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

Abstract

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

Description

[Technical Field]

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

[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 none have yet been commercially available, and the development of a practical tablet is desired. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Patent No. 6181044 [Patent Document 2] Patent No. 5058150 [Overview of the Initiative] [Problems that the invention aims to solve]

[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 content uniformity.

[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. [Means for solving the problem]

[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 0.20 to 0.31 g / cm³ 3A tablet having a bulk density and a compressibility of 25% or less, containing fosravuconazole L-lysine ethanol adduct in a quantity of 58-82% by mass relative to the total mass of the tablet, with 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 containing 2-4% by mass of magnesium stearate relative to the total mass of the tablet. [2] The uncoated 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 uncoated tablet described in [1] or [2] above. [4] (1) Fosravuconazole L-lysine ethanol adduct and 0.20~0.31 g / cm³ 3 A step of obtaining a mixture by mixing crystalline cellulose having a bulk density and a compressibility of 25% or less with magnesium stearate, (2) A step of compressing the mixture to obtain a tablet, A method for producing uncoated tablets containing the following, wherein the content of fosravuconazole L-lysine ethanol adduct is 58 to 82% by mass relative to the total mass of the uncoated tablets, 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 uncoated tablets, and the content of magnesium stearate is 2 to 4% by mass relative to the total mass of the uncoated tablets. [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 tablets using uncoated tablets obtained by the method described in [4] or [5] above. [Effects of the Invention]

[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. [Modes for carrying out the invention]

[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 content of fosravuconazole L-lysine ethanol adduct of 58-82% 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 2-4% 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 mono[(2S)-2,6-diaminohexanoic acid monoethanol adduct] and has the structure shown by the following formula.

[0014] JPEG0007844804000001.jpg44146

[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 tablet of the present invention, the content of hosrabconazole L-lysine ethanol adduct is 58 to 82% by mass, preferably 60 to 80% by mass, and more preferably 65 to 75% by mass based on the total mass of the core tablet. 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, and more preferably 160 μm to 200 μm. Also, D50 is preferably 160 μm to 260 μm, and more preferably 210 μm to 240 μm. The particle size distribution can be measured by a laser diffraction / scattering particle size distribution measuring device.

[0018] The crystalline cellulose used in the present invention has a compressibility of 25% or less. Compressibility can be used as a measure of the fluidity of crystalline cellulose. The smaller the 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] Compressibility is calculated using the following formula based on the fluidity of powders in the 18th revised Japanese Pharmacopoeia, reference information. Compressibility (%) = (ρ tapped - ρ bulk ) / ρ tapped ×100 ρ bulk: Bulk density (g / cm 3 ) ρ tapped : Tap density (g / cm 3 )

[0020] The crystalline cellulose used in the present invention has a bulk density of 0.20 to 0.31 g / cm 3 . By using crystalline cellulose having a bulk density within the above range, the physical properties of the obtained tablets can be improved while maintaining high content uniformity. The bulk density can be measured by the method described in the section of "Crystalline Cellulose" in the 18th revised Japanese Pharmacopoeia.

[0021] Crystalline cellulose having a degree of compression and bulk density within the above range is commercially available. Examples include Ceolus (registered trademark) UF-711, PH-101, etc. manufactured by Asahi Kasei Corporation.

[0022] Crystalline cellulose is contained in an amount such that the total content with phospholuboconazole L-lysine ethanol adduct is 88% by mass or more, preferably 90% to 98% by mass, more preferably 92% to 97% by mass based on the total mass of the tablets. By adjusting the amount of crystalline cellulose within the above range, the balance between content uniformity and the physical properties of the tablets can be maintained at a high level.

[0023] In the tablets of the present invention, magnesium stearate is contained in an amount of 2% to 4% by mass based on the total mass of the tablets. By adjusting the amount of magnesium stearate within the above range, it is possible to obtain tablets having good physical properties while suppressing tableting problems.

[0024] The tablets may contain other additives as long as the effects of the present invention are not impaired. Examples of the additives include excipients, disintegrants, binders, stabilizers, lubricants, fluidizing agents, coloring agents, fragrances, flavoring agents, antioxidants, etc. Any additive that can be used in the pharmaceutical field can 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, acacia gum, 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, sodium starch glycolate, 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, sodium carboxymethylcellulose, 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, magnesium-aluminum 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, for example, lysine, ornithine, histidine, and arginine. Lysine and arginine are preferred, and arginine is more preferred.

[0032] Specific examples of basic polymers include aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, and ethylcellulose.

[0033] Examples of lubricants include stearic acid, calcium stearate, sodium lauryl sulfate, glyceryl monostearate, glyceryl palmitostearate, sodium stearyl fumarate, sucrose fatty acid esters, zinc stearate, talc, carnauba wax, L-leucine, and macrogol. Two or more of these may be used in combination.

[0034] Examples of fluidizing agents include hydrated silicon dioxide, light anhydrous silicic acid, heavy anhydrous silicic acid, and synthetic aluminum silicate, and one or more of these can be used.

[0035] Examples of coloring agents include titanium dioxide, yellow ferric oxide, ferric oxide, riboflavin, Yellow No. 4, Yellow No. 5, Red No. 2, Red No. 3, and Red No. 102, and one or more of these can be used.

[0036] Examples of fragrances include lemon oil, orange oil, cinnamon oil, fennel oil, peppermint oil, vanillin, ethyl vanillin, l-menthol, dl-camphor, lavender oil, peppermint oil, vanilla flavor, and fruit flavor, and one or more of these may be used.

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

[0038] Examples of antioxidants include sodium ascorbate, L-cysteine, sodium sulfite, tocopherol, and soy lecithin, and one or more of these can be used.

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

[0040] There are no particular restrictions on the means of compression molding, and conventionally known equipment such as rotary tablet presses and single-stroke 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, and more preferably 700 to 900 kg. The shape of the punch used for compression molding is preferably circular, and more preferably flat. The rotation speed of the tablet press is preferably 20 to 40 rpm, and more preferably 25 to 35 rpm.

[0041] The uncoated tablets of the present invention exhibit excellent content uniformity. Content uniformity can be expressed by measuring the fosravuconazole L-lysine ethanol adduct content in each of 10 uncoated tablets obtained by compression molding from the same raw material using ultraviolet-visible spectrophotometric measurement, and calculating a judgment value according to the content uniformity test of the Formulation Uniformity Test Method of the 18th edition of the Japanese Pharmacopoeia. Desirable content uniformity of the uncoated tablets is a judgment value of less than 8, more preferably less than 5, and even more preferably less than 3.

[0042] The tablets of the present invention possess excellent physical properties. Specifically, they have high hardness and low abrasion resistance, and are resistant to peeling.

[0043] Hardness can be measured individually using a tablet hardness tester (DR.SCHLEUNIGER Tablet Tester 8M) and expressed as the average value of 10 tablets. In practical terms, a hardness of 3 kgf or higher is desirable, and more preferably 5 kgf or higher.

[0044] The degree of abrasion can be determined by measuring the mass (Wa) of 20 uncoated tablets, placing them in a tablet abrasion tester, rotating them at 25 rpm for 4 minutes, removing any fine powder adhering to the tablets, and measuring the mass (Wb) again. The degree of abrasion is then expressed as the mass percentage of the mass loss due to rotation (Wa-Wb) relative to the mass before rotation (Wa). In practice, a degree of abrasion of 0.7% or less is desirable, and 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 comprises (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. [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] [Table 1]

[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 polybag 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 240 mg per tablet).

[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 polybag 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 240 mg per tablet).

[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 polybag 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 240 mg per tablet).

[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 polybag 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 240 mg per tablet).

[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 polybag 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 240 mg per tablet).

[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 polybag 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 240 mg per tablet).

[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 polybag 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 240 mg per tablet).

[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 polybag 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 240 mg per tablet).

[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 fosravuconazole L-lysine ethanol adduct content in each tablet was measured using 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 Edition of the 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] <Tablet compression malfunction confirmed> The surface of the tablets was visually inspected immediately after manufacturing to evaluate whether or not there were any defects in tableting.

[0071] <Hardness measurement> Immediately after manufacturing the uncoated tablets, the hardness of each tablet 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] <Abrasion Measurement> 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] <Peel test> Twenty uncoated tablets were placed in a tablet abrasion tester and rotated at 25 rpm for 15 minutes. The number of tablets that had peeled off was then counted.

[0074] <Evaluation of physical properties> Tablet properties were evaluated as follows: ○ if the hardness was 3 kgf or higher, the abrasion rate was 0.7% or lower, 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] [Table 2]

[0077] [Table 3]

[0078] [Table 4]

[0079] [Table 5]

[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 polybag 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 240 mg per tablet).

[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 polybag 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 240 mg per tablet).

[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 polybag 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 240 mg per tablet).

[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] [Table 6]

[0086] [Table 7]

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

[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 polybag 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 240 mg per tablet).

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

[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 polybag 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 240 mg per tablet).

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

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

[0094] The uncoated tablets of Examples 7-9 and Comparative Examples 6-8 were evaluated in the same manner as 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] [Table 8]

[0096] [Table 9]

[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. Note that for 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. [Industrial applicability]

[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 is a tablet formed 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 step of obtaining a mixture by mixing crystalline cellulose having a bulk density and a compressibility of 25% or less with magnesium stearate, (2) A step of compressing the mixture to obtain a tablet, A method for producing uncoated tablets containing the following, wherein the content of fosravuconazole L-lysine ethanol adduct is 58 to 82% by mass relative to the total mass of the uncoated tablets, 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 uncoated tablets, and the content of magnesium stearate is 2 to 4% by mass relative to the total mass of the uncoated tablets.

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 a tablet obtained by the method described in claim 4 or 5.

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