Classifications

• • 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
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
• • 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
  • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

• the present invention relates to improving the stability of the active ingredient, [(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid monobenzenesulfonate (hereinafter sometimes referred to as "mirogabalin besylate”), by reducing the reducing sugar contained in an additive used in a pharmaceutical solid formulation.
• Mirogabalin besylate is thought to exert its analgesic effect by inhibiting calcium currents through binding to the ⁇ 2 ⁇ subunit, which plays an auxiliary role in the function of voltage-dependent calcium channels in the nervous system.
• Mirogabalin besylate has been approved for manufacture and sale as a neuropathic pain treatment based on clinical trials conducted both in Japan and overseas, and is currently on sale.
• the inventors discovered that by reducing the reducing sugars contained in additives used in pharmaceutical solid preparations containing mirogabalin besylate as an active ingredient, the stability of the active ingredient, mirogabalin besylate, was dramatically improved, and the problem was solved by using high-purity additives, resulting in the completion of the present invention.
• the present invention relates to a solid formulation and a method for producing the same, which ensures the stability of mirogabalin besylate by using an additive with a low content of reducing sugar in the formulation of mirogabalin besylate.
• Preferred embodiments of the present invention are as follows. [1] Contains mirogabalin or a pharma- ceutically acceptable salt thereof; Containing one or more pharma- ceutically acceptable additives, at least The one or more pharma- ceutically acceptable additives include: Contains excipients and/or disintegrants, A pharmaceutical solid formulation that is substantially free of reducing sugars.
• [2] Contains mirogabalin or a pharma- ceutically acceptable salt thereof, Containing one or more pharma- ceutically acceptable additives, at least The one or more pharma- ceutically acceptable additives include: Contains excipients and/or disintegrants, A pharmaceutical solid preparation, in which the ratio of reducing sugar contained in the pharmaceutical solid preparation to mirogabalin or a pharma- ceutical acceptable salt thereof is 0.9 mol % or less. [3] A solid formulation according to [2], wherein the ratio of reducing sugar contained in one solid formulation to mirogabalin or a pharma- ceutically acceptable salt thereof is 0.7 mol % or less.
• [4] Contains mirogabalin or a pharma- ceutically acceptable salt thereof, Containing one or more pharma- ceutically acceptable additives, at least The one or more pharma- ceutically acceptable additives include: Contains excipients and/or disintegrants, A pharmaceutical solid preparation in which the ratio of related substances contained in one solid preparation to mirogabalin or a pharma- ceutical acceptable salt thereof is less than 0.24%. [5] A solid formulation described in [4], in which the ratio of related substances contained in one solid formulation to mirogabalin or a pharma- ceutically acceptable salt thereof is less than 0.20%.
• [6] A solid formulation described in [4], in which the ratio of related substances contained in one solid formulation to mirogabalin or a pharma- ceutically acceptable salt thereof is less than 0.18%. [7] The solid formulation according to any one of [4] to [6], wherein the related substances are measured after the solid formulation is subjected to an accelerated test under conditions of 40°C and 75% RH for 6 months. [8] 1.
• a solid formulation comprising mannitol as an excipient the solid formulation being any one of [1] to [8].
• a solid dosage form which is any one of [1] to [10] and is a tablet.
• a method for producing a solid formulation according to [2], wherein the ratio of reducing sugar to mirogabalin or a pharma- ceutically acceptable salt thereof in one solid formulation is 0.9 mol % or less.
• the stability of the active ingredient, mirogabalin besylate can be dramatically improved by controlling the amount of reducing sugar in a pharmaceutical solid formulation.
• the present invention makes it possible to provide a solid formulation (particularly a tablet) containing high-quality mirogabalin besylate.
• the content of mirogabalin besylate in the tablet used in the present invention is preferably 0.5-40% by weight, more preferably 0.5-25% by weight, and particularly preferably 0.5-10% by weight (and even more particularly preferably 1.0-5.0% by weight).
• Film-coated tablets containing mirogabalin besylate as the active ingredient are known to contain the following excipients, according to the Pharmaceuticals and Medical Devices Agency website (https://www.pmda.go.jp/PmdaSearch/iyakuSearch): mannitol, crystalline cellulose, carmellose calcium, tocopherol, citric acid hydrate, magnesium aluminometasilicate, magnesium stearate, hypromellose, titanium oxide, talc, yellow ferric oxide, and ferric oxide.
• orally disintegrating tablets containing mirogabalin besylate as the active ingredient are known to contain the following excipients, according to the Pharmaceuticals and Medical Devices Agency website (https://www.pmda.go.jp/PmdaSearch/iyakuSearch): mannitol, crystalline cellulose, carmellose, hydroxypropyl cellulose, tocopherol, citric acid hydrate, magnesium aluminometasilicate, pregelatinized starch, crospovidone, acesulfame potassium, yellow ferric oxide, and magnesium stearate.
• the package insert for the mirogabalin besylate preparation states the following dosage and administration: "Usually, for adults, the initial dose of mirogabalin is 5 mg orally administered twice daily, and then the dose is gradually increased by 5 mg at intervals of at least one week until a dose of 15 mg is administered orally twice daily. The dose may be increased or decreased within the range of 10 mg to 15 mg, depending on age and symptoms, and administered twice daily.”
• “Pharmaceutically acceptable salt” refers to a salt that can be used as a medicine.
• Mirogabalin has an amino group and a carboxy group in its structure, and forms a salt by reacting with the corresponding acid or base, so this refers to the salt.
• Salts based on amino groups include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as hydrochloride, nitrate, perchlorate, sulfate, and phosphate; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, and maleate; and amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate.
• hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide
• they are inorganic acid salts or arylsulfonates, more preferably hydrochloride, benzenesulfonate, or p-toluenesulfonate, and particularly preferably benzenesulfonate (sometimes called besylate).
• Salts based on carboxyl groups include alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; metal salts such as aluminum salts and iron salts; inorganic salts such as ammonium salts; amine salts such as t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts, and organic salts
• “Additives” are important components that, together with active ingredients, form pharmaceuticals and provide benefits such as making the pharmaceutical easier to take (masking bitterness and odors, etc.), improving stability, and ensuring stable release of the active ingredient. They also help to facilitate formulation, and are components that can be used in pharmaceutical solid preparations, such as excipients, disintegrants, binders, lubricants, flow agents, coating agents, colorants, and gloss agents.
• Substantially free means that, when the additive is used, it contains reducing sugars at a lower percentage than the appropriate content.
• the content of reducing sugar is preferably 0.9 mol% or less, and more preferably 0.7 mol% or less, as a ratio (mol%) of the total amount of mirogabalin besylate in the pharmaceutical solid formulation of the present invention.
• the content of related substances relative to the total amount of the pharmaceutical solid preparation of the present invention is preferably less than 0.24%, more preferably less than 0.20%, and even more preferably less than 0.18%.
• Reducing sugar refers to a sugar that forms an aldehyde or ketone group in a basic solution.
• reducing sugars include glucose, fructose, galactose, maltose, lactose, lactulose, cellobiose, glyceraldehyde, arabinose, mannose, xylose, melibiose, maltotriose, and the like, as well as hydrates thereof.
• excipient is defined in general reference books on formulations (for example, “Revised Edition Pharmaceutical Additives Handbook,” Yakuji Nipposha Co., Ltd., February 28, 2007) and refers to ingredients added to formulations such as tablets to achieve a certain size and concentration.
• the content of mannitol used in the present invention is preferably 50-90% by weight, more preferably 75-85% by weight, based on the total weight of the uncoated tablet.
• Disintegrants are those described in general reference books on formulations (for example, “Revised Pharmaceutical Additives Handbook,” Yakuji Nipposha, February 28, 2007) and refer to ingredients added to tablets, etc., to absorb moisture from the body and expand, thereby disintegrating the tablets and facilitating the release of active ingredients.
• Examples include alginic acid, calcium alginate, carboxymethylcellulose (carmellose), carboxymethylcellulose calcium (carmellose calcium), sodium carboxymethylcellulose, crystalline cellulose, powdered cellulose, chitosan, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, low-substituted hydroxypropylcellulose, hydroxypropyl starch, magnesium aluminum methylcellulose silicate, polacrilin potassium, povidone, sodium alginate, sodium starch glycolate, starch, and pregelatinized starch, with carmellose and carmellose calcium being particularly preferred.
• the content of carmellose or carmellose calcium used in the present invention is preferably 2-20% by weight, and more preferably 5-15% by weight, based on the total weight of the uncoated tablet.
• ingredients commonly used in formulations such as binders, lubricants, flow agents, coating agents, colorants, and gloss agents, may also be used within the scope of the present invention without impairing its effects.
• the "binder” may be one or a combination of two or more selected from gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, pullulan, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and macrogol.
• the "lubricant” may be one or a combination of two or more selected from magnesium stearate (e.g., a product conforming to the Japanese Pharmacopoeia), calcium stearate (e.g., a product conforming to the Japanese Pharmacopoeia), sodium stearyl fumarate (e.g., a product conforming to the Pharmaceutical Additives Standards), and talc (e.g., a product conforming to the Japanese Pharmacopoeia).
• magnesium stearate e.g., a product conforming to the Japanese Pharmacopoeia
• calcium stearate e.g., a product conforming to the Japanese Pharmacopoeia
• sodium stearyl fumarate e.g., a product conforming to the Pharmaceutical Additives Standards
• talc e.g., a product conforming to the Japanese Pharmacopoeia.
• Magnesium stearate is particularly preferred.
• the "fluidizing agent” may be one or a combination of two or more selected from hydrated silicon dioxide, light anhydrous silicic acid, and talc.
• the "coating agent” is a coating agent that coats the surface of a plain tablet, the surface of a powdered drug (the surface of a crystal), or the granule surface of a granulated drug, and may include one or a combination of two or more selected from hypromellose, polyethylene glycol, ethyl cellulose, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer, polyvinyl acetal-diethylamino acetate, and polyvinyl acetate resin.
• Coding agents include food dyes such as Food Yellow No. 5, Food Red No. 2, and Food Blue No. 2; food lake color, yellow ferric oxide, ferric oxide, titanium oxide, ⁇ -carotene, and riboflavin, or a combination of two or more selected therefrom.
• Solid dosage form includes any formulation used by those skilled in the art to deliver one or more pharmacologic active ingredients to a patient in solid form.
• Suitable solid formulations are well known to those skilled in the art, and examples of solid formulations of the present invention include, but are not limited to, tablets (including sublingual tablets and tablets that disintegrate in the mouth), capsules (including soft capsules and microcapsules), granules, pills, and lozenges. Tablets are a suitable solid formulation of the present invention.
• the solid formulation of the present invention can be produced by any method commonly used and known to those skilled in the art of pharmaceutical formulation technology, and is not particularly limited thereto.
• the manufacturing method of the tablets is as follows: (1) Direct compression, in which the active ingredient and additives are mixed and compressed in a tablet press. (2) The semi-direct compression method, in which the additives are granulated, mixed with the drug, and compressed into a mold. (3) Dry granulation compression method in which active ingredients and additives are granulated into granules using a dry method, then lubricants and other additives are added and compressed to form the granules. (4) A wet granulation compression method in which the active ingredient and additives are granulated into granules using a wet method, a lubricant is added thereto, and the granules are then compressed and molded.
• Granulation methods that can be used include fluidized bed granulation, high speed stirring granulation, and melting granulation.
• the preferred method for producing the tablets of the present invention is to prepare tablets by directly compressing the mixed powder of the active ingredients without granulating the powder of the active ingredients.
• the active ingredient is mixed in a suitable mixer along with one or more pharma- ceutically acceptable excipients and then transferred directly to a compression machine and pressed into tablets.
• suitable mixer along with one or more pharma- ceutically acceptable excipients
• Other conventional methods such as wet granulation and dry granulation can also be used.
• the tablet of the present invention may be provided with at least one layer of film coating.
• film coating forming equipment of the type well known in the art may be used.
• suitable film coating bases include sugar coating bases, hydrophilic coating bases, enteric coating bases, and sustained release coating bases.
• “Sugar-coating bases” include, for example, sucrose, and may further include one or more of the following additives in combination: talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone, and pullulan.
• the "hydrophilic film base” may be, for example, a cellulose derivative such as hydroxypropyl cellulose, hydroxypropyl methylcellulose (for example, a premix containing hydroxypropyl methylcellulose as the main component, which is commercially available from Japan Colorcon LLC as OPADRY (registered trademark)), hydroxyethyl cellulose, methylhydroxyethyl cellulose, and sodium carboxymethyl cellulose; a synthetic polymer such as polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymer, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, and macrogol; or a polysaccharide such as pullulan, which may be used alone or in combination. More preferably, OPADRY (registered trademark) containing hydroxypropyl methylcellulose as the main component may be used.
• OPADRY registered trademark
• the “enteric coating base” may be, for example, one or more of cellulose derivatives such as hydroxypropylmethylcellulose, phthalate hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S; and natural substances such as shellac, which may be used in combination.
• cellulose derivatives such as hydroxypropylmethylcellulose, phthalate hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate
• acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S
• natural substances such as shellac, which may be used in combination.
• the "sustained release coating base” one or more of the following can be used in combination: cellulose derivatives such as ethyl cellulose; and acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS and ethyl acrylate-methyl methacrylate copolymer emulsion.
• Premixes such as OPADRY®, which are based on hydroxypropyl methylcellulose, are typically used as film coatings. Film coatings also typically contain suitable pharma- ceutically acceptable additives such as plasticizers, excipients, lubricants, opacifiers, colorants, or preservatives, as required.
• the tablets of the present invention can be manufactured by the manufacturing method described below.
• the active ingredient, mirogabalin besylate is crushed to adjust the particle size, and then excipients and/or disintegrants are added and mixed.
• the mixture is sieved using a granulator, a lubricant is added, and the mixture is further mixed and compressed using a tablet press to obtain plain tablets.
• the obtained plain tablets are made into coated tablets using a coating device.
• D-mannitol to which mirogabalin besylate and D-glucose had been added was weighed out in the ratio shown in Table 1, mixed in an 8K bottle for 5 minutes, and then sieved to obtain the sample.
• Mirogabalin besilate, D-mannitol, carmellose calcium, pre-sieved citric acid hydrate, 10x tocopherol powder, magnesium aluminometasilicate, and OPADRY (registered trademark) were weighed out in the ratio shown in Table 4, mixed in an 8K bottle for 5 minutes, and then sieved to obtain a sample of formulation 2.
• PEARLITOL registered trademark 100SD: Roquette Freres 2) Japanese Pharmacopoeia Tocopherol: Mitsubishi Chemical Corporation, CEOLUS (registered trademark) UF-702: Asahi Kasei Corporation 3) ECG-505: Gotoku Pharmaceutical Co., Ltd. 4) Neusilin US2: Fuji Chemical Industry Co., Ltd. 5) Citric acid monohydrate powder EMPROVE ESSENTIAL:Merck KGaA 6) Magnesium stearate (vegetable-based): Taihei Chemical Industry Co., Ltd. 7) OPADRY® 01A440004 (a coating premix consisting of hypromellose, titanium dioxide, talc, yellow ferric oxide and ferric oxide): Colorcon Japan LLC
• the amount of reducing sugar in the D-mannitol used to prepare each sample was measured using a spectrophotometer (UV-2550, Shimadzu Corporation).
• Example 3 Correlation between reducing sugars and related substances contained in D-mannitol
• Sample preparation method for Example 10 Tocopherol and crystalline cellulose were mixed in a ratio of 1:9 using a high-speed stirring granulator to disperse tocopherol 10 times.
• Mirogabalin besilate, D-mannitol, carmellose calcium, magnesium aluminometasilicate, citric acid hydrate, and 10x tocopherol powder were weighed out in the mixing ratio shown in Table 6, mixed in a tumble mixer, sieved through a screening mill, magnesium stearate was added, and the mixture was mixed in a tumble mixer to obtain a mixed powder for tableting.
• the powder mixture for tableting is compressed in a tablet press to produce plain tablets.
• a coating solution consisting of OPADRY (registered trademark) and water is sprayed onto the plain tablets. After spraying, the tablets are dried to obtain film-coated tablets with a coating layer weight of 3-4% of the plain tablet.
• the film-coated tablets are filled into a heat-formed PTP film, heat-sealed with a PTP lid, and the sealed product is then cut into pieces to prepare samples.
• PEARLITOL registered trademark 100SD: Roquette Freres 2
• Japanese Pharmacopoeia Tocopherol Mitsubishi Chemical Corporation
• CEOLUS registered trademark
• UF-702 Asahi Kasei Corporation
• ECG-505 Gotoku Pharmaceutical Co., Ltd.
• Neusilin US2 Fuji Chemical Industry Co., Ltd.
• Citric acid monohydrate powder EMPROVE ESSENTIAL Merck KGaA 6)
• the reducing sugar content of the D-mannitol used to prepare the samples was measured using a spectrophotometer (UV-2550, Shimadzu Corporation).
• Table 7 shows the relationship between the amount of related substances in the sample after storage for 6 months at 40°C, 75% RH/aluminum bag containing a desiccant, and the ratio (mol%) of reducing sugars in D-mannitol to mirogabalin besylate in the formulation. The two showed a high correlation with a correlation coefficient of 0.99 or higher.
• the ratio (mol%) of reducing sugars in D-mannitol to mirogabalin besilate in one tablet is 0.9 mol% or less, more preferably 0.7 mol% or less
• the amount of related substances is set to be within the range of 0.9 mol% or less, as specified in "Revision of the Guidelines on Impurities in Pharmaceuticals Containing New Active Ingredients (Notification No.
• the present invention makes it possible to suppress the generation of related substances to below the standard value "threshold value of 0.2% requiring structural determination of impurities" (0.15 or more and less than 0.25) described in "Revision of the Guidelines on Impurities in Drug Formulations Containing New Active Ingredients (PMDA Notification No. 0624001 dated June 24, 2003)" (https://www.pmda.go.jp/files/000156298.pdf).
• the following is an example of the production of the tablet of the present invention. This example is not to be construed as limiting the present invention.
• (1) Blending and sieving Mirogabalin besylate, D-mannitol, and carmellose calcium were weighed out in the blending ratio shown in Table 8 below, and blended for 2 minutes at 31 rpm using a V-type blender (60 L).
• the mixture was sieved at 600 rpm using a Comil (QC-194S, ⁇ 1.143mm, QUADRO) to obtain the sieved powder.
• magnesium stearate was weighed out in the blending ratio shown in Table 8, added to the sieved powder, and mixed for 6 minutes at 31 rpm using a V-type mixer (60 L).
• Coating OPADRY registered trademark
• the uncoated tablets were coated using a coating device (DRC300, Powrex) at an inlet air temperature of 70°C, an inlet air volume of 1.0 m3 /min, a spray rate of approximately 7 g/min, a pan rotation speed of 20 rpm, and an exhaust temperature end point of approximately 36°C to obtain coated tablets.
• a coating device DRC300, Powrex

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Neurosurgery (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pain & Pain Management (AREA)
• Molecular Biology (AREA)
• Biophysics (AREA)
• Inorganic Chemistry (AREA)
• Biochemistry (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Medicinal Preparation (AREA)

Priority Applications (3)

Applications Claiming Priority (2)

Publications (1)

Family

ID=93658131

Family Applications (1)

Country Status (5)

Cited By (3)

Citations (2)

Family Cites Families (5)

• 2024
  • 2024-05-30 JP JP2025524867A patent/JPWO2024248079A1/ja active Pending
  • 2024-05-30 TW TW113119971A patent/TW202513048A/zh unknown
  • 2024-05-30 WO PCT/JP2024/019828 patent/WO2024248079A1/ja not_active Ceased
  • 2024-05-30 KR KR1020257037178A patent/KR20260018020A/ko active Pending
  • 2024-05-30 CN CN202480035836.7A patent/CN121218983A/zh active Pending

Patent Citations (2)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events