseltamivir phosphate orally disintegrating film-forming agent of the present invention, the film-forming material contains at least polyvinyl alcohol. In other preferred embodiments, the film-forming material contains, in addition to polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, or povidone, wherein the weight percentage of polyvinyl alcohol in the film-forming material is 60% to 100%. In still some preferred embodiments, the film-forming material is polyvinyl alcohol.

[0013] In some preferred embodiments of the oseltamivir phosphate oral dissolving film formulation of the present invention, the filler is microcrystalline cellulose.

[0014] In some preferred embodiments of the oseltamivir phosphate oral dissolving film formulation of the present invention, the plasticizer is selected from propylene glycol, glycerin, polyethylene glycol 400, Tween 80, triethyl glycerol, or polysorbate. In other preferred embodiments, the plasticizer is glycerin.

[0015] In some preferred embodiments of the oseltamivir phosphate oral disintegrating film formulation of the present invention, the other excipients include colorants, antioxidants, and flavoring agents, wherein the colorants are selected from one or any combination of iron oxide pigments, titanium dioxide pigments, and lakes; the antioxidants are selected from one or any combination of sodium sulfite, sodium bisulfite, butylated hydroxytoluene, and butylated hydroxyanisole; and the flavoring agents are selected from one or any combination of sucralose, sodium saccharin, and flavorings.

[0016] Furthermore, the present invention also provides a method for preparing the oseltamivir phosphate oral dissolving film as described above, comprising the following steps:

[0017] (1) First, the film-forming material of the prescription amount is evenly dispersed in room temperature water, then heated to 75-85℃ to dissolve, vacuum degassing, and then cooled to room temperature to obtain a film-forming material solution;

[0018] (2) Add the prescribed amount of filler, plasticizer and other excipients to the film-forming material solution obtained in step (1) and stir until the mixture is uniform to obtain a blank adhesive solution;

[0019] (3) Add the prescribed amount of oseltamivir phosphate to the blank gel obtained in step (2), stir evenly, and obtain drug-containing gel A;

[0020] (4) Vacuum stir the drug-containing adhesive solution A obtained in step (3) until degassing is complete to obtain drug-containing adhesive solution B;

[0021] (5) Coat and dry the drug-containing adhesive solution B obtained in step (4) on a polyester film to obtain oseltamivir phosphate oral dissolving film.

[0022] The oral dissolving film of the present invention has the following advantages:

[0023] 1) Solve the problem of low drug loading in oral dissolving films and increase its drug loading to 50%-80%;

[0024] 2) It has good compliance and is especially suitable for children, the elderly and patients with dysphagia who have vomiting symptoms. It can prevent children from vomiting or choking hazards caused by traditional solid oral preparations.

[0025] 3) Accurate dosage, simple preparation process, low cost, and stable properties;

[0026] 4) No water is needed to take it; it dissolves on the tip of the tongue and quickly dissolves in the mouth, so it can be taken anytime, anywhere.

[0027] 5) It dissolves quickly after administration, releases the drug rapidly, and some of the drug can directly enter the bloodstream through the mucous membrane, avoiding the first-pass effect;

[0028] 6) Small size and light weight, making it easy to carry, store and transport.

[0029] Oral dissolving films are characterized by a relatively small drug loading capacity, typically around 30-40% of the total volume, resulting in a film weight of approximately 20-40 mg. Oseltamivir phosphate comes in a larger specification; a 45 mg dose, if using conventional film-forming materials and fillers such as hydroxypropyl methylcellulose and lactose, would require a film weight of approximately 150 mg, which is impractical. Through research, the inventors discovered that using polyvinyl alcohol as the primary film-forming material and microcrystalline cellulose as a filler can increase the drug loading capacity to as high as 60-80%, while reducing the amount of film-forming material to 15%. This reduces the weight of the 45 mg film to approximately 70 mg, significantly increasing the drug loading capacity of this oseltamivir phosphate oral dissolving film. Furthermore, the resulting product exhibits good stability, dissolving completely in the oral cavity within 10 seconds, meeting patient needs.

[0030] If hydroxypropyl methylcellulose, povidone, or hydroxypropyl cellulose is used alone as the film-forming material, it can be directly mixed with the other excipients during the preparation of the drug-containing adhesive solution. However, because the specifications of oseltamivir phosphate orally disintegrating films are much higher than those of commonly available orally disintegrating film products on the market, the film-forming performance of the films made using the above-mentioned film-forming materials is extremely poor when the drug loading is 50%, and the product is unstable. Polyvinyl alcohol (PVA) is a water-soluble synthetic resin. Its solubility in water is related to its relative molecular weight and degree of alcoholysis. The higher the relative molecular weight, the stronger the crystallinity and the worse the water solubility. Products with a high degree of alcoholysis require hot water to dissolve. When PVA is directly added to hot water at a certain temperature, undissolved PVA clumps will appear in the PVA solution, and even with extended heating time, these PVA clumps are difficult to dissolve. This invention first involves uniformly dispersing a polyvinyl alcohol (PVA) solution in purified water and then heating it until no PVA clumps remain. The resulting PVA solution contains a large number of bubbles. Two degassing methods can be used: high-speed centrifugation and vacuum degassing. High-speed centrifugation, while removing bubbles, also causes a mixing effect, dispersing large bubbles into more numerous and difficult-to-remove fine bubbles, increasing the difficulty of degassing. Vacuum degassing, on the other hand, avoids the increase of fine bubbles, and the high temperature facilitates degassing, ultimately yielding a clear and transparent PVA solution. Attached Figure Description

[0031] Figure 1 These are comparison graphs of the dissolution curves of Examples 2-4, 8, 17-19 and commercially available Tamiflu capsules in aqueous solution;

[0032] Figure 2 This is a comparison chart of the dissolution curves of Examples 2-3, 11-13, and 15 with those of commercially available Tamiflu capsules in aqueous solution;

[0033] Figure 3This is a comparison of the dissolution curves of Examples 2-4, 8, 17-19 and commercially available Tamiflu capsules in pH 1.0 solution;

[0034] Figure 4 This is a comparison of the dissolution curves of Examples 2-3, 11-13, and 15 with those of commercially available Tamiflu capsules in a pH 1.0 solution;

[0035] Figure 5 This is a comparison of the dissolution curves of Examples 2-4, 8, 17-19 and commercially available Tamiflu capsules in a pH 4.5 solution;

[0036] Figure 6 This is a comparison of the dissolution curves of Examples 2-3, 11-13, and 15 with those of commercially available Tamiflu capsules in a pH 4.5 solution;

[0037] Figure 7 This is a comparison of the dissolution curves of Examples 2-4, 8, 17-19 and commercially available Tamiflu capsules in a pH 6.8 solution;

[0038] Figure 8 This is a comparison of the dissolution curves of Examples 2-3, 11-13, and 15 with those of commercially available Tamiflu capsules in a pH 6.8 solution. Detailed Implementation

[0039] The present invention will be further illustrated below through a series of specific embodiments. It should be understood that the embodiments of the present invention are for illustrative purposes only and are not intended to limit the invention. Any technical solutions obtained by making simple modifications to the present invention or by using conventional methods or equivalent substitutions of active ingredients based on the technical solutions of the present invention are all within the protection scope of the present invention.

[0040] The production scale of Examples 1-7 and 9-18 in this invention is 20,000 tablets / batch, and the specification of the target product is 45mg (containing oseltamivir phosphate, calculated as oseltamivir).

[0041] The production scale of Examples 8 and 19 in this invention is 300,000 tablets / batch, and the specification of the target product is 45mg (containing oseltamivir phosphate, calculated as oseltamivir).

[0042] Example 1: The film-forming material used was only hydroxypropyl methylcellulose, which could not form a film.

[0043]

[0044]

[0045] In this embodiment, the content of oseltamivir phosphate is 50%. The prescribed amount of oseltamivir phosphate is added to an aqueous solution and stirred to dissolve. Then, glycerol, sucralose, titanium dioxide and hydroxypropyl methylcellulose are added and stirred to dissolve thoroughly to obtain a drug-containing gel. The gel is allowed to stand and swell. The gel is stirred and degassed under vacuum conditions. After coating and drying, only a drug film of about 10mg can be obtained. If the target specification product of 45mg is to be prepared, the film cannot be formed and the target product cannot be obtained.

[0046] Example 2: The film-forming material used was only polyvinyl chloride, which had poor film-forming properties.

[0047]

[0048] In this embodiment, the content of oseltamivir phosphate is 50%. The prescribed amount of oseltamivir phosphate is added to an aqueous solution and stirred to dissolve. Then, glycerol, sucralose, titanium dioxide and povidone are added and stirred to dissolve thoroughly to obtain a drug-containing gel. The gel is allowed to stand and swell. The gel is stirred and degassed under vacuum conditions. After coating and drying, the toughness and strength of the drug film are extremely poor. It can barely form a film and cannot be mass-produced.

[0049] Example 3: The film-forming material used was only hydroxypropyl cellulose, which could not form a film.

[0050]

[0051] In this embodiment, the content of oseltamivir phosphate is 50%. The prescribed amount of oseltamivir phosphate is added to an aqueous solution and stirred to dissolve. Then, glycerol, sucralose, titanium dioxide and hydroxypropyl cellulose are added and stirred to dissolve thoroughly to obtain a drug-containing gel. The gel is allowed to stand and swell. Stirring and degassing under vacuum conditions can only obtain a drug film of about 15mg. If a 45mg drug film is prepared, the toughness and strength of the drug film after coating and drying are extremely poor, and the target product cannot be obtained.

[0052] Example 4: When polyvinyl alcohol is used as the film-forming material and microcrystalline cellulose is not used as the filler, the film properties are unqualified.

[0053]

[0054] In this embodiment, the content of oseltamivir phosphate is 50%. The polyvinyl alcohol solution is dissolved under high temperature and then cooled to room temperature. The prescribed amount of oseltamivir phosphate, glycerin, sucralose, and titanium dioxide are added and stirred thoroughly to obtain a drug-containing gel. The gel is then allowed to stand. The gel is degassed under vacuum and then coated and dried. Coating and drying are necessary when the drug film thickness is thin. While the toughness and strength are good, it is impossible to obtain the target area of ​​the drug film (45mg specification). Increasing the coating thickness of the drug film results in unevenness on the surface of the drug film during the drying process due to the larger thickness of the product, making it impossible to obtain the target product.

[0055] Example 5: The film-forming material / filler used was hydroxypropyl methylcellulose / microcrystalline cellulose, which could not form a film.

[0056]

[0057] In this embodiment, the content of oseltamivir phosphate is 50%. The prescribed amount of oseltamivir phosphate is added to an aqueous solution and stirred to dissolve. Glycerin, microcrystalline cellulose and hydroxypropyl methylcellulose are then added and stirred to dissolve completely to obtain a drug-containing gel. The gel is allowed to stand and swell. The gel is stirred and degassed under vacuum conditions. After coating and drying, the gel cannot form a film and the target product cannot be obtained.

[0058] Example 6: The film-forming material / filler used was povidone / microcrystalline cellulose, which could not form a film.

[0059]

[0060] In this embodiment, the content of oseltamivir phosphate is 50%. The prescribed amount of oseltamivir phosphate is added to an aqueous solution and stirred to dissolve. Glycerin, microcrystalline cellulose and povidone are then added and stirred to dissolve thoroughly to obtain a drug-containing gel. The gel is allowed to stand and swell. The gel is then stirred and degassed under vacuum conditions. After coating and drying, the toughness and strength of the drug film are extremely poor, and it cannot form a film.

[0061] Example 7: The film-forming material / filler used is hydroxypropyl cellulose / microcrystalline cellulose, which cannot form a film.

[0062]

[0063] In this embodiment, the content of oseltamivir phosphate is 50%. The prescribed amount of oseltamivir phosphate is added to an aqueous solution and stirred to dissolve. Glycerin, microcrystalline cellulose and hydroxypropyl cellulose are then added and stirred to dissolve completely to obtain a drug-containing gel. The gel is allowed to stand and swell. The gel is stirred and degassed under vacuum conditions. After coating and drying, the toughness and strength of the drug film are extremely poor, and the target product cannot be obtained.

[0064] Example 8: Polyvinyl alcohol / microcrystalline cellulose was selected as the film-forming material / filler, resulting in good film formation.

[0065]

[0066] In this embodiment, the content of oseltamivir phosphate is 50%. After dissolving the polyvinyl alcohol solution at high temperature, the solution is cooled to room temperature. The prescribed amount of oseltamivir phosphate, glycerol, and microcrystalline cellulose are added and stirred thoroughly to obtain a drug-containing adhesive solution, which is then allowed to stand. After degassing under vacuum conditions, the solution is coated and dried. The addition of microcrystalline cellulose increases the coating thickness of the drug film. During the drying process, no unevenness appears on the surface of the drug film. The drug film has good toughness, strength, and film-forming properties.

[0067] Example 9: The film-forming material / filler selected was polyvinyl alcohol / pregelatinized starch, but its appearance did not meet the requirements.

[0068]

[0069] In this embodiment, the content of oseltamivir phosphate is 50%. After dissolving the polyvinyl alcohol solution at high temperature, the solution is cooled to room temperature. The prescribed amount of oseltamivir phosphate, glycerin, and pregelatinized starch are added and stirred thoroughly to obtain a drug-containing gel. The solution is then allowed to stand. After degassing under vacuum, the solution is coated and dried. After adding pregelatinized starch to the prescription, the surface of the drug film is coated. During the drying process of the drug film, the unevenness of the surface is improved, but film formation is still not possible.

[0070] Example 10: The film-forming material / filler selected was polyvinyl alcohol / mannitol, but its appearance did not meet the requirements.

[0071]

[0072] In this embodiment, the content of oseltamivir phosphate is 50%. After dissolving the polyvinyl alcohol solution at high temperature and cooling it to room temperature, the prescribed amount of oseltamivir phosphate, glycerin and mannitol are added and stirred thoroughly to obtain a drug-containing adhesive solution, which is then allowed to stand. After degassing under vacuum conditions, it is coated and dried. During the drying process after adding mannitol, the surface of the drug film still shows an uneven phenomenon, which cannot improve the appearance of the drug film.

[0073] Example 11: The film-forming material / filler selected was polyvinyl alcohol and hydroxypropyl methylcellulose / microcrystalline cellulose, which resulted in good film formation.

[0074]

[0075] In this embodiment, the content of oseltamivir phosphate is 50%. After dissolving the polyvinyl alcohol solution at high temperature and cooling it to room temperature, the prescribed amount of oseltamivir phosphate, glycerol, microcrystalline cellulose and hydroxypropyl methylcellulose are added and stirred thoroughly to dissolve and obtain a drug-containing adhesive solution. After standing, the solution is degassed under vacuum and then coated and dried. The drug film has good toughness, mechanical strength and film-forming properties.

[0076] Example 12: Film-forming materials / fillers selected were polyvinyl alcohol and hydroxypropyl methylcellulose / microcrystalline cellulose, which resulted in good film formation.

[0077]

[0078] In this embodiment, the content of oseltamivir phosphate is 50%. After dissolving the polyvinyl alcohol solution at high temperature and cooling it to room temperature, the prescribed amount of oseltamivir phosphate, glycerol, microcrystalline cellulose and hydroxypropyl methylcellulose are added and stirred thoroughly to dissolve and obtain a drug-containing adhesive solution. After standing, the solution is degassed under vacuum and then coated and dried. The drug film has good toughness, mechanical strength and film-forming properties.

[0079] Example 13: The film-forming material / filler selected was polyvinyl alcohol and polyvinyl ketone / microcrystalline cellulose, which resulted in good film formation.

[0080]

[0081]

[0082] In this embodiment, the content of oseltamivir phosphate is 50%. After dissolving the polyvinyl alcohol solution at high temperature and cooling it to room temperature, the prescribed amount of oseltamivir phosphate, glycerin, microcrystalline cellulose and povidone are added and stirred thoroughly to obtain a drug-containing adhesive solution. After standing, the solution is degassed under vacuum and then coated and dried. The target drug film has good toughness, mechanical strength and film-forming properties.

[0083] Example 14: The film-forming material / filler selected was polyvinyl alcohol and polyvinyl ketone / microcrystalline cellulose, which resulted in good film formation.

[0084]

[0085] In this embodiment, the content of oseltamivir phosphate is 50%. After dissolving the polyvinyl alcohol solution at high temperature and cooling it to room temperature, the prescribed amount of oseltamivir phosphate, glycerin, microcrystalline cellulose and povidone are added and stirred thoroughly to obtain a drug-containing adhesive solution. After standing, the solution is degassed under vacuum and then coated and dried. The target drug film has good toughness, mechanical strength and film-forming properties.

[0086] Example 15: Film-forming materials / fillers selected were polyvinyl alcohol and hydroxypropyl cellulose / microcrystalline cellulose, which resulted in good film formation.

[0087]

[0088] In this embodiment, the content of oseltamivir phosphate is 50%. After dissolving the polyvinyl alcohol solution at high temperature and cooling it to room temperature, the prescribed amount of oseltamivir phosphate, glycerol, microcrystalline cellulose and hydroxypropyl cellulose are added and stirred thoroughly to obtain a drug-containing adhesive solution. After standing, the adhesive film is coated and dried under vacuum conditions. The film has good toughness, mechanical strength and film-forming properties.

[0089] Example 16: Film-forming materials / fillers selected were polyvinyl alcohol and hydroxypropyl cellulose / microcrystalline cellulose, which resulted in good film formation.

[0090]

[0091] In this embodiment, the content of oseltamivir phosphate is 50%. After dissolving the polyvinyl alcohol solution at high temperature and cooling it to room temperature, the prescribed amount of oseltamivir phosphate, glycerol, microcrystalline cellulose and hydroxypropyl cellulose are added and stirred thoroughly to obtain a drug-containing adhesive solution. After standing, the adhesive film is coated and dried under vacuum conditions. The film has good toughness, mechanical strength and film-forming properties.

[0092] Example 17: Drug loading 60%

[0093]

[0094] In this embodiment, the oseltamivir phosphate content is 60%. After the prescribed amount of polyvinyl alcohol is completely dispersed, it is heated to 75-85°C to dissolve. After cooling to room temperature, the prescribed amount of microcrystalline cellulose and glycerin are added to the polyvinyl alcohol solution and stirred until homogeneous, serving as a blank adhesive solution. The prescribed amount of oseltamivir phosphate is added to the blank adhesive solution and stirred continuously to obtain the drug-containing adhesive solution. After degassing, the resulting adhesive solution is coated and dried at 60-85°C. The coated solution is then cut into sheets, wrapped, and sealed in a composite film. Polyvinyl alcohol as the film-forming material exhibits good film-forming properties, and the drug-containing film demonstrates good plasticity and flexibility.

[0095] Example 18: Drug loading 70%

[0096]

[0097]

[0098] In this embodiment, the oseltamivir phosphate content is 70%. After the prescribed amount of polyvinyl alcohol is completely dispersed, it is heated to 75-85°C to dissolve. After cooling to room temperature, the prescribed amount of microcrystalline cellulose and glycerin are added to the polyvinyl alcohol solution and stirred until homogeneous, serving as a blank adhesive solution. The prescribed amount of oseltamivir phosphate is added to the blank adhesive solution and stirred continuously to obtain the drug-containing adhesive solution. After degassing, the resulting adhesive solution is coated and dried at 60-85°C. The coated solution is then cut into sheets, wrapped, and sealed in a composite film. Polyvinyl alcohol as the film-forming material exhibits good film-forming properties, and the drug-containing film demonstrates good plasticity and flexibility.

[0099] Example 19: Drug loading 80%

[0100]

[0101] In this embodiment, the oseltamivir phosphate content is 80%. After the prescribed amount of polyvinyl alcohol is completely dispersed, it is heated to 75-85°C to dissolve. After cooling to room temperature, the prescribed amount of microcrystalline cellulose and glycerin are added to the polyvinyl alcohol solution and stirred until homogeneous, serving as a blank adhesive solution. The prescribed amount of oseltamivir phosphate is added to the blank adhesive solution and stirred continuously to obtain the drug-containing adhesive solution. After degassing, the resulting adhesive solution is coated and dried at 60-85°C. The coated solution is then cut into sheets, wrapped, and sealed in a composite film. Polyvinyl alcohol as the film-forming material exhibits good film-forming properties, and the drug-containing film demonstrates good plasticity and flexibility.

[0102] The physical properties, film-forming properties, and stability (the film was placed at 40°C and 75% relative humidity for one month) of the drug film prepared using polyvinyl alcohol as the film-forming material were far superior to those of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and povidone used alone as film-forming materials. The products in Examples 1-4, 8, 11, 13, 15, and 17-19 were placed at 40°C and 75% relative humidity for six months, and the key quality indicators of the products were tested. The results are shown in Tables 1, 2, and 3 below. Using commercially available oseltamivir phosphate capsules (trade name: Tamiflu) as a control drug, the dissolution curves of Examples 2-4, 8, 11-13, 15, and 17-19 of this invention were determined using the slurry method. The results showed that there was no significant difference in dissolution rate between the oseltamivir phosphate oral dissolving film prepared according to this invention and the currently commercially available oseltamivir phosphate capsules; the trends were basically the same. The results are shown in Table 1. Figures 1 to 8 .

[0103] The dissolution curves of the self-made products (the drug films prepared in Examples 2-4, 8, 11-13, 15, and 17-19) and commercially available oseltamivir phosphate capsules were determined using the slurry method in four dissolution media: aqueous solution, pH 1.0 hydrochloric acid solution, pH 4.5 acetate buffer solution, and pH 6.8 phosphate buffer solution. For ease of observation, the dissolution curves of the self-made products and commercially available products under each media condition are shown in two separate graphs. Figure 1-8 .from Figure 1-8 It can be seen that the dissolution rates of Examples 2 and 3 in the four dissolution media are slower than those of commercially available Tamiflu capsules. The dissolution curves of Examples 4, 8, 11-13, 15, and 17-19 in the four dissolution media are basically consistent with those of commercially available Tamiflu capsules and are not pH dependent.

[0104] Table 4 shows that when the drug loading of oseltamivir phosphate orally disintegrating film is 50%, the film-forming material accounts for approximately 40%. Orally disintegrating films made with film-forming materials such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, and povidone have very poor toughness and strength, making film formation impossible. The films are fragile and cannot be properly cut or diced, severely affecting the accuracy of dosage during transportation or clinical use. While polyvinyl alcohol (PVA) as a film-forming material produces films with good flexibility and plasticity, it cannot achieve the target area (45mg specification), and the lack of moisture loss results in an uneven surface after drying. Adding water-insoluble microcrystalline cellulose to the formulation allows for rapid moisture loss from the film surface, achieving the desired film characteristics. Simultaneously, using PVA as the main film-forming material increases the drug loading to 80%, resulting in films with good toughness, strength, and film-forming performance, and greater stability, significantly superior to other film-forming materials.

[0105] Table 1. Accelerated stability results of the products (Examples 1-4)

[0106]

[0107] Table 2. Accelerated stability results of the products (Examples 8, 11, 13, and 15)

[0108]

[0109] Table 3. Accelerated stability results of the products (Examples 17, 18, and 19)

[0110]

[0111] Table 4 Comprehensive Evaluation of Product Appearance and Mechanical Performance

[0112]

[0113] Note: 1. Appearance evaluation: 0 points: unable to form a film, 4 points: the surface of the film is wrinkled and uneven, 8 points: the surface of the film is generally smooth and flat, with slight unevenness, 10 points: the surface of the film is smooth and flat.

[0114] 2. Film-forming properties: 0 points: fragile / unable to form a film, 4 points: barely forms a film, 8 points: good film-forming properties, 10 points: very good film-forming properties.

[0115] 3. Plasticity: 0 points: fragile / unable to form a film, 4 points: poor plasticity of the film, 8 points: good plasticity of the film, 10 points: very good plasticity of the film.

[0116] 4. Mechanical strength: 0 points: fragile / unable to form a film, 4 points: poor mechanical strength of the film, 8 points: good mechanical strength of the film, 10 points: very good mechanical strength of the film.

Claims

1. An orally disintegrating film formulation of oseltamivir phosphate, comprising the following components in weight percentages: Oseltamivir phosphate 50-80% Film-forming material 15~40% The filler is 5% microcrystalline cellulose. Plasticizer 0~10% Other auxiliary materials: 0-10% The film-forming material contains at least polyvinyl alcohol, and the weight percentage of polyvinyl alcohol in the film-forming material is 60% to 100%.

2. The oseltamivir phosphate orally disintegrating film-forming agent according to claim 1, wherein the film-forming material further comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, or povidone.

3. The oseltamivir phosphate oral dissolving film formulation according to claim 1 or 2, wherein the plasticizer is selected from propylene glycol, glycerin, polyethylene glycol 400, Tween 80, or triethyl glycerol.

4. The oseltamivir phosphate oral dissolving film formulation according to claim 1 or 2, wherein the plasticizer is glycerin.

5. The oseltamivir phosphate oral disintegrating film formulation according to claim 1 or 2, wherein the other excipients include colorants, antioxidants, and flavoring agents, wherein the colorants are selected from one or any combination of iron oxide pigments, titanium dioxide pigments, and lakes; the antioxidants are selected from one or any combination of sodium sulfite, sodium bisulfite, butylated hydroxytoluene, and butylated hydroxyanisole; and the flavoring agents are selected from one or any combination of sucralose, sodium saccharin, and flavorings.

6. A method for preparing an orally disintegrating film formulation of oseltamivir phosphate according to any one of claims 1-5, comprising the following steps: (1) First, the film-forming material of the prescription amount is evenly dispersed in room temperature water, then heated to 75~85℃ to dissolve, vacuum degassing, and then cooled to room temperature to obtain a film-forming material solution; (2) Add the prescribed amount of filler, plasticizer and other excipients to the film-forming material solution obtained in step (1) and stir until the mixture is uniform to obtain a blank adhesive solution; (3) Add the prescribed amount of oseltamivir phosphate to the blank gel obtained in step (2), stir evenly, and obtain drug-containing gel A; (4) Vacuum stir the drug-containing adhesive solution A obtained in step (3) until degassing is complete to obtain drug-containing adhesive solution B; (5) Coat and dry the drug-containing adhesive solution B obtained in step (4) on a polyester film to obtain oseltamivir phosphate oral dissolving film.

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