WO2022247883A1 - Composition de film à dissolution orale de cariprazine, procédé de préparation associé et application associée - Google Patents

Composition de film à dissolution orale de cariprazine, procédé de préparation associé et application associée Download PDF

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WO2022247883A1
WO2022247883A1 PCT/CN2022/095122 CN2022095122W WO2022247883A1 WO 2022247883 A1 WO2022247883 A1 WO 2022247883A1 CN 2022095122 W CN2022095122 W CN 2022095122W WO 2022247883 A1 WO2022247883 A1 WO 2022247883A1
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Prior art keywords
cariprazine
film composition
dissolving film
mouth
cyclodextrin
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PCT/CN2022/095122
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English (en)
Chinese (zh)
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郭桢
王璇
付俊
王婷婷
应述欢
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上海博志研新药物技术有限公司
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Publication of WO2022247883A1 publication Critical patent/WO2022247883A1/fr

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    • 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
    • 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
    • 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
    • A61K47/06—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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • 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
    • 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

Definitions

  • the invention relates to a cariprazine orally dissolving film composition, a preparation method and application thereof, and belongs to the field of pharmaceutical compositions.
  • Cariprazine is an oral, once-daily atypical antipsychotic.
  • the drug has been approved for marketing by the FDA in 2015.
  • the product name is Vraylar.
  • the currently approved indications include: (1) Manic or mixed episodes in adult patients with bipolar I affective disorder (manic depression) For emergency treatment, the recommended dosage range is 3-6mg/day; (2) For the treatment of adult patients with schizophrenia, the recommended dosage range is 1.5-6.0mg/day.
  • Cariprazine is a partial D3/D2 receptor agonist that preferentially binds to D3 receptors. Also acts as an antagonist with high/moderate affinity for serotonin 5-HT2B and T-HT2A receptors, histamine H1 receptors, but low affinity for 5-HT2C and ⁇ 1A-adrenoceptors It has no obvious affinity for adrenergic receptors. Compared with traditional psychotropic drugs, it has the advantage of lower incidence of extrapyramidal system.
  • Cariprazine is white or off-white powder, insoluble in water.
  • the common cariprazine tablet in the prior art must now be disintegrated in the stomach to start releasing the drug, resulting in a slow onset of action, thereby limiting bioavailability and taking it is also inconvenient.
  • Patent document CN107970217A discloses an orally disintegrating tablet of cariprazine and a preparation method thereof.
  • the tablet containing cariprazine is prepared into an orally disintegrating tablet by ordinary compression technology, so that it disintegrates rapidly and dissolves rapidly.
  • the present invention provides a cariprazine orally dissolving film composition, which comprises an active ingredient, a film-forming material and a plasticizer, wherein the active ingredient contains A mixture of one or more of the pharmaceutically acceptable salts of perazine, cariprazine and clathrates thereof.
  • the cariprazine is N'-[trans-4-[2-[4-(2,3-dichlorophenyl)-1-piperazine as shown in formula I base]ethyl]cyclohexyl]-N,N-dimethylurea:
  • the active ingredient is selected from one or more mixtures of cariprazine and inclusion complexes of pharmaceutically acceptable salts of cariprazine, for example, selected from cariprazine A mixture of one or more of clathrates and clathrates of pharmaceutically acceptable salts of cariprazine.
  • the inclusion compound is a cyclodextrin inclusion compound, for example, one selected from the cyclodextrin inclusion compound of cariprazine and the cyclodextrin inclusion compound of a pharmaceutically acceptable salt of cariprazine A mixture of one or more.
  • said cyclodextrins are selected from cyclodextrins or derivatives thereof, preferably alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin and sulfobutyl-beta - a mixture of one or more of cyclodextrins.
  • the molar ratio of the active ingredient to the cyclodextrin is selected from (0.25-2.00):1.
  • the active ingredient may have a particle size of D 90 ⁇ 30 ⁇ m.
  • the active ingredient when selected from a mixture of one or more of cariprazine and a pharmaceutically acceptable salt of cariprazine, its particle size D 90 ⁇ 30 ⁇ m, for example 1 ⁇ m ⁇ D 90 ⁇ 29 ⁇ m, examples of which can be 1.7 ⁇ m, 8.4 ⁇ m, 17.3 ⁇ m or 28.4 ⁇ m.
  • the mass percentage of the active ingredient is 1.00% to 30.00%, such as 2.00% to 28.00%, such as 4.00% to 20.00%, and its examples can be 4.90%, 16.70%, 14.30%, 18.90% or 19.0%, wherein, the mass percentage refers to the mass percentage of the active ingredient in the total mass of the mouth-dissolving film composition.
  • the mouth-dissolving film composition may further comprise a combination of one or more of sweeteners, absorption enhancers, disintegrants, saliva stimulating agents, fillers and coloring agents.
  • the film-forming material is a drug carrier.
  • the film-forming material is selected from gelatin, xanthan gum, shellac, gum arabic, starch, dextrin, agar, sodium alginate, zein, hypromellose, hydroxypropyl cellulose, polyethylene One or more of alcohol, polyoxyethylene, acrylic acid copolymer, povidone, polylactic acid and silicone rubber.
  • the mass percentage of the film-forming material may be 30.00% to 75.00%, such as 30.00% to 70.00%, and its examples may be 26.50%, 49.00%, 49.20%, 53.30%, 60.00% , 66.30% or 70.40%, the mass percentage refers to the mass percentage of the film-forming material in the total mass of the mouth-dissolving film composition.
  • the plasticizer is a substance used to lower the glass transition temperature of the film, increase plasticity and toughness, and increase elongation.
  • the plasticizer is selected from one or more of polyethylene glycol, glycerin, propylene glycol, silicone oil, simethicone, polypropylene glycol and hexylene glycol.
  • the mass percentage of the plasticizer may be 5.00% to 30.00%, such as 8.00% to 25.00%, and its examples may be 9.00%, 14.30%, 14.70%, 16.50%, 19.00% , 20.80%, the mass percentage refers to the mass percentage of the plasticizer to the total mass of the mouth-dissolving film composition.
  • the sweetener is a substance that acts as a flavoring agent in the film dosage.
  • the sweetener may be selected from one or more of aspartame, sucralose, fructose, sucrose, stevioside, glycyrrhizin, essence, fragrance, saccharin and sodium saccharin.
  • the mass percentage of the sweetener may be 0.05% to 1.00%, such as 0.10%, 0.20%, 0.50%, 0.71%, 0.83% or 0.95%, and the mass percentage Refers to the percentage of the quality of the sweetener in the total mass of the orally dissolving film composition.
  • the disintegrating agent refers to an excipient that promotes rapid disintegration of the drug into small particles in the gastrointestinal tract.
  • the disintegrant is selected from low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, croscarmellose sodium starch, starch, microcrystalline cellulose, pregelatin One or more of starches.
  • the saliva stimulating agent refers to a substance that stimulates saliva production.
  • the saliva stimulating agent is selected from one or more of citric acid, tartaric acid, malic acid and mannitol.
  • the coloring agent 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.
  • the colorant is selected from one or more of titanium dioxide, pigments and lakes.
  • the thickness of the cariprazine orally dissolving film composition is 10 ⁇ m ⁇ 100 ⁇ m.
  • the cariprazine orally dissolving film composition provided by the present invention can completely dissolve in simulated saliva at 37 ⁇ 1° C. within 30 seconds, and release cariprazine.
  • the present invention also provides a preparation method of the cariprazine orally dissolving film composition, comprising mixing the active ingredient in the cariprazine orally dissolving film composition with other components.
  • the cariprazine orally dissolving film composition comprises an active ingredient, a film-forming material, a plasticizer, an absorption accelerator and a sweetener, and the active ingredient contains cariprazine and/or Its pharmaceutically acceptable salt, and the particle size of the active ingredient is preferably D 90 ⁇ 30 ⁇ m. .
  • the mass percentage of the active ingredient is preferably 1.00% to 30.00%, such as 16.70%, 14.30%, 18.90% or 19.0%, and the mass percentage refers to the mass of the active ingredient in calories The percentage of the total mass of dirazine orosoluble film.
  • the particle size of the active ingredient is preferably D 90 ⁇ 30 ⁇ m, such as 1.7 ⁇ m, 8.4 ⁇ m, 17.3 ⁇ m or 28.4 ⁇ m.
  • the mass percentage of the film-forming material is preferably 30.00% to 75.00%, such as 53.30%, 60.00%, 66.30% or 70.40%, and the mass percentage refers to the mass of the film-forming material Accounting for the percentage of the total mass of the orally dissolving film composition.
  • the mass percentage of the plasticizer is preferably 5.00% to 30.00%, such as 20.80%, 14.30%, 14.70%, and 19.00%, and the mass percentage refers to the mass of the plasticizer Accounting for the percentage of the total mass of the orally dissolving film composition.
  • the mass percentage of the absorption enhancer is preferably 0.10% to 15.00%, such as 8.30%, 10.70% or 9.50%, and the mass percentage means that the mass of the sweetener accounts for the The percentage of the total mass of the mouth-dissolving film composition.
  • the mass percentage of the sweetener is preferably 0.05% to 1.00%, such as 0.83%, 0.71% or 0.95%, and the mass percentage means that the mass of the sweetener accounts for the The percentage of the total mass of the mouth-dissolving film composition.
  • the cariprazine orally dissolving film composition is selected from one of the following formulations:
  • Formula a1 16.70% cariprazine, 45.00% hypromellose, 8.30% polyvinyl alcohol, 20.80% glycerin, 0.83% sucralose;
  • Formula a2 14.30% cariprazine, 13.60% hypromellose, 46.40% polyvinyl alcohol, 10.70% polysorbate 80, 14.30% glycerin, 0.71% sucralose;
  • Formula a3 14.30% cariprazine, 60.00% gelatin, 10.70% polysorbate 80, 14.30% glycerin, 0.71% sucralose;
  • Formula a4 16.70% cariprazine, 53.30% xanthan gum, 8.30% polysorbate 80, 20.80% glycerin, 0.83% sucralose;
  • Formula a5 19.00% cariprazine, 37.10% hypromellose, 33.30% gelatin, 9.50% polysorbate 80, 19.00% glycerin, 0.95% sucralose.
  • Formula a6 18.90% cariprazine, 28.40% hypromellose, 37.90% polyvinyl alcohol, 14.20% glycerin, 0.50% simethicone, 0.10% sucralose, the D90 of cariprazine is 1.7 ⁇ m;
  • Formula a7 18.90% cariprazine, 28.40% hypromellose, 37.90% polyvinyl alcohol, 14.20% glycerin, 0.50% simethicone, 0.10% sucralose, the D90 of cariprazine is 8.4 ⁇ m;
  • Formula a8 18.90% cariprazine, 28.40% hypromellose, 37.90% polyvinyl alcohol, 14.20% glycerin, 0.50% simethicone, 0.10% sucralose, the D90 of cariprazine is 17.3 ⁇ m;
  • Formula a9 18.90% cariprazine, 28.40% hypromellose, 37.90% polyvinyl alcohol, 14.20% glycerin, 0.50% simethicone, 0.10% sucralose, and the D90 of cariprazine is 28.4 ⁇ m.
  • Formula a10 18.90% cariprazine, 28.40% hypromellose, 37.90% polyvinyl alcohol, 14.20% glycerin, 0.50% simethicone, 0.10% sucralose, the D90 of cariprazine is 39.4 ⁇ m.
  • the present invention also provides the preparation method of described cariprazine orally dissolving film composition, it comprises the following steps:
  • step a2) Mix the mixture obtained in step a1) with the film-forming material, heat and stir at 60°C to 70°C, and dissolve to obtain a blank glue solution;
  • step a3) placing the active ingredient in the blank glue solution obtained in step a2), stirring until uniformly dispersed, stirring and defoaming under vacuum conditions, to obtain the drug-containing glue;
  • step a4) Apply the drug-containing glue solution obtained in step a3) after defoaming evenly on the polyester tape with a spatula, heat, dry, and cut to obtain a cariprazine mouth-dissolving film composition.
  • the cariprazine orally dissolving film composition is selected from the orally dissolving film composition of cariprazine clathrate, which comprises active ingredient clathrate, film-forming material, plasticizer and sweetener;
  • the inclusion compound of the active ingredient is composed of the inclusion complex of the active ingredient and cyclodextrin;
  • the active ingredient is selected from cariprazine and/or a pharmaceutically acceptable salt thereof;
  • the cyclodextrin is selected from one or more of ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin.
  • the molar ratio of the active ingredient to the cyclodextrin is preferably (0.25-2.00):1.
  • the mass percentage of the active ingredient is preferably 1.00% to 30.00%, such as 4.90%.
  • the mass percentage refers to the mass percentage of the active ingredient to the total mass of the mouth-dissolving film composition. percentage.
  • the mass percentage of the film-forming material is preferably 30.00% to 70.00%, such as 49.00%, 26.50% or 49.20%, and the mass percentage means that the mass percentage of the film-forming material accounts for the The percentage of the total mass of the mouth-dissolving film composition.
  • the mass percentage of the plasticizer is preferably 5.00% to 30.00%, such as 9.00% or 16.50%. Percentage of the total mass of the composition.
  • the mass percentage of the sweetener is preferably 0.05% to 0.50%, such as 0.20%. percentage of mass.
  • the orally dissolving film composition of the cariprazine inclusion compound is selected from one of the following formulations:
  • Formula b1 4.90% cariprazine, 13.10% ⁇ -cyclodextrin, 24.50% hypromellose, 24.50% polyvinyl alcohol, 24.50% mannitol, 8.20% glycerin, 0.20% simethicone, 0.20% Sucralose;
  • Formula b2 4.90% cariprazine, 13.10% ⁇ -cyclodextrin, 32.70% polyvinyl alcohol, 16.3% gelatin, 24.50% mannitol, 8.20% glycerin, 0.20% simethicone, 0.20% sucralose;
  • Formula b3 4.90% cariprazine, 13.10% hydroxypropyl- ⁇ -cyclodextrin, 2.00% hypromellose, 24.50% gelatin, 16.30% mannitol, 16.30% glycerin, 0.20% simethicone, 0.20% Sucralose;
  • Formula b4 4.90% cariprazine, 13.10% sulfobutyl ⁇ -cyclodextrin, 49.20% polyvinyl alcohol, 16.30% mannitol, 16.30% glycerin, 0.20% simethicone, 0.20% sucralose.
  • the present invention also provides the preparation method of the orally dissolving film composition of described cariprazine clathrate, it comprises the following steps:
  • step b2) adding the filler, plasticizer, and sweetener to the cyclodextrin inclusion compound of the active ingredient obtained in step b1), and stirring evenly to obtain solution A;
  • step b4) The drug-containing glue solution obtained in step b3) is evenly coated on a polyester tape with a spatula, heated and dried, and then cut into a certain size to obtain the orally dissolving film composition of the cariprazine clathrate.
  • the present invention also provides a cariprazine oral film, which comprises the cariprazine oral film composition.
  • the cariprazine oral thin film has a thickness of 10 ⁇ m to 100 ⁇ m.
  • the present invention also provides the application of the cariprazine orally dissolving film composition in the preparation of medicines for treating and/or preventing psychosis, bipolar disorder and acute mania.
  • the present invention also provides a method for treating and/or preventing psychosis, bipolar disorder, and acute mania, which comprises administering a therapeutically effective amount of the cariprazine oral film composition or oral thin film to patients in need .
  • the “multiple” means two or more, such as 2, 3, 4, 5, 6 or more.
  • oral dissolving film means oral dissolving film (Oral Dissolving Film, ODF).
  • the reagents and raw materials used in the present invention are all commercially available.
  • the cariprazine mouth-dissolving film composition provided by the invention has the advantages of thin thickness, good taste, stable properties, instant dissolution in the oral cavity without drinking water, and fast oral absorption speed.
  • the cariprazine mouth-dissolving film composition or cariprazine oral film provided by the invention has a good dissolution rate, does not have a gritty feeling after dissolving in the oral cavity, and can improve the taste of the medicine and increase the patient's compliance sex.
  • the film of the oral cavity film has uniform appearance and good flexibility. Moreover, no sedimentation occurs during the preparation of the film solution of the oral cavity film, and the content uniformity meets the requirements.
  • the cariprazine mouth-dissolving film composition or cariprazine oral thin film provided by the present invention helps to improve poor drug compliance, Vietnamese medicine and vomiting medicine in patients with schizophrenia, and is especially suitable for patients with dysphagia. The prospect of transformation is good.
  • the cariprazine mouth-dissolving film composition or cariprazine oral thin film of the present invention has easy-to-obtain raw materials, simple preparation process, simple operation, high drug loading capacity, and good drug content uniformity, and is suitable for industrial production.
  • composition of the prescription of embodiment A1-A10 is shown in the table below, wherein the percentage marked in each component is the mass percentage content of the described component in the prescription after drying according to its mass calculation:
  • step 2) Add film-forming material to the mixture obtained in step 1), heat and stir at 60°C to 70°C, and obtain a blank glue after melting;
  • step 3 Put the active ingredient in the blank glue solution obtained in step 2), stir until it is uniformly dispersed, and stir and defoam under vacuum conditions to obtain the drug-containing glue;
  • step 4) Apply the drug-containing glue solution obtained in step 3) evenly on the polyester tape with a spatula, heat, dry, and cut to obtain the cariprazine mouth-dissolving film.
  • the experimental data of the above-mentioned examples A1-A10 show that the cariprazine orally dissolving film composition provided by the present invention has the characteristics of thin thickness, good mouthfeel, stable properties, and can be dissolved immediately in the oral cavity without drinking water, and the oral absorption rate is fast. Advantages, at the same time, the process is simple, the drug loading capacity is high, and the drug content uniformity is good. Controlling cariprazine D 90 ⁇ 30 ⁇ m can improve the mouthfeel and appearance of the orolytic film, and the smaller the particle size, the better the content uniformity.
  • test method Take 6 tablets of each of the mouth-dissolving films of Examples A1-A10, and measure the disintegration time limit of the mouth-dissolving films.
  • the test method is as follows: add 100ml of artificial saliva to six 150ml beakers, and heat to 37 ⁇ 1°C. Gently place 6 mouth-melting films in 6 beakers at the same time, and in a standing state, record the time when all 6 mouth-melting films of each embodiment disintegrate and summarize as follows:
  • composition of the prescription of embodiment B1-B5 is shown in the following table, wherein the percentage marked in each component is the mass percentage content of the described component in the prescription after drying according to its mass calculation:
  • step 4) Apply the drug-containing glue solution obtained in step 3) evenly on the polyester tape with a spatula, heat and dry, and cut it into a certain size to obtain cariprazine oral instant film.
  • the cariprazine oral instant film that embodiment B1-B5 obtains is placed in two clamps of electronic tensile testing machine, starts testing machine with the speed of 50mm/min, investigates the mechanical strength of medicine film, and the results are shown in the following table.

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Abstract

L'invention concerne une composition de film à dissolution orale de cariprazine, un procédé de préparation associé et une application associée. La composition de film à dissolution orale comprend un principe actif, un matériau filmogène et un plastifiant, le principe actif étant choisi parmi un élément ou un mélange de plusieurs éléments parmi la cariprazine, un sel pharmaceutiquement acceptable de cariprazine, et un composé d'inclusion de ce dernier. La composition de film à dissolution orale présente les avantages d'une faible épaisseur, d'un bon goût, de propriétés stables, de pouvoir être immédiatement dissoute dans une cavité buccale sans eau potable, et d'une vitesse d'absorption orale élevée ; de plus, le procédé est simple, la capacité de chargement de médicament est élevée, l'uniformité de la teneur en médicament est bonne, et la composition de film à dissolution orale aide à améliorer des phénomènes tels qu'une mauvaise observance de prise de médicament, la dissimulation de médicament et le vomissement de médicament de patients atteints de schizophrénie, elle est particulièrement appropriée pour des patients atteints de dysphagie, et présente de bonnes perspectives commerciales.
PCT/CN2022/095122 2021-05-26 2022-05-26 Composition de film à dissolution orale de cariprazine, procédé de préparation associé et application associée WO2022247883A1 (fr)

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CN117243927A (zh) * 2023-10-17 2023-12-19 深圳市泰力生物医药有限公司 含安全有效掩味剂的盐酸卡利拉嗪口溶膜制剂及其制备方法
CN118680906A (zh) * 2024-08-29 2024-09-24 山东则正医药技术有限公司 一种快速溶出的盐酸卡利拉嗪口溶膜制剂及其制备方法

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CN103784426A (zh) * 2014-02-19 2014-05-14 上海现代药物制剂工程研究中心有限公司 阿立哌唑口溶膜剂及其制备方法
CN105343887A (zh) * 2015-10-30 2016-02-24 济南康和医药科技有限公司 一种右佐匹克隆口腔速溶膜及其制备方法
CN108261394A (zh) * 2017-01-04 2018-07-10 广东东阳光药业有限公司 一种盐酸卡利拉嗪注射制剂及其制备方法和用途
WO2018229794A1 (fr) * 2017-06-13 2018-12-20 Cipla Limited Forme amorphe de cariprazine
US20190160005A1 (en) * 2017-11-24 2019-05-30 Biophore India Pharmaceuticals Pvt. Ltd. Method of Preparing Solid Dispersions of Active Pharmaceutical Ingredients
CN109833311A (zh) * 2017-11-24 2019-06-04 江苏恒瑞医药股份有限公司 一种口溶膜组合物

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CN103784426A (zh) * 2014-02-19 2014-05-14 上海现代药物制剂工程研究中心有限公司 阿立哌唑口溶膜剂及其制备方法
CN105343887A (zh) * 2015-10-30 2016-02-24 济南康和医药科技有限公司 一种右佐匹克隆口腔速溶膜及其制备方法
CN108261394A (zh) * 2017-01-04 2018-07-10 广东东阳光药业有限公司 一种盐酸卡利拉嗪注射制剂及其制备方法和用途
WO2018229794A1 (fr) * 2017-06-13 2018-12-20 Cipla Limited Forme amorphe de cariprazine
US20190160005A1 (en) * 2017-11-24 2019-05-30 Biophore India Pharmaceuticals Pvt. Ltd. Method of Preparing Solid Dispersions of Active Pharmaceutical Ingredients
CN109833311A (zh) * 2017-11-24 2019-06-04 江苏恒瑞医药股份有限公司 一种口溶膜组合物

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