Letermovir-containing pharmaceutical composition and production method and use therefor

Abstract

Provided is a letermovir-containing pharmaceutical composition that has been miniaturized by, in a pharmaceutical composition which includes letermovir or a pharmaceutically acceptable salt thereof as an active ingredient, and a binder, adjusting the proportion of the active ingredient within said composition to be 50 mass% or greater. The viscosity of a 2 mass% aqueous solution of the binder may be 2 mPa・s or greater at 20° C. The binder may be a hydroxyalkyl cellulose. The proportion of the binder may be 1-10 parts by mass per 100 parts by mass of the active ingredient. The pharmaceutical composition may include a granulated product, with the granulated product being a dry granulated product of a granulation composition including the active ingredient and the binder. The granulation composition may further include an excipient. The proportion of the excipient within the pharmaceutical composition may be 10 mass% or less. The excipient may be a sugar alcohol. The pharmaceutical composition may be a tablet.

Description

Letermovir-containing pharmaceutical composition, its manufacturing method and use

[0001] The present invention relates to a pharmaceutical composition containing letermovir or a salt thereof as an active ingredient, as well as a method for producing the same and use thereof.

[0002] 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:

[0003]

[0004] Letermovir is used to prevent and treat cytomegalovirus (CMV) infection by inhibiting the DNA terminase complex necessary for the proliferation (replication) of cytomegalovirus (CMV), such as human cytomegalovirus (HCMV), thereby suppressing the proliferation of CMV.

[0005] As a solid formulation containing letermovir, Japanese Patent No. 6770035 (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.

[0006] Patent No. 6770035

[0007] However, the inventors' investigations revealed that letermovir has high adhesion to punches and other components, making it difficult to consistently produce solid dosage forms. This makes it particularly difficult to produce small-sized dosage forms, which are subject to limitations on the amount of additives used. Perhaps for this reason, even with the method of Patent Document 1, the amount of excipients and other additives used is high, making it impossible to produce small-sized dosage forms. Furthermore, generally, miniaturizing a dosage form limits the proportion of additives used, making it difficult to improve the dissolution rate of the active ingredient. Furthermore, letermovir has low photostability, and the limitations on the types and amounts of additives that result from miniaturization make it difficult to improve photostability.

[0008] Therefore, an object of the present invention is to provide a miniaturized letermovir-containing pharmaceutical composition which has high productivity and dissolution properties, as well as a method for producing the same and uses thereof.

[0009] Another object of the present invention is to provide a miniaturized letermovir-containing pharmaceutical composition which has high stability, including photostability, as well as a method for producing the same and uses thereof.

[0010] As a result of intensive research to achieve the above-mentioned object, the present inventors have found that a compact letermovir-containing pharmaceutical composition can be obtained by combining letermovir or a pharmaceutically acceptable salt thereof as the active ingredient with a binder and adjusting the proportion of the active ingredient to 50% by mass or more in the pharmaceutical composition, and have completed the present invention.

[0011] That is, the present invention includes the following aspects.

[0012] Aspect [1]: A pharmaceutical composition comprising letermovir or a pharmaceutically acceptable salt thereof as an active ingredient and a binder, wherein the proportion of the active ingredient in the pharmaceutical composition is 50% by mass or more.

[0013] 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.

[0014] Aspect [3]: The pharmaceutical composition according to aspect [1] or [2], wherein the binder is a hydroxyalkyl cellulose.

[0015] Aspect [4]: ​​The pharmaceutical composition according to any one of Aspects [1] to [3], comprising a granulation product, wherein the granulation product is a wet granulation product of a granulation composition comprising the active ingredient and the binder.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] Aspect [8]: The pharmaceutical composition of aspect [7], wherein the excipient is a sugar alcohol.

[0020] Aspect [9]: The pharmaceutical composition of aspect [7], wherein the excipient is crystalline cellulose.

[0021] Aspect

[10] : The pharmaceutical composition according to any one of Aspects [1] to [9], which is a tablet.

[0022] 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 that coats the surface of the uncoated tablet portion, and the film-coated portion does not contain a colorant.

[0023] Aspect

[12] : 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, the method comprising a granulation step of wet-granulating a composition containing the active ingredient and the binder by agitation granulation or fluidized bed granulation to obtain a granulated product.

[0024] Aspect

[13] : A method for improving the stability and dissolution properties of a miniaturized tablet in 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, by using as the binder a binder whose viscosity of a 2% by mass aqueous solution at 20°C is 2 mPa s or more.

[0025] In this specification and claims, a numerical range expressed as "A to B" means "A or more and B or less," and is used in the sense that both the numerical values ​​A and B are included.

[0026] In the present invention, the active ingredient, letermovir or a pharmaceutically acceptable salt thereof, is combined with a binder, and the proportion of the active ingredient is adjusted to 50% by mass or more in the pharmaceutical composition, thereby enabling the miniaturization of the letermovir-containing pharmaceutical composition. Furthermore, by selecting the binder, the productivity (or moldability) of the miniaturized letermovir-containing pharmaceutical composition (especially tablets) and the dissolution of the active ingredient can be improved, and the stability of the pharmaceutical composition can also be improved.

[0027] 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 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 pH 4.0 test solution). 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 solution). FIG. 5 is a graph comparing the dissolution rate versus test time for the tablets obtained in Example 1 (initial profile in pH 1.2 test solution) before and after the stability test. FIG. 6 is a graph comparing the dissolution rate versus test time for the tablets obtained in Comparative Example 2 (initial profile in pH 1.2 test solution) 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).

[0028] [Pharmaceutical Composition] 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 preferably an oral solid formulation in that the effects of the present invention are more easily exhibited.

[0029] Examples of oral solid preparations include tablets, powders, fine granules, granules, pills, capsules, dry syrups, etc. Among these, tablets are preferred because they are highly effective in improving productivity.

[0030] (Tablets) Examples of tablets 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. Among these, film-coated tablets are particularly preferred because they facilitate the development of the effects of the present invention.

[0031] The shape (surface shape) of the tablet is not particularly limited, and examples thereof include a circle, an oval, and a polygon (such as a square, a rectangle, or a hexagon), with a circle being preferred.

[0032] The tablet diameter (average diameter) of the tablet is, for example, 3 to 12 mm, preferably 5 to 11.5 mm, further preferably 5.5 to 11 mm, further preferably 6 to 10.5 mm, and most preferably 7 to 10 mm. In the case of an anisotropic tablet, the tablet diameter is the average value of the major axis and the minor axis.

[0033] The thickness of the tablet is, for example, 1 to 5 mm, preferably 1.5 to 4.8 mm, further preferably 2.5 to 4.7 mm, even more preferably 3 to 4.5 mm, and most preferably 3.5 to 4.3 mm.

[0034] From the viewpoint of ease of handling, the pharmaceutical composition of the present invention (particularly tablets) preferably contains a granulation product of a granulation composition containing the active ingredient and the binder, and may be formed solely from the granulation product, or may be formed from a combination of the granulation product and a component other than the granulation product. Of these, the pharmaceutical composition of the present invention is preferably formed from a combination of the granulation product and a component other than the granulation product. In particular, for tablets, it is preferable that the tableting composition (tabletting powder mixture) contains a combination of the granulation product and a powder component.

[0035] (Granulated product) The shape of the granulated product is not particularly limited, and examples thereof include powdery, spherical or nearly spherical, ellipsoidal, polyhedral, plate-like, fibrous, irregular or amorphous shapes. Among these, powdery and amorphous shapes are preferred. The shape of the granulated product may be hollow, but a solid shape is preferred from the viewpoint of ease of miniaturization.

[0036] The cumulative 50% particle size (D ５０ ) can be selected from the range of about 30 to 200 μm, for example, 50 to 180 μm, preferably 60 to 150 μm, further preferably 70 to 130 μm, even more preferably 80 to 120 μm, and most preferably 90 to 110 μm. 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.

[0037] The cumulative 10% particle size (D １０ The cumulative 10% particle size (D) of the granulated product can be selected from the range of about 20 to 100 μm, for example, 30 to 90 μm, preferably 35 to 80 μm, further preferably 40 to 70 μm, further preferably 43 to 60 μm, and most preferably 45 to 55 μm. １０ If the difference ) is too small, productivity may decrease.

[0038] The cumulative 90% particle size (D ９０ ) can be selected from the range of about 50 to 500 μm, for example, 100 to 400 μm, preferably 120 to 350 μm, further preferably 150 to 300 μm, even more preferably 180 to 250 μm, and most preferably 200 to 210 μm.

[0039] In the present specification and claims, the cumulative 10% particle diameter (D １０ ), cumulative 50% particle diameter (D ５０ ) and cumulative 90% particle diameter (D ９０ ) can be measured using a laser diffraction particle size distribution analyzer, and refer to the particle sizes of particles that are, based on volume, 10%, 50%, and 90% cumulatively from the small particle side of the particle size distribution.

[0040] (A) Active Ingredient The granules may contain letermovir as an active ingredient, and letermovir may be in the form of a salt (a pharmaceutically acceptable salt).

[0041] The salt of letermovir is not particularly limited as long as it is a pharmaceutically acceptable salt, and may be a salt with a base or an acid.

[0042] Examples of bases for forming salts include inorganic bases [e.g., ammonia; alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), other metals (zinc, aluminum, etc.)], and 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.).

[0043] Of these, alkali metal salts such as sodium salts and alkaline earth metal salts such as calcium salts are preferred.

[0044] Examples of acids for forming salts include 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.

[0045] Letermovir or a salt thereof (a pharmaceutically acceptable salt) may be in the form of a solvate in the granules. Examples of solvents that form solvates include water, alcohols (e.g., C 100, C 200, C 300, C 400, C 500, C 600, C 700, C 800, C 900, C 1000, C 1100, C 1200, １－４ Examples of suitable solvents include alkanols, ketones (e.g., acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), nitriles (e.g., acetonitrile, propionitrile), esters (e.g., ethyl acetate, isopropyl acetate), ethers (e.g., diethyl ether, t-butyl methyl ether), aliphatic hydrocarbons (e.g., n-pentane, n-hexane, cyclohexane, n-heptane, isooctane), aromatic hydrocarbons (e.g., toluene), amides (e.g., N,N-dimethylformamide, dimethylacetamide), and sulfoxides (dimethyl sulfoxide). These solvents may be used alone or in combination. Hydrates are preferred as solvates. Letermovir or a salt thereof may also be incorporated into the pharmaceutical composition in the form of a hydrate.

[0046] Letermovir or a salt thereof may be amorphous or crystalline (crystal), but is preferably amorphous.

[0047] The size of letermovir or its salt is not particularly limited and may be adjusted as appropriate. For example, when amorphous letermovir is used as a raw material, the cumulative 50% particle diameter (D ５０ ) can be 1 to 50 μm, for example, 10 to 30 μm.

[0048] In the present specification and claims, the cumulative 50% particle diameter (D ５０ ) can be measured on a volume basis using a laser diffraction particle size distribution analyzer.

[0049] The specific surface area of ​​the raw material, letermovil or its salt, is not particularly limited and may be adjusted as appropriate. For example, when amorphous letermovil is used as the raw material, its BET specific surface area is 3 to 5 m. ２ / g.

[0050] The proportion of the active ingredient (letermovir or a salt thereof) in the granule (composition for granulation) can be selected from a range of about 50 to 99% by mass, for example, 60 to 98% by mass, preferably 70 to 97% by mass, further 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, whereas if it is too high, it may be difficult to granulate.

[0051] (B) Binder Although 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, by combining it with a binder (first binder) to increase the content of the active ingredient, a miniaturized pharmaceutical composition (particularly, a tablet) can be produced. In particular, by appropriately selecting a binder, productivity (productivity of the pharmaceutical composition) and dissolution (dissolution of the active ingredient) can be improved. For example, 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. However, by combining it with a specific binder, productivity can be improved.

[0052] As the binder, binders used in pharmaceutical preparations can be used, but from the viewpoint of improving the productivity of the pharmaceutical composition and the dissolution of the active ingredient, 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, and specifically, for example, 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.

[0053] In the present specification and claims, viscosity can be measured by a conventional method, for example, a capillary viscometer method.

[0054] Examples of 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.

[0055] These binders can be used alone or in combination. Among these, hydroxyalkyl celluloses (hydroxyalkyl celluloses such as HPC or alkylhydroxyalkyl celluloses such as HPMC) are preferred, and hydroxy C ２－４ Cellulose ethers having an alkyl group are more preferred, and hydroxy C such as HPC are more preferred. ３－４ C such as alkyl cellulose and HPMC １－３ Alkylhydroxy C ３－４ Alkylcellulose is more preferred, and HPC is most preferred.

[0056] Examples of commercially available HPC products that can be used include those manufactured by Nippon Soda Co., Ltd. under the trade names "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)," and "HPC-M (viscosity of 2% by mass (20°C) aqueous solution: 150 to 400 mPa·s)."

[0057] The proportion of the binder can be selected from a range of about 0.5 to 30 parts by mass (particularly 1 to 20 parts by mass) per 100 parts by mass of the active ingredient, for example, 1.5 to 20 parts by mass, preferably 2 to 10 parts by mass, further 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. If the proportion of the binder is too low, productivity and dissolution may decrease, while if it is too high, it may become difficult to miniaturize the pharmaceutical composition.

[0058] (C) Excipient The pharmaceutical composition of the present invention may further contain an excipient (first excipient) from the viewpoint of improving dissolution properties.

[0059] Examples of excipients include sugars (lactose, glucose, fructose, maltose, sucrose, sucrose, white sugar, powdered reduced maltose starch syrup, etc.), sugar alcohols [sorbitols such as D-sorbitol, mannitols such as D-mannitol, reduced maltose starch 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.

[0060] These excipients can be used alone or in combination of two or more. Among these, sugar alcohols such as D-mannitol and celluloses such as crystalline cellulose are preferred.

[0061] The proportion of the excipient relative to 100 parts by mass of the active ingredient is, for example, 0.5 to 20 parts by mass, preferably 1 to 15 parts by mass, further 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. If the proportion of the excipient is too low, there is a risk that dissolution properties will decrease, and if it is too high, there is a risk that it will be difficult to miniaturize the pharmaceutical composition.

[0062] (D) Disintegrant The pharmaceutical composition of the present invention may further contain a disintegrant (first disintegrant) from the viewpoint of improving dissolution properties.

[0063] Examples of disintegrants include polysaccharides [starchs 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 (gelatin, casein, soybean protein, and the like), and cross-linked polyvinylpyrrolidones (crospovidone, and the like).

[0064] These disintegrants can be used alone or in combination. Among these disintegrants, starches such as corn starch and partially pregelatinized starch, carboxyalkyl celluloses such as carmellose and croscarmellose sodium are preferred, and crosslinked carboxy C such as croscarmellose sodium are also preferred. １－３ Alkylcelluloses are particularly preferred.

[0065] The proportion of the disintegrant relative to 100 parts by mass of the active ingredient is, for example, 1.5 to 20 parts by mass, preferably 2 to 10 parts by mass, further preferably 2.3 to 8 parts by mass, further preferably 2.5 to 6 parts by mass, and most preferably 3 to 5 parts by mass. If the proportion of the disintegrant is too low, there is a risk that the dissolution properties will decrease, whereas if it is too high, there is a risk that it will be difficult to miniaturize the pharmaceutical composition.

[0066] (E) Fluidizer The pharmaceutical composition of the present invention may further contain a fluidizer (first fluidizer) in order to improve productivity.

[0067] Examples of fluidizing agents include minerals (talc, bentonite, synthetic hydrotalcite, kaolin, etc.), silicic acids (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.).

[0068] These fluidizing agents can be used alone or in combination of two or more. Among these fluidizing agents, silicic acids such as light anhydrous silicic acid are preferred.

[0069] The proportion of the fluidizing agent relative to 100 parts by mass of the active ingredient is, for example, 0.1 to 10 parts by mass, preferably 0.3 to 5 parts by mass, more preferably 0.5 to 3 parts by mass, and even more preferably 1 to 2 parts by mass. If the proportion of the fluidizing agent is too low, productivity may decrease, whereas if it is too high, miniaturization of the pharmaceutical composition may become difficult.

[0070] (F) Lubricant The pharmaceutical composition of the present invention may further contain a lubricant (first lubricant) to improve productivity.

[0071] Examples of lubricants include fatty acids or metal salts thereof such as stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, and sodium coconut oil fatty acid; silicon oxides such as hydrous silicon dioxide and silicon dioxide; polyorganosiloxanes such as dimethylpolysiloxane; fats and oils such as hardened oil and cocoa butter; and waxes such as beeswax, white beeswax, carnauba wax, lanolin, paraffin, and petrolatum.

[0072] These lubricants can be used alone or in combination of two or more. Among these lubricants, fatty acid metal salts such as magnesium stearate are preferred.

[0073] The proportion of the lubricant relative to 100 parts by mass of the active ingredient is, for example, 0.1 to 5 parts by mass, preferably 0.2 to 3 parts by mass, 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. If the proportion of the lubricant is too low, productivity may decrease, whereas if it is too high, miniaturization of the pharmaceutical composition may become difficult.

[0074] (G) Other Additives The pharmaceutical 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.

[0075] Common additives include plasticizers (first plasticizers), surfactants, pH adjusters, colorants, sweeteners or flavoring agents, antioxidants, antiseptics or preservatives, humectants, antistatic agents, disintegration aids, and the like.

[0076] These additives can be used alone or in combination of two or more. The total content of these additives in the granules may be 30% by mass or less, preferably 20% by mass or less, further preferably 10% by mass or less, further more preferably 5% by mass or less, and most preferably 0% by mass.

[0077] (Method for producing granulated product) 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.

[0078] Among these wet granulation methods, the mixing / stirring granulation method and the fluidized bed granulation method are preferred from the viewpoint of productivity, and the fluidized bed granulation method is particularly preferred.

[0079] The mixing and stirring granulation method is not particularly limited as long as it is a method in which a composition containing an active ingredient and a granulation solvent is mixed and stirred all at once to obtain a granulated product, and any conventional method can be used.

[0080] The fluidized bed granulation method is not particularly limited as long as it is a method of spraying a granulating liquid containing a granulating solvent onto raw material powder containing an active ingredient fluidized by an air current to obtain granules, and any conventional method can be used. In the fluidized bed granulation method, the granulating liquid preferably contains a binder and a granulating solvent.

[0081] 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. Examples of aqueous solvents include lower alcohols (e.g., C 100, C 200, C 300, C 400, C 500, C 600, C 800, C 900, C 1000, C 1100, C 1200, C 1300 ２－４ Alkanols, aliphatic ketones (e.g., acetone), etc. These solvents can be used alone or in combination.

[0082] Among these granulation solvents, water and / or aqueous solvents are preferred. From the viewpoint of safety, water and / or C ２－４ Alkanols are more preferred, and water and / or ethanol are most preferred.

[0083] The proportion of the 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.

[0084] (Final component) The final component preferably contains a lubricant (second lubricant) and / or a fluidizer (second fluidizer) from the viewpoint of improving productivity of the pharmaceutical composition (particularly, tablets).

[0085] Examples of the second lubricant include the lubricants exemplified as the first lubricant.

[0086] The lubricants can be used alone or in combination of two or more. Among the lubricants, fatty acid metal salts such as magnesium stearate are preferred.

[0087] The proportion of the second lubricant relative to 100 parts by mass of the granules is, for example, 0.1 to 5 parts by mass, preferably 0.2 to 3 parts by mass, further 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. If the proportion of the second lubricant is too low, productivity may decrease, whereas if it is too high, miniaturization of the pharmaceutical composition may become difficult.

[0088] Examples of the second fluidizing agent include the fluidizing agents exemplified as the first fluidizing agent.

[0089] The fluidizing agents can be used alone or in combination of two or more. Among the fluidizing agents, silicic acids such as light anhydrous silicic acid are preferred.

[0090] The proportion of the second fluidizing agent relative to 100 parts by mass of the active ingredient is, for example, 0.1 to 5 parts by mass, preferably 0.2 to 3 parts by mass, further 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. If the proportion of the second fluidizing agent is too low, productivity may decrease, whereas if it is too high, miniaturization of the pharmaceutical composition may become difficult.

[0091] The final component may further contain a disintegrant (second disintegrant) in order to improve the dissolution of the active ingredient.

[0092] Examples of the second disintegrant include the disintegrants exemplified as the first disintegrant. The disintegrants can be used alone or in combination. Among the disintegrants, starches such as corn starch and partially pregelatinized starch, polyvinylpyrrolidones such as crospovidone, and silicic acids such as light anhydrous silicic acid are preferred, and polyvinylpyrrolidones such as crospovidone are particularly preferred.

[0093] The proportion of the second disintegrant relative to 100 parts by mass of the granules is, for example, 0.1 to 10 parts by mass, preferably 0.2 to 5 parts by mass, further 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. If the proportion of the second disintegrant is too low, there is a risk that the dissolution property will decrease, and if it is too high, there is a risk that it will be difficult to miniaturize the pharmaceutical composition.

[0094] The final component may further contain other additives. Examples of the other additives include the binders exemplified as the first binder and the additives exemplified as conventional additives for granules. 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 mass or less (e.g., 0.01 to 5 parts by mass) per 100 parts by mass of the granules, preferably 3 parts by mass or less, and more preferably 2 parts by mass or less.

[0095] (Method for preparing mixed powder for tableting) In tablets, 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 may also be a method using a conventional mixer (such as a homomixer, homogenizer, homodisper, Henschel mixer, Banbury mixer, ribbon mixer, or V-type mixer).

[0096] (Method for manufacturing tablets) Tablets can be manufactured by a conventional method, and are obtained by tableting the powder mixture for tableting. For example, in the case of film-coated tablets, the manufacturing method for tablets may be a manufacturing method including 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.

[0097] In the tableting step, a conventional tableting method can be used. The tableting pressure is, for example, 4 to 20 kN, preferably 5 to 16 kN, and more preferably 6 to 12 kN.

[0098] In the film coating step, a conventional method can be used as the film coating method, and pan coating is preferred.

[0099] The film coating agent preferably contains a binder (third binder). Examples of the third binder include the binders exemplified as the first binder. The binders can be used alone or in combination of two or more. Among the binders, hydroxyalkyl celluloses such as HPMC are preferred, and hydroxy C ２－４Alkyl cellulose ethers are particularly preferred.

[0100] 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.

[0101] The film coating agent may further contain a plasticizer (second plasticizer). Examples of the second plasticizer 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. Among the plasticizers, fat-soluble plasticizers such as triacetin are preferred.

[0102] The proportion of the second plasticizer is, for example, 1 to 100 parts by mass, preferably 5 to 50 parts by mass, and more preferably 10 to 30 parts by mass, per 100 parts by mass of the third binder.

[0103] The film coating agent may further contain a screening agent. Examples of 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.), minerals (bentonite, synthetic hydrotalcite, kaolin, etc.). These screening agents can be used alone or in combination. Among these, silicic acids such as talc and metal oxides such as titanium oxide are preferred, and combinations of silicic acids and metal oxides are particularly preferred.

[0104] The proportion of the shielding agent is, for example, 10 to 200 parts by mass, preferably 30 to 150 parts by mass, more preferably 50 to 100 parts by mass, and even more preferably 70 to 90 parts by mass, per 100 parts by mass of the third binder.

[0105] The film coating agent may further contain a colorant. Examples of 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.

[0106] In particular, in the present invention, despite the use of an active ingredient with low photostability, the pharmaceutical composition has excellent photostability, and therefore photostability can be improved without the use of colorants such as iron sesquioxide, etc. Therefore, the pharmaceutical composition of the present invention is preferably substantially free of colored colorants such as iron sesquioxide, and particularly preferably free of colored colorants.

[0107] In particular, in the present invention, despite the use of an active ingredient with low photostability, the pharmaceutical composition has excellent photostability, and therefore photostability can be improved without the use of a colorant (colored colorant) such as iron sesquioxide. Therefore, the pharmaceutical composition of the present invention is preferably substantially free of colorants such as iron sesquioxide, and particularly preferably free of colorants.

[0108] 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. Among the fluidizing agents, minerals such as talc are preferred.

[0109] In the film coating agent, the proportion of the third fluidizing agent is, for example, 1 to 50 parts by mass, preferably 5 to 45 parts by mass, and more preferably 10 to 40 parts by mass, per 100 parts by mass of the third binder.

[0110] The film coating agent is preferably used as a film coating liquid by further blending a solvent (second solvent). Examples of the solvent include those exemplified as the granulation solvent. The solvents can be used alone or in combination. Among the solvents, water and / or ethanol are preferred, with water being particularly preferred.

[0111] The proportion of the solvent is, for example, 100 to 5,000 parts by mass, preferably 300 to 3,000 parts by mass, and more preferably 400 to 2,000 parts by mass, per 100 parts by mass of the film coating agent.

[0112] The obtained film-coated tablet is composed of an uncoated tablet and a film coating (film coating layer) that covers the uncoated tablet. The proportion of the film coating is, for example, 0.5 to 20 parts by mass, preferably 1 to 10 parts by mass, and more preferably 2 to 5 parts by mass, per 100 parts by mass of the uncoated tablet.

[0113] (Characteristics of the Pharmaceutical Composition) The pharmaceutical composition of the present invention is miniaturized, and therefore has a high concentration of the active ingredient. In the pharmaceutical composition of the present invention, the proportion of the active ingredient in the pharmaceutical composition is not particularly limited as long as it is 50% by mass or more, but is preferably 60% by mass or more, more preferably 70% by mass or more, and 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 more preferably 80 to 85% by mass.

[0114] In the pharmaceutical composition of the present invention, the proportion of excipients in the pharmaceutical composition may be 20% by mass or less, preferably 15% by mass or less, more preferably 10% by mass or less, and even more preferably 7% by mass or less, and specifically, 0.1 to 15% by mass, preferably 1 to 10% by mass, and even more preferably 3 to 7% by mass.

[0115] The hardness of the pharmaceutical composition of the present invention (particularly tablets) is, for example, 50 to 400N, preferably 150 to 300N, further preferably 200 to 280N, even more preferably 230 to 270N, and most preferably 240 to 260N.

[0116] The disintegration time of the pharmaceutical composition of the present invention (particularly tablets) may be 11 minutes or less (for example, 5 to 11 minutes), for example, 10 minutes 30 seconds or less, preferably 10 minutes or less.

[0117] 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. In this specification and claims, the water content of the pharmaceutical composition can be measured, for example, by the Karl Fischer method.

[0118] In the present specification and claims, the hardness and disintegration time of a pharmaceutical composition (particularly a tablet) can be measured by the method described in the Examples below.

[0119] When the pharmaceutical composition of the present invention is a coated tablet, even if the coating portion (coating layer) does not contain a colorant, photostability can be improved, so it is preferable that the coating layer does not substantially contain a colorant (particularly, a colored colorant), and it is particularly preferable that it does not contain a colorant (particularly, a colored colorant).

[0120] To improve identifiability, the surface of the tablet of the present invention may be engraved or printed with a product number, the name of the active ingredient, the content of the active ingredient, the dosage form, the product number, a QR code (registered trademark), a 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, laser printing, etc. 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 viewpoint of identifiability, etc.

[0121] The pharmaceutical composition of the present invention may be packaged in a packaging material. Examples of packaging include PTP packaging, strip packaging, bottle filling, aluminum packaging, etc.

[0122] Examples of materials for PTP packaging that contain tablets and the like include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, and polycarbonate, and 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 PTP-packaged by forming a resin sheet with pockets using a known method, placing tablets in the pockets, and then covering the pockets with aluminum foil.

[0123] The PTP package may be secondary packaged in an aluminum pillow. The aluminum pillow may further contain a desiccant and / or oxygen scavenger. Examples of desiccant include calcium chloride, calcium oxide, magnesium oxide, silica gel, and zeolite. Examples of oxygen scavenger include iron-based oxygen scavengers such as iron powder, and organic oxygen scavengers such as ascorbic acid, isoascorbic acid, hydroquinone, and catechol. Only one type of desiccant and / or oxygen scavenger may be used, or multiple types may be used in combination. A combination of a desiccant and an oxygen scavenger may also be used. An example of a product combining a desiccant and an oxygen scavenger is PharmaKeep (registered trademark) (manufactured by Mitsubishi Gas Chemical Company, Inc.).

[0124] The pharmaceutical composition of the present invention may be filled in a glass or plastic bottle. Examples of materials for the plastic bottle include the resins exemplified above for PTP packaging. The pharmaceutical composition of the present invention may be packaged in aluminum packaging for each dose. The aluminum packaging may be secondary packaged in an aluminum pillow. The aluminum pillow may further contain the above-mentioned desiccant and / or oxygen scavenger.

[0125] The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples. The raw materials and evaluation methods used in the following examples are shown below. The masses of the raw materials used are all solid content masses.

[0126] [Raw material] Letermovir drug substance: specific surface area 4.297 m ２ / g Microcrystalline cellulose a: manufactured by Asahi Kasei Corporation, trade name "CEOLUS PH-101" Microcrystalline cellulose b: manufactured by Asahi Kasei Corporation, trade name "CEOLUS PH-301" Microcrystalline cellulose c: manufactured by Rettenmeyer, trade name "VIVAPUR 105" Microcrystalline cellulose d: manufactured by IFF, trade name "AVICEL PH-105" D-mannitol: manufactured by ROQUETTE, trade name "PEARLITOL 50C" Light anhydrous silicic acid a: manufactured by Freund Corporation, trade name "Adsolider 101" Light anhydrous silicic acid b: manufactured by Nippon Aerosil Co., Ltd., trade name "AEROSIL 200" Povidone: manufactured by BASF Japan Ltd., trade name "Kollidon 25" Hydroxypropyl cellulose a (HPC-a): manufactured by Nippon Soda Co., Ltd., trade name "HPC-M", 2% by mass (20°C) aqueous solution viscosity 150 to 400 mPa·s Hydroxypropyl cellulose b (HPC-b): manufactured by Ashland, trade name "KLUCEL EL", 2% by mass (25°C) aqueous solution viscosity 8 to 12 mPa·s Hydroxypropyl cellulose c (HPC-c): manufactured by Ashland, trade name "KLUCEL LF", 2% by mass (25°C) aqueous solution viscosity 13 to 20 mPa·s Hypromellose: manufactured by Shin-Etsu Chemical Co., Ltd., trade name "TC-5R" Croscarmellose sodium: manufactured by DuPont Nutrition USA Inc. Manufactured by: Daiichi Sankyo Co., Ltd., trade name "Acdisol" Magnesium stearate: Manufactured by: Taihei Chemical Industry Co., Ltd., grade "Vegetable (Taihei)" Lactose hydrate: Manufactured by: DFE Pharma Co., Ltd., trade name "Fine Powder" Triacetin: glycerol triacetate Titanium oxide: Manufactured by: Freund Corporation, trade name "Titanium Oxide FG" Talc: Manufactured by: Hayashi Kasei Co., Ltd., trade name "Talc Hayashi" Iron sesquioxide: Manufactured by: Kishi Kasei Co., Ltd. Coating agent (Opadry): Manufactured by: Colorcon, trade name "Opadry II 85F18422 White"

[0127] [Particle size distribution of sized powder] Particle size distribution of sized powder (D １０ , D ５０ , D ９０) was measured on a volume basis using an ultrasonic vibration sieving particle size distribution measuring device (manufactured by Seishin Enterprise Co., Ltd., trade name "Robot Sifter RPS-205").

[0128] [Specific Volume] 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). Next, the stainless steel cup was vibrated and drug-containing particles were added again, repeatedly, until no volume change occurred. 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).

[0129] [Tablet Hardness] 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 a motorized weight load.

[0130] [Disintegration Time (Japanese Pharmacopoeia, 18th Edition)] A disintegration tester (based on the Japanese Pharmacopoeia) was used. 900 mL of water at 37°C was placed in a glass container, and a basket (with a mesh bottom) containing tablets was moved up and down in the water to measure the time it took for the tablets to completely disintegrate.

[0131] [Dissolution of Tablets (Example 1 and Comparative Examples 1 and 2)] The average dissolution rate of the tablets was measured according to the paddle method of the dissolution test in the 18th edition of the Japanese Pharmacopoeia (pH 1.2, pH 4.0, pH 6.8, 900 mL of water dissolution test solutions 1 to 4, 37°C, 50 or 75 rpm). The dissolution rate was measured using a fiber probe type ultraviolet-visible spectrophotometer (Rainbow, manufactured by Pion) (measurement wavelength: 288 nm).

[0132] [Tablet Dissolution (Example 3)] The average dissolution rate of the tablets was measured according to the paddle method of the United States Pharmacopoeia dissolution test (pH 4.5 + 0.6% Tween 80, 900 mL, 37°C, 75 rpm) using a fiber probe UV-visible spectrophotometer (Rainbow, manufactured by Pion) (measurement wavelength: 288 nm).

[0133] [Color Difference (ΔE)] The obtained plain tablets and coated tablets were irradiated with diffused light of 1.2 million lux, and the color difference before and after the diffused light was measured using a spectrocolorimeter (SE 6000, manufactured by Nippon Denshoku Industries Co., Ltd.).

[0134] [Method for measuring related substances] Related substances were measured using high performance liquid chromatography (HPLC).

[0135] Example 1 [Granulation step] Letermovil and additives (additives other than HPC-a) were lightly mixed in the proportions shown in Table 1 to prepare a prepared powder. HPC-a (hydroxypropyl cellulose) was dissolved in purified water in the proportions shown in Table 1 to prepare a granulation liquid (solid content 1.45% by mass). The prepared powder was placed in a fluidized bed granulation dryer, and the granulation liquid was sprayed at a liquid rate of 6 g / min to granulate, followed by drying to prepare a dry powder, which was a granulated powder. The cumulative 10% particle size (D １０ ) is 54.6 μm, and the cumulative 50% particle diameter (D ５０ ) is 117.4 μm, and the cumulative 90% particle diameter (D ９０ ) was 211.2 μm, the loose specific volume was 4.48 mL / g, and the hardened specific volume was 3.47 mL / g.

[0136] [Sizing step] The obtained dried powder was sized using a sizing machine to prepare a sized powder. １０ ) is 50.3 μm, and the cumulative 50% particle diameter (D ５０ ) is 102.5 μm, cumulative 90% particle diameter (D ９０ ) was 206.3 μm, the loose specific volume was 4.61 mL / g, and the hardened specific volume was 3.64 mL / g.

[0137] [Tableting Powder Preparation Step] The sized powder and croscarmellose sodium were mixed in a diffusion mixer in the proportions shown in Table 1, and magnesium stearate was further added and mixed to prepare tableting powder (composition for tableting).

[0138] The tableting powder was compressed using a rotary tableting machine to prepare uncoated tablets. The uncoated tablets 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.

[0139] [Film Coating Step] 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 obtained solution, dispersion, and talc were mixed to prepare a film coating liquid (solid content 10% by mass).

[0140] 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.

[0141] [Packaging process] The obtained coated tablets were PTP-packaged using a PVC sheet and aluminum foil for PVC in a PTP molding machine to obtain PTP packages. The obtained PTP packages were then packaged in aluminum pillows with an aluminum pillow zipper to obtain aluminum pillow packages.

[0142] Comparative Example 1: Commercially available film-coated Letermovil tablets (active ingredient 240 mg, total mass 618 mg) were used. The uncoated tablets had a 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 thickness of 5.11 mm, a hardness of 297 N, and a disintegration time of 10 minutes 40 seconds to 13 minutes 1 second.

[0143] 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 obtained PTP packages were packaged in aluminum pillows using an aluminum pillow zipper to obtain aluminum pillow packages.

[0144] Comparative Example 2 [Granulation Step] Letermovil and additives were dry granulated using a roller compactor in the proportions shown in Table 1 to prepare a dry powder.

[0145] [Sizing step] The obtained dried powder was sized using a sizing machine to prepare a sized powder. １０ ) is 35.9 μm, and the cumulative 50% particle diameter (D ５０ ) is 139.0 μm, cumulative 90% particle diameter (D ９０ ) was 445.4 μm, the loose specific volume was 2.17 mL / g, and the hardened specific volume was 1.68 mL / g.

[0146] [Tableting powder preparation process] The sized powder, crystalline cellulose, croscarmellose sodium, and light anhydrous silicic acid were mixed in a diffusion mixer in the proportions shown in Table 1, and magnesium stearate was further added and mixed to prepare tableting powder (composition for tableting).

[0147] 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.

[0148] [Film coating step] 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 obtained solution and dispersion were mixed to prepare a film coating solution.

[0149] 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 tablet thickness of 5.24 mm, a hardness of 401 N, and a disintegration time of 9 minutes 44 seconds to 10 minutes 42 seconds.

[0150] [Packaging process] The obtained coated tablets were PTP-packaged using a PVC sheet and aluminum foil for PVC in a PTP molding machine to obtain PTP packages. The obtained PTP packages were then packaged in aluminum pillows with an aluminum pillow zipper to obtain aluminum pillow packages.

[0151]

[0152] The results of comparing the dissolution rates of the coated tablets obtained in Example 1 and Comparative Examples 1 and 2 are shown in Figures 1 to 4. As is clear from Figures 1 to 4, in all four types of test solutions specified in the guidelines, the coated tablets obtained in Example 1, despite their small size, showed dissolution rates equivalent to those of the coated tablets obtained in Comparative Examples 1 and 2. In particular, while there is a tendency for the dissolution rate to decrease when tablets are made smaller, it was a surprising result that the coated tablets of Example 1, despite being smaller in mass to less than half that of Comparative Examples 1 and 2, showed equivalent dissolution rates.

[0153] The plain tablets and coated tablets obtained in Example 1 and Comparative Examples 1 and 2 were irradiated with light and stored, and then the color difference (ΔE) was evaluated. The results are shown in Table 2, and the amounts of related substances generated were measured. The results are shown in Table 3.

[0154]

[0155]

[0156] The tablets obtained in Example 1 had better photostability than those in Comparative Example 2 and were equivalent to those in Comparative Example 1, despite not containing a colorant.

[0157] The PTP packages of 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). Also, the coated tablets obtained in Example 1 and Comparative Examples 1 and 2 were placed in a petri dish, wrapped and sealed with Saran Wrap (registered trademark), and stored at 25°C / 75% RH for 3 months (3M). The amounts of related substances were measured before and after storage, and the results are shown in Table 4.

[0158]

[0159] 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.

[0160] The aluminum (AL) pillow packages of 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 placed in an open petri dish and stored at 25°C / 75% RH for 3 months (3M). The results of a comparison of the dissolution rates before and after storage for the coated tablets obtained in Example 1 are shown in Figure 5, and the results of a comparison of the dissolution rates before and after storage for the coated tablets obtained in Comparative Example 2 are shown in Figure 6. Table 5 also shows the results of 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.

[0161]

[0162] As is clear from Figures 5 and 6, the tablets obtained in Example 1 had dissolution rates equivalent to those of the comparative example.

[0163] 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.

[0164] Example 2 [Granulation step] Letermovil and additives (additives other than 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.

[0165] [Sizing Step] The obtained dried powder was sized using a sizing machine to prepare a sized powder.

[0166] [Tableting powder preparation step] The sized powder and croscarmellose sodium were mixed in a diffusion mixer in the proportions shown in Table 6, and light anhydrous silicic acid was further added and mixed to prepare tableting powder (composition for tableting).

[0167] [Tableting Step] The tableting powder was compressed into tablets using a rotary tableting machine to prepare uncoated tablets.

[0168] [Film Coating Step] A coating agent was dissolved in purified water to prepare a film coating solution.

[0169] 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.

[0170] Example 3 [Granulation step] Letermovil and additives (additives other than 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.

[0171] [Sizing Step] The obtained dried powder was sized using a sizing machine to prepare a sized powder.

[0172] [Tableting powder preparation step] The sized powder and croscarmellose sodium were mixed in a diffusion mixer in the proportions shown in Table 6, and light anhydrous silicic acid was further added and mixed to prepare tableting powder (composition for tableting).

[0173] [Tableting Step] The tableting powder was compressed into tablets using a rotary tableting machine to prepare uncoated tablets.

[0174] [Film Coating Step] A coating agent was dissolved in purified water to prepare a film coating solution.

[0175] 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.

[0176] Example 4 [Granulation step] Letermovil and additives (additives other than HPC-c) were lightly mixed in the proportions shown in Table 6 to prepare a prepared powder. 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 was a granulated powder.

[0177] [Sizing Step] The obtained dried powder was sized using a sizing machine to prepare a sized powder.

[0178] [Tableting Powder Preparation Step] 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).

[0179] [Tableting Step] The tableting powder was compressed into tablets using a rotary tableting machine to prepare uncoated tablets.

[0180] [Film Coating Step] A coating agent was dissolved in purified water to prepare a film coating solution.

[0181] 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.

[0182] Example 5 [Granulation step] Letermovil and additives (additives other than HPC-c) were lightly mixed in the proportions shown in Table 6 to prepare a prepared powder. 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 was a granulated powder.

[0183] [Sizing Step] The obtained dried powder was sized using a sizing machine to prepare a sized powder.

[0184] [Tableting Powder Preparation Step] 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).

[0185] [Tableting Step] The tableting powder was compressed into tablets using a rotary tableting machine to prepare uncoated tablets.

[0186] [Film Coating Step] A coating agent was dissolved in purified water to prepare a film coating solution.

[0187] 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.

[0188]

[0189] The dissolution rates of the coated tablets obtained in Example 3 are shown in Figure 7. As is clear from Figure 7, the coated tablets of Example 3 also showed an excellent dissolution rate.

[0190] 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 preventive or therapeutic agent for CMV infection.

Claims

1. A pharmaceutical composition comprising letermovir or a pharmaceutically acceptable salt thereof as an active ingredient and a binder, wherein the proportion of the active ingredient in the pharmaceutical composition is 50% by weight or more.

2. The pharmaceutical composition according to claim 1, wherein the viscosity of a 2% by weight aqueous solution of the binder at 20°C is 2 mPa·s or more.

3. The pharmaceutical composition according to claim 1 or 2, wherein the binder is a hydroxyalkylcellulose.

4. A pharmaceutical composition according to claim 1 or 2, which comprises a granulated product, said granulated product being a wet granulation of a granulation composition comprising said active ingredient and said binder.

5. The pharmaceutical composition according to claim 4, wherein the ratio of the binder is 1 to 10 parts by weight per 100 parts by weight of the active ingredient.

6. The pharmaceutical composition according to claim 4, wherein the ratio of the binder is 2 to 10 parts by weight per 100 parts by weight of the active ingredient.

7. The pharmaceutical composition according to claim 4, wherein the granulation composition further contains an excipient, and the proportion of the excipient in the pharmaceutical composition is 10% by mass or less.

8. The pharmaceutical composition according to claim 7, wherein the excipient is a sugar alcohol.

9. The pharmaceutical composition according to claim 7, wherein the excipient is crystalline cellulose.

10. The pharmaceutical composition according to claim 1 or 2, which is in the form of a tablet.

11. The pharmaceutical composition according to claim 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.

12. A method for producing a pharmaceutical composition containing 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, the method comprising a granulation step of wet-granulating a granulation composition containing the active ingredient and the binder by agitation granulation or fluidized bed granulation to obtain a granulated product.

13. A method for improving the stability and dissolution of miniaturized tablets in a pharmaceutical composition containing 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, by using as the binder a binder whose viscosity of a 2% by mass aqueous solution at 20°C is 2 mPa·s or more.

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