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WO2017061621A1 - Composition pharmaceutique contenant un composé d'arylalkylamine - Google Patents

Composition pharmaceutique contenant un composé d'arylalkylamine Download PDF

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Publication number
WO2017061621A1
WO2017061621A1 PCT/JP2016/080013 JP2016080013W WO2017061621A1 WO 2017061621 A1 WO2017061621 A1 WO 2017061621A1 JP 2016080013 W JP2016080013 W JP 2016080013W WO 2017061621 A1 WO2017061621 A1 WO 2017061621A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
weight
parts
composition according
coating
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2016/080013
Other languages
English (en)
Japanese (ja)
Inventor
信爾 谷村
宏子 吉井
見二 岩田
直人 井澤
元洋 太田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kyowa Kirin Co Ltd
Original Assignee
Kyowa Hakko Kirin Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP2016197725A external-priority patent/JP6168673B2/ja
Application filed by Kyowa Hakko Kirin Co Ltd filed Critical Kyowa Hakko Kirin Co Ltd
Priority to US15/766,426 priority Critical patent/US10350194B2/en
Priority to EP16853772.8A priority patent/EP3360551A4/fr
Priority to KR1020197019836A priority patent/KR102488488B1/ko
Priority to KR1020187012497A priority patent/KR102000897B1/ko
Priority to CN201680058580.7A priority patent/CN108135883B/zh
Publication of WO2017061621A1 publication Critical patent/WO2017061621A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
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    • 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
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Definitions

  • the present invention relates to a pharmaceutical composition containing an arylalkylamine compound having an activating action on a calcium sensitive receptor (CaSR) and useful as a medicine, particularly a preventive or therapeutic agent for hyperparathyroidism and the like.
  • CaSR calcium sensitive receptor
  • Parathyroid hormone is a hormone that has a physiological function of inducing bone resorption and increasing blood calcium (Ca), and plays a role in maintaining blood Ca homeostasis.
  • PTH blood calcium
  • CaSR Ca-sensitive receptor
  • Patent Document 1 discloses the following structure as an arylalkylamine compound having an activating action or antagonistic action against CaSR (4- ⁇ (3S) -3-[(1R) -1- (naphthalene- 1-yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl) acetic acid [4- ⁇ (3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl acetic acid] (hereinafter “Compound A”).
  • Patent Document 1 does not disclose any physical or chemical properties such as stability of compound A against light, heat (temperature), etc., and a pharmaceutical composition containing compound A that can be used as a medicine. There is also no disclosure about.
  • Patent Document 5 discloses the results of a stability test of Compound A crystals.
  • Patent Document 2 describes that by adding calcium carbonate to the inner core granule of the coated granule, the amount of sulfate ion produced in a temperature and humidity environment is reduced, and the stability of the main drug (topiramate) is improved.
  • Patent Document 3 describes that the presence of an inorganic substance and / or a colorant in the tablet skin improves the light stability of the diarylvinylene compound present in the core tablet by applying a light-shielding film coating.
  • Patent Document 4 describes that by adding crystalline cellulose in a tablet, the amount of impurities produced under a temperature and humidity environment is reduced, and the stability of levothyroxine, which is the main drug, is improved. None of Literatures 2 to 4 disclose a pharmaceutical composition containing Compound A that can be used as a pharmaceutical, as in Patent Literature 1.
  • An object of the present invention is to provide a stable pharmaceutical composition or the like that contains an arylalkylamine compound useful as a preventive or therapeutic agent for hyperparathyroidism and the like and is acceptable as a pharmaceutical product.
  • the present invention relates to the following (1) to (39).
  • a pharmaceutical composition comprising a salt and an excipient.
  • the excipient is lactose, sucrose, maltose, sucrose, mannitol, sorbitol, erythritol, maltitol, xylitol, glucose, crystalline cellulose, corn starch, potato starch, calcium monohydrogen phosphate, calcium dihydrogen phosphate, phosphorus
  • the pharmaceutical composition according to the above (1) or (2) which is one or more substances selected from sodium dihydrogen acid and calcium phosphate.
  • the pharmaceutical composition further comprises one or more additives selected from a binder, a basic additive, a disintegrant, a lubricant, a colorant and a brightener.
  • additives selected from a binder, a basic additive, a disintegrant, a lubricant, a colorant and a brightener.
  • the binder is hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, hydroxypropyl starch, hydroxyethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxyvinyl polymer, polyvinylpyrrolidone,
  • the pharmaceutical composition according to (5) above which is one or more substances selected from polyvinyl alcohol, methacrylic acid copolymer, macrogol, starch, gelatin, dextrin, pullulan, agar and gum arabic.
  • the basic additive is one or more substances selected from basic oxides, basic hydroxides, carbonates, hydrogencarbonates, silicates and metasilicate aluminates (5) ).
  • One type in which the basic additive is selected from magnesium oxide, magnesium hydroxide, aluminum hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate, calcium silicate and magnesium aluminate metasilicate.
  • the pharmaceutical composition according to the above (7) which is the above substance.
  • the disintegrant is at least one substance selected from croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, partially pregelatinized starch, and starch
  • the above-mentioned lubricant is one or more substances selected from magnesium stearate, calcium stearate, talc, glyceryl monostearate, light anhydrous silicic acid, sodium stearyl fumarate and sucrose fatty acid esters ( The pharmaceutical composition as described in 5).
  • the colorant is yellow ferric oxide, titanium oxide, talc, ferric oxide, black iron oxide, copper chlorophyll, copper chlorophyllin sodium, carbon black, medicinal charcoal, food coloring, licorice extract, green tea powder, riboflavin, butyric acid
  • the pharmaceutical composition according to the above (5) which is one or more substances selected from riboflavin, riboflavin sodium phosphate and octyldodecyl myristate.
  • the brightening agent is one or more substances selected from carnauba wax, shellac, beeswax, hydrogenated oil, and magnesium stearate.
  • coating film contains one or more coating agents selected from water-soluble polymers, lactose, sucrose, titanium oxide, and talc.
  • the water-soluble polymer is at least one polymer selected from polyvinyl alcohol polyethylene glycol graft copolymer, polyvinyl pyrrolidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl alcohol acrylic acid methyl methacrylate copolymer and polyethylene glycol.
  • the excipient is mannitol and / or crystalline cellulose
  • the binder is hydroxypropylcellulose
  • the basic additive is calcium carbonate
  • the disintegrant is croscarmellose sodium
  • the lubricant is stearin.
  • the coating agent is at least one coating agent selected from a water-soluble polymer, lactose and titanium oxide
  • the colorant is yellow iron trioxide 2.
  • composition according to any one of (1) to (30), wherein the pharmaceutical composition is a solid preparation (2) The pharmaceutical composition according to (31) above, wherein the solid preparation has the form of a tablet, powder, fine granule, granule, capsule or dry syrup. (33) The pharmaceutical composition according to the above (31), wherein the solid preparation is a tablet. (34) A blister package manufactured using the pharmaceutical composition according to any one of (1) to (33) above, a film laminated with a polymer, and an aluminum foil.
  • the blister package according to (34), wherein the polymer-laminated film is a film in which at least one polymer selected from polypropylene, polyvinyl chloride, polyvinylidene chloride, and polytrifluoroethylene chloride is laminated. .
  • the pharmaceutical package according to (37) or (38), wherein an oxygen scavenger and / or a desiccant is further enclosed in the package.
  • a stable pharmaceutical composition or the like that contains an arylalkylamine compound useful as a preventive or therapeutic agent for hyperparathyroidism or the like and is acceptable as a pharmaceutical product.
  • the pharmaceutical composition of the present invention comprises Compound A or a pharmacologically acceptable salt thereof and an excipient as an arylamine compound which is an active ingredient.
  • the structure of Compound A in the present invention is as described above, and it can be produced by the method disclosed in International Publication No. 2005/115975 or a method analogous thereto.
  • the pharmacologically acceptable salt of Compound A include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and organic base salts such as amine salts.
  • the compound A of the present invention or a pharmacologically acceptable salt thereof includes any of intramolecular salts and adducts thereof, solvates or hydrates thereof.
  • the content of Compound A or a pharmacologically acceptable salt thereof is not particularly limited, but for example, it is preferably 0.01 to 100 mg in the pharmaceutical composition, More preferably, it contains from mg to 20 mg, more preferably contains from 0.5 mg to 5 mg, and particularly preferably contains from 1 mg to 2 mg.
  • the content of Compound A or a pharmacologically acceptable salt thereof is not particularly limited, but is 0.3 to 5.0 parts by weight with respect to 100 parts by weight of the pharmaceutical composition. It is preferably 0.5 to 5.0 parts by weight, more preferably 0.5 to 2.0 parts by weight, still more preferably 0.5 to 1.5 parts by weight.
  • the particle diameter of Compound A or a pharmacologically acceptable salt thereof used in the pharmaceutical composition of the present invention is preferably 100 ⁇ m or less, more preferably 75 ⁇ m or less, and even more preferably 50 ⁇ m or less as the median diameter (D 90 ). Preferably, 35 ⁇ m or less is particularly preferable.
  • the excipient contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medicine.
  • examples thereof include sugars, sugar alcohols, cellulose derivatives, starch derivatives, and inorganic salts.
  • lactose more preferably lactose hydrate
  • sorbitol erythritol
  • maltitol xylitol
  • glucose crystalline cellulose
  • corn starch potato starch
  • Calcium monohydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, calcium phosphate and the like, and these excipients may be used in combination of two or more.
  • the excipient contained in the pharmaceutical composition of the present invention is preferably used in combination of mannitol (preferably D-mannitol) and crystalline cellulose.
  • the content of the excipient is not particularly limited.
  • the excipient is preferably contained in an amount of 0.1 to 99.9 parts by weight with respect to 100 parts by weight of the pharmaceutical composition. 1 to 95 parts by weight is more preferable, and 10 to 90 parts by weight is more preferable.
  • the pharmaceutical composition of the present invention may contain, in addition to Compound A and excipients, other additives used as pharmaceuticals.
  • binders, basic additives, disintegrations used in pharmaceutical formulations One or more additives selected from agents, lubricants, colorants, and brighteners may be included.
  • the binder, basic additive, disintegrant, lubricant, colorant, and brightening agent in the present specification are not limited to the described uses (functions), but for other uses (functions).
  • Can also be used eg, using a binder as an excipient, using an excipient as a binder, etc.).
  • the binder in the present invention is not particularly limited as long as it is used as a medicine.
  • hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose acetate succinate examples include cellulose derivatives such as hydroxypropylmethylcellulose phthalate, hydroxypropyl starch, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, methacrylic acid copolymer, polyethylene glycol (macrogol), starch, gelatin, dextrin, pullulan, agar, gum arabic, etc.
  • Hydroxypropyl cellulose, polyvinyl Alcohol is preferably a polyvinyl pyrrolidone, may be used in combination of two or more of these binders.
  • the content of the binder is not particularly limited. For example, it is preferably 0.1 to 10 parts by weight, and preferably 0.5 to 7 parts by weight with respect to 100 parts by weight of the pharmaceutical composition. More preferably, it is more preferably 1 to 5 parts by weight.
  • the basic additive in the present invention is not particularly limited as long as it is used as a medicine, and examples thereof include basic oxides, carbonates, hydrogen carbonates, silicates, and metasilicate aluminates.
  • the basic oxide include magnesium oxide
  • examples of the basic hydroxide include magnesium hydroxide and aluminum hydroxide
  • examples of the carbonate include magnesium carbonate and calcium carbonate.
  • examples of the hydrogen carbonate include sodium hydrogen carbonate
  • examples of the silicate include calcium silicate
  • examples of the metasilicate aluminate include magnesium aluminate metasilicate.
  • the content of the basic additive is not particularly limited, but for example, it is preferably 0.01 to 50 parts by weight, and preferably 0.1 to 30 parts by weight with respect to 100 parts by weight of the pharmaceutical composition. More preferably, it is more preferably 0.5 to 10 parts by weight.
  • the disintegrant in the present invention is not particularly limited as long as it is used as a medicine.
  • croscarmellose sodium, crospovidone, carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, Partially pregelatinized starch, starch and the like can be mentioned, and croscarmellose sodium, crospovidone and the like are preferable, and these two or more disintegrating agents may be used in combination.
  • the content of the disintegrant is not particularly limited.
  • the content is preferably 0.5 to 20 parts by weight, and preferably 1 to 15 parts by weight with respect to 100 parts by weight of the pharmaceutical composition. More preferably, it is more preferably 3 to 10 parts by weight.
  • the lubricant in the present invention is not particularly limited as long as it is used as a medicine.
  • magnesium stearate, calcium stearate, talc, glyceryl monostearate, light anhydrous silicic acid, sodium stearyl fumarate, sucrose Fatty acid esters for example, sucrose stearate ester, sucrose palmitate ester, sucrose oleate ester, sucrose laurate ester, etc.
  • sucrose Fatty acid esters for example, sucrose stearate ester, sucrose palmitate ester, sucrose oleate ester, sucrose laurate ester, etc.
  • these two or more kinds of lubricants are used in combination. May be.
  • the content of the lubricant is not particularly limited, but it is preferably 0.05 to 10 parts by weight, for example, 0.1 to 5 parts by weight with respect to 100 parts by weight of the pharmaceutical composition. More preferably, it is more preferably 0.5 to 3 parts by weight.
  • the colorant in the present invention is not particularly limited as long as it is used as a medicine.
  • yellow iron dioxide, titanium oxide, talc, iron dioxide Preferably, these two or more colorants may be used in combination.
  • the content of the colorant is not particularly limited, but for example, it is preferably 0.0001 to 10,000 parts by weight with respect to 100 parts by weight of Compound A or a pharmacologically acceptable salt thereof. More preferably 0.01 to 1000 parts by weight, still more preferably 0.1 to 500 parts by weight.
  • the brightening agent in the present invention is not particularly limited as long as it is used as a medicine.
  • carnauba wax, shellac, beeswax, hydrogenated oil, magnesium stearate and the like are preferable.
  • a combination of agents may be used.
  • the content of the brightening agent is not particularly limited. For example, it is preferably 0.0001 to 100 parts by weight, and preferably 0.001 to 10 parts by weight with respect to 100 parts by weight of the pharmaceutical composition. More preferably, it is more preferably 0.01 part by weight to 1 part by weight.
  • excipients include hydrates, solvates, salts, and the like.
  • the pharmaceutical composition of the present invention may not have a coating film (skin), but preferably has a coating film (skin) for the purpose of imparting light stability, storage stability to temperature and humidity, and the like.
  • the coating film can be applied by coating the pharmaceutical composition of the present invention.
  • the coating treatment is performed by applying a coating liquid containing a coating agent to a raw preparation containing Compound A or the like by a spray coating method or the like. This can be done by spraying.
  • the coating agent is used by dissolving, suspending, or dispersing in the coating solution. Examples of the solvent constituting the coating solution include water, alcohols such as methanol and ethanol, and the like. More preferred.
  • a component which comprises the said coating agent For example, water-soluble polymer, lactose, sucrose, titanium oxide, talc, polyvinylpyrrolidone etc. are mentioned, As said water-soluble polymer, polyvinyl alcohol polyethyleneglycol graft copolymer , Polyvinyl pyrrolidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl alcohol acrylic acid methyl methacrylate copolymer, polyethylene glycol and the like.
  • the content of the coating agent is not particularly limited.
  • the coating agent is preferably contained in an amount of 0.1 to 100 parts by weight, more preferably 0.5 to 80 parts by weight, with respect to 100 parts by weight of the coating film. More preferably, it is contained in an amount of 1 to 60 parts by weight.
  • the amount of the coating solution used for the coating treatment is not particularly limited as long as light stability and the like can be imparted to the pharmaceutical composition, but the coating film is applied to 100 parts by weight of the raw preparation (preparation without coating treatment).
  • the (coat) is preferably 0.01 to 90 parts by weight, more preferably 0.05 to 70 parts by weight, and further preferably 0.1 to 50 parts by weight in a dry state.
  • the pharmaceutical composition of the present invention preferably has a first coating film and a second coating film, and the first coating film preferably contains a polyvinyl alcohol polyethylene glycol graft copolymer,
  • the coating film preferably contains one or more coating agents selected from water-soluble polymers, lactose, sucrose, titanium oxide and talc, and one or more types selected from water-soluble polymers, lactose and titanium oxide. More preferably, it contains a coating agent.
  • composition of the present invention 0.5 to 5.0 parts by weight of (4- ⁇ (3S) -3-[(1R) -1- (naphthalene-1- Yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl) acetic acid (compound A) or a pharmaceutically acceptable salt thereof, 50.0 to 90.0 parts by weight of excipient, 1.0 to 5.0 parts by weight of binder, 0.5 to A pharmaceutical containing 5.0 parts by weight basic additive, 2.0-10.0 parts by weight disintegrant, 0.5-3.0 parts by weight lubricant, 3.0-10.0 parts by weight coating agent, and 0.1-1.0 parts by weight colorant.
  • a composition is provided.
  • the excipient is mannitol and / or crystalline cellulose
  • the binder is hydroxypropylcellulose
  • the basic additive is calcium carbonate
  • the disintegrant is croscarmellose sodium
  • the lubricant is stearin. It is preferably magnesium acid
  • the coating agent is one or more coating agents selected from water-soluble polymers, lactose and titanium oxide
  • the colorant is yellow iron trioxide.
  • composition of the present invention 0.5 to 5.0 parts by weight of (4- ⁇ (3S) -3-[(1R) -1- (naphthalene-1- Yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl) acetic acid (compound A) or a pharmaceutically acceptable salt thereof, 50.0-89.0 parts by weight of excipient, 1.0-5.0 parts by weight of binder, 0.5- A pharmaceutical containing 5.0 parts by weight basic additive, 3.0-10.0 parts by weight disintegrant, 0.5-3.0 parts by weight lubricant, 3.0-10.0 parts by weight coating agent, and 0.1-1.0 parts by weight colorant A composition is provided.
  • the excipient is mannitol and / or crystalline cellulose
  • the binder is hydroxypropylcellulose
  • the basic additive is calcium carbonate
  • the disintegrant is croscarmellose sodium
  • the lubricant is stearin. It is preferably magnesium acid
  • the coating agent is one or more coating agents selected from water-soluble polymers, lactose and titanium oxide
  • the colorant is yellow iron trioxide.
  • composition of the present invention 0.5 to 2.0 parts by weight of (4- ⁇ (3S) -3-[(1R) -1- (naphthalene- 1-yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl) acetic acid (Compound A) or a pharmacologically acceptable salt thereof, 70.0-90.0 parts by weight of excipient, 1.0-3.0 parts by weight of binder, Contains 0.5-2.0 parts by weight basic additive, 2.0-5.0 parts by weight disintegrant, 0.5-2.0 parts by weight lubricant, 5.0-10.0 parts by weight coating agent, and 0.1-1.0 parts by weight colorant.
  • a pharmaceutical composition is provided.
  • the excipient is mannitol and / or crystalline cellulose
  • the binder is hydroxypropylcellulose
  • the basic additive is calcium carbonate
  • the disintegrant is croscarmellose sodium
  • the lubricant is stearin. It is preferably magnesium acid
  • the coating agent is one or more coating agents selected from water-soluble polymers, lactose and titanium oxide
  • the colorant is yellow iron trioxide.
  • composition of the present invention 0.5 to 2.0 parts by weight of (4- ⁇ (3S) -3-[(1R) -1- (naphthalene- 1-yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl) acetic acid (compound A) or a pharmaceutically acceptable salt thereof, 70.0-89.0 parts by weight of excipient, 1.0-3.0 parts by weight of binder, Contains 0.5-2.0 parts by weight basic additive, 3.0-5.0 parts by weight disintegrant, 0.5-2.0 parts by weight lubricant, 5.0-10.0 parts by weight coating agent, and 0.1-1.0 parts by weight colorant.
  • a pharmaceutical composition is provided.
  • the excipient is mannitol and / or crystalline cellulose
  • the binder is hydroxypropylcellulose
  • the basic additive is calcium carbonate
  • the disintegrant is croscarmellose sodium
  • the lubricant is stearin. It is preferably magnesium acid
  • the coating agent is one or more coating agents selected from water-soluble polymers, lactose and titanium oxide
  • the colorant is yellow iron trioxide.
  • 0.3 to 5.0 parts by weight preferably 0.5 to 5.0 parts by weight, more preferably 0.5 to 2.0 parts by weight, further preferably 100 parts by weight of the pharmaceutical composition.
  • a pharmaceutical composition containing (preferably 20.0-30.0 parts by weight) of crystalline cellulose is provided. By containing both mannitol and crystalline cellulose as excipients, stabilization of Compound A or a pharmacologically acceptable salt thereof can be achieved.
  • 0.3 to 5.0 parts by weight preferably 0.5 to 5.0 parts by weight, more preferably 0.5 to 2.0 parts by weight, further preferably 100 parts by weight of the pharmaceutical composition.
  • 0.5 to 1.5 parts by weight of (4- ⁇ (3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl) acetic acid (Compound A) or The pharmacologically acceptable salt thereof, 50.0 to 70.0 parts by weight (preferably 50.0 to 60.0 parts by weight) of mannitol (preferably D-mannitol) as an excipient, and 20.0 to 40.0 parts by weight of excipient (
  • a pharmaceutical composition comprising 20.0-30.0 parts by weight of crystalline cellulose and 3.0-10.0 parts by weight (preferably 3.0-5.0 parts by weight) of croscarmellose sodium as a disintegrant.
  • 0.3 to 5.0 parts by weight preferably 0.5 to 5.0 parts by weight, more preferably 0.5 to 2.0 parts by weight, further preferably 100 parts by weight of the pharmaceutical composition.
  • 0.5 to 1.5 parts by weight of (4- ⁇ (3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl) acetic acid (Compound A) or The pharmacologically acceptable salt thereof, 50.0 to 70.0 parts by weight (preferably 50.0 to 60.0 parts by weight) of mannitol (preferably D-mannitol) as an excipient, and 20.0 to 40.0 parts by weight of excipient (
  • a pharmaceutical composition comprising 20.0-30.0 parts by weight of crystalline cellulose and 0.5-5.0 parts by weight (preferably 0.5-2.0 parts by weight) of calcium carbonate as a basic additive.
  • 0.3 to 5.0 parts by weight preferably 0.5 to 5.0 parts by weight, more preferably 0.5 to 2.0 parts by weight, further preferably 100 parts by weight of the pharmaceutical composition.
  • 0.5 to 1.5 parts by weight of (4- ⁇ (3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl) acetic acid (Compound A) or The pharmacologically acceptable salt thereof, 50.0 to 70.0 parts by weight (preferably 50.0 to 60.0 parts by weight) of mannitol (preferably D-mannitol) as an excipient, and 20.0 to 40.0 parts by weight of excipient ( Preferably, 20.0 to 30.0 parts by weight of crystalline cellulose, 0.5 to 5.0 parts by weight (preferably 0.5 to 2.0 parts by weight) calcium carbonate as a basic additive, and 3.0 to 10.0 parts by weight (preferably, a coating agent) 4.0 to
  • 0.3 to 5.0 parts by weight preferably 0.5 to 5.0 parts by weight, more preferably 0.5 to 2.0 parts by weight, further preferably 100 parts by weight of the pharmaceutical composition.
  • 0.5 to 1.5 parts by weight of (4- ⁇ (3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl) acetic acid (Compound A) or The pharmacologically acceptable salt thereof, 50.0 to 70.0 parts by weight (preferably 50.0 to 60.0 parts by weight) of mannitol (preferably D-mannitol) as an excipient, and 20.0 to 40.0 parts by weight of excipient ( Preferably, 20.0 to 30.0 parts by weight) of crystalline cellulose, 0.5 to 5.0 parts by weight (preferably 0.5 to 2.0 parts by weight) of calcium carbonate as a basic additive, 0.5 to 5.0 as a coating agent (first coating film) Parts by
  • 0.3 to 5.0 parts by weight preferably 0.5 to 5.0 parts by weight, more preferably 0.5 to 2.0 parts by weight, further preferably 100 parts by weight of the pharmaceutical composition.
  • 0.5 to 1.5 parts by weight of (4- ⁇ (3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl) acetic acid (Compound A) or The pharmacologically acceptable salt thereof, 50.0 to 70.0 parts by weight (preferably 50.0 to 60.0 parts by weight) of mannitol (preferably D-mannitol) as an excipient, and 20.0 to 40.0 parts by weight of excipient (
  • a pharmaceutical composition is provided containing 20.0-30.0 parts by weight of crystalline cellulose and 1.0-5.0 parts by weight (preferably 1.0-3.0 parts by weight) of hydroxypropylcellulose as a binder.
  • 0.3 to 5.0 parts by weight preferably 0.5 to 5.0 parts by weight, more preferably 0.5 to 2.0 parts by weight, further preferably 100 parts by weight of the pharmaceutical composition.
  • 0.5 to 1.5 parts by weight of (4- ⁇ (3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl) acetic acid (Compound A) or The pharmacologically acceptable salt thereof, 50.0 to 70.0 parts by weight (preferably 50.0 to 60.0 parts by weight) of mannitol (preferably D-mannitol) as an excipient, and 20.0 to 40.0 parts by weight of excipient (
  • a pharmaceutical composition comprising 20.0-30.0 parts by weight of crystalline cellulose and 0.5-3.0 parts by weight (preferably 0.5-2.0 parts by weight) of magnesium stearate as a lubricant.
  • 0.3 to 5.0 parts by weight preferably 0.5 to 5.0 parts by weight, more preferably 0.5 to 2.0 parts by weight, further preferably 100 parts by weight of the pharmaceutical composition.
  • 0.5 to 1.5 parts by weight of (4- ⁇ (3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl) acetic acid (Compound A) or The pharmacologically acceptable salt thereof, 50.0 to 70.0 parts by weight (preferably 50.0 to 60.0 parts by weight) of mannitol (preferably D-mannitol) as an excipient, and 20.0 to 40.0 parts by weight of excipient ( Preferably, 20.0-30.0 parts by weight of crystalline cellulose, and 3.0-10.0 parts by weight (preferably 4.0-7.0 parts by weight) of water-soluble polymer as a coating agent (preferably polyvinyl alcohol polyethylene glycol graft copolymer,
  • 0.3 to 5.0 parts by weight preferably 0.5 to 5.0 parts by weight, more preferably 0.5 to 2.0 parts by weight, further preferably 100 parts by weight of the pharmaceutical composition.
  • 0.5 to 1.5 parts by weight of (4- ⁇ (3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl) acetic acid (Compound A) or The pharmacologically acceptable salt thereof, 50.0 to 70.0 parts by weight (preferably 50.0 to 60.0 parts by weight) of mannitol (preferably D-mannitol) as an excipient, and 20.0 to 40.0 parts by weight of excipient ( Preferably, 20.0 to 30.0 parts by weight of crystalline cellulose, 0.5 to 5.0 parts by weight (preferably 1.0 to 2.0 parts by weight) of a water-soluble polymer (preferably polyvinyl alcohol polyethylene glycol) as a coating agent (first coating film
  • the pharmaceutical composition of the present invention is used, for example, as a prophylactic or therapeutic agent for hypercalcemia in hyperparathyroidism, parathyroid cancer or primary hyperparathyroidism that is inoperable or relapsed after parathyroidectomy.
  • it can be used as a preventive or therapeutic agent for hyperparathyroidism (more preferably, secondary hyperparathyroidism).
  • the pharmaceutical composition of the present invention may be either an oral preparation or a parenteral preparation, and is preferably an oral preparation, and a colorant, a corrigent and the like can be further added to the oral preparation.
  • the shape of the pharmaceutical composition of the present invention is not particularly limited, but is preferably a solid preparation, more preferably a tablet, powder, fine granule, granule, capsule or dry syrup, and a tablet. More preferably.
  • the method for producing the pharmaceutical composition of the present invention is not particularly limited.
  • the pharmaceutical composition can be produced by a method generally used in the technical field of pharmaceutics such as compression molding. (By screw extrusion granulator, roll extrusion granulator, etc.), rolling granulation method (by rotary drum granulator, centrifugal rolling granulator, etc.), fluidized bed granulation method (fluidized bed It can be produced by wet granulation using a granulator, a rolling fluidized bed granulator, etc.), a stirring granulation method (by a stirring granulator, etc.), etc.
  • compound A or a pharmacologically acceptable salt thereof and an additive are mixed, and the resulting mixture is granulated by adding a solvent or a binder solution, and the resulting granulated product is obtained.
  • the method be dried.
  • the solvent to be used include water, ethanol, isopropyl alcohol, and a mixed solvent thereof.
  • the binder solution include water, ethanol, isopropyl alcohol, and a mixture of these in a mixed solvent. Among them, an aqueous solution of a binder is optimal.
  • the resulting dried granulated product may be formed into a tablet using a compression tableting machine.
  • the tableting pressure can be appropriately selected from the range of 300 to 3000 kg / cm 2 , for example.
  • the tablet size is not particularly limited, but for example, those having a weight per tablet of 20 to 3000 mg and a tablet diameter of 5 to 15 mm are preferable.
  • the obtained tablet (plain tablet) is coated with a solution / dispersion in which the coating composition is dissolved / dispersed to form a coating.
  • the solvent for dissolving / dispersing the coating composition include water, ethanol, isopropyl alcohol, a mixed solvent thereof, and the like, among which water is preferable.
  • the coating is performed using, for example, a conventional bread type coating machine, a full-time coating machine, a fluidized bed type coating apparatus, a rolling fluidized type coating apparatus or the like.
  • the blister package of the present invention is manufactured using a pharmaceutical composition containing the compound A and the like, a film laminated with a polymer, and an aluminum foil.
  • the film laminated with the polymer is not particularly limited as long as it is generally used for blister packaging, but is a film laminated with a polymer such as polypropylene, polyvinyl chloride, polyvinylidene chloride, or trifluoroethylene chloride. Etc. are preferred.
  • the aluminum foil is not particularly limited as long as it is used in blister packaging, and may be a general-purpose aluminum foil, but is preferably an aluminum foil with a reduced amount of melamine resin in the adhesive. .
  • the production method of the blister package of the present invention is not particularly limited, but a pocket is formed in a film laminated with the polymer using a generally used blister packaging machine, a tablet is introduced, and aluminum It is obtained by sealing the foil with heat or the like.
  • the pharmaceutical packaged product of the present invention is obtained by enclosing the blister packaged product in a package.
  • the package is not particularly limited as long as it is generally used for pharmaceutical packages, but an aluminum bag or the like is preferable.
  • a product enclosed in a general pharmaceutical package may be enclosed at the same time, and it is preferable to enclose an oxygen scavenger and / or a desiccant simultaneously with the blister package.
  • the pharmaceutical packaged product of the present invention can be produced by enclosing the blister packaged product produced as described above in a package such as an aluminum bag and sealing it using a heat sealer or the like.
  • a method of treatment or prophylaxis comprising administering to a subject, preferably a subject in need thereof, a composition comprising a pharmaceutically acceptable salt and an excipient.
  • This method of treatment or prevention is preferably a method of treatment or prevention of hyperparathyroidism.
  • the excipient contained in the above composition may be the same as the excipient contained in the above pharmaceutical composition of the present invention, and further, similarly to the pharmaceutical composition of the present invention, a binder, One or more additives selected from basic additives, disintegrants, lubricants, colorants and brighteners may be further included.
  • the composition can be used for hypercalcemia in primary hyperparathyroidism in which parathyroid cancer or parathyroidectomy is impossible or relapsed after surgery, similar to the pharmaceutical composition of the present invention described above. it can.
  • (4- ⁇ (3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl) acetic acid or pharmacology thereof (4- ⁇ (3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidine-1 characterized by including an excipient in a chemically acceptable salt
  • a method for stabilizing -yl ⁇ phenyl) acetic acid or a pharmaceutically acceptable salt thereof is provided.
  • stabilization means (4- ⁇ (3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidin-1-yl ⁇ phenyl) acetic acid or its pharmacologically. This means that even when an acceptable salt is stored for a long time (for example, stored at 60 ° C. for 1 month), the production of a related substance is suppressed more than when no excipient is contained. .
  • one or more additives selected from a binder, a basic additive, a disintegrant, a lubricant, a colorant, and a brightener are added. It may be further stabilized by an object or the like.
  • Example 1-1 Preparation of Tablet Using Mannitol as Excipient Compound A 45.0 g, D-mannitol (JP, hereinafter the same) 3757.5 g, crystalline cellulose (Theolas PH301 (registered trademark), Asahi Kasei Chemicals, same hereinafter) 1462.5 g and croscarmellose sodium (Ac-Di-Sol, FMC, hereinafter the same) 292.5 g are mixed in a fluidized bed granulator (FLO-5, Freund Sangyo) and mixed with an 8% by weight hydroxypropylcellulose aqueous solution (HPC -L, Nippon Soda, the same applies hereinafter) 2094 g was sprayed and granulated, and dried to obtain granulated granules.
  • FLO-5 fluidized bed granulator
  • HPC -L 8% by weight hydroxypropylcellulose aqueous solution
  • the obtained granulated granules were sieved with a granulator (Comil QC-197S, Powrec) to obtain granulated granules.
  • the obtained granulated granules (5450 g) and magnesium stearate (111.2 g) were mixed to obtain tablets for tableting.
  • An uncoated tablet was obtained by tableting the obtained granules for tableting using a tableting machine (collect 12, manufactured by Kikusui Seisakusho).
  • Coating mixture 1 [hypromellose (substitution degree type 2910, viscosity 3 mPas in 100 g) (Japan) 52.0 g, titanium oxide (Japan) 23.25 g, macrogol 6000 (Japan) 14.0 g, lactose hydrate (Japan Bureau) 10.0 g, yellow iron sesquioxide (medicinal regulations) 0.5 g, and iron sesquioxide (medicinal regulations 0.25 g included) were dispersed in purified water to prepare a coating solution having a solid content concentration of 10% by weight.
  • the target tablets are coated by coating so that the coating is 5 parts by weight with respect to 100 parts by weight of the uncoated tablets. Obtained.
  • Example 1-2 Preparation of Tablet Using Lactose as Excipient Compound A 10.0 g, lactose hydrate (JP, hereinafter the same) 1043.0 g, and low-substituted hydroxypropylcellulose (L-HPC, Shin-Etsu Chemical) The same applies hereinafter) 195.0 g was mixed in a fluid bed granulator (MP-01, Paulek), sprayed with 487.5 g of HPC-L aqueous solution, granulated and dried to obtain granulated granules. The obtained granulated granule was sieved with a sieve having an aperture of 710 ⁇ m to obtain a granulated granule.
  • MP-01 fluid bed granulator
  • the obtained granulated granules (1089 g) and magnesium stearate (11 g, Parteck LUB MST, Merck, hereinafter the same) were mixed to obtain granules for tableting.
  • the tableting machine Cold 12, manufactured by Kikusui Seisakusho
  • the resulting granules for tableting are tableted to obtain a plain tablet (mass: 130 mg, tablet shape: circular shape (7 mm diameter), Same).
  • the coating mixture 1 (having the same composition as above) was dispersed in purified water to prepare a coating solution having a solid content concentration of 10% by weight.
  • Test example 1 The tablets obtained in Example 1-1 and Example 1-2 are placed in a glass bottle (open) and stored for 1 month at 60 ° C., and related substances under the following measurement conditions (measurement condition 1). The production amount of was evaluated. The results are shown in Table 3. At an RRT (relative retention time) of 0.45, the production of the related substance was not observed in the preparation obtained in Example 1-1, and the production of the related substance was also slight in the preparation obtained in Example 1-2. From these results, it can be understood that good storage stability can be obtained with any excipient of D-mannitol and lactose hydrate.
  • RRT relative retention time
  • Example 2-1 Preparation of Tablet Added with Crystalline Cellulose and Packaged Aluminum Bag thereof Compound A 3.8 g, D-mannitol 646.2 g, Crystalline cellulose (MCC, Theolas PH301 (registered trademark), Asahi Kasei Chemical, the same shall apply hereinafter) 250.0 g And 30.0 g of croscarmellose sodium are mixed in a fluid bed granulator (MP-01, Paulek), sprayed with 375.0 g of 8% by weight hydroxypropylcellulose aqueous solution, dried, and granulated granules are dried. Obtained. Using the granulated granules obtained, tablets were obtained by the same method as in Example 1-1.
  • Example 2-2 Preparation of tablets to which crystalline cellulose was added and aluminum bag packaged products Tablets were prepared in the same manner as in Example 2-1. Further, the obtained tablets were obtained in the same manner as in Example 2-1, using a polypropylene sheet and a general-purpose aluminum foil (UACJ) to obtain a target aluminum bag packaged product.
  • UACJ general-purpose aluminum foil
  • Example 3-1 Preparation of Tablets with Addition of Crystalline Cellulose and Its Aluminum Bag Package
  • Example 2-1 Using Compound A 3.8 g, D-mannitol 746.2 g, Crystalline cellulose 150.0 g and Croscarmellose sodium 50.0 g Tablets were prepared in the same manner as described above.
  • the target aluminum bag packaged product was obtained from the obtained tablets by the same method as in Example 2-2.
  • Example 3-2 Preparation of Tablet without Crystalline Cellulose and Its Aluminum Bag Package Using compound A 3.8 g, D-mannitol 896.2 g and croscarmellose sodium 50.0 g, in the same manner as in Example 2-1, Tablets were prepared.
  • the target aluminum bag packaged product was obtained from the obtained tablets by the same method as in Example 2-2.
  • Table 4 below shows the composition of each component in the tablets obtained in Examples 2-1, 2-2, 3-1, and 3-2.
  • Test example 2 About the aluminum bag packaged product obtained in Example 2-1 and Example 2-2, it was stored for 1 month at 60 ° C., and the amount of the related substances in tablets was evaluated under the same conditions as in Test Example 1. . The results are shown in Table 5. In the tablets in the aluminum bag packages obtained in Example 2-1 and Example 2-2, the amount of individual related substances produced and the total amount of related substances produced were suppressed. The tablets in the aluminum bag packaged product obtained in Example 2-1 (using aluminum foil with a reduced amount of melamine resin in the adhesive) have a relative retention time compared to that in Example 2-2. The production amount of related substances having (RRT) 1.28 and the total production quantity of related substances were further suppressed.
  • Test example 3 About the aluminum bag packaged products obtained in Example 2-1, Example 3-1 and Example 3-2, stored for 1 month at 60 ° C., and related substances of tablets under measurement conditions 2 shown below. The amount produced was evaluated. The results are shown in Table 6. As for the tablets in the aluminum bag packages obtained in Example 2-1, Example 3-1 and Example 3-2, the amount of individual related substances produced and the total amount of related substances produced are suppressed. It was. Further, the tablets in the aluminum bag packages obtained in Example 2-1 and Example 3-1 were more suppressed in the amount of related substances produced than that obtained in Example 3-2. . Further, Example 2-1 in which the amount of crystalline cellulose added was large was more remarkable in the effect of inhibiting the formation of related substances.
  • Example 4-1 Preparation of Tablet with Addition of Calcium Carbonate Compound A 7.69 g, D-mannitol 1272.3 g, crystalline cellulose 500.0 g, croscarmellose sodium 100.0 g and calcium carbonate (JP, Nitto Flour Industries, the same applies hereinafter) 20.0 g was put in a fluidized bed granulator (FLO-2, Freund Sangyo), mixed, sprayed with 750.0 g of 8 wt% hydroxypropylcellulose aqueous solution, granulated and dried to obtain granulated granules.
  • FLO-2 fluidized bed granulator
  • the obtained granulated granules were pulverized with a granulator (Comil QC-197S, Powrec) to obtain granulated granules.
  • the obtained granulated granules (980.0 g) and magnesium stearate (20.0 g) were mixed to obtain tablets for tableting.
  • the tablet for tableting obtained was tableted using a tableting machine to obtain the intended tablet (mass: 130 mg, tablet shape: circular shape (7 mm diameter)).
  • Example 4-2 Preparation of tablets without calcium carbonate Compound A 7.69 g, D-mannitol 1292.3 g, crystalline cellulose 500.0 g and croscarmellose sodium 100.0 g were placed in a fluid bed granulator (FLO-2, Freund Industries). The mixture was mixed and sprayed with 750.0 g of an 8 wt% hydroxypropylcellulose aqueous solution, and dried to obtain granulated granules. Using the resulting granulated granules, the target tablets (mass: 130 mg, tablet shape: circular shape (7 mm diameter)) were obtained in the same manner as in Example 4-1.
  • FLO-2 fluid bed granulator
  • Example 5-1 Preparation of tablets with added calcium carbonate Compound A 7.69 g, D-mannitol 1252.3 g, crystalline cellulose 500.0 g, croscarmellose sodium 100.0 g and calcium carbonate 40.0 g were mixed in a fluid bed granulator (FLO-2). , Freund Sangyo Co., Ltd.), mixed and sprayed with 750.0 g of 8% by weight hydroxypropylcellulose aqueous solution to granulate, and dried to obtain granulated granules. Using the resulting granulated granules, the target tablets (mass: 130 mg, tablet shape: circular shape (7 mm diameter)) were obtained in the same manner as in Example 4-1.
  • FLO-2 fluid bed granulator
  • Table 7 below shows the composition of each component in the tablets obtained in Example 4-1, Example 4-2, and Example 5-1.
  • Test example 4 About the tablet obtained in Example 4-1, Example 4-2, and Example 5-1, it puts into a glass bottle (open
  • Example 5-2 Preparation of uncoated tablet
  • the target uncoated tablet mass: 130 mg, tablet shape: circular (7 mm diameter), the same shall apply hereinafter
  • Example 6 Preparation of Tablet with Coating
  • the coating mixture 1 was dispersed in purified water to prepare a coating solution having a solid concentration of 10% by weight.
  • a tablet coating machine DRC-200, POWREC
  • coating is performed so that the coated skin is 4 parts by weight with respect to 100 parts by weight of uncoated tablets.
  • the target tablet was obtained by performing.
  • Example 7 Preparation of coated tablet
  • the coating mixture 1 was dispersed in purified water to prepare a coating solution having a solid content of 10% by weight.
  • a tablet coating machine DRC-200, POWREC
  • coating is performed so that the coating is 6 parts by weight in a dry state with respect to 100 parts by weight of the uncoated tablet.
  • the target tablet was obtained by performing.
  • Example 8 Preparation of coated tablet
  • the coating mixture 1 was dispersed in purified water to prepare a coating solution having a solid content of 10% by weight.
  • a tablet coating machine DRC-200, POWREC
  • coating is performed so that the coated skin is 8 parts by weight with respect to 100 parts by weight of uncoated tablets.
  • the target tablet was obtained by performing. Table 9 below shows the composition of each component in the tablets obtained in Examples 6 to 8 and Example 5-2.
  • Test Example 5 Obtained in Examples 6 to 8 and Example 5-2, respectively, according to the guidelines for photostability testing of new drug substances and new drugs (November 6, 1996) at the International Conference on Harmonization of EU Tripolar Drug Approval Review (ICH)
  • the obtained tablets were subjected to a stability test under the following conditions. After exposure, the production amount of related substances (RRT (relative retention time) 0.52 and total amount) was evaluated under the measurement condition 1. The results are shown in Table 10.
  • RRT relative retention time
  • Example 5-2 the amount of individual related substances produced and the total amount of related substances produced were suppressed.
  • the tablets of Examples 6 to 8 subjected to the coating treatment produced related substances (RRT (relative retention time) 0.52 and total amount) after exposure. Was more suppressed.
  • Light source Xenon lamp Illuminance: 30,000 lx Exposure time: 40 hours (total illumination 120,000 lxh)
  • Example 9-1 Preparation of aluminum bag package without encapsulating oxygen scavenger and desiccant Compound A 63.1 g, D-mannitol 10432.9 g, crystalline cellulose 4100.0 g, croscarmellose sodium 820.0 g and calcium carbonate 492.0 g
  • the mixture was placed in a fluid bed granulator (FLO-15, Freund Sangyo), mixed, sprayed with 6150.0 g of 8 wt% hydroxypropylcellulose aqueous solution, dried, and granulated granules were obtained.
  • the obtained granulated granule was crushed with a granulator to obtain a granulated granule.
  • the obtained granulated granules (8000.0 g) and magnesium stearate (163.3 g) were mixed with a mixer (TBM-60, Deoksugaku Kogyo, the same shall apply hereinafter) to obtain granules for tableting.
  • An uncoated tablet was obtained by tableting the obtained granules for tableting using a tableting machine (AQUARIUS, manufactured by Kikusui Seisakusho).
  • Coating mixture 2 in 100 g, hypromellose (substitution degree type 2910, viscosity 3 mPa ⁇ s) (JP) 52.0 g, titanium oxide (JP) 20.0 g, Macrogol 6000 (JP) 14.0 g, lactose hydration (Including 10.0 g of JP (Japanese Pharmacopoeia) and 4.0 g of yellow ferric oxide (medicine regulations)) was dispersed in purified water to prepare a coating solution having a solid content of 10% by weight.
  • a tablet coating machine (DRC-500, Powrec) on 3500.0 g of uncoated tablets, 100 tablets by weight of uncoated tablets were coated such that the coating was 5 parts by weight in a dry state to obtain tablets.
  • the obtained tablets are stored for 5 days under the storage conditions of 25 ° C / 60% RH, and then used with a polypropylene sheet (TAS-2230V, Taisei Kako) and aluminum foil (UACJ) with a reduced amount of melamine resin in the adhesive.
  • a blister package was obtained using a PTP packaging machine (No.855PX type, Iwaguro Seisakusho).
  • the obtained blister packaged product was put into an aluminum bag (Houso Hosokawa, the same applies hereinafter) and sealed with a heat sealer (Quick Sealer, Shiga Packaging Machine, the same applies hereinafter) to obtain the intended aluminum bag packaged product.
  • Example 9-2 Aluminum bag package with oxygen scavenger enclosed A blister package was obtained in the same manner as in Example 9-1. Blister package 10 sheets and oxygen scavenger (Pharmakeep KC-20, Mitsubishi Gas Chemical) were put in an aluminum bag (Hosokawa Yoko) and sealed with a heat seal machine to obtain the target aluminum bag package.
  • Example 10 Preparation of Aluminum Bag Package Encapsulated with Desiccant
  • a blister package was obtained in the same manner as in Example 9-1.
  • Blister packaged product 10 sheets and desiccant (MS Serum W 3G, Tokai Chemical Industry) are put in an aluminum bag (Hosokawa Yoko) and sealed with a heat seal machine (Quick Sealer, Shiga Packing Machine, the same applies below).
  • An aluminum bag package was obtained.
  • Table 11 below shows the composition of each component in the tablets obtained in Example 9-1, Example 9-2 and Example 10.
  • Test Example 6 For the aluminum bag packaged products obtained in Example 9-1, Example 9-2 and Example 10, stored for 1 month at 60 ° C., and related substances of tablets under the same conditions as in Test Example 1 above. The amount produced was evaluated. The results are shown in Table 12. In all of the tablets obtained in Example 9-1, Example 9-2 and Example 10, the amount of individual related substances produced and the total amount of related substances produced were suppressed. In addition, the tablets in the aluminum bag packages obtained in Example 9-2 and Example 10 were more suppressed in the total amount of related substances after storage than that in Example 9-1. In particular, the effect was remarkable in Example 9-2.
  • Example 11-1 Preparation of Uncoated Tablet with Polyvinyl Alcohol-Polyethylene Glycol Graft Copolymer Compound A 38.5 g, D-mannitol 6161.5 g, crystalline cellulose 1250.0 g, croscarmellose sodium 250.0 g and calcium carbonate 50.0 g was mixed in a fluidized bed granulator (FLO-15, Freund Sangyo), sprayed with 1875.0 g of 8% by weight hydroxypropylcellulose aqueous solution and dried to obtain granulated granules. The obtained granulated granules were pulverized with a granulator (Comil QC-197S, Powrec) to obtain granulated granules.
  • FLO-15 fluidized bed granulator
  • a granulator Comil QC-197S, Powrec
  • the obtained granulated granules (4410.0 g) and magnesium stearate (90.0 g) were mixed with a mixer (TBM-25, Deoksugaku Kogyo) to obtain granules for tableting.
  • An uncoated tablet was obtained by tableting the obtained granules for tableting using a tableting machine (AQUARIUS, manufactured by Kikusui Seisakusho).
  • the coating mixture 2 was dispersed in purified water to prepare a coating solution having a solid concentration of 10% by weight.
  • a tablet coating machine (DRC-500, Powrec) on 3500.0 g of uncoated tablets 100 tablets by weight of uncoated tablets were coated such that the coating was 8 parts by weight in a dry state to obtain tablets.
  • Example 11-2 Preparation of Tablet Coated with Polyvinyl Alcohol / Polyethylene Glycol / Graft Copolymer
  • An uncoated tablet was obtained in the same manner as in Example 11-1.
  • Polyvinyl alcohol / polyethylene glycol / graft copolymer (Kollicoat IR (registered trademark), BASF) was dissolved in purified water to prepare a coating solution 1 having a solid content concentration of 5% by weight. Further, the coating mixture 2 was dispersed in purified water to prepare a coating liquid 2 having a solid concentration of 10% by weight.
  • the coating solution 1 is applied so that the coating is 2 parts by weight in a dry state with respect to 100 parts by weight of the uncoated tablets.
  • the coating liquid 2 was sprayed to 100 parts by weight so that the coating amount was 5 parts by weight in a dry state, and coating was performed to obtain tablets.
  • Table 13 below shows the composition of each component in the tablets obtained in Example 11-1 and Example 11-2.
  • Test Example 7 About the tablets obtained in Example 11-1 and Example 11-2, put them in a plastic petri dish (open) and store them at 25 ° C./60% RH for 2 weeks and 1 month. The amount of production of related substances was evaluated. The results are shown in Table 14. In the tablets obtained in Example 11-1 and Example 11-2, the amount of individual related substances produced and the total amount of related substances produced were suppressed. In addition, compared with the tablet obtained in Example 11-1, the tablet obtained in Example 11-2 is more suppressed in the generation of related substances (RRT (relative retention time) 0.52 and total amount) after storage. It was done.
  • RRT relative retention time
  • Example 12-1 Preparation of tablets containing no basic additives Compound A 22.5 g, D-mannitol 3780.0 g, crystalline cellulose 1462.5 g and croscarmellose sodium 292.5 g were fluidized bed granulator (FLO-5, Freund Industries) ) And mixed, and thereafter, coated tablets were obtained in the same manner as in Example 1-1.
  • Compound A 22.5 g, D-mannitol 3780.0 g, crystalline cellulose 1462.5 g and croscarmellose sodium 292.5 g were fluidized bed granulator (FLO-5, Freund Industries) ) And mixed, and thereafter, coated tablets were obtained in the same manner as in Example 1-1.
  • Example 12-2 Preparation of Tablet with Addition of Calcium Silicate Compound A 3.8 g, D-mannitol 646.2 g, crystalline cellulose 250.0 g and croscarmellose sodium 50.0 g were added to a fluid bed granulator (MP-01, Paulek). Then, 375.0 g of HPC-L aqueous solution was sprayed and granulated, and dried to obtain granulated granules. The obtained granulated granules were sieved with a granulator (Comil QC-197S, Powrec) to obtain granulated granules.
  • a granulator Comil QC-197S, Powrec
  • Example 12-3 Preparation of Tablet with Addition of Calcium Silicate Mix the granulated granules (380.3 g) obtained in Example 12-2, calcium silicate (11.9 g) and magnesium stearate (7.8 g), Granules for tableting were obtained. Using the tableting machine (Collect 12, manufactured by Kikusui Seisakusho), the desired tablet (mass: 134 mg, tablet shape: circular shape (7 mm diameter)) is obtained by tableting the obtained granules for tableting. )
  • Example 12-4 Preparation of Tablet with Addition of Magnesium Aluminometasilicate Compound A (5.0 g), D-mannitol (840.0 g), crystalline cellulose (325.0 g) and croscarmellose sodium (65.0 g) were mixed in a fluid bed granulator (MP-01, Paulek) ), And granulated by spraying 487.5 g of an aqueous HPC-L solution. After drying, granulated granules were obtained. The obtained granulated granules were sieved with a granulator (Comil QC-197S, Powrec) to obtain granulated granules.
  • a granulator Comil QC-197S, Powrec
  • Table 15 below shows the composition of each component in the tablets obtained in Example 12-1, Example 12-2, Example 12-3 and Example 12-4.
  • Test Example 8 The tablets obtained in Example 12-1, Example 12-2, Example 12-3 and Example 12-4 are placed in a brown glass bottle (open) and stored for 1 month at 40 ° C / 75% RH. Then, the production amount of the related substance was evaluated under the measurement condition 1. The results are shown in Table 16. In the tablets obtained in Example 12-1, Example 12-2, Example 12-3 and Example 12-4, the production amount of each related substance and the total production amount of related substances are suppressed. It was. In addition, compared with the tablets obtained in Example 12-1, the tablets obtained in Example 12-2, Example 12-3 and Example 12-4 were similar substances after storage (RRT (relative Production of retention time) 0.52 and total amount) was further suppressed.
  • RRT Relative Production of retention time
  • Example 13-1 Manufacture of tablets containing croscarmellose sodium as disintegrant Fluidized bed granulation of Compound A 7.69 g, D-mannitol 1252.3 g, crystalline cellulose 500.0 g, croscarmellose sodium 100.0 g and calcium carbonate 40.0 g The mixture was placed in a machine (FLO-2, Freund Sangyo), and thereafter granules for tableting were obtained in the same manner as in Example 4-1. The tablet for tableting obtained was tableted using a tableting machine to obtain the intended tablet (mass: 130 mg, tablet shape: circular shape (7 mm diameter)).
  • Example 13-2 Manufacture of tablets containing low-substituted hydroxypropylcellulose as a disintegrant Compound A 7.69 g, D-mannitol 1152.3 g, crystalline cellulose 500.0 g, low-substituted hydroxypropylcellulose 200.0 g and calcium carbonate 40.0 g Put into a fluidized bed granulator (FLO-2, Freund Sangyo), mix, and then tablet (mass: 130 mg, tablet shape: circular shape (7 mm diameter)) in the same manner as in Example 13-1.
  • FLO-2 fluidized bed granulator
  • Table 17 below shows the composition of each component in the tablets obtained in Example 13-1 and Example 13-2.
  • Test Example 9 The tablets obtained in Example 13-1 and Example 13-2 are placed in a brown glass bottle (open) and stored for one month at 40 ° C./75% RH. The amount produced was evaluated. The results are shown in Table 18. In the tablets obtained in Example 13-1 and Example 13-2, the amount of individual related substances produced and the total amount of related substances produced were suppressed. In addition, compared with the tablet obtained in Example 13-1, the tablet obtained in Example 13-2 is more suppressed in the generation of related substances (RRT (relative retention time) 0.52 and total amount) after storage. It was done.
  • RRT relative retention time

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Abstract

L'invention concerne une composition pharmaceutique ou analogue comprenant de l'acide (4-{(3S)-3-[(1R)-1-(naphthalène-1-yl)éthylamino] pyrrolidine-1-yl}phényl)acétique (composé A) ou un sel pharmacologiquement acceptable de celui-ci et des excipients.
PCT/JP2016/080013 2015-10-07 2016-10-07 Composition pharmaceutique contenant un composé d'arylalkylamine Ceased WO2017061621A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US15/766,426 US10350194B2 (en) 2015-10-07 2016-10-07 Pharmaceutical composition containing an arylalkylamine compound
EP16853772.8A EP3360551A4 (fr) 2015-10-07 2016-10-07 Composition pharmaceutique contenant un composé d'arylalkylamine
KR1020197019836A KR102488488B1 (ko) 2015-10-07 2016-10-07 아릴알킬아민 화합물 함유 의약 조성물
KR1020187012497A KR102000897B1 (ko) 2015-10-07 2016-10-07 아릴알킬아민 화합물 함유 의약 조성물
CN201680058580.7A CN108135883B (zh) 2015-10-07 2016-10-07 含有芳基烷基胺化合物的药物组合物

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WO2018174283A1 (fr) * 2017-03-24 2018-09-27 協和発酵キリン株式会社 Dérivé de polyéthylène glycol
JP2022504943A (ja) * 2018-10-18 2022-01-13 ユハン コーポレーション アミノピリミジン誘導体又はその塩を含む経口投与用医薬組成物

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Publication number Priority date Publication date Assignee Title
WO2018174283A1 (fr) * 2017-03-24 2018-09-27 協和発酵キリン株式会社 Dérivé de polyéthylène glycol
JP2022504943A (ja) * 2018-10-18 2022-01-13 ユハン コーポレーション アミノピリミジン誘導体又はその塩を含む経口投与用医薬組成物
JP7369769B2 (ja) 2018-10-18 2023-10-26 ユハン コーポレーション アミノピリミジン誘導体又はその塩を含む経口投与用医薬組成物
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