WO2023145486A1 - Méthode de production d'une formulation contenant du fumarate de fésotérodine - Google Patents
Méthode de production d'une formulation contenant du fumarate de fésotérodine Download PDFInfo
- Publication number
- WO2023145486A1 WO2023145486A1 PCT/JP2023/000786 JP2023000786W WO2023145486A1 WO 2023145486 A1 WO2023145486 A1 WO 2023145486A1 JP 2023000786 W JP2023000786 W JP 2023000786W WO 2023145486 A1 WO2023145486 A1 WO 2023145486A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fesoterodine fumarate
- fumarate
- fesoterodine
- lubricant
- lactose
- Prior art date
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- MWHXMIASLKXGBU-RNCYCKTQSA-N (e)-but-2-enedioic acid;[2-[(1r)-3-[di(propan-2-yl)amino]-1-phenylpropyl]-4-(hydroxymethyl)phenyl] 2-methylpropanoate Chemical compound OC(=O)\C=C\C(O)=O.C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(CO)C=2)OC(=O)C(C)C)=CC=CC=C1 MWHXMIASLKXGBU-RNCYCKTQSA-N 0.000 title claims abstract description 118
- 229960004524 fesoterodine fumarate Drugs 0.000 title claims abstract description 117
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 36
- 239000000203 mixture Substances 0.000 title abstract description 34
- 238000009472 formulation Methods 0.000 title abstract description 29
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims abstract description 36
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 34
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 34
- 239000000314 lubricant Substances 0.000 claims abstract description 29
- 229920002678 cellulose Polymers 0.000 claims abstract description 26
- 239000001913 cellulose Substances 0.000 claims abstract description 26
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 23
- 229960003943 hypromellose Drugs 0.000 claims abstract description 22
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 20
- 239000008101 lactose Substances 0.000 claims abstract description 20
- 238000002156 mixing Methods 0.000 claims abstract description 6
- 239000000843 powder Substances 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims description 61
- 239000008187 granular material Substances 0.000 claims description 36
- -1 sucrose fatty acid ester Chemical class 0.000 claims description 35
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 34
- 239000000194 fatty acid Substances 0.000 claims description 34
- 229930195729 fatty acid Natural products 0.000 claims description 34
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 30
- 235000011187 glycerol Nutrition 0.000 claims description 28
- 235000010980 cellulose Nutrition 0.000 claims description 23
- 229910052623 talc Inorganic materials 0.000 claims description 14
- 239000000454 talc Substances 0.000 claims description 10
- 229930006000 Sucrose Natural products 0.000 claims description 7
- 239000005720 sucrose Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 abstract description 42
- 239000000126 substance Substances 0.000 abstract description 30
- 239000000654 additive Substances 0.000 abstract description 5
- 230000000996 additive effect Effects 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 4
- 229960004977 anhydrous lactose Drugs 0.000 description 18
- 238000007908 dry granulation Methods 0.000 description 18
- 238000007907 direct compression Methods 0.000 description 14
- 229920003091 Methocel™ Polymers 0.000 description 13
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 13
- 229960001375 lactose Drugs 0.000 description 13
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 13
- 239000000811 xylitol Substances 0.000 description 13
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 13
- 235000010447 xylitol Nutrition 0.000 description 13
- 229960002675 xylitol Drugs 0.000 description 13
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 11
- 239000004372 Polyvinyl alcohol Substances 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 11
- 229920002451 polyvinyl alcohol Polymers 0.000 description 11
- 238000005550 wet granulation Methods 0.000 description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 9
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 9
- 239000008108 microcrystalline cellulose Substances 0.000 description 9
- 229940016286 microcrystalline cellulose Drugs 0.000 description 9
- DMBUODUULYCPAK-UHFFFAOYSA-N 1,3-bis(docosanoyloxy)propan-2-yl docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC DMBUODUULYCPAK-UHFFFAOYSA-N 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 235000010724 Wisteria floribunda Nutrition 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000004386 Erythritol Substances 0.000 description 3
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 229920003086 cellulose ether Polymers 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 3
- 235000019414 erythritol Nutrition 0.000 description 3
- 229940009714 erythritol Drugs 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000007941 film coated tablet Substances 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 229920005862 polyol Polymers 0.000 description 3
- 150000003077 polyols Chemical class 0.000 description 3
- 150000005846 sugar alcohols Chemical class 0.000 description 3
- 241000209094 Oryza Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- DCCSDBARQIPTGU-HSZRJFAPSA-N fesoterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(CO)C=2)OC(=O)C(C)C)=CC=CC=C1 DCCSDBARQIPTGU-HSZRJFAPSA-N 0.000 description 2
- 229960002978 fesoterodine Drugs 0.000 description 2
- 238000004898 kneading Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 239000003605 opacifier Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 229920000058 polyacrylate Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 238000004513 sizing Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 229920001059 synthetic polymer Polymers 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102220487426 Actin-related protein 2/3 complex subunit 3_K15M_mutation Human genes 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229920006243 acrylic copolymer Polymers 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940099371 diacetylated monoglycerides Drugs 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- 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
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
Definitions
- One embodiment of the present invention relates to a method for producing a fesoterodine fumarate-containing preparation.
- Hydrogen fumarate of 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl isobutyrate (hereinafter referred to as fesoterodine fumarate) is It is a therapeutic agent for active bladder. Fesoterodine fumarate is known to degrade under harsh environmental conditions such as high humidity or high temperature. (Patent document 1).
- Patent Document 1 discloses a pharmaceutical composition containing fesoterodine fumarate and specific polyols as a stabilizer, and a wet granulation method as a method for producing the same, which exhibits excellent stability. is described.
- the wet granulation method requires a step of adding water such as preparation of a binding liquid in the pre-granulation process, and a step of drying the granules after granulation.
- the manufacturing process is more complicated and the manufacturing cost is higher.
- polyol-based stabilizers such as xylitol and sorbitol used in Patent Document 1 are not cheap, and since xylitol exhibits deliquescence, it must be handled with care. For these reasons, there is a demand for the development of a pharmaceutical composition containing fesoterodine fumarate that exhibits excellent stability and can be produced by a simpler production method.
- An object of one embodiment of the present invention is to provide a method for producing a stable fesoterodine fumarate-containing preparation that suppresses the production of related substances by using an easy-to-handle general-purpose additive and a simple production method.
- fesoterodine fumarate, lactose, microcrystalline cellulose and lubricant are dry granulated to obtain a granule.
- Methods of making salt-containing formulations are provided.
- the granules may contain sucrose fatty acid ester or glycerin fatty acid ester as a lubricant.
- the obtained granules, lactose, crystalline cellulose, hypromellose, and a lubricant may be mixed and tableted.
- a glycerin fatty acid ester may be included as a lubricant mixed with the granules.
- Talc may be further included as a lubricant mixed with the granules.
- fesoterodine fumarate comprising mixing fesoterodine fumarate, lactose, microcrystalline cellulose, hypromellose and a lubricant and compressing, comprising fesoterodine fumarate , lactose, microcrystalline cellulose, hypromellose, and a lubricant are each mixed as dry powders to produce a fesoterodine fumarate-containing preparation.
- Talc and glycerin fatty acid esters may be included as lubricants.
- a method for producing a stable fesoterodine fumarate-containing preparation that suppresses the production of related substances, using an easy-to-handle general-purpose additive and a simple production method.
- a method for producing a fesoterodine fumarate-containing preparation according to the present invention will be described below.
- the manufacturing method of the fesoterodine fumarate-containing preparation of the present invention should not be construed as being limited to the contents described in the following embodiments and examples.
- xylitol is used as a stabilizer, and xylitol is known to be a deliquescent additive. Therefore, the present inventors investigated the stability of fesoterodine fumarate-containing preparations produced by the wet granulation method described in Patent Document 1 using other non-deliquescent sugar alcohols. . As a result, a marked increase in related substances was observed. Therefore, xylitol was shown to be an essential constituent component as a stabilizer in the formulation containing fesoterodine fumarate described in Patent Document 1, which employs a wet granulation method.
- Table 8 of Patent Document 1 describes the stability results of tablets produced by a direct compression method in the presence of xylitol
- Table 9 shows the stability of tablets produced by a dry granulation method. Results are given. However, both methods have been shown to produce more hydrolyzate and total degradation products than tablets produced by wet granulation.
- Patent Document 1 it is difficult to obtain a stable fesoterodine fumarate-containing preparation by a production method using a direct compression method or a dry granulation method, which are simpler production methods. was suggested.
- the inventors have found that applying dry granulation or direct compression to specific formulations with easy-to-handle common excipients yields stable fesoterodine fumarate-containing formulations. I found Compared to the wet granulation method, the dry granulation method or direct compression method has fewer manufacturing steps and can be manufactured at low cost, so the dry granulation method or direct compression method is easier to manufacture. method.
- fesoterodine fumarate, lactose, crystalline cellulose, and a lubricant are dry granulated, and granulated. Including obtaining granules.
- Granules can be produced using a roller compactor.
- the lactose used in the present embodiment may be an anhydride or a hydrate.
- the fesoterodine fumarate-containing formulation can contain, but is not limited to, 4 mg or 8 mg of fesoterodine fumarate per tablet.
- the content of fesoterodine fumarate can be varied within the range where a therapeutic effect can be obtained.
- the content of lactose contained in the granules may be in the range of 55% by mass to 85% by mass with respect to 100% by mass of the granules.
- the content of crystalline cellulose contained in the granules may be in the range of 5% by mass to 35% by mass with respect to 100% by mass of the granules.
- a sucrose fatty acid ester or a glycerin fatty acid ester can be selected as a lubricant added during dry granulation. That is, the obtained granules can contain sucrose fatty acid ester or glycerin fatty acid ester as a lubricant. In this embodiment, the sucrose fatty acid ester and the glycerin fatty acid ester have little effect on the amount of hydrolyzate and the total amount of related substances in the fesoterodine fumarate-containing preparation. In one embodiment, the content of the lubricant contained in the granules may be in the range of 0.6% by mass to 2.5% by mass with respect to 100% by mass of the granules.
- polyvinyl alcohol can be further added during dry granulation.
- the obtained granules, lactose, crystalline cellulose, hypromellose, and a lubricant are mixed and tableted to produce a fesoterodine fumarate-containing preparation according to the present embodiment.
- the tableting step may be either a dry tableting method or a wet tableting method as long as the granules obtained in the present invention are used.
- the lactose used in the present embodiment may be an anhydride or a hydrate.
- the fesoterodine fumarate-containing preparation according to the present embodiment contains glycerin fatty acid ester as a lubricant mixed with the granules.
- the fesoterodine fumarate-containing formulation may further comprise talc as a lubricant mixed with the granulation.
- high-viscosity HPMC and low-viscosity HPMC can be used in combination as hypromellose (hereinafter also referred to as HPMC) mixed with the granules.
- HPMC hypromellose
- High-viscosity HPMC has a nominal viscosity (measured by an Ubbelohde viscometer) of about 70,000 mPa s to about 150,000 mPa s, preferably about 100,000 mPa at 22° C. in an aqueous solution of about 2% by mass. • s, indicating an HPMC that is 100,000 ⁇ 20,000 mPa ⁇ s.
- high-viscosity HPMC for example, Dow Chemical's METHOCEL (registered trademark) K15M or METHOCEL (registered trademark) K100M can be used.
- low-viscosity HPMC has a nominal viscosity of about 3,000 mPa ⁇ s to about 20,000 mPa ⁇ s, preferably about 4,000 mPa ⁇ s in an aqueous solution of about 2% by mass at 22°C. HPMC is shown to be 4,000 mPa ⁇ s ⁇ 1,000 mPa ⁇ s.
- METHOCEL (registered trademark) E4M or METHOCEL (registered trademark) K4M from Dow Chemical can be used.
- a direct compression method can be used to produce a fesoterodine fumarate-containing formulation that suppresses an increase in the amount of hydrolyzate of fesoterodine fumarate and an increase in the amount of total related substances.
- fesoterodine fumarate, lactose, crystalline cellulose, hypromellose, and a lubricant are mixed, Compression molding (tabletting) is performed using a commonly used tableting machine.
- Compression molding (tabletting) is performed using a commonly used tableting machine.
- fesoterodine fumarate, lactose, microcrystalline cellulose, hypromellose, and lubricant are each mixed as dry powders. That is, no solvents are used in the mixing process.
- the lactose used in the present embodiment may be an anhydride or a hydrate.
- the fesoterodine fumarate-containing formulation can contain, but is not limited to, 4 mg or 8 mg of fesoterodine fumarate per tablet.
- the content of fesoterodine fumarate can be varied within the range where a therapeutic effect can be obtained.
- the lubricant contains talc and glycerin fatty acid ester.
- fesoterodine fumarate-containing preparation can be used in combination with the above-described high-viscosity HPMC and low-viscosity HPMC as hypromellose, detailed description is omitted.
- the fesoterodine fumarate-containing preparation according to this embodiment can also be a film-coated tablet obtained by applying a film coating to an uncoated tablet obtained by a dry granulation method or a direct compression method.
- a general-purpose film composition can be applied as the film to be coated on the fesoterodine fumarate-containing preparation.
- Polymers, plasticizers, colorants, opacifiers, and/or fillers may be included in the film composition. It may also contain minor amounts of flavors, surfactants and waxes.
- Polymers included in the film composition can be cellulose derivatives such as cellulose ethers, acrylic polymers, and copolymers. Polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol and waxy materials can also be used.
- cellulose ethers additives selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and methyl cellulose can be used.
- Acrylic polymers can include synthetic polymers with diverse functional groups. Synthetic polymers may be further modified to enhance their swellability. It can also be combined with materials such as water-soluble cellulose ethers and starches.
- Plasticizers include polyols (glycerol, propylene glycol, macrogol), organic esters (phthalates, basic dibutyl acetate, citrates, triacetin), oils/glycerides (castor oil, acetylated monoglycerides). and fractionated coconut oil) can be used.
- colorants/opacifiers organic dyes and their lakes, inorganic colorants, and natural colorants can be used, and each material can be combined in a specified ratio.
- Film-coated tablets can be produced by spraying film compositions onto uncoated tablets as dispersions or suspensions using various solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons). .
- stability is evaluated by quantification of fesoterodine fumarate hydrolyzate and total related substances using liquid chromatography.
- area percentage method the total peak area of each component of fesoterodine fumarate and fesoterodine fumarate-derived analogues obtained on the chromatogram was set to 100, and the ratio of the peak areas was determined as fesoterodine fumarate. Calculate the total amount (%) of related substances derived from acid salts.
- Example 1 As Example 1, a formulation containing fesoterodine fumarate was produced by direct compression. 4 g fesoterodine fumarate, lactose hydrate (75%)/microcrystalline cellulose (25%) (MEGGLE, MICROCELAC® 100M) 74.75 g, hypromellose (Dow Chemical, METHOCEL® K100M) 60 g , Hypromellose (Dow Chemical, METHOCEL (registered trademark) K4M) 12 g, talc (Fuji Talc Co., Ltd.) 4.25 g, glycerin fatty acid ester (Compritol 888ATO, GATTEFOSSE) 5 g were mixed in a plastic bag, and a tableting machine (Kikusui Co., Ltd. The fesoterodine fumarate-containing preparation of Example 1 was obtained by tableting to a weight of 320 mg using Seisakusho Co., Ltd.
- Example 2 As Example 2, a preparation containing fesoterodine fumarate was produced by dry granulation. Fesoterodine fumarate 8g, anhydrous lactose (DFEPharma, SuperTabNA21) 57g, crystalline cellulose (Asahi Kasei Corporation, CEOLUS (registered trademark) PH-102) 13.7g, polyvinyl alcohol (Mitsubishi Chemical Corporation, EG-05PW) 0 8 g and 0.5 g of glycerin fatty acid ester (GATTEFOSSE, Compritol 888ATO) were added and mixed, and then dry granulation was performed using a roller compactor (TF-MINI, Freund Corporation) at a roll pressure of 100 kgf/cm 2 , A dry granule was obtained.
- TF-MINI glycerin fatty acid ester
- Example 2 using a tableting machine (Kikusui Seisakusho Co., Ltd., VELA5), tableting was performed so that the weight was 320 mg, and the fesoterodine fumarate-containing preparation of Example 2 was obtained.
- a tableting machine Kikusui Seisakusho Co., Ltd., VELA5
- Comparative Example 1 As Comparative Example 1, a preparation containing fesoterodine fumarate was produced by a wet granulation method. Fesoterodine fumarate 8g, anhydrous lactose (DFE Pharma, SuperTabNA21) 57g, crystalline cellulose (Asahi Kasei Corporation, CEOLUS (registered trademark) PH-102) 13.7g, polyvinyl alcohol (Mitsubishi Chemical Corporation, EG-05PW) 0.8 g was put into a mortar and mixed. After that, 5 g of purified water was added, and stirring and kneading were performed.
- Reference Example 1 As Reference Example 1, a fesoterodine fumarate-containing preparation containing xylitol was produced by a wet granulation method according to the method described in Patent Document 1. 8 g of fesoterodine fumarate and 72 g of xylitol (Xylitol P, Mitsubishi Shoji Foodtech Co., Ltd.) were put into a mortar and mixed. After that, 5 g of purified water was added, and stirring and kneading were performed.
- lactose hydrate (75%)/microcrystalline cellulose (25%) (MEGGLE, MICROCELAC (registered trademark) 100M) 77.5 g, hypromellose (Dow Chemical, METHOCEL (registered trademark) K100M) 120 g, hypromellose (Dow Chemical, METHOCEL (registered trademark) K4M) 24 g, talc (Fuji Talc Co., Ltd.) 8.5 g, glycerin fatty acid ester (GATTEFOSSE, Compritol 888ATO) 10 g were mixed in a plastic bag.
- GATTEFOSSE Compritol 888ATO
- Comparative Example 2 Fesoterodine fumarate of Comparative Example 2 was produced in the same manner as in Reference Example 1, except that the sugar alcohol was changed from xylitol to D-mannitol (Mitsubishi Shoji Foodtech Co., Ltd., Mannitol P). A formulation was obtained.
- Comparative Example 3 A fesoterodine fumarate-containing preparation of Comparative Example 3 was obtained in the same manner as the production method of Reference Example 1, except that the sugar alcohol was changed from xylitol to erythritol (Erythritol 100M, Bussan Food Science Co., Ltd.). .
- Example 1 the left value in each column indicates the amount of hydrolyzate, and the right value indicates the total amount of related substances. From the results in Table 1, the fesoterodine fumarate-containing preparation of Example 1 produced using the direct compression method and the fesoterodine fumarate-containing preparation of Example 2 produced using the dry granulation method were: It was found that the fesoterodine fumarate-containing preparation of Reference Example 1 exhibits the same stability.
- the fesoterodine fumarate-containing preparation of Comparative Example 2 produced by wet granulation with D-mannitol instead of xylitol and the fesoterodine fumarate-containing preparation of Comparative Example 3 produced by wet granulation with erythritol in place of xylitol
- the fesoterodine fumarate-containing preparation of Comparative Example 1 produced by wet granulation showed a significant increase in the amount of hydrolyzate and the total amount of related substances.
- Example 3 As Example 3, 74.75 g of lactose hydrate (75%) / crystalline cellulose (25%) (MEGGLE, MICROCELAC (registered trademark) 100M), 54.25 g of anhydrous lactose (DFEPharma, SuperTabNA21), crystalline cellulose (Asahi Kasei Co., Ltd. CEOLUS (registered trademark) PH-102) was changed to 22.5 g, and hypromellose (Dow Chemical, METHOCEL (registered trademark) K4M) was changed to 10 g. Thus, the fesoterodine fumarate-containing formulation of Example 3 was obtained.
- METHOCEL registered trademark
- Example 4 As Example 4, fesoterodine fumarate 8 g, lactose hydrate (Pharmatose 200M, DMV) 45 g, crystalline cellulose (Asahi Kasei Corporation, CEOLUS (registered trademark) PH-102) 25 g, glycerin fatty acid ester (GATTEFOSSE, Compritol 888ATO) After adding and mixing 2.0 g, dry granulation was performed using a roller compactor (TF-MINI, Freund Corporation) at a roll pressure of 100 kgf/cm 2 to obtain dry granules.
- TF-MINI roller compactor
- a fesoterodine fumarate-containing preparation of Example 4 was obtained by the same production method as in Example 2 using the obtained granules.
- Example 5 As Example 5, 8 g of fesoterodine fumarate, 45 g of anhydrous lactose (DFEPharma, SuperTab NA21), 25 g of crystalline cellulose (CEOLUS (registered trademark) PH-102, Asahi Kasei Corporation), glycerin fatty acid ester (GATTEFOSSE, Compritol888ATO)2. After adding 0 g and mixing, dry granulation was performed using a roller compactor (TF-MINI, Freund Corporation) at a roll pressure of 100 kgf/cm 2 to obtain dry granules.
- TF-MINI roller compactor
- Example 6 A fesoterodine fumarate-containing preparation of Example 6 was obtained in the same manner as the production method of Example 2, except that the anhydrous lactose was changed to 66.7 g and the crystalline cellulose was changed to 4 g.
- Example 7 A preparation containing fesoterodine fumarate of Example 7 was obtained in the same manner as in Example 2, except that polyvinyl alcohol was not added and anhydrous lactose was changed to 57.8 g.
- Example 8 Fesoterodine fumarate of Example 8 was prepared in the same manner as in Example 2, except that polyvinyl alcohol was not added, anhydrous lactose was changed to 46.5 g, and crystalline cellulose was changed to 25 g. A containing formulation was obtained.
- Example 9 Fesoterodine of Example 9 was prepared in the same manner as in Example 2, except that polyvinyl alcohol was not added, anhydrous lactose was changed to 57.3 g, and glycerin fatty acid ester was changed to 1.0 g. A fumarate-containing formulation was obtained.
- Example 10 Fesoterodine of Example 10 was prepared in the same manner as in Example 2, except that polyvinyl alcohol was not added, anhydrous lactose was changed to 56.3 g, and glycerin fatty acid ester was changed to 2.0 g. A fumarate-containing formulation was obtained.
- Example 11 Except that polyvinyl alcohol was not added, the anhydrous lactose was changed to 45 g, the crystalline cellulose was changed to 25 g, and the glycerin fatty acid ester was changed to 2.0 g. A fesoterodine fumarate-containing formulation of Example 11 was obtained.
- Example 12 A fesoterodine fumarate-containing preparation of Example 12 was obtained in the same manner as the production method of Example 2, except that glycerin fatty acid ester was changed to sucrose fatty acid ester.
- the left value in each column indicates the amount of hydrolyzate, and the right value indicates the total amount of related substances.
- the fesoterodine fumarate-containing preparation of Example 3 containing lactose hydrate is more stable than the fesoterodine fumarate-containing preparation of Example 3, in which anhydrous lactose is used. It became clear that it showed sexuality. It was also revealed that the fesoterodine fumarate-containing preparation of Example 3 containing anhydrous lactose exhibits higher stability than the fesoterodine fumarate-containing preparations of Reference Example 1 and Example 1.
- the fesoterodine fumarate-containing formulation of Example 2 which contained anhydrous lactose in the granules
- Example 4 which contained lactose hydrate in the granules. It was found that the soterodine fumarate-containing formulation also exhibited equivalent stability.
- fesoterodine fumarate-containing preparation of Example 2 which contains lactose hydrate outside the granules
- fesoterodine fumarate of Example 5 which contains anhydrous lactose outside the granules. It was found that the formulations containing the drug also exhibited the same stability.
- lactose may be anhydrous or hydrate when using the direct compression method or dry granulation method.
- the left value in each column indicates the amount of hydrolyzate, and the right value indicates the total amount of related substances.
- the amount of anhydrous lactose was increased and the amount of crystalline cellulose was reduced. It was found to exhibit stability equivalent to that of salt-containing preparations.
- the fesoterodine fumarate-containing preparation of Example 2 containing polyvinyl alcohol and the fesoterodine fumarate-containing preparation of Example 7 not containing polyvinyl alcohol exhibit equivalent stability.
- rice field Compared to the fesoterodine fumarate-containing preparation of Example 7, the amount of anhydrous lactose was reduced and the amount of crystalline cellulose was increased. It was found to exhibit stability equivalent to that of salt-containing preparations.
- the fesoterodine fumarate-containing preparation of Example 9 in which the content of glycerin fatty acid ester was twice that of the fesoterodine fumarate-containing preparation of Example 8, and the content of glycerin fatty acid ester, in which the content of glycerin fatty acid ester was 4 times. From the stability results of the fesoterodine fumarate-containing formulation of Example 10, even if the content of glycerin fatty acid ester is changed, the amount of hydrolyzate and the total amount of related substances are hardly affected, and the same stability is achieved.
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Abstract
Un mode de réalisation de la présente invention concerne une méthode de production d'une formulation contenant du fumarate de fésotérodine stable. Dans ladite méthode, la génération de substances apparentées est supprimée à l'aide d'un additif à usage général facile à manipuler et d'une méthode simple. Un mode de réalisation de la présente invention concerne une méthode de production d'une formulation contenant du fumarate de fésotérodine, la méthode comprenant la granulation à sec de fumarate de fésotérodine, de lactose, de cellulose cristalline et d'un lubrifiant pour obtenir un matériau aggloméré. En outre, un mode de réalisation de la présente invention concerne une méthode de production d'une formulation contenant du fumarate de fésotérodine, la méthode comprenant le mélange et la compression de fumarate de fésotérodine, de lactose, de cellulose cristalline, d'hypromellose et d'un lubrifiant. Dans la méthode, le fumarate de fésotérodine, le lactose, la cellulose cristalline, l'hypromellose et le lubrifiant sont chacun rendus sous la forme d'une poudre sèche et mélangés.
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2009539802A (ja) * | 2006-06-09 | 2009-11-19 | シュバルツ ファルマ アクチェンゲゼルシャフト | フェソテロジンを含む安定した医薬組成物 |
WO2012136839A1 (fr) * | 2011-04-08 | 2012-10-11 | Lek Pharmaceuticals D.D. | Formulation sèche et composition pharmaceutique comprenant une fésotérodine ou un sel ou un solvate de celle-ci |
JP2018519305A (ja) * | 2015-06-30 | 2018-07-19 | ジェネンテック, インコーポレイテッド | 薬物を含有する即放性錠剤及び錠剤の形成プロセス |
JP2018184375A (ja) * | 2017-04-27 | 2018-11-22 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ダビガトランエテキシラート又は医薬的に許容されるその塩を含む錠剤及びその製造方法 |
WO2019206391A1 (fr) * | 2018-04-26 | 2019-10-31 | Rontis Hellas S.A. | Composition pharmaceutique à libération prolongée contenant de la fésotérodine et son procédé de préparation |
WO2020090969A1 (fr) * | 2018-10-31 | 2020-05-07 | 富士フイルム株式会社 | Emballage pour composition médicale contenant un agent antitumoral |
-
2023
- 2023-01-13 WO PCT/JP2023/000786 patent/WO2023145486A1/fr unknown
- 2023-01-13 JP JP2023576781A patent/JPWO2023145486A1/ja active Pending
- 2023-01-18 TW TW112102169A patent/TWI836872B/zh active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009539802A (ja) * | 2006-06-09 | 2009-11-19 | シュバルツ ファルマ アクチェンゲゼルシャフト | フェソテロジンを含む安定した医薬組成物 |
WO2012136839A1 (fr) * | 2011-04-08 | 2012-10-11 | Lek Pharmaceuticals D.D. | Formulation sèche et composition pharmaceutique comprenant une fésotérodine ou un sel ou un solvate de celle-ci |
JP2018519305A (ja) * | 2015-06-30 | 2018-07-19 | ジェネンテック, インコーポレイテッド | 薬物を含有する即放性錠剤及び錠剤の形成プロセス |
JP2018184375A (ja) * | 2017-04-27 | 2018-11-22 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ダビガトランエテキシラート又は医薬的に許容されるその塩を含む錠剤及びその製造方法 |
WO2019206391A1 (fr) * | 2018-04-26 | 2019-10-31 | Rontis Hellas S.A. | Composition pharmaceutique à libération prolongée contenant de la fésotérodine et son procédé de préparation |
WO2020090969A1 (fr) * | 2018-10-31 | 2020-05-07 | 富士フイルム株式会社 | Emballage pour composition médicale contenant un agent antitumoral |
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