WO2016136849A1 - 固形製剤 - Google Patents
固形製剤 Download PDFInfo
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- WO2016136849A1 WO2016136849A1 PCT/JP2016/055540 JP2016055540W WO2016136849A1 WO 2016136849 A1 WO2016136849 A1 WO 2016136849A1 JP 2016055540 W JP2016055540 W JP 2016055540W WO 2016136849 A1 WO2016136849 A1 WO 2016136849A1
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- tablet
- compound
- salt
- solid preparation
- mass
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
Definitions
- the present invention relates to N- (4- (1- (2,6-difluorobenzyl) -5-((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl)) in solid formulations (eg tablets). -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N′-methoxyurea (also referred to herein as compound A) and its
- the present invention relates to a solid preparation having improved salt stability, and a method for stabilizing Compound A and a salt thereof in the solid preparation.
- Patent Document 1 a compound represented by the general formula including compound A and a salt thereof and a salt thereof have an excellent gonadotropin-releasing hormone antagonistic action, and are used, for example, as a prophylactic or therapeutic agent for hormone-dependent diseases. It is disclosed along with a method for producing the compound.
- Patent Document 2 discloses a preparation containing a compound represented by the above general formula and a salt thereof, which is improved in oral absorbability, characterized by blending an organic acid.
- Compound A and its salt alone are stable with respect to temperature, humidity and the like in the solid state, but the present inventors have made Compound A or its salt into a solid preparation with a formulation containing other components (for example, In the case of tableting, it has been found that there is a problem that degradation products of Compound A or a salt thereof increase with time.
- the present invention aims to solve the problem which is such a new finding, that is, the present invention relates to a solid preparation in which the stability of Compound A and its salt in a solid preparation (eg, tablet) is improved, and It aims at providing the stabilization method of the compound A and its salt in a solid formulation.
- the inventors of the present invention have made the content of compound A or a salt thereof in a tablet 25% by mass or more, so that It was found that degradation over time was suppressed, in other words, compound A and its salt in the tablet were stabilized.
- a low-melting point oily substance selected from polyethylene glycol, glyceryl monostearate and triethyl citrate is added to a solid preparation (eg, tablet). It has been found that compounding suppresses the daily degradation of Compound A and its salt in the solid preparation, in other words, stabilizes Compound A and its salt in the solid preparation. Based on the above findings, the inventors of the present invention have further studied and completed the present invention.
- the present invention provides the following.
- a solid preparation having improved stability of Compound A and its salt in a solid preparation for example, tablet
- a method for stabilizing Compound A and its salt in the solid preparation for example, tablet
- a physiologically acceptable acid addition salt is preferable.
- examples of such salts include salts with inorganic acids (eg, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid) or organic acids (eg, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid) And salts with tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid), and the like.
- inorganic acids eg, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid
- organic acids eg, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid
- tartaric acid maleic acid, citric acid, succinic acid, malic acid, methanes
- the tablet containing compound A or a salt thereof at a high content a tablet containing compound A or a salt thereof at a high content, specifically 25% by mass of compound A or a salt thereof.
- the present invention relates to a tablet containing the above (preferably 35% by mass or more, more preferably 40% by mass or more) (hereinafter sometimes abbreviated as the tablet of the present invention).
- the content of Compound A or a salt thereof is, for example, 80% by mass or less (preferably 75% by mass or less).
- the tablet of the present invention contains compound A or a salt thereof in an amount of 25% by mass or more (preferably 35% by mass or more, more preferably 40% by mass or more). Compared to tablets containing less than 25% by weight), the stability of compound A and its salts in the tablets can be improved. In addition, the tablet of the present invention contains compound A or a salt thereof in a high content, so that the tablet can be miniaturized, and the effect of improving patient compliance can be expected.
- the present inventors have used tablets containing Compound A or a salt thereof as excipients with an average particle size of 60 to 500 ⁇ m (more preferably 60 to 250 ⁇ m, still more preferably 70 to 200 ⁇ m, particularly preferably 80 to 150 ⁇ m).
- D-mannitol granules the compound A or a salt thereof has a high content (for example, 25% by mass or more, preferably 30% by mass or more, more preferably 35% by mass or more, and further preferably 40% by mass). It was found that tablets containing at least% were obtained.
- the average particle diameter is generally called the median diameter, and is a value corresponding to 50% of the cumulative distribution (volume distribution) of the powder particles.
- the average particle size can be measured using a particle laser diffraction type particle size distribution analyzer (HELOS® system and RODOS® dispersion unit, Sympatech) at a dispersion pressure of 2.0 bar.
- D-mannitol grains having an average particle diameter in the above range can be produced by a method known per se, and are not particularly limited, but can be produced, for example, by a spray drying method.
- D-mannitol particles having an average particle diameter in the above range commercially available products (for example, PEARLITO 100SD, PEARLITOL 200SD, PEARLITOL 300DC, PEARLITOL 400DC, all of which are rocket companies) can also be used.
- the D-mannitol granules D-mannitol grains having an average particle size of 75 to 150 ⁇ m (for example, PEARLITOL 100SD) are preferable.
- the content of D-mannitol particles is preferably 10 to 75% by mass, more preferably 12 to 70% by mass, still more preferably 15 to 65% by mass, and even more preferably 15 to 60% by mass. It is.
- the tablet of the present invention may further contain an additive commonly used in the pharmaceutical field.
- the additive include an excipient, a binder, a disintegrant, a lubricant, a colorant, a pH adjuster, a surfactant, a sweetener, a fragrance, a coating base, and a coating additive. These additives are used in amounts conventionally used in the pharmaceutical field unless otherwise specified.
- Excipients include, for example, mannitol (eg, D-mannitol ⁇ eg, PEARLITOL 50C (trade name); Rocket) ⁇ ; crystalline cellulose; corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, alpha Starches such as modified starch and porous starch; anhydrous calcium phosphate; precipitated calcium carbonate; calcium silicate. D-mannitol and crystalline cellulose are preferred.
- the content of the excipient is preferably 10 to 75% by mass, more preferably 20 to 65% by mass.
- the excipient in the present invention is preferably D-mannitol granules or mannitol (eg, D-mannitol), and more preferably D-mannitol granules. Further, D-mannitol and D-mannitol granules may be used alone or in combination. In the present invention, when the above-mentioned D-mannitol granules are used as an excipient, the total amount of the excipient may be in the above range.
- the total amount of the excipient is preferably 10 to 75% by mass, more preferably 12 to 70% by mass, further preferably 15 to 65% by mass, More preferably, it is 15 to 60% by mass.
- the binder for example, crystalline cellulose [eg, crystalline cellulose ⁇ eg, Theolas KG-802 (grade: KG-802) (trade name); Theolas PH-302 (grade: PH-302) (trade name); Asahi Kasei Chemicals Co., Ltd. ⁇ , crystalline cellulose (grains), crystalline cellulose (fine particles)], hydroxypropyl cellulose [eg, grade: L, SL, SSL (trade name); Nippon Soda Co., Ltd.], hydroxypropyl methylcellulose [eg, Examples include hypromellose 2910, TC-5 (grade: MW, E, EW, R, RW) (trade name); Shin-Etsu Chemical Co., Ltd.], povidone (polyvinylpyrrolidone), and copolyvidone, with hydroxypropylcellulose being preferred.
- the content of the binder is preferably 0.5 to 20% by mass, more preferably 1 to 10% by mass
- disintegrant examples include corn starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, croscarmellose sodium (eg, Akzisol), crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl starch, Examples thereof include sodium starch glycolate and magnesium aluminate metasilicate, and croscarmellose sodium and sodium starch glycolate are preferred.
- the content of the disintegrant is preferably 1 to 20% by mass, more preferably 2 to 10% by mass.
- the lubricant examples include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, and sodium stearyl fumarate, and magnesium stearate is preferable.
- the content of the lubricant is preferably 0.1 to 5% by mass, more preferably 0.2 to 3% by mass.
- Examples of the colorant include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2, edible lake pigments, ferric oxide, and yellow ferric oxide.
- pH adjuster examples include citric acid or its salt, phosphoric acid or its salt, carbonic acid or its salt, tartaric acid or its salt, fumaric acid or its salt, acetic acid or its salt, amino acid or its salt.
- surfactant examples include sodium lauryl sulfate, polysorbate 80, and polyoxyethylene (160) polyoxypropylene (30) glycol.
- sweeteners examples include aspartame (trade name), acesulfame potassium, sucralose, thaumatin, saccharin sodium, and dipotassium glycyrrhizinate.
- fragrances include menthol, mint oil, lemon oil, and vanillin.
- coating base examples include sugar coating base, water-soluble film coating base, enteric film coating base, and sustained-release film coating base.
- sugar coating base examples include sucrose, and one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
- water-soluble film coating base examples include hydroxypropyl cellulose [eg, grade: L, SL, SL-T, SSL (trade name); Nippon Soda Co., Ltd.], hydroxypropyl methylcellulose [eg, hypromellose 2910, TC] -5 (grade: MW, E, EW, R, RW) (trade name); Shin-Etsu Chemical Co., Ltd.], cellulosic polymers such as hydroxyethyl cellulose and methylhydroxyethyl cellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer Synthetic polymers such as E [Eudragit E (trade name)] and polyvinylpyrrolidone; and polysaccharides such as pullulan.
- hydroxypropyl cellulose eg, grade: L, SL, SL-T, SSL (trade name); Nippon Soda Co., Ltd.]
- enteric film coating bases include cellulose-based polymers such as hydroxypropyl methylcellulose ⁇ ⁇ ⁇ phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) ], Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)], and natural products such as shellac.
- cellulose-based polymers such as hydroxypropyl methylcellulose ⁇ ⁇ ⁇ phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, and cellulose acetate phthalate
- methacrylic acid copolymer L Eudragit L (trade name)
- Acrylic acid polymers such as methacrylic acid copolymer LD [E
- sustained-release film coating base examples include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate / methyl methacrylate copolymer suspension [ Acrylic polymers such as Eudragit NE (trade name)].
- cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate / methyl methacrylate copolymer suspension [ Acrylic polymers such as Eudragit NE (trade name)].
- Coating additives include: light shielding agents such as titanium oxide; fluidizing agents such as talc; colorants such as iron sesquioxide and yellow sesquioxide; polyethylene glycol (eg, Macrogol 6000), triethyl citrate, castor oil, Plasticizers such as polysorbates; organic acids such as citric acid, tartaric acid, malic acid, and ascorbic acid. Two or more of the above additives may be mixed and used at an appropriate ratio.
- the tablet of the present invention may be film-coated for the purpose of improving dosing properties, formulation strength and the like.
- Examples of the coating base and coating additive used for film coating include those exemplified as the additive.
- the film coating layer is usually formed at a ratio of 1 to 10 parts by weight, preferably 2 to 6 parts by weight with respect to 100 parts by weight of the tablet.
- the content of compound A or a salt thereof and an additive in the uncoated tablet before film coating is preferably in the above-described range.
- the tablet of the present invention preferably comprises Compound A or a salt thereof, an excipient (eg, D-mannitol granules, D-mannitol, preferably D-mannitol granules), a disintegrant (eg, sodium starch glycolate), A binder (eg, hydroxypropylcellulose), a lubricant (eg, magnesium stearate) is contained, and the content of Compound A or a salt thereof is 25% by mass or more (preferably 30% by mass or more, more preferably 35%).
- the tablet is at least mass%, more preferably at least 40 mass%.
- the tablet of the present invention is preferably a compound A or a salt thereof, an excipient (eg, D-mannitol granules), a disintegrant (eg, sodium starch glycolate), a binder (eg, hydroxypropylcellulose), a lubricant.
- an excipient eg, D-mannitol granules
- a disintegrant eg, sodium starch glycolate
- a binder eg, hydroxypropylcellulose
- a film-coated tablet in which a tablet (uncoated tablet) containing a bulk agent (eg, magnesium stearate) is coated with a coating base (eg, hydroxypropylmethylcellulose) and a coating additive (eg, titanium oxide, ferric oxide) And the content of compound A or a salt thereof is 25% by mass or more (preferably 30% by mass or more, more preferably 35% by mass or more, and further preferably 40% by mass or more) with respect to the uncoated tablet. It is.
- a coating base eg, hydroxypropylmethylcellulose
- a coating additive eg, titanium oxide, ferric oxide
- the tablet of the present invention preferably further contains a low melting point oily substance selected from polyethylene glycol, glyceryl monostearate and triethyl citrate.
- a low melting point oily substance selected from polyethylene glycol, glyceryl monostearate and triethyl citrate.
- the tablet of the present invention is produced by appropriately combining operations such as granulation, mixing, tableting (compression molding), and coating.
- the granulation is performed using a granulator such as a stirring granulator, a fluid granulator, or a dry granulator.
- Mixing is performed using mixers, such as a V-type mixer and a tumbler mixer, for example.
- Tableting (compression molding) is performed by, for example, tableting using a single tablet machine or a rotary tableting machine.
- the coating is performed using, for example, a film coating apparatus.
- examples of the coating base include those exemplified as the additive. Two or more of the coating bases described above may be mixed and used at an appropriate ratio. Moreover, you may use a coating additive in the case of coating.
- the tablet of this invention can be manufactured according to the following manufacturing processes, for example. Each raw material in the following manufacturing process is used so that the content in the tablet finally obtained becomes the above-mentioned amount.
- Compound A or a salt thereof, an excipient eg, D-mannitol granules, D-mannitol, crystalline cellulose, preferably D-mannitol granules
- other additives eg, disintegrant (eg, disintegrant ( E.g. sodium starch glycolate)
- a binder e.g. hydroxypropylcellulose
- a solvent or dispersion medium e.g. water
- granulate to obtain a granulated powder (or granulated powder).
- an additive eg, lubricant (eg, magnesium stearate)
- lubricant eg, magnesium stearate
- Tablet the granules to obtain uncoated tablets.
- a film coating solution is sprayed on the obtained uncoated tablet as required to obtain a film coated tablet.
- the present invention also relates to the following method for stabilizing Compound A or a salt thereof.
- compound A or a salt thereof in a tablet is characterized by containing 25% by mass or more (preferably 30% by mass or more, more preferably 40% by mass or more) of compound A or a salt thereof.
- the stabilization method (hereinafter sometimes abbreviated as the method of the present invention).
- compounding and inclusion have the same meaning.
- adding 25% by mass or more of Compound A or a salt thereof to a tablet means containing 25% by mass or more of Compound A or a salt thereof in a tablet. To do.
- D-mannitol grains having an average particle diameter of 60 to 500 ⁇ m preferably 60 to 250 ⁇ m, more preferably 70 to 200 ⁇ m, particularly preferably 80 to 150 ⁇ m
- average D-mannitol having a particle size of 30 to 60 ⁇ m eg, PEARLITO 50C (trade name); Rocket
- PEARLITO 50C trade name
- Rocket average D-mannitol having a particle size of 30 to 60 ⁇ m
- D-mannitol and D-mannitol granules may be used alone or in combination.
- Preparation of the tablet in the method of the present invention is performed in the same manner as the preparation of the tablet of the present invention described above.
- the blending amount of D-mannitol granules or D-mannitol conforms to the amount described in the tablet of the present invention.
- the method of the present invention may include a step of confirming the stabilizing effect (for example, a step of measuring the content of the decomposition product (U-2) of compound A or a salt thereof in the tablet).
- the step of measuring the content of the decomposition product can be performed, for example, according to Test Example 1 described later.
- the solid preparation containing Compound A or a salt thereof and a low-melting point oily substance comprises (1) Compound A or a salt thereof, and (2) polyethylene glycol, glyceryl monostearate and triethyl citrate.
- the present invention relates to a solid preparation containing a selected low melting point oily substance (hereinafter sometimes abbreviated as a solid preparation of the present invention).
- the content of Compound A or a salt thereof is preferably 4% by mass or more and less than 100% by mass, more preferably 4 to 80% by mass, and still more preferably 18 to 50% by mass.
- the solid preparation of the present invention contains a low melting point oily substance selected from polyethylene glycol, glyceryl monostearate and triethyl citrate, thereby improving the stability of Compound A and its salt in the solid preparation. it can.
- These low melting point oily substances may be used alone or in combination of two or more.
- the content of the low melting point oily substance selected from polyethylene glycol, glyceryl monostearate and triethyl citrate is, for example, 0.1 to 10% by mass.
- the preferred range of the content varies depending on the type of low melting point oily substance added to the solid preparation.
- the low melting point oily substance is polyethylene glycol (for example, polyethylene glycol 6000)
- 0.1 to 4.0% by mass preferably 0.2 to 2.0% by mass, more preferably 0.2 to 1.7% by mass, still more preferably 0.2 to 0.4% by mass
- the low melting point oily substance is glyceryl monostearate or triethyl citrate
- it is, for example, 0.1 to 10% by mass (preferably 1.0 to 4.0% by mass).
- polyethylene glycol is particularly preferable as the low melting point oily substance.
- polyethylene glycol include polyethylene glycols having an average molecular weight of 200 to 7000000 (preferably about 6000 to about 120,000, more preferably about 8000 to about 100,000), such as polyethylene glycol 400 (Japan Pharmacopoeia), polyethylene glycol 6000 (Japan) Pharmacopeia), POLYOX WSR N-10 (trade name), POLYOX WSR N-205 (trade name), POLYOX WSR N-12K (trade name), POLYOX WSR 303 (trade name), preferably POLYOX WSR N-10 ( Trade name), polyethylene glycol 6000, more preferably polyethylene glycol 6000).
- polyethylene glycol is a general term for compounds represented by the general formula H (OCH 2 CH 2 ) n OH (where n represents a natural number) (where n is 2000 or more) Sometimes referred to as oxide).
- polyethylene glycol 6000 is also referred to as macrogol 6000 in the Japanese Pharmacopoeia (the average molecular weight is generally said to be 7300-9300).
- Polyethylene glycol 6000 is referred to as polyethylene glycol 8000 in NF (NATIONAL FORMULARY).
- “average molecular weight” in the description of polyethylene glycol means “number average molecular weight”.
- low melting point oils and fats are added to the active ingredient (compound A or a salt thereof) in solid or liquid form.
- the present invention is more advantageously applied to solid preparations (granules, tablets, etc., preferably tablets) produced by molding (granulation, pressure molding, etc.).
- the solid preparation of the present invention is usually produced by blending the above-mentioned low melting point oily substance with an active ingredient (compound A or a salt thereof) and then molding.
- the blending is performed by a blending method generally used in preparations, for example, mixing, kneading, sieving, stirring and the like.
- a low melting point oily substance may be directly added to the active ingredient and mixed, or a solvent may be added and mixed, and kneading, granulation and drying may be performed by a conventional method.
- the low melting point oily substance can be dissolved in a suitable solvent, mixed with the active ingredient, and kneaded, granulated and dried by a conventional method.
- the low melting point oily substance-containing liquid and the active ingredient-containing liquid may be separately sprayed onto powders such as excipients.
- a solvent that does not adversely affect the active ingredient for example, water, dimethylformamide, acetone, ethanol, propyl alcohol, isopropyl alcohol, butyl alcohol, methylene chloride, trichloroethane is used.
- a tablet can be manufactured after completion
- the pressure molding is to form a desired form by compressing under pressure, and generally refers to, for example, tableting.
- the solid preparation of the present invention may further contain additives commonly used in the pharmaceutical field.
- the additive include an excipient, a binder, a disintegrant, a lubricant, a colorant, a pH adjuster, a surfactant, a sweetener, a fragrance, a coating base, and a coating additive. These additives are used in amounts conventionally used in the pharmaceutical field unless otherwise specified. Examples of these additives are the same as those exemplified above for the tablet of the present invention.
- D-mannitol, D-mannitol granules and crystalline cellulose are preferable, and D-mannitol and crystalline cellulose are more preferable.
- the content of the excipient is preferably 10 to 70% by mass, more preferably 16 to 64% by mass.
- hydroxypropyl cellulose is preferable as the binder.
- the content of the binder is preferably 0.5 to 20% by mass, more preferably 1 to 10% by mass.
- croscarmellose sodium is preferred as the disintegrant.
- the content of the disintegrant is preferably 1 to 20% by mass, more preferably 2 to 10% by mass.
- magnesium stearate is preferable as the lubricant.
- the content of the lubricant is preferably 0.1 to 3% by mass, more preferably 0.2 to 2% by mass.
- the solid preparation of the present invention may be film-coated for the purpose of improving dosing properties, preparation strength and the like.
- Examples of the coating base and coating additive used for film coating include those exemplified as the additive.
- the film coating layer is usually formed at a ratio of 1 to 10 parts by weight, preferably 2 to 6 parts by weight with respect to 100 parts by weight of the solid preparation.
- the solid preparation of the present invention is a film-coated tablet, it is preferable that the content of compound A or a salt thereof, a low melting point oily substance and an additive in the uncoated tablet before film coating is in the above-described range. .
- the solid preparation of the present invention is preferably a compound A or a salt thereof; a low melting point oily substance selected from polyethylene glycol, glyceryl monostearate and triethyl citrate; an excipient (eg, D-mannitol, crystalline cellulose) Disintegrants (eg, croscarmellose sodium); binders (eg, hydroxypropylcellulose); lubricants (eg, magnesium stearate).
- a low melting point oily substance selected from polyethylene glycol, glyceryl monostearate and triethyl citrate
- an excipient eg, D-mannitol, crystalline cellulose
- Disintegrants eg, croscarmellose sodium
- binders eg, hydroxypropylcellulose
- lubricants eg, magnesium stearate
- the solid preparation of the present invention is preferably a compound A or a salt thereof; a low melting point oily substance selected from polyethylene glycol, glyceryl monostearate and triethyl citrate; an excipient (eg, D-mannitol, crystalline cellulose) ); Disintegrant (eg, croscarmellose sodium); binder (eg, hydroxypropyl cellulose); lubricant (eg, magnesium stearate) containing tablet (uncoated tablet) coated base (eg, hydroxy) Film coated tablets coated with propylmethylcellulose) and coating additives (e.g., titanium oxide, ferric oxide, yellow ferric oxide).
- a low melting point oily substance selected from polyethylene glycol, glyceryl monostearate and triethyl citrate
- an excipient eg, D-mannitol, crystalline cellulose
- Disintegrant eg, croscarmellose sodium
- binder eg, hydroxypropyl
- the solid preparation of the present invention can be produced, for example, according to the following production steps. Each raw material in the following manufacturing process is used so that the content in the finally obtained solid preparation is the above-mentioned amount.
- Compound A or a salt thereof, an excipient eg, D-mannitol, crystalline cellulose
- a binder eg, hydroxypropylcellulose
- a low melting point oily substance selected from polyethylene glycol, glyceryl monostearate and triethyl citrate is dissolved in a solvent or dispersion medium (eg, water), granulated while sprayed, dried, and adjusted as necessary.
- Granulate to obtain a granulated powder (or sized powder).
- Additives eg, lubricant (eg, magnesium stearate), disintegrant (eg, croscarmellose sodium)
- Additives eg, lubricant (eg, magnesium stearate), disintegrant (eg, croscarmellose sodium)
- Additives eg, lubricant (eg, magnesium stearate), disintegrant (eg, croscarmellose sodium)
- a film coating solution is sprayed on the obtained uncoated tablet as required to obtain a film coated tablet.
- the above-described tablet of the present invention and the solid preparation of the present invention have low toxicity and are mammals (eg, mice, rats, rabbits, cats, dogs, cows, horses). , Monkeys, humans) can be safely administered orally.
- the solid preparation of the present invention is useful for prevention or treatment of, for example, hormone-dependent diseases (for example, prostate cancer).
- hormone-dependent diseases for example, prostate cancer
- the dose of the solid preparation of the present invention is not particularly limited as long as it achieves the purpose of the present invention, depending on the degree of symptoms; age, sex, body weight, sensitivity difference;
- the aforementioned hormone-dependent diseases eg, prostate cancer
- an oral preparation about 0.01 to 30 mg in terms of Compound A free body per kg body weight of a mammal (eg, human)
- about 0.02 to 10 mg, more preferably 0.1 to 10 mg, and most preferably 0.5 to 10 mg can be administered in 1 to 4 divided doses per day.
- the solid preparation of the present invention is preferably a tablet, and its size varies depending on the shape of the tablet (for example, round shape, caplet shape, oblong shape, etc.), but may be any size that can be easily taken by the patient.
- Examples of the solid preparation of the present invention include tablets containing 40 to 120 mg, preferably 80 or 120 mg of Compound A or a salt thereof as Compound A (free form) in one tablet.
- Compound A or a salt thereof can be used in combination with one or more other types of drugs.
- the solid preparation of the present invention preferably contains D-mannitol granules as an excipient.
- the content of D-mannitol particles in the solid preparation of the present invention is the same as that described in detail in “1. Tablets containing Compound A or a salt thereof in high content”.
- the present invention is characterized in that in a solid preparation containing Compound A or a salt thereof, a low melting point oily substance selected from polyethylene glycol, glyceryl monostearate and triethyl citrate is blended.
- a low melting point oily substance selected from polyethylene glycol, glyceryl monostearate and triethyl citrate is blended.
- the present invention relates to a method for stabilizing Compound A or a salt thereof.
- the order of blending the components is not particularly limited. As described above, for example, a low melting point oily substance may be directly added to the active ingredient (Compound A or a salt thereof) and mixed, and a solvent may be added.
- the low-melting oily substance-containing liquid and the active ingredient-containing liquid may be sprayed separately on a powder such as an excipient.
- a tablet can be manufactured after completion
- the solid preparation when the solid preparation is a tablet, granulation is carried out while spraying a solution obtained by dissolving or dispersing a low melting point oily substance in compound A or a salt thereof in a solvent or dispersion medium (eg, water), and drying. Then, a granulated powder is obtained, and the obtained granulated powder is tableted to obtain a tablet.
- a solvent or dispersion medium eg, water
- the preparation of the solid preparation in the method is performed in the same manner as the preparation of the solid preparation of the present invention described above.
- the blending amount of the low melting point oily substance selected from polyethylene glycol, glyceryl monostearate and triethyl citrate is in accordance with the amount described in the solid preparation of the present invention.
- the method may include a step of confirming the stabilizing effect (for example, a step of measuring the content of the decomposition product (U-2) of Compound A or a salt thereof in the solid preparation).
- the step of measuring the content of the decomposition product can be performed, for example, according to Test Example 1 described later.
- D-mannitol PEARLITOL 50C (trade name), manufactured by ROQUETTE
- D-mannitol granules PEARLITOL 100SD (trade name), PEARLITOL 200SD (trade name)
- PEARLITOL 300DC trade name
- PEARLITOL 400DC trade name
- polyethylene glycol 6000 (macrogol 6000 (trade name), manufactured by Sanyo Chemical Industries), titanium oxide (titanium oxide (trade name), Freund Sangyo Co., Ltd. Product), glyceryl monostearate (manufactured by Riken Vitamin Co., Ltd.) (sometimes referred to as GMS in this specification), the 15th revised Japanese Pharmacopoeia compatible product, ), LCW), triethyl citrate (Citroflex 2 (trade name), manufactured by CBC Corporation) 2003-compliant products, magnesium metasilicate aluminate (Neusilin FL2 (trade name), manufactured by Fuji Chemical Industry Co., Ltd.) is Japan Pharmacopoeia Pharmaceutical Standards 2002-compliant product, polyethylene glycol 400 (polyethylene glycol 400 (trade name), Japanese Kosei Pharmaceutical Co., Ltd.
- POLYOX WSR N-10 trade name
- POLYOX WSR N-205 trade name
- POLYOX WSR N-12K trade name
- POLYOX WSR 303 trade name
- the mixed powder was tableted with a rotary tableting machine (small tableting machine, Kikusui Seisakusho) with a 6.0 mm ⁇ punch to obtain 110 mg uncoated tablets per tablet.
- the uncoated tablets were put into a film coating machine (DRC-200, Powrec Co., Ltd.), and a film coating solution having a composition ratio shown in Table 1-2 was sprayed to obtain about 114.0 mg of film-coated tablets per tablet.
- the obtained film-coated tablet was put in a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- croscarmellose sodium and magnesium stearate were added and mixed with a mixer (Tumbler 15L, Showa Chemical Machinery Co., Ltd.) to obtain a mixed powder.
- the mixed powder was tableted with a rotary tableting machine (Correct 12HUK, Kikusui Seisakusho) with a 13.0 ⁇ 7.0 mm punch to obtain 440 mg uncoated tablets per tablet.
- the uncoated tablets were put into a film coating machine (Dria Coater DRC500, Powrec Co., Ltd.), and a film coating solution having a composition ratio shown in Table 2-2 was sprayed to obtain about 456.0 mg of film coated tablets per tablet.
- the obtained film-coated tablet was put in a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- Uncoated tablets containing Compound A were produced as follows at the composition ratio shown in Table 3-1. That is, in a fluidized bed granulator / dryer (FD-5S, Pauleck Co., Ltd.), compound A, D-mannitol, and crystalline cellulose are preheated and mixed with an aqueous solution in which hydroxypropylcellulose is dissolved, and then the same machine. A granulated powder was obtained by drying. The granulated powder was sized using a sizing machine (Power Mill P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- a sizing machine Power Mill P-3, Showa Chemical Machinery Co., Ltd.
- Crystalline cellulose, croscarmellose sodium and magnesium stearate were added to the obtained sized powder and mixed with a mixer (Tumbler 15L, Showa Chemical Machinery Co., Ltd.) to obtain a mixed powder.
- the mixed powder was tableted with a rotary tableting machine (Correct 12HUK, Kikusui Seisakusho) with a 8.0 mm ⁇ punch to obtain 220 mg uncoated tablets per tablet.
- the uncoated tablets were put into a film coating machine (Dria Coater DRC500, Powrec Co., Ltd.), and a film coating solution having a composition ratio shown in Table 3-2 was sprayed to obtain about 228.0 mg of film coated tablets per tablet.
- Uncoated tablets containing Compound A were produced as follows at the composition ratio shown in Table 4-1. That is, in a fluidized bed granulator / dryer (FD-5S, Pauleck Co., Ltd.), compound A, D-mannitol, and crystalline cellulose are preheated and mixed with an aqueous solution in which hydroxypropylcellulose is dissolved, and then the same machine. A granulated powder was obtained by drying. The granulated powder was sized using a sizing machine (Power Mill P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- croscarmellose sodium and magnesium stearate were added and mixed with a mixer (Tumbler 15L, Showa Chemical Machinery Co., Ltd.) to obtain a mixed powder.
- the mixed powder was tableted with a 9.0 mm ⁇ punch with a rotary tableting machine (Correct 12HUK, Kikusui Seisakusho) to obtain 280 mg uncoated tablets per tablet.
- the uncoated tablets were put into a film coating machine (Dria Coater DRC500, Powrec Co., Ltd.), and a film coating solution having a composition ratio shown in Table 4-2 was sprayed to obtain about 290.2 mg of film coated tablets per tablet.
- the obtained film-coated tablet was put in a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- Uncoated tablets containing Compound A were produced as follows at the composition ratio shown in Table 5-1. That is, compound A, D-mannitol granules (PEARLITOL 100SD, Rocket) and sodium starch glycolate are preheated and mixed in a fluidized bed granulator / dryer (FD-5S, POWREC Co., Ltd.) to dissolve hydroxypropylcellulose. The resulting aqueous solution was sprayed and then dried with the same machine to obtain a granulated powder. The granulated powder was sized using a sizing machine (Power Mill P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- a sizing machine Power Mill P-3, Showa Chemical Machinery Co., Ltd.
- Magnesium stearate was added to the obtained sized powder and mixed with a mixer (Tumbler 15L, Showa Chemical Machinery Co., Ltd.) to obtain a mixed powder.
- the mixed powder was tableted with a rotary tableting machine (Collect 12 HUK, Kikusui Seisakusho) with a 8.0 mm ⁇ punch to obtain 200 mg uncoated tablets per tablet.
- the uncoated tablets were put into a film coating machine (Dria Coater DRC500, Powrec Co., Ltd.), and a film coating solution having a composition ratio shown in Table 5-2 was sprayed to obtain about 208 mg of film coated tablets per tablet.
- the obtained film-coated tablet was put in a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- Uncoated tablets containing Compound A were produced in the composition ratios shown in Table 6-1 as follows. That is, compound A, D-mannitol granules (PEARLITOL 100SD, Rocket), magnesium aluminate metasilicate and sodium starch glycolate were preheated and mixed in a fluidized bed granulator / dryer (LAB-1, POWREC Co., Ltd.). Then, an aqueous solution in which hydroxypropylcellulose was dissolved was sprayed and then dried with the same machine to obtain a granulated powder. Magnesium stearate was added to the obtained granulated powder and mixed in a bag to obtain a mixed powder.
- PEARLITOL 100SD D-mannitol granules
- LAB-1 fluidized bed granulator / dryer
- Magnesium stearate was added to the obtained granulated powder and mixed in a bag to obtain a mixed powder.
- the mixed powder was tableted with a rotary tableting machine (small tableting machine, Kikusui Seisakusho) with a 6.0 mm ⁇ punch to obtain 110 mg uncoated tablets per tablet.
- the uncoated tablets were put into a film coating machine (Dria Coater DRC500, Powrec Co., Ltd.), and a film coating solution having a composition ratio shown in Table 6-2 was sprayed to obtain about 114.0 mg of film coated tablets per tablet.
- the obtained film-coated tablet was put in a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- Uncoated tablets containing Compound A were produced as follows at the composition ratio shown in Table 7-1. That is, in a fluidized bed granulator / dryer (MP-01, POWREC Co., Ltd.), compound A, D-mannitol, and crystalline cellulose are preheated and mixed with an aqueous solution in which hydroxypropylcellulose is dissolved. A granulated powder was obtained by drying. To the obtained granulated powder, croscarmellose sodium and magnesium stearate were added and mixed in a bag to obtain a mixed powder.
- the mixed powder was tableted with a 9 mm ⁇ punch using a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain 280 mg uncoated tablets per tablet.
- the uncoated tablets were put into a film coating machine (Freund Sangyo, HC-LABO-20), and a film coating solution having a composition ratio shown in Table 7-2 was sprayed to obtain about 290 mg of film-coated tablets per tablet.
- the obtained film-coated tablet was put in a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- Uncoated tablets containing Compound A were produced as follows at the composition ratio shown in Table 8. That is, in a fluidized bed granulator / dryer (MP-01, POWREC Co., Ltd.), compound A, D-mannitol, and crystalline cellulose are preheated and mixed with an aqueous solution in which hydroxypropylcellulose and polyethylene glycol 6000 are dissolved. The granulated powder was then obtained by drying with the same machine. To the obtained granulated powder, croscarmellose sodium and magnesium stearate were added and mixed in a bag to obtain a mixed powder.
- the mixed powder was tableted with a 9 mm ⁇ punch using a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain 280 mg uncoated tablets per tablet.
- the uncoated tablets were put into a film coating machine (Freund Sangyo, HC-LABO-20), and the film coating solution having the composition ratio shown in Table 7-2 was sprayed to obtain about 290 mg of film-coated tablets per tablet.
- the obtained film-coated tablet was put in a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- Uncoated tablets containing compound A were produced as follows at the composition ratio shown in Table 9. That is, compound A, D-mannitol, and crystalline cellulose are preheated and mixed in a fluidized bed granulator / dryer (MP-01, POWREC Co., Ltd.), and glyceryl monostearate (glyceryl monostearate) ( Hereinafter, a dispersion in which GMS) was dispersed was sprayed, and then dried with the same machine to obtain a granulated powder. To the obtained granulated powder, croscarmellose sodium and magnesium stearate were added and mixed in a bag to obtain a mixed powder.
- a fluidized bed granulator / dryer MP-01, POWREC Co., Ltd.
- glyceryl monostearate glyceryl monostearate
- the mixed powder was tableted with a 9 mm ⁇ punch using a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain 280 mg uncoated tablets per tablet.
- the uncoated tablets were put into a film coating machine (Freund Sangyo, HC-LABO-20), and the film coating solution having the composition ratio shown in Table 7-2 was sprayed to obtain about 290 mg of film-coated tablets per tablet.
- the obtained film-coated tablet was put in a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- Uncoated tablets containing compound A were produced as follows at the composition ratio shown in Table 10. That is, in a fluidized bed granulator / dryer (MP-01, POWREC Co., Ltd.), compound A, D-mannitol, and crystalline cellulose are preheated and mixed with an aqueous solution in which hydroxypropylcellulose and polyethylene glycol 400 are dissolved. The granulated powder was then obtained by drying with the same machine. To the obtained granulated powder, croscarmellose sodium and magnesium stearate were added and mixed in a bag to obtain a mixed powder.
- the mixed powder was tableted with a 9 mm ⁇ punch using a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain 280 mg uncoated tablets per tablet.
- the uncoated tablets were put into a film coating machine (Freund Sangyo, HC-LABO-20), and the film coating solution having the composition ratio shown in Table 7-2 was sprayed to obtain about 290 mg of film-coated tablets per tablet.
- the obtained film-coated tablet was put in a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- Uncoated tablets containing Compound A were produced as follows at the composition ratio shown in Table 11. That is, in a fluidized bed granulator / dryer (MP-01, POWREC Co., Ltd.), compound A, D-mannitol and crystalline cellulose are preheated and mixed with an aqueous solution in which hydroxypropylcellulose and triethylcitrate are dissolved. The granulated powder was then obtained by drying with the same machine. Croscarmellose sodium and magnesium stearate were added to the obtained granulated powder and mixed in a bag to obtain a mixed powder.
- a fluidized bed granulator / dryer MP-01, POWREC Co., Ltd.
- compound A, D-mannitol and crystalline cellulose are preheated and mixed with an aqueous solution in which hydroxypropylcellulose and triethylcitrate are dissolved.
- the granulated powder was then obtained by drying with the same machine. Croscarmellose sodium and magnesium stearate
- the mixed powder was tableted with a 9 mm ⁇ punch using a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain 280 mg uncoated tablets per tablet.
- the uncoated tablets were put into a film coating machine (Freund Sangyo, HC-LABO-20), and the film coating solution having the composition ratio shown in Table 7-2 was sprayed to obtain about 290 mg of film-coated tablets per tablet.
- the obtained film-coated tablet was put in a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- Uncoated tablets containing Compound A were produced as follows at the composition ratio shown in Table 12. That is, in a fluidized bed granulator / dryer (MP-01, POWREC Co., Ltd.), compound A, D-mannitol, and crystalline cellulose are preheated and mixed with a dispersion in which GMS is dispersed in a hydroxypropylcellulose aqueous solution. The granulated powder was then obtained by drying with the same machine. Croscarmellose sodium and magnesium stearate were added to the obtained granulated powder and mixed powder was obtained by bag mixing.
- the mixed powder was tableted with a 9 mm ⁇ punch using a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain 280 mg uncoated tablets per tablet.
- the uncoated tablets were put into a film coating machine (Freund Sangyo, HC-LABO-20), and the film coating solution having the composition ratio shown in Table 7-2 was sprayed to obtain about 290 mg of film-coated tablets per tablet.
- the obtained film-coated tablet was put in a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- HPLC test condition detector ultraviolet absorptiometer (measurement wavelength: 230 nm)
- Mobile phase liquid feeding The mixing ratio of mobile phase A and mobile phase B was controlled as shown in Table 13.
- Test result 1 For the film-coated tablets of Comparative Examples 1 and 2 and Examples 1 to 3, degradation products before storage and after storage at 60 ° C. for 2 weeks were measured, and the results of total degradation products and U-2 are shown in Table 14. It was.
- Test result 2 For the film-coated tablets of Example 5, the decomposition products before storage and after storage at 60 ° C. for 2 weeks were measured. The results of total decomposition products and U-2 are shown in Table 15.
- the production of total decomposition products and decomposition products U-2 was suppressed by adding a low melting point oily substance.
- the production of the decomposition product U-2 which significantly increases when no low melting point oily substance is added, is remarkably suppressed.
- Test result 3 For the film-coated tablets of Examples 7 to 9, degradation products before storage and after storage at 60 ° C. for 2 weeks were measured, and the results of total degradation products and U-2 are shown in Table 16.
- Examples 10 to 12 According to the formulation of Table 17, Compound A, D-mannitol (PEARLITOL 50C, Rocket), hydroxypropylcellulose, sodium starch glycolate and magnesium stearate were mixed in a bottle to obtain a mixed powder for tableting. This mixed powder was tableted with a tabletop tablet molding machine (HANDTAB200, Ichihashi Seiki Co., Ltd.) with a 9.0 mm ⁇ punch to obtain 300 mg uncoated tablets. The obtained uncoated tablet was put into a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- HANDTAB200 Ichihashi Seiki Co., Ltd.
- Test Example 2 For the uncoated tablets of Examples 10 to 12, the decomposition products before storage and after storage at 60 ° C. for 2 weeks were measured using the test method of Test Example 1, and the total decomposition products and the results of U-2 are shown in Table 18. It was shown to.
- Test Example 3 For the uncoated tablets of Comparative Example 3 and Examples 13 to 15, the degradation products before storage and after storage at 60 ° C. for 2 weeks were measured using the test method of Test Example 1, and the total degradation products and U-2 The results are shown in Table 21.
- Uncoated tablets of Examples 16 to 18 containing Compound A were produced as follows at the composition ratio shown in Table 22. That is, Compound A, D-mannitol granules, hydroxypropylcellulose, sodium starch glycolate and magnesium stearate were mixed in a bottle to obtain a mixed powder for tableting. This mixed powder was tableted with a tabletop tablet molding machine (HANDTAB200, Ichihashi Seiki Co., Ltd.) with a 9.0 mm ⁇ punch to obtain 300 mg uncoated tablets. The obtained uncoated tablet was put into a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- Table 22 Table 22
- Test Example 4 For the plain tablets of Examples 16 to 18, the decomposition products before storage and after storage at 60 ° C. for 2 weeks were measured using the test method of Test Example 1, and the total decomposition products and the results of U-2 were measured in Table 23. It was shown to. Table 23 shows the results of the daily stability test for the uncoated tablets of Examples 10 and 13 described above.
- Uncoated tablets of Examples 19 to 21 containing Compound A were produced as follows at the composition ratio shown in Table 24. That is, Compound A, D-mannitol granules, hydroxypropyl cellulose, sodium starch glycolate and magnesium stearate were mixed in a bottle to obtain a mixed powder for tableting. This mixed powder was tableted with a tabletop tablet molding machine (HANDTAB200, Ichihashi Seiki Co., Ltd.) with a 9.0 mm ⁇ punch to obtain 300 mg uncoated tablets. The obtained uncoated tablet was put into a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- Table 24 Table 24. That is, Compound A, D-mannitol granules, hydroxypropyl cellulose, sodium starch glycolate and magnesium stearate were mixed in a bottle to obtain a mixed powder for tableting. This mixed powder was tableted with a tabletop tablet molding machine (HANDTAB200, Ichihashi Seiki Co., Ltd.) with
- Test Example 5 For the uncoated tablets of Examples 19 to 21, the decomposition products before storage and after storage at 60 ° C. for 2 weeks were measured, and the results of total decomposition products and U-2 are shown in Table 25. Table 25 shows the results of the daily stability test on the uncoated tablets of Examples 11 and 14 described above.
- Uncoated tablets containing Compound A were produced as follows at the composition ratio shown in Table 26-1. That is, in a fluidized bed granulator / dryer (FD-5S, Powrec Co., Ltd.), Compound A, D-mannitol granules (PEARLITOL 100SD, Rocket) and sodium starch glycolate were preheated and mixed with hydroxypropylcellulose. The dissolved aqueous solution was sprayed and then dried with the same machine to obtain a granulated powder. The granulated powder was sized using a sizing machine (Power Mill P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- a sizing machine Power Mill P-3, Showa Chemical Machinery Co., Ltd.
- Magnesium stearate was added to the obtained sized powder and mixed with a mixer (Tumbler 15L, Showa Chemical Machinery Co., Ltd.) to obtain a mixed powder.
- the mixed powder was tableted with a rotary tableting machine (small tableting machine, Kikusui Seisakusho) with a 6.0 mm ⁇ punch to obtain 100 mg uncoated tablets per tablet.
- the uncoated tablets were put into a film coating machine (Dria Coater DRC200, Powrec Co., Ltd.), and a film coating solution having a composition ratio shown in Table 26-2 was sprayed to obtain about 104.0 mg of film coated tablets per tablet.
- Uncoated tablets containing Compound A are produced as follows at the composition ratio shown in Table 27. That is, in a fluidized bed granulator / dryer (FD-5S, Powrec Co., Ltd.), Compound A, D-mannitol granules (PEARLITOL 100SD, Rocket) and sodium starch glycolate were preheated and mixed with hydroxypropylcellulose. The dissolved aqueous solution is sprayed and then dried in the same machine to obtain a granulated powder. The granulated powder is sized using a sizing machine (Power Mill P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- a sizing machine Power Mill P-3, Showa Chemical Machinery Co., Ltd.
- Magnesium stearate is added to the obtained sized powder and mixed with a mixer (Tumbler 15L, Showa Chemical Machinery Co., Ltd.) to obtain a mixed powder.
- the mixed powder is tableted with a 7.0 mm ⁇ punch with a rotary tableting machine (small tableting machine, Kikusui Seisakusho) to obtain 125 mg uncoated tablets per tablet.
- the mixed powder was tableted with a 9 mm ⁇ punch using a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain 280 mg uncoated tablets per tablet.
- the uncoated tablets were put into a film coating machine (Freund Sangyo, HC-LABO-20), and the film coating solution having the composition ratio shown in Table 7-2 was sprayed, and about 290 mg of each tablet of Examples 24-29 was used. Film-coated tablets were obtained.
- the obtained film-coated tablet was put in a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- Test Example 6 For the film-coated tablets of Examples 24-29, the degradation products before storage and after storage at 60 ° C. for 2 weeks were measured by the method described in Test Example 1, and the total degradation products and the results of U-2 are shown in Table 29. Shown in For the film-coated tablets of Example 4 described above, the degradation products before storage and after storage at 60 ° C. for 2 weeks were measured in the same manner, and the results of total decomposition products and U-2 are shown in Table 29. Show. Table 29 also shows the results of the daily stability test for the film-coated tablets of Example 5 described above.
- Uncoated tablets containing Compound A were produced as follows at the composition ratios shown in Tables 30-1 and 30-2. That is, in a fluidized bed granulator / dryer (MP-01, POWREC Co., Ltd.), compound A, D-mannitol, and crystalline cellulose are preheated and mixed with an aqueous solution in which hydroxypropylcellulose is dissolved. A granulated powder was obtained by drying.
- croscarmellose sodium, magnesium stearate, and polyethylene glycols having various average molecular weights in Examples 30 to 34 specifically, polyethylene glycol 6000 (average molecular weight: 7300-9300)), POLYOX WSR N-10 (average molecular weight: 100000), POLYOX WSR N-205 (average molecular weight: 600000), POLYOX WSR N-12K (average molecular weight: 1000000), POLYOX WSR 303 (average molecular weight: 7000000))
- Mixing was performed to obtain a mixed powder.
- the mixed powder was tableted with a 9 mm ⁇ punch using a rotary tableting machine (manufactured by Kikusui Seisakusho, Ltd.), and 280 mg (Reference Example 4) and 284.8 mg (Examples 30 to 34) per tablet.
- An uncoated tablet was obtained.
- the obtained uncoated tablet was put into a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- the production of the total degradation product derived from Compound A and the degradation product U-2 was suppressed.
- the production of total degradation products and degradation products U-2 was remarkably suppressed.
- Uncoated tablets containing Compound A were produced as follows at the composition ratio shown in Table 32-1. That is, in a fluid bed granulator / dryer (FD-5S, Powrec Co., Ltd.), Compound A, D-mannitol and crystalline cellulose are preheated and mixed with an aqueous solution in which hydroxypropylcellulose and polyethylene glycol 6000 are dissolved. The granulated powder was then obtained by drying with the same machine. The granulated powder was sized using a sizing machine (Power Mill P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- a sizing machine Power Mill P-3, Showa Chemical Machinery Co., Ltd.
- croscarmellose sodium and magnesium stearate were added and mixed with a mixer (Tumbler 15L, Showa Chemical Machinery Co., Ltd.) to obtain a mixed powder.
- the mixed powder was tableted with a rotary tableting machine (AQUARIUS, Kikusui Seisakusho) with a 12.0 ⁇ 8.4 mm ⁇ punch to obtain 420 mg uncoated tablets per tablet.
- the uncoated tablet is put into a film coating machine (Dria Coater DRC500, Powrec Co., Ltd.), sprayed with a film coating solution having a composition ratio shown in Table 32-2, and then coated with a small amount of carnauba wax (0.012 mg per tablet). About 435 mg of film-coated tablet was obtained per tablet.
- the obtained film-coated tablet was put in a glass bottle, sealed, and stored at 60 ° C. for 2 weeks.
- Example 8 The film-coated tablets of Example 35 were measured for decomposition products before storage and after storage at 60 ° C. for 2 weeks, and the results of total decomposition products and U-2 are shown in Table 33.
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Abstract
Description
特許文献1には、化合物Aおよびその塩を包含する一般式で表される化合物およびその塩が優れた性腺刺激ホルモン放出ホルモン拮抗作用を有し、例えばホルモン依存性疾患の予防または治療剤として用いることができることが、当該化合物の製造法とともに開示されている。
本発明は、かかる新知見である問題の解決を目的とするものであり、すなわち、本発明は、固形製剤(例えば錠剤)中の化合物Aおよびその塩の安定性が改善された固形製剤、並びに固形製剤中の化合物Aおよびその塩の安定化方法を提供することを目的とする。
また、本発明者らは、上記課題を解決するために鋭意検討を行った結果、固形製剤(例えば錠剤)にポリエチレングリコール、モノステアリン酸グリセリンおよびクエン酸トリエチルから選択される低融点油脂状物質を配合することで、固形製剤中の化合物Aおよびその塩の経日的な分解が抑制されること、言い換えれば固形製剤中の化合物Aおよびその塩が安定化されることを見出した。
本発明者らは上記知見に基づき、さらに鋭意検討して本発明を完成させた。
[1]N-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N’-メトキシウレアまたはその塩を25質量%以上含有する錠剤。
[2]平均粒径が60~500μmであるD-マンニトール粒を配合することを特徴とする、上記[1]記載の錠剤。
[3]平均粒径が60~250μmであるD-マンニトール粒を配合することを特徴とする、上記[1]記載の錠剤。
[4]N-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N’-メトキシウレアまたはその塩を25質量%以上配合することを特徴とする、錠剤中のN-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N’-メトキシウレアまたはその塩の安定化方法。
[5]さらに、平均粒径が60~500μmであるD-マンニトール粒を配合することを特徴とする、上記[4]記載の安定化方法。
[6]さらに、平均粒径が60~250μmであるD-マンニトール粒を配合することを特徴とする、上記[4]記載の安定化方法。
[7](1)N-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N’-メトキシウレアまたはその塩、および
(2)ポリエチレングリコール、モノステアリン酸グリセリンおよびクエン酸トリエチルから選択される低融点油脂状物質
を含有する固形製剤。
[8]低融点油脂状物質がポリエチレングリコールである、上記[7]記載の固形製剤。
[9]低融点油脂状物質が、平均分子量約6000ないし約120000のポリエチレングリコールである、上記[7]記載の固形製剤。
[10]N-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N’-メトキシウレアまたはその塩を含有する固形製剤において、ポリエチレングリコール、モノステアリン酸グリセリンおよびクエン酸トリエチルから選択される低融点油脂状物質を配合することを特徴とする、N-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N’-メトキシウレアまたはその塩の安定化方法。
[11]低融点油脂状物質がポリエチレングリコールである、上記[10]記載の安定化方法。
[12]低融点油脂状物質が、平均分子量約6000ないし約120000のポリエチレングリコールである、上記[10]記載の安定化方法。
以下に、本発明を詳細に説明する。
化合物Aの塩としては、生理学的に許容される酸付加塩が好ましい。このような塩としては、例えば無機酸(例、塩酸、臭化水素酸、硝酸、硫酸、リン酸)との塩、または有機酸(例、ギ酸、酢酸、トリフルオロ酢酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸)との塩等が用いられる。
本発明は、一態様として、化合物Aまたはその塩を高含有量で含有する錠剤、具体的には、化合物Aまたはその塩を、25質量%以上(好ましくは35質量%以上、より好ましくは40質量%以上)含有する錠剤(以下、本発明の錠剤と略記することがある)に関する。
本発明の錠剤において、化合物Aまたはその塩の含有量は、例えば80質量%以下(好ましくは、75質量%以下)である。
本発明の錠剤において、賦形剤の含有量は、好ましくは10~75質量%、より好ましくは20~65質量%である。
本発明において賦形剤として上述のD-マンニトール粒を使用する場合は、賦形剤の総量が上記範囲であればよい。
本発明において賦形剤として上述のマンニトールを使用する場合は、賦形剤の総量は、好ましくは10~75質量%、より好ましくは12~70質量%、さらに好ましくは15~65質量%、さらにより好ましくは15~60質量%である。
本発明の錠剤において、結合剤の含有量は、好ましくは0.5~20質量%、より好ましくは1~10質量%である。
本発明の錠剤において、崩壊剤の含有量は、好ましくは1~20質量%、より好ましくは2~10質量%である。
本発明の錠剤において、滑沢剤の含有量は、好ましくは0.1~5質量%、より好ましくは0.2~3質量%である。
上記添加剤は、2種以上を適宜の割合で混合して用いてもよい。
本発明の錠剤がフィルムコーティング錠である場合は、フィルムコーティングを施す前の素錠における、化合物Aまたはその塩および添加剤の含有量が前記した範囲であることが好ましい。
また本発明の錠剤は、好ましくは、化合物Aまたはその塩、賦形剤(例、D-マンニトール粒)、崩壊剤(例、デンプングリコール酸ナトリウム)、結合剤(例、ヒドロキシプロピルセルロース)、滑沢剤(例、ステアリン酸マグネシウム)を含有する錠剤(素錠)が、コーティング基剤(例、ヒドロキシプロピルメチルセルロース)およびコーティング添加剤(例、酸化チタン、三二酸化鉄)でコーティングされたフィルムコーティング錠であって、かつ化合物Aまたはその塩の含有量が素錠に対して25質量%以上(好ましくは30質量%以上、より好ましくは35質量%以上、さらに好ましくは40質量%以上)である錠剤である。
造粒は、例えば、撹拌造粒機、流動造粒機、乾式造粒機などの造粒機を用いて行われる。
混合は、例えば、V型混合機、タンブラー混合機などの混合機を用いて行われる。
打錠(圧縮成形)は、例えば、単発錠剤機、ロータリー式打錠機を用いて打錠することにより行われる。
また、コーティングは、例えば、フィルムコーティング装置を用いて行われる。ここで、コーティング基剤としては、前記添加剤として例示したものが挙げられる。
上記したコーティング基剤は、その2種以上を適宜の割合で混合して用いてもよい。また、コーティングの際に、コーティング添加剤を用いてもよい。
1)化合物Aまたはその塩、賦形剤(例、D-マンニトール粒、D-マンニトール、結晶セルロース、好ましくはD-マンニトール粒)を、必要に応じて、その他の添加剤(例、崩壊剤(例、デンプングリコール酸ナトリウム))と共に混合し、該混合物に結合剤(例、ヒドロキシプロピルセルロース)を溶媒または分散媒(例、水)に溶解または分散した液を噴霧しながら造粒し、乾燥し、必要により整粒して、造粒末(または整粒末)を得る。
2)得られた造粒末(または整粒末)に、必要に応じて、添加剤(例、滑沢剤(例、ステアリン酸マグネシウム))を加え、混合して打錠用顆粒とする。
3)この顆粒を打錠して素錠を得る。
4)得られた素錠に、所望によりフィルムコーティング液を噴霧しフィルムコーティング錠を得る。
本発明は、一態様として、化合物Aまたはその塩を25質量%以上(好ましくは30質量%以上、より好ましくは40質量%以上)配合することを特徴とする、錠剤中の化合物Aまたはその塩の安定化方法(以下、本発明の方法と略記することがある)に関する。
本明細書中、配合と含有とは同意義を示し、例えば、錠剤に化合物Aまたはその塩を25質量%以上配合するとは、錠剤に化合物Aまたはその塩を25質量%以上含有させることを意味する。
本発明の方法において、さらに(1)平均粒径が60~500μm(好ましくは60~250μm、より好ましくは70~200μm、特に好ましくは80~150μm)であるD-マンニトール粒、または(2)平均粒径が30~60μmであるD-マンニトール(例、PEARLITOL 50C(商品名);ロケット社)を配合することが好ましく、上記D-マンニトール粒を配合することがより好ましい。D-マンニトールおよびD-マンニトール粒は単独で用いてもまたは併用してもよい。
本発明の方法における錠剤の調製は、上述した本発明の錠剤の調製と同様の態様にて行われる。例えば、D-マンニトール粒またはD-マンニトールの配合量は、本発明の錠剤において述べた量に準じる。
本発明の方法は、安定化効果を確認する工程(例えば、錠剤中の化合物A又はその塩の分解生成物(U-2)の含有量を測定する工程等)を含んでいてもよい。分解生成物の含有量を測定する工程は、例えば、後述の試験例1に準じて行うことができる。
本発明は、他の態様として、(1)化合物Aまたはその塩、および(2)ポリエチレングリコール、モノステアリン酸グリセリンおよびクエン酸トリエチルから選択される低融点油脂状物質を含有する固形製剤(以下、本発明の固形製剤と略記することがある)に関する。
上記含有量の好ましい範囲は、固形製剤に添加される低融点油脂状物質の種類により異なるが、例えば、上記低融点油脂状物質がポリエチレングリコール(例えば、ポリエチレングリコール6000)である場合には、例えば0.1~4.0質量%(好ましくは、0.2~2.0質量%、より好ましくは、0.2~1.7質量%、さらに好ましくは、0.2~0.4質量%)である。また、上記低融点油脂状物質がモノステアリン酸グリセリンまたはクエン酸トリエチルである場合には、例えば0.1~10質量%(好ましくは、1.0~4.0質量%)である。
ポリエチレングリコールとしては、平均分子量200~7000000(好ましくは、約6000~約120000、より好ましくは、約8000~約100000)のポリエチレングリコール(例えば、ポリエチレングリコール400(日本薬局方)、ポリエチレングリコール6000(日本薬局方)、POLYOX WSR N-10(商品名)、POLYOX WSR N-205(商品名)、POLYOX WSR N-12K(商品名)、POLYOX WSR 303(商品名)、好ましくはPOLYOX WSR N-10(商品名)、ポリエチレングリコール6000、より好ましくはポリエチレングリコール6000)が好ましい。ここで、ポリエチレングリコールとは、一般式H(OCH2CH2)nOH(式中、nは自然数を示す。)で示される化合物の総称である(なお、nが2000以上の化合物は、ポリエチレンオキサイドと称されることもある)。
ここで、ポリエチレングリコール6000は、日本薬局方ではマクロゴール6000とも称される(その平均分子量は、一般的には、7300-9300と言われている)。また、ポリエチレングリコール6000は、NF(NATIONAL FORMULARY)ではpolyethylene glycol 8000と称される。
本明細書において、ポリエチレングリコールの説明における「平均分子量」は、「数平均分子量」を意味する。
配合は、一般に製剤において用いられる配合方法、たとえば混合、練合、篩過、撹拌などにより行なわれる。たとえば低融点油脂状物質を直接有効成分に添加して混合してもよく、さらに溶媒を加えて混合し、常法により練合、造粒、乾燥することもできる。
また低融点油脂状物質を適当な溶媒に溶解した後、有効成分と混合して常法により練合、造粒、乾燥することもできる。さらに低融点油脂状物質含有液および有効成分含有液を別々に賦形剤等の粉末にスプレーしてもよい。
上記した適当な溶媒としては、有効成分に悪影響を及ぼさない溶媒、たとえば水、ジメチルホルムアミド、アセトン、エタノール、プロピルアルコール、イソプロピルアルコール、ブチルアルコール、メチレンクロライド、トリクロルエタンが用いられる。
配合終了後、公知の加圧成型手段を用いることにより錠剤を製造することができる。但し、加圧成型とは、加圧下に圧縮して所望する形態となすことであり、最も一般的にはたとえば打錠などをいう。
これら添加剤は、上述した本発明の錠剤について例示したものと同様のものが例示される。
本発明の固形製剤において、結合剤としては、ヒドロキシプロピルセルロースが好ましい。結合剤の含有量は、好ましくは0.5~20質量%、より好ましくは1~10質量%である。
本発明の固形製剤において、崩壊剤としては、クロスカルメロースナトリウムが好ましい。崩壊剤の含有量は、好ましくは1~20質量%、より好ましくは2~10質量%である。
本発明の固形製剤において、滑沢剤としては、ステアリン酸マグネシウムが好ましい。滑沢剤の含有量は、好ましくは0.1~3質量%、より好ましくは0.2~2質量%である。
本発明の固形製剤がフィルムコーティング錠である場合は、フィルムコーティングを施す前の素錠における、化合物Aまたはその塩、低融点油脂状物質および添加剤の含有量が前記した範囲であることが好ましい。
また本発明の固形製剤は、好ましくは、化合物Aまたはその塩;ポリエチレングリコール、モノステアリン酸グリセリンおよびクエン酸トリエチルから選択される低融点油脂状物質;賦形剤(例、D-マンニトール、結晶セルロース);崩壊剤(例、クロスカルメロースナトリウム);結合剤(例、ヒドロキシプロピルセルロース);滑沢剤(例、ステアリン酸マグネシウム)を含有する錠剤(素錠)が、コーティング基剤(例、ヒドロキシプロピルメチルセルロース)およびコーティング添加剤(例、酸化チタン、三二酸化鉄、黄色三二酸化鉄)でコーティングされたフィルムコーティング錠である。
1)化合物Aまたはその塩、賦形剤(例、D-マンニトール、結晶セルロース)を、必要に応じて、その他の添加剤と共に混合し、該混合物に結合剤(例、ヒドロキシプロピルセルロース)、並びにポリエチレングリコール、モノステアリン酸グリセリンおよびクエン酸トリエチルから選択される低融点油脂状物質を溶媒または分散媒(例、水)に溶解または分散した液を噴霧しながら造粒し、乾燥し、必要により整粒して、造粒末(または整粒末)を得る。
2)得られた造粒末(または整粒末)に、必要に応じて、添加剤(例、滑沢剤(例、ステアリン酸マグネシウム)、崩壊剤(例、クロスカルメロースナトリウム))を加え、混合して打錠用顆粒とする。
3)この顆粒を打錠して素錠を得る。
4)得られた素錠に、所望によりフィルムコーティング液を噴霧しフィルムコーティング錠を得る。
本発明の固形製剤としては、例えば、化合物Aまたはその塩を、化合物A(フリー体)として、1錠中40~120mg、好ましくは80mgまたは120mg含有する錠剤が挙げられる。
各成分の配合順序は特に限定されるものではなく、前述のように、例えば、低融点油脂状物質を直接有効成分(化合物Aまたはその塩)に添加して混合してもよく、さらに溶媒を加えて混合し、常法により練合、造粒、乾燥することもでき;低融点油脂状物質を適当な溶媒に溶解した後、有効成分と均一に混合して常法により練合、造粒、乾燥することもでき;または、低融点油脂状物質含有液および有効成分含有液を別々に賦形剤等の粉末にスプレーしてもよい。配合終了後、公知の加圧成型手段を用いることにより錠剤を製造することができる。
具体的には例えば、固形製剤が錠剤である場合、化合物Aまたはその塩に低融点油脂状物質を溶媒または分散媒(例、水)に溶解または分散した液を噴霧しながら造粒し、乾燥し、造粒末を得、得られた造粒末を打錠することで、錠剤を得る。
該方法における固形製剤の調製は、上述した本発明の固形製剤の調製と同様の態様にて行われる。例えば、ポリエチレングリコール、モノステアリン酸グリセリンおよびクエン酸トリエチルから選択される低融点油脂状物質の配合量は、本発明の固形製剤において述べた量に準じる。
該方法は、安定化効果を確認する工程(例えば、固形製剤中の化合物A又はその塩の分解生成物(U-2)の含有量を測定する工程等)を含んでいてもよい。分解生成物の含有量を測定する工程は、例えば、後述の試験例1に準じて行うことができる。
以下の実施例、比較例、参考例、試験例で用いられるD-マンニトール(PEARLITOL 50C(商品名)、ROQUETTE社製)、D-マンニトール粒(PEARLITOL 100SD(商品名)、PEARLITOL 200SD(商品名)、PEARLITOL 300DC(商品名)またはPEARLITOL 400DC(商品名)、いずれもROQUETTE社製)、結晶セルロース(セオラス PH-101またはKG-802(商品名)、旭化成ケミカルズ社製)、ヒドロキシプロピルセルロース(HPC-L(商品名)、日本曹達社製)、クロスカルメロースナトリウム(Ac-Di-Sol(商品名) FMC社製)、デンプングリコール酸ナトリウム(プリモジェル(商品名)、DMV社製)、ステアリン酸マグネシウム(ステアリン酸マグネシウム(商品名)、太平化学産業社製)、ポリソルベート80(ポリソルベート80(商品名)、三洋化成工業株式会社製)、ヒドロキシプロピルメチルセルロース2910(TC-5(商品名)、信越化学工業株式会社製)(以下、ヒプロメロースと略記することがある)、ポリエチレングリコール6000(マクロゴール6000(商品名)、三洋化成工業株式会社製)、酸化チタン(酸化チタン(商品名)、フロイント産業株式会社製)、モノステアリン酸グリセリン(理研ビタミン社製)(本明細書中、GMSと称することがある。)は、第十五改正日本薬局方適合品を、三二酸化鉄(三二酸化鉄(商品名)、LCW社製)、クエン酸トリエチル(シトロフレックス2(商品名)、CBC株式会社製)は医薬品添加物規格2003適合品を、メタケイ酸アルミン酸マグネシウム(ノイシリンFL2(商品名)、富士化学工業株式会社製)は日本薬局方外医薬品規格2002適合品を、ポリエチレングリコール400(ポリエチレングリコール400(商品名)、和光純薬社製)は試薬グレード品を、POLYOX(POLYOX WSR N-10(商品名)、POLYOX WSR N-205(商品名)、POLYOX WSR N-12K(商品名)、POLYOX WSR 303(商品名)、いずれもDow chemical社製)はNational Formularyグレード品を用いた。
化合物Aを含有する素錠を表1-1に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(LAB-1、(株)パウレック)中で、化合物A、D-マンニトール、および結晶セルロースを予熱混合し、ヒドロキシプロピルセルロースを溶解した水溶液を噴霧し、ついで同機で乾燥することにより造粒末を得た。得られた造粒末にクロスカルメロースナトリウム、およびステアリン酸マグネシウムを加え袋混合し、混合末を得た。混合末をロータリー打錠機(小型打錠機、菊水製作所)で、6.0mmφの杵で打錠し、1錠あたり110mgの素錠を得た。
素錠をフィルムコーティング機(DRC-200、(株)パウレック)に入れ、表1-2に示す組成比のフィルムコーティング液をスプレーし、1錠あたり約114.0mgのフィルムコート錠を得た。得られたフィルムコート錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
化合物Aを含有する素錠を表2-1に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(FD-5S、(株)パウレック)中で、化合物A、D-マンニトール、および結晶セルロースを予熱混合し、ヒドロキシプロピルセルロースを溶解した水溶液を噴霧し、ついで同機で乾燥することにより造粒末を得た。造粒末を整粒機(パワーミルP-3、(株)昭和化学機械工作所)を用いて整粒し、整粒末を得た。得られた整粒末にクロスカルメロースナトリウム、およびステアリン酸マグネシウムを加え混合機(タンブラー15L、(株)昭和化学機械工作所)で混合し、混合末を得た。混合末をロータリー打錠機(コレクト12HUK、菊水製作所)で、13.0X7.0mmの杵で打錠し、1錠あたり440mgの素錠を得た。
素錠をフィルムコーティング機(ドリアコーターDRC500、(株)パウレック)に入れ、表2-2に示す組成比のフィルムコーティング液をスプレーし、1錠あたり約456.0mgのフィルムコート錠を得た。得られたフィルムコート錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
化合物Aを含有する素錠を表3-1に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(FD-5S、(株)パウレック)中で、化合物A、D-マンニトール、および結晶セルロースを予熱混合し、ヒドロキシプロピルセルロースを溶解した水溶液を噴霧し、ついで同機で乾燥することにより造粒末を得た。造粒末を整粒機(パワーミルP-3、(株)昭和化学機械工作所)を用いて整粒し、整粒末を得た。得られた整粒末に結晶セルロース、クロスカルメロースナトリウム、およびステアリン酸マグネシウムを加え混合機(タンブラー15L、(株)昭和化学機械工作所)で混合し、混合末を得た。混合末をロータリー打錠機(コレクト12HUK、菊水製作所)で、8.0mmφの杵で打錠し、1錠あたり220mgの素錠を得た。
素錠をフィルムコーティング機(ドリアコーターDRC500、(株)パウレック)に入れ、表3-2に示す組成比のフィルムコーティング液をスプレーし、1錠あたり約228.0mgのフィルムコート錠を得た。
化合物Aを含有する素錠を表4-1に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(FD-5S、(株)パウレック)中で、化合物A、D-マンニトール、および結晶セルロースを予熱混合し、ヒドロキシプロピルセルロースを溶解した水溶液を噴霧し、ついで同機で乾燥することにより造粒末を得た。造粒末を整粒機(パワーミルP-3、(株)昭和化学機械工作所)を用いて整粒し、整粒末を得た。得られた整粒末にクロスカルメロースナトリウム、およびステアリン酸マグネシウムを加え混合機(タンブラー15L、(株)昭和化学機械工作所)で混合し、混合末を得た。混合末をロータリー打錠機(コレクト12HUK、菊水製作所)で、9.0mmφの杵で打錠し、1錠あたり280mgの素錠を得た。
素錠をフィルムコーティング機(ドリアコーターDRC500、(株)パウレック)に入れ、表4-2に示す組成比のフィルムコーティング液をスプレーし、1錠あたり約290.2mgのフィルムコート錠を得た。得られたフィルムコート錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
化合物Aを含有する素錠を表5-1に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(FD-5S、(株)パウレック)中で、化合物A、D-マンニトール粒(PEARLITOL 100SD、ロケット社)およびデンプングリコール酸ナトリウムを予熱混合し、ヒドロキシプロピルセルロースを溶解した水溶液を噴霧し、ついで同機で乾燥することにより造粒末を得た。造粒末を整粒機(パワーミルP-3、(株)昭和化学機械工作所)を用いて整粒し、整粒末を得た。得られた整粒末にステアリン酸マグネシウムを加え混合機(タンブラー15L、(株)昭和化学機械工作所)で混合し、混合末を得た。混合末をロータリー打錠機(コレクト12HUK、菊水製作所)で、8.0mmφの杵で打錠し、1錠あたり200mgの素錠を得た。
素錠をフィルムコーティング機(ドリアコーターDRC500、(株)パウレック)に入れ、表5-2に示す組成比のフィルムコーティング液をスプレーし、1錠あたり約208mgのフィルムコート錠を得た。得られたフィルムコート錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
化合物Aを含有する素錠を表6-1に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(LAB-1、(株)パウレック)中で、化合物A、D-マンニトール粒(PEARLITOL 100SD、ロケット社)、メタケイ酸アルミン酸マグネシウムおよびデンプングリコール酸ナトリウムを予熱混合し、ヒドロキシプロピルセルロースを溶解した水溶液を噴霧し、ついで同機で乾燥することにより造粒末を得た。得られた造粒末に、ステアリン酸マグネシウムを加え袋混合し、混合末を得た。混合末をロータリー打錠機(小型打錠機、菊水製作所)で、6.0mmφの杵で打錠し、1錠あたり110mgの素錠を得た。
素錠をフィルムコーティング機(ドリアコーターDRC500、(株)パウレック)に入れ、表6-2に示す組成比のフィルムコーティング液をスプレーし、1錠あたり約114.0mgのフィルムコート錠を得た。得られたフィルムコート錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
化合物Aを含有する素錠を表7-1に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(MP-01、(株)パウレック)中で、化合物A、D-マンニトール、および結晶セルロースを予熱混合し、ヒドロキシプロピルセルロースを溶解した水溶液を噴霧し、ついで同機で乾燥することにより造粒末を得た。得られた造粒末にクロスカルメロースナトリウム、およびステアリン酸マグネシウムを加え袋混合し、混合末を得た。混合末をロータリー打錠機(菊水製作所製、小型打錠機)を用いて、9mmφの杵で打錠し、1錠あたり280mgの素錠を得た。
素錠をフィルムコーティング機(フロイント産業、HC-LABO-20)に入れ、表7-2に示す組成比のフィルムコーティング液をスプレーし、1錠あたり約290mgのフィルムコート錠を得た。得られたフィルムコート錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
化合物Aを含有する素錠を表8に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(MP-01、(株)パウレック)中で、化合物A、D-マンニトール、および結晶セルロースを予熱混合し、ヒドロキシプロピルセルロースおよびポリエチレングリコール6000を溶解した水溶液を噴霧し、ついで同機で乾燥することにより造粒末を得た。得られた造粒末にクロスカルメロースナトリウム、およびステアリン酸マグネシウムを加え、袋混合し、混合末を得た。混合末をロータリー打錠機(菊水製作所製、小型打錠機)を用いて、9mmφの杵で打錠し、1錠あたり280mgの素錠を得た。
素錠をフィルムコーティング機(フロイント産業、HC-LABO-20)に入れ、前記した表7-2に示す組成比のフィルムコーティング液をスプレーし、1錠あたり約290mgのフィルムコート錠を得た。得られたフィルムコート錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
化合物Aを含有する素錠を表9に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(MP-01、(株)パウレック)中で、化合物A、D-マンニトール、および結晶セルロースを予熱混合し、ヒドロキシプロピルセルロース水溶液にモノステアリン酸グリセリン(glycerol monostearate)(以下、GMSという)を分散させた分散液を噴霧し、ついで同機で乾燥することにより造粒末を得た。得られた造粒末にクロスカルメロースナトリウム、およびステアリン酸マグネシウムを加え、袋混合し、混合末を得た。混合末をロータリー打錠機(菊水製作所製、小型打錠機)を用いて、9mmφの杵で打錠し、1錠あたり280mgの素錠を得た。
素錠をフィルムコーティング機(フロイント産業、HC-LABO-20)に入れ、前記した表7-2に示す組成比のフィルムコーティング液をスプレーし、1錠あたり約290mgのフィルムコート錠を得た。得られたフィルムコート錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
化合物Aを含有する素錠を表10に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(MP-01、(株)パウレック)中で、化合物A、D-マンニトール、および結晶セルロースを予熱混合し、ヒドロキシプロピルセルロースおよびポリエチレングリコール400を溶解した水溶液を噴霧し、ついで同機で乾燥することにより造粒末を得た。得られた造粒末にクロスカルメロースナトリウム、およびステアリン酸マグネシウムを加え、袋混合し、混合末を得た。混合末をロータリー打錠機(菊水製作所製、小型打錠機)を用いて、9mmφの杵で打錠し、1錠あたり280mgの素錠を得た。
素錠をフィルムコーティング機(フロイント産業、HC-LABO-20)に入れ、前記した表7-2に示す組成比のフィルムコーティング液をスプレーし、1錠あたり約290mgのフィルムコート錠を得た。得られたフィルムコート錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
化合物Aを含有する素錠を表11に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(MP-01、(株)パウレック)中で、化合物A、D-マンニトール、および結晶セルロースを予熱混合し、ヒドロキシプロピルセルロースおよびクエン酸トリエチルを溶解した水溶液を噴霧し、ついで同機で乾燥することにより造粒末を得た。得られた造粒末にクロスカルメロースナトリウム、およびステアリン酸マグネシウムを加え袋混合し混合末を得た。混合末をロータリー打錠機(菊水製作所製、小型打錠機)を用いて、9mmφの杵で打錠し、1錠あたり280mgの素錠を得た。
素錠をフィルムコーティング機(フロイント産業、HC-LABO-20)に入れ、前記した表7-2に示す組成比のフィルムコーティング液をスプレーし、1錠あたり約290mgのフィルムコート錠を得た。得られたフィルムコート錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
化合物Aを含有する素錠を表12に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(MP-01、(株)パウレック)中で、化合物A、D-マンニトール、および結晶セルロースを予熱混合し、ヒドロキシプロピルセルロース水溶液にGMSを分散させた分散液を噴霧し、ついで同機で乾燥することにより造粒末を得た。得られた造粒末にクロスカルメロースナトリウム、およびステアリン酸マグネシウムを加え袋混合により混合末を得た。混合末をロータリー打錠機(菊水製作所製、小型打錠機)を用いて、9mmφの杵で打錠し、1錠あたり280mgの素錠を得た。
素錠をフィルムコーティング機(フロイント産業、HC-LABO-20)に入れ、前記した表7-2に示す組成比のフィルムコーティング液をスプレーし、1錠あたり約290mgのフィルムコート錠を得た。得られたフィルムコート錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
比較例1、2、実施例1~3、5、7~9で得られたフィルムコート錠について、化合物Aの分解生成物(U-2(6-(4-アミノフェニル)-1-(2,6-ジフルオロベンジル)-5-ジメチルアミノメチル-3-(6-メトキシピリダジン-3-イル)チエノ[2,3-d]ピリミジン-2,4(1H,3H)-ジオン):相対保持時間 約19分)及び総分解生成物量をそれぞれ調べた。分解生成物の測定は、錠剤を0.05mol/Lリン酸ナトリウム緩衝液(pH2.0)/アセトニトリル混液(4:1)で抽出しHPLC法で行った。HPLCの試験条件を次に示した。
検出器:紫外吸光光度計(測定波長:230nm)
カラム:Intersil ODS-4,3μm、4.6mm i.d.×15cm(ジーエルサイエンス株式会社)
カラム温度:40℃付近の一定温度
移動相A:0.05mol/Lリン酸ナトリウム緩衝液(pH2.0)/アセトニトリル混液(4:1)
移動相B:アセトニトリル/0.05mol/Lリン酸ナトリウム緩衝液(pH2.0)(3:2)
移動相の送液:移動相A及び移動相Bの混合比を表13のように制御した。
比較例1、2、実施例1~3のフィルムコート錠について、保存前および60℃、2週間保存後の分解生成物を測定し、総分解生成物およびU-2の結果を表14に示した。
実施例5のフィルムコート錠について、保存前および60℃、2週間保存後の分解生成物を測定し、総分解生成物およびU-2の結果を表15に示した。
実施例7~9のフィルムコート錠について、保存前および60℃、2週間保存後の分解生成物を測定し、総分解生成物およびU-2の結果を表16に示した。
表17の処方に従い、化合物A、D-マンニトール(PEARLITOL 50C、ロケット社)、ヒドロキシプロピルセルロース、デンプングリコール酸ナトリウムおよびステアリン酸マグネシウムを瓶混合し、打錠用混合粉末を得た。この混合粉末を卓上錠剤成型機(HANDTAB200、市橋精機(株))で、9.0mmφの杵で打錠し、1錠あたり300mgの素錠を得た。得られた素錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
実施例10~12の素錠について、保存前および60℃、2週間保存後の分解生成物を試験例1の試験法を用いて測定し、総分解生成物およびU-2の結果を表18に示した。
表19の処方に従い、化合物A、D-マンニトール(PEARLITOL 50C、ロケット社)、ヒドロキシプロピルセルロース、デンプングリコール酸ナトリウムおよびステアリン酸マグネシウムを瓶混合し、打錠用混合粉末を得た。この混合粉末を卓上錠剤成型機(HANDTAB200、市橋精機(株))で、9.0mmφの杵で打錠した。
表20の処方に従い、化合物A、D-マンニトール粒(PEARLITOL 100SD、ロケット社)、ヒドロキシプロピルセルロース、デンプングリコール酸ナトリウムおよびステアリン酸マグネシウムを瓶混合し、打錠用混合粉末を得た。この混合粉末を卓上錠剤成型機(HANDTAB200、市橋精機(株))で、9.0mmφの杵で打錠し、1錠あたり300mgの素錠を得た。得られた素錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
比較例3、実施例13~15の素錠について、保存前および60℃、2週間保存後の分解生成物を試験例1の試験法を用いて測定し、総分解生成物およびU-2の結果を表21に示した。
化合物Aを含有する、実施例16~18の素錠を表22に示す組成比で次のように製造した。
すなわち、化合物A、D-マンニトール粒、ヒドロキシプロピルセルロース、デンプングリコール酸ナトリウムおよびステアリン酸マグネシウムを瓶混合し、打錠用混合粉末を得た。この混合粉末を卓上錠剤成型機(HANDTAB200、市橋精機(株))で、9.0mmφの杵で打錠し、1錠あたり300mgの素錠を得た。得られた素錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
実施例16~18の素錠について、保存前および60℃、2週間保存後の分解生成物を試験例1の試験法を用いて測定し、総分解生成物およびU-2の結果を表23に示した。上述した実施例10および13の素錠についての経日安定性試験結果を表23に併せて示す。
化合物Aを含有する、実施例19~21の素錠を表24に示す組成比で次のように製造した。
すなわち、化合物A、D-マンニトール粒、ヒドロキシプロピルセルロース、デンプングリコール酸ナトリウムおよびステアリン酸マグネシウムを瓶混合し、打錠用混合粉末を得た。この混合粉末を卓上錠剤成型機(HANDTAB200、市橋精機(株))で、9.0mmφの杵で打錠し、1錠あたり300mgの素錠を得た。得られた素錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
実施例19~21の素錠について、保存前および60℃、2週間保存後の分解生成物を測定し、総分解生成物およびU-2の結果を表25に示した。上述した実施例11および14の素錠についての経日安定性試験結果を表25に併せて示す。
化合物Aを含有する素錠を表26-1に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(FD-5S、(株)パウレック)中で、化合物A、D-マンニトール粒(PEARLITOL 100SD、ロケット社)、およびデンプングリコール酸ナトリウムを予熱混合し、ヒドロキシプロピルセルロースを溶解した水溶液を噴霧し、ついで同機で乾燥することにより造粒末を得た。造粒末を整粒機(パワーミルP-3、(株)昭和化学機械工作所)を用いて整粒し、整粒末を得た。得られた整粒末にステアリン酸マグネシウムを加え混合機(タンブラー15L、(株)昭和化学機械工作所)で混合し、混合末を得た。混合末をロータリー打錠機(小型打錠機、菊水製作所)で、6.0mmφの杵で打錠し、1錠あたり100mgの素錠を得た。
素錠をフィルムコーティング機(ドリアコーターDRC200、(株)パウレック)に入れ、表26-2に示す組成比のフィルムコーティング液をスプレーし、1錠あたり約104.0mgのフィルムコート錠を得た。
化合物Aを含有する素錠を表27に示す組成比で次のように製造する。
すなわち、流動層造粒乾燥機(FD-5S、(株)パウレック)中で、化合物A、D-マンニトール粒(PEARLITOL 100SD、ロケット社)、およびデンプングリコール酸ナトリウムを予熱混合し、ヒドロキシプロピルセルロースを溶解した水溶液を噴霧し、ついで同機で乾燥することにより造粒末を得る。造粒末を整粒機(パワーミルP-3、(株)昭和化学機械工作所)を用いて整粒し、整粒末を得る。得られた整粒末にステアリン酸マグネシウムを加え混合機(タンブラー15L、(株)昭和化学機械工作所)で混合し、混合末を得る。混合末をロータリー打錠機(小型打錠機、菊水製作所)で、7.0mmφの杵で打錠し、1錠あたり125mgの素錠を得る。
化合物Aを含有する、実施例24~29の素錠を表28-1および28-2に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(MP-01、(株)パウレック)中で、化合物A、D-マンニトール、および結晶セルロースを予熱混合し、ヒドロキシプロピルセルロースおよびポリエチレングリコール6000を溶解した水溶液を噴霧し、ついで同機で乾燥することにより造粒末を得た。得られた造粒末にクロスカルメロースナトリウム、およびステアリン酸マグネシウムを加え、袋混合し、混合末を得た。混合末をロータリー打錠機(菊水製作所製、小型打錠機)を用いて、9mmφの杵で打錠し、1錠あたり280mgの素錠を得た。
素錠をフィルムコーティング機(フロイント産業、HC-LABO-20)に入れ、前記した表7-2に示す組成比のフィルムコーティング液をスプレーし、1錠あたり約290mgの、実施例24~29のフィルムコート錠を得た。得られたフィルムコート錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
実施例24~29のフィルムコート錠について、保存前および60℃、2週間保存後の分解生成物を試験例1に記載の方法で測定し、総分解生成物およびU-2の結果を表29に示す。また、上述した実施例4のフィルムコート錠について、同様の方法で、保存前および60℃、2週間保存後の分解生成物を測定し、総分解生成物およびU-2の結果を表29に示す。上述した実施例5のフィルムコーティング錠についての経日安定性試験結果を表29に併せて示す。
化合物Aを含有する素錠を表30-1および30-2に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(MP-01、(株)パウレック)中で、化合物A、D-マンニトール、および結晶セルロースを予熱混合し、ヒドロキシプロピルセルロースを溶解した水溶液を噴霧し、ついで同機で乾燥することにより造粒末を得た。得られた造粒末にクロスカルメロースナトリウム、ステアリン酸マグネシウム、および実施例30~34においては種々の平均分子量を有するポリエチレングリコール(具体的には、ポリエチレングリコール6000(平均分子量:7300-9300)、POLYOX WSR N-10(平均分子量:100000)、POLYOX WSR N-205(平均分子量:600000)、POLYOX WSR N-12K(平均分子量:1000000)、POLYOX WSR 303(平均分子量:7000000))を加え、袋混合し、混合末を得た。混合末をロータリー打錠機(菊水製作所製、小型打錠機)を用いて、9mmφの杵で打錠し、1錠あたり280mg(参考例4)、284.8mg(実施例30~34)の素錠を得た。
得られた素錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
表30-1および30-2で得られた素錠について、保存前および60℃、2週間保存後の分解生成物を測定し、総分解生成物およびU-2の結果を表31に示した。
化合物Aを含有する素錠を表32-1に示す組成比で次のように製造した。
すなわち、流動層造粒乾燥機(FD-5S、(株)パウレック)中で、化合物A、D-マンニトール、および結晶セルロースを予熱混合し、ヒドロキシプロピルセルロースおよびポリエチレングリコール6000を溶解した水溶液を噴霧し、ついで同機で乾燥することにより造粒末を得た。造粒末を整粒機(パワーミルP-3、(株)昭和化学機械工作所)を用いて整粒し、整粒末を得た。得られた整粒末にクロスカルメロースナトリウム、およびステアリン酸マグネシウムを加え混合機(タンブラー15L、(株)昭和化学機械工作所)で混合し、混合末を得た。混合末をロータリー打錠機(AQUARIUS、菊水製作所)で、12.0×8.4mmφの杵で打錠し、1錠あたり420mgの素錠を得た。
素錠をフィルムコーティング機(ドリアコーターDRC500、(株)パウレック)に入れ、表32-2に示す組成比のフィルムコーティング液をスプレーした後、微量のカルナウバロウでコーティングし(1錠あたり0.012mg)、1錠あたり約435mgのフィルムコート錠を得た。得られたフィルムコート錠をガラスビンに入れ、密栓して60℃条件下で2週間保存した。
実施例35のフィルムコート錠について、保存前および60℃、2週間保存後の分解生成物を測定し、総分解生成物およびU-2の結果を表33に示した。
Claims (12)
- N-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N’-メトキシウレアまたはその塩を25質量%以上含有する錠剤。
- 平均粒径が60~500μmであるD-マンニトール粒を配合することを特徴とする、請求項1記載の錠剤。
- 平均粒径が60~250μmであるD-マンニトール粒を配合することを特徴とする、請求項1記載の錠剤。
- N-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N’-メトキシウレアまたはその塩を25質量%以上配合することを特徴とする、錠剤中のN-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N’-メトキシウレアまたはその塩の安定化方法。
- さらに、平均粒径が60~500μmであるD-マンニトール粒を配合することを特徴とする、請求項4記載の安定化方法。
- さらに、平均粒径が60~250μmであるD-マンニトール粒を配合することを特徴とする、請求項4記載の安定化方法。
- (1)N-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N’-メトキシウレアまたはその塩、および
(2)ポリエチレングリコール、モノステアリン酸グリセリンおよびクエン酸トリエチルから選択される低融点油脂状物質
を含有する固形製剤。 - 低融点油脂状物質がポリエチレングリコールである、請求項7記載の固形製剤。
- 低融点油脂状物質が、平均分子量約6000ないし約120000のポリエチレングリコールである、請求項7記載の固形製剤。
- N-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N’-メトキシウレアまたはその塩を含有する固形製剤において、ポリエチレングリコール、モノステアリン酸グリセリンおよびクエン酸トリエチルから選択される低融点油脂状物質を配合することを特徴とする、N-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N’-メトキシウレアまたはその塩の安定化方法。
- 低融点油脂状物質がポリエチレングリコールである、請求項10記載の安定化方法。
- 低融点油脂状物質が、平均分子量約6000ないし約120000のポリエチレングリコールである、請求項10記載の安定化方法。
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WO2023066941A1 (en) | 2021-10-18 | 2023-04-27 | Myovant Sciences Gmbh | Crystalline form of an ethanol solvate of n-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-n'-methoxyurea |
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FI3263110T3 (fi) | 2023-07-25 |
US10350170B2 (en) | 2019-07-16 |
DK3263110T3 (da) | 2023-07-31 |
US20200000730A1 (en) | 2020-01-02 |
IL254132A0 (en) | 2017-10-31 |
US20180036250A1 (en) | 2018-02-08 |
PL3263110T3 (pl) | 2023-11-06 |
PT3263110T (pt) | 2023-08-01 |
TWI744224B (zh) | 2021-11-01 |
EP4233847A1 (en) | 2023-08-30 |
JP6730978B2 (ja) | 2020-07-29 |
TW201639575A (zh) | 2016-11-16 |
HRP20230613T1 (hr) | 2023-09-29 |
MX2017010945A (es) | 2018-07-06 |
NZ735026A (en) | 2021-09-24 |
RS64377B1 (sr) | 2023-08-31 |
AU2016224503B2 (en) | 2021-07-08 |
EP3263110B1 (en) | 2023-05-10 |
CA2978223A1 (en) | 2016-09-01 |
EP3263110A1 (en) | 2018-01-03 |
MY180680A (en) | 2020-12-06 |
BR112017018173A2 (ja) | 2018-04-10 |
AU2016224503A1 (en) | 2017-09-14 |
CY1126118T1 (el) | 2023-11-15 |
LT3263110T (lt) | 2023-07-10 |
EP3263110A4 (en) | 2018-11-07 |
IL254132B (en) | 2020-02-27 |
SI3263110T1 (sl) | 2023-09-29 |
CN107249590A (zh) | 2017-10-13 |
JPWO2016136849A1 (ja) | 2017-12-07 |
ES2950995T3 (es) | 2023-10-17 |
HUE062269T2 (hu) | 2023-10-28 |
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