Solid preparation containing tofogliflozin and method for producing same

Abstract

To provide a method for producing a pharmaceutical composition which is a tablet containing tofogliflozin as an active ingredient and having improved disintegration and dissolution properties.SOLUTION: Mixing an additive and tofogliflozin to prepare a powder mixture, and obtaining a tablet from the powder mixture by direct compression, wherein the additive comprises one or more excipients.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to tofogliflozin, a spiroketal derivative of 1,1-anhydride. 1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]- The present invention relates to a solid preparation containing [[beta]-D-glucopyranose] and a method for producing the same. [Background technology]

[0002] Spiroketal derivatives having a specific structure have been found to be useful in the prevention or treatment of diabetes. For example, WO2006 / 080421 (Patent Document 1-2) 1) contains the formula (I)

[0003] [ka] The compound represented by the formula: Generic name: Tofogliflozin (chemical name: 1,1-anhydro-1-C-[5 -(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-β-D-glucan This compound has been shown to have excellent SGLT2 inhibitory activity. It is stated that:

[0004] In addition, WO2009 / 154276 (Patent Document 2) discloses a compound represented by formula (I). Hydrate crystals, sodium acetate co-crystals and potassium acetate co-crystals are disclosed. The hydrate crystal (hereinafter referred to as type I crystal) has a powder X-ray diffraction pattern of 3.5°, 6.9°, 10.4°, 13.8°, 16.0°, 17.2°, 18.4°, 20.8° It has been reported that the compound has peaks at diffraction angles (2θ) of approximately 21.4°, 24.4°, and 25.4°. Furthermore, the document states that the sodium acetate cocrystal has the following powder X-ray diffraction pattern: 4.9°, 8.7°, 9.3°, 11.9°, 12.9°, 14.7°, 16.0°, 1 Diffraction angles (2θ) around 7.1°, 17.7°, 19.6°, 21.6°, and 22.0° ) and the potassium acetate cocrystal has a peak at 5.0°, 10.0°, 10.4°, 12.4°, 14.5°, 15.1°, 19.0° , and has peaks at diffraction angles (2θ) around 20.1°, 21.4°, and 25.2°. It is stated that:

[0005] In addition, WO2012 / 115249 (Patent Document 3) discloses a compound represented by formula (I). This monohydrate crystal (hereinafter referred to as type II crystal) is powder. In the X-ray diffraction pattern, 4.0°, 7.5°, 10.8°, 12.7°, 14.0° , diffraction angles around 14.7°, 18.0°, 18.8°, 19.5°, and 22.7° ( 2θ)。Furthermore, the document states that The acetone-water solvated crystal (hereinafter referred to as type III crystal) was found to have the same structure as the acetone-water solvated crystal in the powder X-ray diffraction pattern. The diffraction angles around 11.0°, 12.3°, 19.2°, 20.2° and 21.6° ( 2θ).

[0006] In preparations containing low-melting point drugs, the quality may be significantly reduced due to the melting of the drug during storage at high temperatures. This can be problematic, as the dissolution of the drug can cause aggregation in powders and granules. Even in the case of tablets, there is a risk of drug seepage, spots, discoloration, etc. due to drug melting during storage, and drug adhesion during tableting. The problem is that the tablet melts and sticks to the tablet press. In Patent Document 4, the seepage of low-melting-point substances and the aggregation of powder particles during high-temperature storage are prevented. As a means of dealing with tableting problems such as sticking, calcium silicate and aluminum hydroxide Granulation of low-melting point drugs with adsorption carriers such as mina magnesium and synthetic hydrotalcite In Japanese Patent Laid-Open No. 10-287561, low-melting ibuprofen is mixed with calcium silicate. Solid preparations obtained by adsorbing sodium to porous excipients such as sodium hydroxide and light anhydrous silicic acid have been reported. It is being done.

[0007] In Japanese Patent Laid-Open No. 56-145214 (Patent Document 6), a low-melting substance is stabilized with silicic acid. By adding this, the eutectic point is raised and melting is suppressed, which reduces the variation in the content within a tablet. Also disclosed is a tablet in which changes in dissolution, hardness, etc. are suppressed. In Patent Document 7, a low-melting substance is mixed with and adsorbed onto calcium silicate to prevent punch adhesion. In Japanese Patent Laid-Open No. 2000-239185 (Patent Document 8), a light solid preparation is disclosed. Granulated using high-quality anhydrous silicic acid, it reduces the impact of punch adhesion and irritating components (bitterness, etc.) In JP-A-2005-104934 (Patent Document 9), a low melting point material is described. By mixing and melting calcium silicate in advance, the amount of calcium silicate in one tablet is reduced. The document describes a composition that prevents variations in the content of the compound and extension of the disintegration time (and also improves shelf life).

[0008] From a manufacturing perspective, tablets are either manufactured by compressing a pharmaceutical product into a certain shape (compressed formulation) or Or, the pharmaceutical mixture wetted with a solvent is formed into a certain shape or poured into a certain mold. Compressed preparations are the most widely produced dosage form. Typical methods for producing compressed formulations include direct powder compression (direct blend tableting). The direct compression method involves mixing the powder of the drug and the additives and compressing it as is. This is the most economical method with the fewest number of steps. It has some drawbacks, such as being difficult to assemble, the surface easily becoming powdery, and unevenness between and within tablets. The wet granulation method is a method in which drugs and additives are granulated using a wet method and then compressed into tablets. The number of steps is However, it is easy for the drug to be dispersed uniformly in the tablet, and the surface of the poorly water-soluble drug is made hydrophilic. By treating with a binder, the dissolution rate is improved, the tablet hardness is increased, and the powder on the tablet surface is reduced. This method has many advantages, such as suppressing oxidation, and is widely used (Non-Patent Document 1). [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication WO2006 / 080421 [Patent Document 2] International Publication WO2009 / 154276 [Patent Document 3] International Publication WO2012 / 115249 [Patent Document 4] Patent Publication No. 2006-160730 [Patent Document 5] Patent Publication No. 10-287561 [Patent Document 6] Patent Publication No. 56-145214 [Patent Document 7] Patent Publication No. 63-243034 [Patent Document 8] Patent Publication No. 2000-239185 [Patent Document 9] Patent Publication No. 2005-104934 [Non-patent literature]

[0010] [Non-Patent Document 1] Learning the Science of Pharmaceutical Formulation from the Basics, edited by Keiji Yamamoto, Elsevier Japan, 2008.12.05, pp.126-129 Summary of the Invention [Problem to be solved by the invention]

[0011] As a pharmaceutical product of tofogliflozin, a low-melting compound (the melting point of type I crystal is approximately 71°C) There have been no reports of available solid formulations. When we investigated the manufacturing of solid formulations of Liflozin, we found that the general manufacturing method and formulation did not provide sufficient disintegration and It was revealed that solid preparations with insufficient dissolution properties were obtained.

[0012] The present invention has been made in view of the above circumstances, and its object is to provide a pharmaceutical composition having a high disintegration property and a high dissolution property. The object of the present invention is to provide a solid preparation containing tofogliflozin having improved properties. [Means for solving the problem]

[0013] The present inventors have discovered a compound containing tofogliflozin and one or more excipients, one or more disintegrants and / or By directly mixing and compressing one or more lubricants into tablets, disintegration and dissolution properties are improved. In addition, by limiting the amount of calcium silicate added to a certain weight ratio, disintegration and It was found that the dissolution properties were improved.

[0014] The present invention is based on such findings and specifically provides the following [1] to

[27] . do. [1] A powder mixture of one or more excipients and tofogliflozin is directly mixed and compressed into tablets. It is a tablet containing tofogliflozin as an active ingredient, and the additives include one or more excipients. A pharmaceutical composition comprising: [2] The excipient is corn starch, potato starch, wheat starch, or rice starch. Punch, partially pregelatinized starch, pregelatinized starch, lactose hydrate, fructose, glucose , mannitol, anhydrous calcium hydrogen phosphate, crystalline cellulose and precipitated calcium carbonate The pharmaceutical composition according to [1], wherein the pharmaceutical composition is selected from the group consisting of: [3] The pharmaceutical composition according to [1] or [2], wherein the additive further comprises one or more disintegrants. thing. [4] Disintegrants include sodium starch glycolate, carboxymethylcellulose, and Carboxymethylcellulose calcium, carboxymethyl starch sodium, croscarmellose Lumellose sodium, crospovidone, low-substituted hydroxypropyl cellulose and hyaluronic acid The pharmaceutical composition according to [3], wherein the compound is selected from the group consisting of hydroxypropyl starch. [5] The pharmaceutical composition according to any one of [1] to [4], wherein the additive further comprises one or more lubricants. Pharmaceutical composition. [6] Lubricants include magnesium stearate, calcium stearate, talc, and sucrose.

[0033] selected from the group consisting of fatty acid esters, sodium stearyl fumarate, and hydrogenated oils; 5] The pharmaceutical composition described in [7] The pharmaceutical composition according to any one of [1] to [6], which is substantially free of calcium silicate. composition. [8] The tofogliflozin is a type I crystal, a type II crystal, a type III crystal, or sodium acetate. [1]~[7] The pharmaceutical composition according to any one of the preceding claims. [9] The tofogliflozin is a type I crystal, a type II crystal, an amorphous form, or a mixture thereof. The pharmaceutical composition according to [8],

[10] The weight ratio of the active ingredient, tofogliflozin, to the total composition is 2.5 to 40% by weight. %. The pharmaceutical composition according to any one of [1] to [9].

[11] Any of [5] to

[10] , wherein the lubricant content is less than 4.0% by weight of the total composition. The pharmaceutical composition described in

[12] The excipients make up 20 to 80% by weight of the total composition, and the disintegrant makes up 1.0 to 4.0% of the total composition. 0% by weight of the pharmaceutical composition according to any one of [3] to

[11] .

[13] The additives include a filler, a disintegrant, and a lubricant, and the filler is lactose hydrate and a disintegrant. The disintegrant is croscarmellose sodium, the lubricant is hydrogenated oil, Magnesium stearate or a mixture thereof, [1] to

[12] The pharmaceutical composition described.

[14] A method for producing a pharmaceutical composition that is a tablet containing tofogliflozin as an active ingredient And mixing the excipients and tofogliflozin to prepare a powder mixture; and obtaining tablets from the powder blend by direct blend tableting; wherein the additive comprises one or more excipients.

[15] The excipient is corn starch, potato starch, wheat starch, or comedo Starch, partially pregelatinized starch, pregelatinized starch, lactose hydrate, fructose, grapes Sugar, mannitol, anhydrous calcium hydrogen phosphate, crystalline cellulose and precipitated calcium carbonate The method according to

[14] , wherein the compound is selected from the group consisting of:

[16] The method according to

[14] , wherein the additive further comprises one or more disintegrants.

[17] The disintegrant is sodium starch glycolate, carboxymethylcellulose, Carboxymethylcellulose calcium, carboxymethyl starch sodium, cross Carmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose and The method according to

[16] , wherein the starch is selected from the group consisting of hydroxypropyl starch.

[18] The composition according to any one of

[14] to

[17] , wherein the additive further comprises one or more lubricants. The manufacturing method described above.

[19] Lubricants include magnesium stearate, calcium stearate, talc, and sugar. selected from the group consisting of sugar fatty acid esters, sodium stearyl fumarate, and hydrogenated oils;

[18] The manufacturing method described in

[18] .

[20] Substantially free of calcium silicate, as described in any of

[14] to

[19] Manufacturing method.

[21] The tofogliflozin is a type I crystal, a type II crystal, a type III crystal, or sodium acetate. The method for producing the crystalline ammonium hydroxide solution according to any one of

[14] to

[0020] , wherein the crystalline ammonium hydroxide solution is a co-crystal of ammonium hydroxide, a co-crystal of potassium acetate, an amorphous substance, or a mixture thereof.

[22] The tofogliflozin is a type I crystal, a type II crystal, an amorphous form, or a mixture thereof. The manufacturing method according to

[21] , wherein the product is a

[23] The weight ratio of the active ingredient, tofogliflozin, to the total composition is 2.5 to 40% by weight. %. The method according to any one of

[14] to

[22] .

[24] Any of

[18] to

[23] , wherein the lubricant is less than 4.0% by weight of the total composition. The manufacturing method described above.

[25] The excipients make up 20 to 80% by weight of the total composition, and the disintegrant makes up 1.0 to 4.0% of the total composition. 0% by weight.

[26] The additives are lactose hydrate, crystalline cellulose, croscarmellose sodium, and and hydrogenated oil and / or magnesium stearate,

[14] to

[25] The manufacturing method described above.

[27] The active ingredient is tofogliflozin, lactose monohydrate, crystalline cellulose, and croscalin. A solid containing sodium mellose and hydrogenated oil and / or magnesium stearate formulation.

[28] The solid formulation according to

[27] , wherein the dosage form is selected from tablets, capsules, and granules.

[0015] Any combination of one or more of the above-described aspects may be realized based on the common technical knowledge of a person skilled in the art. It will be understood by those skilled in the art that the invention includes any of the above unless it is technically inconsistent. [Effects of the Invention]

[0016] According to the present invention, a solid preparation having improved disintegration and dissolution properties is provided. By reducing the weight ratio of calcium silicate as an additive to the formulation, disintegration and dissolution properties are improved. By utilizing the method of the present invention, the active ingredient can be rapidly released into the body. It has become possible to provide solid dosage forms for the purpose of releasing the drug. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 is a graph showing the relationship between tablet hardness and disintegration time for direct mix tableting and wet granulation when the active ingredient, tofogliflozin hydrate (type I crystal), is contained in an amount of 20% by weight (Test Example 2). [Figure 2] Factor analysis was performed using quality engineering (Taguchi method, L18) using the f2 function values ​​obtained in Test Example 8. A factor effect diagram is shown based on the level conditions (formulation conditions) listed in Table 6. [Figure 3] FIG. 1 is a graph showing the relationship between disintegration time and compression pressure for initial and accelerated tablets produced by direct mix tableting when the active ingredient, tofogliflozin hydrate (type I crystals), is contained at 40% by weight (Test Example 1). [Figure 4]FIG. 1 is a graph showing the relationship between disintegration time and tableting pressure for initial and accelerated tablets produced by a wet granulation method when the active ingredient, tofogliflozin hydrate (type I crystals), is contained at 40% by weight (Test Example 1). DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention provides a tablet formulation comprising a powder mixture of one or more excipients and tofogliflozin, which is directly mixed and compressed into tablets. The resulting tablet contains tofogliflozin as an active ingredient and the additives include one or more excipients. The present invention relates to a pharmaceutical composition containing the compound or a method for producing the same.

[0019] "Tofogliflozin" in the present invention refers to 1,1-anhydro-1-C-[5-(4 -(2-(hydroxymethyl)phenyl)-β-D-glucopy It is commonly known as ranose and is a compound represented by formula (1).

[0020] [ka]

[0021] The "excipient" in the present invention includes sugars (e.g., lactose, lactose hydrate, fructose, glucose, etc.). etc.), sugar alcohols (e.g., mannitol, etc.), starch (corn starch , potato starch, wheat starch, rice starch, partially pregelatinized starch, alpha cellulose (e.g., crystalline cellulose), inorganic salts (e.g., silica more specific examples include calcium carbonate, anhydrous calcium hydrogen phosphate, precipitated calcium carbonate, etc. These include corn starch, potato starch, wheat starch, rice starch, and partial alginate. Perfluoro starch, pregelatinized starch, lactose hydrate, fructose, glucose, mannitol Examples include anhydrous calcium hydrogen phosphate, crystalline cellulose, and precipitated calcium carbonate. Preferably, lactose, crystalline cellulose, etc. are used.

[0022] The "disintegrant" in the present invention is, for example, starch, sodium glycolate, carboxylate, Dimethylcellulose, carboxymethylcellulose calcium, carboxymethyl starch Sodium croscarmellose, crospovidone, low-substituted hydroxypropyl hydroxypropyl cellulose and hydroxypropyl starch. Examples include scalmellose sodium.

[0023] The "lubricant" in the present invention is, for example, magnesium stearate, calcium stearate, sodium, talc, sucrose fatty acid ester and sodium stearyl fumarate, hydrogenated oil, etc. Preferred examples include magnesium stearate and hydrogenated oil.

[0024] In addition to the above ingredients, the solid preparation of the present invention may contain commonly used binders, lubricating colorants, flavoring agents, etc. Flavoring agents, and if necessary stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, It may contain preservatives, antioxidants, etc. These are generally used as raw materials for solid preparations. It can be formulated by combining ingredients that can be used.

[0025] The "additive" in the present invention includes, for example, an excipient, a disintegrant, a lubricant, a binder, a lubricant colorant, , flavoring agents, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants This refers to ingredients that are generally used as raw materials for solid dosage forms, such as dispersants.

[0026] As used herein, the term "solid preparation" refers to, for example, tablets, powders, fine granules, granules, coated tablets, Examples of dosage forms include capsules, dry syrups, lozenges, and suppositories. The term "solid preparation" refers to the shape of a pharmaceutical product or the like. is preferably in the form of capsules, tablets or granules, more preferably in the form of capsules. These are ingredients commonly used in the pharmaceutical field, and are preferably in the form of tablets. There are no particular limitations on the form, etc., as long as it has a normal shape and size.

[0027] The hardness of the tablets can be adjusted by the type of additives used in tablet preparation and the tableting pressure. The tableting pressure when molding the pharmaceutical composition of the present invention is, for example, 5 to 20 kN, specifically The force is 6.5 to 18.5 kN, more specifically 8 to 12 kN. The hardness of the tablet in this case is, for example, 20 to 200 N, specifically 30 to 150 N, more specifically The force is 50 to 100N.

[0028] Coloring agents used are those permitted to be added to pharmaceuticals. Examples of agents used include cocoa powder, mint, aromatic powder, peppermint oil, borneol, and cinnamon powder.

[0029] These tablets and granules may be coated with sugar or other suitable coatings as needed. Furthermore, when producing liquid preparations such as syrups and injection preparations, The compound or its pharmacologically acceptable salt may be added with a pH adjuster, a solubilizer, an isotonicity adjuster, etc., if necessary. If necessary, a solubilizing agent, a stabilizer, etc. are added to prepare the formulation.

[0030] The "form I crystal" in the present invention is a monohydrate crystal of the compound represented by formula (I), This monohydrate crystal exhibits the following peaks in the powder X-ray diffraction pattern: 3.5°, 6.9°, 10.4° , 13.8°, 16.0°, 17.2°, 18.4°, 20.8°, 21.4°, and It is described that the compound has a peak at a diffraction angle (2θ) of about 24.4°. (Patent Document 2).

[0031] The "type II crystal" in the present invention is a monohydrate crystal of the compound represented by formula (I). The monohydrate crystal exhibited the following X-ray powder diffraction patterns: 4.0°, 7.5°, 10.8° °, 12.7°, 14.0°, 14.7°, 18.0°, 18.8°, 19.5°, and It is described that the chromatic aberration is characterized by having a peak at a diffraction angle (2θ) of about 22.7°. (Patent Document 3).

[0032] The "form III crystal" in the present invention is a crystal of the compound represented by formula (I) in an acetone-water solvent. The powder X-ray diffraction pattern shows the angles of 11.0°, 12.3°, 19.2°, It is reported that it has peaks at diffraction angles (2θ) around 20.2° and 21.6°. (Patent Document 3).

[0033] In the present invention, the "sodium acetate co-crystal" refers to a sodium acetate co-crystal of the compound represented by formula (I). The powder X-ray diffraction pattern shows the angles of 4.9°, 8.7°, 9.3°, 11.9°, 12.9°, 14.7°, 16.0°, 17.1°, 17.7°, 19.6 It is characterized by having peaks at diffraction angles (2θ) of around 21.6°, 22.0°, and 23.0°. It is described that this is the case (Patent Document 2).

[0034] In the present invention, the "potassium acetate co-crystal" refers to a potassium acetate co-crystal of the compound represented by formula (I). The powder X-ray diffraction pattern shows the following: 5.0°, 10.0°, 10.4°, 12.4°, 14.5°, 15.1°, 19.0°, 20.1°, 21.4°, and 2 It is described that it has a peak at a diffraction angle (2θ) of around 5.2° (Patent Document 2).

[0035] Tofogliflozin used in the solid preparation of the present invention is a type I crystal, a type II crystal, or a type I crystal. Form II crystal, sodium acetate co-crystal, potassium acetate co-crystal, amorphous, or a mixture thereof It is more preferable that the tophogly used in the solid preparation is selected from the group consisting of: Flozin is selected from the group consisting of type I crystals, type II crystals, amorphous, and mixtures thereof. More preferably, tofogliflozin used in a solid formulation is a type I crystal. The crystalline form ratio of tofogliflozin was measured by NRI, solid-state NMR, and powder X-ray diffraction. It can be determined by X-ray diffraction or Raman spectroscopy, for example.

[0036] The solid preparation of the present invention contains, in addition to tofogliflozin and one or more excipients, one or more The mixture is produced by directly mixing and compressing the above disintegrant and / or one or more lubricants. The present invention further provides a pharmaceutical composition comprising tofogliflozin and one or more excipients, one or more disintegrants, and and / or a method for producing a solid formulation containing one or more lubricants by direct mix tableting.

[0037] In the present invention, "direct mixing tableting" refers to mixing the powders of the active ingredient and the additives and compressing them as they are. "Wet granulation" is a method of granulating drugs and additives using a wet method. The granulated material can be compressed into tablets. After mixing the additives, spray water directly onto the powder or apply a paste-like water-soluble paste with the binder dissolved or dispersed. This method involves pouring liquid over the material to produce granular particles.

[0038] The tableting pressure during tablet production is adjusted appropriately depending on the ingredients contained in the tablet and the desired tablet hardness. The hardness of the tablet depends on the type of additives used in tablet preparation and the tableting pressure. The tableting pressure when molding the pharmaceutical composition of the present invention can be adjusted, for example, from 5 to 20 kJ. N, specifically 6.5 to 18.5 kN, more specifically 8 to 12 kN. The hardness of the tablet in the pharmaceutical composition of the present invention is, for example, 20 to 200 N, specifically 30 to 150 N, more specifically 50 to 100N.

[0039] The dosage of the solid preparation of the present invention is determined based on the severity of symptoms, age, sex, weight, dosage form, salt type, etc. The type can be appropriately selected depending on the type of drug, the specific type of disease, etc.

[0040] In the present invention, "substantially free of calcium silicate" means that the calcium silicate in the solid preparation is The weight ratio of calcium carbonate is preferably less than 2.5% or less than 2.0%. It refers to the production of a solid preparation by mixed tableting, and more preferably, the production of silicic acid in the solid preparation. Calcium weight ratio is less than 1.75%, less than 1.5%, less than 1.25%, less than 1.0% or This refers to the manufacture of solid preparations by direct blending and tableting so that the content of soluble solids is less than 0.75%.

[0041] In a non-limiting embodiment of the present invention, in addition to calcium silicate, light anhydrous silicic acid, Hydrous silicon dioxide, calcium silicate, magnesium alumina hydroxide, synthetic aluminum silicate The compound essentially contains magnesium, synthetic hydrotalcite, or magnesium aluminometasilicate. It is preferable that the ion exchange layer is not formed, but the present invention is not limited to this.

[0042] In the present invention, the "weight ratio" refers to the weight of the active ingredient or the weight of the additive relative to the weight of the entire preparation. This is a comparison of the above.

[0043] In one embodiment of the present invention, the weight ratio of tofogliflozin in the solid preparation is 1.0% by weight to 80% by weight. Weight%, 1.0wt%~70wt%, 1.0wt%~60wt%, 1.0wt%~50wt %, 2.5% by weight to 40% by weight, 10% by weight to 40% by weight, or 20% by weight to 40% by weight Preferably, but not exclusively, the formulation is prepared using tofogliflozin hydrate. In this case, the weight ratio of tofogliflozin contained in the hydrate can be Calculated based on the weight of the gin.

[0044] From the viewpoint of preventing tableting problems, the weight ratio of tofogliflozin in the solid dosage form should be 60% by weight or more. Preferably, the content is 50% by weight or less, 40% by weight or less, 30% by weight or less, or 20% by weight or less. In addition, 1.0% by weight or more, 2.5% by weight or more, or 5.0% by weight or more is preferable, but is not limited to these. It is not possible.

[0045] In one embodiment of the present invention, the weight ratio of the excipient in the solid preparation is 5.0% by weight to 95% by weight, 1. 0% to 90% by weight, 15% to 85% by weight, or 20% to 80% by weight is preferred However, the present invention is not limited to this.

[0046] In one embodiment of the present invention, the total weight ratio of lactose hydrate and microcrystalline cellulose in the solid preparation is 5 0% to 95% by weight, 10% to 90% by weight, 15% to 85% by weight, or 20% by weight The amount is preferably 80% by weight to 80% by weight, but is not limited to this.

[0047] In one embodiment of the present invention, the weight ratio of the disintegrant in the solid preparation is 50% by weight or less, 30% by weight or less Bottom, 20% by weight or less, 10% by weight or less, 8.0% by weight or less, 6.0% by weight or less, 4.0% by weight % or less, 2.0% by weight or less, or 1.0% by weight or less is preferred, but is not limited thereto. stomach.

[0048] In one embodiment of the present invention, the weight ratio of croscarmellose in the solid preparation is 10% by weight or less, 8.0% by weight or less, 6.0% by weight or less, 4.0% by weight or less, 2.0% by weight or less, or 1.0% by weight or less % or less, and 0.1% by weight or more or 0.5% by weight or more is preferred, but is not limited thereto. It is not possible.

[0049] In one embodiment of the present invention, the weight ratio of the lubricant in the solid preparation is less than 20% by weight, less than 10% by weight. less than 8.0% by weight, less than 6.0% by weight, less than 5.0% by weight, less than 4.0% by weight, less than 3.0% by weight It is preferable that the content is less than 2.0% by weight, and more preferably 0.1% by weight or more, 0.5% by weight or more, or The amount is preferably 1.0% by weight or more, but is not limited to this.

[0050] In one embodiment of the present invention, the total weight of hydrogenated oil and magnesium stearate in the solid preparation The ratio is less than 10% by weight, less than 8.0% by weight, less than 6.0% by weight, less than 5.0% by weight, and less than 4.5% by weight. %, less than 4.0% by weight, less than 3.5% by weight, less than 3.0% by weight or less than 2.5% by weight is preferred. Preferably, the content is 0.1% by weight or more, 0.5% by weight or more, 1.0% by weight or more, or 1.5% by weight or more. is preferred, but is not limited to this.

[0051] In one non-limiting embodiment of the present invention, the active ingredient tofogliflozin is 20% by weight, Sugar hydrate 55% by weight, crystalline cellulose 20% by weight, croscarmellose sodium It contains 2% by weight of cereals, and 3% by weight of hydrogenated oil and magnesium stearate. Tablets are provided.

[0052] As used herein, the term "and / or" when describing combinations of additives The meaning includes any combination of "and" and "or" as appropriate. For example, "fillers, disintegrants and / or lubricants" includes variations of the following additives: be wrapped in; (a) excipients, (b) disintegrants, (c) lubricants, (d) excipients and disintegrants, (e) excipients and (f) disintegrants and lubricants; (g) excipients, disintegrants and lubricants.

[0053] Any combination of one or more of the aspects described in this specification is within the common general technical knowledge of a person skilled in the art. It is understood by those skilled in the art that the invention is included in the present invention unless there is a technical contradiction based on the above. .

[0054] All prior art documents cited in this specification are hereby incorporated by reference. It can be put in. [Example]

[0055] Comparative example 1 (wet granulation method, tofogliflozin hydrate concentration = 40%) The formulation and amount of tofogliflozin hydrate (type I crystal), lactose, and Hydrate, Microcrystalline Cellulose, Low-Substituted Hydroxypropylcellulose and Hydroxypropyl After the pill cellulose was thoroughly mixed in a mortar, 3.5 g of purified water was added and granulation was carried out. The obtained wet powder was sized using a sieve with 710 μm openings, and then heated in an oven at 50°C for 4 hours. Then, the dried powder and magnesium stearate were mixed in a plastic bag to obtain a blended powder. This compound powder was compressed using a static pressure tableting machine at tableting pressures of 500 kgf, 1000 kgf, and 1500 kgf. The tablets were compressed at 2000 kgf and 2000 kgf to produce flat tablets (diameter 7.5 mm, tablet weight 200 mg). Sticking was observed at tableting pressures of 500kgf and 1000kgf, and at 1500kgf At 2000 kgf, slight sticking was observed.

[0056] [Table 1]

[0057] Example 1 (direct blending and compression method, tofogliflozin hydrate concentration = 40%) The formulation and amount of tofogliflozin hydrate (type I crystal), lactose were prepared in the formulation and amount of the preparation in Table 2 below. Hydrate, crystalline cellulose and low-substituted hydroxypropyl cellulose in a V-type mixer. After mixing for 1 minute, magnesium stearate was added and further mixed to obtain a blended powder. This compound powder was compressed using a tableting machine at tableting pressures of 500 kgf, 1000 kgf, 1500 kgf, and 2 The tablets were compressed at 1000 kgf into flat tablets (diameter 7.5 mm, tablet weight 200 mg). Sticking was observed at all tableting pressures.

[0058] [Table 2]

[0059] Test Example 1 (Disintegration test and tablet hardness measurement results for Comparative Example 1 and Example 1) The tablets obtained in Comparative Example 1 and Example 1 were subjected to a disintegration test and tablet hardness measurement. The results are shown in Table 3. There was almost no difference in tablet hardness between the two, but there was a difference in disintegration time In Comparative Example 1, the time was 14.5 to 20.6 minutes, while in Example 1 it was 5.2 to 9. From the above results, it was found that the tofogliflozin hydrate (type I crystal) containing 40% by weight In the production of solid preparations, direct blending tableting is more effective than wet granulation. It was confirmed that the tablets that underwent this treatment had a faster disintegration time despite having the same tablet hardness. It was.

[0060] [Table 3-1]

[0061] [Table 3-2]

[0062] The effects of the tablets obtained in Comparative Example 1 and Example 1 under accelerated conditions (harsh conditions) To evaluate this, the samples were stored at 40°C and 75% RH for 4 hours, and then at 60°C for 2 hours. Samples were prepared and subjected to disintegration tests, and the results are shown in Tables 3-3 and 3-4 and Figures 3 and 4. It was found that the disintegration time of the accelerated product tended to increase in both Comparative Example 1 and Example 1. Because the drug substance is a low-melting compound, the formulation (although stored at a temperature below the melting point) It was presumed that a portion of the drug substance melted during disintegration, causing a delay in disintegration.

[0063] [Table 3-3]

[0064] [Table 3-4]

[0065] Comparative example 2 (wet granulation method, tofogliflozin hydrate concentration = 20%) The formulation and amount of tofogliflozin hydrate (type I crystal), lactose, and Hydrate, Microcrystalline Cellulose, Low-Substituted Hydroxypropylcellulose and Hydroxypropyl After the pill cellulose was thoroughly mixed in a mortar, 5.0 g of purified water was added and granulation was carried out. The obtained wet powder was sized using a sieve with 710 μm openings, and then heated in an oven at 50°C for 4 hours. Then, the dried powder and magnesium stearate were mixed in a plastic bag to obtain a blended powder. This compounded powder was compressed using a static pressure tableting machine at tableting pressures of 300 kgf, 500 kgf, and 1000 kgf. The tablets were compressed into flat tablets (diameter 7.5 mm, tablet weight 200 mg) at 1500 kgf and 1,500 kgf. No sticking was observed at any tableting pressure.

[0066] [Table 4]

[0067] Example 2 (direct blending and compression method, tofogliflozin hydrate concentration = 20%) Tofogliflozin hydrate (Type I), lactose hydrate, and cereals containing tofogliflozin hydrate (Type I) were prepared in the formulation and amounts shown in Table 5 below. The mixture of the cellulose, crystalline cellulose and low-substituted hydroxypropyl cellulose was thoroughly mixed in a V-type mixer. After mixing, magnesium stearate was added and further mixed to obtain a compounded powder. This compound powder was compressed into flat tablets at tableting pressures of 500 kgf, 1000 kgf, and 1500 kgf. (diameter 7.5 mm, tablet weight 200 mg) were compressed into tablets. No sticking was observed.

[0068] [Table 5]

[0069] Test Example 2 (Disintegration test and tablet hardness measurement results for Comparative Example 2 and Example 2) The tablets obtained in Comparative Example 2 and Example 2 were subjected to a disintegration test and tablet hardness measurement. The results are shown in Table 6. The disintegration time was 1.5 to 17.5 minutes in Comparative Example 2. In contrast, it was 0.7 to 2.7 minutes in Example 2. Tablet hardness was 81. In Example 2, the load was 94.4 to 136.3 N. Since differences in tablet hardness were observed between the two, the relationship between hardness and disintegration time was examined for each manufacturing method. The relationship between the hardness and the hardness of the tablets is shown in Figure 1. As a result, even under the same tablet hardness conditions, It was confirmed that the disintegration time was significantly shorter with the granulation method than with the conventional method.

[0070] [Table 6-1]

[0071] [Table 6-2]

[0072] Examples 3 to 9 (direct blending and compression method: investigation of the effect of formulation, drug substance concentration = 20%) The formulation amounts of disintegrants and lubricants, which are generally said to affect the disintegration properties of formulations, were varied. In the following examples, the active ingredient, Tohogu, was used to evaluate its effect on disintegration time. Tofogliflozin hydrate (type I crystals) was added so that the amount of liflozin was the specified amount shown in the table. The weight increase due to the hydrate was calculated by adjusting the amount of lactose hydrate. The weight ratio was adjusted so that the total weight ratio was 100%.

[0073] The formulation and amount of tofogliflozin hydrate (type I crystals), lactose, and hydrate, microcrystalline cellulose and croscarmellose sodium in a rotating container mixer. After mixing, hydrogenated oil and magnesium stearate were added and further mixed to obtain a blended powder. This compounded powder was compressed using a rotary tablet press at tableting pressures of 6 kN, 8 kN, 10 kN, and 12 kN. R tablets (diameter 6.0 mm, tablet weight 100 mg) were compressed at 14 kN and 14 kN. Even at this tableting pressure, no sticking or powdering of the tablet surface was observed.

[0074] [Table 7-1]

[0075] [Table 7-2]

[0076] Test Example 3 (Disintegration test and tablet hardness measurement results for Examples 3 to 9) The tablets obtained in Examples 3 to 9 were subjected to a disintegration test and tablet hardness measurement. The results are shown in Table 8. There was no significant difference in tablet hardness between the formulations, but there was a significant difference in disintegration time. In all examples, the time was within 5 minutes, confirming that the tablets disintegrated quickly. In particular, the total weight ratio of the lubricant, hydrogenated oil and magnesium stearate, was 4.0%. For formulations with a total weight ratio of 4.0% or more (Examples 3, 4, 5, 6, and 8), Compared with the formulations (Examples 7 and 9), the tablets were formed more quickly despite their higher tablet hardness. It was confirmed that it would collapse.

[0077] [Table 8-1]

[0078] [Table 8-2]

[0079] Test Example 4 (Dissolution test results for Examples 3 to 9) A dissolution test was carried out on the tablets obtained in Examples 3 to 9, which were compressed at a tableting pressure of 10 kN. The results are shown in Table 1. 9. In all Examples, 85% or more of tofogliflozin was dissolved within 15 minutes. It was confirmed that the active ingredient was released quickly.

[0080] [Table 9]

[0081] Example 3A (Direct blending tableting method: Investigation of the effect of acceleration on dissolution, drug substance concentration = 20%) To evaluate the effect of acceleration on the 15-minute dissolution rate, the formulations in Tables 9-1 and 9-2 below were used. Tofogliflozin hydrate (type I crystal) was prepared using the same method and amount (preparation formulation as in Example 3). Crystalline cellulose, lactose hydrate, microcrystalline cellulose and croscarmellose sodium are mixed in a rotating container. After thoroughly mixing in a mixer, hydrogenated oil and magnesium stearate are added and further mixed. A compounded powder was obtained. The active ingredient, tofogliflozin, was added in the amount shown in the table. The amount of gliflozin hydrate (type I crystal) was adjusted. The increase in the weight ratio is calculated by adjusting the weight ratio of lactose hydrate so that the total weight ratio becomes 100%. This compounded powder was compressed using a rotary tablet press at tableting pressures of 10 kN, 14 kN, and 1 R tablets (diameter 6.0 mm, tablet weight 100 mg) were compressed at 8 kN. No sticking was observed even under high pressure.

[0082] [Table 9-1]

[0083] [Table 9-2]

[0084] Test Example 4A (Dissolution Test Results of Example 3A) The tablets obtained in Example 3A with tableting pressures of 10 kN, 14 kN, and 18 kN were subjected to 40°C- The tablets were stored in a sealed container at 75% RH and 40°C for 1 month and 3 months, and then a dissolution test was conducted. The results are shown in Table 9-4. In all samples, 85% or more of the tophogliflozin was removed within 15 minutes. It was confirmed that the active ingredient was rapidly released.

[0085] [Table 9-3]

[0086] Examples 10 to 12 (Direct Mixing Tabletting Method: Investigation of the Influence of the Crystalline Form of the Drug Substance, Drug Substance Concentration = 20%) Tofogliflozin hydrate used in manufacturing includes type I crystals, type II crystals, and amorphous It contains three crystalline forms, but the drug substance containing a large amount of each crystalline form is used to make tablets, and the tablets are The effects on the disintegration time and tablet hardness were evaluated. Tofogliflozin hydrate (type I crystal) was added to the specified amount of tofogliflozin shown in the table. The amount of crystalline form II and amorphous form was adjusted to prepare the formulation. The increase in the weight ratio is calculated by adjusting the weight ratio of lactose hydrate so that the total weight ratio becomes 100%. I made it so that.

[0087] The formulation and amounts of tofogliflozin hydrate, lactose hydrate, and granules are shown in Table 10 below. The crystalline cellulose and croscarmellose sodium were thoroughly mixed in a rotary mixer. Then, hydrogenated oil and magnesium stearate were added and further mixed to obtain a blended powder. This compound powder was compressed using a Lee tableting machine at tableting pressures of 6kN, 8kN, 10kN, 12kN, and 14kN. R tablets (diameter 6.0 mm, tablet weight 100 mg) were compressed with N. No sticking was observed in either case.

[0088] [Table 10-1]

[0089] [Table 10-2]

[0090] Test Example 5 (Disintegration test and tablet hardness measurement results for Examples 10 to 12) The tablets obtained in Examples 10 to 12 were subjected to a disintegration test and tablet hardness measurement. The results are shown in Table 11. There was no significant difference in tablet hardness between the formulations. The time required for disintegration was within 5 minutes in all examples, demonstrating that the tablets disintegrated quickly. Confirmed.

[0091] [Table 11-1]

[0092] [Table 11-2]

[0093] Comparative Example 3 (prepared trial formulation based on patent information) Since the melting point of type I crystals of tofogliflozin is approximately 71°C, As described in Test Example 1, there are formulation issues specific to low-melting point compounds in solid preparations. In other words, it was found that the disintegration of the tablet was delayed. Tofogliflozin hydrate (type I crystal) and calcium silicate were mixed with reference to the published patent documents. By mixing these ingredients, we attempted to solve the predicted formulation problems. The amount of tofogliflozin hydrate (type I crystal), lactose hydrate, crystalline cellulose, chloroform Scalmellose sodium and calcium silicate were thoroughly mixed in a V-type blender, and then Magnesium tearate, talc and hardened oil were added and further mixed to obtain a blended powder. , tofogliflozin hydrate so that the active ingredient, tofogliflozin, is present in the specified amount shown in the table. The amount of lactose (type I crystals) added was adjusted. The weight ratio of the hydrate was adjusted so that the total weight ratio was 100%. This compound powder was compressed into R tablets (diameter 6 mm, tablet weight 100 mg) at a tableting pressure of 1000 kgf. The handling (variation in tablet weight), punch adhesion and squeaking were evaluated, and no tableting problems were found. Gender was not recognized.

[0094] [Table 12]

[0095] Test Example 6 (Dissolution Test Results of Comparative Example 3) The tablets obtained in Comparative Example 3 were stored at 50°C and 75% RH for 2 weeks. Dissolution tests were conducted on accelerated samples. The f2 function of the initial tablet and the accelerated tablet was calculated from the dissolution rate at 20 minutes (f2 function If the value is 50 or more, the dissolution properties of the samples before and after acceleration are considered to be equivalent. The results are shown in Table 13. The initial product had an 85% dissolution time of 9.3 minutes, indicating that the active ingredients were rapidly dissolved. On the other hand, the 85% dissolution time of the accelerated product was 39.4 minutes, and It was confirmed that the dissolution of

[0096] [Table 13]

[0097] Samples 1-18 (formulations for investigating the cause of delayed dissolution) Tofogliflozin hydrate (type I crystal) was prepared using the formulations and amounts shown in Tables 14 and 15 below. ), lactose hydrate, microcrystalline cellulose, croscarmellose sodium and calcium silicate After thoroughly mixing the ingredients in a V-type mixer, magnesium stearate, talc and hydrogenated oil were added. The active ingredient, tofogliflozin, was added and further mixed to obtain a blended powder. The amount of tofogliflozin hydrate (type I crystals) added was adjusted so that the amount was The increase in weight ratio due to the lactose hydrate is calculated by adjusting the weight ratio of lactose hydrate so that the total weight ratio is 1 This compounded powder was compressed into tablets at a pressure of 1000 kgf using a single punch tableting machine. Tablets (diameter 6 mm, tablet weight 100 mg) were compressed. Handling (tablet weight variation) The punch adhesion and squeaking were evaluated, but no tableting problems were observed.

[0098] [Table 14-1]

[0099] [Table 14-2]

[0100] [Table 15-1]

[0101] [Table 15-2]

[0102] Test Example 7 (Dissolution test results for samples 1 to 18) The tablets obtained from samples 1 to 18 were compared with the initial product at 50°C-75%RH. Dissolution tests were conducted on accelerated samples stored for 2 weeks. The f2 functions for the initial tablet and the accelerated tablet were calculated from the dissolution rates at 1, 15, and 20 minutes. The results are shown in Table 16. The 85% elution time of the initial product was 7.4 to 12.1 minutes. It was confirmed that the active ingredient was released quickly. On the other hand, the 85% dissolution time of the accelerated product was Between 8.1 and 38.11 minutes, Sample 6, Sample 9, Sample 15, and Sample 1 For 8, the 85% dissolution time was found to exceed 15 minutes. A formulation that significantly delayed dissolution was confirmed.

[0103] [Table 16-1]

[0104] [Table 16-2]

[0105] Test Example 8 To identify the cause of the delayed dissolution, the f2 function value obtained in Test Example 7 was used to perform quality engineering ( Taguchi method, orthogonal array L18:2×3 7 Factor analysis was performed based on the level conditions (preparation). The factors affecting the outcome are shown in Table 17, and the factor effect diagram is shown in Figure 2. In Figure 2, when moving from C1 to C3, It can be seen that the SN ratio (f2 value) decreases as the temperature increases. This shows that the f2 value decreases as the amount of calcium silicate increases. This suggests that this may affect the delayed dissolution after acceleration.

[0106] [Table 17-1]

[0107] [Table 17-2]

[0108] [Reference Example 1] Disintegration test method Using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd.), a specified amount of tablets was dissolved in water in accordance with the procedure specified in the Japanese Pharmacopoeia. The disintegration time of each tablet was measured. The test liquid was water at a temperature of 37±2°C. The average value and standard deviation were calculated from the individual measurement results obtained.

[0109] [Reference Example 2] Tablet hardness measurement method Using a tablet hardness tester (Pharma Test), the hardness of each tablet was measured for a given number of tablets. The hardness of each sample was measured. The average value and standard deviation were calculated from the individual measurement results.

[0110] [Dissolution test method] Using a dissolution tester (Hanson), a specified number of tablets were tested under the following conditions: The test solution was water (900 mL, 37 ± 2°C), and the huddle rotation speed was 50 rpm. pm, sampling time is 2, 5, 10, 15, 20, 30, 60 minutes, sampling The samples were measured by high performance liquid chromatography.

[0111] [How to calculate the f2 function] The f2 function was calculated according to the following formula. The dissolution rates at 5 and 20 minutes were entered and the similarity of the curves between the initial tablet and the accelerated tablet was evaluated. Ta.

[0112]

number

[0113] By using the method of the present invention, a solid preparation for rapid release of a medicinal ingredient can be provided. It became possible to provide

Claims

[Claim 1] A method for producing a pharmaceutical composition that is a tablet containing tofogliflozin as an active ingredient. mixing the excipients and tofogliflozin to prepare a powder mixture; and obtaining tablets from the powder blend by direct blend tableting; wherein the additive comprises one or more excipients.

Images