Fosravuconazole l-lysine ethanol adduct-containing tablet and method for producing same

Abstract

The present invention addresses the problem of providing a fosravuconazole L-lysine ethanol adduct-containing tablet that has excellent content uniformity, suppresses tableting problems, and has good physical properties.　The above problem is solved by combining a fosravuconazole L-lysine ethanol adduct, crystalline cellulose having specific physical properties, and magnesium stearate in predetermined amounts and compression-molding.

Description

Fosravuconazole L-lysine ethanol adduct-containing tablets and method for producing the same

[0001] The present invention relates to tablets containing fosravuconazole L-lysine ethanol adduct and a method for producing the same.

[0002] Fosravuconazole L-lysine ethanol adduct is used as an antifungal agent. Capsules containing fosravuconazole L-lysine ethanol adduct are known (Patent Document 1) and are already commercially available. On the other hand, tablets are generally easier to swallow than capsules, and studies have been conducted on tablets containing fosravuconazole L-lysine ethanol adduct (Patent Document 2), but they have not yet been commercialized, and the development of a practical tablet is desired.

[0003] Patent No. 6181044, Patent No. 5058150

[0004] In capsule formulations approved as pharmaceuticals, the daily dose of fosravuconazole L-lysine ethanol adduct is 169.1 mg. The inventors attempted to manufacture tablets containing this daily dose of fosravuconazole L-lysine ethanol adduct, and found that tableting problems such as sticking (where some of the material adheres to the punch contact surface during tableting), binding (where some of the material adheres to the die contact surface during tableting, creating vertical lines on the side of the tablet), and capping (where the top or bottom surface of the tablet peels off) were prone to occur. They also found that the physical properties of the tablets themselves, such as hardness, abrasion resistance, and ease of peeling, were not good. Furthermore, they found that increasing the amount of additives in the raw materials to solve these problems reduced the content of fosravuconazole L-lysine ethanol adduct, resulting in variations in the content of fosravuconazole L-lysine ethanol adduct from tablet to tablet and poor uniformity of content.

[0005] The object of the present invention is to provide a fosravuconazole L-lysine ethanol adduct-containing tablet that exhibits excellent content uniformity, suppresses tableting problems, and has good physical properties.

[0006] The inventors of the present invention have found that the above problems can be solved by combining fosravuconazole L-lysine ethanol adduct, crystalline cellulose having specific physical properties, and magnesium stearate in predetermined amounts and compressing them, thereby completing the present invention.

[0007] In other words, the present invention encompasses the following embodiments: [1] A tablet made by compression molding fosravuconazole L-lysine ethanol adduct, crystalline cellulose, and magnesium stearate, wherein the crystalline cellulose is present in a concentration of 0.20 to 0.31 g / cm³. 3 [1] A tablet having a bulk density and a compressibility of 25% or less, with a content of fosravuconazole L-lysine ethanol adduct of 58 to 82% by mass relative to the total mass of the tablet, a total content of fosravuconazole L-lysine ethanol adduct and crystalline cellulose of 88% by mass or more relative to the total mass of the tablet, and a content of magnesium stearate of 2 to 4% by mass relative to the total mass of the tablet. [2] The tablet according to [1], wherein the fosravuconazole L-lysine ethanol adduct has a D20 of 75 μm or more and a D50 of 160 μm to 260 μm. [3] A tablet comprising the tablet according to [1] or [2]. [4] (1) Fosravuconazole L-lysine ethanol adduct and 0.20 to 0.31 g / cm 3 A method for producing a tablet, comprising: (1) a step of mixing crystalline cellulose having a bulk density and a compressibility of 25% or less with magnesium stearate to obtain a mixture; (2) a step of compressing the mixture to obtain a tablet, wherein the content of fosravuconazole L-lysine ethanol adduct is 58 to 82% by mass relative to the total mass of the tablet, the total content of fosravuconazole L-lysine ethanol adduct and crystalline cellulose is 88% by mass or more relative to the total mass of the tablet, and the content of magnesium stearate is 2 to 4% by mass relative to the total mass of the tablet. [5] The method according to [4], wherein the fosravuconazole L-lysine ethanol adduct of step (1) has a D20 of 75 μm or more and a D50 of 160 μm to 260 μm. [6] A method for producing a tablet using a tablet obtained by the method according to [4] or [5].

[0008] According to the present invention, it is possible to provide a fosravuconazole L-lysine ethanol adduct-containing tablet that exhibits excellent content uniformity, suppresses tableting problems, and has good physical properties.

[0009] The present invention relates to a tablet obtained by compression molding of fosravuconazole L-lysine ethanol adduct, crystalline cellulose, and magnesium stearate, wherein the crystalline cellulose is present in a concentration of 0.20 to 0.31 g / cm³. 3 The present invention relates to a tablet having a bulk density and a compressibility of 25% or less, with a fosravuconazole L-lysine ethanol adduct content of 58 to 82% by mass relative to the total mass of the tablet, a total content of fosravuconazole L-lysine ethanol adduct and crystalline cellulose of 88% by mass or more relative to the total mass of the tablet, and a magnesium stearate content of 2 to 4% by mass relative to the total mass of the tablet.

[0010] The following describes in detail embodiments for carrying out the present invention (hereinafter sometimes simply referred to as "this embodiment"). It should be noted that the present invention is not limited to the following embodiments, and can be implemented in various modifications within the scope of its gist.

[0011] A plain tablet is a formulation made by compressing and molding powdered raw materials (no processing other than compression molding is performed). In this invention, the powdered raw materials refer to a mixture of fosravuconazole L-lysine ethanol adduct powder with crystalline cellulose, magnesium stearate, and optionally other various additives. The powdered raw materials may also include granules granulated by wet or dry methods.

[0012] The uncoated tablets of the present invention contain fosravuconazole L-lysine ethanol adduct, crystalline cellulose, and magnesium stearate as raw materials.

[0013] Fosravuconazole L-lysine ethanol adduct has the compound name dihydrogen phosphate ({(2R,3R)-3-[4-(4-cyanophenyl)thiazole-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-yl)butan-2-yl}oxy)methyl-[(2S)-2,6-diaminohexanoic acid-ethanol adduct] and has the structure shown in the following formula.

[0014]

[0015] Hosrabconazole L-lysine ethanol adduct is known as an antifungal agent, and its production method is also known, for example, as disclosed in Patent Document 2.

[0016] In the core tablets of the present invention, the content of hosrabconazole L-lysine ethanol adduct is 58 to 82% by mass, preferably 60 to 80% by mass, more preferably 65 to 75% by mass, based on the total mass of the core tablets. By setting the content of hosrabconazole L-lysine ethanol adduct to a high content within the above range, the variation in the content of hosrabconazole L-lysine ethanol adduct per core tablet can be suppressed, and the content uniformity can be improved.

[0017] Hosrabconazole L-lysine ethanol adduct preferably has a specific particle size distribution. For example, D20 is preferably 75 μm or more, more preferably 160 μm to 200 μm. Also, D50 is preferably 160 μm to 260 μm, more preferably 210 μm to 240 μm. The particle size distribution can be measured by a laser diffraction / scattering type particle size distribution measuring device.

[0018] The crystalline cellulose used in the present invention has a degree of compressibility of 25% or less. The degree of compressibility can be used as a measure of the fluidity of crystalline cellulose. The smaller the degree of compressibility, the higher the fluidity, and it is more preferably 22% or less. By using crystalline cellulose with high fluidity, hosrabconazole L-lysine ethanol adduct and crystalline cellulose can be uniformly mixed, and the content uniformity can be improved.

[0019] The degree of compressibility is calculated using the following formula based on the fluidity of powders in the 18th revised Japanese Pharmacopoeia, reference information. Degree of compressibility (%) = (ρ tapped - ρ bulk ) / ρ tapped × 100 ρ bulk : Bulk density at loose packing (g / cm 3 ) ρ tapped : Tap density (g / cm 3)

[0020] The crystalline cellulose used in this invention is 0.20 to 0.31 g / cm³. 3 It has a bulk density within the above range. By using crystalline cellulose having a bulk density within the above range, the physical properties of the resulting tablets can be improved while maintaining high uniformity of content. The bulk density can be measured by the method described in the section on "crystalline cellulose" in the 18th edition of the Japanese Pharmacopoeia.

[0021] Crystalline cellulose having the above-mentioned range of compressibility and bulk density is commercially available, for example, Ceolus® UF-711 and PH-101 manufactured by Asahi Kasei Corporation.

[0022] The crystalline cellulose is included in such an amount that its total content with fosravuconazole L-lysine ethanol adduct is 88% by mass or more, preferably 90% to 98% by mass, and more preferably 92% to 97% by mass, relative to the total mass of the uncoated tablet. By adjusting the amount of crystalline cellulose within the above range, a high level of balance between content uniformity and the physical properties of the uncoated tablet can be maintained.

[0023] In the uncoated tablets of the present invention, magnesium stearate is contained in an amount of 2% to 4% by mass relative to the total mass of the uncoated tablets. By adjusting the amount of magnesium stearate within the above range, tablets with good physical properties can be obtained while suppressing tableting problems.

[0024] The uncoated tablets may contain other additives as long as they do not impair the effects of the present invention. Examples of additives include excipients, disintegrants, binders, stabilizers, lubricants, fluidizers, colorants, fragrances, flavoring agents, antioxidants, etc. Any additive that is usable in the pharmaceutical field may be used.

[0025] Examples of excipients include lactose, sucrose, granulated sugar, glucose, mannitol, maltitol, sorbitol, low-substituted hydroxypropyl cellulose (L-HPC), carmellose, kaolin, calcium hydrogen phosphate, potassium dihydrogen phosphate, calcium sulfate, calcium carbonate, gum arabic, and starch (for example, natural starches such as potato starch, rice starch, wheat starch, and corn starch, and pregelatinized starch). Two or more of these may be used in combination.

[0026] Examples of disintegrants include crospovidone, povidone (polyvinylpyrrolidone, PVP), low-substituted hydroxypropyl cellulose (L-HPC), carmellose calcium, carmellose, croscarmellose sodium, alginic acid, carboxymethyl starch sodium, starch glycolate sodium, and talc. Two or more of these may be used in combination.

[0027] Examples of binders include polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol / polyethylene glycol / graft copolymer, polyvinyl alcohol, hydroxypropyl cellulose (HPC), povidone (polyvinylpyrrolidone, PVP), hydroxypropyl methylcellulose (hypromellose, HPMC), carmellose sodium, polyvinyl alcohol, pregelatinized starch, agar, gelatin, carboxymethylcellulose sodium, dextrin, ethylcellulose, glycerin, guar gum, polyethylene oxide, etc. Two or more of these may be used in combination.

[0028] Examples of stabilizers include basic substances. Specific examples include inorganic bases, organic bases, basic amino acids, and basic polymers. Two or more of these basic substances may be used in combination. In this invention, the basic substance used is one whose 1% by mass aqueous solution or suspension has a pH of 7 or higher, preferably a pH of 8 or higher, and more preferably a pH of 10 or higher.

[0029] Specific examples of inorganic bases include, for example, magnesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, heavy magnesium carbonate, precipitated calcium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, magnesium hydroxide, calcium hydroxide, alumina-magnesium hydroxide, dried aluminum hydroxide gel, magnesium oxide, calcium oxide, barium oxide, calcium silicate, magnesium silicate, aluminum magnesium silicate, magnesium aluminate, magnesium aluminometasilicate, sodium hydrogen phosphate, sodium dihydrogen phosphate, synthetic hydrotalcite, coprecipitates of aluminum hydroxide and magnesium hydroxide, coprecipitates of aluminum hydroxide, magnesium carbonate and calcium carbonate, and coprecipitates of aluminum hydroxide and sodium bicarbonate. Preferably, magnesium carbonate, magnesium oxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, and calcium silicate are used, and more preferably, magnesium carbonate, magnesium hydroxide, magnesium oxide, and sodium bicarbonate.

[0030] Specific examples of organic bases include, for example, calcium stearate, magnesium stearate, sodium stearate, sodium stearyl fumarate, trisodium citrate, sodium benzoate, monoethanolamine, diethanolamine, triethanolamine, tributylamine, dicyclohexylmethylamine, and N-methylpyrrolidine. Preferably, calcium stearate, magnesium stearate, trisodium citrate, and sodium benzoate are used, and more preferably, sodium benzoate.

[0031] Specific examples of basic amino acids include lysine, ornithine, histidine, and arginine. Lysine and arginine are preferred, and arginine is more preferred.

[0032] Specific examples of the basic polymer include, for example, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylamino acetate, ethyl cellulose, and the like.

[0033] Examples of the lubricant include, for example, stearic acid, calcium stearate, sodium lauryl sulfate, glycerin monostearate, glyceryl palmitostearate, sodium stearyl fumarate, sucrose fatty acid ester, zinc stearate, talc, carnauba wax, L-leucine, macrogol, and the like. These may be used in combination of two or more.

[0034] Examples of the fluidizing agent include, for example, hydrous silicon dioxide, light anhydrous silicic acid, heavy anhydrous silicic acid, synthetic aluminum silicate, and the like, and one or more of these can be used.

[0035] Examples of the coloring agent include, for example, titanium oxide, yellow ferric oxide, ferric oxide, riboflavin, food yellow No. 4, food yellow No. 5, food red No. 2, food red No. 3, food red No. 102, and the like, and one or more of these can be used.

[0036] Examples of the fragrance include, for example, lemon oil, orange oil, cinnamon oil, star anise oil, peppermint oil, vanilla, ethylvanillin, l-menthol, dl-camphor, lavender oil, peppermint oil, vanilla flavor, fruit flavor, and the like, and one or more of these can be used.

[0037] Examples of the flavoring agent include, for example, citric acid, malic acid, tartaric acid, fructose, licorice powder, cocoa powder, glycine, l-glutamic acid, aspartame, erythritol, acesulfame potassium, sucralose, saccharin, dipotassium glycyrrhizinate, and the like, and one or more of these can be used.

[0038] Examples of the antioxidant include, for example, sodium ascorbate, L-cysteine, sodium sulfite, tocopherol, soybean lecithin, and the like, and one or more of these can be used.

[0039] The core tablets of the present invention are obtained by compression molding the above raw materials including voriconazole L-lysine ethanol adduct, crystalline cellulose and magnesium stearate.

[0040] There are no particular restrictions on the means of compression molding, and conventionally known devices such as rotary tablet presses and single-shot tablet presses can be used. For example, it is preferable to use a rotary tablet press (manufactured by Kikusui Seisakusho). The tableting pressure is preferably 500 to 1100 kg, more preferably 700 to 900 kg. The shape of the punch used for compression molding is preferably circular, and more preferably a flat punch. The rotation speed of the tablet press is preferably 20 to 40 rpm, more preferably 25 to 35 rpm.

[0041] The core tablets of the present invention have excellent content uniformity. The content uniformity can be represented by the determination value calculated according to the content uniformity test of the 18th revised Japanese Pharmacopoeia, Preparation Uniformity Test Method, by measuring the voriconazole L-lysine ethanol adduct content in each of the 10 core tablets obtained by compression molding from the same raw material by ultraviolet-visible spectrophotometry. The desirable content uniformity of the core tablets is such that the determination value is less than 8, more preferably less than 5, and even more preferably less than 3.

[0042] The core tablets of the present invention have excellent physical properties. Specifically, they have high hardness and low abrasion, and peeling is unlikely to occur.

[0043] The hardness can be represented as the average value of 10 tablets by measuring the hardness of each core tablet using a tablet hardness tester (DR. SCHLEUNIGER Tablet Tester 8M). Practically, it is desirable that the hardness is 3 kgf or more, more preferably 5 kgf or more.

[0044] The abrasion can be represented by the value of the mass percentage of the reduced mass (Wa - Wb) due to rotation with respect to the mass (Wa) before rotation, by measuring the mass (Wa) of 20 core tablets, putting them into a tablet abrasion tester and rotating them at 25 rpm for 4 minutes, removing the fine powder adhering to the core tablets, and then measuring the mass (Wb) again. Practically, it is desirable that the abrasion is 0.7% or less, more preferably 0.2% or less.

[0045] The resistance to peeling can be evaluated by a peeling test in which 20 uncoated tablets are placed in a tablet abrasion tester, rotated at 25 rpm for 15 minutes, and then the number of peeled tablets is checked. In practical terms, it is desirable that 0 out of 20 tablets peel.

[0046] The tablets of the present invention include the uncoated tablets described above. For example, the tablets of the present invention may be uncoated tablets themselves, or coated tablets obtained by coating uncoated tablets. Coated tablets include film-coated tablets (gastric-coated tablets, enteric-coated tablets) in which uncoated tablets are coated with a film formed from a coating agent containing a water-soluble, enteric-coated, or gastric-coated polymer base, and sugar-coated tablets in which uncoated tablets or film-coated tablets are coated with a sugar coating agent. The amount of coating agent applied can be appropriately adjusted according to the desired properties of the film-coated tablets to be manufactured, for example, 0.5 to 15% by mass, preferably 5 to 10% by mass, relative to the total mass of the uncoated tablets. The amount of sugar coating agent applied is, for example, 40 to 160% by mass, preferably 70 to 100% by mass, relative to the total mass of the uncoated tablets.

[0047] Examples of coating agents include water-soluble bases such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (hypromellose, HPMC), methylcellulose, polyvinyl alcohol, polyvinyl alcohol copolymer, and macrogol; water-insoluble bases such as ethylcellulose; enteric-coated bases such as hydroxypropyl methylcellulose phthalate (MPMCP), hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethylcellulose, cellulose acetate phthalate, acrylic acid copolymer, methacrylic acid copolymer, and carboxyvinyl polymer; gastric-soluble bases such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, and polyvinyl acetate diethylaminoacetate; carnauba wax; glycerin fatty acid ester; and white shellac. One or more of these can be used.

[0048] The coating agent may contain additives such as the above-mentioned excipients, disintegrants, binders, stabilizers, lubricants, fluidizers, colorants, fragrances, flavoring agents, and antioxidants. The coating agent may also contain additives such as plasticizers, light-shielding agents, and colorants. Examples of plasticizers include castor oil, macrogol, and polysorbate. Examples of light-shielding agents include titanium dioxide and talc. Examples of colorants include yellow ferric oxide, ferric oxide, food blue No. 2, food red No. 3, and riboflavin.

[0049] Examples of sugar coating agents include those containing hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (hypromellose, HPMC), ethylcellulose, polyvinyl alcohol, povidone (polyvinylpyrrolidone, PVP), carmellose sodium, calcium carbonate, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, granulated sugar, refined sucrose, sucrose, maltitol, refined gelatin, gelatin, pullulan, polyoxyethylene, macrogol, gum arabic, gum arabic powder, carnauba wax, stearic acid, polyoxyl 40 stearate, refined shellac, shellac, white shellac, titanium dioxide, talc, etc., and one or more of these components may be used. Sugar coating agents may also contain additives such as the above-mentioned excipients, disintegrants, binders, stabilizers, lubricants, fluidizers, colorants, flavorings, flavorings, and antioxidants.

[0050] The present invention also relates to a method for producing uncoated tablets. The method of production of the present invention is: (1) fosravuconazole L-lysine ethanol adduct and 0.20 to 0.31 g / cm³ 3 The method comprises (1) a step of mixing crystalline cellulose having a bulk density and a compressibility of 25% or less with magnesium stearate to obtain a mixture, and (2) a step of compressing the mixture to obtain a tablet, wherein the content of fosravuconazole L-lysine ethanol adduct is 58 to 82% by mass relative to the total mass of the tablet, the total content of fosravuconazole L-lysine ethanol adduct and crystalline cellulose is 88% by mass or more relative to the total mass of the tablet, and the content of magnesium stearate is 2 to 4% by mass relative to the total mass of the tablet.

[0051] There are no particular restrictions on the means of mixing in step (1), and conventionally known mixing methods (e.g., Bohle container mixer, cross-rotary mixer, etc.) can be used. Alternatively, the raw materials may be placed in a container such as a plastic bag and mixed manually. In addition to fosravuconazole L-lysine ethanol adduct, crystalline cellulose, and magnesium stearate, additives such as the above-mentioned excipients, disintegrants, binders, stabilizers, lubricants, fluidizers, colorants, fragrances, flavoring agents, and antioxidants may be mixed.

[0052] The conditions for compression molding in step (2) are as described above. The manufacturing method of the present invention, which combines fosravuconazole L-lysine ethanol adduct, crystalline cellulose having specific physical properties, and magnesium stearate in predetermined amounts, can suppress tableting defects during compression molding. Tableting defects can be evaluated by visually inspecting the surface of the uncoated tablet immediately after compression molding to check for the presence or absence of capping, sticking, binding, etc.

[0053] The present invention also relates to a method for manufacturing tablets using the above-mentioned uncoated tablets. When manufacturing film-coated tablets or sugar-coated tablets by coating the above-mentioned uncoated tablets, there are no particular restrictions on the manufacturing method, and conventionally known coating methods (e.g., HiCoater, PowrecCoater, etc.) can be used.

[0054] The tablets of the present invention can be suitably used to treat onychomycosis and hyperkeratotic tinea pedis caused by dermatophyte (Trichophyton) infection.

[0055] The embodiment will be described in detail below with reference to examples and comparative examples, but the embodiment is not limited to these examples.

[0056] [Fosravuconazole L-lysine ethanol adduct] In the following examples and comparative examples, fosravuconazole L-lysine ethanol adduct (D20: 165 μm, D50: 210 μm) (manufactured by Eisai Co., Ltd.) was used.

[0057] [Crystalline Cellulose] Table 1 shows the bulk density and compressibility of the crystalline cellulose used in the following examples and comparative examples.

[0058]

[0059] In the following examples and comparative examples, magnesium stearate-S (manufactured by NOF Corporation), which conforms to the Japanese Pharmacopoeia "Magnesium Stearate," was used.

[0060] [Comparative Example 1] 96.0 g of fosravuconazole L-lysine ethanol adduct, 134.4 g of crystalline cellulose A, 4.8 g of croscarmellose sodium, and 4.8 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0061] [Comparative Example 2] 120.0 g of fosravuconazole L-lysine ethanol adduct, 110.4 g of crystalline cellulose A, 4.8 g of croscarmellose sodium, and 4.8 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0062] [Example 1] 144.0 g of fosravuconazole L-lysine ethanol adduct, 86.4 g of crystalline cellulose A, 4.8 g of croscarmellose sodium, and 4.8 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0063] [Example 2] 168.0 g of fosravuconazole L-lysine ethanol adduct, 62.4 g of crystalline cellulose A, 4.8 g of croscarmellose sodium, and 4.8 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0064] [Example 3] 192.0 g of fosravuconazole L-lysine ethanol adduct, 38.4 g of crystalline cellulose A, 4.8 g of croscarmellose sodium, and 4.8 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0065] [Comparative Example 3] 216.0 g of fosravuconazole L-lysine ethanol adduct, 14.4 g of crystalline cellulose A, 4.8 g of croscarmellose sodium, and 4.8 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0066] [Example 4] 144.0 g of fosravuconazole L-lysine ethanol adduct, 72.0 g of crystalline cellulose A, 19.2 g of croscarmellose sodium, and 4.8 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0067] [Example 5] 192.0 g of fosravuconazole L-lysine ethanol adduct, 24.0 g of crystalline cellulose A, 19.2 g of croscarmellose sodium, and 4.8 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0068] The following evaluations were performed on the uncoated tablets of Comparative Examples 1-3 and Examples 1-5.

[0069] <Content Uniformity Test> For 10 uncoated tablets, the content of fosravuconazole L-lysine ethanol adduct in each tablet was measured by ultraviolet-visible spectrophotometric analysis, and the judgment value was calculated according to the content uniformity test of the Formulation Uniformity Test Method of the 18th Revised Japanese Pharmacopoeia. A judgment value of less than 3 was evaluated as ◎, 3 or more and less than 6 as ○, 6 or more and less than 8 as △, and 8 or more as ×.

[0070] <Confirmation of Tablet Compression Defects> Immediately after manufacturing the uncoated tablets, the surface was visually inspected to evaluate whether or not there were any defects in tablet compression.

[0071] <Hardness Measurement> Immediately after manufacturing the uncoated tablets, the hardness of the tablets was measured using a tablet hardness tester (DR. SCHLEUNIGER Tablet Tester 8M). The hardness of each tablet was measured individually, and the average hardness of 10 tablets was calculated.

[0072] <Measurement of Abrasion Degree> The mass (Wa) of 20 uncoated tablets was measured, and these were placed in a tablet abrasion tester and rotated at 25 rpm for 4 minutes. After that, the fine powder adhering to the tablets was removed and the mass (Wb) was measured again. The abrasion degree was defined as the mass percentage of the mass loss due to rotation (Wa - Wb) relative to the mass before rotation (Wa).

[0073] <Peeling Test> Twenty uncoated tablets were placed in a tablet abrasion tester and rotated at 25 rpm for 15 minutes. Afterwards, the number of tablets that peeled off was counted.

[0074] <Physical Property Evaluation> Tablet properties were evaluated as follows: ○ if the hardness was 3 kgf or more, the abrasion rate was 0.7% or less, and the number of peeled tablets was 0 out of 20 tablets; × if any of the above conditions were not met.

[0075] The formulations (amount and proportion of ingredients) per tablet for Comparative Examples 1-3 and Examples 1-5 are shown in Tables 2 and 4 below, and the evaluation results are shown in Tables 3 and 5.

[0076]

[0077]

[0078]

[0079]

[0080] As is clear from Tables 2 to 5, the tablets of Examples 1 to 5, which contained 60 to 80% by mass of fosravuconazole L-lysine ethanol adduct relative to the total mass of the tablet, and contained crystalline cellulose A in an amount such that the sum of fosravuconazole L-lysine ethanol adduct and crystalline cellulose A was 90 to 96% by mass relative to the total mass of the tablet, and contained 2.0% by mass of magnesium stearate relative to the total mass of the tablet, showed good content uniformity and tablet properties. In Comparative Example 3, some tablets showed tableting defects (capping), but tablets without tableting defects (capping) were used for hardness measurement, abrasion measurement, and peel test.

[0081] [Example 6] 192.0 g of fosravuconazole L-lysine ethanol adduct, 38.4 g of crystalline cellulose B, 4.8 g of croscarmellose sodium, and 4.8 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0082] [Comparative Example 4] 192.0 g of fosravuconazole L-lysine ethanol adduct, 38.4 g of crystalline cellulose C, 4.8 g of croscarmellose sodium, and 4.8 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0083] [Comparative Example 5] 144.0 g of fosravuconazole L-lysine ethanol adduct, 6.4 g of crystalline cellulose D, 4.8 g of croscarmellose sodium, and 4.8 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0084] Example 6 and Comparative Examples 4-5 were evaluated in the same manner as Comparative Examples 1-3 and Examples 1-5. The formulations (amount and proportion of ingredients) per tablet for Example 3, Example 6, and Comparative Examples 4-5 are shown in Table 6 below, and the evaluation results are shown in Table 7.

[0085]

[0086]

[0087] As is clear from Tables 6 and 7, even when the amounts of fosravuconazole L-lysine ethanol adduct, crystalline cellulose, and magnesium stearate were within the range of the present invention, when crystalline cellulose C (Comparative Example 4) or crystalline cellulose D (Comparative Example 5), whose bulk density and / or compressibility were outside the range of the present invention, were used, it was not possible to obtain uncoated tablets with good content uniformity and tablet properties. In the case of Comparative Example 4, since tableting defects (sticking) were observed in most of the uncoated tablets, no selection of uncoated tablets for use in hardness measurement, abrasion measurement, and peel test was performed.

[0088] [Example 7] 169.1 g of fosravuconazole L-lysine ethanol adduct, 56.5 g of crystalline cellulose A, 4.8 g of croscarmellose sodium, and 9.6 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0089] [Example 8] 169.1 g of fosravuconazole L-lysine ethanol adduct, 58.9 g of crystalline cellulose A, 4.8 g of croscarmellose sodium, and 7.2 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0090] [Example 9] 169.1 g of fosravuconazole L-lysine ethanol adduct, 61.3 g of crystalline cellulose A, 4.8 g of croscarmellose sodium, and 4.8 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0091] [Comparative Example 6] 169.1 g of fosravuconazole L-lysine ethanol adduct, 62.5 g of crystalline cellulose A, 4.8 g of croscarmellose sodium, and 3.6 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0092] [Comparative Example 7] 169.1 g of fosravuconazole L-lysine ethanol adduct, 63.7 g of crystalline cellulose A, 4.8 g of croscarmellose sodium, and 2.4 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0093] [Comparative Example 8] 169.1 g of fosravuconazole L-lysine ethanol adduct, 64.9 g of crystalline cellulose A, 4.8 g of croscarmellose sodium, and 1.2 g of magnesium stearate were mixed in a poly bag to obtain mixed granules. These mixed granules were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho) at a compression pressure of approximately 850 kg and a rotation speed of 30 rpm to obtain uncoated tablets (diameter 8.0 mm, weight per tablet 240 mg).

[0094] The uncoated tablets of Examples 7-9 and Comparative Examples 6-8 were evaluated in the same manner as in Examples 1-6 and Comparative Examples 1-5. The formulations (amount and proportion of ingredients) per tablet for Examples 7-9 and Comparative Examples 6-8 are shown in Table 8 below, and the evaluation results are shown in Table 9.

[0095]

[0096]

[0097] As is clear from Tables 8 to 9, in the tablets of Examples 7 to 9, which contained 70.5% by mass of fosravuconazole L-lysine ethanol adduct relative to the total mass of the tablet, and contained crystalline cellulose A in an amount such that the sum of fosravuconazole L-lysine ethanol adduct and crystalline cellulose A was 94.0% to 96.0% by mass relative to the total mass of the tablet, and contained 2.0% to 4.0% by mass of magnesium stearate relative to the total mass of the tablet, no tableting problems occurred, and both the uniformity of content and the physical properties of the tablets were good. On the other hand, in Comparative Examples 6 to 8, which contained 70.5% by mass of fosravuconazole L-lysine ethanol adduct relative to the total mass of the uncoated tablet, and contained crystalline cellulose A in an amount such that the sum of fosravuconazole L-lysine ethanol adduct and crystalline cellulose A was 96.5 to 97.5% by mass relative to the total mass of the uncoated tablet, and contained 0.5 to 1.5% by mass of magnesium stearate relative to the total mass of the uncoated tablet, tableting defects (sticking) were observed in all uncoated tablets. Furthermore, in Comparative Example 8, multiple tableting defects (sticking and binding) were observed, and the uniformity of content was also slightly reduced. The reduction in uniformity of content is thought to be due to the greater degree of surface defects on the uncoated tablet due to tableting defects compared to Comparative Examples 6 and 7. In Comparative Examples 6 to 8, since tableting defects were observed in all uncoated tablets, selection of uncoated tablets for hardness measurement, abrasion measurement, and peel test was not performed.

[0098] According to the present invention, tablets containing fosravuconazole L-lysine ethanol adduct, exhibiting excellent content uniformity, suppression of tableting defects, and good physical properties, can be provided by a simple method.

Claims

1. Fosravuconazole: A tablet made by compression molding of L-lysine ethanol adduct, crystalline cellulose, and magnesium stearate, wherein the crystalline cellulose is present in a concentration of 0.20 to 0.31 g / cm³. 3 A tablet having a bulk density and a compressibility of 25% or less, with a fosravuconazole L-lysine ethanol adduct content of 58 to 82% by mass relative to the total mass of the tablet, a total content of fosravuconazole L-lysine ethanol adduct and crystalline cellulose of 88% by mass or more relative to the total mass of the tablet, and a magnesium stearate content of 2 to 4% by mass relative to the total mass of the tablet.

2. The uncoated tablet according to claim 1, wherein the fosravuconazole L-lysine ethanol adduct has a D20 of 75 μm or more and a D50 of 160 μm to 260 μm.

3. A tablet comprising the uncoated tablet described in claim 1 or 2.

4. (1) Fosravuconazole L-lysine ethanol adduct and 0.20-0.31 g / cm³ 3 A method for producing a tablet comprising: (2) mixing crystalline cellulose having a bulk density and a compressibility of 25% or less with magnesium stearate to obtain a mixture; and (3) compressing the mixture to obtain a tablet, wherein the content of fosravuconazole L-lysine ethanol adduct is 58 to 82% by mass relative to the total mass of the tablet, the total content of fosravuconazole L-lysine ethanol adduct and crystalline cellulose is 88% by mass or more relative to the total mass of the tablet, and the content of magnesium stearate is 2 to 4% by mass relative to the total mass of the tablet.

5. The method according to claim 4, wherein the fosravuconazole L-lysine ethanol adduct of step (1) has a D20 of 75 μm or more and a D50 of 160 μm to 260 μm.

6. A method for producing tablets using uncoated tablets obtained by the method described in claim 4 or 5.

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