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WO2025216283A1 - Composition pharmaceutique contenant du létermovir et son procédé de production et son utilisation - Google Patents

Composition pharmaceutique contenant du létermovir et son procédé de production et son utilisation

Info

Publication number
WO2025216283A1
WO2025216283A1 PCT/JP2025/014330 JP2025014330W WO2025216283A1 WO 2025216283 A1 WO2025216283 A1 WO 2025216283A1 JP 2025014330 W JP2025014330 W JP 2025014330W WO 2025216283 A1 WO2025216283 A1 WO 2025216283A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
mass
active ingredient
binder
parts
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/JP2025/014330
Other languages
English (en)
Japanese (ja)
Inventor
拓哉 伊藤
ハイメ サングラ ペレス
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.)
Towa Pharmaceutical Europe SL
Towa Pharmaceutical Co Ltd
Original Assignee
Towa Pharmaceutical Europe SL
Towa Pharmaceutical 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 Towa Pharmaceutical Europe SL, Towa Pharmaceutical Co Ltd filed Critical Towa Pharmaceutical Europe SL
Publication of WO2025216283A1 publication Critical patent/WO2025216283A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K47/26—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
    • A61K47/36—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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pharmaceutical composition containing letermovir or its salt as an active ingredient, as well as a method for producing the same and its use.
  • Letermovir has the chemical name (4S)-2- ⁇ 8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl ⁇ acetic acid and is a compound represented by the following formula:
  • Letermovir is used to prevent and treat cytomegalovirus (CMV) infection by inhibiting the DNA terminase complex necessary for the proliferation (replication) of cytomegalovirus (CMV), including human cytomegalovirus (HCMV), thereby suppressing the proliferation of CMV.
  • CMV cytomegalovirus
  • HCMV human cytomegalovirus
  • Patent Document 1 discloses a solid pharmaceutical formulation containing letermovir in an amorphous state for use in a solid oral dosage form, and describes that this solid pharmaceutical formulation is obtained by a precipitation method in which amorphous letermovir is precipitated from a water-miscible solvent selected from acetone and acetonitrile in an excess of stirred water, and the resulting letermovir is then isolated by filtration or centrifugation.
  • letermovir has a high adhesiveness to punches and other components, which makes it prone to tableting problems and makes it difficult to consistently produce solid dosage forms. It was also found that producing small dosage forms, which are limited in the amount of additives used, is particularly difficult. Perhaps for this reason, even with the method of Patent Document 1, the amount of excipients and other ingredients added is high, and small dosage forms cannot be produced. Furthermore, generally, when a dosage form is made smaller, the proportion of additives added is limited, making it difficult to improve the dissolution of the active ingredient. Furthermore, letermovir has low photostability, and the limitations on the types and amounts of additives that come with miniaturization make it difficult to improve photostability.
  • an object of the present invention is to provide a miniaturized letermovir-containing pharmaceutical composition that is highly productive and dissolvable, as well as a method for producing the same and uses thereof.
  • Another object of the present invention is to provide a miniaturized letermovir-containing pharmaceutical composition that is highly stable, including photostable, as well as a method for producing the same and its uses.
  • a compact letermovir-containing pharmaceutical composition can be obtained by combining the active ingredient letermovir or a pharmaceutically acceptable salt thereof with a binder and adjusting the proportion of the active ingredient to 50% by mass or more in the pharmaceutical composition, thereby completing the present invention.
  • the present invention includes the following aspects:
  • a pharmaceutical composition comprising letermovir or a pharmaceutically acceptable salt thereof as an active ingredient and a binder, A pharmaceutical composition in which the proportion of the active ingredient in the pharmaceutical composition is 50% by mass or more.
  • Aspect [2] The pharmaceutical composition of aspect [1], wherein a 2% by mass aqueous solution of the binder has a viscosity of 2 mPa ⁇ s or more at 20°C.
  • Aspect [3] The pharmaceutical composition of aspect [1] or [2], wherein the binder is a hydroxyalkyl cellulose.
  • Aspect [5] The pharmaceutical composition of aspect [4], wherein the ratio of the binder is 1 to 10 parts by mass per 100 parts by mass of the active ingredient.
  • Aspect [6] The pharmaceutical composition of aspect [4], wherein the ratio of the binder is 2 to 10 parts by mass per 100 parts by mass of the active ingredient.
  • Aspect [7] The pharmaceutical composition of any one of Aspects [4] to [6], wherein the granulation composition further contains an excipient, and the proportion of the excipient in the pharmaceutical composition is 10% by mass or less.
  • Aspect [8] The pharmaceutical composition of aspect [7], wherein the excipient is a sugar alcohol.
  • Aspect [9] The pharmaceutical composition of aspect [7], wherein the excipient is crystalline cellulose.
  • Aspect [10] The pharmaceutical composition of any one of aspects [1] to [9] above, which is a tablet.
  • Aspect [11] The pharmaceutical composition of aspect [10], wherein the tablet is a film-coated tablet comprising an uncoated tablet portion and a film-coated portion covering the surface of the uncoated tablet portion, and the film-coated portion does not contain a colorant.
  • a method for producing a pharmaceutical composition comprising letermovir or a pharmaceutically acceptable salt thereof as an active ingredient and a binder, wherein the content of the active ingredient is 50% by mass or more,
  • a production method comprising a granulation step of wet granulating a composition for granulation containing the active ingredient and the binder by an agitation granulation method or a fluidized bed granulation method to obtain a granulated product.
  • a pharmaceutical composition comprising letermovir or a pharmaceutically acceptable salt thereof as an active ingredient and a binder, wherein the content of the active ingredient is 50% by mass or more,
  • a binder having a viscosity of 2 mPa ⁇ s or more in a 2 mass % aqueous solution at 20°C as the binder, Methods for improving the stability and dissolution of miniaturized tablets.
  • letermovir or a pharmaceutically acceptable salt thereof as the active ingredient is combined with a binder, and the proportion of the active ingredient is adjusted to 50% by mass or more in the pharmaceutical composition, allowing the size of the letermovir-containing pharmaceutical composition to be reduced. Furthermore, by selecting the binder, the productivity (or moldability) of the reduced-size letermovir-containing pharmaceutical composition (particularly tablets) and the dissolution of the active ingredient can be improved, and the stability of the pharmaceutical composition can also be improved.
  • FIG. 1 is a graph showing the dissolution rate versus test time for the tablets obtained in Example 1 and Comparative Examples 1 and 2 (initial profile in a pH 1.2 test solution).
  • FIG. 2 is a graph showing the dissolution rate versus test time for the tablets obtained in Example 1 and Comparative Examples 1 and 2 (initial profile in a test solution at pH 4.0).
  • FIG. 3 is a graph showing the dissolution rate versus test time for the tablets obtained in Example 1 and Comparative Examples 1 and 2 (initial profile in pH 6.8 test solution).
  • FIG. 4 is a graph showing the dissolution rate versus test time for the tablets obtained in Example 1 and Comparative Examples 1 and 2 (initial profile in aqueous test fluid).
  • FIG. 5 is a graph comparing the dissolution rate (initial profile in pH 1.2 test solution) of the tablets obtained in Example 1 against the test time before and after the stability test.
  • FIG. 6 is a graph comparing the dissolution rate (initial profile in pH 1.2 test solution) of the tablets obtained in Comparative Example 2 against the test time before and after the stability test.
  • FIG. 7 is a graph showing the dissolution rate versus test time for the tablets obtained in Example 3 (initial profile in pH 4.5 test solution).
  • the pharmaceutical composition of the present invention comprises letermovir or a pharmaceutically acceptable salt thereof as an active ingredient and a binder, and is not particularly limited as long as the proportion of the active ingredient in the pharmaceutical composition is 50% by mass or more. However, it is preferable that the pharmaceutical composition be an oral solid formulation, as this makes it easier to achieve the effects of the present invention.
  • Solid oral dosage forms include tablets, powders, fine granules, granules, pills, capsules, and dry syrups. Of these, tablets are preferred due to their significant effect in improving productivity.
  • tablette examples include sugar-coated tablets, gelatin-coated tablets, film-coated tablets, enteric-coated tablets, dry-coated tablets (compression-coated tablets), multi-layer tablets (two-layer or three-layer tablets, etc.), etc.
  • film-coated tablets are particularly preferred because they facilitate the development of the effects of the present invention.
  • the shape (surface shape) of the tablet is not particularly limited, and examples include circular, oval, and polygonal shapes (square, rectangular, hexagonal, etc.), with circular shapes being preferred.
  • the tablet diameter (average diameter) is, for example, 3 to 12 mm, preferably 5 to 11.5 mm, even more preferably 5.5 to 11 mm, even more preferably 6 to 10.5 mm, and most preferably 7 to 10 mm.
  • the tablet diameter is the average of the major and minor axes.
  • the tablet thickness is, for example, 1 to 5 mm, preferably 1.5 to 4.8 mm, even more preferably 2.5 to 4.7 mm, even more preferably 3 to 4.5 mm, and most preferably 3.5 to 4.3 mm.
  • the pharmaceutical composition of the present invention (particularly tablets) preferably contains a granule of a granulation composition containing the active ingredient and the binder.
  • the composition may be formed solely from the granule, or from a combination of the granule with ingredients other than the granule.
  • the pharmaceutical composition of the present invention is preferably formed from a combination of the granule with ingredients other than the granule.
  • the tableting composition tablette mixture
  • the shape of the granules is not particularly limited, and examples thereof include powdery, spherical or nearly spherical, ellipsoidal, polyhedral, plate-like, fibrous, irregular or amorphous shapes. Of these, powdery and amorphous shapes are preferred.
  • the shape of the granules may be hollow, but a solid shape is preferred because it is easier to reduce the size.
  • the volume-based cumulative 50% particle size (D 50 ) of the granules can be selected from the range of about 30 to 200 ⁇ m, for example, 50 to 180 ⁇ m, preferably 60 to 150 ⁇ m, further preferably 70 to 130 ⁇ m, more preferably 80 to 120 ⁇ m, and most preferably 90 to 110 ⁇ m. If the cumulative 50% particle size (median particle size) of the granules is too small, productivity may decrease, and conversely, if it is too large, the pharmaceutical composition may not be miniaturized.
  • the volume-based cumulative 10% particle size (D 10 ) of the granulated product can be selected from the range of about 20 to 100 ⁇ m, for example, 30 to 90 ⁇ m, preferably 35 to 80 ⁇ m, further preferably 40 to 70 ⁇ m, further preferably 43 to 60 ⁇ m, and most preferably 45 to 55 ⁇ m. If the cumulative 10% particle size (D 10 ) of the granulated product is too small, productivity may decrease.
  • the volume-based cumulative 90% particle size (D 90 ) of the granules can be selected from the range of about 50 to 500 ⁇ m, for example, 100 to 400 ⁇ m, preferably 120 to 350 ⁇ m, further preferably 150 to 300 ⁇ m, even more preferably 180 to 250 ⁇ m, and most preferably 200 to 210 ⁇ m.
  • the cumulative 10% particle size ( D10 ), cumulative 50% particle size ( D50 ), and cumulative 90% particle size ( D90 ) of a granulated product can be measured using a laser diffraction particle size distribution analyzer, and refer to the particle sizes of particles that are, based on volume, at the cumulative 10%, cumulative 50%, and cumulative 90% from the small particle side of the particle size distribution, respectively.
  • the granules may contain letermovir as an active ingredient, and letermovir may be in the form of a salt (a pharmaceutically acceptable salt).
  • the salt of letermovir there are no particular limitations on the salt of letermovir, as long as it is a pharmaceutically acceptable salt, and it may be a salt with a base or an acid.
  • Bases for forming salts include, for example, inorganic bases [e.g., ammonia; alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), other metals (zinc, aluminum, etc.)], organic bases (e.g., alkylamines such as methylamine and triethylamine; polyamines; alkanolamines such as ethanolamine and triethanolamine; cyclic amines such as morpholine, piperazine, pyrrolidine, picoline, etc.), etc.).
  • inorganic bases e.g., ammonia; alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), other metals (zinc, aluminum, etc.)
  • organic bases e.g., alkylamines such as methylamine and triethylamine; polyamines; alkanolamines such as ethanolamine and triethanolamine
  • alkali metal salts such as sodium and alkaline earth metal salts such as calcium are preferred.
  • Acids for forming salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, perchloric acid, and phosphoric acid; and organic acids such as oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and acidic amino acids such as glutamic acid and aspartic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, perchloric acid, and phosphoric acid
  • organic acids such as oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tart
  • Letermovir or a salt (a pharmaceutically acceptable salt) thereof may be in the form of a solvate in the granules.
  • solvents that form solvates include water, alcohols (e.g., C 1-4 alkanols such as methanol, ethanol, 1-propanol, and 2-propanol), ketones (e.g., acetone, methyl ethyl ketone, methyl isopropyl ketone, and methyl isobutyl ketone), nitriles (e.g., acetonitrile and propionitrile), esters (e.g., ethyl acetate and isopropyl acetate), ethers (e.g., diethyl ether and t-butyl methyl ether), aliphatic hydrocarbons (e.g., n-pentane, n-hexane, cyclohexane, n-heptane, and is
  • Letermovir or its salt may be amorphous or crystalline, but is preferably amorphous.
  • the size of letermovir or its salt is not particularly limited and may be adjusted appropriately.
  • the volume-based cumulative 50% particle size (D 50 ) can be 1 to 50 ⁇ m, e.g., 10 to 30 ⁇ m.
  • the cumulative 50% particle size (D 50 ) of letermovir or a salt thereof can be measured by volume using a laser diffraction particle size distribution analyzer.
  • the specific surface area of the starting material, letermovil or a salt thereof, is not particularly limited and may be adjusted as appropriate.
  • the BET specific surface area can be set to 3 to 5 m 2 /g.
  • the proportion of the active ingredient (letermovir or a salt thereof) in the granules (composition for granulation) can be selected from a range of approximately 50 to 99% by mass, for example 60 to 98% by mass, preferably 70 to 97% by mass, even more preferably 80 to 95% by mass, even more preferably 83 to 93% by mass, and most preferably 85 to 90% by mass. If the proportion of letermovir or a salt thereof is too low, it may be difficult to miniaturize the pharmaceutical composition, and if it is too high, granulation may be difficult.
  • the pharmaceutical composition of the present invention contains an active ingredient that is highly adhesive and difficult to handle during manufacturing processes such as tableting
  • a binder first binder
  • a miniaturized pharmaceutical composition particularly, a tablet
  • productivity productivity of the pharmaceutical composition
  • dissolution dissolution of the active ingredient
  • the active ingredient has strong adhesion to metal and easily adheres to molds used to manufacture tablets, reducing the productivity or moldability of the tablets.
  • productivity can be improved.
  • the viscosity of a 2% by mass aqueous solution at 20°C may be 2 mPa ⁇ s or more, preferably 5 mPa ⁇ s or more, more preferably 10 mPa ⁇ s or more, more preferably 50 mPa ⁇ s or more, even more preferably 100 mPa ⁇ s or more, and most preferably 150 mPa ⁇ s or more.
  • the viscosity is 2 to 1000 mPa ⁇ s, preferably 5 to 800 mPa ⁇ s, more preferably 10 to 500 mPa ⁇ s, more preferably 50 to 500 mPa ⁇ s, and most preferably 100 to 450 mPa ⁇ s.
  • viscosity can be measured by conventional methods, such as capillary viscometer methods.
  • binders include synthetic polymers such as polyvinylpyrrolidones [polyvinylpyrrolidone (povidone), vinylpyrrolidone copolymers (copolyvidone) such as vinyl acetate-vinylpyrrolidone copolymer, etc.], vinyl alcohol polymers (polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.), carboxyvinyl polymers, polyacrylic acid polymers (sodium polyacrylate, acrylic acid copolymer, etc.), polylactic acid, polyethylene glycol, and polyvinyl acetate; hydroxyalkylcelluloses such as hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (hypromellose or HPMC); and cellulose esters such as cellulose acetate.
  • polyvinylpyrrolidones polyvinylpyrrolidone
  • binders can be used alone or in combination.
  • hydroxyalkyl celluloses hydroxyalkyl celluloses such as HPC or alkylhydroxyalkyl celluloses such as HPMC
  • cellulose ethers having a hydroxy C2-4 alkyl group are more preferred
  • hydroxy C3-4 alkyl celluloses such as HPC and C1-3 alkylhydroxy C3-4 alkyl celluloses such as HPMC are even more preferred
  • HPC is most preferred.
  • HPC-SL viscosity of 2% by mass (20°C) aqueous solution: 3.0 to 5.9 mPa ⁇ s
  • HPC-L viscosity of 2% by mass (20°C) aqueous solution: 6.0 to 10.0 mPa ⁇ s
  • HPC-M viscosity of 2% by mass (20°C) aqueous solution: 150 to 400 mPa ⁇ s.
  • the proportion of binder can be selected from a range of approximately 0.5 to 30 parts by weight (particularly 1 to 20 parts by weight) per 100 parts by weight of the active ingredient, for example, 1.5 to 20 parts by weight, preferably 2 to 10 parts by weight, even more preferably 2.3 to 8 parts by weight, even more preferably 2.5 to 6 parts by weight, and most preferably 3 to 5 parts by weight. If the proportion of binder is too low, productivity and dissolution may decrease, while if it is too high, it may become difficult to miniaturize the pharmaceutical composition.
  • composition of the present invention may further contain an excipient (first excipient) from the viewpoint of improving dissolution properties.
  • excipients examples include sugars (lactose, glucose, fructose, maltose, sucrose, white sugar, powdered reduced maltose syrup, etc.), sugar alcohols [sorbitols such as D-sorbitol, mannitols such as D-mannitol, reduced maltose syrup (maltitol), reduced starch hydrolysates, xylitol, reduced palatinose, tetraoses obtained by fermenting glucose (e.g., erythritol, etc.)], celluloses (crystalline cellulose, microcrystalline cellulose, powdered cellulose, etc.), alkylcelluloses (methylcellulose, ethylcellulose, etc.), etc.
  • excipients can be used alone or in combination.
  • sugar alcohols such as D-mannitol and celluloses such as crystalline cellulose are preferred.
  • the proportion of excipient is, for example, 0.5 to 20 parts by mass, preferably 1 to 15 parts by mass, even more preferably 2 to 12 parts by mass, even more preferably 3 to 10 parts by mass, and most preferably 5 to 8 parts by mass per 100 parts by mass of the active ingredient. If the proportion of excipient is too low, dissolution may decrease, and if it is too high, it may become difficult to miniaturize the pharmaceutical composition.
  • composition of the present invention may further contain a disintegrant (first disintegrant) from the viewpoint of improving dissolution properties.
  • Disintegrants include, for example, polysaccharides [starch such as corn starch, potato starch, pregelatinized starch, partially pregelatinized starch, oxidized starch, dextrin, cyclodextrin, hydroxypropyl starch, carboxymethyl starch, and carboxymethyl starch sodium; cellulose ethers such as carboxymethylcellulose (carmellose or CMC), carmellose sodium, carmellose calcium, carboxymethylethylcellulose (CMEC), croscarmellose sodium, and low-substituted hydroxypropylcellulose (L-HPC); agar, carrageenan, gum arabic, alginic acid, sodium alginate, propylene glycol alginate, guar gum, locust bean gum, tragacanth gum, pullulan, xanthan gum, hyaluronic acid, pectin, and sodium chondroitin sulfate], proteins (such as gelatin, casein, and soy protein), and cross
  • disintegrants can be used alone or in combination.
  • starches such as corn starch and partially pregelatinized starch, and carboxyalkylcelluloses such as carmellose and croscarmellose sodium are preferred, and crosslinked carboxy C 1-3 alkylcelluloses such as croscarmellose sodium are particularly preferred.
  • the proportion of disintegrant is, for example, 1.5 to 20 parts by mass, preferably 2 to 10 parts by mass, even more preferably 2.3 to 8 parts by mass, even more preferably 2.5 to 6 parts by mass, and most preferably 3 to 5 parts by mass, per 100 parts by mass of the active ingredient. If the proportion of disintegrant is too low, dissolution may decrease, while if it is too high, it may become difficult to miniaturize the pharmaceutical composition.
  • the pharmaceutical composition of the present invention may further contain a fluidizer (first fluidizer) in order to improve productivity.
  • fluidizing agents examples include minerals (talc, bentonite, synthetic hydrotalcite, kaolin, etc.), silicates (anhydrous silicic acid such as light anhydrous silicic acid, hydrous silicon dioxide, calcium silicate, magnesium silicate, synthetic aluminum silicate, magnesium aluminometasilicate, hydrous silicon dioxide, etc.).
  • minerals talc, bentonite, synthetic hydrotalcite, kaolin, etc.
  • silicates anhydrous silicic acid such as light anhydrous silicic acid, hydrous silicon dioxide, calcium silicate, magnesium silicate, synthetic aluminum silicate, magnesium aluminometasilicate, hydrous silicon dioxide, etc.
  • fluidizing agents can be used alone or in combination.
  • silicic acids such as light anhydrous silicic acid are preferred.
  • the proportion of the fluidizing agent is, for example, 0.1 to 10 parts by mass, preferably 0.3 to 5 parts by mass, even more preferably 0.5 to 3 parts by mass, and even more preferably 1 to 2 parts by mass, per 100 parts by mass of the active ingredient. If the proportion of the fluidizing agent is too low, productivity may decrease, while if it is too high, it may become difficult to miniaturize the pharmaceutical composition.
  • the pharmaceutical composition of the present invention may further contain a lubricant (first lubricant) to improve productivity.
  • Lubricants include, for example, fatty acids or metal salts thereof such as stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, and sodium cocoate; silicon oxides such as hydrous silicon dioxide and silicon dioxide; polyorganosiloxanes such as dimethylpolysiloxane; fats and oils such as hydrogenated oil and cocoa butter; and waxes such as beeswax, white beeswax, carnauba wax, lanolin, paraffin, and petrolatum.
  • fatty acids or metal salts thereof such as stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, and sodium cocoate
  • silicon oxides such as hydrous silicon dioxide and silicon dioxide
  • polyorganosiloxanes such as dimethylpolysiloxane
  • fats and oils such as hydrogenated oil and cocoa butter
  • waxes such as beeswax, white beeswax, carn
  • lubricants can be used alone or in combination.
  • fatty acid metal salts such as magnesium stearate are preferred.
  • the proportion of lubricant is, for example, 0.1 to 5 parts by mass, preferably 0.2 to 3 parts by mass, even more preferably 0.3 to 2.5 parts by mass, even more preferably 0.5 to 2 parts by mass, and most preferably 1 to 1.5 parts by mass, per 100 parts by mass of the active ingredient. If the proportion of lubricant is too low, productivity may decrease, while if it is too high, it may become difficult to miniaturize the pharmaceutical composition.
  • composition of the present invention may further contain other additives that are commonly used in pharmaceutical compositions, as long as the effects of the present invention are not impaired.
  • plasticizers first plasticizers
  • surfactants pH adjusters
  • colorants sweeteners or flavoring agents
  • antioxidants preservatives or preservatives
  • humectants antistatic agents
  • disintegration aids etc.
  • the total proportion of these additives in the granules may be 30% by mass or less, preferably 20% by mass or less, even more preferably 10% by mass or less, even more preferably 5% by mass or less, and most preferably 0% by mass.
  • the method for producing the granulated product is not particularly limited, and a conventional granulation method can be used.
  • the conventional granulation method may be a dry granulation method, but from the viewpoint of productivity, a wet granulation method is preferred.
  • the wet granulation method may be a method for granulating a granulation composition (a raw material for granulation) using a granulation solvent, and examples thereof include extrusion granulation, tumbling granulation, fluidized bed granulation, mixing/stirring granulation, spray-drying granulation, and vibration granulation. These wet granulation methods may be used in combination.
  • mixing/agitation granulation and fluidized bed granulation are preferred from the standpoint of productivity, with fluidized bed granulation being particularly preferred.
  • the mixing/stirring granulation method is not particularly limited as long as it involves mixing and stirring a composition containing the active ingredient and granulation solvent all at once to obtain a granulated product, and any conventional method can be used.
  • the fluidized bed granulation method is not particularly limited, and any conventional method can be used, as long as it involves spraying a granulating liquid containing a granulating solvent onto raw material powder containing an active ingredient that has been fluidized by an air current to obtain granules.
  • the granulating liquid preferably contains a binder and a granulating solvent.
  • the granulation solvent used in the wet granulation method is not particularly limited, but from the viewpoint of safety, water, aqueous solvents, etc. can be used.
  • aqueous solvents include lower alcohols (e.g., C2-4 alkanols such as ethanol and isopropanol), aliphatic ketones (e.g., acetone), etc. These solvents can be used alone or in combination.
  • water and/or aqueous solvents are preferred, and from the standpoint of safety, water and/or C 2-4 alkanols are more preferred, and water and/or ethanol are most preferred.
  • the proportion of granulation solvent is, for example, 10 to 500 parts by mass, preferably 50 to 400 parts by mass, and more preferably 100 to 300 parts by mass per 100 parts by mass of the active ingredient.
  • the final component preferably contains a lubricant (second lubricant) and/or a flow agent (second flow agent) from the viewpoint of improving productivity of the pharmaceutical composition (particularly, tablets).
  • Examples of the second lubricant include the lubricants exemplified as the first lubricant.
  • the above lubricants can be used alone or in combination.
  • fatty acid metal salts such as magnesium stearate are preferred.
  • the proportion of the second lubricant is, for example, 0.1 to 5 parts by mass, preferably 0.2 to 3 parts by mass, even more preferably 0.3 to 2 parts by mass, even more preferably 0.5 to 1.5 parts by mass, and most preferably 0.8 to 1.2 parts by mass, per 100 parts by mass of the granules. If the proportion of the second lubricant is too low, productivity may decrease, and if it is too high, it may become difficult to miniaturize the pharmaceutical composition.
  • Examples of the second fluidizing agent include the fluidizing agents exemplified as the first fluidizing agent.
  • the above-mentioned fluidizing agents can be used alone or in combination of two or more.
  • silicic acids such as light anhydrous silicic acid are preferred.
  • the proportion of the second fluidizing agent is, for example, 0.1 to 5 parts by mass, preferably 0.2 to 3 parts by mass, even more preferably 0.3 to 2 parts by mass, even more preferably 0.5 to 1.5 parts by mass, and most preferably 0.8 to 1.2 parts by mass, per 100 parts by mass of the active ingredient. If the proportion of the second fluidizing agent is too low, productivity may decrease, while if it is too high, it may become difficult to miniaturize the pharmaceutical composition.
  • the final component may further contain a disintegrant (second disintegrant) to improve the dissolution of the active ingredient.
  • a disintegrant second disintegrant
  • the second disintegrant examples include the disintegrants exemplified as the first disintegrant.
  • the disintegrants can be used alone or in combination of two or more.
  • starches such as corn starch and partially pregelatinized starch, polyvinylpyrrolidones such as crospovidone, and silicic acids such as light anhydrous silicic acid are preferred, with polyvinylpyrrolidones such as crospovidone being particularly preferred.
  • the proportion of the second disintegrant is, for example, 0.1 to 10 parts by mass, preferably 0.2 to 5 parts by mass, even more preferably 0.3 to 3 parts by mass, even more preferably 0.5 to 2 parts by mass, and most preferably 0.8 to 1.5 parts by mass, per 100 parts by mass of the granules. If the proportion of the second disintegrant is too low, dissolution properties may decrease, and if it is too high, it may become difficult to miniaturize the pharmaceutical composition.
  • the final component may further contain other additives.
  • other additives include the binders exemplified as the first binder and the additives exemplified as conventional additives for the granulated product. These other additives may be used alone or in combination of two or more.
  • the total proportion of the other additives may be 5 parts by weight or less (e.g., 0.01 to 5 parts by weight) per 100 parts by weight of the granulated product, preferably 3 parts by weight or less, and more preferably 2 parts by weight or less.
  • the mixed powder for tableting is prepared by mixing the granulated product with the final powder component.
  • the method for mixing the granulated product with the final powder component is not particularly limited, and conventional stirring or kneading means can be used, and a method using a conventional mixer (such as a homomixer, homogenizer, homodisper, Henschel mixer, Banbury mixer, ribbon mixer, or V-type mixer) may also be used.
  • Tablets can be produced by a conventional method, and are obtained by tableting the powder mixture for tableting.
  • the tablet production method may include a tableting step of tableting the powder mixture for tableting (composition for tableting) to obtain uncoated tablets, and a film-coating step of coating the uncoated tablets with a film coating agent to obtain coated tablets.
  • the tableting pressure is, for example, 4 to 20 kN, preferably 5 to 16 kN, and more preferably 6 to 12 kN.
  • pan coating In the film coating process, conventional methods can be used as the film coating method, with pan coating being preferred.
  • the film coating agent preferably contains a binder (third binder).
  • the third binder include the binders exemplified as the first binder.
  • the binders can be used alone or in combination of two or more.
  • hydroxyalkyl celluloses such as HPMC are preferred, and hydroxy C2-4 alkyl cellulose ethers are particularly preferred.
  • the proportion of the third binder in the film coating agent (film coating portion) may be 30% by mass or more, for example, 30 to 90% by mass, preferably 35 to 80% by mass, and more preferably 40 to 60% by mass.
  • the film coating agent may further contain a plasticizer (second plasticizer).
  • second plasticizers include hydrophilic plasticizers such as polyethylene glycol, propylene glycol, and glycerin; and fat-soluble plasticizers such as triacetin, triethyl citrate, diethyl phthalate, dioctyl adipate, lauric acid, stearyl alcohol, and cetanol.
  • the plasticizers can be used alone or in combination. Of the plasticizers, fat-soluble plasticizers such as triacetin are preferred.
  • the proportion of the second plasticizer is, for example, 1 to 100 parts by weight, preferably 5 to 50 parts by weight, and more preferably 10 to 30 parts by weight per 100 parts by weight of the third binder.
  • the film coating agent may further contain a screening agent.
  • screening agents include silicic acids (talc, light anhydrous silicic acid, calcium silicate, magnesium silicate, synthetic aluminum silicate, magnesium aluminometasilicate, etc.), metal oxides (magnesium oxide, titanium oxide, etc.), carbonates (precipitated calcium carbonate, magnesium carbonate, etc.), lactates (calcium lactate, etc.), phosphates (anhydrous calcium hydrogen phosphate, calcium monohydrogen phosphate, etc.), and minerals (bentonite, synthetic hydrotalcite, kaolin, etc.). These screening agents can be used alone or in combination. Of these, silicic acids such as talc and metal oxides such as titanium oxide are preferred, with combinations of silicic acids and metal oxides being particularly preferred.
  • the proportion of the shielding agent is, for example, 10 to 200 parts by weight, preferably 30 to 150 parts by weight, even more preferably 50 to 100 parts by weight, and even more preferably 70 to 90 parts by weight per 100 parts by weight of the third binder.
  • the film coating agent may further contain a colorant.
  • colorants include yellow ferric oxide, ferric oxide, Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Yellow No. 5, Food Green No. 3, Food Red No. 2, Food Red No. 3, Food Red No. 102, Food Red No. 104, Food Red No. 105, Food Red No. 106, food lake color, red iron oxide, turmeric extract, riboflavin, riboflavin phosphate ester sodium, carotene solution, tar color, and caramel. These colorants can be used alone or in combination.
  • the pharmaceutical composition of the present invention has excellent photostability, making it possible to improve photostability without the use of colorants such as iron sesquioxide. Therefore, it is preferable that the pharmaceutical composition of the present invention is substantially free of colored colorants such as iron sesquioxide, and it is particularly preferable that it is free of colored colorants.
  • the pharmaceutical composition has excellent photostability, making it possible to improve photostability without the use of colorants (colored colorants) such as iron sesquioxide. Therefore, it is preferable that the pharmaceutical composition of the present invention is substantially free of colorants such as iron sesquioxide, and it is particularly preferable that it contains no colorants.
  • the film coating agent may further contain a fluidizing agent (third fluidizing agent) in addition to the third binder.
  • the third fluidizing agent may be any of the fluidizing agents exemplified as the first fluidizing agent.
  • the fluidizing agents may be used alone or in combination of two or more. Among the fluidizing agents, minerals such as talc are preferred.
  • the proportion of the third fluidizing agent is, for example, 1 to 50 parts by weight, preferably 5 to 45 parts by weight, and more preferably 10 to 40 parts by weight per 100 parts by weight of the third binder.
  • the film coating agent is preferably used as a film coating liquid by further blending a solvent (second solvent).
  • a solvent second solvent
  • examples of the solvent that can be used include those exemplified as granulation solvents.
  • the solvents can be used alone or in combination of two or more. Of the solvents, water and/or ethanol are preferred, with water being particularly preferred.
  • the ratio of the solvent is, for example, 100 to 5,000 parts by weight, preferably 300 to 3,000 parts by weight, and more preferably 400 to 2,000 parts by weight per 100 parts by weight of the film coating agent.
  • the obtained film-coated tablet is composed of a core tablet and a film coating (film coating layer) that covers the core tablet.
  • the proportion of the film coating per 100 parts by weight of the core tablet is, for example, 0.5 to 20 parts by weight, preferably 1 to 10 parts by weight, and more preferably 2 to 5 parts by weight.
  • the pharmaceutical composition of the present invention is miniaturized, and therefore has a high concentration of the active ingredient.
  • the proportion of the active ingredient in the pharmaceutical composition of the present invention is not particularly limited as long as it is 50% by mass or more in the pharmaceutical composition, but is preferably 60% by mass or more, more preferably 70% by mass or more, and even more preferably 80% by mass or more, and specifically 50 to 95% by mass, preferably 60 to 90% by mass, more preferably 70 to 88% by mass, and even more preferably 80 to 85% by mass.
  • the proportion of excipients in the pharmaceutical composition may be 20% by mass or less, preferably 15% by mass or less, even more preferably 10% by mass or less, and even more preferably 7% by mass or less; specifically, 0.1 to 15% by mass, preferably 1 to 10% by mass, and even more preferably 3 to 7% by mass.
  • the hardness of the pharmaceutical composition of the present invention is, for example, 50 to 400 N, preferably 150 to 300 N, even more preferably 200 to 280 N, even more preferably 230 to 270 N, and most preferably 240 to 260 N.
  • the disintegration time of the pharmaceutical composition of the present invention may be 11 minutes or less (e.g., 5 to 11 minutes), for example, 10 minutes 30 seconds or less, preferably 10 minutes or less.
  • the water content of the pharmaceutical composition of the present invention is not particularly limited, but is preferably 5% by mass or less, and more preferably 3% by mass or less.
  • the lower limit of the water content is not particularly limited and may be 0% by mass, but the water content can be, for example, 0.2% by mass or more.
  • the water content of the pharmaceutical composition can be measured, for example, by the Karl Fischer method.
  • the hardness and disintegration time of pharmaceutical compositions can be measured by the method described in the Examples below.
  • the coating portion does not contain a colorant, photostability can be improved. Therefore, it is preferable that the coating layer is substantially free of colorants (especially colored colorants), and it is particularly preferable that it is free of colorants (especially colored colorants).
  • the surface of the tablet of the present invention may be engraved or printed with the product number, name of the active ingredient, content of the active ingredient, dosage form, product number, QR code (registered trademark), barcode, etc.
  • Engraving or printing may be performed directly on the surface of the plain tablet or film-coated tablet.
  • An appropriate printing method can be selected from, for example, ink printing methods using plate-type transfer printing, gravure printing, offset printing, and inkjet printing, as well as laser printing.
  • the ink used for printing can be selected from edible inks containing dyes and/or pigments, and the ink color may be one color or two or more colors from the perspective of identifiability, etc.
  • the pharmaceutical composition of the present invention may be packaged in a packaging material.
  • packaging include PTP packaging, strip packaging, bottle filling, aluminum packaging, etc.
  • Examples of materials for PTP packaging that contains tablets and the like include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, and polycarbonate, as well as metals such as aluminum. These materials may be used alone or in combination. Examples of material combinations include a laminate of polyvinyl chloride and polyvinylidene chloride, and a laminate of polyvinyl chloride and polychlorotrifluoroethylene. Tablets can be packaged in PTP packaging by forming a resin sheet with pockets using a known method, placing tablets in the pockets, and then covering them with aluminum foil.
  • the PTP package may be secondary packaged in an aluminum pillow.
  • the aluminum pillow may further contain a desiccant and/or oxygen absorber.
  • desiccants include calcium chloride, calcium oxide, magnesium oxide, silica gel, and zeolite.
  • oxygen absorbers include iron-based oxygen absorbers such as iron powder, and organic oxygen absorbers such as ascorbic acid, isoascorbic acid, hydroquinone, and catechol.
  • a single type of desiccant and/or oxygen absorber may be used, or multiple types may be used in combination.
  • a combination of desiccant and oxygen absorber may also be used.
  • An example of a product combining a desiccant and an oxygen absorber is PharmaKeep (registered trademark) (manufactured by Mitsubishi Gas Chemical Company, Inc.).
  • the pharmaceutical composition of the present invention may be filled in a glass or plastic bottle.
  • plastic bottle materials include the resins listed above as examples for PTP packaging.
  • the pharmaceutical composition of the present invention may be packaged in aluminum packaging, with each dose individually wrapped.
  • the aluminum packaging may be secondary packaged in an aluminum pillow.
  • the aluminum pillow may further contain the desiccant and/or oxygen absorber described above.
  • Letermovir drug substance specific surface area 4.297 m 2 /g Crystalline cellulose a: manufactured by Asahi Kasei Corporation, trade name "CEOLUS PH-101" Crystalline cellulose b: Asahi Kasei Corporation, trade name “CEOLUS PH-301” Microcrystalline cellulose c: manufactured by Rettenmeyer, trade name "VIVAPUR 105" Crystalline cellulose d: manufactured by IFF, product name "AVICEL PH-105" D-mannitol: product name "PEARLITOL 50C” manufactured by ROQUETTE Light anhydrous silicic acid a: Freund Corporation, trade name "Adsolider 101" Light anhydrous silicic acid b: Nippon Aerosil Co., Ltd., trade name "AEROSIL200” Povidone: BASF Japan Ltd., trade name "Kollidon 25" Hydroxypropyl cellulose a (HPC-a): Nippon Soda Co., Ltd., trade name "H
  • the particle size distribution (D 10 , D 50 , D 90 ) of the sized powder was measured on a volume basis using a sonic vibration sieving particle size distribution measuring device (manufactured by Seishin Enterprise Co., Ltd., trade name "Robot Sifter RPS-205").
  • the specific volume is expressed as the volume (mL/g) per unit weight of powder.
  • the sized powder was poured into a 100 mL stainless steel cup by gravity, and the raised sample was scraped off with a flat metal plate.
  • the mass of the stainless steel cup containing the sample was then measured to calculate the loose specific volume (mL/g).
  • the stainless steel cup was vibrated and drug-containing particles were added again, repeatedly until there was no change in volume.
  • the raised sample was scraped off with a flat metal plate.
  • the mass of the stainless steel cup containing the sample was then measured to calculate the packed specific volume (mL/g).
  • the tablet hardness was measured using an ERWEKA tablet hardness tester (manufactured by ERWEKA, trade name "Tablet Hardness Tester TBH425TD") by applying a load to the tablet with an indenter using an electric weight load.
  • Example 1 [Pelletization process] Letermovil and additives (except HPC-a) were lightly mixed in the proportions shown in Table 1 to prepare a prepared powder.
  • HPC-a hydroxypropyl cellulose
  • HPC-a hydroxypropyl cellulose
  • the prepared powder was placed in a fluidized bed granulation dryer, and the granulation liquid was sprayed onto the mixture at a rate of 6 g/min to granulate the mixture. The mixture was then dried to prepare a granulated dry powder.
  • the cumulative 10% particle size (D 10 ) of the dried powder was 54.6 ⁇ m
  • the cumulative 50% particle size (D 50 ) was 117.4 ⁇ m
  • the cumulative 90% particle size (D 90 ) was 211.2 ⁇ m
  • the loose specific volume was 4.48 mL/g
  • the hardened specific volume was 3.47 mL/g.
  • the resulting dried powder was sized using a sizer to prepare a sized powder.
  • the sized powder had a cumulative 10% particle size ( D10 ) of 50.3 ⁇ m, a cumulative 50% particle size ( D50 ) of 102.5 ⁇ m, a cumulative 90% particle size ( D90 ) of 206.3 ⁇ m, a loose specific volume of 4.61 mL/g, and a hardened specific volume of 3.64 mL/g.
  • Tablet powder preparation process The sized powder and croscarmellose sodium were mixed in a diffusion mixer in the proportions shown in Table 1, and magnesium stearate was then added and mixed to prepare tableting powder (composition for tableting).
  • the tableting powder was compressed using a rotary tableting machine to prepare uncoated tablets, which had a tablet thickness of 4.21 mm, a hardness of 210 N, and a disintegration time of 7 minutes 12 seconds to 9 minutes 50 seconds.
  • a solution was prepared by dissolving hypromellose and triacetin in purified water in the proportions shown in Table 1. Subsequently, a dispersion was prepared by dispersing titanium oxide in purified water. The resulting solution, dispersion, and talc were mixed to prepare a film coating liquid (solid content 10% by mass).
  • the uncoated tablets were placed in a film coating machine, coated with the film coating solution, and then dried to prepare film-coated tablets (240 mg of active ingredient).
  • the coated tablets had a diameter (circular diameter) of 9.5 mm, a thickness of 4.28 mm, a hardness of 257 N, and a disintegration time of 7 minutes 52 seconds to 10 minutes 15 seconds.
  • Comparative Example 1 Commercially available Letermovil film-coated tablets (active ingredient 240 mg, total mass 618 mg) were used.
  • the uncoated tablets had a tablet thickness of 4.98 mm, a hardness of 239 N, and a disintegration time of 9 minutes 53 seconds to 11 minutes 18 seconds.
  • the film-coated tablets (approximately oval) had a major axis of 16.5 mm and a minor axis of 8.5 mm, a tablet thickness of 5.11 mm, a hardness of 297 N, and a disintegration time of 10 minutes 40 seconds to 13 minutes 1 second.
  • the coated tablets were packaged in PTPs using a PVC sheet and aluminum foil for PVC in a PTP molding machine to obtain PTP packages.
  • the resulting PTP packages were then packaged in aluminum pillows using an aluminum pillow zipper to obtain aluminum pillow packages.
  • the resulting dried powder was sized using a sizer to prepare a sized powder.
  • the sized powder had a cumulative 10% particle size ( D10 ) of 35.9 ⁇ m, a cumulative 50% particle size ( D50 ) of 139.0 ⁇ m, a cumulative 90% particle size ( D90 ) of 445.4 ⁇ m, a loose specific volume of 2.17 mL/g, and a hardened specific volume of 1.68 mL/g.
  • the tableting powder was compressed using a rotary tableting machine to prepare uncoated tablets.
  • the uncoated tablets had a tablet thickness of 5.16 mm, a hardness of 340 N, and a disintegration time of 9 minutes 27 seconds to 10 minutes 57 seconds.
  • a solution was prepared by dissolving hypromellose, lactose hydrate, and triacetin in purified water in the proportions shown in Table 1. Subsequently, a dispersion was prepared by dispersing titanium oxide and yellow ferric oxide in purified water. The resulting solution and dispersion were mixed to prepare a film coating solution.
  • the uncoated tablets were placed in a film coating machine, coated with the film coating solution, and then dried to prepare film-coated tablets (240 mg of active ingredient).
  • the coated tablets (circular diameter) had a major axis of 16.5 mm and a minor axis of 8.5 mm, a thickness of 5.24 mm, a hardness of 401 N, and a disintegration time of 9 minutes 44 seconds to 10 minutes 42 seconds.
  • Figures 1 to 4 show the results of comparing the dissolution rates of the coated tablets obtained in Example 1 and Comparative Examples 1 and 2.
  • the coated tablets obtained in Example 1 despite their smaller size, exhibited dissolution rates equivalent to those of the coated tablets obtained in Comparative Examples 1 and 2.
  • the dissolution rate tends to decrease when tablets are made smaller, it was surprising that the coated tablets of Example 1, despite being smaller in mass to less than half that of Comparative Examples 1 and 2, exhibited an equivalent dissolution rate.
  • Example 1 The plain tablets and coated tablets obtained in Example 1 and Comparative Examples 1 and 2 were exposed to light and stored, and the color difference ( ⁇ E) was evaluated. The results are shown in Table 2, and the amounts of related substances generated were measured. Table 3 shows the results.
  • Example 1 The tablets obtained in Example 1, despite not containing a colorant, had better photostability than those in Comparative Example 2 and were equivalent to those in Comparative Example 1.
  • the PTP packages containing the coated tablets obtained in Example 1 and Comparative Examples 1 and 2 were stored at 40°C/75% RH for 6 months (6M) or at 25°C/60% RH for 6 months (6M).
  • the coated tablets obtained in Example 1 and Comparative Examples 1 and 2 were placed in a petri dish, wrapped in Saran Wrap (registered trademark), and sealed, and stored at 25°C/75% RH for 3 months (3M).
  • the amounts of related substances measured before and after storage are shown in Table 4.
  • Example 1 As is clear from Table 4, the tablets obtained in Example 1 exhibited stability equivalent to that of the comparative example in terms of the amount of related substances.
  • the aluminum (AL) pillow packages containing the coated tablets obtained in Example 1 and Comparative Examples 1 and 2 were sealed in glass bottles and stored at 40°C/75% RH for 6 months (6M) or at 25°C/60% RH for 6 months (6M).
  • the coated tablets obtained in Example 1 and Comparative Examples 1 and 2 were also placed in an open petri dish and stored at 25°C/75% RH for 3 months (3M).
  • Figure 5 shows a comparison of the dissolution rates before and after storage for the coated tablets obtained in Example 1
  • Figure 6 shows a comparison of the dissolution rates before and after storage for the coated tablets obtained in Comparative Example 2.
  • Table 5 also shows a comparison of the tablet thickness, hardness, and disintegration time before and after storage for the coated tablets obtained in Example 1 and Comparative Examples 1 and 2.
  • Example 1 had a dissolution rate equivalent to that of the comparative example.
  • Example 5 As is clear from Table 5, the tablets obtained in Example 1 were equivalent to those of the comparative example in terms of tablet thickness, hardness, and disintegration time.
  • Example 2 [Pelletization process] Letermovil and additives (except HPC-b) were lightly mixed in the proportions shown in Table 6 to prepare a prepared powder.
  • HPC-b was dissolved in purified water in the proportions shown in Table 6 to prepare a granulation liquid.
  • the prepared powder was placed in a high-speed agitating granulator, granulated by spraying the granulation liquid, and then dried in a fluidized bed granulation dryer to prepare a dry powder, which was a granulated powder.
  • Tablet powder preparation process The sized powder and croscarmellose sodium were mixed in a diffusion mixer in the proportions shown in Table 6, and then light anhydrous silicic acid was added and mixed to prepare tableting powder (composition for tableting).
  • the uncoated tablets were placed in a film coating machine, coated with the film coating solution, and then dried to prepare film-coated tablets (240 mg of active ingredient).
  • the coated tablets had a diameter (circular diameter) of 9.5 mm and a thickness of 4.1 mm.
  • Example 3 [Pelletization process] Letermovil and additives (except HPC-b) were lightly mixed in the proportions shown in Table 6 to prepare a prepared powder.
  • HPC-b was dissolved in purified water in the proportions shown in Table 6 to prepare a granulation liquid.
  • the prepared powder was placed in a high-speed agitating granulator, granulated by spraying the granulation liquid, and then dried in a fluidized bed granulation dryer to prepare a dry powder, which was a granulated powder.
  • Tablet powder preparation process The sized powder and croscarmellose sodium were mixed in a diffusion mixer in the proportions shown in Table 6, and then light anhydrous silicic acid was added and mixed to prepare tableting powder (composition for tableting).
  • the uncoated tablets were placed in a film coating machine, coated with the film coating solution, and then dried to prepare film-coated tablets (480 mg of active ingredient).
  • the coated tablets had a tablet diameter (oval diameter) of 17.6 mm x 9.1 mm and a tablet thickness of 5 mm.
  • Example 4 [Pelletization process] A prepared powder was prepared by lightly mixing letermovil and additives (except HPC-c) in the proportions shown in Table 6. HPC-c was dissolved in purified water in the proportions shown in Table 6 to prepare a granulation liquid. The prepared powder was placed in a high-speed agitating granulator, granulated by spraying the granulation liquid, and then dried in a fluidized bed granulation dryer to prepare a dry powder, which is a granulated powder.
  • Tablet powder preparation process The sized powder and light anhydrous silicic acid were mixed in a diffusion mixer in the proportions shown in Table 6 to prepare tableting powder (composition for tableting).
  • the uncoated tablets were placed in a film coating machine, coated with the film coating solution, and then dried to prepare film-coated tablets (240 mg of active ingredient).
  • the coated tablets had a diameter (circular diameter) of 9.5 mm and a thickness of 4.1 mm.
  • Example 5 [Pelletization process] A prepared powder was prepared by lightly mixing letermovil and additives (except HPC-c) in the proportions shown in Table 6. HPC-c was dissolved in purified water in the proportions shown in Table 6 to prepare a granulation liquid. The prepared powder was placed in a high-speed agitating granulator, granulated by spraying the granulation liquid, and then dried in a fluidized bed granulation dryer to prepare a dry powder, which is a granulated powder.
  • Tablet powder preparation process The sized powder and light anhydrous silicic acid were mixed in a diffusion mixer in the proportions shown in Table 6 to prepare tableting powder (composition for tableting).
  • the uncoated tablets were placed in a film coating machine, coated with the film coating solution, and then dried to prepare film-coated tablets (480 mg of active ingredient).
  • the coated tablets had a tablet diameter (oval diameter) of 17.6 mm x 9.1 mm and a tablet thickness of 5 mm.
  • the pharmaceutical composition of the present invention contains letermovir or a salt thereof as an active ingredient and can therefore be effectively used as a drug for the prevention and treatment of CMV infection.

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Abstract

L'invention concerne une composition pharmaceutique contenant du létermovir qui a été miniaturisée, dans une composition pharmaceutique qui contient du létermovir ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif, et un liant, par ajustement de la proportion du principe actif à l'intérieur de ladite composition afin d'atteindre 50 % en masse ou plus. La viscosité d'une solution aqueuse à 2 % en masse du liant peut être de 2 mPa·s ou plus à 20°C. Le liant peut être une hydroxyalkyl cellulose. La proportion du liant peut être comprise entre 1 et 10 parties en masse pour 100 parties en masse du principe actif. La composition pharmaceutique peut comprendre un produit granulé, le produit granulé étant un produit granulé sec d'une composition de granulation comprenant le principe actif et le liant. La composition de granulation peut en outre comprendre un excipient. La proportion de l'excipient à l'intérieur de la composition pharmaceutique peut être inférieure ou égale à 10 % en masse. L'excipient peut être un alcool de sucre. La composition pharmaceutique peut être un comprimé.
PCT/JP2025/014330 2024-04-12 2025-04-10 Composition pharmaceutique contenant du létermovir et son procédé de production et son utilisation Pending WO2025216283A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016522238A (ja) * 2013-06-19 2016-07-28 アイキュリス アンチ−インフェクティブ キュアズ ゲゼルシャフト ミット ベシュレンクテル ハフツング 非晶質レテルモビル及び経口投与のためのその固形医薬製剤
WO2022132676A1 (fr) * 2020-12-16 2022-06-23 Merck Sharp & Dohme Corp. Forme posologique en mini-comprimé d'un inhibiteur de terminase virale et ses utilisations
WO2023118300A1 (fr) * 2021-12-21 2023-06-29 Aic246 Ag & Co. Kg Compositions pharmaceutiques comprenant de l'acétate de 2-[(4s)-8-fluoro-2-[4-(3-méthoxyphényl)pipérazin-1-yl]-3-[2-méthoxy-5-(trifluorométhyl)phényl]-4h-quinazolin-4-yl] et des ions potassium

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016522238A (ja) * 2013-06-19 2016-07-28 アイキュリス アンチ−インフェクティブ キュアズ ゲゼルシャフト ミット ベシュレンクテル ハフツング 非晶質レテルモビル及び経口投与のためのその固形医薬製剤
WO2022132676A1 (fr) * 2020-12-16 2022-06-23 Merck Sharp & Dohme Corp. Forme posologique en mini-comprimé d'un inhibiteur de terminase virale et ses utilisations
WO2023118300A1 (fr) * 2021-12-21 2023-06-29 Aic246 Ag & Co. Kg Compositions pharmaceutiques comprenant de l'acétate de 2-[(4s)-8-fluoro-2-[4-(3-méthoxyphényl)pipérazin-1-yl]-3-[2-méthoxy-5-(trifluorométhyl)phényl]-4h-quinazolin-4-yl] et des ions potassium

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