Oral dissolving film composition of rivaroxaban, method for preparing same, and use thereof

Abstract

Provided are an oral dissolving film composition of rivaroxaban, a method for preparing same, and use thereof. The oral dissolving film composition comprises one or more of rivaroxaban and a pharmaceutically acceptable salt, hydrate, and solvate thereof as an active ingredient, and a film-forming material. Also, the present invention features a simple process, no sedimentation during the preparation of film solutions, qualified content uniformity, high drug loading capacity, and improved patient compliance, and is particularly suitable for patients with dysphagia.

Description

Rivaroxaban Oral Dissolution Film Composition, Its Preparation Method and Application

[0001] This application claims priority to the following two applications: patent application No. 2024118648760, filed with the China National Intellectual Property Administration on December 18, 2024, entitled "Rivaroxaban Oral Dissolving Film Composition, Preparation Method Thereof and Application"; and patent application No. 2025112557762, filed with the China National Intellectual Property Administration on September 3, 2025, entitled "Rivaroxaban Oral Dissolving Film Composition, Preparation Method Thereof and Application". The entire contents of the earlier application are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of pharmaceutical preparations, specifically to rivaroxaban orally disintegrating film compositions, their preparation methods, and applications. Background Technology

[0003] Rivaroxaban (Xarelto), developed by Johnson & Johnson and Bayer, is an anticoagulant used in adult patients undergoing elective hip or knee replacement surgery to prevent venous thrombosis (VTE). It is currently approved for marketing in more than 100 countries worldwide. Rivaroxaban is a highly selective, direct-acting oral anticoagulant that dose-dependently inhibits free factor Xa in plasma and factor Xa in prothrombin complex, thereby inhibiting thrombin production and thrombus formation.

[0004] Rivaroxaban's stable pharmacokinetics, wide therapeutic window, lack of routine monitoring, and ability to meet long-term prophylactic treatment needs have led to its increasingly widespread clinical application, making it a mainstream product in the anticoagulant and antithrombotic drug market. Currently, the only available dosage form of adult rivaroxaban in China is oral tablets. For patients who are bedridden after surgery or elderly individuals who cannot swallow whole tablets, these tablets need to be crushed and mixed with applesauce, resulting in poor compliance. While orally disintegrating tablets, sublingual tablets, and dispersible tablets have addressed these issues to some extent, their manufacturing processes are complex. Furthermore, to accelerate disintegration, large amounts of disintegrants are added during preparation, resulting in these dosage forms being hygroscopic, brittle, and having a gritty texture, placing high demands on production, packaging, and storage.

[0005] Therefore, there is a need to develop a formulation of rivaroxaban to address the problem of poor patient compliance, especially for patients with dysphagia, in order to improve patient adherence. Summary of the Invention

[0006] The present invention provides an orally soluble film composition for rivaroxaban, comprising an active pharmaceutical ingredient and a film-forming material; wherein the active pharmaceutical ingredient is one or more of 5-chloro-nitro-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-azolidin-5-yl}methyl)-2-thiophene-carboxamide as shown in Formula I, its pharmaceutically acceptable salts, hydrates and solvates;

[0007] According to embodiments of the present invention, the mass percentage of the active pharmaceutical ingredient can be 20.00% to 45.00%, for example, 20.00% to 40.00%, exemplary values ​​being 20.62%, 23.81%, 25.00%, 25.97%, 26.49%, 29.40%, 30.00%, 30.17%, 31.25%, 31.74%, 32.00%, 33.00%, 34.00%, 35.00%, 36.00%, 37.00%, 38.00%, 39.00%, or 40.00%, where the mass percentage refers to the percentage of the mass of the active pharmaceutical ingredient relative to the total mass of the rivaroxaban orally soluble film composition.

[0008] According to an embodiment of the present invention, the particle size of the active drug can be D. 90 Not exceeding 75μm, it can also be D 90 Not exceeding 25μm, it can also be used for D 90 No more than 15μm, for example, D 90 The value ranges from 5 to 50 μm, with examples including 10 μm, 15 μm, 20 μm, 22 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 47 μm, or 50 μm.

[0009] According to embodiments of the present invention, the film-forming material is a carrier of the active drug and is selected from one or more of xanthan gum, pectin, gelatin, gum arabic, dextrin, sodium alginate, zein, hydroxypropyl methylcellulose (HPMC), hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), polyvinyl alcohol (PVA), polyvinylpyrrolidone, polyethylene glycol (PEG, e.g., polyethylene glycol 400), polyoxyethylene (PEO), pullulan, acrylic copolymer, polylactic acid, and silicone rubber; for example, the film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyoxyethylene. In some embodiments, the film-forming material is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, or polyoxyethylene; in some embodiments, the film-forming material is selected from a mixture of hydroxypropyl methylcellulose and polyvinyl alcohol, or a mixture of hydroxypropyl methylcellulose and polyoxyethylene.

[0010] According to an embodiment of the present invention, the mass percentage content of the film-forming material can be 40.00% to 80.00%, for example 40.00% to 65.00%, exemplarily 40.00%, 41.00%, 42.00%, 43.00%, 44.00%, 45.00%, 45.25%, 46.88%, 47.62%, 49.99%, 50.00%, 51.46%, 5 1.55%, 51.95%, 52.98%, 53.00%, 54.00%, 55.00%, 56.00%, 57.00%, 58.00%, 59.00%, 59.52%, 60.00%, 61.00%, 62.00%, 63.00%, or 64.00%, whereby the mass percentage refers to the percentage of the mass of the film-forming material to the total mass of the rivaroxaban orally soluble film composition.

[0011] According to embodiments of the present invention, the rivaroxaban orally soluble film composition may further include one or more of a plasticizer, a solubilizer, a filler, a flavoring agent, and a colorant.

[0012] According to an embodiment of the present invention, the plasticizer is used to lower the glass transition temperature of the film-forming material, improve the plasticity and toughness of the finished product, and increase the elongation. It is selected from one or more of glycerol, propylene glycol, polyethylene glycol (PEG, such as polyethylene glycol 400, i.e., PEG400), silicone oil, and polypropylene glycol, such as one or two of glycerol and polyethylene glycol.

[0013] According to embodiments of the present invention, the mass percentage of the plasticizer can be 0 to 30.00%, for example 5.00% to 18.00%, exemplarily 0, 5.00%, 6.00%, 6.25%, 6.49%, 6.62%, 7.35%, 7.94%, 8.00%, 9.00%, 10.00%, 10.31%, 11.00%, 11.91%, 12.00%, 13.00%, 14.00%, 15.00%, 15.08%, 15.63%, 16.00%, 17.00%, or 18.00%, where the mass percentage refers to the percentage of the plasticizer's mass relative to the total mass of the rivaroxaban orally soluble film composition.

[0014] According to an embodiment of the present invention, the solubilizer is a surfactant used to improve the solubility of the active pharmaceutical ingredient, and is selected from one or more of sodium dodecyl sulfate (SDS), sodium dioctyl sulfosuccinate, glyceryl monostearate and sorbitol monolaurate, preferably sodium dodecyl sulfate.

[0015] According to an embodiment of the present invention, the mass percentage of the solubilizer can be 0 to 2.00%, for example 0.10% to 1.80%, exemplarily 0, 1.80%, 1.56%, 1.19%, 1.00%, 1.03%, 0.62%, 0.66%, 0.45%, 0.30%, 0.20%, or 0.10%, where the mass percentage refers to the percentage of the mass of the solubilizer relative to the total mass of the rivaroxaban oral solvent film composition.

[0016] According to an embodiment of the present invention, the filler refers to a solid substance that can be added to the material to improve the film-forming effect or increase volume and weight, and is selected from one or more of lactose, microcrystalline cellulose, mannitol, sorbitol, xylitol, starch and pregelatinized starch, for example, one or more of lactose, microcrystalline cellulose and mannitol.

[0017] According to an embodiment of the present invention, the mass percentage of the filler can be 0 to 20.00%, for example 0, 3.00%, 5.00%, 7.35%, 7.94%, 10.31%, 12.50%, 12.99%, 13.25%, 15.00%, 17.00%, or 19.48%, where the mass percentage refers to the percentage of the filler's mass relative to the total mass of the rivaroxaban orally soluble film composition.

[0018] According to embodiments of the present invention, the flavoring agent refers to a substance that can mask unpleasant tastes or improve drug stability, selected from one or more of sucralose, aspartame, steviol glycosides, fructose, sucrose, neotame, glycyrrhizin, flavorings, fragrances, menthol, sodium chloride, saccharin, and sodium saccharin. For example, it may be one or more of sucralose, aspartame, and flavorings.

[0019] According to an embodiment of the present invention, the mass percentage of the flavoring agent can be 0 to 15.00%, for example 0, 1.00%, 2.00%, 2.60%, 3.57%, 4.41%, 4.68%, 4.76%, 5.63%, 6.18%, 7.00%, 8.00%, 9.00%, 9.05%, 10.00%, 11.00%, 12.00%, 13.00%, or 14.00%, where the mass percentage refers to the percentage of the flavoring agent's mass relative to the total mass of the rivaroxaban oral slurry composition.

[0020] According to an embodiment of the present invention, the colorant mainly refers to an excipient that optimizes the appearance of the oral dissolution membrane and improves patient compliance, and is selected from one or more of titanium dioxide, pigments and lakes.

[0021] According to an embodiment of the present invention, the mass percentage of the colorant can be 0 to 1.00%, for example 0 to 0.10%, exemplarily 0, 0.01%, 0.03%, 0.05% or 0.07%, wherein the mass percentage refers to the percentage of the mass of the colorant relative to the total mass of the rivaroxaban orally soluble film composition.

[0022] In some embodiments, the rivaroxaban orally soluble film composition comprises or consists of the following components: an active pharmaceutical ingredient, a film-forming material, a plasticizer, a solubilizer, and a flavoring agent;

[0023] Preferably, the active pharmaceutical ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof, with a particle size D. 90 The size does not exceed 25 μm, and the mass percentage of the active drug is 20.00% to 45.00%.

[0024] The film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyethylene oxide, and the mass percentage of the film-forming material is 40.00% to 80.00%.

[0025] The plasticizer is selected from one or both of glycerol and polyethylene glycol, and the mass percentage of the plasticizer is 5.00-20.00%.

[0026] The solubilizer is sodium dodecyl sulfate, and the mass percentage of the solubilizer is 0.30-2.00%.

[0027] In some embodiments, the rivaroxaban orally soluble film composition comprises or consists of the following components: an active pharmaceutical ingredient, a film-forming material, a plasticizer, a filler, and a flavoring agent;

[0028] Preferably, the active pharmaceutical ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof, with a particle size D. 90 The size does not exceed 50 μm, and the mass percentage of the active drug is 20.00% to 35.00%.

[0029] The film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyethylene oxide, and the mass percentage of the film-forming material is 40.00% to 80.00%.

[0030] The plasticizer is selected from one or both of glycerol and polyethylene glycol, and the mass percentage of the plasticizer is 5.00-10.00%.

[0031] The filler is selected from one or more of lactose, microcrystalline cellulose and mannitol, and the mass percentage of the filler is 5.00 to 15.00%.

[0032] In some embodiments, the rivaroxaban orally soluble film composition comprises or consists of the following components: an active pharmaceutical ingredient, a film-forming material, a plasticizer, a solubilizer, a filler, and a flavoring agent;

[0033] Preferably, the active pharmaceutical ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof, with a particle size D. 90 The size of the active pharmaceutical ingredient is not more than 15 μm, and the mass percentage of the active pharmaceutical ingredient is 20.00% to 30.00%.

[0034] The film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyethylene oxide, and the mass percentage of the film-forming material is 40.00% to 80.00%.

[0035] The plasticizer is selected from one or both of glycerol and polyethylene glycol, and the mass percentage of the plasticizer is 5.00-20.00%.

[0036] The solubilizer is sodium dodecyl sulfate, and the mass percentage of the solubilizer is 0.30-2.00%.

[0037] The filler is selected from one or more of lactose, microcrystalline cellulose and mannitol, and the mass percentage of the filler is 5.00 to 15.00%.

[0038] In some embodiments, the rivaroxaban orally soluble film composition comprises or consists of the following components: active pharmaceutical ingredient, film-forming material, plasticizer, solubilizer, filler, flavoring agent, and colorant;

[0039] Preferably, the active pharmaceutical ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof, with a particle size D. 90 The size does not exceed 25 μm, and the mass percentage of the active drug is 20.00% to 30.00%.

[0040] The film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyethylene oxide, and the mass percentage of the film-forming material is 40.00% to 80.00%.

[0041] The plasticizer is selected from one or both of glycerol and polyethylene glycol, and the mass percentage of the plasticizer is 5.00-10.00%.

[0042] The solubilizer is sodium dodecyl sulfate, and the mass percentage of the solubilizer is 0.30-2.00%.

[0043] The filler is selected from one or more of lactose, microcrystalline cellulose and mannitol, and the mass percentage of the filler is 5.00 to 15.00%.

[0044] In some embodiments, the rivaroxaban orally soluble film composition comprises or consists of the following components: an active pharmaceutical ingredient, a film-forming material, a plasticizer, a solubilizer, and a filler;

[0045] Preferably, the active pharmaceutical ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof, with a particle size D. 90 The size of the active pharmaceutical ingredient is not more than 15 μm, and the mass percentage of the active pharmaceutical ingredient is 20.00% to 30.00%.

[0046] The film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyethylene oxide, and the mass percentage of the film-forming material is 40.00% to 80.00%.

[0047] The plasticizer is selected from one or both of glycerol and polyethylene glycol, and the mass percentage of the plasticizer is 5.00-10.00%.

[0048] The solubilizer is sodium dodecyl sulfate, and the mass percentage of the solubilizer is 0.30-2.00%.

[0049] The filler is selected from one or more of lactose, microcrystalline cellulose and mannitol, and the mass percentage of the filler is 5.00 to 15.00%.

[0050] In some embodiments, the rivaroxaban orally disintegrating film composition comprises or consists of the following components: an active pharmaceutical ingredient, a film-forming material, a filler, and a flavoring agent;

[0051] Preferably, the active pharmaceutical ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof, with a particle size D. 90 The size does not exceed 25 μm, and the mass percentage of the active drug is 20.00% to 30.00%.

[0052] The film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyethylene oxide, and the mass percentage of the film-forming material is 40.00% to 80.00%.

[0053] The filler is selected from one or more of lactose, microcrystalline cellulose and mannitol, and the mass percentage of the filler is 10.00 to 20.00%.

[0054] In some embodiments, the rivaroxaban orally soluble film composition comprises or consists of the following components: an active pharmaceutical ingredient, a film-forming material, a plasticizer, a filler, a flavoring agent, and a colorant;

[0055] Preferably, the active pharmaceutical ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof, with a particle size D. 90The size does not exceed 50 μm, and the mass percentage of the active drug is 25.00% to 35.00%.

[0056] The film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyethylene oxide, and the mass percentage of the film-forming material is 40.00% to 80.00%.

[0057] The plasticizer is selected from one or both of glycerol and polyethylene glycol, and the mass percentage of the plasticizer is 5.00-10.00%.

[0058] The filler is selected from one or more of lactose, microcrystalline cellulose and mannitol, and the mass percentage of the filler is 5.00 to 15.00%.

[0059] According to embodiments of the present invention, the rivaroxaban orally dissolving film composition may be any of the following formulations:

[0060] Prescription 1: 23.81% rivaroxaban (D) 90 =10μm), 59.52% hydroxypropyl methylcellulose, 11.91% glycerol, 1.19% sodium dodecyl sulfate and 3.57% sucralose, the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition;

[0061] Prescription 2: 40.00% rivaroxaban (D 90 =22μm), 40.00% polyvinyl alcohol, 10.00% polyethylene glycol 400, 1.00% sodium dodecyl sulfate and 9.00% aspartame, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition;

[0062] Prescription 3: 25.97% rivaroxaban (D) 90 =10μm), 51.95% polyvinyl alcohol, 6.49% glycerol, 12.99% microcrystalline cellulose and 2.60% sucralose, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition;

[0063] Prescription 4: 20.62% rivaroxaban (D 90 =10μm), 51.55% hydroxypropyl cellulose, 10.31% polyethylene glycol 400, 1.03% sodium dodecyl sulfate, 10.31% mannitol, 5.15% sucralose and 1.03% flavor, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition;

[0064] Prescription 5: 31.74% rivaroxaban (D 90=47μm), 47.62% polyoxyethylene, 7.94% glycerol, 7.94% lactose and 4.76% aspartame, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition;

[0065] Prescription 6: 25.00% rivaroxaban (D) 90 =22μm), 49.99% hydroxypropyl methylcellulose, 6.25% polyethylene glycol 400, 0.62% sodium dodecyl sulfate, 12.50% mannitol, 4.38% sucralose, 1.25% flavor and 0.01% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition;

[0066] Prescription 7: 26.49% rivaroxaban (D) 90 =10μm), 26.49% hydroxypropyl methylcellulose, 26.49% polyvinyl alcohol, 6.62% glycerol, 0.66% sodium dodecyl sulfate and 13.25% lactose, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition;

[0067] Prescription 8: 25.97% rivaroxaban (D) 90 =22μm), 38.96% hydroxypropyl methylcellulose, 12.99% polyvinyl alcohol, 19.48% mannitol and 2.60% sucralose, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition;

[0068] Prescription 9: 29.40% rivaroxaban (D) 90 =47μm), 14.70% hydroxypropyl methylcellulose, 36.76% polyvinyl alcohol, 7.35% glycerol, 7.35% microcrystalline cellulose, 4.41% sucralose and 0.03% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition;

[0069] Prescription 10: 30.17% rivaroxaban (D) 90 =10μm), 30.17% hydroxypropyl methylcellulose, 15.08% polyoxyethylene, 15.08% glycerol, 0.45% sodium dodecyl sulfate and 9.05% sucralose, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition.

[0070] Prescription 11: 31.25% rivaroxaban (D) 90=10μm), 46.88% hydroxypropyl methylcellulose, 15.63% glycerol, 4.68% sucralose and 1.56% sodium dodecyl sulfate, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition.

[0071] According to embodiments of the present invention, the thickness of the rivaroxaban orally soluble film composition is 10 μm to 300 μm, preferably 20 μm to 120 μm, for example 46 μm, 52 μm, 53 μm, 56 μm, 57 μm, 59 μm, 61 μm, 62 μm, 63 μm, 64 μm, 65 μm, 66 μm, 67 μm, 68 μm, 71 μm, 75 μm, 78 μm, 79 μm, 80 μm, 81 μm, 82 μm, 84 μm, 85 μm, 86 μm, 88 μm, 89 μm, 91 μm, 92 μm, 93 μm, 96 μm, 97 μm, 98 μm or 100 μm.

[0072] According to an embodiment of the present invention, the rivaroxaban orally disintegrating film composition can completely disintegrate within 60 seconds in 1000 mL of simulated saliva at 37±1°C, for example, 20 seconds, 28 seconds, 32 seconds, 38 seconds, 40 seconds, 41 seconds, 43 seconds, 44 seconds, 47 seconds, or 53 seconds.

[0073] The present invention also provides a method for preparing the rivaroxabanon oral film composition, comprising the following steps:

[0074] 1) Dissolve the film-forming material in water at 25℃~70℃ to form a solution;

[0075] 2) At room temperature, add all components except the active drug to the solution obtained in step 1), stir until homogeneous to obtain a blank gel solution;

[0076] 3) Place the active drug in the blank gel obtained in step 2), stir and disperse (until evenly dispersed), and degas to obtain the drug-containing gel;

[0077] 4) The drug-containing adhesive solution obtained in step 3) after degassing is coated evenly onto the release film using a coating machine, heated, dried, and cut to obtain the rivaroxaban oral soluble film composition.

[0078] According to an embodiment of the present invention, in step 1), when the film-forming material is polyvinyl alcohol, the temperature is preferably 60°C to 70°C; when the film-forming material is hydroxypropyl methylcellulose or hydroxypropyl cellulose, the temperature is preferably 25°C to 45°C; and when the film-forming material is polyethylene oxide, the temperature is preferably 25°C to 30°C.

[0079] According to an embodiment of the present invention, in step 3), the degassing includes vacuum degassing and settling, preferably vacuum degassing, with a vacuum degree preferably 0-20 MPa, more preferably 0.1-10 MPa; the vacuum degassing time is preferably 5 minutes to 30 minutes, more preferably 7 minutes; the settling time is preferably 8 hours to 48 hours, more preferably 12 hours to 24 hours; and the vacuum degassing temperature is preferably room temperature.

[0080] According to an embodiment of the present invention, in step 4), the coating thickness is 0.2 mm to 1 mm, preferably 0.4 mm to 0.8 mm; the drying temperature can be 60°C to 100°C, preferably 70°C to 90°C; the cutting is not particularly limited, as long as a rivaroxaban orally soluble film with a length × width of (2.5 to 3.5) cm × (2 to 2.5) cm can be obtained.

[0081] The present invention also provides the application of the rivaroxaban orally disintegrating film composition in the preparation of pharmaceutical formulations, wherein the pharmaceutical formulations may be orally disintegrating films.

[0082] The present invention also provides a pharmaceutical formulation comprising, or prepared from, the above-described rivaroxaban orally soluble film composition.

[0083] According to an embodiment of the present invention, the pharmaceutical preparation is an orally disintegrating film.

[0084] The present invention also provides the use of the rivaroxaban orally disintegrating film composition in the preparation of pharmaceutical formulations for the prevention and / or treatment of venous thrombosis and stroke.

[0085] According to an embodiment of the present invention, the drug is an orally disintegrating film.

[0086] The present invention also provides a method for preventing and / or treating venous thrombosis and stroke, which involves administering a therapeutically effective amount of the rivaroxaban orally disintegrating composition or the pharmaceutical preparation to a patient in need.

[0087] Terminology Definitions and Explanations

[0088] Unless otherwise stated, the definitions of terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, and specific definitions in embodiments, can be arbitrarily combined and combined with each other. Such combinations and combinations shall fall within the scope of this application specification.

[0089] Term "D" 90 "" refers to the volume-weighted particle diameter, where, at the time of measurement, the cumulative 90% of particles have equal or smaller diameters. For example, if the particle swarm's D 90If the diameter is approximately 60 micrometers, then 90% of the volume of particles has a diameter less than or equal to approximately 60 micrometers.

[0090] The term "therapeutic effective amount" refers to the amount of the active pharmaceutical ingredient of this invention sufficient to achieve the intended application (including, but not limited to, the treatment of diseases as defined below). Therapeutic effective amount can vary depending on factors such as the intended application (in vitro or in vivo), the subject being treated, and the condition of the disease, such as the subject's weight and age, the severity of the disease, and the route of administration, which can be readily determined by those skilled in the art. The specific dosage will vary depending on factors such as the specific active ingredient selected, the administration regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system used.

[0091] In this invention, room temperature refers to an ambient temperature of 10℃ to 35℃, for example, 25℃.

[0092] The term "multiple" refers to two or more kinds, such as two, three or more kinds.

[0093] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0094] The reagents and raw materials used in this invention are all commercially available.

[0095] The beneficial effects of this invention are:

[0096] The rivaroxaban orally dissolving film composition provided by this invention has the advantages of good taste, stable properties, good tensile strength, high dissolution rate, and immediate dissolution in the oral cavity without the need for drinking water. It also eliminates the gritty feeling after dissolving in the oral cavity and allows for rapid oral absorption. This effectively solves the shortcomings of existing technologies, such as the limited variety of rivaroxaban dosage forms and low patient compliance.

[0097] Meanwhile, the process of this invention is simple, no sedimentation occurs during the preparation of the membrane solution, the content uniformity meets the requirements, the drug loading is high, and the compliance of clinical patients is effectively improved. It is especially suitable for patients with dysphagia and has good market prospects. Detailed Implementation

[0098] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0099] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods. Experimental methods in the following examples that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0100] Examples 1-11

[0101] The prescriptions for Examples 1-11 are shown in Table 1.

[0102] Table 1 * indicates removal during the process.

[0103] Rivaroxaban orally soluble films were prepared according to the formulation shown in Table 1, using the following steps:

[0104] 1) The film-forming material is dissolved in water at a temperature of 25℃ to 70℃ to form a solution; when the film-forming material is polyvinyl alcohol, the temperature is preferably 60℃ to 70℃; when the film-forming material is hydroxypropyl methylcellulose or hydroxypropyl cellulose, the temperature is preferably 25℃ to 45℃; when the film-forming material is polyethylene oxide, the temperature is preferably 25℃.

[0105] 2) At room temperature, add all components except the active drug to the solution obtained in step 1), stir until homogeneous to obtain a blank gel solution;

[0106] 3) Place the active drug in the blank gel solution obtained in step 2), stir until evenly dispersed, and defoam to obtain a drug-containing gel solution; defoaming includes vacuum defoaming and standing, preferably vacuum defoaming, with a vacuum degree preferably 0-20 MPa, more preferably 0.1-10 MPa; the vacuum defoaming time is preferably 5-30 min, more preferably 7 min. The standing time is preferably 8-48 h, more preferably 12-24 h; the vacuum defoaming temperature is preferably room temperature.

[0107] 4) The degassed drug-containing adhesive solution obtained in step 3) is evenly coated onto the release film using a coating machine, heated, dried, cut, and packaged to obtain rivaroxaban oral soluble film;

[0108] The coating thickness is 0.2–1 mm, preferably 0.4–0.8 mm; the drying temperature is 60–100 °C, preferably 70–90 °C;

[0109] After drying, the membrane was cut to obtain rivaroxaban oral solution membrane with a length × width of (2.5~3.5)cm × (2~2.5)cm.

[0110] Test case

[0111] Using the rivaroxaban orally soluble film-forming agents prepared in Examples 1-11 as samples, their mechanical properties, dissolution rate, related substances, and disintegration time were tested.

[0112] 1. Mechanical strength determination

[0113] Use a texture analyzer (model: Rapid TA) + The mechanical strength of the rivaroxaban orally soluble film formulations from Examples 1 to 11 (manufacturer: Shanghai Tengba Instrument Technology Co., Ltd.) was tested, and the results are shown in Table 2.

[0114] Table 2 Results of Mechanical Strength Test of Rivaroxaban Oral Coating Agent

[0115] Data show that the rivaroxaban orally soluble films prepared in Examples 1-11 of this invention have good tensile strength.

[0116] 2. Dissolution test

[0117] The dissolution rate of the rivaroxaban orally soluble film formulations from Examples 1 to 11 was determined using the following specific methods:

[0118] Test medium: 900 ml pH 4.5 acetate buffer + 0.4% SDS (37℃±0.5℃).

[0119] Dissolution method: Method II (paddle method) of Dissolution and Release Determination, 0931, Chinese Pharmacopoeia 2020 Edition, with a rotation speed of 75 rpm.

[0120] Sampling time: 30 min.

[0121] Six tablets of rivaroxaban orally soluble film preparation were taken and their dissolution was determined using the method described above. The results are shown in Table 3.

[0122] Table 3

[0123] The results showed that the cumulative dissolution rate of the rivaroxaban orally dissolving membrane of the present invention was above 85% after 30 min in a medium of pH 4.5 acetate buffer + 0.4% SDS, indicating high dissolution rate.

[0124] 3. Oral dissolution membrane related substances test

[0125] The rivaroxaban orally soluble film formulations of Examples 1 to 11 were placed at a high temperature of 50°C and under accelerated conditions (40°C ± 2°C, relative humidity 75% ± 5%) for 30 days or 1 month, and the levels of related substances in the formulations were tested.

[0126] The relevant substances were determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0127] Solvent: 0.067% phosphoric acid aqueous solution - acetonitrile (40:60).

[0128] Take 3 tablets of this product and place them in a 100mL volumetric flask. Add solvent to three-quarters of the total volume of the volumetric flask. Shake to completely disintegrate the sample, then sonicate for 10 minutes to dissolve rivaroxaban. Cool the sample, dilute to the mark with solvent, shake well, filter through a PTFE filter membrane, and use the filtrate as the test solution.

[0129] For the reference solution, accurately weigh an appropriate amount of rivaroxaban reference standard and dilute it with the mobile phase to prepare a solution containing approximately 1.2 μg of rivaroxaban per ml.

[0130] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (Waters XBridge C18, 50 mm × 4.6 mm, 3.5 μm or equivalent column); mobile phase A was 0.067% phosphoric acid aqueous solution-acetonitrile (92:8), and mobile phase B was acetonitrile, with gradient elution according to Table 4; detection wavelength was 250 nm; flow rate was 1.0 mL per minute; column temperature was 45 °C; injection volume was 5 μl.

[0131] Table 4

[0132] The system suitability requirements are that the theoretical plate number in the reference solution, calculated based on the rivaroxaban peak, should not be less than 10,000, and the tailing factor should not exceed 1.5.

[0133] The test solution and the reference solution are precisely measured and injected separately into the liquid chromatograph.

[0134] If impurity peaks are present in the chromatogram of the test solution, the percentage of a single impurity shall not exceed 0.2% according to the external standard method of principal component without correction factor; the total percentage of impurities shall not exceed 0.5%, and the reporting limit shall be 0.1%.

[0135] The results of the relevant substance tests are shown in Table 5 ( / indicates not detected).

[0136] Table 5

[0137] The results show that the embodiments 1 to 11 of the present invention have good stability.

[0138] 4. Detection of oral film thickness and disintegration time

[0139] The disintegration time of rivaroxaban orally soluble films from Examples 1 to 11 (Chinese Pharmacopoeia 2020 Edition 0921 Disintegration Time Test Method, in 1000 mL of simulated saliva at 37±1℃) was determined, and the results are shown in Table 6.

[0140] Table 6

[0141] Based on the above experimental data, it can be seen that the rivaroxaban orally soluble film composition provided by the present invention has the advantages of thin thickness, stable properties, good mechanical properties, high dissolution rate and fast disintegration rate.

[0142] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A film composition for oral delivery of rivaroxaban, characterized in that: The rivaroxaban orally soluble film composition comprises an active pharmaceutical ingredient and a film-forming material; the active pharmaceutical ingredient is one or more of 5-chloro-nitro-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-azolidin-5-yl}methyl)-2-thiophene-carboxamide as shown in Formula I, its pharmaceutically acceptable salts, hydrates and solvates; 2. The rivaroxaban orally soluble film composition according to claim 1, characterized in that: The active pharmaceutical ingredient has a mass percentage content of 20.00% to 45.00%, where mass percentage refers to the percentage of the mass of the active pharmaceutical ingredient relative to the total mass of the rivaroxaban oral soluble film composition; And / or, The particle size D of the active drug is not more than 75 μm 90 not more than 75 μm, also D 90 not more than 25 μm, also D 90 not more than 15 μm; And / or, The film-forming material is selected from one or more of xanthan gum, pectin, gelatin, gum arabic, dextrin, sodium alginate, zein, hydroxypropyl methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyoxyethylene, pullulan, acrylic acid copolymer, polylactic acid, and silicone rubber. And / or, The mass percentage of the film-forming material is 40.00% to 80.00%, where mass percentage refers to the percentage of the mass of the film-forming material relative to the total mass of the rivaroxaban oral solvent film composition.

3. The film composition according to claim 1, wherein: The rivaroxaban orally soluble film composition further comprises one or more of a plasticizer, a solubilizer, a filler, a flavoring agent, and a colorant.

4. The rivaroxaban orally soluble film composition according to claim 3, characterized in that: The plasticizer is selected from one or more of glycerin, propylene glycol, polyethylene glycol, silicone oil, and polypropylene glycol; And / or, The solubilizer is selected from one or more of sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, glyceryl monostearate, and sorbitol monolaurate. And / or, The filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, sorbitol, xylitol, starch, and pregelatinized starch; And / or, The flavoring agent is selected from one or more of sucralose, aspartame, steviol glycosides, fructose, sucrose, neotame, glycyrrhizin, flavoring, fragrance, menthol, sodium chloride, saccharin, and sodium saccharin. And / or, The colorant is selected from one or more of titanium dioxide, pigments, and lakes.

5. The rivaroxaban orally soluble film composition according to claim 3, characterized in that: The plasticizer has a mass percentage content of 0-30.00%, where mass percentage refers to the percentage of the plasticizer's mass relative to the total mass of the rivaroxaban orally soluble film composition; And / or, The mass percentage of the solubilizer is 0-2.00%, and the mass percentage refers to the percentage of the mass of the solubilizer relative to the total mass of the rivaroxaban oral solvent film composition; And / or, The filler has a mass percentage content of 0-20.00%, where the mass percentage content refers to the percentage of the filler's mass relative to the total mass of the rivaroxaban orally soluble film composition; And / or, The flavoring agent has a mass percentage content of 0-15.00%, where the mass percentage content refers to the percentage of the flavoring agent's mass relative to the total mass of the rivaroxaban oral soluble film composition; And / or, The colorant has a mass percentage content of 0 to 1.00%, where mass percentage refers to the percentage of the colorant's mass relative to the total mass of the rivaroxaban oral sol-solution composition.

6. The film composition according to claim 1, wherein: The rivaroxaban orally soluble film composition is any of the following formulations: Prescription 1: 23.81% rivaroxaban (D) 90 =10μm), 59.52% hydroxypropyl methylcellulose, 11.91% glycerol, 1.19% sodium dodecyl sulfate and 3.57% sucralose, the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition; Prescription 2: 40.00% rivaroxaban (D 90 =22μm), 40.00% polyvinyl alcohol, 10.00% polyethylene glycol 400, 1.0% sodium dodecyl sulfate and 9.0% aspartame, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition; Prescription 3: 25.97% rivaroxaban (D) 90 =10μm), 51.95% polyvinyl alcohol, 6.49% glycerol, 12.99% microcrystalline cellulose and 2.60% sucralose, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition; Prescription 4: 20.62% rivaroxaban (D 90 =10μm), 51.55% hydroxypropyl cellulose, 10.31% polyethylene glycol 400, 1.03% sodium dodecyl sulfate, 10.31% mannitol, 5.15% sucralose and 1.03% flavor, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition; Prescription 5: 31.74% rivaroxaban (D 90 =47μm), 47.62% polyoxyethylene, 7.94% glycerol, 7.94% lactose and 4.76% aspartame, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition; Prescription 6: 25.00% rivaroxaban (D) 90 =22μm), 49.99% hydroxypropyl methylcellulose, 6.25% polyethylene glycol 400, 0.62% sodium dodecyl sulfate, 12.50% mannitol, 4.38% sucralose, 1.25% flavor and 0.01% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition; Prescription 7: 26.49% rivaroxaban (D) 90 =10μm), 26.49% hydroxypropyl methylcellulose, 26.49% polyvinyl alcohol, 6.62% glycerol, 0.66% sodium dodecyl sulfate and 13.25% lactose, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition; Prescription 8: 25.97% rivaroxaban (D) 90 =22μm), 38.96% hydroxypropyl methylcellulose, 12.99% polyvinyl alcohol, 19.48% mannitol and 2.60% sucralose, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition; Prescription 9: 29.40% rivaroxaban (D) 90 =47μm), 14.70% hydroxypropyl methylcellulose, 36.76% polyvinyl alcohol, 7.35% glycerol, 7.35% microcrystalline cellulose, 4.41% sucralose and 0.03% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition; Prescription 10: 30.17% rivaroxaban (D) 90 =10μm), 30.17% hydroxypropyl methylcellulose, 15.08% polyoxyethylene, 15.08% glycerol, 0.45% sodium dodecyl sulfate and 9.05% sucralose, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition; Prescription 11: 31.25% rivaroxaban (D) 90 =10μm), 46.88% hydroxypropyl methylcellulose, 15.63% glycerol, 4.68% sucralose and 1.56% sodium dodecyl sulfate, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the rivaroxaban orally soluble film composition.

7. The rivaroxaban orally soluble film composition according to any one of claims 1 to 6, characterized in that: The thickness of the rivaroxaban orally soluble film composition is 10 μm to 300 μm; And / or, The rivaroxaban orally disintegrating film composition described herein can completely disintegrate within 60 seconds in 1000 mL of simulated saliva at 37±1 °C.

8. The method of preparing the film composition for oral administration of rivaroxaban according to any one of claims 1 to 7, characterized in that Includes the following steps: 1) Dissolve the film-forming material in water at 25℃~70℃ to form a solution; 2) At room temperature, add all components except the active drug to the solution obtained in step 1), stir until homogeneous to obtain a blank gel solution; 3) Place the active drug in the blank gel obtained in step 2), stir until it is evenly dispersed, and degas to obtain the drug-containing gel; 4) The drug-containing adhesive solution obtained in step 3) after degassing is evenly coated onto the release film using a coating machine, heated, dried, and cut to obtain the rivaroxaban orally soluble film composition.

9. The use of the rivaroxaban orally disintegrating film composition according to any one of claims 1 to 7 in the preparation of pharmaceutical formulations for the prevention and / or treatment of venous thrombosis and stroke; Preferably, the pharmaceutical preparation is an orally disintegrating film.

10. A pharmaceutical preparation comprising the rivaroxaban orally disintegrating film composition as described in any one of claims 1 to 7, preferably the pharmaceutical preparation being an orally disintegrating film.

11. A method for preventing and / or treating venous thrombosis and stroke, comprising administering to a patient in need a therapeutically effective amount of the rivaroxaban orally disintegrating composition of any one of claims 1 to 7 or the pharmaceutical preparation of claim 10.

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