Blonanserin oral soluble film composition as well as preparation method and application thereof

Abstract

The present invention provides a blonanserin oral soluble film composition, which comprises an active drug, a film forming material and a plasticizer, and the active drug is one or more of 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5, 6, 7, 8, 9, 10-hexahydrocyclooctane pyridine represented by a formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate of the 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5, 6, 7, 8, 9, 10-hexahydrocyclooctane pyridine. The blonanserin oral soluble film composition has the advantages of being thin in thickness, good in taste, stable in property, good in dissolution rate, capable of being instantly dissolved in the oral cavity without drinking water, especially suitable for patients with dysphagia, free of grit feeling after being dissolved in the oral cavity, high in oral absorption speed, uniform in appearance, good in flexibility, simple in process, low in cost and suitable for industrial production. And sedimentation cannot occur in the membrane liquid preparation process, the content uniformity meets the requirement, the drug loading capacity is high, and the marketization prospect is good. # imgabs0 #

Description

[0001] This application claims the priority of the following prior applications:

[0002] The priority right of the prior application of patent application number 202410334171.1 filed with the State Intellectual Property Office of China on March 22, 2024, with the invention title of “Bunanserin oral dissolving film composition, preparation method and application thereof”;

[0003] The priority right of the prior application of patent application number 202410568138.5 filed with the State Intellectual Property Office of China on May 9, 2024, with the invention title of "Bunanserin orosoluble film composition, preparation method and application thereof";

[0004] The priority right of the prior application of patent application number 202410867474.X filed with the State Intellectual Property Office of China on June 28, 2024, with the invention title of “Bunanserin orosoluble film composition, preparation method and application thereof”;

[0005] The priority right of the prior application of patent application number 202410934643.7 filed with the State Intellectual Property Office of China on July 11, 2024, with the invention title of "Bunanserin orosoluble film composition, preparation method and application thereof";

[0006] The entirety of said prior application is incorporated into the present application by reference. Technical Field

[0007] The invention relates to the field of pharmaceutical preparations, and in particular to a bunanserin orosoluble film composition, a preparation method and application thereof. Background Art

[0008] Schizophrenia is a serious chronic mental illness with unknown etiology. Its clinical symptoms are diverse, involving sensation, thinking, emotion, will and behavior, cognitive function, etc. Typical positive symptoms include hallucinations, delusions, mania, irritability, disordered speech and behavior, etc. Typical negative symptoms include emotional blunting, lack of will, cognitive impairment, etc. The clinical symptoms of schizophrenia patients vary greatly from person to person. Most of them develop in young and middle-aged people, often with a slow onset and a prolonged course.

[0009] Schizophrenia affects approximately 21 million people worldwide, with approximately 3.5 million patients in the United States. Currently, the schizophrenia treatment drugs approved for marketing worldwide mainly have the mechanism of action of dopamine D2 receptor blocking, which has a good effect on controlling the patient's positive symptoms, but is almost powerless to improve negative symptoms. In addition, due to their low selectivity for other dopamine receptor subtypes (D1, D3, D4, D5) and D2 receptor sites, classic antipsychotics usually cause drug-induced negative symptoms and extrapyramidal side effects. Some atypical psychiatric drugs targeting 5-HT2 are mainly used to reduce extrapyramidal side effects. They are not truly effective drug targets for schizophrenia and have not brought about improvements in clinical efficacy.

[0010] Blonanserin (2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridine) is a new type of atypical antipsychotic developed by Sumitomo Pharma of Japan. It is a serotonin and dopamine antagonist with the function of blocking dopamine D2 receptors and 5-HT2A receptors. Compared with other antipsychotic drugs on the market, blonanserin has fewer extrapyramidal side effects. At the same time, its affinity for D2 receptors is 20 and 94 times that of haloperidol and risperidone, respectively, while its affinity for adrenaline α1, α2 and β receptors, as well as histamine H1 receptors and cholinergic M1 receptors is lower. While effectively improving the positive and negative symptoms of schizophrenia, it reduces the risk of adverse reactions. Among the nine antipsychotic drugs including aripiprazole, haloperidol, olanzapine, paliperidone, quetiapine and risperidone, blonanserin also has the lowest risk of weight gain. The current clinical dosage form is ordinary tablets, which are difficult to swallow and are not suitable for patients to take. They are also not convenient for patients to take without water.

[0011] Therefore, there is a need to develop a dosage form of blonanserin to solve the problem of poor medication compliance in patients, which is particularly suitable for patients with dysphagia, in order to improve patient compliance. Summary of the invention

[0012] The technical problem solved by the present invention is to provide a blonanserin orodispersible film composition, a preparation method and application thereof in order to overcome the defects of the prior art such as the limited types of blonanserin dosage forms and the low patient compliance.

[0013] The present invention provides a bunanserin orally dissolving film composition, 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-hexahydrocyclooctanopyridine as shown in formula I, and pharmaceutically acceptable salts, hydrates and solvates thereof;

[0014]

[0015] According to an embodiment of the present invention, the particle size of the active drug is D90≤30.0 μm, for example, 0.5 μm≤D 90 ≤25.0μm or D90≤20.0μm, exemplified by 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 an embodiment of the present invention, the mass percentage of the active drug can be 2.0% to 25.0%, for example 4.0% to 22.0%, exemplified by 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%, wherein the mass percentage refers to the mass of the active drug as a percentage of the total mass of the bunanserin oral film composition.

[0017] According to an embodiment of the present invention, the film-forming material is a carrier of active drugs, selected from one or more of hydroxypropyl cellulose (such as one or more different types of hydroxypropyl cellulose such as hydroxypropyl cellulose-JF and hydroxypropyl cellulose-L), hydroxypropyl methylcellulose (also known as hypromellose), 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, for example, 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%, such as 40.0% to 80.0%, for example 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%, and the mass percentage refers to the percentage of the mass of the film-forming material to the total mass of the Bunanserin oral film-soluble 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 glycerol.

[0021] According to an embodiment of the present invention, the mass percentage 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%, 31.0%, 32.0%, 33.0%, 34.0%, 35.0%, 36.0%, 37.0%, 38.0%, 39.0%, 40.0%, 41.0%, 42.0%, 43.0%, 44.0%, 45.0%, 46.0%, 47.0%, 48.0%, 49.0%, 50.0%, 51.0%, 52.0%, 53.0%, 54.0%, 55.0%, 56.0%, 57.0%, 58.0%, 59.0%, 59.0%, 50.0%, 59.0%, 51.0%, 59.0%, 51.0%, 59.0%, 5 1%, 32.0%, 33%, 34%, 35.0%, 36%, 37%, 38.0% or 39%, wherein the mass percentage refers to the mass percentage of the plasticizer to the total mass of the Bunanserin oral film-soluble composition.

[0022] According to an embodiment of the present invention, the Bunanserin orodispersible 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 and can be used to identify the concentration of the preparation, distinguish the application method and reduce the patient's aversion to taking the medicine, such as titanium dioxide.

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

[0025] According to an embodiment of the present invention, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked 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%, 9.0%, and the mass percentage refers to the mass of the disintegrant as a percentage of the total mass of the blonanserin orosoluble 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, flavors, menthol, sodium chloride, neotame, acesulfame potassium, saccharin and saccharin sodium.

[0028] According to an embodiment of the present invention, the mass percentage of the flavoring agent is 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%, 19.0%, and the mass percentage refers to the mass of the flavoring agent as a percentage of the total mass of the bunanserin orosoluble film composition.

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

[0030] According to an embodiment of the present invention, the mass percentage of the filler can be 0-50.0%, for example 0-40.0%, exemplified by 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%, and the mass percentage refers to the percentage of the mass of the filler to the total mass of the Bunanserin oral dissolving film composition.

[0031] According to one embodiment of the present invention, the blonanserin orodispersible film composition comprises: 2.0% to 25.0% blonanserin, 45.0% to 80.0% hypromellose, and 10.0% to 40.0% polyethylene glycol, and the particle size D90 of the blonanserin is ≤20.0 μm.

[0032] According to one embodiment of the present invention, the blonanserin orodispersible film composition comprises: 2.0% to 25.0% blonanserin, 45.0% to 60.0% hydroxypropyl methylcellulose, 10.0% to 20.0% polyethylene glycol, and 20.0% to 30.0% filler. The particle size D90 of the blonanserin is less than 20.0 μm.

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

[0034] According to one embodiment of the present invention, the blonanserin orosoluble film composition comprises: 2.0% to 25.0% blonanserin, 40.0% to 65.0% polyvinyl alcohol, 5.0% to 35.0% polyethylene glycol, and 20.0% to 30.0% microcrystalline cellulose. The particle size D90 of the blonanserin is less than 20.0 μm.

[0035] According to one embodiment of the present invention, the blonanserin orosoluble film composition comprises: 2.0% to 25.0% blonanserin, 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. The particle size D90 of the blonanserin is <20.0 μm.

[0036] According to one embodiment of the present invention, the blonanserin orosoluble film composition comprises: 2.0% to 25.0% blonanserin, 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. The particle size D90 of the blonanserin is 1 to 30 μm.

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

[0038] Or further contain 10.0% to 30.0% of microcrystalline cellulose.

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

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

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

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

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

[0044] Prescription 4: 13.6% blonanserin, 67.8% hypromellose, 16.9% polyethylene glycol and 1.7% titanium dioxide, the particle size D90 of the blonanserin is 5 μm;

[0045] Prescription 5: 11.6% blonanserin, 58.0% hypromellose, 29.0% polyethylene glycol and 1.4% titanium dioxide, wherein the particle size D90 of the blonanserin is 5 μm;

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

[0047] Prescription 7: 10.1% blonanserin, 50.6% hypromellose, 12.7% polyethylene glycol, 25.3% microcrystalline cellulose and 1.3% titanium dioxide, the particle size D90 of the blonanserin is 10 μm;

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

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

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

[0051] Prescription 11: 13.6% blonanserin, 67.8% hydroxypropylcellulose-JF, 16.9% polyethylene glycol and 1.7% titanium dioxide, the particle size D90 of the blonanserin is 5 μm;

[0052] Prescription 12: 13.6% blonanserin, 67.8% hydroxypropylcellulose-L, 16.9% polyethylene glycol and 1.7% titanium dioxide, the particle size D90 of the blonanserin is 5 μm;

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

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

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

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

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

[0058] Prescription 18: 7.4% blonanserin, 5S.6% polyvinyl alcohol, 9.2% polyethylene glycol and 27.8% microcrystalline cellulose, the particle size D90 of the blonanserin is 10 μm;

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

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

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

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

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

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

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

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

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

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

[0069] Prescription 29: 8.16% blonanserin, 40.82% hydroxypropyl cellulose, 10.20% pullulan, 20.41% polyethylene glycol, 20.41% microcrystalline cellulose, the particle size D90 of the blonanserin is 1 to 30 μm;

[0070] Prescription 29: 9.09% blonanserin, 45.45% hydroxypropyl cellulose, 11.36% pullulan, 11.36% glycerol, 22.74% microcrystalline cellulose, the particle size D90 of the blonanserin is 1 to 30 μm;

[0071] Prescription 30: 16.00% blonanserin, 60.00% hydroxypropyl cellulose, 20.00% glycerin, 4.00% titanium dioxide, the particle size D90 of the blonanserin is 1 to 30 μm;

[0072] Prescription 31: 16.00% blonanserin, 60.00% hydroxypropyl cellulose, 20.00% polyethylene glycol, 4.00% titanium dioxide, the particle size D90 of the blonanserin is 1 to 30 μm;

[0073] Prescription 32: 14.81% blonanserin, 37.04% hydroxypropyl cellulose, 11.11% polyethylene glycol, 37.04% microcrystalline cellulose, the particle size D90 of the blonanserin is 1 to 30 μm;

[0074] Prescription 33: 14.81% blonanserin, 37.04% hydroxypropyl cellulose, 11.11% glycerol, 37.04% microcrystalline cellulose, the particle size D90 of the blonanserin is 1 to 30 μm;

[0075] Prescription 34: 8.89% blonanserin, 66.67% hydroxypropyl cellulose, 22.22% polyethylene glycol, 2.22% titanium dioxide, the particle size D90 of the blonanserin is 1 to 30 μm;

[0076] Prescription 35: 8.89% blonanserin, 66.67% hydroxypropyl cellulose, 22.22% glycerin, 2.22% titanium dioxide, the particle size D90 of the blonanserin is 1 to 30 μm;

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

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

[0079] The present invention also provides a method for preparing the Bunanserin oral film-soluble composition, which comprises the following steps:

[0080] 1) heating the film-forming material to dissolve in water at room temperature to 70° C. to form a solution;

[0081] 2) adding each component except the active drug and the film-forming material to the solution obtained in step 1), and stirring evenly to obtain a blank glue solution;

[0082] 3) placing the active drug in the blank glue solution obtained in step 2), stirring until uniformly dispersed, and stirring and degassing under vacuum conditions to obtain a drug-containing glue solution;

[0083] 4) The drug-containing glue obtained in step 3) is evenly coated on the release film by a coating machine, and then dried and cut to obtain the Bunanserin orally soluble film composition.

[0084] Step 3) high pressure shearing was used to treat the adhesive solution, but bubbles were easily generated, which made it difficult to defoam the adhesive solution, and the defoaming time was long and the defoaming rate was low. However, vacuum degassing can achieve defoaming effect within 10 minutes, which greatly improves defoaming efficiency, shortens time cost and effectively improves process efficiency.

[0085] According to an embodiment of the present invention, the bunanserin oral dissolving film composition has a thickness of 10 μm to 210 μm, such as 50 μm to 210 μm, for example, 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 blonanserin orosoluble film composition can completely disintegrate in 900 mL of simulated saliva (e.g., water) at 37±1°C within 120 seconds, 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 cumulative dissolution rate of the active ingredient of the blonanserin oral film-dissolving composition in pH 6.8 phosphate buffer and 0.1% T80 medium at 60 min is not less than 75%, such as not less than 80%, and preferably not less than 85%.

[0088] The present invention also provides use of the blonanserin orosoluble film composition in preparing a drug for treating and / or preventing schizophrenia.

[0089] The present invention also provides a method for treating schizophrenia, which comprises administering a therapeutically effective amount of the blonanserin orosoluble film composition to a patient in need.

[0090] According to an embodiment of the present invention, the blonanserin orodispersible film composition is a pharmaceutical preparation, and the dosage form of the pharmaceutical preparation can be an orodispersible film, an orodisintegrating tablet or a buccal film.

[0091] Definition and explanation of terms

[0092] Unless otherwise specified, the definitions of terms recorded in the specification and claims of this application, including definitions as examples, exemplary definitions, preferred definitions, specific definitions in embodiments, etc., may be arbitrarily combined and coupled with each other. Such combinations and couplings shall fall within the scope of the specification of this application.

[0093] According to an embodiment of the present invention, the "D90" refers to the volume-weighted particle diameter, wherein when measured, a cumulative 90 v / v% of the particles have an equal or smaller diameter. For example, if the D90 of a particle population is about 10 microns, 90% of the volume of the particles have a diameter less than or equal to about 10 microns.

[0094] The term "therapeutically effective amount" refers to the amount of the active ingredient of the pharmaceutical composition of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases defined below). The therapeutically effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject and disease condition treated such as the weight and age of the subject, the severity of the disease condition and the mode of administration, etc., which can be easily determined by a person of ordinary skill in the art. The specific dosage will vary depending on the following factors: the specific active ingredient selected, the dosage regimen relied on, whether to be administered in combination with other compounds, the time arrangement of administration, the tissue administered and the physical delivery system carried.

[0095] The term "plurality" means two or more.

[0096] The reagents and raw materials used in the present invention are commercially available.

[0097] The "room temperature" mentioned in the present invention refers to an ambient temperature of 10°C to 40°C.

[0098] Beneficial effects of the present invention:

[0099] The blonanserin orodispersible film composition of the present invention has the advantages of thin thickness, good taste, stable properties, good dissolution rate, and can be quickly dissolved in the oral cavity without drinking water, is particularly suitable for patients with dysphagia, has good patient compliance, does not have a gritty feeling after dissolving in the oral cavity (i.e., has a suitable taste), has a fast oral absorption rate, and has a uniform appearance, good flexibility, and good stability.

[0100] The preparation process of the composition is simple, no sedimentation occurs during the preparation of the membrane liquid, the content uniformity meets the requirements, the drug loading capacity is high, and the market prospect is good. DETAILED DESCRIPTION

[0101] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations 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 included in the scope that the present invention is intended to protect.

[0102] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. The experimental methods in the following examples without specifying specific conditions were selected according to conventional methods and conditions or according to the product specifications.

[0103] Folding resistance: the number of times a piece of paper breaks or has obvious creases after being folded at the same position;

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

[0105] Percent elongation: refers to the ratio of the increased length when the film is stretched by external force and breaks to the original length.

[0106] Examples 1-38

[0107] The prescriptions 1 to 6 of the orodispersible film composition of Bunanselin are shown in Table 1:

[0108] Table 1 Examples 1 to 6

[0109]

[0110] *Indicates removal during the process;

[0111] **Indicates the weight of raw materials and auxiliary materials after removing water.

[0112] The prescriptions 7 to 12 of the orodispersible film composition of Bunanselin are shown in Table 2:

[0113] Table 2 Examples 7 to 12

[0114]

[0115] *Indicates removal during the process;

[0116] **Indicates the weight of raw materials and auxiliary materials after removing water.

[0117] Prescriptions 13 to 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 raw materials and auxiliary materials after removing water.

[0123] Prescriptions 20 to 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 raw materials and auxiliary materials after removing water.

[0128] Prescriptions 26 to 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 raw materials and auxiliary materials after removing water.

[0134]

[0135] In any of the formulations of Examples 29-38, the D90 of blonanserin may be any number ranging 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) adding all components except the active drug and the film-forming material to the solution obtained in step 1), and stirring evenly to obtain a blank glue solution;

[0139] 3) placing the active drug in the blank glue obtained in step 2), stirring until uniformly dispersed, and stirring and degassing under vacuum conditions to obtain drug-containing glue; (using high-pressure shearing to treat the glue is prone to generate bubbles, which is not conducive to subsequent defoaming. At the same time, vacuum degassing can achieve defoaming effect within 10 minutes, so that the defoaming efficiency is greatly improved and the time cost is shortened.)

[0140] 4) The drug-containing glue obtained in step 3) is evenly coated on the release film by a coating machine, and then dried and cut to obtain the Bunanserin orally soluble film composition.

[0141] Comparative Example 1

[0142] Referring to the preparation prescriptions of Examples 1 to 4 in patent CN117838667A, it was found that the viscosity of the glue was too large, there was no fluidity, and a high shear emulsifier could not be used; therefore, the preferred embodiment in the patent application, namely Example 1, was selected, and water was added on the basis of its prescription to prepare a sample.

[0143] Table 7 Comparative Example 1

[0144]

[0145] *Indicates removal during the process;

[0146] **Indicates the weight of raw materials and auxiliary materials after removing water.

[0147] Preparation method:

[0148] 1) Stir polyethylene glycol 400 and water evenly at room temperature;

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

[0150] 3) Stirring and degassing under vacuum conditions to obtain drug-containing glue; (Using high-pressure shearing to treat the glue solution is prone to produce bubbles, which is not conducive to subsequent defoaming. At the same time, vacuum degassing can achieve the defoaming effect within 10 minutes, which greatly improves the defoaming efficiency and shortens the time cost.)

[0151] 4) The drug-containing glue obtained in step 3) is evenly coated on the release film with a coating machine at a thickness of 0.5 mm, dried (50° C., 40 minutes), and cut to obtain the Bunanserin orally soluble film composition.

[0152] 1. Disintegration time test

[0153] According to the prescriptions of Examples 1 to 6 and 14 to 28, the preparation method provided by the present invention was used to prepare the orodispersible film preparation of Bunanserin and the disintegration time thereof was measured. The specific measurement method is as follows:

[0154] Randomly take 6 tablets of the obtained medicine film of each example, put them into 900 ml of water at 37±1°C, test the disintegration time, and record the disintegration time of the last tablet. The results are shown in Table 8.

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

[0156]

[0157]

[0158] According to the above results, the orodispersible film compositions of Bunanserin prepared according to the embodiments of the present invention can be completely disintegrated within 120 seconds.

[0159] 2. Dissolution results determination

[0160] The dissolution curves of the orodispersible film preparations of Bunanselin prepared by the prescriptions of Examples 1 to 19 were measured. The specific measurement method is as follows:

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

[0162] Dissolution method: "Chinese Pharmacopoeia" 2020 edition 0931 Dissolution and Release Determination Method 2 (Paddle Method) + Sinking Basket, rotation speed is 50rpm.

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

[0164] The dissolution curve of the Bunanserin oral film-dissolving preparation was determined according to the above method. The results are shown in Table 9.

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

[0166]

[0167] According to the above results, the solubility of the Bunanserin oral film-dissolving composition prepared according to the embodiment of the present invention is above 75% or 80% in 60 minutes, preferably above 85%.

[0168] 3. Sample stability test

[0169] According to the prescriptions of Example 1, Example 13, Example 28 and Comparative Example 1, the orodispersible film preparation of Bunanselin was prepared by the corresponding preparation method provided by the present invention, and its stability under light, high humidity, 50° C. and accelerated conditions was measured. The results are shown in Table 10:

[0170] Table 10 Stability results of Example 1, Example 13, Example 28 and Comparative Example 1

[0171]

[0172] Analyzing the above results, we can see that:

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

[0174] 2. When using Hydroxypropyl Methylcellulose as the film-forming material, it has good stability under light and high humidity conditions, but the content of active drugs tends to decrease at 50°C and under accelerated conditions, so it is necessary to pay attention to the storage temperature;

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

[0176] 4. The preparation prescriptions of Examples 1 to 4 in the patent document CN117838667A have poor reproducibility. The preferred embodiment - Example 1 is selected, and water is added thereto to prepare the maximum single impurity and total impurity of the sample. The maximum single impurity and total impurity show an increasing trend during the high temperature stability period, and the content shows a decreasing trend. The sample stability is poor.

[0177] Based on the above experimental data, it can be seen that the blonanserin orodispersible 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 fast oral absorption.

[0178] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A Bunanserin orally dissolving film composition, characterized in that: The bunanserin orally dissolving film composition 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-hexahydrocyclooctanopyridine as shown in Formula I, and pharmaceutically acceptable salts, hydrates and solvates thereof; 2. The orosoluble film composition of Bunanserin according to claim 1, characterized in that: The particle size of the active drug is D90≤30.0 μm, for example D90≤20.0 μm; and / or, The mass percentage of the active drug is 2.0% to 25.0%, and the mass percentage refers to the percentage of the mass of the active drug to the total mass of the Bunanserin orosoluble film composition.

3. The orosoluble film composition of Bunanserin according to claim 1, characterized in that: The film-forming material is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol and pullulan; and / or, The plasticizer is selected from one or more of polyethylene glycol, propylene glycol and glycerol.

4. The orosoluble film composition of Bunanserin according to claim 1 or 2, characterized in that: The mass percentage of the film-forming material is 30.0% to 80.0%, for example 40.0% to 80.0%, wherein the mass percentage refers to the mass percentage of the film-forming material to the total mass of the Bunanserin oral film-soluble composition; and / or, The mass percentage of the plasticizer is 5.0% to 40.0%, and the mass percentage refers to the percentage of the mass of the plasticizer to the total mass of the Bunanserin oral film-soluble composition.

5. The orosoluble film composition of Bunanserin according to claim 1, characterized in that: The Bunanserin orodispersible film composition further comprises a colorant, a disintegrant, a flavoring agent and / or a filler.

6. The orosoluble film composition of Bunanserin according to claim 5, characterized in that: The colorant is selected from titanium dioxide; and / or, The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch and starch; and / or, The flavoring agent is selected from one or more of aspartame, sucralose, fructose, sucrose, steviol glycosides, glycyrrhizin, flavor, menthol, sodium chloride, neotame, acesulfame potassium, saccharin and saccharin sodium; and / or, The filler is selected from one or more of microcrystalline cellulose, starch, mannitol and lactose.

7. The orosoluble film composition of Bunanserin according to claim 5 or 6, characterized in that: The mass percentage of the colorant is 0 to 5.0%, for example 0 to 3.0%, and the mass percentage refers to the mass percentage of the colorant to the total mass of the Bunanserin oral film-soluble composition; and / or, The mass percentage of the disintegrant is 0-10.0%, and the mass percentage refers to the mass percentage of the disintegrant to the total mass of the Bunanserin orosoluble film composition; and / or, The mass percentage of the flavoring agent is 0 to 20.0%, and the mass percentage refers to the mass percentage of the flavoring agent to the total mass of the Bunanserin orosoluble film composition; and / or, The mass percentage of the filler is 0-50.0%, and the mass percentage refers to the percentage of the mass of the filler to the total mass of the Bunanserin oral film composition.

8. The orosoluble film composition of Bunanserin according to claim 1, characterized in that: The Bunanserin orodispersible film composition is any of the following prescriptions: Prescription 1: 13.6% blonanserin, 67.8% hypromellose, 16.9% polyethylene glycol and 1.7% titanium dioxide, wherein the particle size D90 of the blonanserin is 10 μm; Prescription 2: 10.1% blonanserin, 75.9% hydroxypropyl methylcellulose, 12.7% polyethylene glycol and 1.3% titanium dioxide, wherein the particle size D90 of the blonanserin is 10 μm; Prescription 3: 20.5% blonanserin, 51.3% hypromellose, 25.6% polyethylene glycol and 2.6% titanium dioxide, the particle size D90 of the blonanserin is 10 μm; Prescription 4: 13.6% blonanserin, 67.8% hydroxypropyl methylcellulose, 16.9% polyethylene glycol and 1.7% titanium dioxide, wherein the particle size D90 of the blonanserin is 5 μm; Prescription 5: 11.6% blonanserin, 58.0% hydroxypropyl methylcellulose, 29.0% polyethylene glycol and 1.4% titanium dioxide, wherein the particle size D90 of the blonanserin is 5 μm; Prescription 6: 10.1% blonanserin, 50.6% hydroxypropyl methylcellulose, 38.0% polyethylene glycol and 1.3% titanium dioxide, wherein the particle size D90 of the blonanserin is 5 μm; Prescription 7: 10.1% blonanserin, 50.6% hypromellose, 12.7% polyethylene glycol, 25.3% microcrystalline cellulose and 1.3% titanium dioxide, the particle size D90 of the blonanserin is 10 μm; Prescription 8: 10.1% blonanserin, 50.6% hydroxypropyl methylcellulose, 12.7% polyethylene glycol, 25.3% mannitol and 1.3% titanium dioxide, the particle size D90 of the blonanserin is 5 μm; Prescription 9: 10.1% blonanserin, 50.6% hydroxypropyl methylcellulose, 12.7% polyethylene glycol, 25.3% lactose and 1.3% titanium dioxide, wherein the particle size D90 of the blonanserin is 5 μm; Prescription 10: 10.3% blonanserin, 51.3% pullulan, 12.8% polyethylene glycol and 25.6% microcrystalline cellulose, wherein the particle size D90 of the blonanserin is 5 μm; Prescription 11: 13.6% blonanserin, 67.8% hydroxypropylcellulose-JF, 16.9% polyethylene glycol and 1.7% titanium dioxide, wherein the particle size D90 of the blonanserin is 5 μm; Prescription 12: 13.6% blonanserin, 67.8% hydroxypropylcellulose-L, 16.9% polyethylene glycol and 1.7% titanium dioxide, wherein the particle size D90 of the blonanserin is 5 μm; Prescription 13: 20.5% blonanserin, 51.3% polyvinyl alcohol, 25.6% polyethylene glycol and 2.6% titanium dioxide, wherein the particle size D90 of the blonanserin is 10 μm; Prescription 14: 6.8% blonanserin, 50.8% polyvinyl alcohol, 16.9% polyethylene glycol and 25.5% microcrystalline cellulose, wherein the particle size D90 of the blonanserin is 10 μm; Prescription 15: 7.4% blonanserin, 46.3% polyvinyl alcohol, 18.5% polyethylene glycol and 27.8% microcrystalline cellulose, wherein the particle size D90 of the blonanserin is 10 μm; Prescription 16: 6.3% blonanserin, 54.7% polyvinyl alcohol, 15.6% polyethylene glycol and 23.4% microcrystalline cellulose, wherein the particle size D90 of the blonanserin is 10 μm; Prescription 17: 7.4% blonanserin, 55.6% polyvinyl alcohol, 18.5% polyethylene glycol and 18.5% microcrystalline cellulose, wherein the particle size D90 of the blonanserin is 10 μm; Prescription 18: 7.4% blonanserin, 55.6% polyvinyl alcohol, 9.2% polyethylene glycol and 27.8% microcrystalline cellulose, wherein the particle size D90 of the blonanserin is 10 μm; Prescription 19: 6.3% blonanserin, 46.9% polyvinyl alcohol, 23.4% polyethylene glycol and 23.4% microcrystalline cellulose, wherein the particle size D90 of the blonanserin is 10 μm; Prescription 20: 7.4% blonanserin, 55.6% polyvinyl alcohol, 9.2% propylene glycol and 27.8% microcrystalline cellulose, wherein the particle size D90 of the blonanserin is 4 μm; Prescription 21: 6.8% blonanserin, 50.8% polyvinyl alcohol, 16.9% propylene glycol and 25.5% microcrystalline cellulose, wherein the particle size D90 of the blonanserin is 4 μm; Prescription 22: 6.3% blonanserin, 46.9% polyvinyl alcohol, 23.4% propylene glycol and 23.4% microcrystalline cellulose, wherein the particle size D90 of the blonanserin is 4 μm; Prescription 23: 7.4% blonanserin, 55.6% polyvinyl alcohol, 9.2% glycerol and 27.8% microcrystalline cellulose, wherein the particle size D90 of the blonanserin is 4 μm; Prescription 24: 6.8% blonanserin, 50.8% polyvinyl alcohol, 16.9% glycerol and 25.5% starch, wherein the particle size D90 of the blonanserin is 4 μm; Prescription 25: 6.3% blonanserin, 46.9% polyvinyl alcohol, 23.4% glycerol and 23.4% starch, wherein the particle size D90 of the blonanserin is 4 μm; Prescription 26: 6.8% blonanserin, 50.8% polyvinyl alcohol, 16.9% polyethylene glycol and 25.5% microcrystalline cellulose, wherein the particle size D90 of the blonanserin is 8 μm; Prescription 27: 6.8% blonanserin, 50.8% polyvinyl alcohol, 16.9% polyethylene glycol and 25.5% microcrystalline cellulose, wherein the particle size D90 of the blonanserin is 4 μm; Prescription 28: 6.8% blonanserin, 50.8% polyvinyl alcohol, 16.9% polyethylene glycol and 25.5% microcrystalline cellulose, wherein the particle size D90 of the blonanserin is 6 μm; Prescription 29: 8.16% blonanserin, 40.82% hydroxypropyl cellulose, 10.20% pullulan, 20.41% polyethylene glycol, 20.41% microcrystalline cellulose, the particle size D90 of the blonanserin is 1 to 30 μm; Prescription 30: 9.09% blonanserin, 45.45% hydroxypropyl cellulose, 11.36% pullulan, 11.36% glycerol, 22.74% microcrystalline cellulose, the particle size D90 of the blonanserin is 1 to 30 μm; Prescription 31: 16.00% blonanserin, 60.00% hydroxypropyl cellulose, 20.00% glycerin, 4.00% titanium dioxide, the particle size D90 of the blonanserin is 1 to 30 μm; Prescription 32: 16.00% blonanserin, 60.00% hydroxypropyl cellulose, 20.00% polyethylene glycol, 4.00% titanium dioxide, the particle size D90 of the blonanserin is 1 to 30 μm; Prescription 33: 14.81% blonanserin, 37.04% hydroxypropyl cellulose, 11.11% polyethylene glycol, 37.04% microcrystalline cellulose, the particle size D90 of the blonanserin is 1 to 30 μm; Prescription 34: 14.81% blonanserin, 37.04% hydroxypropyl cellulose, 11.11% glycerol, 37.04% microcrystalline cellulose, the particle size D90 of the blonanserin is 1 to 30 μm; Prescription 35: 8.89% blonanserin, 66.67% hydroxypropyl cellulose, 22.22% polyethylene glycol, 2.22% titanium dioxide, the particle size D90 of the blonanserin is 1 to 30 μm; Prescription 36: 8.89% blonanserin, 66.67% hydroxypropyl cellulose, 22.22% glycerin, 2.22% titanium dioxide, the particle size D90 of the blonanserin is 1 to 30 μm; Prescription 37: 7.27% blonanserin, 54.55% hydroxypropyl cellulose, 18.18% polyethylene glycol, 1.82% titanium dioxide and 18.18% microcrystalline cellulose, wherein the particle size D90 of the blonanserin is 1 to 30 μm; Prescription 38: 7.27% blonanserin, 54.55% hydroxypropyl cellulose, 18.18% glycerol, 1.82% titanium dioxide and 18.18% microcrystalline cellulose, the particle size D90 of the blonanserin is 1 to 30 μm.

9. The orosoluble film composition of Bunanserin according to any one of claims 1 to 8, characterized in that: The thickness of the Bunanserin oral dissolving film composition is 10 μm to 210 μm, for example, 50 μm to 210 μm; and / or, The blonanserin orosoluble film composition can completely disintegrate within 120 seconds in 900 mL of simulated saliva at 37±1°C.

10. The method for preparing the orosoluble film composition of Bunanserin according to any one of claims 1 to 8, characterized in that The following steps are involved: 1) The film-forming material is heated and dissolved in water at room temperature to 70°C to form a solution; 2) adding all components except the active drug and the film-forming material to the solution obtained in step 1), and stirring evenly to obtain a blank glue solution; 3) placing the active drug in the blank glue solution obtained in step 2), stirring until uniformly dispersed, and stirring and degassing under vacuum conditions to obtain drug-containing glue; 4) The drug-containing glue obtained in step 3) is evenly coated on the release film by a coating machine, and then dried and cut to obtain the Bunanserin orally soluble film composition.

11. Use of the orosoluble film composition of Bunanserin according to any one of claims 1 to 8 in the preparation of a drug for treating and / or preventing depression and schizophrenia.

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