Blonanserin oral soluble film composition, preparation method therefor, and use thereof

Abstract

A blonanserin oral soluble film composition, comprising an active drug, a film-forming material, and a plasticizer. The active drug is one or more of 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctapyridine as represented by formula I and a pharmaceutically acceptable salt, a hydrate, and a solvate thereof. The blonanserin oral soluble film composition has the advantages of thin thickness, good taste, stable properties, good dissolution rate, instant dissolution in the oral cavity without drinking water, particular suitability for patients suffering from dysphagia, no gravel feeling after dissolution in the oral cavity, and fast oral absorption rate. The composition also has a uniform appearance, good flexibility, a simple process, no sedimentation in the process of film liquid preparation, content uniformity meeting the requirements, a high drug loading capacity, and good marketing prospects.

Description

Bunanserin orally dissolving film composition, preparation method and application thereof

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

[0002] Priority to the prior application for patent application number 202410334171.1 filed with the State Intellectual Property Office of China on March 22, 2024, entitled “Bunanserin orally dissolving film composition, preparation method and application thereof”;

[0003] Priority to the prior application for patent application number 202410568138.5 filed with the State Intellectual Property Office of China on May 9, 2024, entitled “Bunanserin orally dissolving film composition, preparation method and application thereof”;

[0004] Priority to the prior application for patent application number 202410867474.X filed with the State Intellectual Property Office of China on June 28, 2024, entitled “Bunanserin orally dissolving film composition, preparation method and application thereof”;

[0005] Priority to the prior application for patent application number 202410934643.7 filed with the State Intellectual Property Office of China on July 11, 2024, entitled “Bunanserin orally dissolving film composition, preparation method and application thereof”;

[0006] The entire contents of said prior application are incorporated into the present application by reference. Technical Field

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

[0008] Schizophrenia is a severe, chronic mental illness of unknown etiology. Its clinical symptoms are diverse, affecting sensory, thinking, emotional, behavioral, and cognitive functions. Typical positive symptoms include hallucinations, delusions, mania, irritability, and disorganized speech and behavior. Typical negative symptoms include blunted affect, apathy, and cognitive impairment. Schizophrenia presents with significant individual variability, with onset typically occurring in young adults, with a gradual onset and a prolonged course. The World Health Organization estimates the global lifetime prevalence of schizophrenia to be approximately 3.8 to 8.4 percent.

[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 primarily act through the mechanism of dopamine D2 receptor blockade, which is effective in controlling patients' positive symptoms but has little effect on improving negative symptoms. In addition, 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 psychiatric drugs targeting 5-HT2 are primarily used to reduce extrapyramidal side effects and are not truly effective drug targets for schizophrenia, nor have they improved clinical efficacy.

[0010] Blonanserin (2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridine) is a new atypical antipsychotic developed by Sumitomo Pharma Pharma of Japan. It is a serotonin and dopamine antagonist that blocks dopamine D2 receptors and 5-HT2A receptors. Compared with other antipsychotic drugs currently 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 adrenergic 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 also 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.

[0012] Summary of the Invention

[0013] The technical problem solved by the present invention is to overcome the defects of the prior art such as limited types of blonanserin dosage forms and low patient compliance, and to provide a blonanserin orally dissolving film composition, a preparation method and application thereof.

[0014] The present invention provides a bunanserin orally dissolving film composition, which comprises an active drug, a film-forming material, and a plasticizer. The active drug is one or more of 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctapyridine as shown in Formula I, and pharmaceutically acceptable salts, hydrates, and solvates thereof;

[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%, where the mass percentage refers to the percentage of the mass of the active drug to the total mass of the Bunanserin orally disintegrating 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, 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%, 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-dissolving 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%, 32.0%, 33%, 34%, 35.0%, 36%, 37%, 38.0% or 39%, 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.

[0022] According to an embodiment of the present invention, the Bunanserin orally disintegrating 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, for example, selected from 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 Bunanserin orally disintegrating 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, essence, 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 percentage of the mass of the flavoring agent to the total mass of the Bunanserin orally disintegrating film composition.

[0029] According to an embodiment of the present invention, the filler refers to a solid substance added to the 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%, where the mass percentage refers to the percentage of the mass of the filler to the total mass of the Bunanserin oral film-dissolving composition.

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

[0032] According to one embodiment of the present invention, the blonanserin orally disintegrating film composition comprises: 2.0% to 25.0% of blonanserin, 45.0% to 60.0% of hypromellose, 10.0% to 20.0% of polyethylene glycol, and 20.0% to 30.0% of a filler. The particle size D90 of the blonanserin is ≤20.0 μm.

[0033] According to one embodiment of the present invention, the blonanserin orally disintegrating 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 orally disintegrating film composition of blonanserin comprises: 2.0% to 25.0% of blonanserin, 40.0% to 65.0% of polyvinyl alcohol, 5.0% to 35.0% of polyethylene glycol, and 20.0% to 30.0% of microcrystalline cellulose. The particle size D90 of the blonanserin is ≤20.0 μm.

[0035] According to one embodiment of the present invention, the blonanserin orally dissolving 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 orally disintegrating film composition comprises: 2.0% to 25.0% of blonanserin, 20.0% to 75.0% of hydroxypropyl cellulose, 5.0% to 20.0% of pullulan, 10.0% to 30.0% of polyethylene glycol or glycerol, and 10.0% to 30.0% of microcrystalline cellulose. The particle size D90 of the blonanserin is 1 to 30 μm.

[0037] According to one embodiment of the present invention, the orally dissolving film composition of blonanserin comprises: 2.0% to 25.0% blonanserin, 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 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 orally disintegrating film composition of blonanserin 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 orally dissolving film composition may be any of the following formulations:

[0041] 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;

[0042] Prescription 2: 10.1% blonanserin, 75.9% hypromellose, 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% hypromellose, 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, wherein 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% hypromellose, 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, wherein the particle size D90 of the blonanserin is 10 μm;

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

[0049] Prescription 9: 10.1% blonanserin, 50.6% hypromellose, 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, wherein 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, wherein 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, 55.6% polyvinyl alcohol, 9.2% polyethylene glycol, and 27.8% microcrystalline cellulose, wherein 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% glycerin, 1.82% titanium dioxide and 18.18% microcrystalline cellulose, the particle size D90 of the blonanserin is 1 to 30 μm.

[0079] The present invention also provides a method for preparing the Bunanserin orally dissolving film 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 all components except the active drug and film-forming material to the solution obtained in step 1), and stirring to obtain a blank glue solution;

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

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

[0084] Step 3) High-pressure shearing was attempted, but this easily generated bubbles, making subsequent defoaming difficult, time-consuming, and low. Vacuum degassing, on the other hand, can achieve defoaming within 10 minutes, significantly improving defoaming efficiency, reducing time and cost, and significantly increasing process efficiency.

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

[0086] According to an embodiment of the present invention, the bunanserin orally disintegrating film composition can be completely disintegrated 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 bunanserin orally dissolving film composition in pH 6.8 phosphate buffer and 0.1% T80 medium is not less than 75%, such as not less than 80%, and preferably not less than 85% at 60 minutes.

[0088] The present invention also provides use of the blonanserin orally disintegrating 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 orally disintegrating film composition to a patient in need.

[0090] According to an embodiment of the present invention, the blonanserin orally disintegrating film composition is a pharmaceutical preparation, which can be in the form of an orally disintegrating film, an orally disintegrating tablet, or a buccal film.

[0091] Definitions and Explanations of Terms

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

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

[0094] The term "therapeutically effective amount" refers to an amount of the active ingredient of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases as 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 being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be easily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the specific active ingredient selected, the dosage regimen based on, whether to be administered in combination with other compounds, the time schedule of administration, the tissue to be administered, and the physical delivery system carried.

[0095] The term "plurality" refers to 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 orally disintegrating film composition of the present invention has the advantages of thin thickness, good mouthfeel, stable properties, good dissolution rate, rapid dissolution in the oral cavity without drinking water, being particularly suitable for patients with dysphagia, good patient compliance, no gritty feeling after dissolution in the oral cavity (i.e., a suitable mouthfeel), rapid oral absorption, uniform appearance, good flexibility, and good stability.

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

[0101] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative 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 encompassed within the scope of protection that the present invention is intended to protect.

[0102] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions or selected according to the product specifications.

[0103] Folding endurance: 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 dissolved film.

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

[0106] Examples 1-38

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

[0108] Table 1 Examples 1 to 6 *Indicates removal during the process; **Indicates the weight of raw materials and auxiliary materials after removing water.

[0109] The prescriptions 7 to 12 of the orally dissolving film composition of Bunanselin are shown in Table 2:

[0110] Table 2 Examples 7 to 12 *Indicates removal during the process; **Indicates the weight of raw materials and auxiliary materials after removing water.

[0111] Prescriptions 13 to 19 are shown in Table 3:

[0112] Table 3 Examples 13 to 19 *Indicates removal during the process; **Indicates the weight of raw materials and auxiliary materials after removing water.

[0113] Prescriptions 20 to 25 are shown in Table 4:

[0114] Table 4 Examples 20 to 25 *Indicates removal during the process; **Indicates the weight of raw materials and auxiliary materials after removing water.

[0115] Prescriptions 26 to 28 are shown in Table 5:

[0116] Table 5 Examples 26 to 28 *Indicates removal during the process; **Indicates the weight of raw materials and auxiliary materials after removing water.

[0117] In any of the formulations of Examples 29-38, the D90 of blonanserin can be any number ranging from 1 to 30 μm.

[0118] Preparation method:

[0119] 1) Heat the film-forming material in water at room temperature to 70°C to form a solution;

[0120] 2) adding all components except the active drug and the film-forming material to the solution obtained in step 1), stirring uniformly to obtain a blank glue solution;

[0121] 3) placing the active drug in the blank adhesive obtained in step 2), stirring until uniformly dispersed, and degassing under vacuum conditions to obtain the drug-containing adhesive; (Using high-pressure shearing to treat the adhesive easily generates bubbles, which is not conducive to subsequent defoaming. At the same time, vacuum degassing can achieve defoaming effect within 10 minutes, greatly improving defoaming efficiency and shortening time costs.)

[0122] 4) The drug-containing glue obtained in step 3) is evenly coated on the release film using a coating machine, dried, and cut to obtain the Bunanserin orally disintegrating film composition.

[0123] Comparative Example 1

[0124] Referring to the preparation formula of Examples 1 to 4 in patent CN117838667A, it was found that the viscosity of the glue was too high, 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 to its formula to prepare a sample.

[0125] Table 7 Comparative Example 1 *Indicates removal during the process; **Indicates the weight of raw materials and auxiliary materials after removing water.

[0126] Preparation method:

[0127] 1) Stir polyethylene glycol 400 and water at room temperature;

[0128] 2) Add the prescribed amount of HPMC-E5 and the active drug to step 1) and stir evenly; raise the temperature to 50° C., add the prescribed amount of HPMC-E15 and stir evenly, then add the prescribed amount of sucralose and banana essence and stir until evenly mixed;

[0129] 3) Stirring and degassing under vacuum conditions to obtain drug-containing glue; (Using high-pressure shearing to treat the glue liquid easily generates bubbles, which is not conducive to subsequent defoaming. At the same time, vacuum degassing can achieve defoaming effect within 10 minutes, which greatly improves defoaming efficiency and shortens time cost.)

[0130] 4) The drug-containing glue obtained in step 3) was 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 disintegrating film composition.

[0131] 1. Disintegration time test

[0132] 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 orally disintegrating film preparation of Blonanserin and the disintegration time thereof was measured. The specific measurement method is as follows:

[0133] Randomly take 6 tablets obtained in each example, place them in 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.

[0134] Table 8 Disintegration time of Examples 1 to 6 and Examples 14 to 28

[0135] According to the above results, the Bunanserin orally disintegrating film compositions prepared according to the examples of the present invention can be completely disintegrated within 120 seconds.

[0136] 2. Dissolution results determination

[0137] The dissolution curves of the orally dissolving film preparations of Blonanserin prepared according to the prescriptions of Examples 1 to 19 were measured. The specific measurement method is as follows:

[0138] Test medium: 900 ml pH 6.8 phosphate buffer + 0.1% T80 medium (37°C ± 0.5°C).

[0139] Dissolution method: "Chinese Pharmacopoeia" 2020 edition 0931 Dissolution and Release Determination Method 2 (Paddle Method) + Sinking Basket, rotation speed is 50 rpm.

[0140] Sampling time: 5min, 10min, 15min, 20min, 30min, 45min, 60min.

[0141] The dissolution curve of the orally dissolving film preparation of Blonanserin was measured according to the above method. The results are shown in Table 9.

[0142] Table 9 Dissolution results of Examples 1 to 19 and Examples 26 to 28 in pH 6.8 phosphate buffer + 0.1% T80 medium

[0143] According to the above results, the solubility of the Buonanserin orally dissolving film composition prepared according to the embodiment of the present invention is above 75% or 80%, preferably above 85% in 60 minutes.

[0144] 3. Sample stability test

[0145] According to the formulations of Example 1, Example 13, Example 28 and Comparative Example 1, the orally disintegrating film preparation of Bunanselin was prepared using the corresponding preparation method provided by the present invention, and its stability under light, high humidity, 50°C and accelerated conditions was tested. The results are shown in Table 10:

[0146] Table 10 Stability results of Example 1, Example 13, Example 28 and Comparative Example 1

[0147] Analyzing the above results, we can see that:

[0148] 1. The product prepared according to the present invention has good stability at least under light and high humidity;

[0149] 2. When using Hydroxypropyl Methylcellulose as the film-forming material, it has good stability under light and high humidity conditions. However, the content of active drugs tends to decrease at 50°C and under accelerated conditions. Therefore, attention should be paid to the storage temperature.

[0150] 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;

[0151] 4. The reproducibility of the preparation formulas of Examples 1 to 4 in patent document CN117838667A is poor. The preferred embodiment - Example 1 is selected, and water is added thereto to prepare the sample. The maximum single impurity and total impurity of the sample show an increasing trend during the high temperature stability period, and the content shows a decreasing trend, indicating that the sample stability is poor.

[0152] Based on the above experimental data, it can be seen that the orally disintegrating film composition of Bulnanserin provided by the present invention has the advantages of thin thickness, good taste, stable properties, instant dissolution in the mouth without drinking water, and rapid oral absorption.

[0153] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection 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-hexahydrocyclooctapyridine as shown in Formula I, or a pharmaceutically acceptable salt, hydrate and solvate thereof; 2. The orally dissolving film composition of Bhunanserin according to claim 1, wherein: 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 orally disintegrating film composition.

3. The orally dissolving film composition of Bhunanserin according to claim 1, wherein: The film-forming material is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol and pullulan; and / or, The plasticizer is selected from one or more of polyethylene glycol, propylene glycol and glycerol.

4. The orally dissolving film composition of Bhunanserin 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-dissolving 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 orally dissolving film composition of Bhunanserin according to claim 1, wherein: The Bunanserin orally disintegrating film composition further comprises a colorant, a disintegrant, a flavoring agent and / or a filler.

6. The orally dissolving film composition of Bhunanserin according to claim 5, wherein: 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, essence, 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 orally dissolving film composition of Bhunanserin 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%, where 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 to 10.0%, and the mass percentage refers to the mass percentage of the disintegrant to the total mass of the Bunanserin orally disintegrating film composition; and / or, The mass percentage of the flavoring agent is 0 to 20.0%, and the mass percentage refers to the percentage of the mass of the flavoring agent to the total mass of the Bunanserin orally disintegrating 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-dissolving composition.

8. The orally dissolving film composition of Bhunanserin according to claim 1, wherein: The Bunanserin orally dissolving film composition is any of the following formulas: 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% hypromellose, 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, wherein the particle size D90 of the blonanserin is 10 μm; Prescription 4: 13.6% blonanserin, 67.8% hypromellose, 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% hypromellose, 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% hypromellose, 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, wherein the particle size D90 of the blonanserin is 10 μm; Prescription 8: 10.1% blonanserin, 50.6% hypromellose, 12.7% polyethylene glycol, 25.3% mannitol, and 1.3% titanium dioxide, wherein the particle size D90 of the blonanserin is 5 μm; Prescription 9: 10.1% blonanserin, 50.6% hypromellose, 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% glycerin, 1.82% titanium dioxide and 18.18% microcrystalline cellulose, the particle size D90 of the blonanserin is 1 to 30 μm.

9. The method according to any one of claims 1 to 8 The Bunanserin orally dissolving film composition is characterized by: 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 Bunanserin orally disintegrating film composition can completely disintegrate within 120 seconds in 900 mL of simulated saliva at 37±1°C.

9. The method for preparing the orally dissolving film composition of Bhunanserin according to any one of claims 1 to 8, characterized in that it comprises the following steps: 1) Heat the film-forming material 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), stirring uniformly to obtain a blank glue solution; 3) placing the active drug into the blank glue 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 using a coating machine, dried, and cut to obtain the Bunanserin orally disintegrating film composition.

10. Use of the orally disintegrating film composition of Blonanserin according to any one of claims 1 to 8 in the preparation of a medicament for treating and / or preventing depression and schizophrenia.

Images