Brimonidine oral osmotic film composition, its preparation method and application

Abstract

The application provides a buccal film composition of brexpiprazole, which comprises an active drug, a film-forming material and a plasticizer, wherein the active drug is one or more of 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta-pyridine, a pharmaceutically acceptable salt, a hydrate and a solvate thereof. The buccal film composition of brexpiprazole has the advantages of thin thickness, good taste, stable property, good dissolution rate, immediate dissolution in the oral cavity without drinking water, special suitability for patients with difficulty in swallowing, no grit feeling after dissolution in the oral cavity, fast oral absorption speed, uniform appearance, good flexibility, simple process, no sedimentation during the preparation of the film liquid, required content uniformity, high drug loading and good market prospect.

Description

[0001] This application claims priority over the following earlier applications:

[0002] Priority is claimed to the earlier application filed with the China National Intellectual Property Administration on March 22, 2024, with patent application number 202410334171.1 and invention title "Bunanselin Oral Dissolution Film Composition, Preparation Method Thereof and Application".

[0003] Priority is claimed to the earlier application filed with the China National Intellectual Property Administration on May 9, 2024, with patent application number 202410568138.5 and invention title "Bunanselin Oral Dissolution Film Composition, Preparation Method Thereof and Application".

[0004] Priority is claimed to the earlier application filed with the China National Intellectual Property Administration on June 28, 2024, with patent application number 202410867474.X and invention title "Bunanselin Oral Dissolution Film Composition, Preparation Method Thereof and Application".

[0005] Priority is claimed to the earlier application filed with the China National Intellectual Property Administration on July 11, 2024, with patent application number 202410934643.7 and invention title "Bunanselin Oral Dissolution Film Composition, Preparation Method Thereof and Application".

[0006] The full text of the prior application is incorporated herein by reference. Technical Field

[0007] This invention relates to the field of pharmaceutical preparations, specifically to a buspirone oral soluble film composition, its preparation method, and its application. Background Technology

[0008] Schizophrenia is a severe, chronic mental illness of unknown etiology. Its clinical symptoms are diverse, affecting multiple aspects including sensation, thought, emotion, volition, behavior, and cognitive function. Typical positive symptoms include hallucinations, delusions, mania, irritability, and disordered speech and behavior. Typical negative symptoms include emotional blunting and apathy, poverty of volition, and cognitive impairment. Individual differences in clinical symptoms among schizophrenia patients are significant. It often begins in young adulthood, with a slow onset and prolonged course.

[0009] Schizophrenia affects approximately 21 million people worldwide, with about 3.5 million patients in the United States. Currently approved medications for schizophrenia primarily utilize dopamine D2 receptor blockade, which is effective in controlling positive symptoms but largely ineffective in improving negative symptoms. Furthermore, classic antipsychotics often cause drug-induced negative symptoms and extrapyramidal side effects due to their low selectivity for other dopamine receptor subtypes (D1, D3, D4, D5) and D2 receptor sites. Some atypical psychotropic drugs targeting 5-HT2 are mainly used to reduce extrapyramidal side effects and are not truly effective targets for schizophrenia medications, nor have they improved clinical efficacy.

[0010] Bronaseline (2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridine) is a novel atypical antipsychotic developed by Sumitomo Pharmaceuticals of Japan. It belongs to the class of serotonin and dopamine antagonists, blocking dopamine D2 receptors and 5-HT2A receptors. Compared to other antipsychotic drugs currently on the market, bronaseline has fewer extrapyramidal side effects. Furthermore, its affinity for D2 receptors is 20 times that of haloperidol and 94 times that of risperidone, while its affinity for adrenaline α1, α2, and β receptors, as well as histamine H1 and cholinergic M1 receptors, is relatively low. This effectively improves both positive and negative symptoms of schizophrenia while reducing the risk of adverse reactions. Among nine antipsychotic drugs, including aripiprazole, haloperidol, olanzapine, paliperidone, quetiapine, and risperidone, bronaseline also has the lowest risk of weight gain. Currently, the clinical dosage form is ordinary tablets. However, ordinary tablets are difficult to swallow, making them unsuitable for patients when taking this type of medication. They are also inconvenient for patients to take without water.

[0011] Therefore, there is a need to develop a dosage form of buprofen to address the problem of poor patient compliance, especially for patients with dysphagia, in order to improve patient adherence. Summary of the Invention

[0012] The technical problem solved by this invention is to overcome the shortcomings of existing technologies, such as the limited variety of bunamserin dosage forms and low patient compliance, by providing a bunamserin oral dissolution film composition, its preparation method, and its application.

[0013] The present invention provides a buspirone oral soluble film composition comprising an active pharmaceutical ingredient, a film-forming material, and a plasticizer, wherein the active pharmaceutical ingredient is one or more selected from 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridine as shown in Formula I, its pharmaceutically acceptable salts, hydrates, and solvates.

[0014]

[0015] According to an embodiment of the present invention, the particle size D90 of the active drug is ≤30.0 μm, for example, 0.5 μm ≤D90. 90 ≤25.0μm or D90≤20.0μm, for example 25μm, 24μm, 23μm, 22μm, 21μm, 20μm, 19μm, 18μm, 16μm, 15μm, 14.0μm, 13.0μm, 12.0μm, 11.0μm, 10.0μm, 9.0μm, 8.0μm, 7.0μm, 6.0μm, 5.0μm, 4.0μm, 3.0μm, 2.0μm or 1.0μm.

[0016] According to embodiments of the present invention, the mass percentage of the active pharmaceutical ingredient can be 2.0% to 25.0%, for example 4.0% to 22.0%, exemplarily 21.0%, 20.5%, 20.0%, 19.0%, 18.0%, 17.0%, 16.0%, 15.0%, 14.0%, 13.6%, 13.0%, 12.0%, 11.6%, 11.0%, 10.3%, 10.1%, 10.0%, 9.0%, 8.0%, 7.4%, 7.0%, 6.8%, 6.3%, 6.0%, 5.0%, or 3.0%, where the mass percentage refers to the percentage of the mass of the active pharmaceutical ingredient relative to the total mass of the Brnoserin oral slurry composition.

[0017] According to an embodiment of the present invention, the film-forming material is a carrier of the active drug and is selected from one or more of hydroxypropyl cellulose (e.g., one or more different types of hydroxypropyl cellulose such as hydroxypropyl cellulose-JF and hydroxypropyl cellulose-L), hydroxypropyl methylcellulose (also known as hydroxypropyl methylcellulose), polyvinyl alcohol, and pullulan.

[0018] In one embodiment, the film-forming material is hydroxypropyl cellulose and pullulan, for example, the mass ratio of hydroxypropyl cellulose to pullulan is (1-6):1, such as 2:1, 3:1, 4:1 or 5:1.

[0019] According to an embodiment of the present invention, the mass percentage of the film-forming material can be 30.0% to 80.0%, for example, 40.0% to 80.0%, such as 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 41%, 42.0%, 43.0%, 44.0%, 45.0%, 46.0%, 46.3%, 46.9%, 47.0%, 48.0%, 49.0%, 50.0%, 50.6%, 50.8%, 51.3%, 54.7%, 55.6%, 58.0%, 60.0%, 65.0%, 67.8%, 70.0%, 75.9%, or 78.0%, where the mass percentage refers to the percentage of the mass of the film-forming material relative to the total mass of the Bunanserin oral sol-gel composition.

[0020] According to an embodiment of the present invention, the plasticizer is used to lower the glass transition temperature of the film, increase plasticity and toughness, and improve elongation, and is selected from one or more of polyethylene glycol, propylene glycol, and glycerin.

[0021] According to embodiments of the present invention, the mass percentage content of the plasticizer can be 5.0% to 40.0%, for example 6.0%, 7.0%, 8.0%, 9.0%, 9.2%, 10.0%, 11%, 12%, 12.7%, 12.8%, 13%, 14%, 15%, 15.6%, 16%, 16.9%, 17%, 18.5%, 19%, 20.0%, 21%, 22%, 23%, 23.4%, 23.5%, 24%, 25%, 25.6%, 27%, 28%, 29.0%, 30.0%, 3 1%, 32.0%, 33%, 34%, 35.0%, 36%, 37%, 38.0%, or 39%, whereby the mass percentage refers to the percentage of the plasticizer's mass relative to the total mass of the Bunanserin oral sol-gel composition.

[0022] According to an embodiment of the present invention, the Bunanserin oral soluble film composition may further include one or more of a colorant, a disintegrant, a flavoring agent, and / or a filler.

[0023] According to an embodiment of the present invention, the colorant refers to a substance that can improve the appearance color of the preparation, can be used to identify the concentration of the preparation, distinguish the method of application, and reduce the patient's aversion to taking the medication, such as titanium dioxide.

[0024] According to an embodiment of the present invention, the mass percentage of the colorant can be 0 to 5.0%, for example 0 to 3.0%, such as 0, 0.02%, 0.05%, 1.3%, 1.40%, 1.7%, 2.6%, 3%, 3.5%, 4% or 4.5%, whereby the mass percentage refers to the percentage of the mass of the colorant to the total mass of the Bunsenkel oral sol-gel composition.

[0025] According to an embodiment of the present invention, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, and starch.

[0026] According to an embodiment of the present invention, the mass percentage of the disintegrant is 0 to 10.0%, for example 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, or 9.0%, whereby the mass percentage refers to the percentage of the mass of the disintegrant relative to the total mass of the Bunanserin oral soluble film composition.

[0027] According to an embodiment of the present invention, the flavoring agent is selected from one or more of aspartame, sucralose, fructose, sucrose, steviol glycosides, glycyrrhizin, flavoring, menthol, sodium chloride, neotame, acesulfame potassium, saccharin, and sodium saccharin.

[0028] According to an embodiment of the present invention, the flavoring agent has a mass percentage content of 0 to 20.0%, for example, 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 16.0%, 17.0%, 18.0%, and 19.0%, where the mass percentage content refers to the percentage of the flavoring agent's mass to the total mass of the Bunanserin oral soluble film composition.

[0029] According to an embodiment of the present invention, the filler refers to a solid substance that, when added to a material, can improve the material's properties, or increase its volume or weight, thereby reducing the material's cost, and is selected from one or more of microcrystalline cellulose, starch, mannitol, and lactose.

[0030] According to embodiments of the present invention, the mass percentage of the filler can be 0 to 50.0%, for example 0 to 40.0%, exemplarily 0, 2.0%, 5.0%, 8.0%, 10.0%, 11%, 12%, 13%, 14%, 15.0%, 16%, 17%, 18%, 18.5%, 19%, 20.0%, 21%, 22%, 23%, 23.4%, 25%, 25.3%, 25.5%, 25.6%, 26%, 27%, 27.8%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, or 39%, where the mass percentage refers to the percentage of the filler's mass relative to the total mass of the Bunanserin oral sol-gel composition.

[0031] According to one embodiment of the present invention, the bunamserin oral soluble film composition comprises: 2.0% to 25.0% bunamserin, 45.0% to 80.0% hydroxypropyl methylcellulose, and 10.0% to 40.0% polyethylene glycol, wherein the particle size D90 of the bunamserin is ≤20.0 μm.

[0032] According to one embodiment of the present invention, the bunamserin oral soluble film composition comprises: 2.0% to 25.0% bunamserin, 45.0% to 60.0% hydroxypropyl methylcellulose, 10.0% to 20.0% polyethylene glycol, and 20.0% to 30.0% filler, wherein the particle size D90 of the bunamserin is <20.0 μm.

[0033] According to one embodiment of the present invention, the bunamserin oral soluble film composition comprises: 2.0% to 25.0% bunamserin, 60.0% to 70.0% hydroxypropyl cellulose, and 10.0% to 20.0% polyethylene glycol, wherein the particle size D90 of the bunamserin is ≤20.0 μm.

[0034] According to one embodiment of the present invention, the bunamserin oral soluble film composition comprises: 2.0% to 25.0% bunamserin, 40.0% to 65.0% polyvinyl alcohol, 5.0% to 35.0% polyethylene glycol, and 20.0% to 30.0% microcrystalline cellulose, wherein the particle size D90 of the bunamserin is <20.0 μm.

[0035] According to one embodiment of the present invention, the bunamserin oral soluble film composition comprises: 2.0% to 25.0% bunamserin, 40.0% to 65.0% polyvinyl alcohol, 5.0% to 30.0% propylene glycol or glycerol, and 20.0% to 30.0% microcrystalline cellulose or starch, wherein the particle size D90 of the bunamserin is <20.0 μm.

[0036] According to one embodiment of the present invention, the bunamserin oral soluble film composition comprises: 2.0% to 25.0% bunamserin, 20.0% to 75.0% hydroxypropyl cellulose, 5.0% to 20.0% pullulan, 10.0% to 30.0% polyethylene glycol or glycerol, and 10.0% to 30.0% microcrystalline cellulose, wherein the particle size D90 of the bunamserin is 1 to 30 μm.

[0037] According to one embodiment of the present invention, the bunamserin oral soluble film composition comprises: 2.0% to 25.0% bunamserin, 50.0% to 70.0% hydroxypropyl cellulose, 10% to 40% glycerol or polyethylene glycol, and 0.5% to 5.0% colorant, wherein the particle size D90 of the bunamserin is 1 to 30 μm;

[0038] It may further contain 10.0% to 30.0% microcrystalline cellulose.

[0039] According to one embodiment of the present invention, the bunamserin oral soluble film composition comprises: 2.0% to 25.0% bunamserin, 30.0% to 50.0% hydroxypropyl cellulose, 5% to 20% glycerol or polyethylene glycol, and 25% to 50% microcrystalline cellulose, wherein the particle size D90 of the bunamserin is 1 to 30 μm.

[0040] According to an embodiment of the present invention, the Bunansserin oral soluble film composition may be any of the following formulations:

[0041] Formula 1: 13.6% Bunanserin, 67.8% hydroxypropyl methylcellulose, 16.9% polyethylene glycol and 1.7% titanium dioxide, wherein the particle size D90 of the Bunanserin is 10 μm;

[0042] Formula 2: 10.1% Bunaseline, 75.9% hydroxypropyl methylcellulose, 12.7% polyethylene glycol and 1.3% titanium dioxide, wherein the particle size D90 of the Bunaseline is 10 μm;

[0043] Formula 3: 20.5% Brønsserin, 51.3% hydroxypropyl methylcellulose, 25.6% polyethylene glycol and 2.6% titanium dioxide, wherein the particle size D90 of the Brønsserin is 10 μm;

[0044] Formula 4: 13.6% Brønsserin, 67.8% hydroxypropyl methylcellulose, 16.9% polyethylene glycol and 1.7% titanium dioxide, wherein the particle size D90 of the Brønsserin is 5 μm;

[0045] Formula 5: 11.6% Brønsserin, 58.0% hydroxypropyl methylcellulose, 29.0% polyethylene glycol and 1.4% titanium dioxide, wherein the particle size D90 of the Brønsserin is 5 μm;

[0046] Formula 6: 10.1% Brønsserin, 50.6% hydroxypropyl methylcellulose, 38.0% polyethylene glycol and 1.3% titanium dioxide, wherein the particle size D90 of the Brønsserin is 5 μm;

[0047] Formula 7: 10.1% Bunanserin, 50.6% hydroxypropyl methylcellulose, 12.7% polyethylene glycol, 25.3% microcrystalline cellulose and 1.3% titanium dioxide, wherein the particle size D90 of the Bunanserin is 10 μm;

[0048] Formula 8: 10.1% Bunaseline, 50.6% hydroxypropyl methylcellulose, 12.7% polyethylene glycol, 25.3% mannitol and 1.3% titanium dioxide, wherein the particle size D90 of the Bunaseline is 5 μm;

[0049] Formula 9: 10.1% Brønsserin, 50.6% hydroxypropyl methylcellulose, 12.7% polyethylene glycol, 25.3% lactose and 1.3% titanium dioxide, wherein the particle size D90 of the Brønsserin is 5 μm;

[0050] Formula 10: 10.3% Brønsserin, 51.3% pullulan, 12.8% polyethylene glycol and 25.6% microcrystalline cellulose, wherein the particle size D90 of the Brønsserin is 5 μm;

[0051] Formula 11: 13.6% Bunanserin, 67.8% hydroxypropyl cellulose-JF, 16.9% polyethylene glycol and 1.7% titanium dioxide, wherein the particle size D90 of the Bunanserin is 5 μm;

[0052] Formula 12: 13.6% Bunanserin, 67.8% hydroxypropyl cellulose-L, 16.9% polyethylene glycol and 1.7% titanium dioxide, wherein the particle size D90 of the Bunanserin is 5 μm;

[0053] Formula 13: 20.5% Bunansserin, 51.3% polyvinyl alcohol, 25.6% polyethylene glycol and 2.6% titanium dioxide, wherein the particle size D90 of the Bunansserin is 10 μm;

[0054] Formula 14: 6.8% Bunanserin, 50.8% polyvinyl alcohol, 16.9% polyethylene glycol and 25.5% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 10 μm;

[0055] Formula 15: 7.4% Bunanserin, 46.3% polyvinyl alcohol, 18.5% polyethylene glycol and 27.8% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 10 μm;

[0056] Formula 16: 6.3% Bunanserin, 54.7% polyvinyl alcohol, 15.6% polyethylene glycol and 23.4% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 10 μm;

[0057] Formula 17: 7.4% Bunanserin, 55.6% polyvinyl alcohol, 18.5% polyethylene glycol and 18.5% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 10 μm;

[0058] Formula 18: 7.4% Bunansserin, 5.6% polyvinyl alcohol, 9.2% polyethylene glycol and 27.8% microcrystalline cellulose, wherein the particle size D90 of the Bunansserin is 10 μm;

[0059] Formula 19: 6.3% Bunanserin, 46.9% polyvinyl alcohol, 23.4% polyethylene glycol and 23.4% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 10 μm;

[0060] Formula 20: 7.4% Bunanserin, 55.6% polyvinyl alcohol, 9.2% propylene glycol and 27.8% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 4 μm;

[0061] Formula 21: 6.8% Bunanserin, 50.8% polyvinyl alcohol, 16.9% propylene glycol and 25.5% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 4 μm;

[0062] Formula 22: 6.3% Bunanserin, 46.9% polyvinyl alcohol, 23.4% propylene glycol and 23.4% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 4 μm;

[0063] Formula 23: 7.4% Bunanserin, 55.6% polyvinyl alcohol, 9.2% glycerol and 27.8% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 4 μm;

[0064] Formula 24: 6.8% Brønsserin, 50.8% polyvinyl alcohol, 16.9% glycerol and 25.5% starch, wherein the particle size D90 of the Brønsserin is 4 μm;

[0065] Formula 25: 6.3% Brønsserin, 46.9% polyvinyl alcohol, 23.4% glycerol and 23.4% starch, wherein the particle size D90 of the Brønsserin is 4 μm;

[0066] Formula 26: 6.8% Bunanserin, 50.8% polyvinyl alcohol, 16.9% polyethylene glycol and 25.5% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 8 μm;

[0067] Formula 27: 6.8% Bunanserin, 50.8% polyvinyl alcohol, 16.9% polyethylene glycol and 25.5% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 4 μm;

[0068] Formula 28: 6.8% Bunanserin, 50.8% polyvinyl alcohol, 16.9% polyethylene glycol and 25.5% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 6 μm;

[0069] Formula 29: 8.16% Bunaseline, 40.82% Hydroxypropyl cellulose, 10.20% Pullulan, 20.41% Polyethylene glycol, 20.41% Microcrystalline cellulose, wherein the particle size D90 of the Bunaseline is 1-30 μm;

[0070] Formula 29: 9.09% Brønsserin, 45.45% hydroxypropyl cellulose, 11.36% pullulan, 11.36% glycerol, 22.74% microcrystalline cellulose, wherein the particle size D90 of the Brønsserin is 1-30 μm;

[0071] Formula 30: 16.00% Bunaseline, 60.00% Hydroxypropyl cellulose, 20.00% Glycerin, 4.00% Titanium Dioxide, wherein the particle size D90 of the Bunaseline is 1-30 μm;

[0072] Formula 31: 16.00% Bunanserin, 60.00% Hydroxypropyl cellulose, 20.00% Polyethylene glycol, 4.00% Titanium dioxide, wherein the particle size D90 of the Bunanserin is 1-30 μm;

[0073] Formula 32: 14.81% Bunamsserin, 37.04% hydroxypropyl cellulose, 11.11% polyethylene glycol, 37.04% microcrystalline cellulose, wherein the particle size D90 of the Bunamsserin is 1-30 μm;

[0074] Formula 33: 14.81% Bunaseline, 37.04% Hydroxypropyl cellulose, 11.11% Glycerin, 37.04% Microcrystalline cellulose, wherein the particle size D90 of the Bunaseline is 1-30 μm;

[0075] Formula 34: 8.89% Bunanserin, 66.67% hydroxypropyl cellulose, 22.22% polyethylene glycol, 2.22% titanium dioxide, wherein the particle size D90 of the Bunanserin is 1-30 μm;

[0076] Formula 35: 8.89% Bunanserin, 66.67% hydroxypropyl cellulose, 22.22% glycerol, 2.22% titanium dioxide, wherein the particle size D90 of the Bunanserin is 1-30 μm;

[0077] Formula 36: 7.27% Bunanserin, 54.55% hydroxypropyl cellulose, 18.18% polyethylene glycol, 1.82% titanium dioxide and 18.18% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 1-30 μm;

[0078] Formula 37: 7.27% Brønsserin, 54.55% hydroxypropyl cellulose, 18.18% glycerol, 1.82% titanium dioxide and 18.18% microcrystalline cellulose, wherein the particle size D90 of the Brønsserin is 1-30 μm.

[0079] The present invention also provides a method for preparing the aforementioned Brønsserin oral soluble film composition, which includes the following steps:

[0080] 1) The film-forming material is heated and dissolved in water at room temperature to 70°C to form a solution;

[0081] 2) Add all components except the active drug and film-forming material to the solution obtained in step 1), stir evenly to obtain a blank gel solution;

[0082] 3) Place the active drug in the blank gel solution obtained in step 2), stir until evenly dispersed, and stir under vacuum to remove bubbles, to obtain a drug-containing gel solution;

[0083] 4) The medicated adhesive obtained in step 3) is evenly coated onto the release film using a coating machine, dried, and cut to obtain the Bunanselin oral soluble film composition.

[0084] Step 3) Attempting to treat the adhesive using high-pressure shearing easily generates bubbles, which are difficult to defoam subsequently, resulting in long defoaming times and low defoaming rates. Vacuum defoaming, on the other hand, can achieve defoaming within 10 minutes, significantly improving defoaming efficiency, reducing time costs, and effectively enhancing process efficiency.

[0085] According to an embodiment of the present invention, the thickness of the Bunanserin oral sol-gel composition is 10 μm to 210 μm, for example 50 μm to 210 μm, such as 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 80 μm, 100 μm, 110 μm, 120 μm, 160 μm or 210 μm, etc.

[0086] According to an embodiment of the present invention, the Bunanserin oral soluble film composition can completely disintegrate within 120 seconds in 900 mL of simulated saliva (e.g., water) at 37±1°C, for example, 79 seconds, 71 seconds, 66 seconds, 65 seconds, 64 seconds, 62 seconds, 47 seconds, 46 seconds, 45 seconds, 42 seconds, 41 seconds, 40 seconds, 39 seconds, 38 seconds, 37 seconds, 35 seconds, 34 seconds, 32 seconds, or 30 seconds.

[0087] According to an embodiment of the present invention, the Brenner serin oral soluble film composition, in pH 6.8 phosphate buffer and 0.1% T80 medium, exhibits a cumulative dissolution rate of the active ingredient of not less than 75% after 60 min, for example not less than 80%, and more preferably not less than 85%.

[0088] The present invention also provides the use of the described bromelain oral soluble film composition in the preparation of medicaments for the treatment and / or prevention of schizophrenia.

[0089] The present invention also provides a method for treating schizophrenia, which involves administering a therapeutically effective amount of the aforementioned buspirone oral soluble film composition to a patient in need.

[0090] According to an embodiment of the present invention, the buspirone orally disintegrating film composition is a pharmaceutical preparation. The dosage form of the pharmaceutical preparation may be an orally disintegrating film, an orally disintegrating tablet, or a buccal film.

[0091] Terminology Definitions and Explanations

[0092] 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.

[0093] According to an embodiment of the invention, "D90" refers to the volume-weighted particle diameter, wherein, at the time of measurement, a cumulative 90 v / v% of the particles have a diameter equal to or smaller than that of the particle swarm. For example, if the D90 of the particle swarm is about 10 micrometers, then 90% of the volume of particles have a diameter less than or equal to about 10 micrometers.

[0094] 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.

[0095] The term "multiple" refers to two or more.

[0096] The reagents and raw materials used in this invention are all commercially available.

[0097] In this invention, "room temperature" refers to an ambient temperature of 10℃ to 40℃.

[0098] The beneficial effects of this invention are:

[0099] The Brnoselin oral dissolving film composition of the present invention has the advantages of thin thickness, good taste, stable properties, good dissolution rate, rapid dissolution in the oral cavity without drinking water, especially suitable for patients with swallowing difficulties, good patient compliance, no gritty feeling after dissolving in the oral cavity (i.e., suitable taste), fast oral absorption, uniform appearance, good flexibility, and good stability.

[0100] The preparation process of this composition is simple, no sedimentation occurs during the preparation of the membrane solution, the content uniformity meets the requirements, the drug loading capacity is high, and the market prospects are good. Detailed Implementation

[0101] 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.

[0102] 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.

[0103] Folding endurance: the number of times a folded object can break or develop a noticeable crease after being folded in the same location.

[0104] Tensile strength: also called ultimate tensile strength, refers to the maximum force required to break the film.

[0105] Percentage elongation: refers to the ratio of the length increase of a membrane when it breaks due to external stretching to its original length.

[0106] Examples 1-38

[0107] Formulations 1 to 6 of the Bronsen oral soluble film compositions are shown in Table 1:

[0108] Table 1 Examples 1 to 6

[0109]

[0110] * indicates removal during the process;

[0111] ** indicates the weight of the raw materials after water has been removed.

[0112] The formulations 7–12 of the Bronsen oral soluble film compositions are shown in Table 2:

[0113] Table 2 Examples 7 to 12

[0114]

[0115] * indicates removal during the process;

[0116] ** indicates the weight of the raw materials after water has been removed.

[0117] Prescriptions 13-19 are shown in Table 3:

[0118] Table 3 Examples 13 to 19

[0119]

[0120]

[0121] * indicates removal during the process;

[0122] ** indicates the weight of the raw materials after water has been removed.

[0123] Prescriptions 20-25 are shown in Table 4:

[0124] Table 4 Examples 20 to 25

[0125]

[0126] * indicates removal during the process;

[0127] ** indicates the weight of the raw materials after water has been removed.

[0128] Prescriptions 26-28 are shown in Table 5:

[0129] Table 5 Examples 26 to 28

[0130]

[0131]

[0132] * indicates removal during the process;

[0133] ** indicates the weight of the raw materials after water has been removed.

[0134]

[0135] In any of the formulations in Examples 29-38, the D90 of bunamserin can be any number from 1 to 30 μm.

[0136] Preparation method:

[0137] 1) The film-forming material is heated and dissolved in water at room temperature to 70°C to form a solution;

[0138] 2) Add all components except the active drug and film-forming material to the solution obtained in step 1), stir evenly to obtain a blank gel solution;

[0139] 3) Place the active drug into the blank gel solution obtained in step 2), stir until evenly dispersed, and then stir under vacuum to remove bubbles, obtaining the drug-containing gel. (Using high-pressure shearing to process the gel solution easily generates bubbles, which is not conducive to subsequent defoaming. At the same time, vacuum defoaming can achieve the defoaming effect within 10 minutes, which greatly improves the defoaming efficiency and shortens the time cost.)

[0140] 4) The medicated adhesive solution obtained in step 3) is evenly coated onto the release film using a coating machine, dried, and cut to obtain the Bunsenol oral soluble film composition.

[0141] Comparative Example 1

[0142] Referring to the formulations prepared in Examples 1 to 4 of patent CN117838667A, it was found that the viscosity of the adhesive was too high, it had no fluidity, and it could not be used with a high-shear emulsifier. Therefore, the preferred embodiment in the patent application, namely Example 1, was selected, and water was added to its formulation to prepare the sample.

[0143] Table 7 Comparative Example 1

[0144]

[0145] * indicates removal during the process;

[0146] ** indicates the weight of the raw materials after water has been removed.

[0147] Preparation method:

[0148] 1) Mix polyethylene glycol 400 with water at room temperature until homogeneous;

[0149] 2) Add the prescribed amount of HPMC-E5 and active drug to step 1) and stir well; heat to 50°C, add the prescribed amount of HPMC-E15, stir well, then add the prescribed amount of sucralose and banana flavoring, and stir until well mixed.

[0150] 3) Stir and degas under vacuum conditions to obtain the medicated adhesive; (Using high-pressure shearing to process the adhesive solution easily generates bubbles, which is not conducive to subsequent defoaming. Meanwhile, vacuum degassing can achieve defoaming within 10 minutes, significantly improving defoaming efficiency and reducing time costs.)

[0151] 4) The drug-containing adhesive solution obtained in step 3) is evenly coated onto the release film using a coating machine with a thickness of 0.5 mm. After drying (50°C, 40 minutes) and cutting, the buspirone oral soluble film composition is obtained.

[0152] 1. Collapse Time Limit Test

[0153] According to the formulations of Examples 1 to 6 and Examples 14 to 28, the oral soluble film formulations of bromelain were prepared using the preparation method provided by the present invention, and their disintegration time was determined. The specific determination method is as follows:

[0154] Six tablets of the drug film obtained from each example were randomly placed in 900ml of water at 37±1℃, and the disintegration time was tested. The disintegration time of the last tablet was recorded. The results are shown in Table 8.

[0155] Table 8. Disintegration time limits of Examples 1 to 6 and Examples 14 to 28

[0156]

[0157]

[0158] Based on the above results, the Bunanserin oral soluble film compositions prepared according to the embodiments of the present invention can all completely disintegrate within 120 seconds.

[0159] 2. Determination of dissolution results

[0160] The dissolution profiles of the buspirone oral dissolution film formulations prepared according to Examples 1-19 were determined using the following specific methods:

[0161] Test medium: 900 ml pH 6.8 phosphate buffer + 0.1% T80 medium (37℃±0.5℃).

[0162] Dissolution method: Method II (paddle method) of Dissolution and Release Determination in Chinese Pharmacopoeia 2020 Edition 0931 + sedimentation basket, with a rotation speed of 50 rpm.

[0163] Sampling time: 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min.

[0164] Take the oral dissolution film preparation of Brenaseline and determine the dissolution curve according to the above method. The results are shown in Table 9.

[0165] Table 9. Dissolution results of Examples 1-19 and Examples 26-28 in pH 6.8 phosphate buffer + 0.1% T80 medium.

[0166]

[0167] Based on the above results, the dissolution rate of the Bunanserin oral soluble film composition prepared according to the embodiments of the present invention is 75% or 80% or more, preferably 85% or more, at 60 min.

[0168] 3. Sample stability testing

[0169] According to the formulations of Examples 1, 13, 28 and Comparative Example 1, the oral soluble film formulations of buspirone were prepared using the corresponding preparation methods provided by this invention, and their stability under light, high humidity, 50°C and accelerated conditions was determined. The results are shown in Table 10:

[0170] Table 10 shows the stability results of Examples 1, 13, 28, and Comparative Example 1.

[0171]

[0172] Analysis of the above results shows that:

[0173] 1. The product prepared according to the present invention has good stability, at least under light and high humidity conditions;

[0174] 2. When hydroxypropyl methylcellulose is used as the film-forming material, it has good stability under light and high humidity conditions, but the content of active drug tends to decrease under 50℃ and accelerated conditions, so the storage temperature needs to be paid attention to.

[0175] 3. When polyvinyl alcohol is used as the film-forming material, the prepared product has good stability under light, high humidity, 50℃ and accelerated conditions;

[0176] 4. The reproducibility of the formulations prepared in Examples 1 to 4 of patent document CN117838667A is poor. The maximum single impurity and total impurity of the sample prepared by adding water to the preferred example 1 showed an increasing trend during the high temperature stability period, while the content showed a decreasing trend. The sample stability is poor.

[0177] Based on the above experimental data, it can be seen that the Brønsserin oral dissolving film composition provided by the present invention has the advantages of thin thickness, good taste, stable properties, instant dissolution in the oral cavity without drinking water, and rapid oral absorption.

[0178] 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 Bunansserin oral sol-gel composition, characterized in that, The Bunansserin oral soluble film composition comprises: an active pharmaceutical ingredient, a film-forming material, a plasticizer, and a colorant; The active pharmaceutical ingredient is 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridine as shown in Formula I; Formula I; The particle size D90 of the active drug is ≤20.0 μm; The active pharmaceutical ingredient has a mass percentage content of 2.0% to 25.0%, where the mass percentage content refers to the percentage of the mass of the active pharmaceutical ingredient relative to the total mass of the Bunanserin oral soluble film composition; The film-forming material is selected from polyvinyl alcohol; The plasticizer is selected from polyethylene glycol, propylene glycol, or glycerin; The mass percentage of the film-forming material is 40.0% to 60.0%, where the mass percentage refers to the percentage of the mass of the film-forming material relative to the total mass of the Bunanserlin oral sol-solution film composition. The plasticizer has a mass percentage content of 5.0% to 30.0%, where mass percentage refers to the percentage of the mass of the plasticizer relative to the total mass of the Bunanserin oral sol-gel composition; The colorant has a mass percentage content of 0.02% to 5.0%, where mass percentage refers to the percentage of the colorant's mass relative to the total mass of the Bunanselin oral sol-gel composition.

2. A Bunansserin oral sol-gel composition, characterized in that, The Bunansserin oral soluble film composition comprises: an active pharmaceutical ingredient, a film-forming material, a plasticizer, and a filler; The active pharmaceutical ingredient is 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridine as shown in Formula I; Formula I; The particle size D90 of the active drug is ≤20.0 μm; The active pharmaceutical ingredient has a mass percentage content of 2.0% to 25.0%, where the mass percentage content refers to the percentage of the mass of the active pharmaceutical ingredient relative to the total mass of the Bunanserin oral soluble film composition; The film-forming material is selected from polyvinyl alcohol; The plasticizer is selected from polyethylene glycol, propylene glycol, or glycerin; The filler is selected from microcrystalline cellulose or starch; The mass percentage of the film-forming material is 40.0% to 60.0%, where the mass percentage refers to the percentage of the mass of the film-forming material relative to the total mass of the Bunanserlin oral sol-solution film composition. The plasticizer has a mass percentage content of 5.0% to 30.0%, where mass percentage refers to the percentage of the mass of the plasticizer relative to the total mass of the Bunanserin oral sol-gel composition; The filler has a mass percentage content of 15.0% to 32.0%, where mass percentage refers to the percentage of the filler's mass relative to the total mass of the Bunanserin oral sol-gel composition.

3. The Bunansserin oral sol-gel composition as described in claim 1 or 2, characterized in that: The particle size D90 of the active drug is ≤10.0 μm; And / or, the active pharmaceutical ingredient has a mass percentage content of 4.0% to 22.0%; And / or, the plasticizer has a mass percentage content of 5.0% to 28.0%; And / or, the mass percentage of the film-forming material is 43.0% to 58.0%.

4. The Bunansserin oral sol-gel composition as described in claim 1 or 2, characterized in that: The film-forming material has a mass percentage content of 50.6%, 51.3%, 50.8%, 46.3%, 54.7%, 55.6%, 46.9%, or 58.0%. And / or, The plasticizer has a mass percentage content of 16.9%, 12.7%, 25.6%, 29.0%, 12.8%, 18.5%, 15.6%, 9.2%, 23.4%, or 23.5%.

5. The Bunansserin oral sol-gel composition as described in claim 1, characterized in that: The colorant is selected from titanium dioxide.

6. The Bunansserin oral sol-gel composition as described in claim 1 or 2, characterized in that: The described Bunsensen oral soluble film composition further includes a flavoring agent.

7. The Bunansserin oral sol-gel composition as described in claim 6, characterized in that: The flavoring agent is selected from one or more of aspartame, sucralose, fructose, sucrose, steviol glycosides, glycyrrhizin, flavoring, menthol, sodium chloride, neotame, acesulfame potassium, saccharin, and sodium saccharin.

8. The Bunansserin oral sol-gel composition as described in claim 6, characterized in that: The flavoring agent has a mass percentage content of 0~20.0%, where the mass percentage content refers to the percentage of the flavoring agent's mass relative to the total mass of the Bunanserin oral sol-gel composition.

9. The Bunansserin oral sol-gel composition as described in claim 2, characterized in that: The aforementioned bunamserin oral soluble film composition comprises: 2.0%–25.0% bunamserin, 40.0%–65.0% polyvinyl alcohol, 5.0%–35.0% polyethylene glycol, and 20.0%–30.0% microcrystalline cellulose, wherein the particle size D90 of the bunamserin is ≤20.0 μm; Alternatively, the bunamserin oral soluble film composition comprises: 2.0%–25.0% bunamserin, 40.0%–65.0% polyvinyl alcohol, 5.0%–30.0% propylene glycol or glycerol, and 20.0%–30.0% microcrystalline cellulose or starch, wherein the particle size D90 of the bunamserin is ≤20.0 μm.

10. The Bunansserin oral sol-gel composition as described in claim 1, characterized in that: The bunamserin oral soluble film composition has the following formulation: 20.5% bunamserin, 51.3% polyvinyl alcohol, 25.6% polyethylene glycol and 2.6% titanium dioxide, wherein the particle size D90 of the bunamserin is 10 μm.

11. The Bunansserin oral sol-gel composition as described in claim 2, characterized in that: The aforementioned Bunsenkel oral soluble film composition is any of the following formulations: Formula 14: 6.8% Bunanserin, 50.8% polyvinyl alcohol, 16.9% polyethylene glycol and 25.5% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 10 μm; Formula 15: 7.4% Bunanserin, 46.3% polyvinyl alcohol, 18.5% polyethylene glycol and 27.8% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 10 μm; Formula 16: 6.3% Bunanserin, 54.7% polyvinyl alcohol, 15.6% polyethylene glycol and 23.4% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 10 μm; Formula 17: 7.4% Bunanserin, 55.6% polyvinyl alcohol, 18.5% polyethylene glycol and 18.5% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 10 μm; Formula 18: 7.4% Bunanserin, 55.6% polyvinyl alcohol, 9.2% polyethylene glycol and 27.8% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 10 μm; Formula 19: 6.3% Bunanserin, 46.9% polyvinyl alcohol, 23.4% polyethylene glycol and 23.4% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 10 μm; Formula 20: 7.4% Bunanserin, 55.6% polyvinyl alcohol, 9.2% propylene glycol and 27.8% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 4 μm; Formula 21: 6.8% Bunanserin, 50.8% polyvinyl alcohol, 16.9% propylene glycol and 25.5% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 4 μm; Formula 22: 6.3% Bunanserin, 46.9% polyvinyl alcohol, 23.4% propylene glycol and 23.4% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 4 μm; Formula 23: 7.4% Bunanserin, 55.6% polyvinyl alcohol, 9.2% glycerol and 27.8% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 4 μm; Formula 24: 6.8% Brønsserin, 50.8% polyvinyl alcohol, 16.9% glycerol and 25.5% starch, wherein the particle size D90 of the Brønsserin is 4 μm; Formula 25: 6.3% Brønsserin, 46.9% polyvinyl alcohol, 23.4% glycerol and 23.4% starch, wherein the particle size D90 of the Brønsserin is 4 μm; Formula 26: 6.8% Bunanserin, 50.8% polyvinyl alcohol, 16.9% polyethylene glycol and 25.5% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 8 μm; Formula 27: 6.8% Bunanserin, 50.8% polyvinyl alcohol, 16.9% polyethylene glycol and 25.5% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 4 μm; Formula 28: 6.8% Bunanserin, 50.8% polyvinyl alcohol, 16.9% polyethylene glycol and 25.5% microcrystalline cellulose, wherein the particle size D90 of the Bunanserin is 6 μm.

12. The Bunansserin oral sol-gel composition according to any one of claims 1 and 2, characterized in that: The thickness of the Bunansserin oral sol-gel composition is 10 μm to 210 μm; And / or, The described Bunanserin oral soluble film composition can completely disintegrate within 120 seconds in 900 mL of simulated saliva at 37±1℃.

13. The method for preparing the Bunansserin oral soluble film composition according to any one of claims 1 to 12, characterized in that, Includes the following steps: 1) The film-forming material is heated and dissolved in water at room temperature to 70°C to form a solution; 2) Add all components except the active drug and film-forming material to the solution obtained in step 1), stir evenly to obtain a blank gel solution; 3) Place the active drug in the blank gel solution obtained in step 2), stir until it is evenly dispersed, and stir under vacuum to remove bubbles to obtain the drug-containing gel; 4) The medicated adhesive obtained in step 3) is evenly coated onto the release film using a coating machine, dried, and cut to obtain the Bunsenol oral soluble film composition.

14. Use of the bromelain oral soluble film composition according to any one of claims 1 to 12 in the preparation of medicaments for the treatment and / or prevention of depression and schizophrenia.

15. The use as described in claim 14, wherein the drug is an orally dissolving film or buccal film.

16. A pharmaceutical preparation, characterized in that, It is prepared from the Bunanserin oral sol-gel composition according to any one of claims 1 to 12.

17. The pharmaceutical formulation as described in claim 16, characterized in that, The pharmaceutical preparation is an oral dissolving film or buccal film.

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