NZ615452B2 - Solid preparation containing 6-((7s)-7-hydroxy-6,7-dihydro-5h-pyrrolo-[1,2-c]imidazol-7-yl)-n-methyl-2-naphthamide - Google Patents

Solid preparation containing 6-((7s)-7-hydroxy-6,7-dihydro-5h-pyrrolo-[1,2-c]imidazol-7-yl)-n-methyl-2-naphthamide Download PDF

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NZ615452B2
NZ615452B2 NZ615452A NZ61545212A NZ615452B2 NZ 615452 B2 NZ615452 B2 NZ 615452B2 NZ 615452 A NZ615452 A NZ 615452A NZ 61545212 A NZ61545212 A NZ 61545212A NZ 615452 B2 NZ615452 B2 NZ 615452B2
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solid preparation
film
tablet
give
manufactured
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NZ615452A
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NZ615452A (en
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Wataru Hoshina
Masafumi Misaki
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Takeda Pharmaceutical Company Limited
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Priority claimed from PCT/JP2012/059276 external-priority patent/WO2012133918A1/en
Publication of NZ615452A publication Critical patent/NZ615452A/en
Publication of NZ615452B2 publication Critical patent/NZ615452B2/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens

Abstract

Provided is a stable solid preparation comprising 6-((7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide (orteronel), D-mannitol and an alkaline earth metal salt selected from magnesium aluminometasilicate or calcium silicate. It is preferred that the D-mannitol used is produced by a spray dry production method to provide a downsized preparation. 6-((7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide is an anti-cancer agent. produced by a spray dry production method to provide a downsized preparation. 6-((7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide is an anti-cancer agent.

Description

DESCRIPTION SOLID PREPARATION CONTAINING 6-((7S)HYDROXY-6,7-DIHYDRO-5HPYRROLO [1,2-C]IMIDAZOLYL)-N-METHYLNAPHTHAMIDE Technical Field of the Invention
[0001] The present invention relates to a solid preparation containing 6-((7S)hydroxy-6,7-dihydro-5H-pyrrolo[1,2- c]imidazolyl)-N-methylnaphthamide or a salt thereof, and a method of stabilizing 6-((7S)hydroxy-6,7-dihydro-5H- pyrrolo[1,2-c]imidazolyl)-N-methylnaphthamide or a salt thereof in the solid preparation. ound of the Invention 6-((7S)Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol- 7-yl)-N-methylnaphthamide is known to be a nd useful for the prophylaxis or treatment of tumors such as prostate cancer, breast cancer and the like (patent document 1). As a preparation containing 6-((7S)hydroxy-6,7-dihydro-5H- pyrrolo[1,2-c]imidazolyl)-N-methylnaphthamide, preparations described in patent documents 2 to 4 are known.
[Document List] t Documents] patent document 1: WO2002/040484 patent document 2: WO2004/075890 patent document 3: WO2004/082679 patent document 4: /093353 [Summary of the Invention] Problems to be Solved by the Invention
[0004] The t inventors have found a new problem of achieving a high content of the active ingredient and a downsized preparation for the ement of administration compliance of a solid preparation containing 6-((7S) y-6,7-dihydro-5H-pyrrolo[1,2-c]imidazolyl)-N-methyl- 2-naphthamide or a salt thereof as an active ingredient.
In solving the problem of achieving a high content of the active ingredient and a downsized preparation, moreover, new problems of suppression of g weights of preparation and varying contents of the active ingredient, as well as improvement of preparation preservation stability (suppression of production or increase of dehydrated form and related substances, which are decomposed products of the active ingredient) were found.
Since variation in the weights of preparation and the contents of the active ient may lead to severe side effects in patients, it is desirable to reduce such ions as much as le. As for the preparation preservation stability, it is desirable to suppress production or increase of dehydrated form and related substances, which are decomposed products of the active ingredient, as much as possible, so that the efficacy of the active ingredient can be appropriately exerted in patients.
The present invention provides a solid preparation containing 6—((7S)—7—hydroxy—6,7—dihydro—5H—pyrrolo[1,2— c]imidazol—7-yl)—N—methyl—2—naphthamide or a salt thereof at a high content (e.g., 40 wt% or more) as an active ingredient, wherein variation in the weight and the content is suppressed.
The present invention also aims to provide a solid preparation n the active ingredient is ized, and a stabilizing method thereof. Here, the ization of the active ingredient means that the production or increase of dehydrated form and related substances, which are decomposed products of the active ingredient contained in the solid preparation, is suppressed.
Means of Solving the Problems The t inventors have Conducted intensive studies in an attempt to solve the aforementioned problems and found that a solid preparation containing 6—((7S)—7-hydroxy—6,7—dihydro- 2012/059276 BH—pyrrolo[l,2-c]imidazol—7—yl)—N—methyl—2—naphthamide or a salt thereof as an active ingredient, D—mannitol and an ne earth metal salt Selected from, magnesium aluminometasilicate and calcium silicate es superior effects of high content (e.g., 40 w %§or more) of the active » ingredient, suppression of variation in preparation weight and active ingredient content, and improved preparation preservation ity (suppression of production or increase of dehydrated form and related substances, which are decomposed products of the active ingredient). The present inventors have ted the present invention based on these findings.
Accordingly, the present invention is as follows. [1] A solid preparation comprising (1) 6—((7S)—7—hydroxy—6,7-dihydro—5H—pyrrolo[1,2—c]imidazol—7— yl) —N—methyl—2—naphthamide or a salt thereof, ( 2) D—mannitol and (3) an alkaline earth metal salt selected from ium aluminometasilicate and calcium silicate (hereinafter sometimes to be abbreviated as the solid preparation of the present invention).
The solid preparation of the above—mentioned [1], wherein the alkaline earth metal salt is magnesium aluminometasilicate. [3] The solid preparation of the mentioned [1], wherein the alkaline earth metal salt is basic ium aluminometasilicate.
The solid preparation of the mentioned [1], wherein the D—mannitol is produced by a spray dry production method. [5] The solid preparation of the above—mentioned [1], further comprising hydroxypropylcellulose.
The solid preparation of the above—mentioned [1], wherein the content of 6—((7S)-7—hydroxy—6,7—dihydro—5H—pyrrolo[1,2— c]imidazol—7—yl)—N—methyl—2—naphthamide or a salt thereof is 50 — 80 wt%.
A method of stabilizing 6~((7S)—7—hydroxy—6,7—dihydro-5H- pyrrolo[l,2—c]imidazol—7—yl)—N—methyl—2—naphthamide or a salt thereof, comprising adding an alkaline earth metal salt selected from ium aluminometasilicate and calcium silicate to a solid preparation containing 6—((7S)—7—hydroxy- 6,7—dihydro—5H—pyrrolo[l,2—c]imidazol-7—yl)—N—methyl—2— amide or a salt thereof (hereinafter sometimes to be abbreviated as the stabilization method of the present invention). [8] The method of the above—mentioned [7], wherein the alkaline earth metal salt is basic magnesium aluminometasilicate.
Effect of the Invention According to the present ion, a solid preparation ning 6—((7S)~7—hydroxy—6,7—dihydro—5H—pyrrolo[1,2— c]imidazol—7—yl)-N—methyl—2—naphthamide or a salt f at a high content (e.g., 40 wt% or more) as an active ingredient, which can suppress variation in preparation weight and content of active ingredient can be provided. According to the present invention, er, a solid preparation wherein the active ingredient is stabilized, namely, a solid preparation wherein ation preservation stability is improved, and production or increase of dehydrated form and related substances, which are decomposed products of the active ingredient, is suppressed, can be provided.
[Description of Embodiments] 6—((7S)-7—Hydroxy—6,7—dihydro—5H-pyrrolo[l,2—c]imidazol— 7—yl)—N—methyl—2—naphthamide (to be also referred to as compound A in the present specification) or a salt thereof can be produced by a known method, for example, the method described in W02002/O40484 or a method analogous o.
Examples of the salt of compound A include acid addition salts, for example, inorganic acid salts (e.g., hydrochloride, lsulfate, hydrobromide, phosphate), and organic acid salts (e.g., acetate, trifluoroacetate, ate, maleate, fumarate, propionate, citrate, tartrate, lactate, e, methanesulfonate, p—toluenesulfonate). The salt of compound A may be a hydrate. Of compound A and a salt thereof, preferred is compound A.
The content of compound A or a salt thereof in the solid preparation of the present invention is generally 40 — 90 wt%, preferably 50 - 80 wt%, more preferably 60 — 70 wt%;
[0010] The solid preparation of the present invention contains itol.
To provide a downsized ation, D—mannitol to be used in the present invention preferably has an average particle size of 50 um — 250 pm, more preferably 100 um — 200 um. es of D—mannitol to be used in the present invention include D—mannitol produced by the spray dry production method (e.g., PEARLITOL ZOOSD (trade name) (manufactured by ROQUETTE), TOL lOOSD (trade name) (manufactured by ROQUETTE), PARTECK 100M (trade name) (manufactured by Merck), and PARTECK 200M (trade name) (manufactured by ). Of these, PEARLITOL ZOOSD (trade name) (manufactured by ROQUETTE) and PEARLITOL lOOSD (trade name) (manufactured by ROQUETTE) are preferable, and PEARLITOL ZOOSD (trade name) (manufactured by ROQUETTE) is more preferable, from the aspects of manufacturability.
The content of D~mannitol in the solid preparation of the present invention is generally 5 — 45 wt%, preferably 10 — 30 wt%, more preferably 15 — 25 wt%.
[0011] The solid preparation of the present invention contains an ne earth metal salt selected from magnesium aluminometasilicate and calcium silicate. The solid preparation of the present invention may n both magnesium ometasilicate and calcium silicate.
The alkaline earth metal salt selected from magnesium aluminometasilicate and calcium silicate to be used in the present invention is preferably magnesium aluminometasilicate, more preferably basic magnesium aluminometasilicate, from the aspects of improved preservation stability of the solid preparation lization of nd A or a salt thereof) and suppression of ion in the weight of the solid preparation and the content of the active ingredient.
In addition, as the alkaline earth metal salt selected from magnesium aluminometasilicate and calcium silicate to be used in the present invention is preferably basic ium aluminometasilicate or basic calcium silicate, more preferably basic magnesium aluminometasilicate, from the aspect of stabilization of compound A or a salt thereof.
In the present specification, basic magnesium aluminometasilicate generally shows pH of 8.5 - 10.0 when a sample thereof (2 g) is weighed, water is added to the total' amount of 50 mL, the mixture is stirred, left standing for 2 min, and measured by a pH meter. 2d In the present ication, basic m silicate generally shows pH of 8.5 — 9.8 when a sample thereof (5.0 g) is weighed, water is added to the total amount of 100 mL, the mixture is stirred and centrifuged, and the supernatant-is measured by a pH meter.
As basic magnesium aluminometasilicate and basic calcium silicate, commercially available products can also be used. es of basic ium aluminometasilicate include Neusilin FLl.and Neusilin FL2 (trade name) (both manufactured by Fuji Chemical Industry Co., Ltd.). Examples of basic calcium silicate include Florite RE (trade name) (manufactured by Eisai Food & Chemical Co., Ltd.).
The content of the alkaline earth metal salt in the solid preparation of the t invention, which is selected from magnesium aluminometasilicate and calcium silicate, is generally 0.5 — 10 wt%, preferably 0.5 — 5 wt%, more preferably 0.5 — 2.5 wt%.
The solid preparation of the present invention may further contain crystalline cellulose to optimize physicochemical property of the preparation (e.g., manufacturability, tablet disintegration property, tablet hardness).
When the solid preparation of the present invention contains crystalline cellulose, the content of the crystalline ose in the solid preparation is generally 1 - 30 wt%, preferably 2 — 15 wt%, more preferably 3 — 10 wt%.
The solid preparation of the present invention preferably further contains hydroxypropylcellulose to optimize ochemical property of the ation (e.g., manufacturability, tablet hardness).
When the solid preparation of the present invention contains hydroxypropylcellulose, the content of the hydroxypropylcellulose in the solid preparation is generally 1 ~ 10 wt%, preferably 3 — 5 wt%, more_preferably 2 — 4 wt%.
The solid preparation of the present invention preferably further contains low-substituted ypropylcellulose to ze physicochemical property of the preparation (e.g., dissolution property of active substance, manufacturability, tablet hardness).
As the low—substituted hydroxypropylcellulose to be used in the present invention, for e, low-substituted hydroxypropylcellulose wherein the content of a ypropoxy group is 5 — 16% can be used.
The grade of low—substituted hydroxypropylcellulose to be used in the present invention is, for e, LH—ll, LH—Zl, LH-22 or LH-Bl (trade name) (manufactured by Shin—Etsu Chemical Co., Ltd.).
When the solid preparation of the t invention contains low-substituted hydroxypropylcellulose, the content of the low—substituted hydroxypropylcellulose in the solid ation is generally 2 — 20 wt%, preferably 5 — 15 wt%, more preferably 7 — 13 wt%.
The solid preparation of the present invention preferably further contains a surfactant to optimize ochemical property of the preparation (e.g., manufacturability, tablet disintegration property, dissolution property). es of the tant to be'used_in the present invention include sodium lauryl sulfate, e ester of fatty acid, polysorbate 20, rbate 60, polysorbate 80, and polyoxyethylene hydrogenated castor oil 60. The surfactant to be used in the present invention is preferably polysorbate 80 from the aspect of the manufacturability of the solid preparation of the present ion.
When the solid ation of the present invention contains a surfactant, the content of the surfactant in the solid preparation is generally 0.05 - 5 wt%, preferably 0.1 — 3 wt%, more preferably 0.3 — 1.5 wt%.
The solid preparation of the present invention can contain a pharmaceutically able carrier besides the above—mentioned components, as long as it does not inhibit the effect of the present invention. As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances conventionally used as preparation materials can be used. They are appropriately added as, for example, excipient, binder, disintegrant, glidant or lubricant in an appropriate amount.
Examples of the excipient include sugar alcohol other than D—mannitol (e.g., D-sorbitol, erythritol, xylitol), lactose, sucrose, glucose, malt sugar, corn starch, wheat starch, light anhydrous silicic acid, dextrin, carboxymethyl , gelatin, magnesium oxide, calcium phosphate, calcium WO 33918 2012/059276 carbonate, and m sulfate.
Examples of the binder include gelatin, pullulan, hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), polyvinylpyrrolidone (PVP), macrogol, gum arabic, dextran, polyvinyl alcohol (PVA), and starch glue.
Examples of the disintegrant e carmellose, carmellose m, crosslinked polyvinylpyrrolidone, carmellose sodium, croscarmellose sodium, sodium starch glycolate, crospovidone, cation exchange resin, partly pregelatinized starch, and corn starch.
Examples of the glidant include light ous silicic acid, and hydrated silicon dioxide.
Examples of the lubricant include stearic acid, ium stearate, calcium stearate, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, and light anhydrous silicic acid. l The solid preparation of the present ion may be coated with a coating agent, a film coating agent and the like according to a method known per se, for the purpose of masking Athe taste of compound A or a salt thereof, improvement of light stability, improvement of appearance, controlled release and the like.
As the coating agent, polymers such as hydroxypropyl methylcellulose (for example, hydroxypropyl methylcellulose 2910), ethylcellulose, hydroxypropylcellulose and the like are used. As the film coating agent, polymers such as hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose , nylpyrrolidone (PVP), ethylcellulose, polyvinyl acetal diethylamino acetate, cellulose acetate phthalate, methacrylic acid copolymers (e.g., methyl methacrylate— methacrylic acid copolymer (Eudragit (trade name) L100, 8100, manufactured by Rohm), methacrylic acid-ethyl acrylate mer (Eudragit L100—55, L3OD—55), methacrylic acid-methyl acrylate—methyl methacrylate copolymer (Eudragit FS30D (trade WO 33918 name), manufactured by Rohm)), hydroxypropyl methylcellulose phthalate (HP—55 (trade name), HP-50 (trade name), ctured by Shin-Etsu Chemical Co., Ltd.), carboxymethyl ethylcellulose (CMEC, manufactured by Freund Corporation), hydroxypropylcellulose e succinate (HPMCAS manufactured by Shin-Etsu Chemical Co., Ltd.), polyvinyl acetate phthalate, shellac and the like are used. These may be used alone or two or more kinds of rs may be used in combination, or two or more kinds of polymers may be applied sively.
The above—mentioned coating agent and film coating agent may contain hylene glycol (for example, polyethylene glycol 6000 (macrogol 6000), polyethylene glycol 8000), Tween 80, titanium oxide, ferric oxide (e.g., red ferric oxide, yellow ferric oxide) and the like. Specific preferable examples of the film coating agent include Opadry Red (trade name) (manufactured by Colorcon), and Opadry Yellow (trade name) (manufactured by Colorcon). ic preferable examples of the solid preparation of the present invention include the following. (1) A solid preparation sing compound A, D—mannitol, magnesium aluminometasilicate and hydroxypropylcellulose. (2) The solid preparation of the above—mentioned (1), r comprising crystalline cellulose, sodium starch glycolate and magnesium stearate. (3) The solid preparation of the above-mentioned (1), further comprising low-substituted hydroxypropylcellulose, polysorbate 80 and magnesium stearate. (4) The solid preparation of the above—mentioned (2) or (3), further comprising hydroxypropyl methylcellulose, polyethylene glycol, titanium oxide and a colorant (red ferric oxide and/or yellow ferric oxide).
Examples of the dosage form Of the solid preparation of the present invention include tablet (e.g., core tablet, film— coated tablet) and the like.
The solid preparation of the present invention can be produced by a method conventionally used in the pharmaceutical field.
For example, compound A or a salt thereof, D—mannitol, an alkaline earth metal salt selected from ium aluminometasilicate and m silicate, and an optional carrier or additive (e.g., excipient such as crystalline cellulose and the like, low—substituted hydroxypropylcellulose) are mixed, the mixture is granulated using an s solution of a binder (e.g., hydroxypropylcellulose) containing an optional r or additive (e.g., surfactant such as polysOrbate 80 and the like), and the granules are sieved when d. To the obtained sieved powder are added an optional carrier or additive (e.g., disintegrant such as sodium starch glycolate, hydroxypropylcellulose and the like, lubricant such as magnesium stearate and the like), they are mixed, molded and further dried when desired, whereby the solid preparation of the present ion is produced. Mixing and granulation can be performed using, for example, a fluid bed dryer granulator and the like. VMolding can be performed by tableting using, for example, a single punch tableting machine.
A film-coated tablet can be produced by, for e, coating a core tablet obtained by the above—mentioned method, by spraying an aqueous solution of a film coating agent (e.g., a mixture of film coating base such as ypropyl methylcellulose 2910 and the like, plasticizer such as hylene glycol 6000 and the like, and dye such as titanium oxide, red ferric oxide, yellow ferric oxide and the like) by a film coating machine and the like.
The solid ation of the present invention is preferably produced by a fluid bed granulation method. A solid preparation produced by a fluid bed granulation method, particularly a tablet, shows a remarkable effect of the present invention.
The weight of the solid preparation of the present invention is generally 150 — 500 mg, preferably 150 — 350 mg.
The solid preparation of the t invention can be downsized by the use of D—mannitol produced by a spray dry production method. To be precise, when D—mannitol produced by a spray dry production method is used, the weight of a solid ation containing nd A or a salt thereof at a high content (e.g., 40% or more) can be generally set to not more than 500 mg, ably not more than 400 mg, more preferably not more than 200 mg.
The solid preparation of the present invention has superior effects as a medicament, and particularly shows a superior inhibitory activity against steroid Cn,m lyase.
Since the solid preparation of the present invention is low in toxicity and has fewer side effects, it is useful for mammals (e.g., human, bovine, horse, swine, dog, cat, monkey, mouse, rat, particularly human) as, for example, (i) an androgen or estrogen reducer, (ii) an agent for the prophylaxis or ent of various androgen— or estrogen—related diseases, such as (1) primary cancer, metastasis or recurrence of ant tumor (e.g., prostate cancer, breast cancer, uterine cancer, ovarian cancer etc.), (2) various symptoms associated with those cancers (e.g., pain, ia etc.), (3) prostatic rophy, virilism, hirsutism, male pattern alopecia, precocious puberty, endometriosis, uterus myoma, adenomyosis of uterus, mastopathy, polycystic ovary syndrome and the like, or (iii) an agent for the treatment or prophylaxis of androgen—independent cancer (e.g., androgen—independent prostate cancer).
In the present specification, an androgen— or en— reducer means a medicament having an action to suppress androgen production and uent estrogen production (estrogen is synthesized with androgen as a substrate).
The solid preparation of the t ion can be administered orally and safely to a mammal.
While the dose of the solid preparation of the present ion varies depending on the subject of administration, administration ncy and the like, the ation shows effectiveness over a wide range. For example, the daily dose of the solid preparation of the present invention to an adult patient with solid tumor (e.g., prostate cancer patient) is generally about 100 to about 1200 mg, preferably about 300 to about 1000 mg, more preferably about 400 to about 800 mg, as an effective amount of compound A or a salt thereof contained in the solid preparation of the present invention. When the solid preparation is combined with other anti—cancer agent, the dose f is generally lower than the above doses.
However, the dose of the solid preparation to be actually administered is determined according to various preparation forms, age, body weight and sex of the patient, disease level, administration route, term and interval of the administration, and the like, and can be altered at any time based on the judgment of the doctor.
The term and interval of the administration of the solid preparation of the present invention vary depending on various conditions, and can be altered at any time based on the judgment of the doctor. Divided administration, consecutive administration, ittent administration, high dose short period administration, repeat administration and the like can, be ed. For oral administration, for example, the daily dose is desirably administered in one to several portions a day (especially two or three doses per day). In addition, the solid preparation of the present invention can also be administered as a ned—release preparation.
The present invention also relates to a method of 2012/059276 stabilizing compound A or‘a salt thereof, comprising adding an ne earth metal salt selected from magnesium aluminometasilicate and calcium silicate to a solid ation containing compound A or a salt thereof. In the stabilization method of the present invention, the “solid preparation containing nd A or a salt thereof” may contain both magnesium aluminometasilicate and m silicate.
The amount of the alkaline earth metal salt selected from magnesium aluminometasilicate and calcium silicate, which is used for the stabilization method of the present invention is, for example, a range similar to the content of the alkaline earth metal salt selected from magnesium aluminometasilicate and calcium te in the above—mentioned solid ation of the present invention.
As an alkaline earth metal salt selected from magnesium aluminometasilicate and calcium silicate, which is used for the ization method of the present invention, magnesium aluminometasilicate cularly, basic magnesium aluminometasilicate), and basic calcium silicate are preferable, and basic magnesium aluminometasilicate is more able.
In the stabilization method of the present invention, the content of compound A or a salt thereof in the “solid preparation containing compound A or a salt thereof” is, for example, a range similar to the content of compound A or a salt thereof in the above—mentioned solid preparation of the present invention. The “solid preparation containing compound A or a salt thereof” in the stabilization method of the present invention may contain components similar to, for example, the components explained for the above—mentioned solid preparation of the present invention, and can be produced in the same manner.
The stabilization method of the present ion shows superior effects in a solid preparation produced by a fluid bed granulation method, particularly a tablet.
The stabilization method of the present invention also es a method of stabilizing compound A or a salt thereof, comprising adding (I) an ne earth metal salt ed from magnesium aluminometasilicate and m silicate and (2) D—mannitol to a sclid preparation containing compound A or a salt f.
In the stabilization method of the present invention, the “solid preparation containing compound A or a salt thereof” may contain magnesium aluminometasilicate, calcium silicate and Damannitol.
The amount of the D—mannitol to be used in the stabilization method of the present invention is, for example, a range similar to the content of D—mannitol in the above— ned solid preparation of the present invention.
Examples The present invention is explained in more detail in the_following by referring to Comparative es, Reference Examples, Examples and Experimental Examples, which are not to be construed as limitative.
In the following Comparative Examples, Reference Examples, Examples and EXperimental Examples, D-mannitol (PEARLITOL ZOOSD (trade name), manufactured by ROQUETTE), crystalline cellulose, hydroxypropylcellulose, sodium starch glycolate, croscarmellose sodium, light anhydrous silicic acid IL 200 (trade name), manufactured by NIPPON AEROSIL), magnesium te, polysorbate 80 (POLYSORBATE 80 (trade name), manufactured by Sanyo Chemical Industries, Ltd.), low— substituted hydroxypropylcellulose (LH—Zl (trade name), ctured by Shin—Etsu Chemical Co., Ltd.), hydrOxypropyl methylcellulose 2910 (TC—5 (trade name), manufactured by Shin— Etsu Chemical Co., Ltd.), macrogol 6000 (MACROGOL 6000 (trade name), manufactured by Sanyo Chemical Industries, Ltd.), titanium oxide (Titanium oxide (trade name), manufactured by Freund Corporation) used are the Japanese Pharmacopoeia Fifteenth Edition compatible ts, crospovidone, calcium silicate (Florite RE (trade name), manufactured by Eisai Food & Chemical Co., Ltd.), and red ferric oxide (Red iron oxide (trade name), manufactured by LCW) used are Japanese Pharmaceutical Excipients 2003 compatible products, and magnesium aluminometasilicate (Neusilin FL2 (trade name), ctured by Fuji Chemical Industry Co., Ltd.) used is the Japanese Pharmacopoeia Japanese Pharmaceutical Codex 2002 compatible product. As a film coating agent, Opadry Red (trade name) (manufactured by on) which is a premix of hydroxypropyl methylcellulose 2910, ol 6000, titanium oxide and red ferric oxide was used and, as a film coating agent, Opadry Yellow (trade name) (manufactured by Colorcon) which is a premix of hydroxypropyl methylcellulose 2910, macrogol 6000, um oxide and yellow ferric oxide was used.
Comparative Example 1 Compound A (267.4 g), 0—mannitol‘(98.4 g) and crystalline cellulose (21.4 g) were placed in a fluid bed dryer granulator (manufactured by POWREX CORPORATION), ted and mixed, and an aqueous solution (213.9 g) of hydroxypropylcellulose (12.8 g) was sprayed to give a granulated powder. The total amount of the obtained granulated powder was passed through a sieve No. 20 to give a sieved powder. The ed sieved powder (360 g), sodium starch glycolate (18 g) and magnesium stearate (5.4 g) were mixed in a polyethylene bag to give a mixed powder. The mixed powder (383.4 g) was tableted by a tableting e (manufactured by Kikusui Seisakusho Ltd.) to give core tablets (320 mg per tablet). On the other hand, Opadry Red (86.62 g) and Opadry Yellow (173.24 g) were dissolved in purified water (2338.7 g) to give a coating agent. The obtained coating agent was sprayed on the aforementioned core WO 33918 tablets in a film coating machine actured by Freund Corporation) to apply a coating (13 mg per tablet), whereby film—coated tablets containing 200 mg of compound A per tablet were obtained.
Example 1 Compound A (267.4 g), D—mannitol (85.6 g), crystalline ose (21.4 g), and magnesium aluminometasilicate (12.8 g) were placed in a fluid bed dryer granulator (manufactured by POWREX CORPORATION), preheated and mixed, and an aqueous solution (213.9 g) of ypropylcellulose (12.8 g) was sprayed to give a granulated powder. The total amount of the obtained granulated powder was passed through a sieve No. 20 to give a sieved powder. The obtained sieved powder (360 g), sodium starch ate (18 g) and magnesium stearate (5.4 g) were mixed in a hylene bag to give a mixed powder. The mixed powder (383.4 g) was tableted by a tableting machine (manufactured by Kikusui Seisakusho Ltd.) to give core tablets (320 mg per ). On the other hand, Opadry Red (86.62 g) and Opadry Yellow (173.24 g) were ved in purified water (2338.7 g) to give a coating agent. The obtained coating agent was sprayed on the aforementioned core tablets in a film coating machine (manufactured by Freund Corporation) to apply a coating (13 mg per tablet), whereby film-coated tablets containing 200 mg of compound A per tablet were obtained.
Comparative Example 2 Compound A (267.4 g), D—mannitol (94.1 g), crystalline cellulose (21.4 g), and light anhydrous silicic acid (4.3 g) were placed in a fluid bed dryer granulator (manufactured by POWREX CORPORATION), preheated and mixed, and an aqueous solution (213.9 g) of hydroxypropylcellulose (12.8 g) was sprayed to give a granulated powder. The total amount of the obtained granulated powder was passed through a sieve No. 20 to give a sieved powder. The obtained sieved powder (360 g), sodium starch glycolate (18 g) and magnesium stearate (5.4 g) were mixed in a polyethylene bag to give a mixed powder. The mixed powder (383.4 g) was tableted by a ing machine (manufactured by Kikusui Seisakusho Ltd.) to give core tablets (320 mg per tablet). On the other hand, Opadry Red (86.62 g) and Opadry Yellow (173.24 g) were dissolved in ed water (2338.7 g) to give a coating agent. The obtained coating agent was sprayed on the aforementioned core tablets in a film coating machine (manufactured by Freund Corporation) to apply a coating (13 mg per tablet), whereby film—coated tablets containing 200 mg of compound A per tablet were ed.
Example 2 Compound A (267.4 g), D—mannitol (85.6 g), crystalline cellulose (21.4 g), and m silicate (12.8 g) were placed in a fluid bed dryer granulator (manufactured by POWREX CORPORATION), preheated and mixed, and an aqueous solution (213.9 g) of hydroxypropylcellulose (12.8 g) was sprayed to give a granulated powder. The total amount of the obtained granulated powder was passed through a sieve No. 20 to give a sieved powder. The obtained sieved powder (360 g), sodium starch glycolate (18 g) and magnesium stearate (5.4 g) were mixed in a polyethylene bag to give a mixed powder. The mixed powder (383.4 g) was ed by a tableting machine (manufactured by Kikusui Seisakusho Ltd.) to give core tablets (320 mg per tablet). On the other hand, Opadry Red (86.62 g) and Opadry Yellow (173.24 g) were dissolved in purified water (2338.7 g) to give a coating agent. The ed coating agent was sprayed on the aforementioned core s in a film coating machine (manufactured by Freund Corporation) to apply a coating (13 mg per tablet), y film—coated tablets containing 200 mg of compound A per tablet were obtained.
Example 3 ' nd A (267.4 g), D—mannitol (94.1 g), crystalline cellulose (21.4 g), and magnesium aluminometasilicate (4.3 g) were placed in a fluid bed dryer granulator (manufactured by POWREX CORPORATION), preheated and mixed, and an aqueous on (213.9 g) of hydroxypropylcellulose (12.8 g) was sprayed to give a granulated powder. The total amount of the obtained ated powder was passed through a sieve No. 20 to give a sieved powder. The obtained sieved powder (360 g), sodium starch glycolate (18 g) and magnesium stearate (5.4 g) were mixed in a polyethylene bag to give a mixed powder. The mixed powder (383.4 g) was tableted by a ing machine (manufactured by Kikusui Seisakusho Ltd.) to give core tablets (320 mg per tablet). On the other hand, Opadry Red (86.62 g) and Opadry Yellow (173.24 g) were dissolved in purified water (2338.7 g) to give a coating agent. The obtained coating agent was sprayed on the aforementioned core tablets in a film coating e (manufactured by Freund Corporation) to apply a coating (13 mg per tablet), whereby oated tablets containing 200 mg of compound A per tablet were obtained.
Example 4 Compound A (267.4 g), D—mannitol (77 g), crystalline cellulose (21.4 g), and magnesium aluminometasilicate (21.4 g) were placed in a fluid bed dryer granulator (manufactured by POWREX CORPORATION), preheated and mixed, and an aqueous solution (209.4 g) of hydroxypropylcellulose (12.6 g) was sprayed to give a granulated powder. The total amount of the obtained granulated powder was passed through a sieve No. 20 to give a sieved powder. The obtained sieved powder (360 g), sodium starch glycolate (10.8 g) and magnesium stearate (5.4 g) were mixed in a polyethylene bag to give a mixed .
The mixed powder (383.4 g) was tableted by a tableting machine (manufactured by i Seisakusho Ltd.) to give core tablets (320 mg per tablet). On the other hand, Opadry Red (86.62 g) and Opadry Yellow (173.24 g) were ved in purified water (2338.7 g) to give a coating agent. The obtained coating agent was sprayed on the aforementioned core tablets in a film coating machine (manufactured by Freund Corporation) to apply a coating (13 mg per tablet), whereby film—coated tablets containing 200 mg of compound A per tablet were obtained.
Reference Example 1 Compound A (802.1 g), D—mannitol (295.2 g), and crystalline cellulose (64.2 g) Were placed in a fluid bed dryer ator (manufactured by POWREX CORPORATION), preheated and mixed, and an aqueous solution (641.7 g) of hydroxypropylcellulose (38.5 g) was sprayed to give a ated powder. The obtained granulated powder was applied to a power mill (manufactured by SHOWA KAGAKU KIKAI CO., LTD.) to give a sieved .
[0033] Reference Example 2 Compound A (802.1 g), D—mannitol (256.7 g), crystalline cellulose (64.2 g), and magnesium ometasilicate (38.5 g) were placed in a fluid bed dryer granulator (manufactured by POWREX CORPORATION), preheated and mixed, and an aqueous solution (641.7 g) of hydroxypropylcellulose (38.5 g) was sprayed to give a granulated powder. The obtained granulated powder was applied to a power mill (manufactured by SHOWA KAGAKU KIKAI CO., LTD.) to give a sieved powder.
[0034] Comparative Example 3 The sieved powder (360 g) produced in Reference Example 1, sodium starch glycolate (18 g) and magnesium te (5.4 g) were mixed in.a polyethylene bag to give a mixed powder. The mixed powder (383.4 g) was tableted by a tableting machine (manufactured by Kikusui Seisakusho Ltd.) to give core tablets (320 mg per ). On the other hand, Opadry Red (86.62 g) and Opadry Yellow (173.24 g) were dissolved in purified water 7 g) to give a coating agent. The ed coating agent was sprayed on the aforementioned core tablets in'a film coating machine (manufactured by Freund Corporation) to apply a coating (13 mg per tablet), whereby film—coated tablets containing 200 mg of compound A per tablet were obtained.
Comparative Example 4 The sieved powder (360 g) produced in Reference e 1, croscarmellose sodium (18 g) and magnesium stearate (5.4 g) were mixed in a polyethylene bag to give a mixed powder. The mixed powder (383.4 g) was tableted by a tableting e (manufactured by Kikusui Seisakusho Ltd.) to give core tablets (320 mg per tablet). On the other hand, Opadry Red (86.62 g) and Opadry Yellow (173.24 g) were dissolved in purified water (2338.7 g) to give a coating agent. The obtained coating agent was sprayed on the aforementioned core s in a film g machine (manufactured by_Freund Corporation) to apply a coating (13 mg per tablet), whereby film—coated tablets containing 200 mg of compound A per tablet were obtained. ative Example 5 The sieved powder (360 g) produced in Reference e 1, crospovidone (18 g) and magnesium stearate (5.4 g) were mixed in a polyethylene bag to give a mixed powder. The mixed powder (383.4 g) was tableted by a tableting machine (manufactured by Kikusui Seisakusho Ltd.) to give core tablets (320 mg per -tablet). On the other hand, Opadry Red (86.62 g) and Opadry Yellow (173.24 g) were dissolved in purified water (2338.7 g) to give a coating agent. The obtained g agent was sprayed on the aforementioned core tablets in a film coating machine (manufactured by Freund Corporation) to apply a coating (13 mg per tablet), whereby film—coated s; containing 200 mg of compound A per tablet were obtained.
Example 5 The sieved powder (360 g) produced in Reference e 2, sodium starch glycolate (18 g) and magnesium stearate (5.4 g) were mixed in a polyethylene bag-to give a mixed powder. The mixed powder (383.4 g) was tableted by a tableting machine (manufactured by Kikusui usho Ltd.) to give core tablets (320 mg per tablet). On the other hand, Opadry Red (86.62 g) and Opadry Yellow (173.24 g) were dissolved in ed Water (2338.7 g) to give a coating agent. The obtained coating agent was sprayed on the aforementioned core tablets in a film coating machine (manufactured by Freund Corporation) to apply a coating (13 mg per tablet), whereby film-coated tablets containing 200 mg of compound A per tablet were obtained.
Example 6 The sieved powder (360 g) produced in Reference Example 2, croscarmellose sodium (18 g) and magnesium stearate (5.4 g) were mixed in a polyethylene bag to give a mixed powder. The mixed powder (383.4 g) was tableted by a tableting machine (manufactured by Kikusui Seisakusho Ltd.) to give core s (320 mg per ). On the other hand, Opadry Red (86.62 g) and Opadry Yellow (173.24 g) were dissolved in purified water (2338.7 g) to give a coating agent. The obtained coating agent was sprayed on the aforementioned core tablets in a film coating machine (manufactured by Freund Corporation) to apply a coating (13 mg per tablet), whereby oated tablets containing 200 mg of compound A per tablet were obtained.
[0039] Example 7 The sieved powder (360 g) produced in Reference Example 2, vidone (18 g) and magnesium stearate (5.4 g) were mixed in a polyethylene bag to give a mixed powder. The mixed powder (383.4 g) was tableted by a tableting machine (manufactured by Kikusui Seisakusho Ltd.) to give core tablets (320 mg per tablet). On the other hand, Opadry Red (86.62 g) and Opadry Yellow (173.24 g) were dissolved in purified water 7 g) to give a coating agent. The ed coating agent was sprayed on the aforementioned core tablets in a film coating‘ machine (manufactured by Freund Corporation) to apply a coating (13 mg per tablet), whereby film—coated tablets containing 200 mg of compound A per tablet were obtained.
Comparative Example 6 Compound A (300.0 g), D—mannitol (109.2 g), and low— substituted ypropylcellulose (48.0 g) were placed in a fluid bed dryer granulator (manufactured by POWREX ATION), preheated and mixed, and an s solution (281.3 g) of hydroxypropylcellulose (14.4 g) and rbate 80 (3.6 g) was sprayed to give a granulated powder. The total 'amount of the obtained granulated powder was passed h a sieve No. 20 to give a sieved powder. [The obtained sieved ‘powder (396 g) and magnesium stearate (4.0 g) were mixed in a polyethylene bag to give a mixed powder. The mixed powder (400.0 g) was tableted by a tableting machine (manufactured by i Seisakusho Ltd.) to give core tablets (160 mg per tablet). On the other hand, titanium oxide (6.5 g) and red ferric oxide (0.4 g) were dispersed in purified water (100 g) and the obtained dispersion and a solution of hydroxypropyl cellulose 2910 (48.5 g) and macrogol 6000 (10 g) in purified water (488.6 g) were mixed to give a g agent.
The obtained coating agent was d on the aforementioned core tablets in a film coating machine (manufactured by Freund Corporation) to apply a coating (6.54 mg per tablet), whereby film—coated tablets containing 100 mg of compound A per tablet were obtained.
Comparative Example 7 Compound A (300.0 g), D—mannitol (112.8 g), and lowA substituted hydroxypropylcellulose (48.0 g) were placed in a fluid bed dryer granulator (manufactured by POWREX CORPORATION), preheated and mixed, and an aqueous solution (240.0 g) of hydroxypropylcellulose (14.4 g) was sprayed to give a granulated powder. The total amount of the obtained granulated powder was passed through a sieve No. 20 to give a 'sieved powder. The obtained sieved powder (396 g) and magnesium stearate (4.0 g) were mixed in a polyethylene bag to give a mixed powder. The mixed powder (400.0 g) was tableted by a tableting machine (manufactured by Kikusui Seisakusho Ltd.) to give core s (160 mg per ). On the other hand, titanium oxide (6.5 g) and red ferric oxide (0.4 g) were dispersed in purified water (100 g) and the obtained dispersion and a on of hydroxypropyl methylcellulose 2910 (48.5 g) and macrogol 6000 (10 g) in purified water (488.6 g) were mixed to give a coating agent. The obtained coating agent was sprayed on the aforementioned core tablets in a film coating machine (manufactured by Freund Corporation) to apply a coating (6.54 mg per ), whereby film—coated tablets containing 100 mg of compound A per tablet were obtained.
Example 8 Compound A (300.0 g), D—mannitol (105.6 g), low— tuted hydroxypropylcellulose (48.0 g) and magnesium aluminometasilicate (3.6 g) were placed in a fluid bed dryer ator (manufactured by POWREX CORPORATION), preheated and mixed, and an aqueous solution (281.3 g) of hydroxypropylcellulose (14.4 g) and polysorbate 80 (3.6 g) was sprayed to give a granulated powder. The total amount of the obtained ated powder was passed through a sieve No. 20 to give a sieved powder. The obtained sieved powder (396 g) , and magnesium stearate (4.0 g) were mixed in a polyethylene bag to give a mixed powder. The mixed powder (400.0 g) was tableted by a ing machine (manufactured by Kikusui Seisakusho Ltd.) to give core tablets (160 mg per tablet). On the other hand, titanium oxide (6.5 g) and red ferric oxide (0.4 g) were dispersed in purified water (100 g) and the obtained dispersion and a solution of hydroxypropyl methylcellulose 2910 (48.5 g) and macrogol 6000 (10 g) in ‘ ' PCT/JPZOlZ/059276 - purified water (488.6 g) were mixed to give a coating agent.
The obtained coating agent was sprayed on the aforementioned core tablets in a film coating machine (manufactured by Freund Corporation) to apply a coating (6.54 mg per tablet), whereby film—coated tablets ning 100 mg of compound A per tablet were obtained.
Comparative Example 8 Compound A (300.0 g), D—mannitol (123.6 g), and low— tuted hydroxypropylcellulose (33.6 g) were placed in a fluid bed dryer granulator (manufactured by POWREX CORPORATION), ted and mixed, and an aqueous solution (281.3 g) of hydroxypropylcellulose (14.4 g) and polysorbate 80 (3.6 g) was sprayed to give a ated powder. The total amount of the ed granulated powder was passed through a sieve No. 20 to give a sieved powder. The obtained sieved powder (396 g) and magnesium stearate (4.0 g) were mixed in a hylene bag to give a mixed powder. The mixed powder (400.0 g) was tableted by a tableting machine (manufactured by i Seisakusho Ltd.) to give core tablets (160 mg per tablet). On the other hand, um oxide (6.5 g) and red ferric oxide (0.4 g) were dispersed in purified water (100 g) and the obtained dispersion and a solution of hydroxypropyl methylcellulose 2910 (48.5 g) and macrogol 6000 (10 g) in purified water (488.6 g) were mixed to give a coating agent.
The ed coating agent was sprayed on the aforementioned core tablets in a film coating machine (manufactured by Freund Corporation) to apply a coating (6.54 mg per tablet), whereby film—coated tablets containing 100 mg of compound A per tablet were obtained.
Example 9 Compound A (300.0 g), D—mannitol (118.8 g), low— substituted hydroxypropylcellulose (33.6 g) and magnesium aluminometasilicate (4.8 g) were placed in a fluid bed dryer granulator (manufactured by POWREX CORPORATION), preheated and mixed, and an aqueous solution (281.3 g) of hydroxypropylcellulose (14.4 g) and polysorbate 80 (3.6 g) was sprayed to give a granulated powder. The total amount of the ed granulated powder was passed through a sieve No. 20 to give a sieved powder. The obtained sieved powder (396 g) and magnesium stearate (4.0 g) were mixed in a polyethylene bag to give a mixed powder. The mixed powder (400.0 g) was tableted by a tableting machine (manufactured by Kikusui Seisakusho Ltd.) to give core tablets (160 mg per tablet). On the other hand, titanium oxide (6.5 g) and red ferric oxide (0.4 g) were dispersed in purified water (100 g) and the obtained dispersion and a solution of hydroxypropyl methylcellulose 2910 (48.5 g) and macrogol 6000 (10 g) in ed water (488.6 g) were mixed to give a coating agent.
The ed Coating agent was sprayed on the aforementioned core tablets in a film g machine (manufactured by Freund Corporation) to apply a coating (6.54 mg per tablet), y oated tablets containing 100 mg of compound A per tablet were obtained.
Example 10 The mixed powder obtained in Example 8 was tableted by a tableting machine to give core tablets (320 mg and 480 mg per tablet). Using the coating agent obtained in Example 8 and a film g machine, the coating agent was sprayed on the entioned core tablets to apply a coating (13.08 mg per tablet and 19.62 mg per tablet), whereby film—coated tablets ning 200 mg or 300 mg of compound A per tablet were obtained.
Example 11 The mixed powder obtained in Example 9 was tableted by a tableting machine to give core tablets (320 mg and 480 mg per tablet). Using the coating agent obtained in Example 9 and a film coating machine, the coating agent was sprayed on the aforementioned core tablets to apply a coating (13.08 mg per tablet and 19.62 mg per tablet), whereby film—coated tablets containing 200 mg or 300 mg of compound A per tablet were obtained.
Experimental Example 1 The film-coated tablets containing magnesium aluminometasilicate and produced in Example 1 and the film- coated tablets without magnesium aluminometasilicate and produced in Comparative Example 1 were measured for the weight of core tablet and oated tablet, and the minimum value and maximum value thereof, as well as coefficient of variation were evaluated. In addition, the amount of compound A ned in the film—coated tablets was measured by high performance liquid chromatography, and the t of compound A in the film—coated tablet (ratio of the weight (Found) of compound A contained in film—coated tablet to charged weight of nd A in film—coated tablet) was calculated, as well as the minimum value and maximum value thereof and coefficient of variation were ted. As a result, as shown in [Table 1], Example 1 containing magnesium ometasilicate showed marked ssion of the variation of the weight of core tablet and film-coated tablet and variation of compound A content of film—coated tablet, as compared to Comparative Example 1 showing large variation.
Similarly, the film—coated tablets containing calcium silicate and produced in e 2 were measured for the weight of the core tablet and film—coated tablet, and the minimum value and maximum value thereof, as well as coefficient of variation were evaluated. In addition, the content of compound A in the film—coated tablets was measured by high performance liquid tography, and the minimum value and maximum value thereof, as well as coefficient of variation were evaluated. As a result, as shown in [Table 2], various variations confirmed in ative Example 1 were improved in e 2.
In each Table, n shows the number of tablets subjected to the test.
Table 1 Comparative Example 1 Example 1 average value of core tablet 323.0 320.1 weight (mg) (n=20) minimum value and maximum % value of core tablet weight 311.0—336.l 318.3—322.0 (mg) (n=20) coefficient of variation (%) 3 ' 2 0 of tablet weight (n=20) ' 4 core average value of film—coated 333'6_ 333°4 tablet weight (mg) (n=20) A minimum value, and maximum value of film—coated tablet 312.3—346.2 33l.8—334.6 weight (mg) (n=20) cient of variation (%) of film—coated tablet weight 3.6 (n=20) ' average value of compound A content (%) of oated 100.7 tablet (n=10) minimum value and maximum value of compound A content 93.1—108.0 98.5—99.6 (%) of film-COated tablet (n=10) coefficient of variation (%) of compound A content of . 5.8 0.4 film-coated tablet (n=lO) Table 2 Example 2 average value of core tablet ‘1 320 3 weight (mg) (n=20) ' minimum value and maximum value of core tablet weight 316.3—324.4 (mg) (n=20) coefficient of variation (%) 0 8 core tablet weight (n=20) average value of film—coated *1 332 3 tablet weight (mg) (n=20) ' m value, and maximum value of film-coated tablet 327.6—335.8 weight (mg) (n=20) coefficient of variation (%) of film—coated tablet weight 0.8 (n=20) e value of compound A content (%) of film-coated 97.3 tablet (n=10) J minimum value and m value of compound A content 96'6_99'6 (%) of film—coated tablet (n=10) coefficient of variation (%) of compound A content of 0.8 film—coated tablet (n=lO) Experimental Example 2 The film—coated tablet ning magnesium aluminometasilicate and ed in Example 1 and the film— coated tablet without magnesium aluminometasilicate and produced in Comparative Example 1 were stored in an opened glass bottle at 40°C/75%RH for about 3 months. The contents of ated form and related nces were measured by high ' performance liquid chromatography and the stability of the preparations was compared. As a result, as shown in [Table 3], production of dehydrated form was remarkable and the total related substances also increased in Comparative Example 1. On the other hand, Example 1 containing magnesium aluminometasilicate showed remarkable suppression of the production of dehydrated form and increase of total related substances.
In addition, the film—coated tablet ning calcium silicate and produced in Example 2 and the film—coated tablet containing light anhydrous silicic acid and produced in Comparative Example 2 were stored in an opened glass bottle at 40°C/75%RH for about 3 months. The ts of dehydrated form and related substances were measured by high performance liquid chromatography and the stability of the preparations was compared. .As a result, as shown in [Table 4], production~ of ated form was remarkable and the total related nces also increased in ative Example 2. On the other hand, Example 2 containing calcium silicate did not show remarkable increase of dehydrated form or increase of total d substances.
It was confirmed that Examples 1 and 2 are stable even after preservation with time, as compared to Initial.
Table 3 Comparative e 1 Example 1 . . 40°C 75%RH . . 40°C 75%RH Initial Initial 3 months 3 months dehydrated form (%) <0.02 0.10 <0.02 total related substances (%) [Table 4] Comparative Example 2 Example 2 . a 40°C 75%RH Inltlal Inltlal'. . 40°C 75%RH 3 months 3_months dehydrated form (%) 0.04 0.26 0.04 total related substances (%) Experimental Example 3 The film—coated tablets containing magnesium [aluminometasilicate and produced in Examples 3 and 4 (containing 1% and 5% magnesium ometasilicate relative to core tablet weight) were stored in an opened glass bottle at 40°C/75%RH for about 3 months. The contents of ated form and related substances were measured by high performance liquid chromatography and the ity of the preparations was compared. As a result, as shown in [Table 5], increase of dehydrated form was more remarkably suppressed in e 4 with high magnesium ometasilicate content.
[Table 5] Example 3 Example 4 40°C 75%RH 40°C 75%RH Initial Initial 3 months 3 months dehydrated form —0.02 0.02 total ncesrelated) Experimental Example 4 The film—coated tablets produced in Example 5, Example 6 and Example 7, which contained magnesium aluminometasilicate and sodium starch glycolate, croscarmellose sodium and crospovidone, respectively, as a disintegrant, the film—coated tablets produced in Comparative Example 3, Comparative Example 4 and Comparative Example 5, which did not contain magnesium aluminometasilicate but containing sodium starch glycolate, croscarmellose sodium and crospovidone, respectively, as a disintegrant, were stored in an opened glass bottle at 40°C/75%RH for about 3 months. The ts of dehydrated form and related substances were ed by high mance liquid chromatography and the stability of the preparations was compared. As a result, as shown in [Table 6], [Table 7] and [Table 8], production of dehydrated form was remarkable and the total related substances also increased in Comparative WO 33918 Example group free of magnesium aluminometasilicate. On the other hand, in Examples 5 — 7 containing magnesium aluminometasilicate, production of dehydrated form and increase of the total related substances were remarkably suppressed. It was confirmed that Examples 5 - 7 are stable even after preservation with time, as compared to Initial.
[Table 6] Comparative Example 3 e 5 40°C 75%RH 40°C 75%RH Initial . 3 months Initial 3 months dehydrated form(%) 0.12 total related substances (%)
[0057] [Table 7] Comparative Example 4 Example 6 40°C 75%RH 40°C 75%RH l 3 months Initial 3 months dehydrated form(%) 0.18 total related substances (%) [Table 8] Comparative Example 5 Example 7 40°C 75%RH 40°C 75%RH Initial 3 months l 3 months dehydrated form(%) <0.02 0.10 <0.02 0.02 total related substances (%) Experimental Example 5 The film—coated s containing magnesium aluminometasilicate and produced in Example 8, the film—coated 2012/059276 tablets without magnesium aluminometasilicate and produced in Comparative Example 6, and the oated tablets without magnesium aluminometasilicate and polysorbate 80 and produced in Comparative e 7 were measured for the weight of core tablet and film—coated tablet, and the minimum value and maximum value thereof, as well as coefficient of variation were evaluated. In addition, the amount of compound A contained in the film—coated tablets was measured by high performance liquid chromatography, and the content of compound A in the film-coated tablet (ratio of the weight (Found) of compound A contained in film—coated tablet to charged weight of compound A in film—coated tablet) was calculated, as well as the minimum value and maximum value thereof and coefficient of variation were evaluated. As a result, as shown in [Table 9], Example 8 containing magnesium aluminometasilicate showed marked suppression of the variation of the weight of core tablet and film—coated tablet and ion of compound A content of film—coated tablet, as ed to Comparative Example 6 and Comparative e 7 showing large variation.
Similarly, the film—coated tablets containing magnesium aluminometaSilicate and produced in Example 9 and the film- coated tablets without magnesium aluminometasilicate and produced in Comparative Example 8 were measured for the weight of the core tablet and oated tablet, and the minimum value and maximum value thereof, as well as coefficient of variation were ted. In addition, the content of compound A in the film—coated tablets was measured by high performance liquid chromatography, and the minimum value and maximum value thereof, as well as coefficient of ion were ted.
As a , as shown in [Table 10], various variations confirmed in Comparative Example 8 were improved in Example 9.
In each Table, n shows the number of tablets subjected to the test.
[Table 9] Comparative Comparative Example 6 VExample 7 Example average value tablet weight (mg) 161.1 160. 9 (n=20) m value and m value of core l53.3-167.6 152.3—169.6 lS8.l-l62.4 tablet weight (mg) (n=20) coefficient of variation (%) of core tablet weight (n=20) llllllllilllll average value of film— coated tablet weight (mg) (n=20) minimum value, and maximum value of film— l6l.6—l73.8 155.6—179.8 165.1-167.0 coated tablet weight (mg) (n=20) coefficient of variation ‘(%) of film—coated 5.3 0.8 tablet weight (n=20) average value of compound A content ( % ) 98.4 98.9 of film-coated tablet (n=lO) m value and maximum value of compound A content (%) 93.9—104.1 88.6—106.6 96.9-lOO.6 of film—coated tablet (n=10) coefficient of variation (%) of compound A 3.2 5.9 0.7 content of film—coated tablet (n=lO) [Table 10} Comparative Example 9 Example 8 average value of core 160.4 159.7 tablet weight (mg) (n=20) minimum value and maximum value of core tablet 154.8—164.9 157.1—162.2 weight (mg) (n=20) coefficient of variation (%) of core tablet weight (n=20) -average value of film— coated tablet weight (mg) (n=20) m value, and maximum value of film-coated l60.3-l71.2 l64.3-l67.l tablet weight (mg) (n=20) coefficient of variation (%) of film—coated tablet 2.8 0.9 weight (n=20) average value of compound A content (%) of film- 99.4 98.3 coated tablet (n=lO) minimum value and maximum value of nd A 94'9-105°1 97'1’99-9 content (%) of film—coated tablet (n=10) coefficient of variation (%) of compound A content 3.3 0.6 of film-coated tablet (n=lO) mental Example 6 The film-coated tablet containing ium aluminometasilicate and ed in Example 8, the film—coated tablet without magnesium aluminometasilicate and produced in Comparative Example 6, and the oated tablet without magnesium aluminometasilicate and polysorbate 80 and produced in Comparative Example 7 were stored in an opened glass bottle at 40°C/75%RH for about 3 months. The contents of dehydrated form and related substances were measured by high performance liquid chromatography and the stability of the preparations was compared. As a result, as shown in [Table 11], production of ated form was remarkable and the total related substances also sed in Comparative Example 6 and Comparative Example 7. On the other hand, Example 8 containing magnesium ometasilicate showed able suppression of the production of dehydrated form and increase of total d substances.
In addition, the film-coated tablet containing magnesium aluminometasilicate and produced in e 9 and the film— coated tablet without magnesium aluminometasilicate and produced in Comparative Example 8 were stored in an opened glass bottle at 40°C/75%RH for about 3 months. The contents of dehydrated form and related substances were measured by high performance liquid chromatography and the stability of the preparations was compared. As a result, as shown in [Table 12], production of dehydrated form was remarkable, the total related substances also increased in ative Example 8. On the other hand, Example 9 containing magnesium aluminometasilicate showed remarkable suppression of the production of dehydrated form and increase of total related substances.
It was med that Examples 8 and 9 are stable even after preservation with time, as compared to Initial.
[Table 11] Comparative Comparative Example 8 Example 6 Example 7 40°C 40°C 40°C 75%RH 75%RH 75%RH 3 '3 3 Initial months Initial months Initial mOnths dehydrated <0.02 0.09 <0.02 0.09 <0.02 <0.02 form (%) total ”lat” 0.41 0.51 0.41 0.54 0.41 0.42 substances [Table 12] Comparative Example 8 Example 9 40°C 75%RH 40°C 75%RH l 3 months Initial 3 months dehydrated <0.02 0.08 <0.02 <0.02 form (%) total related 0.41 0.51 substances Industrial Applicability
[0065] According to the t invention, a solid preparation containing 6-((7S)~7—hydroxy—6,7—dihydro-5H—pyrrolo[l,2— c]imidazol—7—yl)—N—methyl—2—naphthamide or a salt thereof at a high content (e.g., 40 wt% or more) as an active ingredient, which can suppress variation in preparation weight and content of active ingredient can be provided. According to the present invention, moreover, a solid preparation wherein the active ingredient is stabilized, namely, a solid ation wherein preparation vation stability is improved, and production or increase of dehydrated form and related substances, which are decomposed products of the active ingredient, is suppressed, can be provided.
This ation is based on a patent application No. 2011—082301 filed in Japan, the contents of which are incorporated in full herein.

Claims (10)

1. A solid preparation comprising (1) 6-((7S)hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol 5 yl)-N-methylnaphthamide or a salt thereof, (2) itol and (3) an ne earth metal salt selected from magnesium aluminometasilicate and calcium silicate. 10
2. The solid preparation according to claim 1, wherein the alkaline earth metal salt is magnesium aluminometasilicate.
3. The solid ation according to claim 1, wherein the alkaline earth metal salt is basic magnesium 15 aluminometasilicate.
4. The solid preparation according to any one of claims 1 to 3, wherein the D-mannitol is produced by a spray dry production method.
5. The solid preparation according to any one of claims 1 to 4, further comprising hydroxypropylcellulose.
6. The solid preparation according to any one of claims 1 to 5, 25 wherein the content of 6-((7S)hydroxy-6,7-dihydro-5H- o[1,2-c]imidazolyl)-N-methylnaphthamide or a salt thereof is 50 - 80 wt%.
7. A method of stabilizing 6-((7S)hydroxy-6,7-dihydro-5H- 30 pyrrolo[1,2-c]imidazolyl)-N-methylnaphthamide or a salt thereof, sing adding an alkaline earth metal salt selected from ium aluminometasilicate and calcium silicate to a solid preparation containing 6-((7S)hydroxy- 6,7-dihydro-5H-pyrrolo[1,2-c]imidazolyl)-N-methyl 35 naphthamide or a salt thereof.
8. The method according to claim 7, n the alkaline earth metal salt is basic magnesium aluminometasilicate. 5
9. The solid preparation according to claim 1, substantially as herein described with reference to any one of the Examples thereof.
10. The method according to claim 7, substantially as herein 10 described with reference to any one of the Examples thereof.
NZ615452A 2011-04-01 2012-03-29 Solid preparation containing 6-((7s)-7-hydroxy-6,7-dihydro-5h-pyrrolo-[1,2-c]imidazol-7-yl)-n-methyl-2-naphthamide NZ615452B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2011082301 2011-04-01
JP2011-082301 2011-04-01
PCT/JP2012/059276 WO2012133918A1 (en) 2011-04-01 2012-03-29 Solid preparation

Publications (2)

Publication Number Publication Date
NZ615452A NZ615452A (en) 2015-05-29
NZ615452B2 true NZ615452B2 (en) 2015-09-01

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