Amenamevir-containing pharmaceutical composition, method for producing same, and method for inhibiting crystallization

Abstract

To provide an amenamevir-containing pharmaceutical composition having superior solubility in water, a production method therefor, and a crystallization inhibition method for a solid dispersion containing amenamevir.SOLUTION: A pharmaceutical composition includes a solid dispersion containing amenamevir and a water-soluble polymer.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition containing amenamevir, as well as a method for producing the same and a method for inhibiting crystallization thereof. [Background technology]

[0002] Amenamevir has the chemical name N-(2,6-dimethylphenyl)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)-1,1-dioxothiane-4-carboxamide and is a compound represented by the following chemical formula (1).

[0003] [ka]

[0004] Amenamevir is an anti-herpes virus drug that inhibits the enzymatic activity of the viral helicase-primase complex, but it is poorly water-soluble, so its solubility and oral absorption need to be improved.

[0005] It has been known that a solid dispersion containing polyvinyl alcohol having a predetermined degree of saponification is used to improve the solubility of poorly water-soluble drugs (Patent Document 1). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent No. 7180592 Summary of the Invention [Problem to be solved by the invention]

[0007] However, among poorly water-soluble drugs, amenamevir has a solubility of 5 μg / mL in water, and its solubility remains unchanged in the pH range of 1.1 to 9.0, making it practically insoluble in water. Therefore, there is a need for pharmaceutical compositions containing amenamevir, particularly those formulated as solid dispersions, to improve the solubility.

[0008] Furthermore, if amorphous amenamevir crystallizes, its solubility may decrease further, and therefore, maintaining its amorphous state is also important.

[0009] The present invention has been made in consideration of the above points, and its main object is to provide an amenamevir-containing pharmaceutical composition having excellent solubility in water, a method for producing the same, and a method for inhibiting crystallization of a solid dispersion containing amenamevir. [Means for solving the problem]

[0010] A pharmaceutical composition according to one aspect of the present invention is characterized by comprising a solid dispersion containing amenamevir and a water-soluble polymer.

[0011] In the pharmaceutical composition, the water-soluble polymer is preferably at least one selected from the group consisting of hydroxypropyl cellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and hypromellose acetate succinate, and more preferably hydroxypropyl cellulose.

[0012] In addition, in the pharmaceutical composition, the blending ratio of the amenamevir to the water-soluble polymer is preferably 5:1 to 1:5 by weight.

[0013] The pharmaceutical composition may be in the form of a tablet.

[0014] In another embodiment of the present invention, the pharmaceutical composition is packaged in a press-through package (PTP).

[0015] The package is preferably further packaged in an aluminum pillow.

[0016] In addition, it is preferable that the aluminum pillow in the package contains a desiccant.

[0017] Alternatively, in the package, the PTP is preferably a moisture-proof PTP.

[0018] A package according to yet another embodiment of the present invention is characterized in that a pharmaceutical composition containing amenamevir and a water-soluble polymer is packaged in an aluminum pillow.

[0019] In the package, it is preferable that a desiccant is contained inside the aluminum pillow, and it is also preferable that the water-soluble polymer is hydroxypropyl cellulose.

[0020] A manufacturing method according to yet another aspect of the present invention is a manufacturing method for the pharmaceutical composition, characterized in that it includes the steps of dissolving and / or suspending amenamevir and a water-soluble polymer in a solvent, and then spray-drying the solution to obtain a solid dispersion, and granulating the solid dispersion.

[0021] Furthermore, when the pharmaceutical composition is in the form of a tablet, a production method according to yet another embodiment of the present invention includes, in addition to the above steps, a step of tableting the obtained granules.

[0022] A package according to yet another embodiment of the present invention is a package in which a pharmaceutical composition containing amenamevir is packaged in an aluminum pillow.

[0023] In the package, the pharmaceutical composition preferably further contains a water-soluble polymer.

[0024] More preferably, the package contains a desiccant inside the aluminum pillow.

[0025] In the package, the water-soluble polymer is preferably at least one selected from hydroxypropyl cellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and hypromellose acetate succinate.

[0026] A pharmaceutical composition according to yet another aspect of the present invention comprises amenamevir and a water-soluble polymer, and the water-soluble polymer may be at least one selected from the group consisting of hydroxypropyl cellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and hypromellose acetate succinate.

[0027] A further aspect of the present invention relates to a method for inhibiting crystallization of amenamevir in a pharmaceutical composition containing a solid dispersion comprising amenamevir and a water-soluble polymer, and is characterized in that it comprises inhibiting an increase in the moisture content of the pharmaceutical composition containing the solid dispersion.

[0028] In the crystallization suppression method, the means for suppressing an increase in moisture content preferably includes packaging the pharmaceutical composition in a press-through package (PTP).

[0029] In the crystallization suppression method, it is preferable that the means for suppressing an increase in moisture content further includes packaging in an aluminum pillow and / or using a moisture-proof PTP as the PTP.

[0030] Furthermore, in the crystallization suppression method, a desiccant may be placed inside the aluminum pillow. [Effects of the Invention]

[0031] According to the present invention, it is possible to provide an amenamevir-containing pharmaceutical composition having excellent solubility in water, a method for producing the same, and a method for inhibiting crystallization of a solid dispersion containing amenamevir. [Brief explanation of the drawings]

[0032] [Figure 1] FIG. 1 is a graph showing the dissolution behavior of the solid dispersions of Examples 1 to 4. [Figure 2] FIG. 2 is a graph showing the dissolution behavior of the simply mixed powders of Comparative Examples 1 to 7. [Figure 3] FIG. 3 is an XRD graph showing the presence or absence of crystallization in the solid dispersion of Example 2. [Figure 4] FIG. 4 is a graph showing the dissolution properties of the tablets of Examples 5 and 6 in water. [Figure 5] FIG. 5 is a graph showing the dissolution properties of the tablets of Examples 5 and 6 in a test solution (pH 6.8). [Figure 6] FIG. 6 is a graph showing the dissolution properties in water of the tablets of Examples 8 to 10. [Figure 7] FIG. 7 is a graph showing the dissolution properties of the tablets of Examples 8 to 10 in a test solution (pH 6.8). DETAILED DESCRIPTION OF THE INVENTION

[0033] Hereinafter, embodiments of the present invention will be described, but the present invention is not limited to these.

[0034] <Pharmaceutical Composition> The pharmaceutical composition of this embodiment can improve the poor water solubility of amenamevir by containing amenamevir and a water-soluble polymer. This effect is particularly pronounced when the pharmaceutical composition is prepared as a solid dispersion containing amenamevir and a water-soluble polymer.

[0035] The pharmaceutical composition of this embodiment contains amenamevir as an active ingredient, which is N-(2,6-dimethylphenyl)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)-1,1-dioxothiane-4-carboxamide represented by the following formula (1):

[0036] [ka]

[0037] Amenamevir is sold in Japan under the brand name "Amenalef Tablets 200mg" as a treatment for herpes virus infection. Amenamevir is a poorly water-soluble drug in its crystalline form, and from the standpoints of solubility and absorption in the body, it is preferable to use it in its amorphous form.

[0038] The amount of amenamevir in the pharmaceutical composition of this embodiment is preferably such that the daily dose of amenamevir for a human patient is typically 400 mg for herpes zoster, whereas the daily dose of amenamevir for a human patient is preferably 1200 mg for recurrent herpes simplex.

[0039] Therefore, although it varies depending on the dosage form, the pharmaceutical composition of this embodiment typically contains 100 to 400 mg of amenamevir. The actual dose appropriate for each patient can be determined appropriately depending on the patient's age, weight, symptoms, etc.

[0040] The pharmaceutical composition of this embodiment also includes a water-soluble polymer. Examples of the water-soluble polymer include hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, carboxyvinyl polymer, polyacrylic acid, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and hypromellose acetate succinate. Preferred examples include hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and hypromellose acetate succinate. More preferred examples include hydroxypropyl cellulose. These may be used alone or in combination of two or more.

[0041] Among hydroxypropyl celluloses, those having a viscosity of 6 to 10 (mPa*s) in a 2% aqueous solution at 20°C are more preferred.

[0042] By preparing a solid dispersion containing such a water-soluble polymer, the pharmaceutical composition of this embodiment can improve the solubility of amenamevir in water.

[0043] The pharmaceutical composition of this embodiment preferably contains amenamevir and the water-soluble polymer in a weight ratio of 5:1 to 1:5. This is believed to further improve the solubility. A more preferred weight ratio is 2:1 to 1:2.

[0044] The solid dispersion contains amenamevir and the water-soluble polymer as a carrier. The solvent that can be used in producing the solid dispersion of this embodiment by the solvent method is not particularly limited as long as it dissolves amenamevir and the water-soluble polymer. Examples of solvents that can be used include water (purified water), acetone, methanol, and ethanol. The solvents may be used alone or in combination.

[0045] The dosage form of the pharmaceutical composition of the present embodiment is not particularly limited as long as it contains the solid dispersion, and may be, for example, a solid preparation such as a tablet, capsule, granule, powder, or pill; a semi-solid preparation such as an oral jelly; or a liquid preparation such as an elixir, suspension, emulsion, or lemonade.

[0046] Depending on the dosage form, the pharmaceutical composition of this embodiment may contain excipients and various additives in addition to the amenamevir and the water-soluble polymer.

[0047] The excipient is not particularly limited as long as it is an excipient normally used in dry syrups, tablets, etc., and examples that can be used include sugar, sugar alcohol, crystalline cellulose, ethyl cellulose, hydroxypropyl cellulose, dextrin, corn starch, calcium silicate, anhydrous calcium hydrogen phosphate, etc. These may be used alone or in combination of two or more.

[0048] Furthermore, various additives may be appropriately blended as needed, such as pharmaceutically acceptable additives, within the range that does not impair the effects of the present invention.

[0049] Specific additives include binders such as pregelatinized starch, carmellose sodium, hydroxypropyl cellulose, polyvinyl alcohol, alginate, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and methylcellulose; fluidizers such as light anhydrous silicic acid, hydrous silicic acid dioxide, magnesium aluminum metasilicate, talc, and calcium stearate; disintegrants such as starch, crospovidone, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, and partially pregelatinized starch; aspartame, acesulfame potassium, saccharin, and sucrose. Sweeteners such as maltose, stevia, and white sugar; flavorings such as l-menthol, yogurt microns, pineapple microns, peppermint microns, lemon microns, and orange microns; colorants and light-blocking agents such as titanium oxide, food yellow no. 4, food yellow no. 4 aluminum lake, food yellow no. 5, food red no. 2, food red no. 3, food red no. 102, black iron oxide, red iron oxide, yellow red iron oxide, and blue no. 2 aluminum lake; lubricants such as magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, magnesium silicate, magnesium oxide, sucrose fatty acid esters, glyceryl behenate, and talc; and granulation binders such as sucrose and gelatin.

[0050] The content of excipients and additives in the pharmaceutical composition of the present embodiment is not particularly limited and can be determined appropriately depending on the dosage form. For example, the following contents can be used. The amount of excipients can be 1% by mass or more and 90% by mass or less of the entire formulation (pharmaceutical composition), preferably 10% by mass or more, more preferably 20% by mass or more, and preferably 50% by mass or less, more preferably 40% by mass or less. The amount of the disintegrant can be 1% by mass or more and 30% by mass or less, and preferably 5% by mass or more and 25% by mass or less, based on the total amount of the preparation (pharmaceutical composition). The binder content may be 0.1% by mass or more and 10% by mass or less of the total formulation (pharmaceutical composition), preferably 0.5% by mass or more, more preferably 1% by mass or more, even more preferably 2% by mass or more, and preferably 5% by mass or less. The lubricant content may be 0.05% by mass or more and 5% by mass or less of the total formulation (pharmaceutical composition), preferably 0.1% by mass or more, more preferably 0.5% by mass or more, and preferably 4% by mass or less, more preferably 2% by mass or less. The content of the fluidizing agent may be 0.05% by mass or more and 5% by mass or less of the total formulation (pharmaceutical composition), preferably 0.1% by mass or more, more preferably 0.5% by mass or more, and preferably 4% by mass or less, more preferably 2% by mass or less. Sweeteners and flavorings may be added in trace amounts within the range in which their respective effects are exhibited. Furthermore, colorants are preferably added in an amount of 0.01% by mass or more and 0.1% by mass or less based on the total amount of the preparation (pharmaceutical composition).

[0051] Furthermore, the water content in the solid dispersion contained in the pharmaceutical composition of this embodiment is, for example, preferably 2% or less, more preferably 1% or less, from the viewpoint of suppressing crystallization.

[0052] In the present embodiment, the "moisture value" is a value measured by the Karl Fischer method, and is a value (% by mass) calculated with the mass of the solid dispersion being 100%.

[0053] The volume-based cumulative 50% particle diameter (D 50 ) is not particularly limited, but is preferably about 2.0 to 10.0 μm. 50 is a value measured using a laser diffraction particle size distribution analyzer (MS3000).

[0054] The pH of the solid dispersion of this embodiment is preferably about 5.0 to 8.0 in a solution in which the ratio of water to dispersion is 1:1.

[0055] The pharmaceutical composition of this embodiment is useful for treating and preventing diseases associated with herpes viruses, particularly shingles and recurrent herpes simplex.

[0056] <Manufacturing method> The pharmaceutical composition of this embodiment can be prepared by preparing a solid dispersion containing amenamevir and the water-soluble polymer, granulating the solid dispersion with excipients and the like to obtain a granulated product, and then mixing other additives as necessary. Furthermore, the granulated product obtained above can be mixed with other additives and compressed to prepare tablets.

[0057] More specifically, the method for producing the pharmaceutical composition of this embodiment includes, for example, a step of dissolving and / or suspending amenamevir and a water-soluble polymer in a solvent, followed by spray drying to obtain a solid dispersion, and a step of granulating the solid dispersion.

[0058] The step of obtaining a solid dispersion is not particularly limited, but is preferably carried out by a spray drying method. Specifically, first, the amenamevir and the water-soluble polymer are blended in a weight ratio of 5:1 to 1:5, and then dissolved and / or suspended in a solvent. The solvent is not particularly limited as long as it is a pharmaceutically acceptable solvent, and examples thereof include water (purified water), acetone, methanol, and ethanol. One solvent may be used alone, or two or more solvents may be used in combination. Among these, a mixed solvent of acetone and water is particularly preferred.

[0059] After dissolving and / or suspending in a solvent, the solvent is evaporated by spray drying to obtain a solid dispersion. Any known spray drying method can be used.

[0060] The granulation step can be carried out by a known method, for example, by adding excipients and, if necessary, other additives to the solid dispersion obtained above, mixing the mixture, granulating, and sizing to obtain a sized powder. The blending ratio of the solid dispersion, excipients, additives, etc. can be appropriately selected depending on the desired dosage form, active ingredient content, etc.

[0061] Specific granulation methods include, for example, wet granulation, in which a solvent is sprayed onto rolled or fluidized fine raw material powder to bond them together, and dry granulation, in which a lubricant is blended with the raw material powder, and pressure is applied to form it into a bulk shape such as a plate, followed by pulverization and sizing. Dry granulation, which does not use a solvent such as water, is preferred because it does not require drying.

[0062] When the pharmaceutical composition is in the form of a tablet, the production method of this embodiment further includes, in addition to the above steps, a step of compressing the obtained sized powder into tablets.

[0063] In this case, the sized powder obtained in the granulation step is subjected to the tableting step described below, but the particle size of the granules may be adjusted before that. The sizing step can be carried out, for example, by utilizing the centrifugal force of a rotating rotor.

[0064] In this embodiment, the tableting step can also be carried out using a known method. That is, tablets can be produced by mixing external additives with the sized powder obtained as described above and tableting using a known means (for example, a tableting pressure of 3 to 20 kN). Furthermore, the tablets (plain tablets) obtained by tableting may be film-coated to form film-coated tablets. As a film-coating method, a conventional method can be used, but pan coating is particularly preferred.

[0065] In this embodiment, the ratio of the sized powder to the external additive can be appropriately selected depending on the type of tablet, the content of the active ingredient, and the like.

[0066] Tableting is preferably carried out by compression molding, and for example, a tableting die, upper and lower punches for tableting used for molding tablets can be used, and a hydraulic hand press, a single punch tableting machine, a rotary tableting machine, etc. The tableting pressure can be appropriately set depending on the weight of the tablets to be produced.

[0067] Although the above description has been given regarding tablets, the dosage form of the pharmaceutical composition obtained by the production method of this embodiment is not particularly limited, and may be a dry syrup formulation, powder, granules, capsules, pills, etc., in addition to tablets. Tablets are preferred.

[0068] The shape of the tablet of this embodiment is not particularly limited, but may be disc-shaped, doughnut-shaped, polygonal plate-shaped, spherical, elliptical, or the like.

[0069] <Crystallization suppression method> This embodiment also includes a method for inhibiting crystallization of a pharmaceutical composition containing amenamevir and a water-soluble polymer, which comprises inhibiting an increase in the water content of the pharmaceutical composition.

[0070] In this embodiment, the "moisture value" has the same meaning as the moisture value described above.

[0071] Furthermore, suppressing the moisture content in the pharmaceutical composition of this embodiment means controlling the moisture content in the solid dispersion contained in the pharmaceutical composition to 1% or less.

[0072] The inventors have found that by suppressing an increase in the moisture content in a pharmaceutical composition, the amorphous state of a solid dispersion containing amenamevir can be maintained for a long period of time, i.e., crystallization of a solid dispersion containing amenamevir can be suppressed.

[0073] The means for suppressing the increase in moisture content includes, for example, packaging the pharmaceutical composition in a press-through package (PTP). Furthermore, the PTP-packaged pharmaceutical composition may be packaged in an aluminum pillow. This is believed to more reliably suppress the increase in moisture content of the solid dispersion contained in the pharmaceutical composition. Alternatively, a moisture-proof PTP may be used as the PTP. When the pharmaceutical composition is in the dosage form of a tablet, the moisture content is preferably suppressed to approximately 5% or less.

[0074] A PTP package is usually made of a base sheet formed of resin and having a plurality of pockets for accommodating oral solid preparations, and a lid (or cover) which is a film having an aluminum layer and seals the solid preparations accommodated in the pockets. In the PTP package, it is sufficient that at least the pockets are formed of a resin sheet, and from the viewpoint of productivity, it is preferable that the base sheet is formed of a resin sheet.

[0075] The film having an aluminum layer may be an aluminum foil, a laminate of an aluminum foil and a resin layer, or an aluminum-deposited film. The average thickness of the film having an aluminum layer is, for example, 0.03 to 1 mm, preferably 0.05 to 0.5 mm, and more preferably 0.1 to 0.3 mm.

[0076] Examples of resins that can be used to form resin sheets include olefin-based resins such as polyethylene, polypropylene, cyclic polyolefin (COC), ethylene-vinyl acetate copolymer (EVA), ethylene-vinyl alcohol copolymer, ionomer resin (IO), and ethylene-methacrylic acid copolymer (EMAA); chlorine-containing resins such as polyvinyl chloride (PVC) and polyvinylidene chloride (PVDC); and fluororesins such as polychlorotrifluoroethylene (PCTFE), tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PFA), tetrafluoroethylene-hexafluoropropylene copolymer (FEP), tetrafluoroethylene-hexafluoropropylene-perfluoroalkyl vinyl ether (EPA), tetrafluoroethylene-ethylene copolymer (ETFE), polyvinylidene fluoride (PVDF), and chlorotrifluoroethylene-ethylene copolymer (ECTFE). These resins can be used alone or in combination.

[0077] The resin sheet may be formed by laminating different types of resin sheets in order to adjust the moisture permeability. Also, the thickness of the resin sheet may be adjusted to adjust the moisture permeability, as will be described later.

[0078] Preferred resin sheets include olefin-based resin sheets such as non-oriented polypropylene (CPP) sheets and COC sheets, chlorine-containing resin sheets such as PVC sheets and PVDC sheets, and laminated sheets of a fluororesin layer and a chlorine-containing resin layer, such as a laminated sheet of a PCTFE layer and a PVC layer, with laminated sheets of a fluororesin layer and a chlorine-containing resin layer being particularly preferred because of their high moisture resistance and ability to improve the stability of amorphous amenamevir.

[0079] In a laminate sheet of a fluororesin layer (particularly a PCTFE layer) and a chlorine-containing resin layer (particularly a PVC layer), the thickness of the chlorine-containing resin layer is, for example, 2 to 30 times, preferably 3 to 20 times, more preferably 5 to 15 times, and even more preferably 6 to 10 times the thickness of the fluororesin layer. If the thickness ratio of the fluororesin layer is too small, moisture resistance may decrease, and conversely, if it is too large, moldability may decrease.

[0080] The average thickness of the resin sheet is, for example, 0.05 to 3 mm, preferably 0.1 to 1 mm, and more preferably 0.15 to 0.5 mm.

[0081] Furthermore, a conventional aluminum pillow package can be used as the aluminum pillow package. The aluminum pillow package may be a pillow package formed from a film having an aluminum layer, and may be a pillow package formed from a laminate film (laminate film) of aluminum foil and plastic film, or a pillow package formed from a plastic film having an aluminum vapor deposition film (aluminum vapor deposition film). Examples of plastic films include films formed from polyolefins such as polyethylene and polypropylene; films formed from polyesters such as polyethylene terephthalate; and polyamide films formed from polyamides such as polyamide 6.

[0082] It is more preferable to use a moisture-proof PTP as the PTP package. In order to suppress crystallization of the pharmaceutical composition of this embodiment, it is preferable to make the moisture permeability of the moisture-proof PTP as low as possible (to make the moisture-proof property as high as possible).

[0083] The moisture permeability of the moisture-proof PTP packaging is 3.0 g / m 2 / 24hr or less, and more preferably 1.5g / m 2 / 24hr or less, and more preferably 0.8g / m 2 / 24hr or less, and more preferably 0.4g / m 2 / 24hr or less, and most preferably 0.3g / m 2 In this specification, the moisture permeability can be measured by a conventional method, for example, a method in accordance with JIS K7129 or JIS Z0208.

[0084] Commercially available moisture-proof PTP packaging materials can also be used, and specific examples include, but are not limited to, the TAS (registered trademark) series manufactured by Taisei Chemical Co., Ltd., the Superfoil (registered trademark) and Vinifoil (registered trademark) series manufactured by Mitsubishi Chemical Corporation, the Sumilite (registered trademark) series manufactured by Sumitomo Bakelite Co., Ltd., and medical PTP sheets manufactured by ZACROS (using Aclar (registered trademark) manufactured by Honeywell).

[0085] Furthermore, a desiccant may be placed inside the aluminum pillow. Conventional desiccants can be used as the desiccant, such as silica gel, calcium chloride, and zeolite. Furthermore, oxygen scavengers such as iron-based oxygen scavengers and organic oxygen scavengers can also be placed inside the aluminum pillow.

[0086] By using the above-mentioned means for suppressing an increase in moisture content, the solid dispersion containing amenamevir can remain amorphous even after 2 months under conditions of 40°C and 75% RH.

[0087] Furthermore, in order to further suppress crystallization of the solid dispersion, it is preferable to avoid applying heat to the pharmaceutical composition.

[0088] <Package> To suppress crystallization, the pharmaceutical composition of this embodiment is preferably provided as a press-through package (PTP). Furthermore, the package is preferably packaged in an aluminum pillow. It is also preferable that a desiccant be contained inside the aluminum pillow, and the PTP is preferably a moisture-proof PTP. All of the above-mentioned packages are encompassed by this embodiment.

[0089] The present invention will be explained in more detail below with reference to examples, but the scope of the present invention is not limited to these examples. [Example]

[0090] First, the reagents used in this example will be described.

[0091] (For solid dispersions or simple mixed powders) Drug substance: Amenamevir (volume-based cumulative 10% particle size (D 10 ) 1.36 μm, volume-based cumulative 50% particle diameter (D 50 ) 4.29 μm, cumulative 90% particle diameter (D 90 )18.66μm) Hydroxypropyl methylcellulose: "TC-5R" Hydroxypropyl cellulose: "HPC-L" (viscosity of 2% aqueous solution at 20°C: 6.0-10.0 mPa*s) Hydroxypropyl cellulose: "HPC-SSL" (viscosity of 2% aqueous solution at 20°C: 2.0-2.9 mPa*s) Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer: "Soluplus" Copovidone: "Kollidon VA64" Hydroxypropyl cellulose: "HPC-UL" (viscosity of 2% aqueous solution at 20°C: 2.0 mPa*s or less) Hypromellose acetate succinate "Shin-Etsu AQOAT AS-LG"

[0092] (for tablets) Low-substituted hydroxypropyl cellulose: "LH-B1" Magnesium stearate: "vegetable" Calcium silicate: "Fluorite PS-200" Croscarmellose sodium: "Acdisol" Crospovidone: Polyplasdone INF-10

[0093] (for film coating) Hydroxypropyl methylcellulose: "TC-5R" Macrogol 6000: Powder Titanium oxide: "Titanium oxide FG" Talc: "Talc Hayashi" Yellow ferric oxide

[0094] (packaging) Polyethylene bags: "Unipack Mark MARK-E" Aluminum pillow chuck included: Model No. AL-14 Desiccant: MS Ceram-W3G

[0095] <Preparation of solid dispersion> Example 1 20 g of amenamevir and 10 g of hydroxypropylmethylcellulose "TC-5R" were dissolved in 270 g of acetone and 30 g of purified water, and the solution was spray-dried using a mini spray dryer B-290 (manufactured by BUCHI) to obtain solid dispersion powder 1 containing 66.67% by mass of amenamevir. The spray drying conditions were as follows: Intake air temperature (℃): 100 (check exhaust temperature and adjust accordingly) Exhaust temperature (℃): 70 Air supply air volume setting (%): 100 Liquid speed (g / min):6 Atomizing air volume (NL / min): 50

[0096] Example 2 Solid dispersion powder 2 was obtained in the same manner as in Example 1, except that 20 g of amenamevir and 10 g of hydroxypropyl cellulose "HPC-L" were dissolved in 270 g of acetone and 30 g of purified water.

[0097] Example 3 Solid dispersion powder 3 was obtained in the same manner as in Example 1, except that 20 g of amenamevir and 10 g of hydroxypropyl cellulose "HPC-SSL" were dissolved in 270 g of acetone and 30 g of purified water.

[0098] Example 4 Solid dispersion powder 4 was obtained in the same manner as in Example 1, except that 20 g of amenamevir and 10 g of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer "Soluplus" were dissolved in 270 g of acetone and 30 g of purified water.

[0099] (Comparative Example 1) 2 g of amenamevir and 1 g of hydroxypropyl methylcellulose "TC-5R" were weighed into a glass bottle and mixed for 30 seconds to obtain a simple mixed powder 1 containing 66.67% by mass of amenamevir.

[0100] (Comparative Example 2) A simple mixed powder 2 was obtained in the same manner as in Comparative Example 1, except that 2 g of amenamevir and 1 g of copovidone "Kollidon VA64" were weighed into a glass bottle.

[0101] (Comparative Example 3) A simple mixed powder 3 was obtained in the same manner as in Comparative Example 1, except that 2 g of amenamevir and 1 g of hydroxypropyl cellulose "HPC-L" were weighed into a glass bottle.

[0102] Comparative Example 4 2 g of amenamevir and 1 g of hydroxypropyl cellulose "HPC-SSL" were weighed into a glass bottle, and the other procedures were the same as in Comparative Example 1 to obtain a simple mixed powder 4.

[0103] (Comparative Example 5) 2 g of amenamevir and 1 g of hydroxypropyl cellulose "HPC-UL" were weighed into a glass bottle, and the other procedures were the same as in Comparative Example 1 to obtain a simple mixed powder 5.

[0104] (Comparative Example 6) 2 g of amenamevir and 1 g of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer "Soluplus" were weighed into a glass bottle, and the other procedures were the same as in Comparative Example 1 to obtain a simple mixed powder 6.

[0105] (Comparative Example 7) 2 g of amenamevir and 1 g of hypromellose acetate succinate "shin-Etsu AQOAT AS-LG" were weighed into a glass bottle, and the other procedures were the same as in Comparative Example 1 to obtain simple mixed powder 7.

[0106] (Evaluation of dissolution behavior of solid dispersion powder and simple mixed powder) A dissolution test (μ-diss) was conducted using 500 mL of Japanese Pharmacopoeia Dissolution Test Fluid I (pH 1.2) as the test fluid, and the dissolution behavior of the solid dispersion powders obtained in Examples 1 to 4 and the simply mixed powders obtained in Comparative Examples 1 to 7 was evaluated. The details are as follows. The containers containing the test solutions heated to 37±0.5°C were placed in the dissolution tester, and 100 mg of the solid dispersion or simple mixed powder to be tested was then added. The device was operated at a rotation speed of 250 rpm from 0 to 3 minutes, 200 rpm from 3 to 5 minutes, and 50 rpm from 5 minutes onwards, and the solubility was measured appropriately up to 5 hours.

[0107] The results are shown in Figure 1 (Examples 1 to 4) and Figure 2 (Comparative Examples 1 to 7). As is clear from Figure 1, all solid dispersions showed good dissolution behavior, but the results of Example 2 showed particularly excellent dissolution. On the other hand, as shown in Figure 2, the simply mixed powder did not show the same dissolution behavior as the solid dispersions.

[0108] (Stability evaluation of solid dispersions) Next, the stability of the solid dispersion of Example 2 was evaluated. First, here's a sample: Sample 1: 5 g of the solid dispersion of Example 2 was placed in an open glass bottle. Sample 2: 5 g of the solid dispersion of Example 2 was placed in a polyethylene bag, which was then placed in an aluminum pillow zipper and sealed by heat sealing. Sample 3: 5 g of the solid dispersion of Example 2 was placed in a polyethylene bag, which was then placed in an aluminum pillow chuck, and a desiccant was placed inside, followed by heat sealing.

[0109] Each sample was then stored for two months at a temperature of 40°C and a humidity of 75%RH, and then evaluated by powder X-ray diffraction (XRD). Structural analysis was performed using a fully automated multipurpose X-ray diffractometer (Bruker AXS "D8 ADVANCE") at a scanning angle 2θ of 2 to 40° under the following measurement conditions and range (see Table 1). Measurement conditions: Transmission method Scan Type: TwoTheta Scan mode: PSD high speed scan High Sensitivity Mode

[0110] [Table 1]

[0111] The results are shown in Figure 3. For reference, the figure also shows a mixture of 95% HPC-L and 5% amenamevir crystals (Sample I) and solid dispersion powder 2 (Sample II) immediately after preparation in Example 2. From Figure 2, a peak of amenamevir crystals was observed in Sample 1 (the area circled in the figure). In contrast, no such peak was observed in Samples 2 and 3, which were packaged, confirming that amenamevir remained amorphous.

[0112] <Tablet manufacturing> Example 5 The solid dispersion obtained in Example 2 and low-substituted hydroxypropyl cellulose were placed in a glass bottle and mixed in the formulation amounts (mg) shown in Table 2 below (the same applies to all additives hereinafter). Magnesium stearate was then added and mixed to obtain a pre-granulation mixed powder. The obtained pre-granulation mixed powder was slug-formed using a single-punch tablet press (HANDTAB, Ichihashi Seiki Kogyo Co., Ltd.) and pulverized in a mortar. The pulverized product was then sized using a 30M sieve (mesh opening: 500 μm) to obtain a granulated powder. The obtained granulated powder was placed in a glass bottle and mixed with calcium silicate, croscarmellose sodium, and crospovidone. Magnesium stearate was then added and mixed to obtain a tableting powder. The obtained tableting powder was compressed using a single-punch tablet press to obtain amenamevir tablets.

[0113] Example 6 Amenamevir tablets were obtained in the dosage (mg) shown in Table 2 below in the same manner as in Example 5.

[0114] [Table 2]

[0115] (Dissolution test) Using water and 900 mL of Japanese Pharmacopoeia Dissolution Test Fluid II (pH 6.8) as test fluids, dissolution tests were carried out on the tablets of Examples 5 and 6. The details are as follows. After placing each container containing the test solution heated to 37±0.5°C in the dissolution tester, one test tablet was added and the device was operated at 50 rpm. Test solution samples were collected at specified intervals (water: 0, 5, 10, 15, 30, 45, 60, 90, 120, and 180 minutes; Japanese Pharmacopoeia Dissolution Test Solution II: 0, 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes). Approximately 33 mg of amenamevir was weighed separately and accurately adjusted to a total volume of 100 mL with acetonitrile. 2 mL of this solution was accurately measured and 3 mL of the test solution was added to prepare the standard solution. The amount of amenamevir in the collected test solution was measured using an ultraviolet spectrophotometer, and the dissolution rate (%) was calculated. The results are shown in Figure 4 (dissolution in water) and Figure 5 (dissolution in Japanese Pharmacopoeia dissolution test fluid II).

[0116] As is clear from Figures 4 and 5, all of the tablets of the examples showed sufficient dissolution properties.

[0117] <Manufacturing of film-coated tablets> Example 7 Uncoated tablets prepared using the same formulation as in Example 5 were subjected to a film coating treatment. The film coating solution used for film coating was prepared as follows. Hydroxypropyl methylcellulose and macrogol 6000 were dissolved in purified water. Talc was added to this solution and dispersed to obtain Dispersion I. Separately from Dispersion I, titanium oxide and yellow ferric oxide were dispersed in purified water to obtain Dispersion II. Dispersion I and Dispersion II were mixed to obtain a film coating solution. The uncoated tablets were placed in a coating pan machine, coated with the film coating solution, and then dried to obtain tablets containing amenamevir (film-coated tablets). The weight per tablet of the obtained tablets is as shown in Table 3 below.

[0118] [Table 3]

[0119] <Preparation of solid dispersion> Furthermore, solid dispersions of Examples 8 to 10 were prepared by changing the blending ratio of the solvent and the carrier.

[0120] Example 8 200 g of amenamevir and 200 g of hydroxypropyl cellulose "HPC-SSL" were dissolved in 6000 g of acetone and spray-dried using a turning-type spray dryer TR160 (manufactured by PRECI) to obtain solid dispersion powder 8 containing 50% by weight of amenamevir. 50 The particle size was 5.2 μm. The pH of the solution prepared in a water:dispersion ratio of 1:1 was 6.0. The spray drying conditions were as follows: Intake air temperature (℃): 80 Exhaust temperature (℃): 54~57 Air supply air volume setting (%): 100 Spray pressure (MPa): 0.3 Liquid speed (g / min): 55~60

[0121] Example 9 300 g of amenamevir and 75 g of hydroxypropyl cellulose "HPC-SSL" were dissolved in 4500 g of acetone, and the other procedures were the same as in Example 8 to obtain solid dispersion powder 9. 50 The particle size was 6.1 μm. The pH of the solution prepared in a water:dispersion ratio of 1:1 was 7.7.

[0122] Example 10 800 g of amenamevir and 400 g of hydroxypropyl cellulose "HPC-SSL" were dissolved in 12,000 g of acetone, and the other procedures were the same as in Example 8 to obtain solid dispersion powder 10. 50 The particle size was 5.9 μm. The pH of the solution prepared in a water:dispersion ratio of 1:1 was 6.2.

[0123] (Dissolution test) The dissolution rates (%) were determined using the solid dispersions of Examples 8 to 10 in the same manner as in the dissolution test described above. The results are shown in Figure 6 (dissolution in water) and Figure 7 (dissolution in Japanese Pharmacopoeia dissolution test fluid II). As is clear from Figures 6 and 7, all of the tablets of the Examples showed sufficient dissolution.

[0124] <Tablet manufacturing> (Examples 11 to 13) The solid dispersions obtained in Examples 8 to 10 and low-substituted hydroxypropyl cellulose were placed in a glass bottle and mixed in the formulation amounts (mg) shown in Table 4 below. Magnesium stearate was then added and mixed to obtain a pre-granulation mixed powder. The obtained pre-granulation mixed powder was slug-formed using a single-punch tableting machine (HANDTAB, Ichihashi Seiki Kogyo Co., Ltd.) and pulverized in a mortar. The pulverized product was then sized using a 30M sieve (mesh opening: 500 μm) to obtain a granulated powder. The obtained granulated powder was placed in a glass bottle and mixed with calcium silicate, croscarmellose sodium, and crospovidone. Magnesium stearate was then added and mixed to obtain a tableting powder. The obtained tableting powder was compressed using a single-punch tableting machine at 8 kN to obtain amenamevir tablets (tablet diameter: 14.8 × 8.1 mm, tablet hardness: 165 N in Example 11, 171 N in Example 12, and 102 N in Example 13).

[0125] [Table 4]

Claims

1. A pharmaceutical composition comprising a solid dispersion containing amenamevir and a water-soluble polymer.

2. 2. The pharmaceutical composition according to claim 1, wherein the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and hypromellose acetate succinate.

3. The pharmaceutical composition according to claim 2, wherein the water-soluble polymer is hydroxypropyl cellulose.

4. 2. The pharmaceutical composition according to claim 1, wherein the weight ratio of amenamevir to the water-soluble polymer is 5:1 to 1:

5.

5. The pharmaceutical composition of claim 1 , wherein the dosage form is a tablet.

6. A package in which the pharmaceutical composition according to any one of claims 1 to 5 is packaged in a press-through package (PTP).

7. The package according to claim 6, further packaged in an aluminum pillow.

8. The package according to claim 7, further comprising a desiccant inside the aluminum pillow.

9. The package according to claim 6, wherein the PTP is a moisture-proof PTP.

10. dissolving and / or suspending amenamevir and a water-soluble polymer in a solvent, followed by spray drying to obtain a solid dispersion; The method for producing the pharmaceutical composition according to any one of claims 1 to 4, comprising a step of granulating the solid dispersion.

11. The method for producing a pharmaceutical composition according to claim 10, further comprising a step of compressing the granules obtained in the granulation step into tablets.

12. A package in which a pharmaceutical composition containing amenamevir is packaged in an aluminum pillow.

13. The package according to claim 12, wherein the pharmaceutical composition further comprises a water-soluble polymer.

14. The package according to claim 12, further comprising a desiccant inside the aluminum pillow.

15. The package according to claim 13, wherein the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and hypromellose acetate succinate.

16. A pharmaceutical composition comprising amenamevir and a water-soluble polymer, The pharmaceutical composition, wherein the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and hypromellose acetate succinate.

17. A method for inhibiting crystallization of amenamevir in a pharmaceutical composition containing a solid dispersion containing amenamevir and a water-soluble polymer, comprising: and inhibiting an increase in the moisture content of a pharmaceutical composition comprising the solid dispersion.

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