WO2023145486A1 - Method for producing fesoterodine fumarate-containing formulation - Google Patents
Method for producing fesoterodine fumarate-containing formulation Download PDFInfo
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- 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
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- Prior art keywords
- fesoterodine fumarate
- fumarate
- fesoterodine
- lubricant
- lactose
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- 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
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- 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
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- 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
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- 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.
Abstract
One embodiment of the present invention provides a method for producing a stable fesoterodine fumarate-containing formulation. In said method the generation of related substances is suppressed by using an easy-to-handle general-purpose additive and a simple method. One embodiment of the present invention provides a method for producing a fesoterodine fumarate-containing formulation, the method comprising dry-granulating fesoterodine fumarate, lactose, crystalline cellulose, and a lubricant to obtain an agglomerated material. Further, one embodiment of the present invention provides a method for producing a fesoterodine fumarate-containing formulation, the method comprising mixing and tableting fesoterodine fumarate, lactose, crystalline cellulose, hypromellose, and a lubricant. In the method, the fesoterodine fumarate, the lactose, the crystalline cellulose, the hypromellose, and the lubricant are each rendered as a dry powder and mixed.
Description
本発明の一実施形態は、フェソテロジンフマル酸塩含有製剤の製造方法に関する。
One embodiment of the present invention relates to a method for producing a fesoterodine fumarate-containing preparation.
２－［（１Ｒ）－３－（ジイソプロピルアミノ）－１－フェニルプロピル］－４－（ヒドロキシメチル）フェニルイソブチレートのフマル酸水素塩（以下、フェソテロジンフマル酸塩と称する。）は過活動膀胱の治療剤である。フェソテロジンフマル酸塩は、多湿又は高温などの過酷な環境条件下では分解することが知られている。（特許文献１）。
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).
そこで、特許文献１では、フェソテロジンフマル酸塩および安定化剤として特定のポリオール類を含む医薬組成物、ならびにその製造方法として湿式造粒法が開示されており、優れた安定性を示すことが記載されている。
Therefore, 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.
しかしながら、湿式造粒法は、造粒の前工程で結合液の調製などの加水操作を行い、造粒後には造粒物を乾燥する工程が必要であるため、乾式造粒法や直接圧縮法に比べて、製造工程が複雑であり、製造コストも高くなる。また、特許文献１で用いられているキシリトールやソルビトールなどのポリオール系安定化剤は安価とは言い難く、キシリトールは潮解性を示すため取り扱いにも注意が必要である。このような理由から、より簡便な製造方法で製造可能な優れた安定性を示すフェソテロジンフマル酸塩を含む医薬組成物の開発が求められている。
However, 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. Moreover, 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.
本発明の一実施形態は、取り扱いが容易な汎用添加剤と簡便な製造方法を用いて、類縁物質の生成を抑制した安定なフェソテロジンフマル酸塩含有製剤の製造方法を提供することを課題の一つとする。
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. be one of
本発明の一実施形態によると、フェソテロジンフマル酸塩と、乳糖と、結晶セルロースと、滑沢剤とを乾式造粒して、造粒物を得ることを、含む、フェソテロジンフマル酸塩含有製剤の製造方法が提供される。
According to one embodiment of the present invention, fesoterodine fumarate, lactose, microcrystalline cellulose and lubricant are dry granulated to obtain a granule. Methods of making salt-containing formulations are provided.
造粒物は、滑沢剤として、ショ糖脂肪酸エステル又はグリセリン脂肪酸エステルを含んでもよい。
The granules may contain sucrose fatty acid ester or glycerin fatty acid ester as a lubricant.
得られた造粒物と、乳糖と、結晶セルロースと、ヒプロメロースと、滑沢剤と、を混合して、打錠してもよい。
The obtained granules, lactose, crystalline cellulose, hypromellose, and a lubricant may be mixed and tableted.
造粒物と混合される滑沢剤として、グリセリン脂肪酸エステルを含んでもよい。
A glycerin fatty acid ester may be included as a lubricant mixed with the granules.
造粒物と混合される滑沢剤として、タルクを更に含んでもよい。
Talc may be further included as a lubricant mixed with the granules.
本発明の一実施形態によると、フェソテロジンフマル酸塩と、乳糖と、結晶セルロースと、ヒプロメロースと、滑沢剤と、を混合して、打錠することを含み、フェソテロジンフマル酸塩と、乳糖と、結晶セルロースと、ヒプロメロースと、滑沢剤とはそれぞれ乾燥粉末として混合される、フェソテロジンフマル酸塩含有製剤の製造方法が提供される。
According to one embodiment of the present invention, 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.
滑沢剤として、タルク及びグリセリン脂肪酸エステルを含んでもよい。
Talc and glycerin fatty acid esters may be included as lubricants.
本発明の一実施形態によると、取り扱いが容易な汎用添加剤と簡便な製造方法を用いて、類縁物質の生成を抑制した安定なフェソテロジンフマル酸塩含有製剤の製造方法が提供される。
According to one embodiment of the present invention, there is provided 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.
以下、本発明に係るフェソテロジンフマル酸塩含有製剤の製造方法について説明する。なお、本発明のフェソテロジンフマル酸塩含有製剤の製造方法は、以下に示す実施の形態及び実施例の記載内容に限定して解釈されるものではない。
A method for producing a fesoterodine fumarate-containing preparation according to the present invention will be described below. In addition, 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.
特許文献１に記載された医薬組成物においては、安定化剤としてキシリトールが用いられているが、キシリトールは潮解性を示す添加剤であることが知られている。このため、本発明者らが、潮解性を示さない他の糖アルコールを用いて、特許文献１に記載された湿式造粒法により製造したフェソテロジンフマル酸塩含有製剤について安定性を検討した。その結果、顕著な類縁物質の増加が認められた。したがって、湿式造粒法を採用した特許文献１に記載されたフェソテロジンフマル酸塩含有製剤においては、安定化剤としてキシリトールが必須の構成成分であることが示された。
In the pharmaceutical composition described in Patent Document 1, 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.
また、特許文献１の第８表には、キシリトールの存在下で、直接圧縮法により製造した錠剤の安定性結果が記載され、第９表には、乾式造粒法により製造した錠剤の安定性結果が記載されている。しかし、何れの方法においても、湿式造粒法により製造した錠剤よりも加水分解物及び総分解産物が増加することが示されている。
In addition, Table 8 of Patent Document 1 describes the stability results of tablets produced by a direct compression method in the presence of xylitol, and 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.
したがって、特許文献１の記載からは、より簡便な製造方法である直接圧縮法や乾式造粒法を用いた製造方法では、安定なフェソテロジンフマル酸塩含有製剤を得るのは困難であることが示唆された。
Therefore, from the description of 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.
しかしながら、本発明者らは、取り扱いが容易な汎用添加剤を用いた特定の処方に乾式造粒法又は直接圧縮法を適用することにより、安定なフェソテロジンフマル酸塩含有製剤が得られることを見出した。乾式造粒法又は直接圧縮法は、湿式造粒法に比べて、製造工程数が少なく、低コストでの製造が可能であることから、乾式造粒法又は直接圧縮法は、より簡便な製造方法といえる。
However, 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.
［乾式造粒法］
本実施形態に係る乾式造粒法によるフェソテロジンフマル酸塩含有製剤の製造方法は、フェソテロジンフマル酸塩と、乳糖と、結晶セルロースと、滑沢剤とを乾式造粒して、造粒物を得ることを含む。造粒物はローラーコンパクターを用いて製造することができる。なお、本実施形態に用いる乳糖は、無水物であってもよく、水和物であってもよい。 [Dry granulation method]
In the method for producing a fesoterodine fumarate-containing preparation by dry granulation according to the present embodiment, fesoterodine fumarate, lactose, crystalline cellulose, and a lubricant are dry granulated, and granulated. Including obtaining granules. Granules can be produced using a roller compactor. In addition, the lactose used in the present embodiment may be an anhydride or a hydrate.
本実施形態に係る乾式造粒法によるフェソテロジンフマル酸塩含有製剤の製造方法は、フェソテロジンフマル酸塩と、乳糖と、結晶セルロースと、滑沢剤とを乾式造粒して、造粒物を得ることを含む。造粒物はローラーコンパクターを用いて製造することができる。なお、本実施形態に用いる乳糖は、無水物であってもよく、水和物であってもよい。 [Dry granulation method]
In the method for producing a fesoterodine fumarate-containing preparation by dry granulation according to the present embodiment, fesoterodine fumarate, lactose, crystalline cellulose, and a lubricant are dry granulated, and granulated. Including obtaining granules. Granules can be produced using a roller compactor. In addition, the lactose used in the present embodiment may be an anhydride or a hydrate.
一実施形態において、フェソテロジンフマル酸塩含有製剤は、フェソテロジンフマル酸塩を、１錠あたり４ｍｇ又は８ｍｇ含むことができるが、これらに限定されるものではない。治療効果を得られる範囲でフェソテロジンフマル酸塩の含有量を変更することができる。
In one embodiment, 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.
一実施形態において、造粒物に含まれる乳糖の含有量は、造粒物１００質量％に対して、５５質量％～８５質量％の範囲であってもよい。
In one embodiment, 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.
一実施形態において、造粒物に含まれる結晶セルロースの含有量は、造粒物１００質量％に対して、５質量％～３５質量％の範囲であってもよい。
In one embodiment, 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.
乾式造粒する際に添加される滑沢剤として、ショ糖脂肪酸エステル又はグリセリン脂肪酸エステルを選択することができる。即ち、得られる造粒物は、滑沢剤として、ショ糖脂肪酸エステル又はグリセリン脂肪酸エステルを含むことができる。本実施形態においては、ショ糖脂肪酸エステルと、グリセリン脂肪酸エステルは、フェソテロジンフマル酸塩含有製剤における加水分解物の量や総類縁物質量にほとんど影響を与えない。また、一実施形態において、造粒物に含まれる滑沢剤の含有量は、造粒物１００質量％に対して、０．６質量％～２．５質量％の範囲であってもよい。
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.
また、一実施形態において、乾式造粒する際に、ポリビニルアルコールをさらに添加することができる。
Also, in one embodiment, polyvinyl alcohol can be further added during dry granulation.
得られた造粒物と、乳糖と、結晶セルロースと、ヒプロメロースと、滑沢剤と、を混合して、打錠することにより、本実施形態に係るフェソテロジンフマル酸塩含有製剤を製造することができる。なお、本発明で得られた造粒物であれば、打錠工程は乾式打錠法、湿式打錠法のいずれであってもよい。なお、本実施形態に用いる乳糖は、無水物であってもよく、水和物であってもよい。
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. be able to. 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. In addition, the lactose used in the present embodiment may be an anhydride or a hydrate.
本実施形態に係るフェソテロジンフマル酸塩含有製剤は、造粒物と混合される滑沢剤として、グリセリン脂肪酸エステルを含む。一実施形態において、フェソテロジンフマル酸塩含有製剤は、造粒物と混合される滑沢剤として、タルクを更に含んでもよい。
The fesoterodine fumarate-containing preparation according to the present embodiment contains glycerin fatty acid ester as a lubricant mixed with the granules. In one embodiment, the fesoterodine fumarate-containing formulation may further comprise talc as a lubricant mixed with the granulation.
本実施形態に係るフェソテロジンフマル酸塩含有製剤は、造粒物と混合されるヒプロメロース（以下、ＨＰＭＣとも称する。）として、高粘度のＨＰＭＣと低粘度のＨＰＭＣとを組み合わせて用いることができる。高粘度のＨＰＭＣとは、約２質量％の水溶液において、２２℃での公称粘度（ウベローデ粘度計により測定）が、約７０，０００ｍＰａ・ｓ～約１５０，０００ｍＰａ・ｓ、好ましくは約１００，０００ｍＰａ・ｓであり、１００，０００±２０，０００ｍＰａ・ｓであるＨＰＭＣを示す。このような高粘度のＨＰＭＣとして、例えば、Ｄｏｗ ＣｈｅｍｉｃａｌのＭＥＴＨＯＣＥＬ（登録商標）Ｋ１５Ｍ又はＭＥＴＨＯＣＥＬ（登録商標）Ｋ１００Ｍを用いることができる。また、低粘度のＨＰＭＣとは、約２質量％の水溶液において、２２℃での公称粘度が、約３，０００ｍＰａ・ｓ～約２０，０００ｍＰａ・ｓ、好ましくは約４，０００ｍＰａ・ｓであり、４，０００ｍＰａ・ｓ±１，０００ｍＰａ・ｓであるＨＰＭＣを示す。このような低粘度のＨＰＭＣとして、例えば、Ｄｏｗ ＣｈｅｍｉｃａｌのＭＥＴＨＯＣＥＬ（登録商標）Ｅ４Ｍ又はＭＥＴＨＯＣＥＬ（登録商標）Ｋ４Ｍを用いることができる。
In the preparation containing fesoterodine fumarate according to the present embodiment, high-viscosity HPMC and low-viscosity HPMC can be used in combination as hypromellose (hereinafter also referred to as HPMC) mixed with the granules. . 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. As such high-viscosity HPMC, for example, Dow Chemical's METHOCEL (registered trademark) K15M or METHOCEL (registered trademark) K100M can be used. In addition, 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. As such low-viscosity HPMC, for example, METHOCEL (registered trademark) E4M or METHOCEL (registered trademark) K4M from Dow Chemical can be used.
本実施形態においては、乾式造粒法を用いてフェソテロジンフマル酸塩含有粒子を製造することにより、フェソテロジンフマル酸塩の加水分解物量の増加や総類縁物質量の増加を抑制することができる。
In the present embodiment, by producing fesoterodine fumarate-containing particles using a dry granulation method, an increase in the amount of fesoterodine fumarate hydrolyzate and an increase in the total amount of related substances can be suppressed. can be done.
［直接圧縮法］
一実施形態において、直接圧縮法により、フェソテロジンフマル酸塩の加水分解物量の増加や総類縁物質量の増加を抑制したフェソテロジンフマル酸塩含有製剤を製造することができる。 [Direct compression method]
In one embodiment, 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.
一実施形態において、直接圧縮法により、フェソテロジンフマル酸塩の加水分解物量の増加や総類縁物質量の増加を抑制したフェソテロジンフマル酸塩含有製剤を製造することができる。 [Direct compression method]
In one embodiment, 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.
本実施形態に係る直接圧縮法によるフェソテロジンフマル酸塩含有製剤の製造方法は、フェソテロジンフマル酸塩と、乳糖と、結晶セルロースと、ヒプロメロースと、滑沢剤と、を混合して、通常用いられる打錠機で圧縮成形（打錠）する。本実施形態においては、フェソテロジンフマル酸塩と、乳糖と、結晶セルロースと、ヒプロメロースと、滑沢剤とはそれぞれ乾燥粉末として混合される。即ち、混合工程において種々の溶媒は用いられない。なお、本実施形態に用いる乳糖は、無水物であってもよく、水和物であってもよい。
In the method for producing a fesoterodine fumarate-containing preparation by direct compression according to the present embodiment, fesoterodine fumarate, lactose, crystalline cellulose, hypromellose, and a lubricant are mixed, Compression molding (tabletting) is performed using a commonly used tableting machine. In this embodiment, fesoterodine fumarate, lactose, microcrystalline cellulose, hypromellose, and lubricant are each mixed as dry powders. That is, no solvents are used in the mixing process. In addition, the lactose used in the present embodiment may be an anhydride or a hydrate.
一実施形態において、フェソテロジンフマル酸塩含有製剤は、フェソテロジンフマル酸塩を、１錠あたり４ｍｇ又は８ｍｇ含むことができるが、これらに限定されるものではない。治療効果を得られる範囲でフェソテロジンフマル酸塩の含有量を変更することができる。
In one embodiment, 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.
一実施形態において、滑沢剤として、タルク及びグリセリン脂肪酸エステルを含む。
In one embodiment, the lubricant contains talc and glycerin fatty acid ester.
本実施形態に係るフェソテロジンフマル酸塩含有製剤は、ヒプロメロースとして、上述した高粘度のＨＰＭＣと低粘度のＨＰＭＣとを組み合わせて用いることができるため、詳細な説明は省略する。
Since the fesoterodine fumarate-containing preparation according to the present embodiment can be used in combination with the above-described high-viscosity HPMC and low-viscosity HPMC as hypromellose, detailed description is omitted.
本実施形態においては、直接圧縮法を用いてフェソテロジンフマル酸塩含有粒子を製造することにより、フェソテロジンフマル酸塩の加水分解物量の増加や総類縁物質量の増加を抑制することができる。
In the present embodiment, by producing fesoterodine fumarate-containing particles using a direct compression method, it is possible to suppress an increase in the amount of fesoterodine fumarate hydrolyzate and an increase in the total amount of related substances. can.
［フィルムコート錠］
一実施形態において、本実施形態に係るフェソテロジンフマル酸塩含有製剤は、乾式造粒法又は直接圧縮法により得られた素錠にフィルムコーティングを施したフィルムコート錠とすることもできる。 [Film-coated tablets]
In one embodiment, 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.
一実施形態において、本実施形態に係るフェソテロジンフマル酸塩含有製剤は、乾式造粒法又は直接圧縮法により得られた素錠にフィルムコーティングを施したフィルムコート錠とすることもできる。 [Film-coated tablets]
In one embodiment, 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.
フェソテロジンフマル酸塩含有製剤にコーティングするフィルムとしては、汎用のフィルム組成物を適用することができる。フィルム組成物中には、ポリマー、可塑剤、着色剤、乳白剤、及び／又は充填剤を含むことができる。また、微量の風味剤、界面活性剤及びワックスを含んでもよい。フィルム組成物中に含まれるポリマーは、セルロースエーテル類などのセルロース誘導体、アクリルポリマー類、及びコポリマー類を用いることができる。ポリエチレングリコール、ポリビニルピロリドン、ポリビニルアルコール及びワックス状の材料を用いることもできる。
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.
セルロースエーテル類としては、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース及びメチルセルロースからなる群から選択される添加剤を用いることができる。アクリルポリマーとしては、多様な官能基を有する合成ポリマーを含むことができる。合成ポリマーをさらに修飾して膨潤性を高めてもよい。また、水溶性セルロースエーテル類及びデンプン類などの材料と組み合わせることもできる。
As 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.
可塑剤として、ポリオール類（グリセロール、プロピレングリコール、マクロゴール類）、有機エステル類（フタル酸エステル類、塩基性酢酸ジブチル、クエン酸エステル類、トリアセチン）、油／グリセリド類（ヒマシ油、アセチル化モノグリセリド類、分画ココナツ油）を用いることができる。
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.
着色剤／乳白剤として、有機染料及びそのレーキ、無機着色料、天然着色料を用いることができ、各材料を規定の比率で組み合わせることもできる。
As 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.
フィルム組成物を、種々の溶媒（水、アルコール、ケトン、エステル、塩素化炭化水素）を用いた分散液又は懸濁液として、素錠に噴霧することにより、フィルムコート錠を製造することができる。
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). .
［安定性の評価］
本明細書において、安定性の評価は、液体クロマトグラフィを用いたフェソテロジンフマル酸塩の加水分解物及び総類縁物質の定量により行う。面積百分率法により、クロマトグラム上に得られたフェソテロジンフマル酸塩及びフェソテロジンフマル酸塩由来の類縁物質の各成分のピーク面積の総和を１００とし、ピーク面積の比からフェソテロジンフマル酸塩由来の総類縁物質量（％）を算出する。また、フェソテロジンフマル酸塩及びフェソテロジンフマル酸塩由来の類縁物質の各成分のピーク面積の総和を１００とし、フェソテロジンフマル酸塩の加水分解物のピーク面積の比から加水分解物量（％）を算出する。 [Evaluation of stability]
As used herein, stability is evaluated by quantification of fesoterodine fumarate hydrolyzate and total related substances using liquid chromatography. By the 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. Further, the sum of the peak areas of each component of fesoterodine fumarate and fesoterodine fumarate-derived analogues was taken as 100, and the amount of hydrolyzate was calculated from the ratio of the peak areas of the hydrolyzate of fesoterodine fumarate. (%) is calculated.
本明細書において、安定性の評価は、液体クロマトグラフィを用いたフェソテロジンフマル酸塩の加水分解物及び総類縁物質の定量により行う。面積百分率法により、クロマトグラム上に得られたフェソテロジンフマル酸塩及びフェソテロジンフマル酸塩由来の類縁物質の各成分のピーク面積の総和を１００とし、ピーク面積の比からフェソテロジンフマル酸塩由来の総類縁物質量（％）を算出する。また、フェソテロジンフマル酸塩及びフェソテロジンフマル酸塩由来の類縁物質の各成分のピーク面積の総和を１００とし、フェソテロジンフマル酸塩の加水分解物のピーク面積の比から加水分解物量（％）を算出する。 [Evaluation of stability]
As used herein, stability is evaluated by quantification of fesoterodine fumarate hydrolyzate and total related substances using liquid chromatography. By the 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. Further, the sum of the peak areas of each component of fesoterodine fumarate and fesoterodine fumarate-derived analogues was taken as 100, and the amount of hydrolyzate was calculated from the ratio of the peak areas of the hydrolyzate of fesoterodine fumarate. (%) is calculated.
［実施例１］
実施例１として、直接圧縮法により、フェソテロジンフマル酸塩含有製剤を製造した。フェソテロジンフマル酸塩４ｇ、乳糖水和物（７５％）／結晶セルロース（２５％）（ＭＥＧＧＬＥ、ＭＩＣＲＯＣＥＬＡＣ（登録商標）１００Ｍ）７４．７５ｇ、ヒプロメロース（Ｄｏｗ Ｃｈｅｍｉｃａｌ、ＭＥＴＨＯＣＥＬ（登録商標）Ｋ１００Ｍ）６０ｇ、ヒプロメロース（Ｄｏｗ Ｃｈｅｍｉｃａｌ、ＭＥＴＨＯＣＥＬ（登録商標）Ｋ４Ｍ）１２ｇ、タルク（富士タルク株式会社））４．２５ｇ、グリセリン脂肪酸エステル（Ｃｏｍｐｒｉｔｏｌ８８８ＡＴＯ、ＧＡＴＴＥＦＯＳＳＥ）５ｇをビニール袋で混合し、打錠機（株式会社菊水製作所社、ＶＥＬＡ５）を用い、重量３２０ｍｇとなるように打錠し、実施例１のフェソテロジンフマル酸塩含有製剤を得た。 [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., VELA5).
実施例１として、直接圧縮法により、フェソテロジンフマル酸塩含有製剤を製造した。フェソテロジンフマル酸塩４ｇ、乳糖水和物（７５％）／結晶セルロース（２５％）（ＭＥＧＧＬＥ、ＭＩＣＲＯＣＥＬＡＣ（登録商標）１００Ｍ）７４．７５ｇ、ヒプロメロース（Ｄｏｗ Ｃｈｅｍｉｃａｌ、ＭＥＴＨＯＣＥＬ（登録商標）Ｋ１００Ｍ）６０ｇ、ヒプロメロース（Ｄｏｗ Ｃｈｅｍｉｃａｌ、ＭＥＴＨＯＣＥＬ（登録商標）Ｋ４Ｍ）１２ｇ、タルク（富士タルク株式会社））４．２５ｇ、グリセリン脂肪酸エステル（Ｃｏｍｐｒｉｔｏｌ８８８ＡＴＯ、ＧＡＴＴＥＦＯＳＳＥ）５ｇをビニール袋で混合し、打錠機（株式会社菊水製作所社、ＶＥＬＡ５）を用い、重量３２０ｍｇとなるように打錠し、実施例１のフェソテロジンフマル酸塩含有製剤を得た。 [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., VELA5).
［実施例２］
実施例２として、乾式造粒法により、フェソテロジンフマル酸塩含有製剤を製造した。フェソテロジンフマル酸塩８ｇ、無水乳糖（ＤＦＥＰｈａｒｍａ、ＳｕｐｅｒＴａｂＮＡ２１）５７ｇ、結晶セルロース（旭化成株式会社、ＣＥＯＬＵＳ（登録商標）ＰＨ－１０２）１３．７ｇ、ポリビニルアルコール（三菱ケミカル株式会社、ＥＧ―０５ＰＷ）０．８ｇ、グリセリン脂肪酸エステル（ＧＡＴＴＥＦＯＳＳＥ、Ｃｏｍｐｒｉｔｏｌ８８８ＡＴＯ）０．５ｇを加えて混合した後、ローラーコンパクター（ＴＦ－ＭＩＮＩ、フロイント産業株式会社）を使用しロール圧１００ｋｇｆ／ｃｍ２にて乾式造粒を行い、乾式造粒物を得た。 [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.
実施例２として、乾式造粒法により、フェソテロジンフマル酸塩含有製剤を製造した。フェソテロジンフマル酸塩８ｇ、無水乳糖（ＤＦＥＰｈａｒｍａ、ＳｕｐｅｒＴａｂＮＡ２１）５７ｇ、結晶セルロース（旭化成株式会社、ＣＥＯＬＵＳ（登録商標）ＰＨ－１０２）１３．７ｇ、ポリビニルアルコール（三菱ケミカル株式会社、ＥＧ―０５ＰＷ）０．８ｇ、グリセリン脂肪酸エステル（ＧＡＴＴＥＦＯＳＳＥ、Ｃｏｍｐｒｉｔｏｌ８８８ＡＴＯ）０．５ｇを加えて混合した後、ローラーコンパクター（ＴＦ－ＭＩＮＩ、フロイント産業株式会社）を使用しロール圧１００ｋｇｆ／ｃｍ２にて乾式造粒を行い、乾式造粒物を得た。 [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.
得られた造粒物を篩２２号で整粒した後、乳糖水和物（７５％）／結晶セルロース（２５％）（ＭＥＧＧＬＥ、ＭＩＣＲＯＣＥＬＡＣ（登録商標）１００Ｍ）７８ｇ、ヒプロメロース（Ｄｏｗ Ｃｈｅｍｉｃａｌ、ＭＥＴＨＯＣＥＬ（登録商標）Ｋ１００Ｍ）１２０ｇ、ヒプロメロース（Ｄｏｗ Ｃｈｅｍｉｃａｌ、ＭＥＴＨＯＣＥＬ（登録商標）Ｋ４Ｍ）２４ｇ、タルク（富士タルク株式会社））８．５ｇ、グリセリン脂肪酸エステル（ＧＡＴＴＥＦＯＳＳＥ、Ｃｏｍｐｒｉｔｏｌ８８８ＡＴＯ）９．５ｇをビニール袋で混合し、打錠機（株式会社菊水製作所社、ＶＥＬＡ５）を用い、重量３２０ｍｇとなるように打錠し、実施例２のフェソテロジンフマル酸塩含有製剤を得た。
After sizing the obtained granules with Sieve No. 22, 78 g of lactose hydrate (75%)/microcrystalline cellulose (25%) (MEGGLE, MICROCELAC (registered trademark) 100M), 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) 9.5 g were mixed in a plastic bag. , 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.
［比較例１］
比較例１として、湿式造粒法により、フェソテロジンフマル酸塩含有製剤を製造した。フェソテロジンフマル酸塩８ｇ、無水乳糖（ＤＦＥ Ｐｈａｒｍａ、ＳｕｐｅｒＴａｂＮＡ２１）５７ｇ、結晶セルロース（旭化成株式会社、ＣＥＯＬＵＳ（登録商標）ＰＨ－１０２）１３．７ｇ、ポリビニルアルコール（三菱ケミカル株式会社、ＥＧ―０５ＰＷ）０．８ｇ、を乳鉢に投入して混合した。その後、精製水５ｇを加えて、攪拌練合を行った。 [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.
比較例１として、湿式造粒法により、フェソテロジンフマル酸塩含有製剤を製造した。フェソテロジンフマル酸塩８ｇ、無水乳糖（ＤＦＥ Ｐｈａｒｍａ、ＳｕｐｅｒＴａｂＮＡ２１）５７ｇ、結晶セルロース（旭化成株式会社、ＣＥＯＬＵＳ（登録商標）ＰＨ－１０２）１３．７ｇ、ポリビニルアルコール（三菱ケミカル株式会社、ＥＧ―０５ＰＷ）０．８ｇ、を乳鉢に投入して混合した。その後、精製水５ｇを加えて、攪拌練合を行った。 [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.
得られた造粒物を乾燥および篩２２号で整粒した後、乳糖水和物（７５％）／結晶セルロース（２５％）（ＭＥＧＧＬＥ、ＭＩＣＲＯＣＥＬＡＣ（登録商標）１００Ｍ）７８ｇ、ヒプロメロース（Ｄｏｗ Ｃｈｅｍｉｃａｌ、ＭＥＴＨＯＣＥＬ（登録商標）Ｋ１００Ｍ）１２０ｇ、ヒプロメロース（Ｄｏｗ Ｃｈｅｍｉｃａｌ、ＭＥＴＨＯＣＥＬ（登録商標）Ｋ４Ｍ）２４ｇ、タルク（富士タルク株式会社））８．５ｇ、グリセリン脂肪酸エステル（ＧＡＴＴＥＦＯＳＳＥ、Ｃｏｍｐｒｉｔｏｌ８８８ＡＴＯ）１０ｇをビニール袋で混合し、打錠機（菊水製作所社、ＶＥＬＡ５）を用い、重量３２０ｍｇとなるように打錠し、比較例１のフェソテロジンフマル酸塩含有製剤を得た。
After drying the obtained granules and sieving them with a No. 22 sieve, 78 g of lactose hydrate (75%)/microcrystalline cellulose (25%) (MEGGLE, MICROCELAC (registered trademark) 100M), hypromellose (Dow Chemical, 120 g of METHOCEL (registered trademark) K100M), 24 g of hypromellose (Dow Chemical, METHOCEL (registered trademark) K4M), 8.5 g of talc (Fuji Talc Co., Ltd.), and 10 g of glycerin fatty acid ester (GATTEFOSSE, Compritol 888ATO) were mixed in a plastic bag. , using a tableting machine (Kikusui Seisakusho Co., Ltd., VELA5), tableting was performed so that the weight was 320 mg, and a fesoterodine fumarate-containing preparation of Comparative Example 1 was obtained.
［参考例１］
参考例１として、特許文献１に記載された方法に準じて、湿式造粒法により、キシリトールを含むフェソテロジンフマル酸塩含有製剤を製造した。フェソテロジンフマル酸塩 ８ｇ、キシリトール（三菱商事フードテック株式会社、キシリットＰ）７２ｇを乳鉢に投入して混合した。その後、精製水５ｇを加えて、攪拌練合を行った。 [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.
参考例１として、特許文献１に記載された方法に準じて、湿式造粒法により、キシリトールを含むフェソテロジンフマル酸塩含有製剤を製造した。フェソテロジンフマル酸塩 ８ｇ、キシリトール（三菱商事フードテック株式会社、キシリットＰ）７２ｇを乳鉢に投入して混合した。その後、精製水５ｇを加えて、攪拌練合を行った。 [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.
得られた造粒物を乾燥および篩２２号で整粒した後、乳糖水和物（７５％）／結晶セルロース（２５％）（ＭＥＧＧＬＥ、ＭＩＣＲＯＣＥＬＡＣ（登録商標）１００Ｍ）７７．５ｇ、ヒプロメロース（Ｄｏｗ Ｃｈｅｍｉｃａｌ、ＭＥＴＨＯＣＥＬ（登録商標）Ｋ１００Ｍ）１２０ｇ、ヒプロメロース（Ｄｏｗ Ｃｈｅｍｉｃａｌ、ＭＥＴＨＯＣＥＬ（登録商標）Ｋ４Ｍ）２４ｇ、タルク（富士タルク株式会社）８．５ｇ、グリセリン脂肪酸エステル（ＧＡＴＴＥＦＯＳＳＥ、Ｃｏｍｐｒｉｔｏｌ８８８ＡＴＯ）１０ｇをビニール袋で混合し、打錠機（菊水製作所社、ＶＥＬＡ５）を用い、重量３２０ｍｇとなるように打錠し、参考例１のフェソテロジンフマル酸塩含有製剤を得た。
After drying the obtained granules and sieving them with a No. 22 sieve, 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. Then, using a tableting machine (Kikusui Seisakusho Co., Ltd., VELA5), the mixture was tableted to a weight of 320 mg to obtain a preparation containing fesoterodine fumarate of Reference Example 1.
［比較例２］
糖アルコールをキシリトールからＤ－マンニトール（三菱商事フードテック株式会社、マンニットＰ）に変更したこと以外は、参考例１の製造方法と同様の方法により、比較例２のフェソテロジンフマル酸塩含有製剤を得た。 [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.
糖アルコールをキシリトールからＤ－マンニトール（三菱商事フードテック株式会社、マンニットＰ）に変更したこと以外は、参考例１の製造方法と同様の方法により、比較例２のフェソテロジンフマル酸塩含有製剤を得た。 [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.
［比較例３］
糖アルコールをキシリトールからエリスリトール（物産フードサイエンス株式会社、エリスリトール１００Ｍ）に変更したこと以外は、参考例１の製造方法と同様の方法により、比較例３のフェソテロジンフマル酸塩含有製剤を得た。 [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.). .
糖アルコールをキシリトールからエリスリトール（物産フードサイエンス株式会社、エリスリトール１００Ｍ）に変更したこと以外は、参考例１の製造方法と同様の方法により、比較例３のフェソテロジンフマル酸塩含有製剤を得た。 [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.). .
［安定性の評価］
実施例１～２、参考例１及び比較例１～３のフェソテロジンフマル酸塩含有製剤を６０℃の密栓条件下で２週間保存した。製造直後と、保存後の各フェソテロジンフマル酸塩含有製剤について、安定性を評価した。ＣＯＲＴＥＣＳＣ１８、φ３．０×１５０ｍｍ、２．７μｍを用いて、１０ｍＭリン酸塩緩衝液（ｐＨ３．０）及びメタノールを移動相として、フォトダイオードアレイ検出器（測定波長：２２０ｎｍ）を用いた液体クロマトグラフィにより、総類縁物質量と加水分解物量を測定した。測定結果を表１に示す。 [Evaluation of stability]
The fesoterodine fumarate-containing formulations of Examples 1 and 2, Reference Example 1 and Comparative Examples 1 and 3 were stored under sealed conditions at 60°C for 2 weeks. Stability was evaluated for each fesoterodine fumarate-containing formulation immediately after manufacture and after storage. Using CORTEC SC18, φ3.0 × 150 mm, 2.7 μm, 10 mM phosphate buffer (pH 3.0) and methanol as mobile phases, liquid chromatography using a photodiode array detector (measurement wavelength: 220 nm) , total related substances and hydrolysates were measured. Table 1 shows the measurement results.
実施例１～２、参考例１及び比較例１～３のフェソテロジンフマル酸塩含有製剤を６０℃の密栓条件下で２週間保存した。製造直後と、保存後の各フェソテロジンフマル酸塩含有製剤について、安定性を評価した。ＣＯＲＴＥＣＳＣ１８、φ３．０×１５０ｍｍ、２．７μｍを用いて、１０ｍＭリン酸塩緩衝液（ｐＨ３．０）及びメタノールを移動相として、フォトダイオードアレイ検出器（測定波長：２２０ｎｍ）を用いた液体クロマトグラフィにより、総類縁物質量と加水分解物量を測定した。測定結果を表１に示す。 [Evaluation of stability]
The fesoterodine fumarate-containing formulations of Examples 1 and 2, Reference Example 1 and Comparative Examples 1 and 3 were stored under sealed conditions at 60°C for 2 weeks. Stability was evaluated for each fesoterodine fumarate-containing formulation immediately after manufacture and after storage. Using CORTEC SC18, φ3.0 × 150 mm, 2.7 μm, 10 mM phosphate buffer (pH 3.0) and methanol as mobile phases, liquid chromatography using a photodiode array detector (measurement wavelength: 220 nm) , total related substances and hydrolysates were measured. Table 1 shows the measurement results.
表１において各欄の左の値は、加水分解物量を示し、右の値は、総類縁物質量を示す。表１の結果より、直接圧縮法を用いて製造した実施例１のフェソテロジンフマル酸塩含有製剤並びに乾式造粒法を用いて製造した実施例２のフェソテロジンフマル酸塩含有製剤は、参考例１のフェソテロジンフマル酸塩含有製剤と同等の安定性を示すことが明らかとなった。一方、キシリトールをＤ－マンニトールに変更して湿式造粒法により製造した比較例２のフェソテロジンフマル酸塩含有製剤及びキシリトールをエリスリトールに変更して湿式造粒法により製造した比較例３のフェソテロジンフマル酸塩含有製剤においては、加水分解物量及び総類縁物質量の著しい増加が認められた。また、実施例２と同じ処方であっても、湿式造粒により製造した比較例１のフェソテロジンフマル酸塩含有製剤においては、加水分解物量及び総類縁物質量の著しい増加が認められた。
In Table 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. On the other hand, 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 Significant increases in hydrolyzate and total related substances were observed in formulations containing soterodine fumarate. In addition, even with the same formulation as in Example 2, 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.
［実施例３］
実施例３として、乳糖水和物（７５％）／結晶セルロース（２５％）（ＭＥＧＧＬＥ、ＭＩＣＲＯＣＥＬＡＣ（登録商標）１００Ｍ）７４．７５ｇを、無水乳糖（ＤＦＥＰｈａｒｍａ、ＳｕｐｅｒＴａｂＮＡ２１）５４．２５ｇ、結晶セルロース（旭化成株式会社、ＣＥＯＬＵＳ（登録商標）ＰＨ－１０２）２２．５ｇに変更し、ヒプロメロース（Ｄｏｗ Ｃｈｅｍｉｃａｌ、ＭＥＴＨＯＣＥＬ（登録商標）Ｋ４Ｍ）を１０ｇに変更したこと以外は、実施例１と製造方法と同様の方法により、実施例３のフェソテロジンフマル酸塩含有製剤を得た。 [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.
実施例３として、乳糖水和物（７５％）／結晶セルロース（２５％）（ＭＥＧＧＬＥ、ＭＩＣＲＯＣＥＬＡＣ（登録商標）１００Ｍ）７４．７５ｇを、無水乳糖（ＤＦＥＰｈａｒｍａ、ＳｕｐｅｒＴａｂＮＡ２１）５４．２５ｇ、結晶セルロース（旭化成株式会社、ＣＥＯＬＵＳ（登録商標）ＰＨ－１０２）２２．５ｇに変更し、ヒプロメロース（Ｄｏｗ Ｃｈｅｍｉｃａｌ、ＭＥＴＨＯＣＥＬ（登録商標）Ｋ４Ｍ）を１０ｇに変更したこと以外は、実施例１と製造方法と同様の方法により、実施例３のフェソテロジンフマル酸塩含有製剤を得た。 [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.
［実施例４］
実施例４として、フェソテロジンフマル酸塩８ｇ、乳糖水和物（Ｐｈａｒｍａｔｏｓｅ２００Ｍ、ＤＭＶ）４５ｇ、結晶セルロース（旭化成株式会社、ＣＥＯＬＵＳ（登録商標）ＰＨ－１０２）２５ｇ、グリセリン脂肪酸エステル（ＧＡＴＴＥＦＯＳＳＥ、Ｃｏｍｐｒｉｔｏｌ８８８ＡＴＯ）２．０ｇを加えて混合した後、ローラーコンパクター（ＴＦ－ＭＩＮＩ、フロイント産業株式会社）を使用しロール圧１００ｋｇｆ／ｃｍ２にて乾式造粒を行い、乾式造粒物を得た。 [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.
実施例４として、フェソテロジンフマル酸塩８ｇ、乳糖水和物（Ｐｈａｒｍａｔｏｓｅ２００Ｍ、ＤＭＶ）４５ｇ、結晶セルロース（旭化成株式会社、ＣＥＯＬＵＳ（登録商標）ＰＨ－１０２）２５ｇ、グリセリン脂肪酸エステル（ＧＡＴＴＥＦＯＳＳＥ、Ｃｏｍｐｒｉｔｏｌ８８８ＡＴＯ）２．０ｇを加えて混合した後、ローラーコンパクター（ＴＦ－ＭＩＮＩ、フロイント産業株式会社）を使用しロール圧１００ｋｇｆ／ｃｍ２にて乾式造粒を行い、乾式造粒物を得た。 [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.
得られた造粒物を用いて、実施例２と同様の製造方法により、実施例４のフェソテロジンフマル酸塩含有製剤を得た。
A fesoterodine fumarate-containing preparation of Example 4 was obtained by the same production method as in Example 2 using the obtained granules.
［実施例５］
実施例５として、フェソテロジンフマル酸塩８ｇ、無水乳糖（ＤＦＥＰｈａｒｍａ、ＳｕｐｅｒＴａｂＮＡ２１）４５ｇ、結晶セルロース（旭化成株式会社、ＣＥＯＬＵＳ（登録商標）ＰＨ－１０２）２５ｇ、グリセリン脂肪酸エステル（ＧＡＴＴＥＦＯＳＳＥ、Ｃｏｍｐｒｉｔｏｌ８８８ＡＴＯ）２．０ｇを加えて混合した後、ローラーコンパクター（ＴＦ－ＭＩＮＩ、フロイント産業株式会社）を使用しロール圧１００ｋｇｆ／ｃｍ２にて乾式造粒を行い、乾式造粒物を得た。 [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.
実施例５として、フェソテロジンフマル酸塩８ｇ、無水乳糖（ＤＦＥＰｈａｒｍａ、ＳｕｐｅｒＴａｂＮＡ２１）４５ｇ、結晶セルロース（旭化成株式会社、ＣＥＯＬＵＳ（登録商標）ＰＨ－１０２）２５ｇ、グリセリン脂肪酸エステル（ＧＡＴＴＥＦＯＳＳＥ、Ｃｏｍｐｒｉｔｏｌ８８８ＡＴＯ）２．０ｇを加えて混合した後、ローラーコンパクター（ＴＦ－ＭＩＮＩ、フロイント産業株式会社）を使用しロール圧１００ｋｇｆ／ｃｍ２にて乾式造粒を行い、乾式造粒物を得た。 [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.
得られた造粒物を篩２２号で整粒した後、乳糖水和物（７５％）／結晶セルロース（２５％）（ＭＥＧＧＬＥ、ＭＩＣＲＯＣＥＬＡＣ（登録商標）１００Ｍ）７８ｇを、無水乳糖（ＤＦＥＰｈａｒｍａ、ＳｕｐｅｒＴａｂＮＡ２１）５８ｇ、結晶セルロース（旭化成株式会社、ＣＥＯＬＵＳ（登録商標）ＰＨ－１０２）２０ｇに変更したこと以外は実施例２と同様の製造方法により、実施例５のフェソテロジンフマル酸塩含有製剤を得た。
After sizing the obtained granules with Sieve No. 22, 78 g of lactose hydrate (75%)/microcrystalline cellulose (25%) (MEGGLE, MICROCELAC (registered trademark) 100M) was added to anhydrous lactose (DFEPharma, SuperTabNA21 ) and 20 g of crystalline cellulose (CEOLUS (registered trademark) PH-102, Asahi Kasei Co., Ltd.) were changed to 20 g. rice field.
［実施例６］
無水乳糖を６６．７ｇに変更し、結晶セルロースを４ｇに変更したこと以外は、実施例２の製造方法と同様の方法により、実施例６のフェソテロジンフマル酸塩含有製剤を得た。 [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.
無水乳糖を６６．７ｇに変更し、結晶セルロースを４ｇに変更したこと以外は、実施例２の製造方法と同様の方法により、実施例６のフェソテロジンフマル酸塩含有製剤を得た。 [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.
［実施例７］
ポリビニルアルコールを添加せず、無水乳糖を５７．８ｇに変更したこと以外は、実施例２の製造方法と同様の方法により、実施例７のフェソテロジンフマル酸塩含有製剤を得た。 [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.
ポリビニルアルコールを添加せず、無水乳糖を５７．８ｇに変更したこと以外は、実施例２の製造方法と同様の方法により、実施例７のフェソテロジンフマル酸塩含有製剤を得た。 [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.
［実施例８］
ポリビニルアルコールを添加せず、無水乳糖を４６．５ｇに変更し、結晶セルロースを２５ｇに変更したこと以外は、実施例２の製造方法と同様の方法により、実施例８のフェソテロジンフマル酸塩含有製剤を得た。 [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.
ポリビニルアルコールを添加せず、無水乳糖を４６．５ｇに変更し、結晶セルロースを２５ｇに変更したこと以外は、実施例２の製造方法と同様の方法により、実施例８のフェソテロジンフマル酸塩含有製剤を得た。 [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.
［実施例９］
ポリビニルアルコールを添加せず、無水乳糖を５７．３ｇに変更し、グリセリン脂肪酸エステルを１．０ｇに変更したこと以外は、実施例２の製造方法と同様の方法により、実施例９のフェソテロジンフマル酸塩含有製剤を得た。 [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.
ポリビニルアルコールを添加せず、無水乳糖を５７．３ｇに変更し、グリセリン脂肪酸エステルを１．０ｇに変更したこと以外は、実施例２の製造方法と同様の方法により、実施例９のフェソテロジンフマル酸塩含有製剤を得た。 [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.
［実施例１０］
ポリビニルアルコールを添加せず、無水乳糖を５６．３ｇに変更し、グリセリン脂肪酸エステルを２．０ｇに変更したこと以外は、実施例２の製造方法と同様の方法により、実施例１０のフェソテロジンフマル酸塩含有製剤を得た。 [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.
ポリビニルアルコールを添加せず、無水乳糖を５６．３ｇに変更し、グリセリン脂肪酸エステルを２．０ｇに変更したこと以外は、実施例２の製造方法と同様の方法により、実施例１０のフェソテロジンフマル酸塩含有製剤を得た。 [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.
［実施例１１］
ポリビニルアルコールを添加せず、無水乳糖を４５ｇに変更し、結晶セルロースを２５ｇに変更し、グリセリン脂肪酸エステルを２．０ｇに変更したこと以外は、実施例２の製造方法と同様の方法により、実施例１１のフェソテロジンフマル酸塩含有製剤を得た。 [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.
ポリビニルアルコールを添加せず、無水乳糖を４５ｇに変更し、結晶セルロースを２５ｇに変更し、グリセリン脂肪酸エステルを２．０ｇに変更したこと以外は、実施例２の製造方法と同様の方法により、実施例１１のフェソテロジンフマル酸塩含有製剤を得た。 [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.
［実施例１２］
グリセリン脂肪酸エステルをショ糖脂肪酸エステルに変更したこと以外は、実施例２の製造方法と同様の方法により、実施例１２のフェソテロジンフマル酸塩含有製剤を得た。 [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.
グリセリン脂肪酸エステルをショ糖脂肪酸エステルに変更したこと以外は、実施例２の製造方法と同様の方法により、実施例１２のフェソテロジンフマル酸塩含有製剤を得た。 [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.
［安定性の評価］
実施例１～１２のフェソテロジンフマル酸塩含有製剤を６０℃の密栓条件下で２週間保存した。製造直後と、保存後の各フェソテロジンフマル酸塩含有製剤について、上述した方法により、安定性を評価した。測定結果を表２及び表３に示す。 [Evaluation of stability]
The fesoterodine fumarate-containing formulations of Examples 1 to 12 were stored under sealed conditions at 60° C. for 2 weeks. The stability of each fesoterodine fumarate-containing preparation immediately after production and after storage was evaluated by the method described above. Tables 2 and 3 show the measurement results.
実施例１～１２のフェソテロジンフマル酸塩含有製剤を６０℃の密栓条件下で２週間保存した。製造直後と、保存後の各フェソテロジンフマル酸塩含有製剤について、上述した方法により、安定性を評価した。測定結果を表２及び表３に示す。 [Evaluation of stability]
The fesoterodine fumarate-containing formulations of Examples 1 to 12 were stored under sealed conditions at 60° C. for 2 weeks. The stability of each fesoterodine fumarate-containing preparation immediately after production and after storage was evaluated by the method described above. Tables 2 and 3 show the measurement results.
表２において各欄の左の値は、加水分解物量を示し、右の値は、総類縁物質量を示す。直接圧縮法で製造した場合、乳糖水和物を含む実施例１のフェソテロジンフマル酸塩含有製剤に対して、無水乳糖に変更した実施例３のフェソテロジンフマル酸塩含有製剤においても安定性を示すことが明らかとなった。また、無水乳糖を含む実施例３のフェソテロジンフマル酸塩含有製剤は、参考例１及び実施例１のフェソテロジンフマル酸塩含有製剤よりも高い安定性を示すことが明らかとなった。
In Table 2, the left value in each column indicates the amount of hydrolyzate, and the right value indicates the total amount of related substances. When produced by a direct compression method, 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.
乾式造粒法を用いた場合、造粒物中に無水乳糖を含む実施例２のフェソテロジンフマル酸塩含有製剤に対して、造粒物中に乳糖水和物を含む実施例４のフェソテロジンフマル酸塩含有製剤においても同等の安定性を示すことが明らかとなった。また、造粒物の外部に乳糖水和物を含む実施例２のフェソテロジンフマル酸塩含有製剤に対して、造粒物の外部に無水乳糖を含む実施例５のフェソテロジンフマル酸塩含有製剤においても同等の安定性を示すことが明らかとなった。
When dry granulation was used, the fesoterodine fumarate-containing formulation of Example 2, which contained anhydrous lactose in the granules, was compared with the fesoterodine fumarate-containing formulation of Example 4, which contained lactose hydrate in the granules. It was found that the soterodine fumarate-containing formulation also exhibited equivalent stability. Further, in contrast to the 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.
したがって、直接圧縮法又は乾式造粒法を用いる場合、乳糖は、無水物であってもよく、水和物であってもよいことが示された。
Therefore, it was shown that lactose may be anhydrous or hydrate when using the direct compression method or dry granulation method.
表３において各欄の左の値は、加水分解物量を示し、右の値は、総類縁物質量を示す。実施例２のフェソテロジンフマル酸塩含有製剤に対して、無水乳糖を増量し、結晶セルロースを減量した実施例６のフェソテロジンフマル酸塩含有製剤は、実施例２のフェソテロジンフマル酸塩含有製剤と同等の安定性を示すことが明らかとなった。また、ポリビニルアルコールを含む実施例２のフェソテロジンフマル酸塩含有製剤と、ポリビニルアルコールを含まない実施例７のフェソテロジンフマル酸塩含有製剤では、同等の安定性を示すことが明らかとなった。実施例７のフェソテロジンフマル酸塩含有製剤に対して、無水乳糖を減量し、結晶セルロースを増量した実施例８のフェソテロジンフマル酸塩含有製剤は、実施例７のフェソテロジンフマル酸塩含有製剤と同等の安定性を示すことが明らかとなった。
In Table 3, the left value in each column indicates the amount of hydrolyzate, and the right value indicates the total amount of related substances. Compared to the fesoterodine fumarate-containing preparation of Example 2, 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. In addition, it was revealed that 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.
実施例８のフェソテロジンフマル酸塩含有製剤に対して、グリセリン脂肪酸エステルの含有量が２倍の実施例９のフェソテロジンフマル酸塩含有製剤、グリセリン脂肪酸エステルの含有量が４倍の実施例１０のフェソテロジンフマル酸塩含有製剤の安定性の結果より、グリセリン脂肪酸エステルの含有量を変更しても、加水分解物量及び総類縁物質量にはほとんど影響せず、同等の安定性を示すことが明らかとなった。実施例１０のフェソテロジンフマル酸塩含有製剤に対して、無水乳糖を減量し、結晶セルロースを増量した実施例１１のフェソテロジンフマル酸塩含有製剤は、実施例１０のフェソテロジンフマル酸塩含有製剤と同等の安定性を示すことが明らかとなった。グリセリン脂肪酸エステルをショ糖脂肪酸エステルに変更した実施例１２のフェソテロジンフマル酸塩含有製剤は、実施例２のフェソテロジンフマル酸塩含有製剤と同等の安定性を示すことが明らかとなった。
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. It became clear to show Compared to the fesoterodine fumarate-containing preparation of Example 10, 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. It was clarified that the fesoterodine fumarate-containing preparation of Example 12, in which the glycerin fatty acid ester was changed to a sucrose fatty acid ester, exhibits stability equivalent to that of the fesoterodine fumarate-containing preparation of Example 2. .
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. It became clear to show Compared to the fesoterodine fumarate-containing preparation of Example 10, 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. It was clarified that the fesoterodine fumarate-containing preparation of Example 12, in which the glycerin fatty acid ester was changed to a sucrose fatty acid ester, exhibits stability equivalent to that of the fesoterodine fumarate-containing preparation of Example 2. .
Claims (7)
- フェソテロジンフマル酸塩と、乳糖と、結晶セルロースと、滑沢剤とを乾式造粒して、造粒物を得ることを、含む、フェソテロジンフマル酸塩含有製剤の製造方法。 A method for producing a fesoterodine fumarate-containing preparation, comprising dry granulating fesoterodine fumarate, lactose, crystalline cellulose, and a lubricant to obtain a granule.
- 前記造粒物は、前記滑沢剤として、ショ糖脂肪酸エステル又はグリセリン脂肪酸エステルを含む、請求項１に記載のフェソテロジンフマル酸塩含有製剤の製造方法。 The method for producing a fesoterodine fumarate-containing preparation according to claim 1, wherein the granules contain sucrose fatty acid ester or glycerin fatty acid ester as the lubricant.
- 得られた前記造粒物と、乳糖と、結晶セルロースと、ヒプロメロースと、滑沢剤と、を混合して、打錠する、請求項１又は２に記載のフェソテロジンフマル酸塩含有製剤の製造方法。 The fesoterodine fumarate-containing preparation according to claim 1 or 2, wherein the obtained granules, lactose, crystalline cellulose, hypromellose and a lubricant are mixed and tableted. Production method.
- 前記造粒物と混合される前記滑沢剤として、グリセリン脂肪酸エステルを含む、請求項３に記載のフェソテロジンフマル酸塩含有製剤の製造方法。 The method for producing a fesoterodine fumarate-containing preparation according to claim 3, wherein glycerin fatty acid ester is included as the lubricant mixed with the granules.
- 前記造粒物と混合される前記滑沢剤として、タルクを更に含む、請求項４に記載のフェソテロジンフマル酸塩含有製剤の製造方法。 The method for producing a fesoterodine fumarate-containing preparation according to claim 4, further comprising talc as the lubricant mixed with the granules.
- フェソテロジンフマル酸塩と、乳糖と、結晶セルロースと、ヒプロメロースと、滑沢剤と、を混合して、打錠することを含み、
前記フェソテロジンフマル酸塩と、前記乳糖と、前記結晶セルロースと、前記ヒプロメロースと、前記滑沢剤とはそれぞれ乾燥粉末として混合される、フェソテロジンフマル酸塩含有製剤の製造方法。 Mixing fesoterodine fumarate, lactose, crystalline cellulose, hypromellose and a lubricant, and tableting,
A method for producing a fesoterodine fumarate-containing preparation, wherein the fesoterodine fumarate, the lactose, the crystalline cellulose, the hypromellose, and the lubricant are each mixed as dry powders. - 前記滑沢剤として、タルク及びグリセリン脂肪酸エステルを含む、請求項６に記載のフェソテロジンフマル酸塩含有製剤の製造方法。
7. The method for producing a fesoterodine fumarate-containing preparation according to claim 6, wherein the lubricant comprises talc and glycerin fatty acid ester.
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| JP2009539802A (en) * | 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 | Stable pharmaceutical composition comprising fesoterodine |
| WO2012136839A1 (en) * | 2011-04-08 | 2012-10-11 | Lek Pharmaceuticals D.D. | Dry formulation and pharmaceutical composition comprising fesoterodine or a salt or a solvate thereof |
| JP2018519305A (en) * | 2015-06-30 | 2018-07-19 | ジェネンテック， インコーポレイテッド | Immediate release tablets containing drugs and process for forming tablets |
| JP2018184375A (en) * | 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 | Tablet comprising dabigatran etexilate or pharmaceutically acceptable salt thereof and method for producing the same |
| WO2019206391A1 (en) * | 2018-04-26 | 2019-10-31 | Rontis Hellas S.A. | Extended release pharmaceutical composition containing fesoterodine and process for the preparation thereof |
| WO2020090969A1 (en) * | 2018-10-31 | 2020-05-07 | 富士フイルム株式会社 | Package for medical composition containing anti-tumor agent |
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| JP2009539802A (en) * | 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 | Stable pharmaceutical composition comprising fesoterodine |
| WO2012136839A1 (en) * | 2011-04-08 | 2012-10-11 | Lek Pharmaceuticals D.D. | Dry formulation and pharmaceutical composition comprising fesoterodine or a salt or a solvate thereof |
| JP2018519305A (en) * | 2015-06-30 | 2018-07-19 | ジェネンテック， インコーポレイテッド | Immediate release tablets containing drugs and process for forming tablets |
| JP2018184375A (en) * | 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 | Tablet comprising dabigatran etexilate or pharmaceutically acceptable salt thereof and method for producing the same |
| WO2019206391A1 (en) * | 2018-04-26 | 2019-10-31 | Rontis Hellas S.A. | Extended release pharmaceutical composition containing fesoterodine and process for the preparation thereof |
| WO2020090969A1 (en) * | 2018-10-31 | 2020-05-07 | 富士フイルム株式会社 | Package for medical composition containing anti-tumor agent |
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