WO2020230676A1 - 経鼻投与用の粉末製剤及びその製造方法 - Google Patents

経鼻投与用の粉末製剤及びその製造方法 Download PDF

Info

Publication number
WO2020230676A1
WO2020230676A1 PCT/JP2020/018456 JP2020018456W WO2020230676A1 WO 2020230676 A1 WO2020230676 A1 WO 2020230676A1 JP 2020018456 W JP2020018456 W JP 2020018456W WO 2020230676 A1 WO2020230676 A1 WO 2020230676A1
Authority
WO
WIPO (PCT)
Prior art keywords
composite particles
water
active ingredient
insoluble polysaccharide
powder preparation
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.)
Ceased
Application number
PCT/JP2020/018456
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
俊志 治田
陽 園田
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.)
Shin Nippon Biomedical Laboratories Ltd
Original Assignee
Shin Nippon Biomedical Laboratories 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
Priority to JP2021519385A priority Critical patent/JPWO2020230676A1/ja
Priority to CN202080032083.6A priority patent/CN113784703A/zh
Priority to KR1020217040454A priority patent/KR20220009407A/ko
Priority to MX2021013442A priority patent/MX2021013442A/es
Priority to AU2020273810A priority patent/AU2020273810B2/en
Priority to CA3138846A priority patent/CA3138846A1/en
Application filed by Shin Nippon Biomedical Laboratories Ltd filed Critical Shin Nippon Biomedical Laboratories Ltd
Priority to BR112021021841A priority patent/BR112021021841A2/pt
Priority to EP20806255.4A priority patent/EP3970696A4/en
Priority to US17/595,381 priority patent/US12478581B2/en
Publication of WO2020230676A1 publication Critical patent/WO2020230676A1/ja
Anticipated expiration legal-status Critical
Priority to JP2024099620A priority patent/JP2024111203A/ja
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K9/0043—Nose
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • 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
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a powder preparation for nasal administration and a method for producing the same.
  • Patent Document 1 discloses "a powdery nasal administration composition containing a non-peptide / proteinaceous drug and a crystalline cellulose aggregate as a carrier thereof".
  • Patent Document 1 discloses a method of mixing a drug and crystalline cellulose in a mortar as a method for producing a powdery nasal administration composition.
  • the drug and the crystalline cellulose may be separated, and the mucosal adhesion effect of the crystalline cellulose may not be fully utilized. As a result, there is a problem that the expected medicinal effect is not exhibited.
  • An object of the present invention is to provide a powder preparation for nasal administration and a method for producing the same, which efficiently exerts a medicinal effect.
  • composite particles that efficiently exhibit their medicinal effects can be obtained by stirring, granulating, fluidized bed, or freeze-drying a mixture containing an active ingredient and a water-insoluble polysaccharide. It was.
  • the present invention includes the following embodiments.
  • a powder formulation for nasal administration containing composite particles in which the active ingredient and water-insoluble polysaccharide are attached to each other.
  • a method for producing a powder formulation for nasal administration [10] A step of forming a fluidized bed granule of a mixture containing an active ingredient and a water-insoluble polysaccharide to form composite particles in which the active ingredient and the water-insoluble polysaccharide are attached to each other is included. A method for producing a powder formulation for nasal administration. [11] A step of freeze-drying a mixture containing an active ingredient and a water-insoluble polysaccharide to form composite particles in which the active ingredient and the water-insoluble polysaccharide are attached to each other. A method for producing a powder formulation for nasal administration.
  • An electron micrograph of the test preparation of Example 7 is shown. An electron micrograph of the test preparation of Example 10 is shown. An electron micrograph of the test preparation of Example 15 is shown. An electron micrograph of the test preparation of Example 16 is shown. An electron micrograph of the test preparation of Comparative Example 1 is shown. An electron micrograph of the test preparation of Comparative Example 2 is shown.
  • One embodiment of the present invention relates to a powder preparation for nasal administration containing composite particles in which an active ingredient and a water-insoluble polysaccharide are attached to each other.
  • composite particles in the present specification are particles (aggregates) formed by adhesion of an active ingredient and a water-insoluble polysaccharide to each other. Therefore, the “composite particles” in the present specification are clearly distinguished from a simple mixture of a drug and crystalline cellulose as disclosed in, for example, Patent Document 1.
  • the active ingredient and the water-insoluble polysaccharide form composite particles
  • the active ingredient and the water-insoluble polysaccharide are integrated into the nasal mucosa. Adhere to. Since the water-insoluble polysaccharide has a mucosal adhesion effect, the active ingredient adheres to the nasal mucosa due to the effect, and the medicinal effect of the active ingredient is efficiently exhibited.
  • the active ingredient and the water-insoluble polysaccharide are simply mixed, the active ingredient may not be mixed uniformly, and the amount of the active ingredient may vary between powder preparations. On the other hand, in the present embodiment, since the active ingredient and the water-insoluble polysaccharide form composite particles, such variation can be suppressed.
  • the fluidity of the powder preparation is improved.
  • the powder preparation can be uniformly and easily filled in the container, and the injection rate of the powder preparation from the administration device is improved.
  • a powder preparation containing particles with a small particle size is administered into the nasal cavity, it may pass through the nasal cavity and reach the lungs.
  • the active ingredient and the water-insoluble polysaccharide form composite particles and the particle size is increased, the passage through the nasal cavity can be suppressed.
  • the composite particles of the present embodiment are formed by adhering the constituent particles of the composite particles to each other, they have a larger particle diameter than each constituent component.
  • Examples of the lower limit of the average primary particle diameter of the composite particles of the present embodiment include 20 ⁇ m, 25 ⁇ m, 30 ⁇ m, 35 ⁇ m, 40 ⁇ m and the like, and the upper limit thereof are, for example, 350 ⁇ m, 300 ⁇ m, 250 ⁇ m, 200 ⁇ m and 150 ⁇ m. , 100 ⁇ m and the like.
  • a specific range can be defined by appropriately combining the lower limit and the upper limit. For example, it can be in the range of 20 to 350 ⁇ m, 25 to 300 ⁇ m, 30 to 250 ⁇ m, 35 to 200 ⁇ m, and 40 to 150 ⁇ m.
  • the average primary particle size is measured according to the method described in the examples below.
  • the average primary particle diameter is measured under a dispersion pressure of 2 bar, if the constituent components of the composite particles are not attached to each other, the composite particles are decomposed into each component by the dispersion pressure.
  • the measurement conditions for the average primary particle size below, since the particles are decomposed, they are significantly different from the average primary particle size of the composite particles of the present embodiment.
  • the lower limit of the specific surface area of the composite particles of the present embodiment for example, 0.10m 2 /g,0.15m 2 /g,0.20m 2 /g,0.25m 2 /g,0.30m 2 / g etc. can be mentioned, as the upper limit, for example, cited 2.3m 2 /g,2.0m 2 /g,1.8m 2 /g,1.6m 2 /g,1.4m 2 / g or the like be able to.
  • a specific range can be defined by appropriately combining the lower limit and the upper limit.
  • the specific surface area is measured according to the method described in the examples below.
  • Examples of the upper limit of the Hauser ratio of the composite particles of the present embodiment include 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2 and the like.
  • the lower limit is not particularly limited.
  • the Hauser ratio is measured according to the method described in the examples below.
  • Diseases to be diagnosed, prevented or treated by the powder preparation of the present embodiment include, for example, cerebral hemorrhage, cerebral infarction, central nervous system infection, brain tumor, Parkinson's disease, epilepsy, muscular atrophic lateral sclerosis, Alzheimer's disease, etc.
  • Levy body dementia progressive supranuclear palsy, cerebral cortical basal nucleus degeneration, Pick's disease, frontotemporal dementia, multiple sclerosis, schizophrenia, depression, bipolar disorder, dysthymia, Adaptation disorder, social anxiety disorder, panic disorder, compulsive disorder, autism spectrum disorder, attentionlessness / hyperactivity disorder, sleep disorder, insomnia, traumatic brain injury, pain, migraine, headache, fever, inflammation, Rheumatoid arthritis, epilepsy, cerebral circulatory metabolism, muscle laxity, autonomic neuropathy, dizziness, hypertension, angina, arrhythmia, allergies, bronchial dilatation / asthma, other respiratory diseases (antitussive, sputum, etc.), digestive ulcers, Other gastrointestinal diseases (antidiarrhea, intestinal regulation, stomachic, digestive promotion, glutton, etc.), gout / hyperuricemia, dyslipidemia, diabetes, hormone-related diseases (pituitary hormone, corticosteroid, sex hormone, etc.
  • the active ingredient of the present embodiment one kind may be used alone, or a plurality of kinds of active ingredients may be used in combination.
  • the active ingredient include low molecular weight compounds, medium molecular weight drugs (for example, peptide drugs), protein drugs (for example, antibody drugs), nucleic acid drugs, cell drugs, regenerative medicine, vaccine antigens (for example, peptide antigens) and the like. ..
  • More specific active ingredients include, for example, tissue plasminogen activator, edaravon, ozagrel sodium, selective thrombin inhibitor, bidarabin, acyclovir, gancyclovir, balgancyclovir, didobudin, didanosin, sarcitabine, nevirapin, delabirdin, sakinavir, ritonavir.
  • More specific active ingredients include, for example, vaccine antigens against the following viruses or pathogens.
  • water-insoluble polysaccharide in the present specification means a polysaccharide that dissolves 0.001 g or less in 1000 ml of water (20 ° C.).
  • water-insoluble polysaccharide one type may be used alone, or a plurality of types of water-insoluble polysaccharides may be used in combination.
  • water-insoluble polysaccharide examples include cellulose, hemicellulose, chitosan, chitin, etc., preferably cellulose or hemicellulose, more preferably cellulose, and particularly preferably crystalline cellulose.
  • crystalline cellulose examples include PH grade of CEOLUS (registered trademark), PH grade of AVICEL (registered trademark), and more specifically, CEOLUS (registered trademark) PH-F20JP, AVICEL ( Examples thereof include (registered trademark) PH-105 and CEOLUS (registered trademark) PH-UF702.
  • the composite particles of the present embodiment may further contain a binder.
  • a binder When the composite particle contains a binder, the adhesion strength between the active ingredient and the water-insoluble polysaccharide can be increased, and the primary particle size and disintegration property of the composite particle can be adjusted.
  • the binder one type may be used alone, or a plurality of types of binders may be used in combination.
  • binder examples include purified water, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose, carboxymethyl cellulose, pregelatinized starch, partially pregelatinized starch, salts thereof and the like, and are preferable. Hydroxypropyl methylcellulose or pregelatinized starch.
  • the composite particles of the present embodiment may further contain additives.
  • the additive include an absorption promoter, a dissolution aid / solubilizer, a stabilizer, a fluidizing agent, a disintegrant, a masking agent, a flavoring agent, a preservative, an immunostimulant and the like.
  • the absorption promoter examples include surfactants, chelating agents, cyclodextrins, cell-penetrating peptides and the like.
  • the surfactant examples include anionic surfactants such as sodium lauryl sulfate and sodium caprice, and nonionic surfactants such as n-dodecyl- ⁇ -D-maltoside and tetradodecyl- ⁇ -D-maltoside. , Dipalmitoylphosphatidylcholine, sodium taurocholate and other zwitterionic surfactants can be mentioned.
  • the chelating agent examples include EDTA, citrate, pyrophosphate and the like.
  • Examples of the cyclodextrin include ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin and the like.
  • Examples of the cell-penetrating peptide include penetratin, HIV-1 Tat, HIV-1 Rev, arginine octamer, arginine decoder, pVEC, Ems, RRL helix, PRL4 and the like.
  • solubilizing / solubilizing agent examples include cyclodextrin, capric acid, lecithin, dipalmitoyl glycerophosphatidylcholine, dodecyl maltoside, dodecylphosphocholine, polyethylene glycol and the like.
  • Stabilizers include, for example, disaccharides (eg, sucrose, lactulose, lactose, maltose, trehalose, cellobiose, xylobiose, maltulose, galactosucrose, derivatives thereof), vitamins (eg, ascorbic acid, tocopherol), amino acids (eg, ascorbic acid, tocopherol).
  • disaccharides eg, sucrose, lactulose, lactose, maltose, trehalose, cellobiose, xylobiose, maltulose, galactosucrose, derivatives thereof
  • vitamins eg, ascorbic acid, tocopherol
  • amino acids eg, ascorbic acid, tocopherol
  • Examples of the fluidizing agent include crystalline cellulose and tertiary calcium phosphate.
  • disintegrant examples include cellulose, starch, crospovidone and the like.
  • Examples of the masking agent include mannitol and the like.
  • flavoring agent examples include asparagus, menthol and the like.
  • preservative examples include chimerosal and the like.
  • immunostimulant examples include cyclodextrin, aluminum salt, CpG oligonucleotide and the like.
  • a mixture containing an active ingredient and a water-insoluble polysaccharide is subjected to stirring granulation, fluidized bed granulation, or freeze-drying, and the active ingredient and the water-insoluble polysaccharide are attached to each other as composite particles.
  • the present invention relates to a method for producing a powder formulation for nasal administration, which comprises a step of forming
  • the method by stirring granulation, the method by fluidized bed granulation, and the method by freeze-drying are referred to as "stirring granulation method", "fluidized bed granulation method”, and “freeze-drying method”, respectively.
  • the constituent components of the composite particles are as described in the above item ⁇ Powder formulation>.
  • the amount of the binder added in the stirring granulation method is preferably 5 mL to 150 mL, more preferably 15 mL to 100 mL, and further preferably 20 mL to 75 mL per 100 g of the total weight of the powder in the granulation tank.
  • Composite particles having preferable properties can be obtained by stirring and granulating with the amount of the additive liquid added.
  • the spray rate of the binder in the fluidized layer granulation method is preferably 0.001 g / min to 0.4 g / min, more preferably 0.005 g / min to 0. per 50 g of the total weight of the powder in the granulation tank. It is 3 g / min, more preferably 0.01 g / min to 0.25 g / min.
  • the total amount added as a binder in the fluidized bed granulation method is preferably 0.01 g to 4.0 g, more preferably 0.05 g to 3.0 g, still more preferably, per 50 g of the total weight of the powder in the granulation tank. Is 0.1 g to 2.5 g.
  • the freezing temperature in the freeze-drying method is preferably ⁇ 100 ° C. to ⁇ 10 ° C., more preferably ⁇ 80 ° C. to ⁇ 15 ° C., and even more preferably ⁇ 60 ° C. to ⁇ 20 ° C. By freezing at such a temperature, composite particles having preferable properties can be obtained.
  • Freeze-drying method Put ultra-pure water in a 200 mL aluminum tray in advance, freeze the inner bottom of the aluminum tray at -20 ° C, mix the active ingredient, water-insoluble polysaccharide, binder, and additive with the phosphate buffer, and put it in the aluminum tray. , Pre-frozen at ⁇ 20 ° C. for 2 hours and placed in a shelf-type freeze-dryer (FreeZone Triad Freeze Dry System, Labconco Corp.) to obtain a freeze-dried product under the following conditions. As the freeze-drying conditions, the primary drying was carried out at ⁇ 25 ° C. for 30 hours under a reduced pressure of 105 mTorr, and the secondary drying was further carried out at 30 ° C. for 37 hours. The prepared freeze-dried product was crushed in a glass mortar and used as a test preparation.
  • Crystalline cellulose was added to a glass mortar and blinded to remove excess crystalline cellulose.
  • the active ingredient, water-insoluble polysaccharide, and additive were added to this glass mortar and mixed for 10 minutes using a glass pestle to prepare a test preparation.
  • FIGS. 1 to 6 show electron micrographs of the test preparations of Examples 7, 10, 15 and 16 and Comparative Examples 1 and 2, respectively.
  • a state in which various components aggregated to form composite particles was observed.
  • the average primary particle size of the test preparation was measured under a dispersion pressure of 2 bar by connecting a dry automatic dispersion unit (Sirocco 2000, Malvern) to a particle size distribution measuring device (Mastersizer 2000, Malvern) based on the laser diffraction method. .. Table 2 shows the results of the average primary particle size calculated based on the particle size distribution analysis by the volume conversion method.
  • the average primary particle size of the test preparation of the example is significantly larger than that of the test preparation of the comparative example, which indicates that various components form composite particles.
  • ⁇ Average content and content uniformity> Measured by reverse phase chromatography. Specifically, pH 2.8 acetonitrile / 0.05% trifluoroacetic acid (5/95) was used as the mobile phase, the test preparation was diluted with the mobile phase to an appropriate concentration, and a 0.45 ⁇ m syringe filter was used. The filtered filtrate was measured by high performance liquid chromatography (LC-2010 or LC-2030C 3D plus, Shimadzu Corporation), and the levodopa content in the test preparation was calculated.
  • LC-2010 or LC-2030C 3D plus, Shimadzu Corporation high performance liquid chromatography
  • This operation was performed three times for each test preparation, and the average value and relative standard deviation of the measured levodopa content with respect to the theoretical levodopa content contained in the test preparation amount used for the measurement were calculated, and the content (%) and content uniformity were calculated for each. It was set to (%).
  • Indomethacin-containing test preparation Measured by reverse phase chromatography. Specifically, a filtrate using methanol / 0.1% phosphoric acid (28/12) as a mobile phase, the test preparation diluted with the mobile phase to an appropriate concentration, and filtered through a 0.45 ⁇ m syringe filter. was measured by high performance liquid chromatography (LC-2030C 3D plus, Shimadzu Corporation), and the indomethacin content in the test preparation was calculated. This operation was performed three times for each test preparation, and the average value and relative standard deviation of the measured indomethacin content with respect to the theoretical indomethacin content contained in the test preparation amount used for the measurement were calculated, and the content (%) and content uniformity were calculated for each. It was set to (%).
  • the test preparation is dried under suction and reduced pressure at 100 ° C. for 1 hour, and then the specific surface area is determined by the BET method using a specific surface area measuring device (Autosorb-iQ-MP, cantachrome) based on the gas adsorption method using nitrogen gas. It was measured. The results are shown in Table 3. The specific surface area of the test preparations of the examples was significantly smaller than that of the test preparations of the comparative examples, indicating that the various components formed composite particles.
  • ⁇ Measurement of injection rate> A 20 mg test preparation was filled in capsules (HPMC capsules, Size2, Qualicaps), set in a pub riser (Forte Glow Medical Co., Ltd.), and then the weight of the pub riser was measured. After the test preparation was injected by pushing the pump of the pub riser only once, the weight of the pub riser was measured again, and the weight difference before and after the injection was taken as the injection amount. The injection amount (injection rate) was calculated when the weight of the filled test preparation was 100%. The results are shown in Table 5. It has been shown that the test formulations of the examples were injected at a significantly higher rate than the test formulations of the comparative examples.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Otolaryngology (AREA)
  • Inorganic Chemistry (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/JP2020/018456 2019-05-16 2020-05-01 経鼻投与用の粉末製剤及びその製造方法 Ceased WO2020230676A1 (ja)

Priority Applications (10)

Application Number Priority Date Filing Date Title
BR112021021841A BR112021021841A2 (pt) 2019-05-16 2020-05-01 Formulação de pó para administração intranasal, e método de fabricação da mesma
CN202080032083.6A CN113784703A (zh) 2019-05-16 2020-05-01 经鼻施予用粉末制剂及其制造方法
KR1020217040454A KR20220009407A (ko) 2019-05-16 2020-05-01 경비 투여용의 분말 제제 및 그 제조 방법
MX2021013442A MX2021013442A (es) 2019-05-16 2020-05-01 Formulacion en polvo para administracion intranasal y metodo de fabricacion de la misma.
AU2020273810A AU2020273810B2 (en) 2019-05-16 2020-05-01 Powder formulation for intranasal administration, and manufacturing method thereof
JP2021519385A JPWO2020230676A1 (https=) 2019-05-16 2020-05-01
US17/595,381 US12478581B2 (en) 2019-05-16 2020-05-01 Powder formulation for intranasal administration, and manufacturing method thereof
CA3138846A CA3138846A1 (en) 2019-05-16 2020-05-01 Powder formulation for intranasal administration, and manufacturing method thereof
EP20806255.4A EP3970696A4 (en) 2019-05-16 2020-05-01 POWDER PREPARATION FOR TRANSNASAL ADMINISTRATION AND MANUFACTURING METHOD THEREOF
JP2024099620A JP2024111203A (ja) 2019-05-16 2024-06-20 経鼻投与用の粉末製剤及びその製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2019093150 2019-05-16
JP2019-093150 2019-05-16

Publications (1)

Publication Number Publication Date
WO2020230676A1 true WO2020230676A1 (ja) 2020-11-19

Family

ID=73290206

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2020/018456 Ceased WO2020230676A1 (ja) 2019-05-16 2020-05-01 経鼻投与用の粉末製剤及びその製造方法

Country Status (10)

Country Link
US (1) US12478581B2 (https=)
EP (1) EP3970696A4 (https=)
JP (2) JPWO2020230676A1 (https=)
KR (1) KR20220009407A (https=)
CN (1) CN113784703A (https=)
AU (1) AU2020273810B2 (https=)
BR (1) BR112021021841A2 (https=)
CA (1) CA3138846A1 (https=)
MX (1) MX2021013442A (https=)
WO (1) WO2020230676A1 (https=)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2025514928A (ja) * 2022-04-21 2025-05-13 メルク・シャープ・アンド・ドーム・エルエルシー 凝集した結晶質中鎖脂肪酸ナトリウム塩を調製するプロセス
WO2025225629A1 (ja) * 2024-04-23 2025-10-30 株式会社メディラボRfp 経鼻投与用組成物

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117503703B (zh) * 2023-11-09 2024-11-22 广州新济药业科技有限公司 一种左旋多巴鼻喷雾剂及其制备方法及应用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05246841A (ja) * 1991-12-27 1993-09-24 Fuji Yakuhin Kogyo Kk 局所用製剤
JPH09291026A (ja) * 1996-02-28 1997-11-11 Teijin Ltd 即効性と持続性を兼ね備えた粉末状経鼻投与用組成物
JPH1059841A (ja) * 1996-02-27 1998-03-03 Teijin Ltd 吸収性が改善された粉末状経鼻投与組成物
JP2002187852A (ja) * 2000-03-21 2002-07-05 Jcr Pharmaceuticals Co Ltd 生理活性ペプチド含有粉末
WO2006016530A1 (ja) 2004-08-10 2006-02-16 Translational Research, Ltd. 速効性でかつ高い吸収性を可能とする経鼻投与用組成物
JP2006176461A (ja) * 2004-12-24 2006-07-06 Dai Ichi Seiyaku Co Ltd 粒状物
JP2017036214A (ja) * 2013-12-10 2017-02-16 株式会社ダイセル 炭酸塩を含む口腔内崩壊錠剤用組成物及び口腔内崩壊錠剤
WO2017223566A1 (en) * 2016-06-24 2017-12-28 Opiant Pharmaceuticals, Inc. Compositions, devices, and methods for the treatment of alcohol use disorder

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3634380B2 (ja) * 1996-02-27 2005-03-30 帝人株式会社 粉末状経鼻投与組成物
JP3197222B2 (ja) 1996-02-28 2001-08-13 帝人株式会社 粉末状経鼻投与組成物
JP2001055323A (ja) * 1999-08-12 2001-02-27 Teijin Ltd 粉末状経鼻投与用組成物
KR20030027108A (ko) * 2001-07-05 2003-04-03 트렌스레셔널 리서치 가부시키가이샤 인슐린의 경비 투여용 조성물
JPWO2006064906A1 (ja) 2004-12-17 2008-06-12 小野薬品工業株式会社 非晶質性組成物
ITRM20050443A1 (it) 2005-08-12 2007-02-13 Opocrin Spa Preparati oftalmici a base di polisaccaridi mucoadesivi con capacita' riepitelizzante della cornea.
CA2672134C (en) * 2006-12-07 2015-02-10 Daiichi Sankyo Company, Limited Solid medicinal preparation containing mannitol or lactose
US8337817B2 (en) * 2006-12-26 2012-12-25 Shin Nippon Biomedical Laboratories, Ltd. Preparation for transnasal application
CN101428009B (zh) * 2008-04-09 2013-01-09 上海医药工业研究院 胰岛素经鼻吸入粉雾剂
WO2009135646A2 (en) 2008-05-05 2009-11-12 Farmaprojects, Sa Stable pharmaceutical compositions and their processes for preparation suitable for industrial scale
WO2010131486A1 (en) * 2009-05-15 2010-11-18 Shin Nippon Biomedical Laboratories, Ltd. Intranasal pharmaceutical compositions with improved pharmacokinetics
ES2663335T3 (es) 2010-03-19 2018-04-12 Daiichi Sankyo Company, Limited Composición para administración transnasal y método para prepararla
EP3493789A2 (en) * 2016-08-05 2019-06-12 Shin Nippon Biomedical Laboratories, Ltd. Intranasal pharmaceutical powder compositions
US11135217B2 (en) * 2016-12-26 2021-10-05 Shionogi & Co., Ltd. Manufacturing process of formulation having improved content uniformity
US11744967B2 (en) * 2017-09-26 2023-09-05 Shin Nippon Biomedical Laboratories, Ltd. Intranasal delivery devices

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05246841A (ja) * 1991-12-27 1993-09-24 Fuji Yakuhin Kogyo Kk 局所用製剤
JPH1059841A (ja) * 1996-02-27 1998-03-03 Teijin Ltd 吸収性が改善された粉末状経鼻投与組成物
JPH09291026A (ja) * 1996-02-28 1997-11-11 Teijin Ltd 即効性と持続性を兼ね備えた粉末状経鼻投与用組成物
JP2002187852A (ja) * 2000-03-21 2002-07-05 Jcr Pharmaceuticals Co Ltd 生理活性ペプチド含有粉末
WO2006016530A1 (ja) 2004-08-10 2006-02-16 Translational Research, Ltd. 速効性でかつ高い吸収性を可能とする経鼻投与用組成物
JP2006176461A (ja) * 2004-12-24 2006-07-06 Dai Ichi Seiyaku Co Ltd 粒状物
JP2017036214A (ja) * 2013-12-10 2017-02-16 株式会社ダイセル 炭酸塩を含む口腔内崩壊錠剤用組成物及び口腔内崩壊錠剤
WO2017223566A1 (en) * 2016-06-24 2017-12-28 Opiant Pharmaceuticals, Inc. Compositions, devices, and methods for the treatment of alcohol use disorder

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3970696A4

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2025514928A (ja) * 2022-04-21 2025-05-13 メルク・シャープ・アンド・ドーム・エルエルシー 凝集した結晶質中鎖脂肪酸ナトリウム塩を調製するプロセス
WO2025225629A1 (ja) * 2024-04-23 2025-10-30 株式会社メディラボRfp 経鼻投与用組成物

Also Published As

Publication number Publication date
JP2024111203A (ja) 2024-08-16
EP3970696A4 (en) 2023-03-01
EP3970696A1 (en) 2022-03-23
US12478581B2 (en) 2025-11-25
BR112021021841A2 (pt) 2022-01-04
US20220183971A1 (en) 2022-06-16
JPWO2020230676A1 (https=) 2020-11-19
CN113784703A (zh) 2021-12-10
MX2021013442A (es) 2022-01-06
AU2020273810A1 (en) 2021-11-18
AU2020273810B2 (en) 2025-10-09
KR20220009407A (ko) 2022-01-24
CA3138846A1 (en) 2020-11-19

Similar Documents

Publication Publication Date Title
JP5415769B2 (ja) 経鼻投与用製剤
CN101460150B (zh) 用于口腔崩解片剂的可直接压片复合物
EP2898899B1 (en) Disintegrating particle composition containing acid-type carboxymethylcellulose and crystalline cellulose, and orally disintegrating tablet containing said composition
JP2024111203A (ja) 経鼻投与用の粉末製剤及びその製造方法
EP3862318A1 (en) Porous silica particle composition
CN101132769A (zh) 用于药物的跨黏膜给药的药物组合物
EP1027037A1 (en) Pharmaceutical preparation comprising clodronate as active ingredient and silicified microcrystalline cellulose as excipient
ZA200502693B (en) Pharmaceutical excipients comprising inorganic particles in association with an organic polymeric material and forming a solid reticulated matrix, compositions, manufacturing and use thereof.
JP2002187852A (ja) 生理活性ペプチド含有粉末
US11318115B2 (en) Oral pharmaceutical composition of Tecovirimat and preparation method thereof
CN102178657B (zh) 一种奥氮平口腔崩解片
CN1613442A (zh) 一种有效掩味的口腔崩解片及制备方法
JP7282735B2 (ja) 粉末製剤、カートリッジ、及びデバイス
CN106999436B (zh) 含有分娩控制物质的口服崩解固体药物剂量单元
CN106667944A (zh) 含有前列腺素类药物的缓释制剂
JP2015515974A5 (https=)
JP2001055323A (ja) 粉末状経鼻投与用組成物
CN106821976A (zh) 一种治疗埃博拉的枸橼酸托瑞米芬纳米混悬剂、枸橼酸托瑞米芬片及其制备方法
CN105555262A (zh) 含有崩解性颗粒组合物的口腔内崩解片剂
CN108324957A (zh) 一种s-羧甲基-l-半胱氨酸包合物及其肠溶制剂组合物
KR20160068975A (ko) 약학 조성물
CN106265559B (zh) 奥氮平口腔崩解片及其制备方法
CN1981746A (zh) 盐酸氟西汀口腔崩解片及其制备方法
CN104870018A (zh) 具有改善的活性物质的释放作为药物制剂中载体的碱式碳酸镁
TW201609193A (zh) 含有碳酸鹽之口腔內崩解錠劑用組成物及口腔內崩解錠劑

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20806255

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2021519385

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 3138846

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: MX/A/2021/013442

Country of ref document: MX

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112021021841

Country of ref document: BR

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020273810

Country of ref document: AU

Date of ref document: 20200501

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20217040454

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2020806255

Country of ref document: EP

Ref document number: 2021137151

Country of ref document: RU

ENP Entry into the national phase

Ref document number: 2020806255

Country of ref document: EP

Effective date: 20211216

ENP Entry into the national phase

Ref document number: 112021021841

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20211029

WWP Wipo information: published in national office

Ref document number: MX/A/2021/013442

Country of ref document: MX

WWP Wipo information: published in national office

Ref document number: 2021137151

Country of ref document: RU

WWG Wipo information: grant in national office

Ref document number: MX/A/2021/013442

Country of ref document: MX

WWG Wipo information: grant in national office

Ref document number: 17595381

Country of ref document: US

WWR Wipo information: refused in national office

Ref document number: 1020217040454

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: 2021137151

Country of ref document: RU

WWR Wipo information: refused in national office

Ref document number: 1020217040454

Country of ref document: KR

WWC Wipo information: continuation of processing after refusal or withdrawal

Ref document number: 1020217040454

Country of ref document: KR