WO2017061621A1 - Pharmaceutical composition containing aryl alkyl amine compound - Google Patents
Pharmaceutical composition containing aryl alkyl amine compound Download PDFInfo
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- 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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- 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
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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
Description
(1)(4-{(3S)-3-[(1R)-1-(ナフタレン-1-イル)エチルアミノ]ピロリジン-1-イル}フェニル)酢酸(化合物A)またはその薬理学的に許容される塩および賦形剤を含む、医薬組成物。
(2)賦形剤が、糖、糖アルコール、セルロース誘導体、デンプン誘導体および無機塩から選ばれる1種以上の物質である、前記(1)に記載の医薬組成物。
(3)賦形剤が、乳糖、白糖、マルトース、スクロース、マンニトール、ソルビトール、エリスリトール、マルチトール、キシリトール、グルコース、結晶セルロース、コーンスターチ、ポテトスターチ、リン酸一水素カルシウム、リン酸二水素カルシウム、リン酸二水素ナトリウムおよびリン酸カルシウムから選ばれる1種以上の物質である、前記(1)または(2)に記載の医薬組成物。
(4)医薬組成物100重量部に対し、賦形剤を0.1重量部~99.9重量部含む、前記(1)~(3)のいずれか1項に記載の医薬組成物。
(5)医薬組成物が、結合剤、塩基性添加剤、崩壊剤、滑沢剤、着色剤および光沢化剤から選ばれる1種以上の添加物をさらに含む、前記(1)~(4)のいずれか1項に記載の医薬組成物。
(6)結合剤が、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、カルボキシメチルセルロース、カルボキシメチルエチルセルロース、ヒドロキシプロピルスターチ、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、カルボキシビニルポリマー、ポリビニルピロリドン、ポリビニルアルコール、メタアクリル酸コポリマー、マクロゴール、デンプン、ゼラチン、デキストリン、プルラン、カンテンおよびアラビアゴムから選ばれる1種以上の物質である、前記(5)に記載の医薬組成物。
(7)塩基性添加剤が、塩基性酸化物、塩基性水酸化物、炭酸塩、炭酸水素塩、ケイ酸塩およびメタケイ酸アルミン酸塩から選ばれる1種以上の物質である、前記(5)に記載の医薬組成物。
(8)塩基性添加剤が、酸化マグネシウム、水酸化マグネシウム、水酸化アルミニウム、炭酸ナトリウム、炭酸カリウム、炭酸マグネシウム、炭酸カルシウム、炭酸水素ナトリウム、ケイ酸カルシウムおよびメタケイ酸アルミン酸マグネシウムから選ばれる1種以上の物質である、前記(7)に記載の医薬組成物。
(9)崩壊剤が、クロスカルメロースナトリウム、クロスポビドン、カルボキシメチルスターチナトリウム、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、部分α化デンプンおよびデンプンから選ばれる1種以上の物質である、前記(5)に記載の医薬組成物。
(10)滑沢剤が、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、モノステアリン酸グリセリン、軽質無水ケイ酸、フマル酸ステアリルナトリウムおよびショ糖脂肪酸エステル類から選ばれる1種以上の物質である、前記(5)に記載の医薬組成物。
(11)着色剤が、黄色三二酸化鉄、酸化チタン、タルク、三二酸化鉄、黒酸化鉄、銅クロロフィル、銅クロロフィリンナトリウム、カーボンブラック、薬用炭、食用色素、カンゾウエキス、緑茶末、リボフラビン、酪酸リボフラビン、リン酸リボフラビンナトリウムおよびミリスチン酸オクチルドデシルから選ばれる1種以上の物質である、前記(5)に記載の医薬組成物。
(12)光沢化剤が、カルナウバロウ、シェラック、ミツロウ、硬化油およびステアリン酸マグネシウムから選ばれる1種以上の物質である、(5)に記載の医薬組成物。
(13)医薬組成物100重量部に対し、添加物を0.1重量部~99.9重量部含む、前記(1)~(12)のいずれか1項に記載の医薬組成物。
(14)医薬組成物が、コーティング被膜を有する、前記(1)~(13)のいずれか1項に記載の医薬組成物。
(15)コーティング被膜が、水溶性ポリマー、乳糖、白糖、酸化チタンおよびタルクから選ばれる1種以上のコーティング剤を含む、前記(14)に記載の医薬組成物。
(16)水溶性ポリマーが、ポリビニルアルコールポリエチレングリコールグラフトコポリマー、ポリビニルピロリドン、ヒプロメロース、ヒドロキシプロピルセルロース、ポリビニルアルコール、ポリビニルアルコールアクリル酸メタクリル酸メチル共重合体およびポリエチレングリコールから選ばれる1種以上のポリマーである、前記(15)に記載の医薬組成物。
(17)コーティング被膜100重量部に対し、コーティング剤を0.1重量部~100重量部含む、前記(14)~(16)のいずれか1項に記載の医薬組成物。
(18)ポリビニルアルコールポリエチレングリコールグラフトコポリマーを含有する第一のコーティング被膜と、水溶性ポリマー、乳糖、白糖、酸化チタンおよびタルクから選ばれる1種以上のコーティング剤を含有する第ニのコーティング被膜を有する前記(14)~(17)のいずれか1項に記載の医薬組成物。
(19)第ニのコーティング被膜が水溶性ポリマー、乳糖、および酸化チタンから選ばれる1種以上のコーティング剤を含有する前記(18)に記載の医薬組成物
(20)第ニのコーティング被膜が着色剤を含有する前記(19)に記載の医薬組成物。
(21)医薬組成物100重量部に対し、
0.5~5.0重量部の(4-{(3S)-3-[(1R)-1-(ナフタレン-1-イル)エチルアミノ]ピロリジン-1-イル}フェニル)酢酸(化合物A)またはその薬理学的に許容される塩、
50.0~90.0重量部の賦形剤、
1.0~5.0重量部の結合剤、
0.5~5.0重量部の塩基性添加剤、
2.0~10.0重量部の崩壊剤、
0.5~3.0重量部の滑沢剤、
3.0~10.0重量部のコーティング剤、および
0.1~1.0重量部の着色剤を含有する医薬組成物。
(22)医薬組成物100重量部に対し、
0.5~2.0重量部の(4-{(3S)-3-[(1R)-1-(ナフタレン-1-イル)エチルアミノ]ピロリジン-1-イル}フェニル)酢酸(化合物A)またはその薬理学的に許容される塩、
70.0~90.0重量部の賦形剤、
1.0~3.0重量部の結合剤、
0.5~2.0重量部の塩基性添加剤、
2.0~5.0重量部の崩壊剤、
0.5~2.0重量部の滑沢剤、
5.0~10.0重量部のコーティング剤、および
0.1~1.0重量部の着色剤を含有する医薬組成物。
(23)さらに医薬組成物100重量部に対して0.01~1重量部の光沢化剤を含有する前記(21)または(22)に記載の医薬組成物。
(24)賦形剤がマンニトールおよび/または結晶セルロースであり、結合剤がヒドロキシプロピルセルロースであり、塩基性添加剤が炭酸カルシウムであり、崩壊剤がクロスカルメロースナトリウムであり、滑沢剤がステアリン酸マグネシウムであり、コーティング剤が水溶性ポリマー、乳糖および酸化チタンから選ばれる1種以上のコーティング剤であり、着色剤が黄色三ニ酸化鉄である、前記(21)~(23)のいずれか1項に記載の医薬組成物。
(25)水溶性ポリマーがポリビニルアルコールポリエチレングリコールグラフトコポリマー、ヒプロメロースおよびポリエチレングリコールから選ばれる1種以上の水溶性ポリマーである前記(24)に記載の医薬組成物。
(26)(4-{(3S)-3-[(1R)-1-(ナフタレン-1-イル)エチルアミノ]ピロリジン-1-イル}フェニル)酢酸(化合物A)またはその薬理学的に許容される塩のメジアン径(D90)が75μm以下である、前記(1)~(25)のいずれか1項に記載の医薬組成物。
(27)(4-{(3S)-3-[(1R)-1-(ナフタレン-1-イル)エチルアミノ]ピロリジン-1-イル}フェニル)酢酸(化合物A)またはその薬理学的に許容される塩のメジアン径(D90)が50μm以下である、前記(1)~(25)のいずれか1項に記載の医薬組成物。
(28)(4-{(3S)-3-[(1R)-1-(ナフタレン-1-イル)エチルアミノ]ピロリジン-1-イル}フェニル)酢酸(化合物A)またはその薬理学的に許容される塩のメジアン径(D90)が35μm以下である、前記(1)~(25)のいずれか1項に記載の医薬組成物。
(29)医薬組成物が、副甲状腺機能亢進症の予防用組成物または治療用組成物である、前記(1)~(28)のいずれか1項に記載の医薬組成物。
(30)医薬組成物が、経口用製剤である、前記(1)~(29)のいずれか1項に記載の医薬組成物。
(31)医薬組成物が、固形製剤である、前記(1)~(30)のいずれか1項に記載の医薬組成物。
(32)固形製剤が、錠剤、散剤、細粒剤、顆粒剤、カプセル剤またはドライシロップの形状を有する、前記(31)に記載の医薬組成物。
(33)固形製剤が、錠剤である、前記(31)に記載の医薬組成物。
(34)前記(1)~(33)のいずれか1項に記載の医薬組成物、ならびにポリマーをラミネートしたフィルムおよびアルミ箔を用いて製造された、ブリスター包装品。
(35)ポリマーをラミネートしたフィルムが、ポリプロピレン、ポリ塩化ビニル、ポリ塩化ビニリデンおよびポリ塩化トリフルオロエチレンから選ばれる1種以上のポリマーをラミネートしたフィルムである、前記(34)に記載のブリスター包装品。
(36)アルミ箔が、接着剤中のメラミン樹脂量を低減したアルミ箔である、前記(34)または(35)に記載のブリスター包装品。
(37)前記(34)~(36)のいずれか1項に記載のブリスター包装品が包装体に封入された、医薬包装品。
(38)包装体が、アルミ袋である、前記(37)に記載の医薬包装品。
(39)包装体内に、さらに脱酸素剤および/または乾燥剤が封入された、前記(37)または(38)に記載の医薬包装品。 The present invention relates to the following (1) to (39).
(1) (4-{(3S) -3-[(1R) -1- (Naphthalen-1-yl) ethylamino] pyrrolidin-1-yl} phenyl) acetic acid (Compound A) or pharmacologically acceptable A pharmaceutical composition comprising a salt and an excipient.
(2) The pharmaceutical composition according to (1), wherein the excipient is one or more substances selected from sugar, sugar alcohol, cellulose derivative, starch derivative and inorganic salt.
(3) 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.
(4) The pharmaceutical composition according to any one of the above (1) to (3), comprising 0.1 to 99.9 parts by weight of an excipient with respect to 100 parts by weight of the pharmaceutical composition.
(5) The above (1) to (4), wherein 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. The pharmaceutical composition according to any one of the above.
(6) 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.
(7) The basic additive is one or more substances selected from basic oxides, basic hydroxides, carbonates, hydrogencarbonates, silicates and metasilicate aluminates (5) ).
(8) 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.
(9) 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 pharmaceutical composition according to (5) above.
(10) 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).
(11) 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.
(12) The pharmaceutical composition according to (5), wherein the brightening agent is one or more substances selected from carnauba wax, shellac, beeswax, hydrogenated oil, and magnesium stearate.
(13) The pharmaceutical composition according to any one of (1) to (12), wherein the additive is contained in an amount of 0.1 to 99.9 parts by weight per 100 parts by weight of the pharmaceutical composition.
(14) The pharmaceutical composition according to any one of (1) to (13), wherein the pharmaceutical composition has a coating film.
(15) The pharmaceutical composition according to (14), wherein the coating film contains one or more coating agents selected from water-soluble polymers, lactose, sucrose, titanium oxide, and talc.
(16) 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 pharmaceutical composition according to (15) above.
(17) The pharmaceutical composition according to any one of (14) to (16), wherein the coating agent is contained in an amount of 0.1 to 100 parts by weight with respect to 100 parts by weight of the coating film.
(18) having a first coating film containing a polyvinyl alcohol polyethylene glycol graft copolymer and a second coating film containing one or more coating agents selected from water-soluble polymers, lactose, sucrose, titanium oxide and talc The pharmaceutical composition according to any one of (14) to (17).
(19) The pharmaceutical composition according to (18) above, wherein the second coating film contains one or more coating agents selected from water-soluble polymers, lactose, and titanium oxide. (20) The second coating film is colored. The pharmaceutical composition according to the above (19), containing an agent.
(21) For 100 parts by weight of the pharmaceutical composition,
0.5-5.0 parts by weight of (4-{(3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidin-1-yl} phenyl) acetic acid (Compound A) or pharmacology thereof Acceptable salts,
50.0-90.0 parts by weight of excipients,
1.0-5.0 parts by weight binder,
0.5 to 5.0 parts by weight of basic additive,
2.0-10.0 parts by weight of disintegrant,
0.5-3.0 parts by weight of lubricant,
3.0 to 10.0 parts by weight of coating agent, and
A pharmaceutical composition comprising 0.1 to 1.0 part by weight of a colorant.
(22) For 100 parts by weight of the pharmaceutical composition,
0.5 to 2.0 parts by weight of (4-{(3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidin-1-yl} phenyl) acetic acid (Compound A) or pharmacology thereof Acceptable salts,
70.0-90.0 parts by weight of excipients,
1.0-3.0 parts by weight binder,
0.5 to 2.0 parts by weight of basic additive,
2.0-5.0 parts by weight of disintegrant,
0.5 to 2.0 parts by weight of lubricant,
5.0-10.0 parts by weight of coating agent, and
A pharmaceutical composition comprising 0.1 to 1.0 part by weight of a colorant.
(23) The pharmaceutical composition according to (21) or (22), further comprising 0.01 to 1 part by weight of a brightening agent relative to 100 parts by weight of the pharmaceutical composition.
(24) The excipient is mannitol and / or crystalline cellulose, the binder is hydroxypropylcellulose, the basic additive is calcium carbonate, the disintegrant is croscarmellose sodium, and the lubricant is stearin. Any of the above (21) to (23), which is magnesium acid, the coating agent is at least one coating agent selected from a water-soluble polymer, lactose and titanium oxide, and the colorant is yellow iron trioxide 2. A pharmaceutical composition according to item 1.
(25) The pharmaceutical composition according to the above (24), wherein the water-soluble polymer is at least one water-soluble polymer selected from polyvinyl alcohol polyethylene glycol graft copolymer, hypromellose and polyethylene glycol.
(26) (4-{(3S) -3-[(1R) -1- (Naphthalen-1-yl) ethylamino] pyrrolidin-1-yl} phenyl) acetic acid (Compound A) or a pharmacologically acceptable salt thereof The pharmaceutical composition according to any one of (1) to (25), wherein the salt has a median diameter (D 90 ) of 75 μm or less.
(27) (4-{(3S) -3-[(1R) -1- (Naphthalen-1-yl) ethylamino] pyrrolidin-1-yl} phenyl) acetic acid (Compound A) or a pharmacologically acceptable salt thereof The pharmaceutical composition according to any one of (1) to (25) above, wherein the salt has a median diameter (D 90 ) of 50 μm or less.
(28) (4-{(3S) -3-[(1R) -1- (Naphthalen-1-yl) ethylamino] pyrrolidin-1-yl} phenyl) acetic acid (Compound A) or a pharmacologically acceptable salt thereof The pharmaceutical composition according to any one of (1) to (25), wherein the salt has a median diameter (D 90 ) of 35 μm or less.
(29) The pharmaceutical composition according to any one of the above (1) to (28), wherein the pharmaceutical composition is a composition for preventing or treating hyperparathyroidism.
(30) The pharmaceutical composition according to any one of (1) to (29), wherein the pharmaceutical composition is an oral preparation.
(31) The pharmaceutical composition according to any one of (1) to (30), wherein the pharmaceutical composition is a solid preparation.
(32) 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.
(35) 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. .
(36) The blister package according to (34) or (35), wherein the aluminum foil is an aluminum foil in which the amount of melamine resin in the adhesive is reduced.
(37) A pharmaceutical package in which the blister package according to any one of (34) to (36) is enclosed in a package.
(38) The pharmaceutical package according to (37), wherein the package is an aluminum bag.
(39) The pharmaceutical package according to (37) or (38), wherein an oxygen scavenger and / or a desiccant is further enclosed in the package.
化合物A 45.0 g、D-マンニトール(日局、以下同じ)3757.5 g、結晶セルロース(セオラスPH301(登録商標)、旭化成ケミカルズ、以下同じ)1462.5 gおよびクロスカルメロースナトリウム(Ac-Di-Sol、FMC、以下同じ)292.5 gを流動層造粒機(FLO-5、フロイント産業)に入れて混合し、8重量%ヒドロキシプロピルセルロース水溶液(HPC-L、日本曹達、以下同じ) 2094 gをスプレーして造粒し、乾燥後、造粒顆粒を得た。得られた造粒顆粒を整粒機(コーミルQC-197S、パウレック)で篩過し、整粒顆粒とした。得られた整粒顆粒(5450 g)およびステアリン酸マグネシウム(111.2 g)を混合し、打錠用顆粒を得た。打錠機(コレクト12、菊水製作所製)を用いて、得られた打錠用顆粒を製錠することにより、素錠を得た。被膜混合物1[100g中にヒプロメロース(置換度タイプ2910、粘度3 mPas)(日局)52.0g、酸化チタン(日局)23.25g、マクロゴール6000(日局)14.0g、乳糖水和物(日局)10.0g、黄色三二酸化鉄(薬添規)0.5g、三二酸化鉄(薬添規)0.25gを含む]を精製水に分散し、固形分濃度10重量%のコーティング液を調製した。素錠4885 gに錠剤コーティング機(HC-Multi、フロイント産業)を用いて、素錠100重量部に対し剤皮が乾燥状態で5重量部になるようにコーティングを行うことにより目的とする錠剤を得た。 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. 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. Using a tablet coating machine (HC-Multi, Freund Sangyo Co., Ltd.) on uncoated tablets 4885 g, 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.
化合物A 10.0 g、乳糖水和物(日局、以下同じ)1043.0 g、および低置換度ヒドロキシプロピルセルロース(L-HPC、信越化学、以下同じ)195.0 gを流動層造粒機(MP-01、パウレック)に入れて混合し、HPC-L水溶液 487.5 gをスプレーして造粒し、乾燥後、造粒顆粒を得た。得られた造粒顆粒を目開き710 μm篩で篩過し、整粒顆粒とした。得られた整粒顆粒(1089 g)およびステアリン酸マグネシウム(11 g、Parteck LUB MST、メルク、以下同じ)を混合し、打錠用顆粒を得た。打錠機(コレクト12、菊水製作所製)を用いて、得られた打錠用顆粒を製錠することにより、素錠(質量:130 mg、錠剤の形状:円形状(7 mm径)、以下同じ)を得た。被膜混合物1(上記と同様の組成を有する)を精製水に分散し、固形分濃度10重量%のコーティング液を調製した。素錠200 gに錠剤コーティング機(DRC-200、パウレック)を用いて、素錠100重量部に対し剤皮が乾燥状態で4重量部になるようにコーティングを行うことにより目的とする錠剤を得た。
以下の第1表に、実施例1-1および実施例1-2で得られた錠剤における各成分の組成を示した。 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 μm to obtain a granulated granule. 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. By using the tableting machine (Collect 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. Using a tablet coating machine (DRC-200, POWREC) on 200 g of uncoated tablets, the desired tablets are obtained by coating the uncoated tablets to 100 parts by weight so that the coating is 4 parts by weight in the dry state. It was.
Table 1 below shows the composition of each component in the tablets obtained in Example 1-1 and Example 1-2.
実施例1-1および実施例1-2で得られた錠剤について、ガラス瓶(開放)に入れ、60℃の条件で1ヵ月保存し、以下に示す測定条件(測定条件1)にて、類縁物質の生成量を評価した。結果を第3表に示す。RRT(相対保持時間)0.45において、実施例1-1で得られた製剤では類縁物質の生成は認められず、実施例1-2で得られた製剤でも類縁物質の生成はわずかであった。これらの結果から、D-マンニトールおよび乳糖水和物の何れの賦形剤においても良好な保存安定性が得られることが理解できる。ここで、RRT(相対保持時間)とは、化合物Aの保持時間に対する、類縁物質の相対保持時間を意味する。 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. Here, RRT (relative retention time) means the relative retention time of the related substance with respect to the retention time of compound A.
検出器:紫外吸光光度計(測定波長:220 nm)
カラム:L-column2 (CERI) 4.6mm I.D.×150mm
カラム温度:約40℃の一定温度
移動相A:水/アセトニトリル/トリフルオロ酢酸(1900/100/1)
移動相B:アセトニトリル/水/トリフルオロ酢酸(1800/200/1)
流量:1.0mL/分
移動相の送液方法:移動相Aおよび移動相Bの混合比を、以下のように変更して濃度勾配を制御し、送液した。 (Measurement condition 1)
Detector: UV absorptiometer (measurement wavelength: 220 nm)
Column: L-column2 (CERI) 4.6mm ID x 150mm
Column temperature: A constant temperature of about 40 ° C Mobile phase A: Water / acetonitrile / trifluoroacetic acid (1900/100/1)
Mobile phase B: acetonitrile / water / trifluoroacetic acid (1800/200/1)
Flow rate: 1.0 mL / min Liquid phase feeding method: The mixture ratio of mobile phase A and mobile phase B was changed as follows to control the concentration gradient, and the liquid was fed.
化合物A 3.8 g、D-マンニトール646.2 g、結晶セルロース(MCC、セオラス PH301(登録商標)、旭化成ケミカル、以下同じ) 250.0 gおよびクロスカルメロースナトリウム30.0 gを流動層造粒機(MP-01、パウレック)に入れて混合し、8重量%ヒドロキシプロピルセルロース水溶液 375.0 gをスプレーして造粒し、乾燥後、造粒顆粒を得た。得られた造粒顆粒を用いて、実施例1-1と同様の方法により、錠剤を得た。得られた錠剤をポリプロピレン製シート(TAS-2230V、大成化工、以下同じ)および接着剤中のメラミン樹脂量を低減したアルミ箔(UACJ)を用いて、半自動PTPシート調製機(FABNTASY、O.M.A.R社、以下同じ)により包装し、ブリスター包装品を得た。得られたブリスター包装品をアルミ袋(細川洋行)に入れてヒートシーラー(クイックシーラー、志賀包装機、以下同じ)によりシールし、目的とするアルミ袋包装品を得た。 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. Using the resulting tablet made of polypropylene sheet (TAS-2230V, Taisei Kako, same below) and aluminum foil (UACJ) with reduced amount of melamine resin in adhesive, semi-automatic PTP sheet preparation machine (FABNTASY, OMAR, The same shall apply hereinafter) to obtain a blister package. The obtained blister packaged product was put in an aluminum bag (Yoyuki Hosokawa) and sealed with a heat sealer (Quick Sealer, Shiga Packing Machine, the same shall apply hereinafter) to obtain the intended aluminum bag packaged product.
実施例2-1と同様に錠剤を調製した。さらに、得られた錠剤をポリプロピレン製シートおよび汎用のアルミ箔(UACJ)を用いて、実施例2-1と同様の方法により、目的とするアルミ袋包装品を得た。 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.
化合物A 3.8 g、D-マンニトール746.2 g、結晶セルロース150.0 gおよびクロスカルメロースナトリウム50.0 gを用いて、実施例2-1と同様の方法により、錠剤を調製した。実施例2-2と同様の方法により、得られた錠剤から目的とするアルミ袋包装品を得た。 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.
化合物A 3.8 g、D-マンニトール896.2 gおよびクロスカルメロースナトリウム50.0 gを用いて実施例2-1と同様の方法により、錠剤を調製した。実施例2-2と同様の方法により、得られた錠剤から目的とするアルミ袋包装品を得た。 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.
実施例2-1および実施例2-2で得られたアルミ袋包装品について、60℃の条件で1ヵ月保存し、試験例1と同様の条件にて錠剤の類縁物質の生成量を評価した。結果を第5表に示す。実施例2-1および実施例2-2で得られたアルミ袋包装品中の錠剤は、何れも個々の類縁物質の生成量や類縁物質の総生成量が抑制されていた。また、実施例2-1で得られたアルミ袋包装品(接着剤中のメラミン樹脂量を低減したアルミ箔を使用)中の錠剤は、実施例2-2のそれと比較して、相対保持時間(RRT)1.28を有する類縁物質の生成量や類縁物質の総生成量がより抑制されていた。
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.
実施例2-1、実施例3-1および実施例3-2で得られたアルミ袋包装品について、60℃の条件で1ヵ月保存し、以下に示す測定条件2にて錠剤の類縁物質の生成量を評価した。結果を第6表に示す。実施例2-1、実施例3-1および実施例3-2で得られたアルミ袋包装品中の錠剤は、何れも個々の類縁物質の生成量や類縁物質の総生成量が抑制されていた。また、実施例2-1および実施例3-1で得られたアルミ袋包装品中の錠剤は、実施例3-2で得られたそれと比較して、類縁物質の生成量がより抑制された。さらに結晶セルロースの添加量が多い実施例2-1は類縁物質の生成抑制効果がより顕著であった。 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.
検出器:紫外吸光光度計(測定波長:220 nm)
カラム:L-column2 (CERI) 4.6mm I.D.×150mm
カラム温度:約40℃の一定温度
移動相A:水/アセトニトリル/トリフルオロ酢酸(1900/100/1)
移動相B:アセトニトリル/水/トリフルオロ酢酸(1800/200/1)
流量:1.0mL/分
移動相の送液方法;移動相A/移動相B(79/21)にて送液した。 (Measurement condition 2)
Detector: UV absorptiometer (measurement wavelength: 220 nm)
Column: L-column2 (CERI) 4.6mm ID x 150mm
Column temperature: A constant temperature of about 40 ° C Mobile phase A: Water / acetonitrile / trifluoroacetic acid (1900/100/1)
Mobile phase B: acetonitrile / water / trifluoroacetic acid (1800/200/1)
Flow rate: 1.0 mL / min Mobile phase feeding method: Mobile phase A / mobile phase B (79/21).
化合物A 7.69 g、D-マンニトール1272.3 g、結晶セルロース500.0 g、クロスカルメロースナトリウム100.0 gおよび炭酸カルシウム(日局、日東粉化工業、以下同じ)20.0 gを流動層造粒機(FLO-2、フロイント産業)に入れて混合し、8重量%ヒドロキシプロピルセルロース水溶液 750.0 gをスプレーして造粒し、乾燥後、造粒顆粒を得た。得られた造粒顆粒を整粒機(コーミルQC-197S、パウレック)で解砕し、整粒顆粒とした。得られた整粒顆粒(980.0 g)およびステアリン酸マグネシウム(20.0 g)を混合し、打錠用顆粒を得た。打錠機を用いて、得られた打錠用顆粒を製錠することにより、目的とする錠剤(質量:130mg、錠剤の形状:円形状(7 mm径))を得た。 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. 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)).
化合物A 7.69 g、D-マンニトール1292.3 g、結晶セルロース500.0 gおよびクロスカルメロースナトリウム100.0 gを流動層造粒機(FLO-2、フロイント産業)に入れて混合し、8重量%ヒドロキシプロピルセルロース水溶液 750.0 gをスプレーして造粒し、乾燥後、造粒顆粒を得た。得られた造粒顆粒を用いて、実施例4-1と同様の方法により、目的とする錠剤(質量:130mg、錠剤の形状:円形状(7 mm径))を得た。 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.
化合物A 7.69 g、D-マンニトール1252.3 g、結晶セルロース500.0 g、クロスカルメロースナトリウム100.0 gおよび炭酸カルシウム40.0 gを流動層造粒機(FLO-2、フロイント産業)に入れて混合し、8重量%ヒドロキシプロピルセルロース水溶液750.0 gをスプレーして造粒し、乾燥後、造粒顆粒を得た。得られた造粒顆粒を用いて、実施例4-1と同様の方法により、目的とする錠剤(質量:130mg、錠剤の形状:円形状(7 mm径))を得た。 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.
実施例4-1、実施例4-2および実施例5-1で得られた錠剤について、ガラス瓶(開放)に入れ、40℃/75%RHの条件で1ヵ月保存し、前記測定条件1にて、類縁物質の生成量を評価した。結果を第8表に示す。実施例4-1、実施例4-2および実施例5-1で得られた錠剤は、何れも個々の類縁物質の生成量や類縁物質の総生成量が抑制されていた。また、実施例4-2で得られた錠剤と比較して、炭酸カルシウムを添加した実施例4-1および実施例5-1で得られた錠剤は、保存後の類縁物質(RRT(相対保持時間)0.52および総量)の生成がより抑制された。さらに実施例5-1ではその効果が顕著であった。 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 | release), and preserve | saves it on the conditions of 40 degreeC / 75% RH for one month, and it is the said measurement condition 1 Thus, the amount of related substances produced was evaluated. The results are shown in Table 8. In the tablets obtained in Example 4-1, Example 4-2 and Example 5-1, the amount of each related substance produced and the total amount of related substances produced were suppressed. In addition, compared with the tablet obtained in Example 4-2, the tablets obtained in Example 4-1 and Example 5-1 to which calcium carbonate was added were related substances after storage (RRT (relative retention) The production of time) 0.52 and total amount) was more suppressed. Furthermore, the effect was remarkable in Example 5-1.
実施例1-2と同様の手法により、目的とする素錠(質量:130 mg、錠剤の形状:円形状(7 mm径)、以下同じ)を得た。 Example 5-2 Preparation of uncoated tablet In the same manner as in Example 1-2, the target uncoated tablet (mass: 130 mg, tablet shape: circular (7 mm diameter), the same shall apply hereinafter) Got.
前記被膜混合物1を精製水に分散し、固形分濃度10重量%のコーティング液を調製した。前記実施例5-2で得られた素錠に対し錠剤コーティング機(DRC-200、パウレック)を用いて、素錠100重量部に対し剤皮が乾燥状態で4重量部になるようにコーティングを行うことにより目的とする錠剤を得た。 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. Using a tablet coating machine (DRC-200, POWREC) on the uncoated tablets obtained in Example 5-2, 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.
前記被膜混合物1を精製水に分散し、固形分濃度10重量%のコーティング液を調製した。前記実施例5-2で得られた素錠に対し錠剤コーティング機(DRC-200、パウレック)を用いて、素錠100重量部に対し剤皮が乾燥状態で6重量部になるようにコーティングを行うことにより目的とする錠剤を得た。 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. Using a tablet coating machine (DRC-200, POWREC) on the uncoated tablet obtained in Example 5-2, 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.
前記被膜混合物1を精製水に分散し、固形分濃度10重量%のコーティング液を調製した。前記実施例5-2で得られた素錠に対し錠剤コーティング機(DRC-200、パウレック)を用いて、素錠100重量部に対し剤皮が乾燥状態で8重量部になるようにコーティングを行うことにより目的とする錠剤を得た。
以下の第9表に、実施例6~8および実施例5-2で得られた錠剤における各成分の組成を示した。 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. Using a tablet coating machine (DRC-200, POWREC) on the uncoated tablets obtained in Example 5-2, 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.
日米EU三極医薬品承認審査調和国際会議(ICH)における新原薬および新製剤の光安定性試験ガイドライン(1996年11月6日)に従って、実施例6~8および実施例5-2でそれぞれ得られた錠剤に関して、以下に示す条件で安定性試験を行った。曝光後、前記測定条件1にて、類縁物質(RRT(相対保持時間)0.52および総量)の生成量を評価した。結果を第10表に示す。実施例6~8および実施例5-2で得られた錠剤は、何れも個々の類縁物質の生成量や類縁物質の総生成量が抑制されていた。また、実施例5-2で得られた錠剤と比較して、コーティング処理が施された実施例6~8の錠剤は、曝光後の類縁物質(RRT(相対保持時間)0.52および総量)の生成がより抑制された。 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. In the tablets obtained in Examples 6 to 8 and Example 5-2, the amount of individual related substances produced and the total amount of related substances produced were suppressed. In addition, compared with the tablets obtained in Example 5-2, 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.
光源:キセノンランプ
照度:30,000 lx
曝光時間:40時間(総照度120,000 lxh)
Light source: Xenon lamp Illuminance: 30,000 lx
Exposure time: 40 hours (total illumination 120,000 lxh)
化合物A 63.1 g、D-マンニトール 10432.9 g、結晶セルロース 4100.0 g、クロスカルメロースナトリウム 820.0 gおよび炭酸カルシウム 492.0 gを流動層造粒機(FLO-15、フロイント産業)に入れて混合し、8重量%ヒドロキシプロピルセルロース水溶液 6150.0 gをスプレーして造粒し、乾燥後、造粒顆粒を得た。得られた造粒顆粒を整粒機で解砕し、整粒顆粒とした。得られた整粒顆粒(8000.0 g)およびステアリン酸マグネシウム(163.3 g)を混合機(TBM-60、徳寿工作所、以下同じ)で混合し、打錠用顆粒を得た。打錠機(AQUARIUS、菊水製作所製)を用いて、得られた打錠用顆粒を製錠することにより、素錠を得た。被膜混合物2(100g中に、ヒプロメロース(置換度タイプ2910、粘度3 mPa・s)(日局)52.0g、酸化チタン(日局)20.0g、マクロゴール6000(日局)14.0g、乳糖水和物(日局)10.0g、黄色三二酸化鉄(薬添規)4.0gを含む)を精製水に分散し、固形分濃度10重量%のコーティング液を調製した。素錠3500.0 gに錠剤コーティング機(DRC-500、パウレック)を用いて、素錠100重量部に対し剤皮が乾燥状態で5重量部になるようにコーティングを行うことにより錠剤を得た。得られた錠剤を25℃/60%RH の保存条件で5日間保存後、ポリプロピレン製シート(TAS-2230V、大成化工)および接着剤中のメラミン樹脂量を低減したアルミ箔(UACJ)を用いて、PTP包装機(No.855PX型、岩黒製作所)により、ブリスター包装品を得た。得られたブリスター包装品をアルミ袋(細川洋行、以下同じ)に入れてヒートシール機(クイックシーラー、志賀包装機、以下同じ)によりシールし、目的とするアルミ袋包装品を得た。 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. Using 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.
実施例9-1と同様の方法により、ブリスター包装品を得た。ブリスター包装品 10シートおよび脱酸素剤(ファーマキープKC-20、三菱ガス化学)をアルミ袋(細川洋行)に入れてヒートシール機によりシールし、目的とするアルミ袋包装品を得た。 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.
実施例9-1と同様の方法により、ブリスター包装品を得た。ブリスター包装品 10シートおよび乾燥剤(MSセラムW 3G、東海化学工業所)をアルミ袋(細川洋行)に入れてヒートシール機(クイックシーラー、志賀包装機、以下同じ)によりシールし、目的とするアルミ袋包装品を得た。 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.
実施例9-1、実施例9-2および実施例10で得られたアルミ袋包装品について、60℃の条件で1ヵ月保存し、前記試験例1と同様の条件にて錠剤の類縁物質の生成量を評価した。結果を第12表に示す。実施例9-1、実施例9-2および実施例10で得られた錠剤は、何れも個々の類縁物質の生成量や類縁物質の総生成量が抑制されていた。また、実施例9-2および実施例10で得られたアルミ袋包装品中の錠剤は、実施例9-1のそれと比較して、保存後の類縁物質の総生成量がより抑制された。特に実施例9-2でその効果が顕著であった。 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.
化合物A 38.5 g、D-マンニトール6161.5 g、結晶セルロース1250.0 g、クロスカルメロースナトリウム 250.0 gおよび炭酸カルシウム50.0 gを流動層造粒機(FLO-15、フロイント産業)に入れて混合し、8重量%ヒドロキシプロピルセルロース水溶液 1875.0 gをスプレーして造粒し、乾燥後、造粒顆粒を得た。得られた造粒顆粒を整粒機(コーミルQC-197S、パウレック)で解砕し、整粒顆粒とした。得られた整粒顆粒(4410.0 g)およびステアリン酸マグネシウム(90.0 g)を混合機(TBM-25、徳寿工作所)で混合し、打錠用顆粒を得た。打錠機(AQUARIUS、菊水製作所製)を用いて、得られた打錠用顆粒を製錠することにより、素錠を得た。前記被膜混合物2を精製水に分散し、固形分濃度10重量%のコーティング液を調製した。素錠3500.0 gに錠剤コーティング機(DRC-500、パウレック)を用いて、素錠100重量部に対し剤皮が乾燥状態で8重量部になるようにコーティングを行うことにより錠剤を得た。 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. 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. Using 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.
実施例11-1と同様の方法により、素錠を得た。ポリビニルアルコール・ポリエチレングリコール・グラフトコポリマー(コリコートIR(登録商標)、BASF)を精製水に溶解し、固形分濃度5重量%のコーティング液1を調製した。さらに前記被膜混合物2を精製水に分散し、固形分濃度10重量%のコーティング液2を調製した。素錠200.0 gに錠剤コーティング機(DRC-200、パウレック)を用いて、素錠100重量部に対し剤皮が乾燥状態で2重量部になるように前記コーティング液1を、続いて、素錠100重量部に対し剤皮が乾燥状態で5重量部になるように前記コーティング液2をそれぞれ噴霧し、コーティングを行うことにより錠剤を得た。 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. Using a tablet coating machine (DRC-200, POWREC) to 200.0 g of uncoated tablets, 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.
実施例11-1および実施例11-2で得られた錠剤について、プラスチックシャーレ(開放)に入れ、25℃/60%RHの条件で2週間および1ヵ月保存し、前記測定条件1にて、類縁物質の生成量を評価した。結果を第14表に示す。実施例11-1および実施例11-2で得られた錠剤は、何れも個々の類縁物質の生成量や類縁物質の総生成量が抑制されていた。また、実施例11-1で得られた錠剤と比較して、実施例11-2で得られた錠剤は、保存後の類縁物質(RRT(相対保持時間)0.52および総量)の生成がより抑制された。
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.
化合物A 22.5 g、D-マンニトール3780.0 g、結晶セルロース1462.5 gおよびクロスカルメロースナトリウム292.5 gを流動層造粒機(FLO-5、フロイント産業)に入れて混合し、以降、実施例1-1と同様の方法でコーティング錠を得た。 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.
化合物A 3.8 g、D-マンニトール646.2 g、結晶セルロース250.0 gおよびクロスカルメロースナトリウム50.0 gを流動層造粒機(MP-01、パウレック)に入れて混合し、HPC-L水溶液 375.0 gをスプレーして造粒し、乾燥後、造粒顆粒を得た。得られた造粒顆粒を整粒機(コーミルQC-197S、パウレック)で篩過し、整粒顆粒とした。得られた整粒顆粒(388.1 g)、ケイ酸カルシウム(4.0 g、ナカライテスク、以下同じ)およびステアリン酸マグネシウム(7.9 g)を混合し、打錠用顆粒を得た。打錠機(コレクト12、菊水製作所製)を用いて、得られた打錠用顆粒を製錠することにより、目的とする錠剤(質量:131 mg、錠剤の形状:円形状(7 mm径))を得た。 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. The obtained granulated granules (388.1 g), calcium silicate (4.0 g, Nacalai Tesque, the same applies hereinafter) and magnesium stearate (7.9 g) were mixed to obtain granules for tableting. Using the tableting machine (Correct 12, manufactured by Kikusui Seisakusho), the desired tablet (mass: 131 mg, tablet shape: circular shape (7 mm diameter)) is obtained by tableting the obtained granules for tableting. )
実施例12-2で得られた整粒顆粒(380.3 g)、ケイ酸カルシウム(11.9 g)およびステアリン酸マグネシウム(7.8 g)を混合し、打錠用顆粒を得た。打錠機(コレクト12、菊水製作所製)を用いて、得られた打錠用顆粒を製錠することにより、目的とする錠剤(質量:134 mg、錠剤の形状:円形状(7 mm径))を得た。 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. )
化合物A 5.0 g、D-マンニトール840.0 g、結晶セルロース325.0 gおよびクロスカルメロースナトリウム65.0 gを流動層造粒機(MP-01、パウレック)に入れて混合し、HPC-L水溶液 487.5 gをスプレーして造粒し、乾燥後、造粒顆粒を得た。得られた造粒顆粒を整粒機(コーミルQC-197S、パウレック)で篩過し、整粒顆粒とした。得られた整粒顆粒(384.3 g)、メタケイ酸アルミン酸マグネシウム(7.8 g、ノイシリンFH2(登録商標)、富士化学工業)およびステアリン酸マグネシウム(7.8 g)を混合し、打錠用顆粒を得た。打錠機(コレクト12、菊水製作所製)を用いて、得られた打錠用顆粒を製錠することにより、目的とする錠剤(質量:133 mg、錠剤の形状:円形状(7 mm径))を得た。 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. The resulting granulated granules (384.3 g), magnesium metasilicate aluminate (7.8 g, Neusilin FH2 (registered trademark), Fuji Chemical) and magnesium stearate (7.8 g) were mixed to obtain granules for tableting. . Using the tableting machine (Correct 12, manufactured by Kikusui Seisakusho), the tablets for tableting obtained were tableted to obtain the desired tablets (mass: 133 mg, tablet shape: circular (7 mm diameter) )
実施例12-1、実施例12-2、実施例12-3および実施例12-4で得られた錠剤について、褐色ガラス瓶(開放)に入れ、40℃/75%RHの条件で1ヵ月保存し、前記測定条件1にて、類縁物質の生成量を評価した。結果を第16表に示す。実施例12-1、実施例12-2、実施例12-3および実施例12-4で得られた錠剤は、何れも個々の類縁物質の生成量や類縁物質の総生成量が抑制されていた。また、実施例12-1で得られた錠剤と比較して、実施例12-2、実施例12-3および実施例12-4で得られた錠剤は、保存後の類縁物質(RRT(相対保持時間)0.52および総量)の生成がより抑制された。 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.
化合物A 7.69 g、D-マンニトール1252.3 g、結晶セルロース500.0 g、クロスカルメロースナトリウム100.0 gおよび炭酸カルシウム40.0 gを流動層造粒機(FLO-2、フロイント産業)に入れて混合し、以降、実施例4-1と同様の方法で打錠用顆粒を得た。打錠機を用いて、得られた打錠用顆粒を製錠することにより、目的とする錠剤(質量:130 mg、錠剤の形状:円形状(7 mm径))を得た。 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)).
化合物A 7.69 g、D-マンニトール1152.3 g、結晶セルロース500.0 g、低置換度ヒドロキシプロピルセルロース200.0 gおよび炭酸カルシウム40.0 gを流動層造粒機(FLO-2、フロイント産業)に入れて混合し、以降、実施例13-1と同様の方法で錠剤(質量:130 mg、錠剤の形状:円形状(7 mm径))を得た。 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. Got.
実施例13-1および実施例13-2で得られた錠剤について、褐色ガラス瓶(開放)に入れ、40℃/75%RHの条件で1ヵ月保存し、前記測定条件1にて、類縁物質の生成量を評価した。結果を第18表に示す。実施例13-1および実施例13-2で得られた錠剤は、何れも個々の類縁物質の生成量や類縁物質の総生成量が抑制されていた。また、実施例13-1で得られた錠剤と比較して、実施例13-2で得られた錠剤は、保存後の類縁物質(RRT(相対保持時間)0.52および総量)の生成がより抑制された。 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.
Claims (39)
- (4-{(3S)-3-[(1R)-1-(ナフタレン-1-イル)エチルアミノ]ピロリジン-1-イル}フェニル)酢酸(化合物A)またはその薬理学的に許容される塩および賦形剤を含む、医薬組成物。 (4-{(3S) -3-[(1R) -1- (Naphthalen-1-yl) ethylamino] pyrrolidin-1-yl} phenyl) acetic acid (Compound A) or a pharmaceutically acceptable salt thereof And a pharmaceutical composition comprising excipients.
- 賦形剤が、糖、糖アルコール、セルロース誘導体、デンプン誘導体および無機塩から選ばれる1種以上の物質である、請求項1に記載の医薬組成物。 2. The pharmaceutical composition according to claim 1, wherein the excipient is one or more substances selected from sugar, sugar alcohol, cellulose derivative, starch derivative and inorganic salt.
- 賦形剤が、乳糖、白糖、マルトース、スクロース、マンニトール、ソルビトール、エリスリトール、マルチトール、キシリトール、グルコース、結晶セルロース、コーンスターチ、ポテトスターチ、リン酸一水素カルシウム、リン酸二水素カルシウム、リン酸二水素ナトリウムおよびリン酸カルシウムから選ばれる1種以上の物質である、請求項1または2に記載の医薬組成物。 Excipients are lactose, sucrose, maltose, sucrose, mannitol, sorbitol, erythritol, maltitol, xylitol, glucose, crystalline cellulose, corn starch, potato starch, calcium monohydrogen phosphate, calcium dihydrogen phosphate, dihydrogen phosphate The pharmaceutical composition according to claim 1 or 2, which is one or more substances selected from sodium and calcium phosphate.
- 医薬組成物100重量部に対し、賦形剤を0.1重量部~99.9重量部含む、請求項1~3のいずれか1項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 3, comprising 0.1 to 99.9 parts by weight of an excipient with respect to 100 parts by weight of the pharmaceutical composition.
- 医薬組成物が、結合剤、塩基性添加剤、崩壊剤、滑沢剤、着色剤および光沢化剤から選ばれる1種以上の添加物をさらに含む、請求項1~4のいずれか1項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition further comprises one or more additives selected from binders, basic additives, disintegrants, lubricants, colorants and brighteners. The pharmaceutical composition as described.
- 結合剤が、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、カルボキシメチルセルロース、カルボキシメチルエチルセルロース、ヒドロキシプロピルスターチ、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、カルボキシビニルポリマー、ポリビニルピロリドン、ポリビニルアルコール、メタアクリル酸コポリマー、マクロゴール、デンプン、ゼラチン、デキストリン、プルラン、カンテンおよびアラビアゴムから選ばれる1種以上の物質である、請求項5に記載の医薬組成物。 The binder is hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, hydroxypropyl starch, hydroxyethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, 6. The pharmaceutical composition according to claim 5, which is one or more substances selected from methacrylic acid copolymer, macrogol, starch, gelatin, dextrin, pullulan, agar and gum arabic.
- 塩基性添加剤が、塩基性酸化物、塩基性水酸化物、炭酸塩、炭酸水素塩、ケイ酸塩およびメタケイ酸アルミン酸塩から選ばれる1種以上の物質である、請求項5に記載の医薬組成物。 6. The basic additive according to claim 5, wherein the basic additive is one or more substances selected from basic oxides, basic hydroxides, carbonates, hydrogen carbonates, silicates, and metasilicate aluminates. Pharmaceutical composition.
- 塩基性添加剤が、酸化マグネシウム、水酸化マグネシウム、水酸化アルミニウム、炭酸ナトリウム、炭酸カリウム、炭酸マグネシウム、炭酸カルシウム、炭酸水素ナトリウム、ケイ酸カルシウムおよびメタケイ酸アルミン酸マグネシウムから選ばれる1種以上の物質である、請求項7に記載の医薬組成物。 One or more substances whose basic additives are 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 claim 7, wherein
- 崩壊剤が、クロスカルメロースナトリウム、クロスポビドン、カルボキシメチルスターチナトリウム、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、部分α化デンプンおよびデンプンから選ばれる1種以上の物質である、請求項5に記載の医薬組成物。 The disintegrant is one or more substances selected from croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, partially pregelatinized starch, and starch. 5. The pharmaceutical composition according to 5.
- 滑沢剤が、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、モノステアリン酸グリセリン、軽質無水ケイ酸、フマル酸ステアリルナトリウムおよびショ糖脂肪酸エステル類から選ばれる1種以上の物質である、請求項5に記載の医薬組成物。 6. The lubricant according to claim 5, wherein the 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. Pharmaceutical composition.
- 着色剤が、黄色三二酸化鉄、酸化チタン、タルク、三二酸化鉄、黒酸化鉄、銅クロロフィル、銅クロロフィリンナトリウム、カーボンブラック、薬用炭、食用色素、カンゾウエキス、緑茶末、リボフラビン、酪酸リボフラビン、リン酸リボフラビンナトリウムおよびミリスチン酸オクチルドデシルから選ばれる1種以上の物質である、請求項5に記載の医薬組成物。 Coloring agents are yellow iron sesquioxide, titanium oxide, talc, iron sesquioxide, black iron oxide, copper chlorophyll, copper chlorophyllin sodium, carbon black, medicinal charcoal, food coloring, licorice extract, green tea powder, riboflavin, riboflavin butyrate, phosphorus 6. The pharmaceutical composition according to claim 5, which is at least one substance selected from sodium riboflavin acid and octyldodecyl myristate.
- 光沢化剤が、カルナウバロウ、シェラック、ミツロウ、硬化油およびステアリン酸マグネシウムから選ばれる1種以上の物質である、請求項5に記載の医薬組成物。 6. The pharmaceutical composition according to claim 5, wherein the brightening agent is one or more substances selected from carnauba wax, shellac, beeswax, hydrogenated oil, and magnesium stearate.
- 医薬組成物100重量部に対し、添加物を0.1重量部~99.9重量部含む、請求項1~12のいずれか1項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 12, comprising 0.1 to 99.9 parts by weight of an additive with respect to 100 parts by weight of the pharmaceutical composition.
- 医薬組成物が、コーティング被膜を有する、請求項1~13のいずれか1項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 13, wherein the pharmaceutical composition has a coating film.
- コーティング被膜が、水溶性ポリマー、乳糖、白糖、酸化チタンおよびタルクから選ばれる1種以上のコーティング剤を含む、請求項14に記載の医薬組成物。 15. The pharmaceutical composition according to claim 14, wherein the coating film contains one or more coating agents selected from water-soluble polymers, lactose, sucrose, titanium oxide and talc.
- 水溶性ポリマーが、ポリビニルアルコールポリエチレングリコールグラフトコポリマー、ポリビニルピロリドン、ヒプロメロース、ヒドロキシプロピルセルロース、ポリビニルアルコール、ポリビニルアルコールアクリル酸メタクリル酸メチル共重合体およびポリエチレングリコールから選ばれる1種以上のポリマーである、請求項15に記載の医薬組成物。 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 methyl methacrylate copolymer and polyethylene glycol. 15. The pharmaceutical composition according to 15.
- コーティング被膜100重量部に対し、コーティング剤を0.1重量部~100重量部含む、請求項14~16のいずれか1項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 14 to 16, comprising 0.1 to 100 parts by weight of a coating agent with respect to 100 parts by weight of the coating film.
- ポリビニルアルコールポリエチレングリコールグラフトコポリマーを含有する第一のコーティング被膜と、水溶性ポリマー、乳糖、白糖、酸化チタンおよびタルクから選ばれる1種以上のコーティング剤を含有する第ニのコーティング被膜を有する、請求項14~17のいずれか1項に記載の医薬組成物。 A first coating film containing a polyvinyl alcohol polyethylene glycol graft copolymer and a second coating film containing one or more coating agents selected from water-soluble polymers, lactose, sucrose, titanium oxide and talc. The pharmaceutical composition according to any one of 14 to 17.
- 第ニのコーティング被膜が水溶性ポリマー、乳糖、および酸化チタンから選ばれる1種以上のコーティング剤を含有する、請求項18に記載の医薬組成物 The pharmaceutical composition according to claim 18, wherein the second coating film contains one or more coating agents selected from water-soluble polymers, lactose, and titanium oxide.
- 第ニのコーティング被膜が着色剤を含有する、請求項19に記載の医薬組成物。 20. The pharmaceutical composition according to claim 19, wherein the second coating film contains a colorant.
- 医薬組成物100重量部に対し、
0.5~5.0重量部の(4-{(3S)-3-[(1R)-1-(ナフタレン-1-イル)エチルアミノ]ピロリジン-1-イル}フェニル)酢酸(化合物A)またはその薬理学的に許容される塩、
50.0~90.0重量部の賦形剤、
1.0~5.0重量部の結合剤、
0.5~5.0重量部の塩基性添加剤、
2.0~10.0重量部の崩壊剤、
0.5~3.0重量部の滑沢剤、
3.0~10.0重量部のコーティング剤、および
0.1~1.0重量部の着色剤を含有する、医薬組成物。 For 100 parts by weight of the pharmaceutical composition,
0.5-5.0 parts by weight of (4-{(3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidin-1-yl} phenyl) acetic acid (Compound A) or pharmacology thereof Acceptable salts,
50.0-90.0 parts by weight of excipients,
1.0-5.0 parts by weight binder,
0.5 to 5.0 parts by weight of basic additive,
2.0-10.0 parts by weight of disintegrant,
0.5-3.0 parts by weight of lubricant,
3.0 to 10.0 parts by weight of coating agent, and
A pharmaceutical composition comprising 0.1 to 1.0 part by weight of a colorant. - 医薬組成物100重量部に対し、
0.5~2.0重量部の(4-{(3S)-3-[(1R)-1-(ナフタレン-1-イル)エチルアミノ]ピロリジン-1-イル}フェニル)酢酸(化合物A)またはその薬理学的に許容される塩、
70.0~90.0重量部の賦形剤、
1.0~3.0重量部の結合剤、
0.5~2.0重量部の塩基性添加剤、
2.0~5.0重量部の崩壊剤、
0.5~2.0重量部の滑沢剤、
5.0~10.0重量部のコーティング剤、および
0.1~1.0重量部の着色剤を含有する、医薬組成物。 For 100 parts by weight of the pharmaceutical composition,
0.5 to 2.0 parts by weight of (4-{(3S) -3-[(1R) -1- (naphthalen-1-yl) ethylamino] pyrrolidin-1-yl} phenyl) acetic acid (Compound A) or pharmacology thereof Acceptable salts,
70.0-90.0 parts by weight of excipients,
1.0-3.0 parts by weight binder,
0.5 to 2.0 parts by weight of basic additive,
2.0-5.0 parts by weight of disintegrant,
0.5 to 2.0 parts by weight of lubricant,
5.0-10.0 parts by weight of coating agent, and
A pharmaceutical composition comprising 0.1 to 1.0 part by weight of a colorant. - さらに医薬組成物100重量部に対して0.01~1重量部の光沢化剤を含有する、請求項21または22に記載の医薬組成物。 The pharmaceutical composition according to claim 21 or 22, further comprising 0.01 to 1 part by weight of a brightening agent relative to 100 parts by weight of the pharmaceutical composition.
- 賦形剤がマンニトールおよび/または結晶セルロースであり、結合剤がヒドロキシプロピルセルロースであり、塩基性添加剤が炭酸カルシウムであり、崩壊剤がクロスカルメロースナトリウムであり、滑沢剤がステアリン酸マグネシウムであり、コーティング剤が水溶性ポリマー、乳糖および酸化チタンから選ばれる1種以上のコーティング剤であり、かつ着色剤が黄色三ニ酸化鉄である、請求項21~23のいずれか1項に記載の医薬組成物。 The excipient is mannitol and / or crystalline cellulose, the binder is hydroxypropylcellulose, the basic additive is calcium carbonate, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate. The coating agent according to any one of claims 21 to 23, wherein the coating agent is one or more coating agents selected from water-soluble polymers, lactose and titanium oxide, and the colorant is yellow iron trioxide. Pharmaceutical composition.
- 水溶性ポリマーがポリビニルアルコールポリエチレングリコールグラフトコポリマー、ヒプロメロースおよびポリエチレングリコールから選ばれる1種以上の水溶性ポリマーである、請求項24に記載の医薬組成物。 25. The pharmaceutical composition according to claim 24, wherein the water-soluble polymer is at least one water-soluble polymer selected from polyvinyl alcohol polyethylene glycol graft copolymer, hypromellose and polyethylene glycol.
- (4-{(3S)-3-[(1R)-1-(ナフタレン-1-イル)エチルアミノ]ピロリジン-1-イル}フェニル)酢酸(化合物A)またはその薬理学的に許容される塩のメジアン径(D90)が75μm以下である、請求項1~25のいずれか1項に記載の医薬組成物。 (4-{(3S) -3-[(1R) -1- (Naphthalen-1-yl) ethylamino] pyrrolidin-1-yl} phenyl) acetic acid (Compound A) or a pharmaceutically acceptable salt thereof The pharmaceutical composition according to any one of claims 1 to 25, wherein the median diameter (D 90 ) is 75 μm or less.
- (4-{(3S)-3-[(1R)-1-(ナフタレン-1-イル)エチルアミノ]ピロリジン-1-イル}フェニル)酢酸(化合物A)またはその薬理学的に許容される塩のメジアン径(D90)が50μm以下である、請求項1~25のいずれか1項に記載の医薬組成物。 (4-{(3S) -3-[(1R) -1- (Naphthalen-1-yl) ethylamino] pyrrolidin-1-yl} phenyl) acetic acid (Compound A) or a pharmaceutically acceptable salt thereof The pharmaceutical composition according to any one of claims 1 to 25, wherein the median diameter (D 90 ) is 50 μm or less.
- (4-{(3S)-3-[(1R)-1-(ナフタレン-1-イル)エチルアミノ]ピロリジン-1-イル}フェニル)酢酸(化合物A)またはその薬理学的に許容される塩のメジアン径(D90)が35μm以下である、請求項1~25のいずれか1項に記載の医薬組成物。 (4-{(3S) -3-[(1R) -1- (Naphthalen-1-yl) ethylamino] pyrrolidin-1-yl} phenyl) acetic acid (Compound A) or a pharmaceutically acceptable salt thereof The pharmaceutical composition according to any one of claims 1 to 25, wherein the median diameter (D 90 ) is 35 μm or less.
- 医薬組成物が、副甲状腺機能亢進症の予防用組成物または治療用組成物である、請求項1~28のいずれか1項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 28, wherein the pharmaceutical composition is a composition for preventing or treating hyperparathyroidism.
- 医薬組成物が、経口用製剤である、請求項1~29のいずれか1項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 29, wherein the pharmaceutical composition is an oral preparation.
- 医薬組成物が、固形製剤である、請求項1~30のいずれか1項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 30, wherein the pharmaceutical composition is a solid preparation.
- 固形製剤が、錠剤、散剤、細粒剤、顆粒剤、カプセル剤またはドライシロップの形状を有する、請求項31に記載の医薬組成物。 32. The pharmaceutical composition according to claim 31, wherein the solid preparation has the form of a tablet, powder, fine granule, granule, capsule or dry syrup.
- 固形製剤が、錠剤である、請求項31に記載の医薬組成物。 32. The pharmaceutical composition according to claim 31, wherein the solid preparation is a tablet.
- 請求項1~33のいずれか1項に記載の医薬組成物、ならびにポリマーをラミネートしたフィルムおよびアルミ箔を用いて製造された、ブリスター包装品。 A blister package manufactured using the pharmaceutical composition according to any one of claims 1 to 33, a film laminated with a polymer, and an aluminum foil.
- ポリマーをラミネートしたフィルムが、ポリプロピレン、ポリ塩化ビニル、ポリ塩化ビニリデンおよびポリ塩化トリフルオロエチレンから選ばれる1種以上のポリマーをラミネートしたフィルムである、請求項34に記載のブリスター包装品。 35. The blister package according to claim 34, wherein the polymer-laminated film is a film in which at least one polymer selected from polypropylene, polyvinyl chloride, polyvinylidene chloride, and polytrifluoroethylene is laminated.
- アルミ箔が、接着剤中のメラミン樹脂量を低減したアルミ箔である、請求項34または35に記載のブリスター包装品。 36. The blister packaged product according to claim 34 or 35, wherein the aluminum foil is an aluminum foil in which the amount of melamine resin in the adhesive is reduced.
- 請求項34~36のいずれか1項に記載のブリスター包装品が包装体に封入された、医薬包装品。 A pharmaceutical packaged product in which the blister packaged product according to any one of claims 34 to 36 is enclosed in a package.
- 包装体が、アルミ袋である、請求項37に記載の医薬包装品。 38. The pharmaceutical package according to claim 37, wherein the package is an aluminum bag.
- 包装体内に、さらに脱酸素剤および/または乾燥剤が封入された、請求項37または38に記載の医薬包装品。 The pharmaceutical package according to claim 37 or 38, wherein an oxygen scavenger and / or a desiccant is further enclosed in the package.
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EP16853772.8A EP3360551A4 (en) | 2015-10-07 | 2016-10-07 | Pharmaceutical composition containing aryl alkyl amine compound |
US15/766,426 US10350194B2 (en) | 2015-10-07 | 2016-10-07 | Pharmaceutical composition containing an arylalkylamine compound |
KR1020197019836A KR102488488B1 (en) | 2015-10-07 | 2016-10-07 | Pharmaceutical composition containing aryl alkyl amine compound |
KR1020187012497A KR102000897B1 (en) | 2015-10-07 | 2016-10-07 | An arylalkylamine compound-containing pharmaceutical composition |
CN201680058580.7A CN108135883B (en) | 2015-10-07 | 2016-10-07 | Pharmaceutical composition containing arylalkylamine compound |
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JP2016197725A JP6168673B2 (en) | 2015-10-07 | 2016-10-06 | Arylalkylamine compound-containing pharmaceutical composition |
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