Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• the present invention relates to orally disintegrating tablets.
• orally disintegrating tablets are not only easy to take without water, but also increase the possibility of launching new products by proving their bioequivalence with already approved formulations. Development is underway.
• orally disintegrating tablets have the advantage of reducing dispensing operations such as crushing and suspending in clinical settings, leading to the need for orally disintegrating tablets.
• canagliflozin, its pharmaceutically acceptable salt, or its hydrate can be used to treat diseases or disorders associated with SGLT activity, specifically, for example, diabetes mellitus (type 1 and type 2). It has been described that it is useful for treating, preventing, or delaying the progression or onset of diabetic complications (diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc.) and diabetic complications (diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc.).
• Patent Document 3 describes a tablet containing a high content of canagliflozin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a lubricant consisting of talc and sodium stearyl fumarate.
• Patent Document 4 describes a tablet that exhibits rapid disintegration in the oral cavity and a good feeling when taken, and has an appropriate strength that does not crumble during the distribution process. Also, US Pat. No. 5,001,302 describes tablets that disintegrate rapidly in the mouth with soluble diluents used in the form of directly compressible products.
• orally disintegrating tablets are difficult to design because they are required to have a moderate strength that does not cause excessive wear and tear during the distribution process or during packaging, and excellent disintegration properties in the oral cavity.
• additives such as disintegrants and excipients.
• orally disintegrating tablets that improve patient convenience is desired, development of orally disintegrating tablets containing a high content of canagliflozin, its pharmaceutically acceptable salt, or its hydrate is desired. is also desired.
• orally disintegrating tablets that contain canagliflozin, its pharmaceutically acceptable salts, or its hydrates as an active ingredient and rapidly disintegrate in the oral cavity have not been found, and their formulation and The manufacturing method was unknown.
• Patent Document 3 does not describe the formulation or manufacturing method for orally disintegrating tablets containing a high content of canagliflozin, a pharmaceutically acceptable salt thereof, or a hydrate thereof. Further, in both the techniques of Patent Documents 4 and 5, when the content ratio of the active pharmaceutical ingredient in the formulation is high, the disintegration property in the oral cavity decreases.
• the present invention provides orally disintegrating tablets.
• a solid preparation containing canagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient contains canagliflozin at a high concentration and is To provide an orally disintegrating tablet which has appropriate strength to prevent wear and tear and has rapid disintegration properties in the oral cavity.
• the active ingredient canagliflozin, its pharmaceutically acceptable salt, or its hydrate has high water conductivity, and although it is an active ingredient, it can also be used as a disintegrant.
• the present inventors have been able to improve the disintegration properties of tablets in the oral cavity and the appropriate strength during the distribution process, even in the absence of disintegrants or when the content of additives is reduced. It has been found that both can be maintained.
• the present inventors have discovered an orally disintegrating tablet that can contain the active ingredient at a high concentration.
• the excipient is one or a combination of two or more selected from the group consisting of D-mannitol, lactose, lactose hydrate, and crystalline cellulose.
• the disintegrant is one or a combination of two or more selected from the group consisting of croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, crospovidone, and carmellose. , the orally disintegrating tablet according to any one of [3] to [8] above.
• the lubricant is one or more selected from the group consisting of sodium stearyl fumarate, calcium stearate, magnesium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate, and talc.
• Orally disintegrating tablets containing the compound represented by the above, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, an excipient, and a lubricant have a light transmittance of 10% or less for wavelengths less than 393 nm.
• a method for suppressing discoloration of an orally disintegrating tablet due to light comprising packaging the orally disintegrating tablet using an ultraviolet absorbing film material, aluminum foil, a laminate film, a light-shielding bottle, or a paper box.
• orally disintegrating tablets containing the compound represented by or a pharmaceutically acceptable salt thereof, or a hydrate thereof, an excipient, and a lubricant, blocking 90% or more of light with a wavelength of less than 393 nm.
• a method for suppressing discoloration caused by light in an orally disintegrating tablet [25] The orally disintegrating tablet according to any one of [1] to [17] above, which further contains other active ingredients. [26] Oral disintegration according to [25] above, wherein the other active ingredient is one or more selected from the group consisting of hypoglycemic agents, antihypertensive agents, and antihyperlipidemic agents. Tablet.
• [27] Contains a hypoglycemic drug as another active ingredient, The orally disintegrating tablet according to [25] or [26] above, wherein the hypoglycemic agent is teneligliptin, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
• a package in which the tablet is packaged with a packaging material contains an active ingredient containing teneligliptin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and one or two selected from the group consisting of excipients, disintegrants, binders, and lubricants. Contains the above additives, When the package is stored at 40°C and 75% relative humidity for 6 months, the water activity value of the tablet is 0.25 Aw or less, and the content of the main related substances of the active ingredient is A package that is packaged to have a concentration of 0.3% or less. [30] The package according to [29] above, wherein the tablet and a desiccant are packaged.
• a method for suppressing the production of main related substances of active ingredients contained in tablets comprising:
• the tablet contains an active ingredient containing teneligliptin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and one or two selected from the group consisting of excipients, disintegrants, binders, and lubricants.
• the method described above includes the step of reducing the water activity value of the tablet to 0.25 Aw or less when the tablet is stored for 6 months under conditions of 40° C. and 75% relative humidity.
• an orally disintegrating tablet that exhibits rapid disintegration while having an appropriate strength that is resistant to wear and tear due to external forces generated during the distribution process.
• Figure 1A shows the change in plasma concentration of canagliflozin when an orally disintegrating tablet containing canagliflozin (Canagle (registered trademark) OD tablet 100 mg) is taken without water, and the change in plasma concentration of canagliflozin when an orally disintegrating tablet containing canagliflozin (Canagle (registered trademark) OD tablet 100 mg) is taken without water.
• 10 is a graph showing the change in plasma concentration of canagliflozin when 100 mg (registered trademark) tablet [regular tablet]) is taken with water.
• Figure 1B shows the change in plasma concentration of canagliflozin when an orally disintegrating tablet containing canagliflozin (Canaglu (registered trademark) OD tablet 100 mg) was taken with water, and the change in plasma concentration of canagliflozin when an orally disintegrating tablet containing canagliflozin (Canaglu (registered trademark) OD tablet 100 mg) was taken with water.
• 2 is a graph showing the change in plasma concentration of canagliflozin when 100 mg (registered trademark) tablet (regular tablet) is taken with water.
• FIG. 2A is a graph showing the correlation between the water activity value of tablets containing teneligliptin and the amount of produced main related substances depending on the packaging format.
• FIG. 2B is a graph showing the correlation between the water activity value of tablets containing teneligliptin and the production amount of main related substances depending on the packaging material and the desiccant.
• the active ingredient in the orally disintegrating tablet of the present invention is represented by the following formula (A):
• Examples include the compound represented by (hereinafter also referred to as "canagliflozin”), a pharmaceutically acceptable salt thereof, or a hydrate thereof.
• the chemical name of canagliflozin is 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene. That is, the orally disintegrating tablet in one embodiment contains canagliflozin, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
• the present inventors discovered for the first time that canagliflozin, a pharmaceutically acceptable salt thereof, or a hydrate thereof exhibits excellent water conductivity.
• “canagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof” is also collectively referred to as "canagliflozin etc.”
• the content of canagliflozin, its pharmaceutically acceptable salt, or its hydrate in the orally disintegrating tablet of the present invention is usually 95% by mass or less, preferably 90% by mass or less, and more preferably is 80% by mass or less, and usually 5% by mass or more, preferably 10% by mass or more, and more preferably 30% by mass or more.
• the orally disintegrating tablet of the present invention is, for example, 5% by mass or more and 95% by mass or less, 5% by mass or more and 90% by mass or less, 5% by mass or more and 80% by mass or less, 10% by mass or more 95 mass% or less, 10 mass% or more and 90 mass% or less, 10 mass% or more and 80 mass% or less, 30 mass% or more and 95 mass% or less, 30 mass% or more and 90 mass% or less, or 30 mass% or more and 80 mass% or less It is.
• the content of canagliflozin, etc. in the orally disintegrating tablet of the present invention within the above range, it can be easily taken with saliva or a small amount of water, and is especially suitable for patients with fluid restriction such as kidney disease and those who have difficulty swallowing. It can be taken even by patients with severe symptoms.
• Canagliflozin, a pharmaceutically acceptable salt thereof, or a hydrate thereof is disclosed in, for example, U.S. Patent Application Publication No. 2005/233988, U.S. Patent Application Publication No. 2008/146515, and U.S. Patent Application Publication No. 2008/146515. Examples include compounds described in Publication No. 2013/052266. Canagliflozin and the like can be synthesized and easily obtained, for example, by the methods described in these documents.
• compositions of canagliflozin include, for example, salts with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, and phosphoric acids; formic, acetic, propionic, and sulfuric acids.
• acids, salts with organic acids such as malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid; asparagine
• examples of hydrates of canagliflozin include hemihydrates.
• Canagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof is preferably canagliflozin hemihydrate.
• the orally disintegrating tablet of the present invention may further contain one or more additives selected from the group consisting of excipients, lubricants, disintegrants, and colorants.
• excipients include sugars such as lactose, lactose hydrate, sucrose, glucose, reduced maltose, D-mannitol, sorbitol, xylitol, and trehalose; Starches such as dextrin, pullulan, corn starch, and potato starch; Celluloses such as crystalline cellulose and microcrystalline cellulose; Magnesium aluminate metasilicate; Silicon dioxide; Light anhydrous silicic acid; Amino acids, etc. .
• excipients can be used alone or in combination of two or more.
• the excipient is preferably D-mannitol, lactose, lactose hydrate, crystalline cellulose, or a mixture thereof, and more preferably D-mannitol.
• the lower limit of the content of the "excipient” used in the present invention is not particularly limited, but for example, it is usually 3% by mass or more, preferably 7% by mass or more, based on 100% by mass of the tablet, More preferably it is 10% by mass or more, and still more preferably 20% by mass or more.
• the upper limit of the content of "excipient” is not particularly limited, but for example, it is usually 80% by mass or less, preferably 65% by mass or less, based on 100% by mass of the tablet.
• the content of excipients in the orally disintegrating tablet of the present invention is, for example, 3% by mass or more and 80% by mass or less, 3% by mass or more and 65% by mass or less, 7% by mass or more and 80% by mass or less, 7% by mass or more and 65% by mass or more.
• the content is 10% by mass or more and 80% by mass or less, 10% by mass or more and 65% by mass or less, 20% by mass or more and 80% by mass or less, or 20% by mass or more and 65% by mass or less.
• the "lubricating agent" that can be used in the present invention is any lubricant commonly used in pharmaceutical preparations, especially if it improves the productivity during tabletting of orally disintegrating tablets. Not limited.
• lubricants include sodium stearyl fumarate; stearic acid metal salts such as calcium stearate, magnesium stearate, and zinc stearate; glycerin higher fatty acid esters such as glyceryl monostearate and glyceryl palmitostearate; higher sucrose; Fatty acid ester; talc, etc. can be mentioned. These lubricants can be used alone or in combination of two or more.
• the lubricant is preferably sodium stearyl fumarate, calcium stearate, magnesium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate, or talc; It is more preferable to use calcium phosphate or talc, and it is particularly preferable to use sodium stearyl fumarate.
• the lower limit of the content of the "lubricant” used in the present invention is not particularly limited, but is usually 0.1% by mass or more, preferably 0.5% by mass or more, based on 100% by mass of the tablet.
• the content is more preferably 1% by mass or more.
• the upper limit of the content of the "lubricating agent” is not particularly limited, but it is usually 5% by mass or less, preferably 3% by mass or less, based on 100% by mass of the tablet.
• the content of the lubricant in the orally disintegrating tablet of the present invention is, for example, 0.1% by mass or more and 5% by mass or less, 0.1% by mass or more and 3% by mass or less, 0.5% by mass or more and 5% by mass or less.
• the orally disintegrating tablet of the present invention preferably further contains a disintegrant.
• a disintegrant examples include low-substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone, sodium alginate, sodium carboxymethyl starch, carmellose calcium, carmellose sodium, and crystalline cellulose carmellose. Examples include loose sodium and carmellose. These disintegrants can be used alone or in combination of two or more.
• croscarmellose sodium one or a combination of two or more selected from the group consisting of croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, crospovidone, and carmellose is preferred; Propylcellulose or croscarmellose sodium is more preferred, and croscarmellose sodium is particularly preferred.
• canagliflozin since canagliflozin, its pharmaceutically acceptable salt, or its hydrate exhibits excellent water conductivity, canagliflozin itself can also function as a disintegrant.
• the orally disintegrating tablet of the present invention containing canagliflozin, etc. in one embodiment exhibits disintegration properties in the oral cavity without adding a "disintegrant". It is possible. That is, orally disintegrating tablets containing canagliflozin and the like may not contain a disintegrant, but may contain a disintegrant from the viewpoint of further improving disintegration properties in the oral cavity.
• the lower limit of the content of the "disintegrant" in the orally disintegrating tablet is not specified, but it can be, for example, more than 0% by mass.
• an orally disintegrating tablet with higher performance can be prepared.
• the upper limit of the content of the "disintegrant” is not particularly limited, but is usually 9% by mass or less, preferably 8% by mass or less, and more preferably 7% by mass or less, based on 100% by mass of the tablet.
• the content of the disintegrant in the orally disintegrating tablet of the present invention may be, for example, 0% by mass (that is, not contained), or more than 0% by mass and not more than 9% by mass, more than 0% by mass and not more than 8% by mass. , or more than 0% by mass and 7% by mass or less.
• canagliflozin and the like are excluded from the term "disintegrant" in this specification.
• the content of "disintegrant” does not include the content of canagliflozin, etc.
• the orally disintegrating tablet of the present invention preferably further contains a coloring agent.
• the "coloring agent” that can be used in the present invention is not particularly limited, but includes, for example, iron oxide pigments, tar pigments, and the like.
• iron oxide pigments include yellow iron oxide, yellow iron sesquioxide, iron sesquioxide, brown iron oxide, and black iron oxide.
• tar-based pigments include Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Yellow No. 102, Food Yellow No. 4, Food Yellow No. 4 Aluminum Lake, Food Blue No. 2 Aluminum Lake, and Food Blue No. 1.
• the number etc. These colorants can be used alone or in combination of two or more.
• iron oxide pigments are preferable, and iron oxide pigments consisting of one or more iron oxides selected from the group consisting of yellow iron sesquioxide, iron sesquioxide, and black iron oxide are more preferable.
• yellow iron sesquioxide is particularly preferably included.
• the lower limit of the content of the "coloring agent" used in the present invention is not particularly limited, but may be 0% by mass (i.e., not contained), and when the orally disintegrating tablet contains a coloring agent, for example, 0% by mass. % or more.
• the upper limit of the coloring agent content is usually 2% by mass or less, preferably 1% by mass or less, based on 100% by mass of the tablet.
• the content of the colorant may not be contained, or is, for example, more than 0% by mass and not more than 2% by mass, or more than 0% by mass and not more than 1% by mass.
• discoloration of canagliflozin, etc. can be prevented by, for example, adopting a predetermined light shielding method or packaging method.
• a predetermined light shielding method or packaging method include ultraviolet absorbing film materials with a light transmittance of 10% or less for wavelengths less than 393 nm, aluminum foil, laminate films (films made by laminating aluminum foil with plastic films such as polyethylene), etc.
• the orally disintegrating tablet of the present invention is packaged using various packaging materials, such as containers such as light-shielding bottles and paper boxes made of plastic or glass, to obtain a package in which the tablet is packaged.
• the packaging material may be used alone or in combination of two or more. Thereby, discoloration of canagliflozin and the like due to light can be effectively suppressed. Furthermore, by blocking 90% or more of light with a wavelength of less than 393 nm for the orally disintegrating tablet of the present invention, the active ingredient canagliflozin, its pharmaceutically acceptable salt, or its hydrate can be can effectively suppress discoloration caused by light.
• the light shielding method is not particularly limited, but for example, a light shielding method such as coating or packaging a tablet using one or more of the above-mentioned packaging materials can be exemplified.
• the light transmittance of the member used in the light shielding method can be measured, for example, by a measurement method using a spectrophotometer specified in Section 4.3.1 of JIS R 3106.
• the method for measuring the light transmittance is commonly used in the description of this specification.
• a desiccant is included. It is preferable to package it so that it is That is, in one embodiment, it is preferable to use a package in which a tablet as a packaged object and a desiccant are packaged.
• the desiccant used in the package is not particularly limited, and examples include one or more desiccant selected from zeolite, silica gel, and calcium chloride.
• the desiccant may be included in the package, such as allowing the desiccant to coexist in a bottle or box filled with tablets regardless of whether or not it comes into contact with the tablets, or in a PTP sheet in which the tablets are packaged.
• examples include a mode in which the desiccant is packaged with aluminum foil or the like, or a mode in which the desiccant is attached to the inner surface or inside of the lid of a bottle or box filled with tablets.
• non-toxic and inert additives commonly used in the pharmaceutical field may be added as long as they do not affect the effects of the present invention.
• additives include those that do not substantially affect the effects of the present invention and are generally added as pharmaceutical additives.
• Other additives can be used alone or in combination of two or more.
• additives include, for example, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinyl alcohol, completely saponified polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl acetal diethylaminoacetate, and aminomethacrylate copolymers; sodium lauryl sulfate, etc.
• binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinyl alcohol, completely saponified polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl acetal diethylaminoacetate, and aminomethacrylate copolymers
• sodium lauryl sulfate etc.
• Ionic surfactants or polysorbates (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, etc.), sucrose fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene hydrogenated castor oil, poloxamers (e.g., nonionic surfactants such as poloxamer 188); sweeteners such as aspartame, saccharin, sodium saccharin, acesulfame potassium, sucralose, stevia, thaumatin; l-menthol, sodium chloride, sodium citrate, sodium glutamate, baking soda, Benequat ( (registered trademark), malic acid, and other flavoring agents; lemon flavor, orange oil, grapefruit flavor, yuzu flavor (dry coated yuzu), strawberry flavor, peppermint oil, fennel oil, cinnamon oil, clove oil, turpentine oil, eucalyptus oil, yogurt Flavors, fragrances such as coffee flavor, etc.
• poloxamers
• the orally disintegrating tablet of the present invention contains one or more selected from sweeteners and flavoring agents, or one or more selected from sweeteners, flavoring agents, and flavoring agents. It becomes easier to feel the sensation of taking it.
• more preferable elution properties can be obtained by containing one or more surfactants selected from ionic surfactants and nonionic surfactants instead of or in addition to these. become more susceptible to
• one or more other additives such as a pH adjuster, a fluidizing agent, a coating agent, etc. can also be added. These other additives can be contained in appropriate amounts as necessary.
• the content of the other additives is not particularly limited, but can be exemplified in the following ranges.
• the content of the sweetener is, for example, in the range of 0.1% by mass to 5% by mass, preferably in the range of 0.3% by mass to 3% by mass, based on 100% by mass of the tablet. Preferably, it is in the range of 0.5% to 2% by weight.
• the content of the flavoring agent is, for example, in the range of 0.1% by mass to 5% by mass, preferably in the range of 0.3% by mass to 3% by mass, more preferably in the range of 0.3% by mass, based on 100% by mass of the tablet. It is in the range of 5% by mass to 2% by mass.
• the content of the fragrance is, for example, in the range of 0.01% by mass to 3% by mass, preferably in the range of 0.01% by mass to 2% by mass, more preferably 0.01% by mass, based on 100% by mass of the tablet.
• the range is from 1% to 1% by mass.
• canagliflozin, its pharmaceutically acceptable salt, or its hydrate to be incorporated into the orally disintegrating tablet of the present invention a dry product such as a powder with or without post-treatment such as classification may be used. Can be done. In addition to or in place of this, canagliflozin and the like can also be used in the form of molded products such as granules. The granules can be obtained, for example, by granulating a mixture containing canagliflozin or the like or other active ingredients, excipients, and binders described below.
• the granules are produced by stirring and granulating a mixture of canagliflozin hydrate (hemihydrate), D-mannitol (excipient), hydroxypropylcellulose (binder), and water. (wet granulation), drying, and sizing.
• the method for producing the granules is not limited to wet granulation, and, for example, dry granulation may also be used.
• canagliflozin hemihydrate used in the examples described below is 82.3% by mass
• D-mannitol (excipient) is 14% by mass.
• premix products sold by additive manufacturers can also be used instead of or in addition to the excipients, disintegrants, and the like.
• the additives contained in the premix product include, for example, one or more types selected from the group consisting of the above excipients, disintegrants, and binders.
• the additives contained in the premix product include low-substituted hydroxypropyl cellulose as a disintegrant, D-mannitol as an excipient, and polyvinyl alcohol as a binder. Can be mentioned.
• the premix product include SmartEX (registered trademark) sold by Shin-Etsu Chemical Co., Ltd.
• each component in SmartEX (registered trademark) is 90.0% by mass to 95.0% by mass of D-mannitol (excipient), and 5.0% by mass of low-substituted hydroxypropylcellulose (disintegrant).
• the amount of completely saponified polyvinyl alcohol (binder) is 0.1% to 0.3% by weight.
• additives that can be incorporated into the orally disintegrating tablet of the present invention including the premix products, commercially available products may be used as they are, or particles obtained through a preliminary process such as granulation may be used.
• the orally disintegrating tablet of the present invention when forming an orally disintegrating tablet containing a high content of the drug substance (i.e., active ingredient), it is possible to use granulated additives to stabilize the drug substance. This method is preferable because it allows the manufacture of tablets in which the medicine is uniformly mixed. As such an additive, it is particularly preferable to use SmartEX (registered trademark).
• the orally disintegrating tablet of the present invention has a part or all of its surface coated with a coating agent for the purpose of masking the bitter taste caused by the contained ingredients and stabilizing light-shielding properties, moisture-proofing properties, etc. Good too.
• the coating agent that can be used for the orally disintegrating tablet of the present invention is not particularly limited, but preferably includes, for example, a bentonite-containing moisture-proof film for OD tablets (RADIFIL (registered trademark); Toray Industries, Inc.). By coating with such a coating agent, the friability of the orally disintegrating tablet of the present invention can be further reduced.
• the coating treatment makes it possible to maintain sufficient disintegration of the tablet in the oral cavity and to make the tablet strong enough to withstand external forces generated during the distribution process.
• per tablet means “per tablet” unless otherwise specified.
• the orally disintegrating tablet of the present invention preferably includes: (1) canagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof (preferably canagliflozin hemihydrate), with a content per tablet of 95% by mass or less; (2) An excipient whose content per tablet is 3% to 80% by mass (preferably one or two selected from the group consisting of D-mannitol, lactose, lactose hydrate, and crystalline cellulose) and (3) the content per tablet is 0.1% to 5% by mass (preferably 0.5% to 3% by mass, more preferably 1% to 3% by mass). ) (preferably sodium stearyl fumarate, calcium stearate, magnesium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate, or talc). be.
• the orally disintegrating tablet of the present invention more preferably includes: (1) canagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof (preferably canagliflozin hemihydrate), with a content per tablet of 90% by mass or less; (2) An excipient whose content per tablet is 3% to 80% by mass (preferably one or two selected from the group consisting of D-mannitol, lactose, lactose hydrate, and crystalline cellulose) and (3) the content per tablet is 0.1% to 5% by mass (preferably 0.5% to 3% by mass, more preferably 1% to 3% by mass). ) (preferably sodium stearyl fumarate, calcium stearate, magnesium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate, or talc). be.
• the orally disintegrating tablet of the present invention further preferably includes: (1) canagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof (preferably canagliflozin hemihydrate), with a content per tablet of 80% by mass or less; (2) An excipient whose content per tablet is 10% to 80% by mass (preferably one or two selected from the group consisting of D-mannitol, lactose, lactose hydrate, and crystalline cellulose) (3) a lubricant whose content per tablet is 1% to 5% by mass (preferably sodium stearyl fumarate, calcium stearate, magnesium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate, or talc) It is an orally disintegrating tablet containing.
• Another preferred embodiment of the orally disintegrating tablet of the present invention is (1) Canagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof (preferably canagliflozin hemihydrate), with a content per tablet of 10% to 80% by mass.
• An excipient whose content per tablet is 10% to 80% by mass preferably one or two selected from the group consisting of D-mannitol, lactose, lactose hydrate, and crystalline cellulose is a combination of more than one species
• a disintegrant whose content per tablet is 8% by mass or less preferably a group consisting of croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, crospovidone, and carmellose
• a lubricant whose content per tablet is 1% to 5% by mass preferably sodium stearyl fumarate, calcium stearate, magnesium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate, or talc
• Another more preferred embodiment of the orally disintegrating tablet of the present invention is (1) canagliflozin hemihydrate, whose content per tablet is 30% by mass to 80% by mass; (2) One type or a combination of two or more types selected from the group consisting of D-mannitol, lactose, lactose hydrate, and crystalline cellulose, with a content per tablet of 10% by mass to 65% by mass. excipients, (3) A disintegrant that is croscarmellose sodium, low-substituted hydroxypropyl cellulose, or a combination thereof, whose content per tablet is 8% by mass or less, and (4) a disintegrant whose content per tablet is 1% by mass. Orally disintegrating tablets containing a lubricant of sodium stearyl fumarate at ⁇ 5% by weight.
• Yet another preferred embodiment of the orally disintegrating tablet of the present invention is (1) canagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof (preferably canagliflozin hemihydrate), with a content per tablet of 80% by mass or less; (2) An excipient whose content per tablet is 10% to 80% by mass (preferably one or two selected from the group consisting of D-mannitol, lactose, lactose hydrate, and crystalline cellulose) is a combination of more than one species), (3) A lubricant whose content per tablet is 1% to 5% by mass (preferably sodium stearyl fumarate, calcium stearate, magnesium stearate, zinc stearate, glyceryl monostearate, palmitostearic acid) (5) a coloring agent whose content per tablet is from 0.1% by mass to 2% by mass (preferably iron oxide pigments or tar pigments, more preferably, iron oxide selected from the group consisting of yellow iron sesquioxide, iron sesqui
• Yet another more preferred embodiment of the orally disintegrating tablet of the present invention is: (1) Canagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof (preferably canagliflozin hemihydrate), with a content per tablet of 10% to 80% by mass.
• An excipient whose content per tablet is 10% to 80% by mass preferably one or two selected from the group consisting of D-mannitol, lactose, lactose hydrate, and crystalline cellulose is a combination of more than one species
• a disintegrant whose content per tablet is 8% by mass or less preferably a group consisting of croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, and carmellose
• a lubricant whose content per tablet is 1% to 5% by mass preferably sodium stearyl fumarate, calcium stearate, magnesium stearate, zinc stearate, glyceryl monostearate, palmitostearic acid
• glyceryl or talc yellow iron sesquioxide having a content of 0.1% to 2% by mass per tablet.
• Yet another particularly preferred embodiment of the orally disintegrating tablet of the present invention is (1) canagliflozin hemihydrate, whose content per tablet is 30% by mass to 80% by mass; (2) A supplement that is one or a combination of two or more selected from the group consisting of D-mannitol, lactose, lactose hydrate, and crystalline cellulose, with a content per tablet of 15% by mass to 65% by mass.
• a disintegrant which is croscarmellose sodium, low substituted hydroxypropyl cellulose, or a combination thereof, with a content per tablet of 8% by mass or less; (4) a lubricant that is sodium stearyl fumarate, the content of which is 1% to 5% by weight per tablet, and (5) a yellow color whose content per tablet is 0.1% to 2% by weight.
• the orally disintegrating tablet of the present invention containing the components (1) to (3) above or the components (1) to (4) above has the property of rapidly disintegrating in the oral cavity, and is suitable for manufacturing, distribution, and dispensing. It exhibits physical strength that makes it difficult to break during various processes such as packaging, tablet removal, etc.
• the orally disintegrating tablet of the present invention has a disintegration time in the oral cavity of 60 seconds or less, preferably 45 seconds or less, and more preferably 30 seconds or less.
• the orally disintegrating tablet of the present invention has a hardness (as measured by a tablet hardness meter) of usually 20N to 120N, preferably 20N to 80N, more preferably 40N to 80N.
• the orally disintegrating tablet of the present invention has a friability of 1% or less, more specifically 1.00% or less, and the lower the friability, the more preferable.
• the lower limit of the degree of friability is 0% or more, and more specifically, for example, 0.00% or more, or 0.01% or more is realistic.
• the orally disintegrating tablet of the present invention is formulated with a specific coloring agent (component (5) above) such as an iron oxide pigment or a tar pigment, so that the active ingredient canagliflozin or Discoloration of the pharmaceutically acceptable salt or hydrate thereof due to light can be effectively suppressed.
• a specific coloring agent such as an iron oxide pigment or a tar pigment
• light-shielding conditions such as coating or packaging with a UV-absorbing film material, aluminum foil, light-shielding bottle, or other packaging material that has a light transmittance of 10% or less for wavelengths less than 393 nm may be used.
• the orally disintegrating tablet of the present invention By storing the orally disintegrating tablet of the present invention in the container, it is possible to obtain the same effect of suppressing discoloration due to light as when the above-mentioned coloring agent is added. As mentioned above, it is not precluded to combine the combination of a specific coloring agent and storage under light-shielding conditions. By employing these in combination, the effect of suppressing discoloration caused by light can be obtained over a long period of time.
• orally disintegrating tablet of the present invention include the components (1) to (3) above, the components (1) to (4) above, the components (1) to (3) and (5) above, Or, in addition to the ingredients (1) to (5) above, an orally disintegrating tablet containing appropriate amounts of other additives as described above, or an orally disintegrating tablet as described above Examples include orally disintegrating tablets coated with a tablet coating agent (eg, bentonite-containing moisture-proof film for OD tablets (RADIFIL (registered trademark); Toray Industries, Inc.)).
• a tablet coating agent eg, bentonite-containing moisture-proof film for OD tablets (RADIFIL (registered trademark); Toray Industries, Inc.)
• the shape of the orally disintegrating tablet of the present invention is not particularly limited, and examples include circular, oval, spherical, and rectangular shapes.
• the size of the orally disintegrating tablet of the present invention is not particularly limited, but specifically, for example, in the case of a circular tablet, the diameter of the tablet is 3 mm to 20 mm, preferably 5 to 15 mm, more preferably 7 to 20 mm. A diameter of 10 mm makes it easier to take and improves medication compliance.
• the mass per orally disintegrating tablet of the present invention is not particularly limited, but is usually 100 to 500 mg, preferably 130 to 310 mg.
• “friability” refers to the tablet friability test method (18th edition Japanese Pharmacopoeia It means the amount of mass loss (%) in the test according to the tablet friability test method described in .
• disintegration time in the oral cavity means that each healthy adult (1 to 3 people) takes one orally disintegrating tablet in their mouth, chews, and licks it without water. This refers to the time calculated by measuring the time required for the tablet to completely disintegrate due to saliva in the mouth without any action, and taking the arithmetic mean of the measurements.
• the disintegration time of the orally disintegrating tablet of the present invention is within about 240 seconds, preferably within about 180 seconds, and more preferably within about 120 seconds.
• the disintegration time is the orally disintegrating tablet when the disintegration test was conducted using the disintegration test apparatus described in the 18th edition of the Japanese Pharmacopoeia, using water as the test liquid, and at a liquid temperature of 37 ⁇ 2°C. It means the time until it completely collapses.
• the hardness of the orally disintegrating tablet of the present invention is preferably 20N (Newton) or more, more preferably 30N or more. If the tablet has such hardness, even when the tablet is pushed out from the press-through package (PTP) packaging, it can effectively prevent the tablet from disintegrating due to external force. . Further, the upper limit of the hardness of the orally disintegrating tablet of the present invention is not particularly limited, but from the viewpoint of ease of handling the tablet, it is preferably 120N or less.
• the hardness of the orally disintegrating tablet of the present invention refers to the force required to break the tablet, measured using a tablet hardness meter (Tablet Tester 8M manufactured by Schleuniger).
• color difference ⁇ E * ab is a numerical representation of the difference in color, which was standardized by the Commission Internationale de l'Eclairage (CIE) in 1976 and adopted in JIS Z 8781-4. It means the distance between two points (two colors) existing in the L * a * b * color space (L * : lightness, a * b * : chromaticity (hue and saturation)), which is a color system.
• CIE Commission Internationale de l'Eclairage
• the degree of approximation of the color of the measured object to the reference color at each angle is ⁇ L * (lightness difference), ⁇ a * (red difference), ⁇ b * (yellow difference), and It is expressed as ⁇ E * ab (color difference).
• the lightness (L * ) and chromaticity (a * b * ) can be measured with a spectrophotometer (for example, SE6000 manufactured by Nippon Denshoku Industries Co., Ltd.), and the measured values can be used as color indicators. can.
• a spectrophotometer for example, SE6000 manufactured by Nippon Denshoku Industries Co., Ltd.
• color (standard) of the orally disintegrating tablet of the present invention immediately after manufacture changes after being left (stored) for a certain period of time under certain conditions specifically, means that the color change (color difference ⁇ E * ab ) of the orally disintegrating tablet after exposure to a total illuminance of 1.2 million lux/hr is less than 15, and the lower limit is 0 (zero) or more. do.
• the color change (color difference ⁇ E * ab ) of the orally disintegrating tablet of the present invention under the above conditions is preferably less than 10, more preferably less than 6.5. The smaller this color difference is, the less the change in color will be, so that the good color tone of the tablet immediately after manufacture can be maintained for a long period of time, and as a result, the appearance of the tablet can be maintained good.
• the orally disintegrating tablet of the present invention may be packaged.
• "packaging” includes PTP packaging, SP (Strip Package) packaging, bulk packaging, bottle packaging, pillow packaging, and the like.
• PTP packaging or SP packaging is preferable from the viewpoint of achieving both ease of handling during the distribution process and ease of taking out the tablets when taking them.
• the orally disintegrating tablet of the present invention may be packaged using an ultraviolet absorbing film material having a light transmittance of 10% or less for wavelengths less than 393 nm. preferable.
• the ultraviolet absorbing film material examples include thermoplastic materials such as polyvinyl chloride, polyvinylidene chloride, polypropylene, polyethylene, polychlorotrifluoroethylene, and polyethylene terephthalate. Among these, polyvinylidene chloride, polypropylene, or polyethylene is preferable as the ultraviolet absorbing film material.
• the method for producing the orally disintegrating tablet of the present invention is not particularly limited.
• the tablets can be manufactured using ordinary tablet manufacturing equipment without using any special tablet manufacturing equipment by blending the drug and lubricant and using the usual method for manufacturing tablets as shown below.
• the orally disintegrating tablet of the present invention can be prepared, for example, by the following steps: 1) Mix canagliflozin or its pharmaceutically acceptable salt, or its hydrate (e.g., canagliflozin hemihydrate), an excipient, and a binder, add purified water, and granulate with stirring.
• step 2) canagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof (e.g. canagliflozin hemihydrate) is used instead of the granules obtained in step 1). May be used.
• a commercially available premix product containing an excipient, a disintegrant, and a binder instead of or in addition to the excipient e.g., SmartEX (registered trademark) (Shin-Etsu Chemical Co., Ltd.) (manufactured by the company) may be used.
• any method can be used for mixing, granulating, drying and sizing, but for example, a container rotating type mixer such as a double cone mixer , a fluidized bed granulator, a high-speed stirring granulator, etc. can be used.
• a container rotating type mixer such as a double cone mixer , a fluidized bed granulator, a high-speed stirring granulator, etc.
• the mixture can be further sieved, for example, using a Japanese Pharmacopoeia 22 mesh sieve, if necessary.
• the step 3) of compression molding the tableting granules can be carried out using a conventional tableting machine such as a single-shot tabletting machine or a rotary tableting machine.
• the tableting pressure can be appropriately selected depending on the characteristics such as the hardness of the target tablet, but it is about 1 to 20 kN/punch, preferably about 1 to 15 kN/punch, particularly preferably about 1 to 12 kN. / Can be used as a pestle.
• a compaction analyzer manufactured by Kikusui Seisakusho as the tableting machine, for example, when using a punch with a diameter of 9.5 mm, it is preferable to compress the tablets at a tableting pressure of 2 to 12 kN/punch.
• the orally disintegrating tablet of the present invention also includes the following steps: 1') Mixing canagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof (e.g. canagliflozin hemihydrate), an excipient, and, if necessary, a binder and a coloring agent.
• step 2' A step of stirring and granulating by adding ethanol, wet crushing the resulting granulated product, drying and sizing; 2') A step of mixing the granules obtained in step 1') with a lubricant, and if necessary, a disintegrating agent, a sweetener (or a flavoring agent), and a flavoring agent to obtain granules for tabletting; It can also be produced by a method including the step of 3') compressing (tableting) the tableted granules obtained in step 2') to obtain the orally disintegrating tablet of the present invention.
• the tablets obtained by the above manufacturing method can be used as uncoated tablets. If necessary, the surface of the uncoated tablet obtained by the above manufacturing method may be coated by further performing a coating step with the above-described known coating agent for orally disintegrating tablets.
• the coating method it can be manufactured according to a method known in the technical field of pharmaceutical formulations. For example, a liquid containing a coating agent for orally disintegrating tablets (e.g., an aqueous dispersion, an ethanol solution, an ethanol/aqueous solution, an ethanol/aqueous dispersion, etc.) is coated while being added by means such as spraying. By drying the coated product, a coated orally disintegrating tablet of the present invention can be obtained.
• a top spray method, a tangential spray method, or a bottom spray method may be adopted.
• the orally disintegrating tablet of the present invention contains canagliflozin etc. as an active ingredient, it can be used as a selective inhibitor of SGLT2, for example, diabetes (type 1 and type 2 diabetes, etc.), diabetic complications (diabetic retina, etc.). (diabetic neuropathy, diabetic nephropathy, etc.), delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, hyperfatty acidemia, hyperglycerolemia, dyslipidemia, obesity, hypertriglyceridemia, It is useful for treating, preventing or delaying the progression or onset of syndrome X, atherosclerosis, hypertension and the like.
• the orally disintegrating tablet of the present invention can be safely orally administered to mammals such as humans.
• the dosage of the orally disintegrating tablet of the present invention is determined depending on the age, body weight, general health condition, gender, diet, administration time, administration method, excretion rate, drug combination, or the medical condition of the patient being treated at the time. These and other factors will be taken into consideration depending on the severity.
• the dosage of the orally disintegrating tablet of the present invention varies depending on the patient's condition, body weight, etc., but for example, for adults, the active ingredient canagliflozin should be administered in an amount of 50 to 200 mg, preferably 100 mg, per day. Preferably, it is administered.
• the frequency of administration of the orally disintegrating tablet of the present invention is not particularly limited, and may be, for example, once, twice, or three times a day, once every two days, etc., and preferably once a day. be.
• the orally disintegrating tablet of the present invention can be combined with other formulations, such as formulations for enhancing the action of the orally disintegrating tablet of the present invention, formulations for preventing or treating other diseases (lifestyle-related diseases, etc.), etc. May be used in combination.
• these other formulations may be oral formulations such as granules, tablets, capsules, and the like.
• the orally disintegrating tablet of the present invention may further contain other active ingredients for enhancing or supplementing the action of the orally disintegrating tablet of the present invention. These other active ingredients may be contained as they are or in the form of granules or the like produced by a method known per se.
• active ingredients means active ingredients other than canagliflozin and the like.
• hypoglycemic drugs such as teneligliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, a drug for treating hypertension, and a drug for treating hyperlipidemia. etc., but are not limited to these.
• teneligliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof will be collectively referred to as “teneligliptin, etc.”
• Orally disintegrating tablets containing canagliflozin and other active ingredients are in the form of so-called combination preparations.
• Such orally disintegrating tablets include, for example, embodiments in which each active ingredient is mixed and molded.
• an orally disintegrating tablet is formed integrally with a first part containing canagliflozin etc. and a second part containing other active ingredients. Examples include the following aspects.
• One or more of the first part and the second part can be contained in the tablet, each independently.
• an orally disintegrating tablet is formed by including a first part and a second part, it is preferable that the active ingredient contained in the second part is substantially not contained in the first part. Further, it is preferable that the active ingredient contained in the first part is substantially not contained in the second part.
• substantially not contained means that no active ingredient other than the desired active ingredient is contained when producing the first or second part constituting the orally disintegrating tablet. Therefore, in the above-mentioned "substantially free” form, other ingredients are unavoidably mixed in, for example, at the contact surfaces where the parts containing the active ingredient in the tablet are in contact with each other, or during the manufacturing process such as during molding. It is permissible to do so.
• Orally disintegrating tablets containing a first part and a second part can be prepared by, for example, preparing each part by itself, along with the excipients, lubricants, disintegrants, coloring agents, and/or other additives, if necessary. It can be produced by compression molding the blended mixture according to known methods or by coating one part with the other.
• an orally disintegrating tablet in the form of a combination containing canagliflozin and other active ingredients can be manufactured, for example, according to the following steps.
• the part containing canagliflozin etc. and the part containing teneligliptin etc. may be configured to be in contact with each other, and each part may be in contact with each other. They may be configured so that they do not come into contact.
• an inert intermediate layer may be provided between each portion.
• the intermediate layer means a layer that does not substantially contain any active ingredients such as canagliflozin and teneligliptin.
• substantially not included refers to the above-mentioned explanation of "substantially not included” as appropriate.
• the shapes of the portion containing canagliflozin and the like and the portions containing teneligliptin and the like are not particularly limited, but for example, they can each be made into granules independently.
• preferably, for example, canagliflozin, etc. or teneligliptin, etc., and an excipient are granulated using a solvent dispersion of a binder, and a granulated product obtained is dried and then regulated.
• Granules are obtained by mixing a sized powder obtained by granulation, a disintegrant, a lubricant, and, if necessary, an excipient.
• the granule may be coated. may form an inert intermediate layer.
• the material for the intermediate layer examples include those exemplified as the coating agent described above.
• the content of the intermediate layer per tablet is usually 0.1 to 50% by mass, preferably 0.5 to 45% by mass, and more preferably 1 to 20% by mass. be.
• the intermediate layer can be formed by a conventional method.
• the intermediate layer may be formed not only of one layer but of a plurality of layers (preferably 2 to 3 layers).
• adverse effects caused by the active ingredients interacting with each other can be more effectively suppressed.
• adverse effects include, for example, a decrease in storage stability such as decomposition of the active ingredient over time and a decrease in activity, and a decrease in elution stability such as a change in the elution pattern of the active ingredient over time.
• the orally disintegrating tablet of the present invention includes, for example, a tablet obtained by alternately arranging first portions and second portions.
• the orally disintegrating tablet of this embodiment comprises granules as a first part containing canagliflozin etc. and granules as a second part containing teneligliptin etc. in a layered (two-layer or three-layer) structure.
• Examples include layered tablets manufactured by arranging the tablets in multiple layers (more than one layer), stacking the layers alternately and compression molding (preferably tableting).
• the layer including the first portion and the layer including the second portion may be arranged in contact with each other, or may be arranged so that the layers do not contact each other.
• granules whose surfaces have been coated may be used, or the intermediate layer described above may be placed between the layer containing the first portion and the layer containing the second portion. .
• the orally disintegrating tablet has a center portion formed by one of the first portion and the second portion, and a coating covering the outer surface of the center portion with the other portion.
• examples include tablets containing part. Specifically, for example, an uncoated tablet containing granules as a first part containing canagliflozin etc. is used as an inner core tablet, and granules as a second part containing teneligliptin etc. are used as an outer layer part and compression molded (preferably). Alternatively, an uncoated tablet containing granules as a second part containing teneligliptin etc. is used as an inner core tablet, and granules as a first part containing canagliflozin etc. are used as an outer layer part and compression molded. (preferably tableting, for example, step 3)).
• film-coated orally disintegrating tablets produced by film-coating the above laminated tablets or dry-coated tablets with a coating agent.
• the present invention includes a package in which a tablet such as an orally disintegrating tablet of the present invention is packaged with a packaging material.
• the tablet packaged in the package contains, for example, an active ingredient including teneligliptin, and one or more additives selected from the group consisting of excipients, disintegrants, binders, and lubricants.
• an orally disintegrating tablet containing teneligliptin, etc., canagliflozin, etc. as active ingredients is packaged with a packaging material is preferable.
• the orally disintegrating tablets or packages of the present invention are such that when stored for 6 months at 40°C and 75% relative humidity, the water activity value of the tablets is below a predetermined value.
• the configuration is configured.
• the water activity value of the tablet under the above conditions is, for example, 0.25 Aw or less, preferably 0.20 Aw or less, more preferably 0.15 Aw or less.
• water activity refers to free water in the water molecules present in the tablet. Free water refers to water molecules present in the tablet that are not adsorbed to the tablet components through physical or chemical interactions.
• the water activity value can be measured, for example, by a method using an electrical resistance type water activity measuring device specified by the Food Sanitation Act.
• the tablet or packaged body of the orally disintegrating tablet of the present invention should be stored for 6 months at 40°C and 75% relative humidity.
• the content of the main related substances derived from teneligliptin or the like be below a predetermined value.
• the content of main related substances derived from teneligliptin etc. when stored under the above conditions is, for example, 0.3% or less, preferably 0.2% or less, more preferably 0.1% or less. It is configured so that The content of the main related substance in the tablet is preferably as low as possible, but it is realistically 0.0% or more. By setting the content of the main related substances within this range, it is possible to provide tablets and high-quality tablets in which reduction of the active ingredients in the tablets is suppressed.
• the present invention also provides a method for suppressing the production of main related substances of active ingredients contained in tablets.
• the suppression method includes the step of reducing the water activity value of the tablet to 0.25 Aw or less when the tablet or the package containing the same is stored for 6 months at 40° C. and 75% relative humidity.
• the above-mentioned range can be used as a suitable water activity value.
• the above-described tablet contains, for example, teneligliptin, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.
• main related substance refers to a substance that is produced in large amounts among decomposition products, derivatives, etc. derived from teneligliptin, and may be one type or two or more types.
• content of main related substances refers to the production amount of one or more main related substances, that is, the production of main related substances relative to the total content of teneligliptin, etc. per tablet. means a percentage of an amount.
• the content of main related substances can be measured, for example, by liquid chromatography.
• a column filled with pentafluorophenylpropyl silylated silica gel can be used, using a mixture of phosphate buffer and acetonitrile as the mobile phase.
• a sample dissolved in a mobile phase can be injected into liquid chromatography, measurement can be started, and the content of related substances can be calculated from the total value of each peak area.
• tablets may be packaged using multiple types of packaging materials such as aluminum foil or plastic, such as PTP sheets.
• the desiccant may be packaged as an object to be packaged, and the desiccant may be included in the package. More specifically, the package includes, for example, a PTP sheet containing tablets and a desiccant as the packaged items, and the packaged items are wrapped with aluminum foil or a laminate film of aluminum foil and plastic.
• the desiccant to be included in the package is not particularly limited as long as it can reduce the moisture content in the package and maintain the stability of the active ingredient contained in the tablet, and specific examples include the same as above.
• the desiccant is preferably zeolite.
• Thermoplastic resin is preferably used as the plastic for the packaging material.
• thermoplastic resins include polyolefin resins such as polyethylene, polypropylene, and cyclic polyolefin; vinyl chloride resins such as polyvinyl chloride and polyvinylidene chloride; and copolymers with monomers constituting these resins. It will be done. These can be used alone or in combination of two or more.
• % means “mass %” unless otherwise specified.
• drug ratio means the percentage of the total content of canagliflozin hemihydrate per tablet.
• Canaglu registered trademark
• Canagliflozin hemihydrate 102 mg
• D-mannitol manufactured by Bussan Food Science Co., Ltd.
• hydroxypropyl cellulose manufactured by Nippon Soda Co., Ltd. 4 mg
• FM-VG-400 manufactured by Powrex Co., Ltd.
• the agitated granulated product was sized using a sizing machine QC-U20 (manufactured by Powrec Co., Ltd.), dried using a fluidized bed dryer FD-WSG-120TW (manufactured by Freund Sangyo Co., Ltd.), and then transferred to a sizing machine P-3S.
• Canaglu registered trademark
• Examples 1 to 9 and Example 11 Regarding the tablets of Examples 1 to 9 and Example 11, according to the formulations in Tables 1-1 to 1-3, each component in an amount 1000 times the formulation was thoroughly mixed, and then the tablets were prepared using a rotary tablet machine VELA2 (Kikusui Seisakusho Co., Ltd.). Tablets with a diameter of 9.5 mm were obtained by compressing the tablets using the following methods:
• Example 10 Regarding the tablet of Example 10, according to the recipe in Table 1-3, after thoroughly mixing 5000 times the amount of each ingredient in the recipe, the tablet was compressed using a rotary tablet machine VELA2 (manufactured by Kikusui Seisakusho Co., Ltd.). Tablets with a diameter of 9.5 mm were obtained.
• a rotary tablet machine VELA2 manufactured by Kikusui Seisakusho Co., Ltd.
• Examples 12-17 Regarding the tablets of Examples 12 to 17, according to the formulations in Tables 2-1 and 2-2, each component in an amount 150,000 times the formulation was thoroughly mixed, and then the tablets were prepared using a rotary tablet machine AQU30518SW2AIII (manufactured by Kikusui Seisakusho Co., Ltd.). Tablets with a diameter of 9.5 mm were obtained by compressing the tablets at the tablet hardness shown in Tables 2-1 and 2-2.
• Examples 20-21 Regarding the tablets of Examples 20 to 21, according to the prescription in Table 2-3, after thoroughly mixing each component in an amount 1000 times the prescription, using a rotary tablet press VELA2 (manufactured by Kikusui Seisakusho Co., Ltd.), Tablets with a diameter of 9.5 mm were obtained by compressing each sample at the tablet hardness described in 3.
• a rotary tablet press VELA2 manufactured by Kikusui Seisakusho Co., Ltd.
• Example 22 Regarding the tablet of Example 22, according to the prescription in Table 3, each component in an amount 5000 times the prescription was thoroughly mixed, and then compressed using a rotary tablet press VELA2 (manufactured by Kikusui Seisakusho Co., Ltd.) to a diameter of 9. .5 mm tablets were obtained.
• a rotary tablet press VELA2 manufactured by Kikusui Seisakusho Co., Ltd.
• a rotary tablet machine VELA2 manufactured by Kikusui Seisakusho Co., Ltd.
• Example 25 Regarding the tablet of Example 25, according to the prescription in Table 4, each component in an amount 1000 times the prescription was thoroughly mixed, and then compressed using a rotary tablet press VELA2 (manufactured by Kikusui Seisakusho Co., Ltd.) to a diameter of 9. .5 mm tablets were obtained.
• a rotary tablet press VELA2 manufactured by Kikusui Seisakusho Co., Ltd.
• Example 26 The tablet of Example 26 was manufactured using canagliflozin hemihydrate in place of canagle granules. That is, according to the recipe in Table 4, after thoroughly mixing 1000 times the amount of each ingredient in the recipe, tablets with a diameter of 9.5 mm were obtained by compressing using a rotary tablet press VELA2 (manufactured by Kikusui Seisakusho Co., Ltd.). Ta.
• Examples 27-32 Regarding the tablets of Examples 27 to 32, according to the formulations in Tables 5-1 and 5-2, each component in an amount of 150,000 times the formulation was thoroughly mixed, and then the tablets were prepared using a rotary tablet press AQU30518SW2AIII (manufactured by Kikusui Seisakusho Co., Ltd.). Tablets with a diameter of 9.5 mm were obtained by compressing the tablets with the tablet hardness shown in Tables 5-1 and 5-2.
• Example 33 Regarding the tablet of Example 33, according to the prescription in Table 5-2, after thoroughly mixing each component in an amount 1000 times the prescription, the tablet was compressed using a rotary tablet machine VELA2 (manufactured by Kikusui Seisakusho Co., Ltd.). Tablets with a diameter of 7 mm were obtained.
• a rotary tablet machine VELA2 manufactured by Kikusui Seisakusho Co., Ltd.
• Examples 34-38 Regarding the tablets of Examples 34 to 38, according to the prescriptions in Tables 6-1 and 6-2, each component in an amount of 400 times the prescription was thoroughly mixed, and then the tablets were prepared using a rotary tablet press VELA2 (manufactured by Kikusui Seisakusho Co., Ltd.). By compressing the mixture, tablets with a diameter of 9.5 mm were obtained.
• a rotary tablet press VELA2 manufactured by Kikusui Seisakusho Co., Ltd.
• Examples 39-43 Regarding the tablets of Examples 39 to 43, according to the prescriptions in Tables 7-1 and 7-2, each component was mixed in an amount 50 times the amount of the prescription, and then a single tablet machine TK-TB20kN (manufactured by Tokushu Keizoku Co., Ltd.) was used. Tablets with a diameter of 9.5 mm were obtained by compression using a compressor.
• TK-TB20kN manufactured by Tokushu Keizoku Co., Ltd.
• Example 44 Regarding the tablet of Example 44, according to the prescription in Table 8, each component in an amount 3000 times the prescription was thoroughly mixed, and then compressed using a rotary tablet press VELA2 (manufactured by Kikusui Seisakusho Co., Ltd.) to a diameter of 7 mm. tablets were obtained.
• a rotary tablet press VELA2 manufactured by Kikusui Seisakusho Co., Ltd.
• Example 45 Regarding the tablet of Example 45, the following steps (1) to (3) were carried out according to the prescription in Table 9, and in addition to canagliflozin etc., teneligliptin hydrobromide hydrate, which is another active ingredient, was added.
• a tablet containing the following was prepared.
• This example is an orally disintegrating tablet in the form of a so-called combination drug.
• the active ingredients in this example are canagliflozin etc. and teneligliptin.
• Comparative example 1 Regarding Comparative Example 1, after thoroughly mixing 1000 times the amount of each component according to the recipe in Table 4, compression was attempted using a rotary tablet machine VELA2 (manufactured by Kikusui Seisakusho Co., Ltd.), but the tablets failed to form. could not.
• a rotary tablet machine VELA2 manufactured by Kikusui Seisakusho Co., Ltd.
• Comparative examples 2 to 4 Regarding the tablets of Comparative Examples 2 to 4, according to the prescription in Table 6-2, each component in an amount 400 times the prescription was thoroughly mixed, and then compressed using a rotary tablet press VELA2 (manufactured by Kikusui Seisakusho Co., Ltd.). As a result, tablets with a diameter of 9.5 mm were obtained.
• Comparative example 5 Regarding the tablets of Comparative Example 5, according to the recipe in Table 6-3, after thoroughly mixing 133 times the amount of each ingredient in the recipe, the tablets were compressed using a rotary tablet machine VELA2 (manufactured by Kikusui Seisakusho Co., Ltd.). Tablets with a diameter of 9.5 mm were obtained.
• a rotary tablet machine VELA2 manufactured by Kikusui Seisakusho Co., Ltd.
• Comparative example 6 Regarding the tablets of Comparative Example 6, according to the prescription in Table 6-3, after thoroughly mixing 67 times the amount of each ingredient in the prescription, the tablets were compressed using a rotary tablet press VELA2 (manufactured by Kikusui Seisakusho Co., Ltd.) to reduce the diameter. 9.5 mm tablets were obtained.
• a rotary tablet press VELA2 manufactured by Kikusui Seisakusho Co., Ltd.
• Comparative example 7 Regarding the tablets of Comparative Example 7, according to the recipe in Table 6-3, after thoroughly mixing 400 times the amount of each ingredient in the recipe, the tablets were compressed using a rotary tablet machine VELA2 (manufactured by Kikusui Seisakusho Co., Ltd.). Tablets with a diameter of 9.5 mm were obtained.
• a rotary tablet machine VELA2 manufactured by Kikusui Seisakusho Co., Ltd.
• Comparative example 8 Regarding the tablets of Comparative Example 8, according to the recipe in Table 7-2, 50 times the amount of each ingredient in the recipe was thoroughly mixed, and then compressed using a single-shot tablet machine TK-TB20kN (manufactured by Tokushu Keizoku Co., Ltd.). , tablets with a diameter of 9.5 mm were obtained.
• TK-TB20kN manufactured by Tokushu Keizoku Co., Ltd.
• Test example 1 oral disintegration test
• the measurement of oral disintegration time is carried out using a healthy adult between the ages of 25 and 45, and the starting time is the time when the measurer takes the orally disintegrating tablet. Measure the time when it completely collapses. Then, the time declared by the measurer from the start time is defined as the collapse time.
• the term "completely disintegrated” refers to the time when the disintegrated orally disintegrating tablet no longer feels rough to the touch in the oral cavity.
• Table 1-1 Table 1-2, Table 1-3, Table 2-1, Table 2-2, Table 2-3, Table 3, Table 4, Table 5-1, Table 5-2. , shown in Tables 8 and 9.
• Tables 1-1 to 5-2, Tables 8 and 9 the oral disintegration time of the tablets of Examples 1 to 33, 44 and 45 was all within 60 seconds.
• Comparative Example 1 lacking excipients as shown in Table 4, tablets could not be formed.
• Test example 2 The friability of the tablet was expressed as a mass reduction rate (%) according to the "Tablet friability test method" described in the 18th edition of the Japanese Pharmacopoeia.
• the mass reduction rate is the percentage of the mass of the tablet after being subjected to the friability tester relative to the mass of the tablet before being subjected to the friability tester.
• the accurately weighed tablet samples of Examples 27 to 33, 44, and 45 were placed in the drum of a friability tester PTF 30ERA (manufactured by Pharma Test), and the drum was rotated at 100 rpm at 25 rpm. Rotated.
• Test example 3 A photostability test was conducted on the tablets obtained in Examples 34 to 43 and Comparative Examples 2 to 8 using LTL-200A5-15WCD (manufactured by Nagano Science Co., Ltd.).
• Test example 4 A bioequivalence test between these tablets was conducted using the orally disintegrating tablet shown in Example 10 and the ordinary tablet prepared by the method described in US Patent Application Publication No. 2013/052266. All of these tablets have the same amount of active ingredient.
• the orally disintegrating tablet containing canagliflozin is also referred to as "Canaglu (registered trademark) OD tablet 100 mg", including in Tables 10-1, 10-2, FIGS. 1A and 1B.
• regular tablets containing canagliflozin are also expressed as "Canagle (registered trademark) tablets 100 mg [regular tablets]."
• the bioequivalence study involved a single oral administration of Canaglu OD Tablets 100 mg or Canaglu Tablets 100 mg [regular tablets] to healthy adult men who had fasted for 10 hours or more, and conducted a randomized, open-label, cross-over study. It was carried out. A total of 70 subjects were assigned, with 48 subjects taking Canaglu OD Tablets 100 mg without water and 22 subjects taking Canaglu OD Tablets 100 mg with water. Regarding Canaglu Tablets 100 mg [regular tablet], each subject took it with water.
• the evaluation items for this test were the following (a) to (d).
• Plasma concentration of unchanged canagliflozin (d)
• Safety endpoints adverse events and side effects
• Test example 5 (stability test under humidity control conditions) The tablets of Example 45 were stored for 24 hours under the humidity-controlled conditions shown in Table 11-1, and the humidity-controlled tablets were packaged in an aluminum bag to be used as a package for stability testing. Samples were also prepared in which a desiccant was enclosed in a humidity-controlled aluminum tablet bag. The prepared specimens were stored at 40°C and 75% RH for 6 months, and the chemical stability was determined by measuring the water activity (Aw) of the tablets after storage and the amount of produced main related substances derived from teneligliptin. was evaluated. The smaller the amount of related substances produced, the higher the chemical stability. The results are shown in Table 11-1 and FIG. 2A.
• the water activity value was measured using a water activity measuring device (equipment name: LabMASTER-aw, manufactured by Novasina AG) using an electrical resistance type device specified by the Food Sanitation Law.
• the amount of the main related substances produced was measured according to the method using liquid chromatography described above.
• Example 45 The tablets of Example 45 were packaged in a press-through package (PTP) and packaged in an aluminum bag together with a desiccant to form a package for stability testing.
• the desiccant used and the material of the PTP packaging used are shown in Table 11-2.
• the prepared specimens were stored at 40°C and 75% RH for 6 months, and the chemical stability was determined by measuring the water activity (Aw) of the tablets after storage and the amount of produced main related substances derived from teneligliptin. was evaluated. The results are shown in Table 11-2 and FIG. 2B.
• the orally disintegrating tablet of the present invention has a suitable strength (hardness) that does not disintegrate due to external forces generated during the distribution process, etc., and shows rapid disintegration in the oral cavity, so it can be used by elderly people and patients who have difficulty swallowing. It is possible to provide safe and easy-to-use formulations.
• the orally disintegrating tablet of the present invention contains canagliflozin or the like as an active ingredient, more rapid disintegration can be achieved due to its excellent water conductivity.
• the orally disintegrating tablet of the present invention can be prepared by adding a coloring agent (for example, an iron oxide pigment or a tar pigment) and/or by packaging or blocking light using an ultraviolet absorbing film material or the like.
• the orally disintegrating tablet of the present invention does not require any special equipment and can be easily manufactured.
• the orally disintegrating tablet of the present invention contains canagliflozin etc. as an active ingredient, it can be used to treat diabetes (type 1 and type 2 diabetes, etc.), diabetic complications (diabetic retinopathy, diabetic neuropathy, diabetic (nephropathy, etc.), delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, hyperfatty acidemia, hyperglycerolemia, dyslipidemia, obesity, hypertriglyceridemia, X syndrome, atherosclerosis, It is useful as a therapeutic agent for hypertension, etc.

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