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WO2025194717A1 - Composition de film soluble oral de blonansérine, procédé de préparation s'y rapportant et utilisation associée - Google Patents

Composition de film soluble oral de blonansérine, procédé de préparation s'y rapportant et utilisation associée

Info

Publication number
WO2025194717A1
WO2025194717A1 PCT/CN2024/118283 CN2024118283W WO2025194717A1 WO 2025194717 A1 WO2025194717 A1 WO 2025194717A1 CN 2024118283 W CN2024118283 W CN 2024118283W WO 2025194717 A1 WO2025194717 A1 WO 2025194717A1
Authority
WO
WIPO (PCT)
Prior art keywords
blonanserin
particle size
prescription
polyethylene glycol
bunanserin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/118283
Other languages
English (en)
Chinese (zh)
Inventor
应述欢
付俊
张贤
郭桢
王婷婷
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Aurora Biotechnology Co Ltd
Original Assignee
Shanghai Aurora Biotechnology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Aurora Biotechnology Co Ltd filed Critical Shanghai Aurora Biotechnology Co Ltd
Publication of WO2025194717A1 publication Critical patent/WO2025194717A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets

Definitions

  • 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.
  • 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, a gradual onset, and a protracted course. The World Health Organization estimates the global lifetime prevalence of schizophrenia to be approximately 3.8 to 8.4 percent.
  • Schizophrenia affects approximately 21 million people worldwide, with approximately 3.5 million patients in the United States.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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;
  • the particle size of the active drug is D90 ⁇ 30.0 ⁇ m, for example, 0.5 ⁇ m ⁇ D90 ⁇ 25.0 ⁇ m or D90 ⁇ 20.0 ⁇ m, exemplified by 25 ⁇ m, 24 ⁇ m, 23 ⁇ m, 22 ⁇ m, 21 ⁇ m, 20 ⁇ m, 19 ⁇ m, 18 ⁇ m, 16 ⁇ m, 15 ⁇ m, 14.0 ⁇ m, 13.0 ⁇ m, 12.0 ⁇ m, 11.0 ⁇ m, 10.0 ⁇ m, 9.0 ⁇ m, 8.0 ⁇ m, 7.0 ⁇ m, 6.0 ⁇ m, 5.0 ⁇ m, 4.0 ⁇ m, 3.0 ⁇ m, 2.0 ⁇ m or 1.0 ⁇ m.
  • 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.
  • 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.
  • 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 also known as hypromellose
  • 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.
  • 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.
  • 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.
  • the Buonanserin orally disintegrating film composition may further include one or more of a colorant, a disintegrant, a flavoring agent and/or a filler.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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%, wherein the mass percentage refers to the percentage of the mass of the filler to the total mass of the Bunanserin orally dissolving film composition.
  • 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 ⁇ m.
  • 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 ⁇ m.
  • 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 ⁇ m.
  • 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 ⁇ m.
  • 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 ⁇ m.
  • 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 ⁇ m.
  • 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 ⁇ m;
  • the orally dissolving film composition of Blonanserin comprises: 2.0% to 25.0% of Blonanserin, 30.0% to 50.0% of hydroxypropyl cellulose, 5% to 20% of glycerol or polyethylene glycol, and 25% to 50% of microcrystalline cellulose.
  • the particle size D90 of the blonanserin is 1 to 30 ⁇ m.
  • the Bunanserin orally dissolving film composition may be any of the following formulations:
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m;
  • 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 ⁇ m.
  • the present invention also provides a method for preparing the Bunanserin orally dissolving film composition, which comprises the following steps:
  • step 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;
  • step 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;
  • step 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.
  • 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.
  • the thickness of the bunanserin oral dissolving film composition is 10 ⁇ m to 210 ⁇ m, such as 50 ⁇ m to 210 ⁇ m, for example, 10 ⁇ m, 20 ⁇ m, 30 ⁇ m, 40 ⁇ m, 50 ⁇ m, 80 ⁇ m, 100 ⁇ m, 110 ⁇ m, 120 ⁇ m, 160 ⁇ m or 210 ⁇ m, etc.
  • 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.
  • simulated saliva e.g., water
  • 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 at 60 minutes is not less than 75%, for example not less than 80%, and preferably not less than 85%.
  • the present invention also provides use of the blonanserin orally disintegrating film composition in preparing a drug for treating and/or preventing schizophrenia.
  • 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.
  • the Bunanserin orally dissolving film composition is a pharmaceutical preparation.
  • the dosage form of the agent can be an orally disintegrating film, an orally disintegrating tablet or a buccal film.
  • 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 relied upon, whether to be administered in combination with other compounds, the time schedule for administration, the tissue to be administered, and the physical delivery system carried.
  • the reagents and raw materials used in the present invention are commercially available.
  • the “room temperature” mentioned in the present invention refers to an ambient temperature of 10°C to 40°C.
  • 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.
  • 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.
  • Folding endurance the number of times a piece of paper breaks or has obvious creases after being folded at the same position
  • Tensile strength also called ultimate strength, refers to the maximum force used to break the dissolved film.
  • 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.
  • Table 1 Examples 1 to 6 *Indicates removal during the process; **Indicates the weight of raw materials after removing water.
  • the D90 of blonanserin can be any number ranging from 1 to 30 ⁇ m.
  • step 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;
  • step 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.)
  • step 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.
  • step 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;
  • step 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.
  • 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:
  • Test medium 900 ml pH 6.8 phosphate buffer + 0.1% T80 medium (37°C ⁇ 0.5°C).
  • Dissolution method "Chinese Pharmacopoeia” 2020 edition 0931 Dissolution and Release Determination Method 2 (Paddle Method) + Sinking Basket, rotation speed is 50 rpm.
  • 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.
  • Example 1 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:
  • the product prepared according to the present invention has good stability at least under light and high humidity
  • 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.
  • the prepared product has good stability under light, high humidity, 50°C and accelerated conditions;
  • 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 fast oral absorption.

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Abstract

L'invention concerne une composition de film soluble oral de blonansérine, comprenant un médicament actif, un matériau filmogène et un plastifiant. Le médicament actif est un ou plusieurs éléments parmi la 2-(4-éthyl-1-pipérazinyl)-4-(4-fluorophényl)-5,6,7,8,9,10-hexahydrocyclooctapyridine telle que représentée par la formule I et un sel pharmaceutiquement acceptable, un hydrate et un solvate de celui-ci. La composition de film soluble oral de blonansérine présente les avantages suivants : une épaisseur mince, un bon goût, des propriétés stables, une bonne vitesse de dissolution, une dissolution instantanée dans la cavité buccale sans eau potable, une aptitude particulière à des patients souffrant de dysphagie, une absence de sensation de grippage après dissolution dans la cavité buccale et un taux d'absorption orale rapide. La composition présente également une apparence uniforme, une bonne flexibilité, un procédé simple, aucune sédimentation lors de la préparation du liquide pour film, une uniformité du contenu répondant aux exigences, une grande capacité de charge en principe actif et de bonnes perspectives commerciales.
PCT/CN2024/118283 2024-03-22 2024-09-11 Composition de film soluble oral de blonansérine, procédé de préparation s'y rapportant et utilisation associée Pending WO2025194717A1 (fr)

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CN202410568138 2024-05-09
CN202410867474 2024-06-28
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CN202410934643 2024-07-11
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