TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to a solid preparation improved in the stability during light irradiation, which comprises a pharmaceutically active ingredient as defined in claim 1, titanium oxide, a plasticizer and a chain organic acid which is fumaric acid, and a stabilizing method thereof.
(Background of the Invention)
[0002] Nonpeptidic pharmaceutically active ingredients having a primary or secondary amino group are widely used for various diseases. For example, patent document 1 describes a compound represented by the following formula and a salt thereof as agents for the treatment or prophylaxis of peptic ulcer, gastritis, erosive esophagitis and the like.
wherein r
1 is a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle, the monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent(s), r
2 is an optionally substituted C
6-14 aryl group, an optionally substituted thienyl group or an optionally substituted pyridyl group, r
3 and r
4 are each a hydrogen atom, or one of r
3 and r
4 is a hydrogen atom, and the other is an optionally substituted lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and r
5 is an alkyl group.
[0003] Patent document 2 describes a proton pump inhibitor (PPI) comprising a compound represented by the following formula or a salt thereof, or a prodrug thereof as an agent for the treatment or prophylaxis of peptic ulcer, gastritis, erosive esophagitis and the like.
wherein Z and W are the same or different and each is a bond or a spacer having 1 to 20 atoms in the main chain, r
6 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, r
7, r
8 and r
9 are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted thienyl group, an optionally substituted benzo[b]thienyl group, an optionally substituted furyl group, an optionally substituted pyridyl group, an optionally substituted pyrazolyl group, an optionally substituted pyrimidinyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and r
10 and r
11 are the same or different and each is a hydrogen atom or an optionally substituted hydrocarbon group.
[0004] Patent document 3 describes N-(1-octyl-5-carboxymethyl-4, 6-dimethylindolin-7-yl)-2,2-dimethylpropaneamide (the following formula) or a pharmacologically acceptable salt thereof as an active ingredient of a stabilized pharmaceutical composition containing an indoline compound.
[0005] Patent document 4 describes, as an improved preparation for oral use of a compound, a pharmaceutical composition for oral administration, which comprises at least a) ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzoimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate represented by the following formula or one of the pharmaceutically acceptable salts thereof and b) one or more pharmaceutically acceptable organic acids having water-solubility higher than 1 g/250 ml at 20°C.
[0006] On the other hand, regarding a stabilizer of a pharmaceutically active ingredient in a pharmaceutical composition, patent document 5 discloses an aqueous pharmaceutical solution comprising an aqueous solution containing an organic acid salt of a polymyxin antibiotic and carboxylic acid (organic acid, as a stabilizer).
[0007] In addition, non-patent document 1 describes, for stabilization of peptide (P66) in a nonaqueous solvent, acidification of peptide by addition of HCl, TFA, H
3PO
4 and the like.
[0008] Beside the above, patent document 6 describes a pharmaceutical composition comprising a proton pump antagonist (acid pump antagonist, APA) and one or more basic excipients to stabilize APA, and patent document 7 describes a sustained-release pharmaceutical composition comprising reversible PPI, wherein APA is stabilized with one or more basic excipients (carbonate, magnesium salt etc.).
[0009] Patent document 8 discloses a stabilized pharmaceutical preparation coated with a coating agent containing a) a light shielding agent capable of generating free radical by UV light, and b) a free radical scavenger. In addition, as the light shielding agent capable of generating free radical by UV light, metal oxides such as titanium oxide and the like are described, and as the free radical scavenger, for example, organic acids such as benzoic acid and the like are described.
[0010] Patent document 9 is directed to a solid, orally administrable, composition comprising painkillers containing tilidine and a light stabiliser.
[0011] Patent document 10 describes a stabilised pharmaceutical preparation which is coated with a coating agent comprising an agent for protection from light, said agent being capable of producing free radicals when exposed to ultraviolet rays, and a free radical scavenger.
[0012] Patent document 11 is directed to a stable pharmaceutical preparation containing an aminobenzenesulfonic acid derivative.
[0013] Patent document 12 relates to a preparation of ramosetron which is stable under irradiation with light.
[0014] In addition, non-patent document 2 describes the principles of photocatalytic reaction of titanium oxide, and explains the Honda Fujiyama effect that various substances adsorbed to a photocatalytic surface are oxidized and reduced when titanium oxide, which is one kind of the photocatalysts, is exposed to a light having a wavelength of 380 nm or below.
[Citation List]
[Patent Literature]
[Non Patent Literature]
SUMMARY OF THE INVENTION
PROBLEMS TO BE SOLVED BY THE INVENTION
[0017] An object of the present invention is to provide a solid preparation improved in the stability of a pharmaceutically active ingredient during light irradiation, for use of a pharmaceutically active ingredient as a solid active ingredient of a pharmaceutical composition, and a stabilizing method thereof.
MEANS OF SOLVING THE PROBLEMS
[0018] The present inventors have conducted intensive studies of photostabilization of a pharmaceutical composition and found that the stability of a pharmaceutically active ingredient during light irradiation can be improved by adding titanium oxide and a chain organic acid, namely fumaric acid, to a solid preparation comprising the pharmaceutically active ingredient as defined in claim 1, which resulted in the completion of the invention.
[0019] Accordingly, the present invention relates to
- [1] a solid preparation improved in the stability during light irradiation, comprising a pharmaceutically active ingredient, titanium oxide, a plasticizer and a chain organic acid wherein the chain organic acid is fumaric acid, and wherein the pharmaceutically active ingredient is 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, or a salt thereof, or N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine, or a salt thereof,
- [2] the solid preparation of the above-mentioned [1], wherein the plasticizer is represented by the formula
HOCH2(CH2OCH2)nCH2OH
(n=an integer of 2 - 870), - [3] the solid preparation of the above-mentioned [1], wherein the plasticizer is polyethylene glycol (PEG),
- [4] the solid preparation of the above-mentioned [1], wherein the chain organic acid has pH 6.0 or below when dissolved or dispersed in water,
- [5] the solid preparation of the above-mentioned [1], wherein the chain organic acid has an acid dissociation constant (pKa) of a proton complex of 4.0 or below when dissolved or dispersed in water,
- [6] the solid preparation of the above-mentioned [1], wherein the content (%) of the chain organic acid is 0.01 - 50 wt%,
- [7] a method of stabilizing a solid preparation comprising a pharmaceutically active ingredient, titanium oxide and a plasticizer during light irradiation, comprising adding a chain organic acid to the solid preparation, wherein the chain organic acid is fumaric acid and the pharmaceutically active ingredient is 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, or a salt thereof, or N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine, or a salt thereof.
EFFECT OF THE INVENTION
[0020] According to the present invention, a solid preparation improved in the stability of a pharmaceutically active ingredient to light irradiation is provided. To be specific, a solid preparation stable to light irradiation can be provided by, when the pharmaceutically active ingredient contained in the solid preparation is exposed to light, shielding the light and suppressing an increase in a decomposed product.
(Detailed Description of the Invention)
[0021] The present invention is explained in detail by referring to a specific embodiment.
[0022] The solid preparation of the present invention contains a pharmaceutically active ingredient, titanium oxide, a plasticizer and a chain organic acid, wherein the chain organic acid is fumaric acid, and wherein the pharmaceutically active ingredient is 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, or a salt thereof, or N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine, or a salt thereof and is characteristically a solid preparation improved in the stability during light irradiation.
[0023] When a pharmaceutically active ingredient unstable to light irradiation is formulated into a preparation, titanium oxide (TiO
2) is generally used together with a film coating agent (also referred to as a coating agent) for shielding to ensure light-stability of the preparation. However, TiO
2 shows a shielding function due to its high refractive index, but also shows a strong oxidation action caused by hole generation during light irradiation. The cause is presumed to be that 1) titanium oxide in a coating agent develops a free radical due to UV light, 2) the drug and alcohols in the coating agent such as polyethylene glycol are decomposed due to free radical, 3) a decomposed product of alcohols (e.g., polyethylene glycol), for example, aldehydes such as formaldehyde and acetoaldehyde, an acid such as formic acid, and peroxide in the coating agent further cause decomposition of the drug. To improve the light-stability of the preparation, therefore, it is necessary to suppress the decomposed product due to its strong oxidation action while utilizing the light shielding effect of TiO
2. Conventionally, as a means to suppress an increase in the decomposed product, a method including forming an intermediate layer between a film coating and a core tablet and a method including removing PEG (plasticizer) from a film coating component have generally been employed. However, these methods may decrease the productivity during film coating, which may influence the final appearance of a film-coated tablet.
[0024] The present inventors have found an effect of suppressing a decomposed product during light irradiation by adding a chain organic acid to the solid preparation (either core or film), without decreasing the productivity during film coating.
[0025] The solid preparation of the present invention improved in the light stability is explained in the following.
[Pharmaceutically active ingredient (component I)]
[0026] The form of the pharmaceutically active ingredient to be used in the present invention may be, for example, any of solid, powder, crystal, oil and solution, and its efficacy is not particularly limited.
[0027] The pharmaceutically active ingredient is 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, or a salt thereof, or N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine, or a salt thereof.
[0028] When the pharmaceutically active ingredient has isomers such as optical isomer, stereoisomer, positional isomer and rotational isomer, any isomers and mixtures are encompassed in the pharmaceutically active ingredient. For example, when the pharmaceutically active ingredient has an optical isomer, an optical isomer separated from a racemate is also encompassed in the pharmaceutically active ingredient. These isomers can be obtained as independent products by a synthesis means or a separation means (e.g., concentration, solvent extraction column chromatography and recrystallization).
[0029] The pharmaceutically active ingredient may be a crystal, and both a single crystal and crystal mixtures are encompassed in the pharmaceutically active ingredient. Crystals can be produced by crystallization according to crystallization methods known
per se.
[0030] The pharmaceutically active ingredient may be a solvate (e.g., hydrate) or a non-solvate, both of which are encompassed in the pharmaceutically active ingredient.
[0031] A compound labeled with an isotope (e.g.,
3H,
14C,
35S and
125I) is also encompassed in the pharmaceutically active ingredient.
[0032] The pharmaceutically active ingredient can be produced, for example, according to the method described in
WO 2007/026916.
[0033] Examples of the salt of the above-mentioned "pharmaceutically active ingredient" include metal salt, ammonium salt, salt with organic base, salt with inorganic acid, salt with organic acid and salt with basic or acidic amino acid.
[0034] Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; and aluminum salt. Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine and N,N'-dibenzylethylenediamine. Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid. Preferable examples of the salt with an organic acid include salts with adipic acid, ascorbic acid, benzoic acid, oleic acid, succinic acid, acetic acid, tartaric acid, sorbic acid, fumaric acid, lactic acid, maleic acid, malonic acid, citric anhydride, maleic anhydride, phthalic acid, phthalic anhydride, malic acid, formic acid, trifluoroacetic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. Preferable examples of the salt with a basic amino acid include salts with arginine, lysine and ornithine, and preferable examples of the salt with an acidic amino acid include salts with aspartic acid and glutamic acid.
[0035] Of these, a salt with an organic acid is preferable for the pharmaceutical composition of the present invention. Examples of the salt with an organic acid for such pharmaceutically active ingredient include salts with, for example, adipic acid, ascorbic acid, benzoic acid, oleic acid, succinic acid, acetic acid, tartaric acid, sorbic acid, fumaric acid, lactic acid, maleic acid, malonic acid, citric anhydride, maleic anhydride, phthalic anhydride and malic acid. In addition, of the organic acid salts, a salt with an unsaturated carboxylic acid is particularly preferably used. Examples of the salt with such unsaturated carboxylic acid include salts with fumaric acid, sorbic acid, maleic acid, oleic acid, succinic acid and tartaric acid. Of these, the salts with fumaric acid, succinic acid and tartaric acid are preferable.
The present invention has a remarkable effect for improving the stability of a pharmaceutically active ingredient as defined in claim 1 to light irradiation.
[Titanium oxide (component II)]
[0036] In the present invention, titanium oxide has a superior shielding effect against light. The particle size of titanium oxide to be used in the present invention is generally about 0.01 - about 1.5 µm, preferably about 0.1 - about 0.7 µm. When titanium oxide is added to a coating agent for, for example, film-coated tablets, the content of titanium oxide is such an amount capable of achieving the object of shielding of the pharmaceutical preparation, which is preferably about 5 - about 30 wt%, more preferably about 5 - about 20 wt%, of the coating agent.
[Plasticizer (component III)]
[0037] Examples of the "plasticizer" to be used in the present invention include plasticizers generally used in a pharmaceutical preparation. Specifically, for example, esters such as triethyl citrate, medium-chain triglyceride, diethyl phthalate, dibutyl phthalate, triacetine (triacetyl glycerol), butyl phthalyl butyl glycolate and glyceryl caprylate; alcohols such as glycerol, propylene glycol and polyethylene glycol. As the plasticizer, a compound of the chemical formula [HOCH
2(CH
2OCH
2)
nCH
2OH (n=integer of 2 - 870)] is preferable, and polyethylene glycol (PEG) is particularly preferable. Examples of PEG actually used as the plasticizer include macrogol (manufactured by Sanyo chemical industries, Ltd.). While the average molecular weight of PEG is not particularly limited, it is preferably not less than 200, more preferably 200 - 20000, since a smaller average molecular weight increases hygroscopicity. When PEG is added to a coating agent for a film-coated tablet, for example, the content of PEG is preferably about 5 - about 30 wt%, especially about 10 - 25 wt%, more preferably about 10 - about 20 wt%, of the coating agent.
[Chain organic acid (component IV)]
[0038] In the solid preparation of the present invention, titanium oxide is used for shielding. However, it is known that since titanium oxide has a strong oxidation action as mentioned above, when a coating agent containing a light shielding agent such as titanium oxide and a plasticizer such as, for example, polyethylene glycol is applied to a drug-containing tablet during formulation of a preparation of a drug unstable to light, the obtained film-coated tablet becomes inferior to the tablet before a coating treatment in the stability to light. The present invention effectively suppresses, without decreasing the productivity during film coating, generation of a decomposed product during light irradiation by adding an organic acid, particularly a chain organic acid, together with titanium oxide to, for example, a solid preparation such as a film coating agent. The chain organic acid is fumaric acid. The chain organic acid preferably has pH 6.0 or below when dissolved or dispersed in water.
[0039] The pH of a chain organic acid is measured under the following conditions. To be specific, the pH of an aqueous solution or dispersion obtained by dissolving or dispersing a measurement target in water at 1 %w/v is measured at 25°C with a commercially available pH meter.
[0040] The content (%) of the chain organic acid in the whole pharmaceutical composition of the present invention is preferably 0.1 - 20% (more preferably 0.1 - 19%), further preferably 1 - 10%, particularly preferably 2 - 10%. In another embodiment, it is 0.01 - 50%, preferably 0.05 - 19%, more preferably 0.1 - 10%.
[0041] When producing the pharmaceutical composition of the present invention, the "chain organic acid" may be added as a powder in a granulation step or a mixing step. In addition, a chain organic acid can be sprayed by dissolving or dispersing in a binder solution in the granulation step or in a film coating solution in a film coating step.
[0042] The solid preparation containing the pharmaceutically active ingredient of the present invention has low toxicity, and can be safely administered orally or parenterally (e.g., topical, rectal and intravenous administration) as it is or in the form of a pharmaceutical composition containing a pharmacologically acceptable carrier according to a method known per se, for example, as preparations such as tablet (for example, core tablet, sugar-coated tablet and film-coated tablet), powder, granule, capsule (including soft capsule), orally disintegrating tablet, suppository and sustained-release preparation. The pharmaceutical composition of the present invention is preferably administered as an oral preparation such as tablet, granule and capsule. Of these, tablet and capsule are preferable, and a sugar-coated tablet and a film-coated tablet are especially preferable.
[0043] Examples of the pharmacologically acceptable carrier that can be used for the production of the pharmaceutical composition of the present invention include various organic or inorganic carrier substances conventionally used as preparation materials. For example, filler, lubricant, binder, disintegrant, water-soluble polymer and basic inorganic salt for solid preparations; solvent, solubilizing agent, suspending agent, isotonicity agent, buffering agent and soothing agent for liquid preparation can be mentioned. Where necessary, general additives such as preservative, antioxidant, colorant, sweetening agent, foaming agent and flavor can also be used.
[0044] The pharmaceutical composition of the present invention does not have to contain a souring agent.
[0045] Now, as one embodiment of the present invention, an example wherein a solid preparation containing a pharmaceutically active ingredient, titanium oxide, a plasticizer and a chain organic acid, as explained above, is applied to a film-coated tablet is explained in the following. The film-coated tablet is obtained by coating a core tablet (core) containing a pharmaceutically active ingredient with a film coating layer comprising the following film coating polymer. Generally, a pharmaceutically active ingredient is contained in a core, but titanium oxide, a chain organic acid and a plasticizer may be contained in either or both of a core or(and) a film coating layer. Particularly, titanium oxide and a plasticizer are preferably contained in a film coating layer. In addition, a core material containing a chain organic acid and a layer containing an active ingredient do not need to be separated by a separating layer.
[0046] A film coating solution is sprayed on a solid preparation (preferably tablet, more preferably ellipse or round tablet), and dried as necessary. The "film coating solution" is prepared by, for example, dissolving or suspending a film coating polymer in a solvent. The film coating solution may further contain, for example, a colorant (preferably, diiron trioxide and yellow ferric oxide), a light shielding agent (preferably, titanium oxide). Examples of the "film coating polymer" include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, acrylic resin (for example, methacrylic acid - acrylic acid copolymer, aminoalkylmethacrylate copolymer), shellac, polyvinyl acetatephthalate, gum arabic, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate and carboxymethylethylcellulose. Examples of the "solvent" include water, alcohols (e.g., ethanol, isopropyl alcohol, n-propyl alcohol and methanol), acetone, ethyl acetate, dichloromethane, chloroform, hexane, toluene and heptane. The amount of the "film coating polymer" to be used can be selected according to the kind of the solid preparation and, when the solid preparation is a tablet, it is, for example, about 0.5 - 10
wt% of a tablet. The spraying temperature is generally 25 - 80°C, the spraying time is generally 5 min - 24 hr, and the drying conditions are generally 30 - 80°C for about 1 min - 24 hr. The film coating layer of the present invention can be formed at a ratio of generally 1 - 10 parts by weight, preferably 2 - 6 parts by weight, per 100 parts by weight of the solid preparation (preferably tablet, more preferably ellipse or round tablet) of the present invention.
[0047] The pharmaceutical composition of the present invention can be formulated into a preparation for oral administration (film-coated tablet) by, for example, adding, where necessary, an excipient to the above-mentioned component I and component IV to give a granulated powder, adding, where necessary, for example a binder, a disintegrant or a lubricant thereto, tableting the obtained mixture by a method known per se and, where necessary, coating the tablet by a method known per se for masking of taste, enteric coating or sustained release.
[0048] The core tablet of the pharmaceutical composition of the present invention can be obtained by adding an excipient and the above-mentioned component IV (chain organic acid) to the above-mentioned component I (pharmaceutically active ingredient), adding, where necessary, a binder, sieving the obtained granulated powder, adding, where necessary, a disintegrant and, where necessary, a lubricant, mixing the mixture, and punching the obtained mixed powder. The obtained core tablet can be formulated into a film-coated tablet of the pharmaceutical composition of the present invention by coating the core tablet by a method known per se.
[0049] A binder can be added by spraying an aqueous solution thereof.
[0050] The coating by a method known per se includes, for example, separately preparing a coating solution using, for example, a disperser or a propeller stirring machine, and spraying and coating the solution on tablets charged in a film coating machine.
[0051] As the "excipient", preferred is an excipient having pH 4.5 or above when dissolved or dispersed in water.
[0052] Examples of such excipient include mannitol, croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, polyvinylpyrrolidone, crystalline cellulose, lactose, sucrose, starch, cornstarch, titanium oxide (TiO
2) and light anhydrous silicic acid. These excipients may be used alone or two or more kinds thereof may be used in combination. Of these, as the excipient, mannitol, hydroxypropylcellulose and crystalline cellulose are preferable.
[0053] Examples of the "binder" include hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan and low-substituted hydroxypropylcellulose.
[0054] Examples of the "disintegrant" include (1) crospovidone, (2) disintegrants referred to as super disintegrants such as croscarmellose sodium (FMC-Asahi Kasei) and carmellose calcium (Gotoku Yakuhin), (3) sodium carboxymethyl starch (e.g., manufactured by Matsutani Chemical Industry Co., Ltd.), (4) low-substituted hydroxypropylcellulose (e.g., manufactured by Shin-Etsu Chemical Co., Ltd.), (5) cornstarch. The "crospovidone" may be any crosslinked polymer having a chemical name of 1-ethenyl-2-pyrrolidinone homopolymer including polyvinylpolypyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinone homopolymer. Specific examples thereof include Kollidon CL (manufactured by BASF), Polyplasdone XL (manufactured by ISP), Polyplasdone XL-10 (manufactured by ISP) and Polyplasdone INF-10 (manufactured by ISP.
[0055] Examples of the "lubricant" include magnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc and stearic acid.
[0056] The pharmaceutical composition of the present invention is superior in the stability during light irradiation.
EXAMPLES
[0057] The present invention is explained in more detail in the following by referring to Comparative Examples, Examples and Experimental Examples, which are not to be construed as limitative. In the formulations described as Examples, Pharmacopoeia compatible products and Japanese Pharmaceutical Excipients compatible products were used as the components other than the active ingredient (additives). In the following Examples and Comparative Examples, the Japanese Pharmacopoeia 15th Edition or Japanese Pharmaceutical Excipients 2003 compatible products were used as the preparation additives (e.g., lactose, D-mannitol, hydroxypropylcellulose, crospovidone, magnesium stearate, crystalline cellulose).
[0058] Unless otherwise specified, % in the following means wt%.
[0059] The solid preparation of the present invention containing a pharmaceutically active ingredient as defined in claim 1, titanium oxide, a plasticizer and a chain organic acid, wherein the chain organic acid is fumaric acid, was evaluated for the stability during light irradiation. The results are now explained by Examples 45 - 71 and Comparative Examples 7 - 9.
Example 45 (sample 51)
[0060] A plain tablet (core tablet) containing 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate (hereinafter to be referred to as compound A) was produced as follows at the composition ratio shown in Table 53.
[0061] That is, compound A (24.340 g), mannitol (4350.2 g) and crystalline cellulose (540.1 g) were placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture was preheated and mixed. The mixture was granulated while spraying an aqueous solution (2700.0 g) of hydroxypropylcellulose (162.1 g) to give a granulated powder. The obtained granulated powder (4568.1 g) was passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder (Batch 1).
[0062] Compound A (24.341 g), mannitol (4350.0 g) and crystalline cellulose (540.0 g) were placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture was preheated and mixed. The mixture was granulated while spraying an aqueous solution (2700.0 g) of hydroxypropylcellulose (162.0 g) to give a granulated powder. The obtained granulated powder (4568.1 g) was passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder (Batch 2).
[0063] The sized powders (Batch 1 and Batch 2, 8460.0 g), croscarmellose sodium (450.0 g) and magnesium stearate (90.007 g) were placed in a tumbler mixer (TM-60S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The mixed powder was tableted by a rotary tableting machine (AQUARIUS 08242L2JI, manufactured by Kikusui Seisakusho, Ltd.) using a 9 mmφ punch to give plain tablets (core tablets, 300 mg per tablet).
[Table 53]
composition of plain tablet (core tablet) containing compound A (sample 51) |
composition | amount (mg) |
1) compound A* |
1.336 |
2) mannitol |
241.664 |
3) crystalline cellulose |
30 |
4) hydroxypropylcellulose |
9 |
5) croscarmellose sodium |
15 |
6) magnesium stearate |
3 |
total |
300.0 |
* Where necessary, the content was amended using mannitol as an adjustment component. |
Example 46 (sample 52) (Reference)
[0064] The plain tablets (core tablets) obtained in Example 45 (sample 51, 30.0 g) were placed in a film coating machine (DRC-200, manufactured by POWREX CORPORATION), and film-coated tablets (about 312 mg per tablet) were obtained while spraying a film coating solution (65.9 g) having the composition ratio shown in Table 54. The obtained film-coated tablets were arranged on a plastic petri dish (45 sample cup, manufactured by Shinwa Kagaku), and exposed to xenon light (1200000 Lux/hr) by a xenon fade meter (SX75, manufactured by Suga Test Instruments).
[Table 54]
Composition of aqueous film coating solution |
composition | amount (mg) |
1) hypromellose |
8.8 |
2) macrogol 6000 |
2 |
3 )titanium oxide |
1 |
4) diiron trioxide |
0.2 |
5) purified water |
108 |
total |
120.0 |
Example 47 (sample 53)
[0065] The plain tablets (core tablets) obtained in Example 45 (sample 51, 30.0 g) were placed in a film coating machine (DRC-200, manufactured by POWREX CORPORATION), and film-coated tablets (about 312 mg per tablet) were obtained while spraying a film coating solution (66.2 g) having the composition ratio shown in Table 55. The obtained film-coated tablets were arranged on a plastic petri dish (45 sample cup, manufactured by Shinwa Kagaku), and samples shielded with aluminum foil and non-shielded samples were exposed to xenon light (1200000 Lux/hr).
[Table 55]
Composition of aqueous film coating solution |
composition | amount (mg) |
1) hypromellose |
8.595 |
2) macrogol 6000 |
1.953 |
3) titanium oxide |
0.977 |
4) diiron trioxide |
0.195 |
5) fumaric acid |
0.28 |
6) purified water |
108 |
total |
120.0 |
Example 48 (sample 54)
[0066] The plain tablets (core tablets) obtained in Example 45 (sample 51, 30.0 g) were placed in a film coating machine (DRC-200, manufactured by POWREX CORPORATION), and film-coated tablets (about 312 mg per tablet) were obtained while spraying a film coating solution (75.1 g) having the composition ratio shown in Table 56. The obtained film-coated tablets were arranged on a plastic petri dish (45 sample cup, manufactured by Shinwa Kagaku), and exposed to xenon light (1200000 Lux/hr) by a xenon fade meter (SX75, manufactured by Suga Test Instruments).
[Table 56]
Composition of aqueous film coating solution |
composition | amount (mg) |
1) hypromellose |
8.389 |
2) macrogol 6000 |
1.907 |
3) titanium oxide |
0.953 |
4 )diiron trioxide |
0.191 |
5) fumaric acid |
0.56 |
6) purified water |
108 |
total |
120.0 |
Example 49 (sample 55)
[0067] A plain tablet (core tablet) containing compound A was produced as follows at the composition ratio shown in Table 57.
[0068] That is, compound A (2.4074 g), mannitol (432.3 g), crystalline cellulose (54.0 g) and fumaric acid (2.70 g) were placed in a fluidized bed dryer granulator (LAB-1, manufactured by POWREX CORPORATION), and the mixture was preheated and mixed. The mixture was granulated while spraying an aqueous solution (270.0 g) of hydroxypropylcellulose (16.2 g) to give a granulated powder. The obtained granulated powder was passed through a 16M (1000 µm) sieve to give a sized powder. Croscarmellose sodium (22.50 g) and magnesium stearate (4.5011 g) were added to the sized powder (423.0 g), and mixed to give a mixed powder. The mixed powder was tableted by a rotary tableting machine (COLLECT 19K, manufactured by Kikusui Seisakusho, Ltd.) using a 9 mmφ punch to give plain tablets (core tablets, 300 mg per tablet).
[Table 57]
composition of plain tablet (core tablet) containing compound A (sample 55) |
composition | amount (mg) |
1) compound A* |
1.336 |
2) mannitol |
240.164 |
3) crystalline cellulose |
30 |
4) hydroxypropylcellulose |
9 |
5) fumaric acid |
1.5 |
6) croscarmellose sodium |
15 |
7) magnesium stearate |
3 |
total |
300.0 |
* Where necessary, the content was amended using mannitol as an adjustment component. |
Example 50 (sample 56)
[0069] A plain tablet (core tablet) containing compound A was produced as follows at the composition ratio shown in Table 58.
[0070] That is, compound A (2.4080 g), mannitol (429.6 g), crystalline cellulose (54.0 g) and fumaric acid (5.40 g) were placed in a fluidized bed dryer granulator (LAB-1, manufactured by POWREX CORPORATION), and the mixture was preheated and mixed. The mixture was granulated while spraying an aqueous solution (270.0 g) of hydroxypropylcellulose (16.2 g) to give a granulated powder. The obtained granulated powder was passed through a 16M (1000 µm) sieve to give a sized powder. Croscarmellose sodium (22.50 g) and magnesium stearate (4.5012 g) were added to the sized powder (423.0 g), and mixed to give a mixed powder. The mixed powder was tableted by a rotary tableting machine (COLLECT 19K, manufactured by Kikusui Seisakusho, Ltd.) using a 9 mmφ punch to give plain tablets (core tablets, 300 mg per tablet).
[Table 58]
composition of plain tablet (core tablet) containing compound A (sample 56) |
composition | amount (mg) |
1) compound A* |
1.336 |
2) mannitol |
238.664 |
3) crystalline cellulose |
30 |
4) hydroxypropylcellulose |
9 |
5) fumaric acid |
3 |
6) croscarmellose sodium |
15 |
7) magnesium stearate |
3 |
total |
300.0 |
* Where necessary, the content was amended using mannitol as an adjustment component. |
Example 51 (sample 57)
[0071] A plain tablet (core tablet) containing compound A was produced as follows at the composition ratio shown in Table 59.
[0072] That is, compound A (2.4095 g), mannitol (422.4 g), crystalline cellulose (54.0 g) and fumaric acid (12.60 g) were placed in a fluidized bed dryer granulator (LAB-1, manufactured by POWREX CORPORATION), and the mixture was preheated and mixed. The mixture was granulated while spraying an aqueous solution (270.0 g) of hydroxypropylcellulose (16.2 g) to give a granulated powder. The obtained granulated powder was passed through a 16M (1000 µm) sieve to give a sized powder. Croscarmellose sodium (22.50 g) and magnesium stearate (4.5017 g) were added to the sized powder (423.0 g), and mixed to give a mixed powder. The mixed powder was tableted by a rotary tableting machine (COLLECT 19K, manufactured by Kikusui Seisakusho, Ltd.) using a 9 mmφ punch to give plain tablets (core tablets, 300 mg per tablet).
[Table 59]
composition of plain tablet (core tablet) containing compound A (sample 57) |
composition | amount (mg) |
1) compound A* |
1.336 |
2) mannitol |
234.664 |
3) crystalline cellulose |
30 |
4) hydroxypropylcellulose |
9 |
5) fumaric acid |
7 |
6) croscarmellose sodium |
15 |
7) magnesium stearate |
3 |
total |
300.0 |
* Where necessary, the content was amended using mannitol as an adjustment component. |
Example 52 (sample 58)
[0073] The plain tablets (core tablets) obtained in Example 49 (sample 55, 100.0 g) were placed in a film coating machine (DRC-200, manufactured by POWREX CORPORATION), and film-coated tablets (about 312 mg per tablet) were obtained while spraying a film coating solution (49.2 g) having the composition ratio shown in Table 60. The obtained film-coated tablets were arranged on a plastic petri dish (45 sample cup, manufactured by Shinwa Kagaku), and exposed to xenon light (1200000 Lux/hr) by a xenon fade meter (SX75, manufactured by Suga Test Instruments).
[Table 60]
Composition of aqueous film coating solution |
composition | amount (mg) |
1) hypromellose |
8.8 |
2) macrogol 6000 |
2 |
3) titanium oxide |
1 |
4) diiron trioxide |
0.2 |
5) purified water |
108 |
total |
120.0 |
Example 53 (sample 59)
[0074] The plain tablets (core tablets) obtained in Example 50 (sample 56, 100.0 g) were placed in a film coating machine (DRC-200, manufactured by POWREX CORPORATION), and film-coated tablets (about 312 mg per tablet) were obtained while spraying a film coating solution (61.4 g) having the composition ratio shown in Table 61. The obtained film-coated tablets were arranged on a plastic petri dish (45 sample cup, manufactured by Shinwa Kagaku), and exposed to xenon light (1200000 Lux/hr) by a xenon fade meter (SX75, manufactured by Suga Test Instruments).
[Table 61]
Composition of aqueous film coating solution |
composition | amount (mg) |
1) hypromellose |
8.8 |
2) macrogol 6000 |
2 |
3) titanium oxide |
1 |
4) diiron trioxide |
0.2 |
5) purified water |
108 |
total |
120.0 |
Example 54 (sample 60)
[0075] The plain tablets (core tablets) obtained in Example 51 (sample 57, 100.0 g) were placed in a film coating machine (DRC-200, manufactured by POWREX CORPORATION), and film-coated tablets (about 312 mg per tablet) were obtained while spraying a film coating solution (59.5 g) having the composition ratio shown in Table 62. The obtained film-coated tablets were arranged on a plastic petri dish (45 sample cup, manufactured by Shinwa Kagaku), and exposed to xenon light (1200000 Lux/hr) by a xenon fade meter (SX75, manufactured by Suga Test Instruments).
[Table 62]
Composition of aqueous film coating solution |
composition | amount (mg) |
1) hypromellose |
8.8 |
2) macrogol 6000 |
2 |
3) titanium oxide |
1 |
4) diiron trioxide |
0.2 |
5) purified water |
108 |
total |
120.0 |
Comparative Example 7 (sample 61)
[0076] A plain tablet (core tablet) containing compound A was produced as follows at the composition ratio shown in Table 63.
[0077] That is, compound A (24.491 g), mannitol (4350.0 g) and crystalline cellulose (540.0 g) were placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture was preheated and mixed. The mixture was granulated while spraying an aqueous solution (2700.0 g) of hydroxypropylcellulose (162.0 g) to give a granulated powder. The obtained granulated powder (4568.0 g) was passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4230.0 g), croscarmellose sodium (225.0 g) and magnesium stearate (45.007 g) were placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The mixed powder was tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 9 mmφ punch to give plain tablets (core tablets, 300 mg per tablet).
[Table 63]
composition of plain tablet (core tablet) containing compound A (sample 61) |
composition | amount (mg) |
1) compound A* |
1.336 |
2) mannitol |
241.664 |
3) crystalline cellulose |
30 |
4) hydroxypropylcellulose |
9 |
5) croscarmellose sodium |
15 |
6) magnesium stearate |
3 |
total |
300.0 |
* Where necessary, the content was amended using mannitol as an adjustment component. |
Comparative Example 8 (sample 62)
[0078] The plain tablets (core tablets) obtained in Comparative Example 7 (sample 61, 3300.0 g) were placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 312 mg per tablet) were obtained while spraying a film coating solution (1372.0 g) having the composition ratio shown in Table 64. The obtained film-coated tablets were arranged on a plastic petri dish (45 sample cup, manufactured by Shinwa Kagaku), and exposed to xenon light (1200000 Lux/hr) by a xenon fade meter (SX75, manufactured by Suga Test Instruments).
[Table 64]
Composition of aqueous film coating solution |
composition | amount (mg) |
1) hypromellose |
10.8 |
2) titanium oxide |
1 |
3) diiron trioxide |
0.2 |
4) purified water |
108 |
total |
120.0 |
Example 55 (sample 63)
[0079] A plain tablet (core tablet) containing compound A is produced as follows at the composition ratio shown in Table 65.
[0080] That is, compound A (641.28 g), mannitol (3503.52 g), fumaric acid (132.0 g) and crystalline cellulose (528.0 g) are placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture is preheated and mixed. The mixture is granulated while spraying an aqueous solution (2640.0 g) of hydroxypropylcellulose (158.4 g) to give a granulated powder. The obtained granulated powder (4653.0 g) is passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4342.8 g), croscarmellose sodium (231.0 g) and magnesium stearate (46.2 g) are placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The mixed powder is tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 6.5 mmφ punch to give plain tablets (core tablets, 110 mg per tablet). The obtained plain tablets (core tablets, 3300.0 g) are placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 114.4 mg per tablet) are obtained while spraying a film coating solution (1380.0 g) having the composition ratio shown in Table 66.
[Table 65]
composition of plain tablet (core tablet) containing compound A |
composition | amount (mg) |
1) compound A |
13.36 |
2) mannitol |
72.99 |
3) crystalline cellulose |
11 |
4) hydroxypropylcellulose |
3.3 |
5) fumaric acid |
2.75 |
6) croscarmellose sodium |
5.5 |
7) magnesium stearate |
1.1 |
total |
110.0 |
[Table 66]
composition of aqueous film coating solution |
composition | amount (mg) |
1) hypromellose |
6.6 |
2) macrogol 6000 |
1.5 |
3) titanium oxide |
0.75 |
4) yellow ferric oxide |
0.075 |
5) diiron trioxide |
0.075 |
6) purified water |
81 |
total |
90.0 |
Example 56 (sample 64)
[0081] A plain tablet (core tablet) containing compound A is produced as follows at the composition ratio shown in Table 67.
[0082] That is, compound A (641.28 g), mannitol (3503.52 g), fumaric acid (132.0 g) and crystalline cellulose (528.0 g) are placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture is preheated and mixed. The mixture is granulated while spraying an aqueous solution (2640.0 g) of hydroxypropylcellulose (158.4 g) to give a granulated powder. The obtained granulated powder (4653.0 g) is passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4342.8 g), croscarmellose sodium (231.0 g) and magnesium stearate (46.2 g) are placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The mixed powder is tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 7 mmφ punch to give plain tablets (core tablets, 165 mg per tablet). The obtained plain tablets (core tablets, 3300.0 g) are placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 171.6 mg per tablet) are obtained while spraying a film coating solution (1380.0 g) having the composition ratio shown in Table 66.
[Table 67]
composition of plain tablet (core tablet) containing compound A |
composition | amount (mg) |
1) compound A |
20.04 |
2) mannitol |
109.485 |
3) crystalline cellulose |
16.5 |
4) hydroxypropylcellulose |
4.95 |
5) fumaric acid |
4.125 |
6) croscarmellose sodium |
8.25 |
7) magnesium stearate |
1.65 |
total |
165.0 |
Example 57 (sample 65)
[0083] A plain tablet (core tablet) containing compound A is produced as follows at the composition ratio shown in Table 68.
[0084] That is, compound A (641.28 g), mannitol (3503.52 g), fumaric acid (132.0 g) and crystalline cellulose (528.0 g) are placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture is preheated and mixed. The mixture is granulated while spraying an aqueous solution (2640.0 g) of hydroxypropylcellulose (158.4 g) to give a granulated powder. The obtained granulated powder (4653.0 g) is passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4342.8 g), croscarmellose sodium (231.0 g) and magnesium stearate (46.2 g) are placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The mixed powder is tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 9.5 mmφ punch to give plain tablets (core tablets, 330 mg per tablet). The obtained plain tablets (core tablets, 3300.0 g) is placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 343.2 mg per tablet) is obtained while spraying a film coating solution (1380.0 g) having the composition ratio shown in Table 66.
[Table 68]
composition of plain tablet (core tablet) containing compound A |
composition | amount (mg) |
1) compound A |
40.08 |
2) mannitol |
218.97 |
3) crystalline cellulose |
33 |
4) hydroxypropylcellulose |
9.9 |
5) fumaric acid |
8.25 |
6) croscarmellose sodium |
16.5 |
7) magnesium stearate |
3.3 |
total |
330.0 |
Example 58 (sample 66)
[0085] A plain tablet (core tablet) containing compound A is produced as follows at the composition ratio shown in Table 69.
[0086] That is, compound A (641.28 g), mannitol (3503.52 g), fumaric acid (132.0 g) and crystalline cellulose (528.0 g) are placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture is preheated and mixed. The mixture is granulated while spraying an aqueous solution (2640.0 g) of hydroxypropylcellulose (158.4 g) to give a granulated powder. The obtained granulated powder (4653.0 g) is passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4342.8 g), croscarmellose sodium (231.0 g) and magnesium stearate (46.2 g) are placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The mixed powder is tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 14×8 mmφ punch to give plain tablets (core tablets, 440 mg per tablet). The obtained plain tablets (core tablets, 3300.0 g) are placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 457.6 mg per tablet) are obtained while spraying a film coating solution (1380.0 g) having the composition ratio shown in Table 66.
[Table 69]
composition of plain tablet (core tablet) containing compound A |
composition | amount (mg) |
1) compound A |
53.44 |
2) mannitol |
291.96 |
3) crystalline cellulose |
44 |
4) hydroxypropylcellulose |
13.2 |
5) fumaric acid |
11 |
6) croscarmellose sodium |
22 |
7) magnesium stearate |
4.4 |
total |
440 |
Example 59 (sample 67)
[0087] A plain tablet (core tablet) containing compound A is produced as follows at the composition ratio shown in Table 70.
[0088] That is, compound A (881.76 g), mannitol (3263.04 g), fumaric acid (132.0 g) and crystalline cellulose (528.0 g) are placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture is preheated and mixed. The mixture is granulated while spraying an aqueous solution (2640.0 g) of hydroxypropylcellulose (158.4 g) to give a granulated powder. The obtained granulated powder (4653.0 g) is passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4342.8 g), croscarmellose sodium (231.0 g) and magnesium stearate (46.2 g) are placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The mixed powder is tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 6.5 mmφ punch to give plain tablets (core tablets, 120 mg per tablet). The obtained plain tablets (core tablets, 3300.0 g) are placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 124.8 mg per tablet) are obtained while spraying a film coating solution (1380 g) having the composition ratio shown in Table 66.
[Table 70]
composition of plain tablet (core tablet) containing compound A |
composition | amount (mg) |
1) compound A |
20.04 |
2) mannitol |
74.16 |
3) crystalline cellulose |
12 |
4) hydroxypropylcellulose |
3.6 |
5) fumaric acid |
3 |
6) croscarmellose sodium |
6 |
7) magnesium stearate |
1.2 |
total |
120 |
Example 60 (sample 68)
[0089] A plain tablet (core tablet) containing compound A is produced as follows at the composition ratio shown in Table 71.
[0090] That is, compound A (881.76 g), mannitol (3263.04 g), fumaric acid (132.0 g) and crystalline cellulose (528.0 g) are placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture is preheated and mixed. The mixture is granulated while spraying an aqueous solution (2640.0 g) of hydroxypropylcellulose (158.4 g) to give a granulated powder. The obtained granulated powder (4653.0 g) is passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4342.8 g), croscarmellose sodium (231.0 g) and magnesium stearate (46.2 g) are placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The mixed powder is tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 7 mmφ punch to give plain tablets (core tablets, 160 mg per tablet). The obtained plain tablets (core tablets, 3300.0 g) are placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 166.4 mg per tablet) are obtained while spraying a film coating solution (1380 g) having the composition ratio shown in Table 66.
[Table 71]
composition of plain tablet (core tablet) containing compound A |
composition | amount (mg) |
1) compound A |
26.72 |
2) mannitol |
98.88 |
3) crystalline cellulose |
16 |
4) hydroxypropylcellulose |
4.8 |
5) fumaric acid |
4 |
6) croscarmellose sodium |
8 |
7) magnesium stearate |
1.6 |
total |
160 |
Example 61 (sample 69)
[0091] A plain tablet (core tablet) containing compound A is produced as follows at the composition ratio shown in Table 72.
[0092] That is, compound A (881.76 g), mannitol (3263.04 g), fumaric acid (132.0 g) and crystalline cellulose (528.0 g) are placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture is preheated and mixed. The mixture is granulated while spraying an aqueous solution (2640.0 g) of hydroxypropylcellulose (158.4 g) to give a granulated powder. The obtained granulated powder (4653.0 g) is passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4342.8 g), croscarmellose sodium (231.0 g) and magnesium stearate (46.2 g) are placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The mixed powder is tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 8 mmφ punch to give plain tablets (core tablets, 240 mg per tablet). The obtained plain tablets (core tablets, 3300.0 g) are placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 249.6 mg per tablet) are obtained while spraying a film coating solution (1380 g) having the composition ratio shown in Table 66.
[Table 72]
composition of plain tablet (core tablet) containing compound A |
composition | amount (mg) |
1) compound A |
40.08 |
2) mannitol |
148.32 |
3) crystalline cellulose |
24 |
4) hydroxypropylcellulose |
7.2 |
5) fumaric acid |
6 |
6) croscarmellose sodium |
12 |
7) magnesium stearate |
2.4 |
total |
240 |
Example 62 (sample 70)
[0093] A plain tablet (core tablet) containing compound A is produced as follows at the composition ratio shown in Table 73.
[0094] That is, compound A (881.76 g), mannitol (3263.04 g), fumaric acid (132.0 g) and crystalline cellulose (528.0 g) are placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture is preheated and mixed. The mixture is granulated while spraying an aqueous solution (2640.0 g) of hydroxypropylcellulose (158.4 g) to give a granulated powder. The obtained granulated powder (4653.0 g) is passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4342.8 g), croscarmellose sodium (231.0 g) and magnesium stearate (46.2 g) are placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The mixed powder is tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 9.5 mmφ punch to give plain tablets (core tablets, 320 mg per tablet). The obtained plain tablets (core tablets, 3300.0 g) are placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 332.8 mg per tablet) are obtained while spraying a film coating solution (1380 g) having the composition ratio shown in Table 66.
[Table 73]
composition of plain tablet (core tablet) containing compound A |
composition | amount (mg) |
1) compound A |
53.44 |
2) mannitol |
197.76 |
3) crystalline cellulose |
32 |
4) hydroxypropylcellulose |
9.6 |
5) fumaric acid |
8 |
6) croscarmellose sodium |
16 |
7) magnesium stearate |
3.2 |
total |
320 |
Example 63 (sample 71)
[0095] A plain tablet (core tablet) containing compound A is produced as follows at the composition ratio shown in Table 74.
[0096] That is, compound A (961.92 g), mannitol (3182.88 g), fumaric acid (132.0 g) and crystalline cellulose (528.0 g) are placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture is preheated and mixed. The mixture is granulated while spraying an aqueous solution (2640.0 g) of hydroxypropylcellulose (158.4 g) to give a granulated powder. The obtained granulated powder (4653.0 g) is passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4342.8 g), croscarmellose sodium (231.0 g) and magnesium stearate (46.2 g) are placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The mixed powder is tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 8 mmφ punch to give plain tablets (core tablets, 220 mg per tablet). The obtained plain tablets (core tablets, 3300.0 g) are placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 228.8 mg per tablet) are obtained while spraying a film coating solution (1380 g) having the composition ratio shown in Table 66.
[Table 74]
composition of plain tablet (core tablet) containing compound A |
composition | amount (mg) |
1) |
compound A |
40.08 |
2) |
mannitol |
132.62 |
3) |
crystalline cellulose |
22 |
4) |
hydroxypropylcellulose |
6.6 |
5) |
fumaric acid |
5.5 |
6) |
croscarmellose sodium |
11 |
7) |
magnesium stearate |
2.2 |
total |
220 |
Example 64 (sample 72)
[0097] The plain tablets (core tablets) obtained in Example 12 (detailed below) (sample 14, 3300.0 g) were placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 229 mg per tablet) were obtained while spraying a film coating solution (1480.9 g) having the composition ratio shown in Table 29 (shown below). The obtained film-coated tablets were exposed to xenon light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga Test Instruments).
Example 12 (sample 14)
[0098] A plain tablet (core tablet) containing compound A was produced as follows at the composition ratios shown in Table 14.
[0099] That is, compound A (80.890 g), mannitol (4065.0 g), crystalline cellulose (528.0 g) and fumaric acid (132.0 g) were placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture was preheated and mixed. The mixture was granulated while spraying an aqueous solution (2640.0 g) of hydroxypropylcellulose (158.4 g) to give a granulated powder. The obtained granulated powder (4550.0 g) was passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4239.0 g), croscarmellose sodium (225.5 g) and magnesium stearate (45.10 g) were placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed therein to give a mixed powder. The mixed powder was tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 8 mmφ punch to give plain tablets (core tablets, 220 mg per tablet).
[Table 14]
Composition of plain tablet (core tablet) containing compound A (sample 14) |
composition | amount (mg) |
1) compound A* |
3.34 |
2) mannitol |
169.36 |
3) crystalline cellulose |
22 |
4) hydroxypropylcellulose |
6.6 |
5) fumaric acid |
5.5 |
6) croscarmellose sodium |
11 |
7) magnesium stearate |
2.2 |
total |
220.0 |
* Where necessary, the content was amended using mannitol as an adjustment component. |
[Table 29]
Composition of aqueous film coating solution |
composition | amount (mg) |
1) hypromellose |
6.6 |
2) macrogol 6000 |
1.5 |
3) titanium oxide |
0.75 |
4) yellow ferric oxide |
0.075 |
5) diiron trioxide |
0.075 |
6) purified water |
81 |
total |
90.0 |
Example 65 (sample 73)
[0100] The plain tablets (core tablets) obtained in Example 13 (detailed below) (sample 15, 3300.0 g) were placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 229 mg per tablet) were obtained while spraying a film coating solution (1501.0 g) having the composition ratio shown in Table 30 (shown below). The obtained film-coated tablets were exposed to xenon light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga Test Instruments).
Example 13 (sample 15)
[0101] A plain tablet (core tablet) containing compound A was produced as follows at the composition ratios shown in Table 15.
[0102] That is, compound A (161.8 g), mannitol (3984.0 g), crystalline cellulose (528.0 g) and fumaric acid (132.0 g) were placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture was preheated and mixed. The mixture was granulated while spraying an aqueous solution (2640.0 g) of hydroxypropylcellulose (158.4 g) to give a granulated powder. The obtained granulated powder (4550.0 g) was passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4239.0 g), croscarmellose sodium (225.5 g) and magnesium stearate (45.1 g) were placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed therein to give a mixed powder. The mixed powder was tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 8 mmφ punch to give plain tablets (core tablets, 220 mg per tablet).
[Table 15]
Composition of plain tablet (core tablet) containing compound A (sample 15) |
composition | amount (mg) |
1) compound A* |
6.68 |
2) mannitol |
166.02 |
3) crystalline cellulose |
22 |
4) hydroxypropylcellulose |
6.6 |
5) fumaric acid |
5.5 |
6) croscarmellose sodium |
11 |
7) magnesium stearate |
2.2 |
total |
220.0 |
* Where necessary, the content was amended using mannitol as an adjustment component. |
[Table 30]
Composition of aqueous film coating solution |
composition | amount (mg) |
1) hypromellose |
6.6 |
2) macrogol 6000 |
1.5 |
3) titanium oxide |
0.75 |
4) yellow ferric oxide |
0.075 |
5) diiron trioxide |
0.075 |
6) purified water |
81 |
total |
90.0 |
Example 66 (sample 74)
[0103] The plain tablets (core tablets) obtained in Example 14 (detailed below) (sample 16, 3300.0 g) were placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 229 mg per tablet) were obtained while spraying a film coating solution (1514.0 g) having the composition ratio shown in Table 31 (shown below). The obtained film-coated tablets were exposed to xenon light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga Test Instruments).
Example 14 (sample 16)
[0104] A plain tablet (core tablet) containing compound A was produced as follows at the composition ratios shown in Table 16.
[0105] That is, compound A (323.5 g), mannitol (3824.0 g), crystalline cellulose (528.0 g) and fumaric acid (132.0 g) were placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture was preheated and mixed. The mixture was granulated while spraying an aqueous solution (2640.0 g) of hydroxypropylcellulose (158.4 g) to give a granulated powder. The obtained granulated powder (4550.0 g) was passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4239.0 g), croscarmellose sodium (225.5 g) and magnesium stearate (45.1 g) were placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed therein to give a mixed powder. The mixed powder was tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 8 mmφ punch to give plain tablets (core tablets, 220 mg per tablet).
[Table 16]
Composition of plain tablet (core tablet) containing compound A (sample 16) |
composition | amount (mg) |
1) compound A* |
13.36 |
2) mannitol |
159.34 |
3) crystalline cellulose |
22 |
4) hydroxypropylcellulose |
6.6 |
5) fumaric acid |
5.5 |
6) croscarmellose sodium |
11 |
7) magnesium stearate |
2.2 |
total |
220.0 |
* Where necessary, the content was amended using mannitol as an adjustment component. |
[Table 31]
Composition of aqueous film coating solution |
composition | amount (mg) |
1) hypromellose |
6.6 |
2) macrogol 6000 |
1.5 |
3 )titanium oxide |
0.75 |
4) yellow ferric oxide |
0.075 |
5) diiron trioxide |
0.075 |
6) purified water |
81 |
total |
90.0 |
Example 67 (sample 75)
[0106] The plain tablets (core tablets) obtained in Example 15 (detailed below) (sample 17, 3300.0 g) were placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 229 mg per tablet) were obtained while spraying a film coating solution (1374.0 g) having the composition ratio shown in Table 32 (shown below). The obtained film-coated tablets were exposed to xenon light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga Test Instruments).
Example 15 (sample 17)
[0107] A plain tablet (core tablet) containing compound A was produced as follows at the composition ratios shown in Table 17.
[0108] That is, compound A (647.1 g), mannitol (3504.0 g), crystalline cellulose (528.0 g) and fumaric acid (132.0 g) were placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture was preheated and mixed. The mixture was granulated while spraying an aqueous solution (2640.0 g) of hydroxypropylcellulose (158.4 g) to give a granulated powder. The obtained granulated powder (4550.0 g) was passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4239.0 g), croscarmellose sodium (225.5 g) and magnesium stearate (45.1 g) were placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed therein to give a mixed powder. The mixed powder was tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 8 mmφ punch to give plain tablets (core tablets, 220 mg per tablet).
[Table 17]
Composition of plain tablet (core tablet) containing compound A (sample 17) |
composition | amount (mg) |
1) compound A* |
26.72 |
2) mannitol |
145.98 |
3) crystalline cellulose |
22 |
4) hydroxypropylcellulose |
6.6 |
5) fumaric acid |
5.5 |
6) croscarmellose sodium |
11 |
7) magnesium stearate |
2.2 |
total |
220.0 |
* Where necessary, the content was amended using mannitol as an adjustment component. |
[Table 32]
Composition of aqueous film coating solution |
composition | amount (mg) |
1) hypromellose |
6.6 |
2) macrogol 6000 |
1.5 |
3) titanium oxide |
0.75 |
4) yellow ferric oxide |
0.075 |
5) diiron trioxide |
0.075 |
6) purified water |
81 |
total |
90.0 |
Comparative Example 9 (sample 76)
[0109] The plain tablets (core tablets) obtained in Comparative Example 3 (detailed below) (sample 33, 200.0 g) were placed in a film coating machine (DRC-200, manufactured by POWREX CORPORATION), and film-coated tablets (about 312 mg per tablet) were obtained while spraying a film coating solution (96.8 g) having the composition ratio shown in Table 34 (shown below). The obtained film-coated tablets were exposed to xenon light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga Test Instruments).
Comparative Example 3 (sample 33)
[0110] A plain tablet (core tablet) containing N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine fumarate (hereinafter to be referred to as compound B) was produced as follows at the composition ratio shown in Table 33.
[0111] That is, compound B (2.680 g), mannitol (483.320 g) and crystalline cellulose (60.0 g) were placed in a fluidized bed dryer granulator (LAB-1, manufactured by POWREX CORPORATION), and the mixture was preheated and mixed. The mixture was granulated while spraying an aqueous solution (300.0 g) of hydroxypropylcellulose (18.0 g) to give a granulated powder. The obtained granulated powder was passed through a 16M (1000 µm) sieve to give a sized powder. Croscarmellose sodium (27.00 g) and magnesium stearate (5.400 g) were added to the sized powder (507.6 g) and mixed to give a mixed powder. The mixed powder was tableted by a rotary tableting machine (COLLECT 19K, manufactured by Kikusui Seisakusho, Ltd.) using a 9 mmφ punch to give plain tablets (core tablets, 300 mg per tablet).
[Table 33]
Composition of plain tablet (core tablet) containing compound B |
composition | amount (mg) |
1) compound B |
1.340 |
2) mannitol |
241.66 |
3) crystalline cellulose |
30 |
4) hydroxypropylcellulose |
9 |
5) croscarmellose sodium |
15 |
6) magnesium stearate |
3 |
total |
300.0 |
[Table 34]
composition of aqueous film coating solution |
composition | amount (mg) |
1) hypromellose |
8.8 |
2) polyethylene glycol |
2 |
3) titanium oxide |
1 |
4) diiron trioxide |
0.2 |
5) purified water |
108 |
total |
120.0 |
Example 68 (sample 77)
[0112] The plain tablets (core tablets) obtained in Example 31 (detailed below) (sample 35, 3300.0 g) were placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 312 mg per tablet) were obtained while spraying a film coating solution (1432.0 g) having the composition ratio shown in Table 34. The obtained film-coated tablets were exposed to xenon light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga Test Instruments).
Example 31 (sample 35)
[0113] A plain tablet (core tablet) containing compound B was produced as follows at the composition ratio shown in Table 35.
[0114] That is, compound B (24.54 g), mannitol (4223.0 g), crystalline cellulose (540.0 g) and fumaric acid (126.0 g) were placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture was preheated and mixed. The mixture was granulated while spraying an aqueous solution (2700.0 g) of hydroxypropylcellulose (162.0 g) to give a granulated powder. The obtained granulated powder (4568.0 g) was passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4230.0 g), croscarmellose sodium (225.0 g) and magnesium stearate (45.00 g) were placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The mixed powder was tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 9 mmφ punch to give plain tablets (core tablets, 300 mg per tablet).
[Table 35]
Composition of plain tablet (core tablet) containing compound B |
composition | amount (mg) |
1) compound B |
1.340 |
2) mannitol |
234.66 |
3) crystalline cellulose |
30 |
4) hydroxypropylcellulose |
9 |
5) fumaric acid |
7 |
6) croscarmellose sodium |
15 |
7) magnesium stearate |
3 |
total |
300.0 |
Example 69 (sample 78)
[0115] The plain tablets (core tablets) obtained in Example 35 (detailed below) (sample 39, 3300.0 g) were placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 156 mg per tablet) were obtained while spraying a film coating solution (1470.0 g) having the composition ratio shown in Table 37 (shown below). The obtained film-coated tablets were exposed to xenon light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga Test Instruments).
Example 35 (sample 39)
[0116] A plain tablet (core tablet) containing compound B was produced as follows at the composition ratio shown in Table 38.
[0117] That is, compound B (24.54 g), mannitol (4223.0 g), crystalline cellulose (540.0 g) and fumaric acid (126.0 g) were placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture was preheated and mixed. The mixture was granulated while spraying an aqueous solution (2700.0 g) of hydroxypropylcellulose (162.0 g) to give a granulated powder. The obtained granulated powder (4568.0 g) was passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4230.0 g), croscarmellose sodium (225.0 g) and magnesium stearate (45.00 g) were placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The mixed powder was tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 7 mmφ punch to give plain tablets (core tablets, 150 mg per tablet).
[Table 38]
Composition of plain tablet (core tablet) containing compound B |
composition | amount (mg) |
1) compound B |
0.67 |
2) mannitol |
117.33 |
3) crystalline cellulose |
15 |
4) hydroxypropylcellulose |
4.5 |
5) fumaric acid |
3.5 |
6) croscarmellose sodium |
7.5 |
7) magnesium stearate |
1.5 |
total |
150.0 |
[Table 37]
composition of aqueous film coating solution |
composition | amount (mg) |
1) hypromellose |
4.47 |
2) macrogol 6000 |
1.02 |
3) titanium oxide |
0.508 |
4) yellow ferric oxide |
0.051 |
5) diiron trioxide |
0.051 |
6) purified water |
54.9 |
total |
61.0 |
Example 70 (sample 79)
[0118] The plain tablets (core tablets) obtained in Example 37 (detailed below) (sample 41, 3300.0 g) were placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 312 mg per tablet) were obtained while spraying a film coating solution (1425.0 g) having the composition ratio shown in Table 37. The obtained film-coated tablets were exposed to xenon light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga Test Instruments).
Example 37 (sample 41)
[0119] A plain tablet (core tablet) containing compound B was produced as follows at the composition ratio shown in Table 39.
[0120] That is, compound B (245.4 g), mannitol (4003.0 g), crystalline cellulose (540.0 g) and fumaric acid (126.0 g) were placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture was preheated and mixed. The mixture was granulated while spraying an aqueous solution (2700.0 g) of hydroxypropylcellulose (162.0 g) to give a granulated powder. The obtained granulated powder (4568.0 g) was passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4230.0 g), croscarmellose sodium (225.0 g) and magnesium stearate (45.00 g) were placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The mixed powder was tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 9 mmφ punch to give plain tablets (core tablets, 300 mg per tablet).
[Table 39]
Composition of plain tablet (core tablet) containing compound B |
composition | amount (mg) |
1) compound B |
13.4 |
2) mannitol |
222.6 |
3) crystalline cellulose |
30 |
4) hydroxypropylcellulose |
9 |
5) fumaric acid |
7 |
6) croscarmellose sodium |
15 |
7) magnesium stearate |
3 |
total |
300.0 |
Example 71 (sample 80)
[0121] The plain tablets (core tablets) obtained in Example 39 (detailed below) (sample 43, 3300.0 g) were placed in a film coating machine (DRC-500, manufactured by POWREX CORPORATION), and film-coated tablets (about 312 mg per tablet) were obtained while spraying a film coating solution (1417.2 g) having the composition ratio shown in Table 37. The obtained film-coated tablets were exposed to xenon light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga Test Instruments).
Example 39 (sample 43)
[0122] A plain tablet (core tablet) containing compound B was produced as follows at the composition ratio shown in Table 40.
[0123] That is, compound B (981.5 g), mannitol (3267.0 g), crystalline cellulose (540.0 g) and fumaric acid (126.0 g) were placed in a fluidized bed dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and the mixture was preheated and mixed. The mixture was granulated while spraying an aqueous solution (2700.0 g) of hydroxypropylcellulose (162.0 g) to give a granulated powder. The obtained granulated powder (4568.0 g) was passed through a powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. The sized powder (4230.0 g), croscarmellose sodium (225.0 g) and magnesium stearate (45.00 g) were placed in a tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The mixed powder was tableted by a rotary tableting machine (COLLECT 12HUK, manufactured by Kikusui Seisakusho, Ltd.) using a 9 mmφ punch to give plain tablets (core tablets, 300 mg per tablet).
[Table 40]
Composition of plain tablet (core tablet) containing compound B |
composition | amount (mg) |
1) compound B |
53.6 |
2) mannitol |
182.4 |
3) crystalline cellulose |
30 |
4) hydroxypropylcellulose |
9 |
5) fumaric acid |
7 |
6) croscarmellose sodium |
15 |
7) magnesium stearate |
3 |
total |
300.0 |
Experimental Example 5 (measurement method of decomposed product)
[0124] The film-coated tablets of Examples 46 - 48, Examples 52 - 54, Examples 64 - 67 and Comparative Example 8 were examined for the production of compound A decomposed product, before xenon light irradiation and after xenon light irradiation. The decomposed product U-6 was measured by extracting the tablets with 0.05 mol/L phosphoric acid/MeCN mixture (19:1) or water/MeCN mixture (19:1) by HPLC. The HPLC test conditions are as follows.
detector: ultraviolet absorption spectrophotometer (measurement wavelength: 230 nm)
column: CAPCELL PAK C18 MGII, 3 µm, 4.6 mm i.d.×150 mm (manufactured by Shiseido Co., Ltd.)
column temperature: fixed temperature around 25°C
mobile phase A: 0.05 mol/L sodium phosphate buffer (pH 6.0)/acetonitrile mixture (95:5)
mobile phase B: 0.05 mol/L sodium phosphate buffer (pH 6.0)/acetonitrile mixture (40:60)
mobile phase delivery: density gradient was controlled by changing mixing ratio of mobile phase A and mobile phase B as follows.
[Table 75]
time (min) after injection | mobile phase A (%) | mobile phase B (%) |
0 |
100 |
0 |
10 |
80 |
20 |
60 |
70 |
30 |
110 |
0 |
100 |
110.1 |
100 |
0 |
120 |
100 |
0 |
measurement range of peak area: 110 min |
Experiment results 6
[0125] The compound A decomposed product U-6 (relative retention time: about 0.7) and other decomposed products were measured before xenon light irradiation and after xenon light irradiation, and the results of the total decomposed products are shown in Table 76. [Table 76]
sample | PEG addition to film part | compound concentration (%) | organic acid concentration (%) | total decomposed product (%) |
core tablet part | film part | before xenon light irradiation | after xenon light irradiation |
sample 52 |
added |
0.4 |
0 |
0 |
0.70 |
1.59 |
sample 53 |
added |
0.4 |
0 |
2.3 |
0.71 |
1.05 |
sample 54 |
added |
0.4 |
0 |
4.7 |
0.85 |
0.84 |
sample 58 |
added |
0.4 |
0.5 |
0 |
0.84 |
1.15 |
sample 59 |
added |
0.4 |
1.0 |
0 |
0.85 |
1.03 |
sample 60 |
added |
0.4 |
2.3 |
0 |
0.83 |
0.92 |
sample 72 |
added |
1.5 |
2.5 |
0 |
0.74 |
0.76 |
sample 73 |
added |
3.0 |
2.5 |
0 |
0.71 |
0.73 |
sample 74 |
added |
6.1 |
2.5 |
0 |
0.79 |
0.74 |
sample 75 |
added |
12.1 |
2.5 |
0 |
0.68 |
0.70 |
sample 62 Comparative Example |
not added |
0.4 |
0 |
0 |
1.00 |
1.12 |
* organic acid concentration (%) of core tablet part = (organic acid mass contained in core tablet part/core tablet mass)×100
* organic acid concentration (%) of film part = (organic acid mass contained in film part/film mass)×100
* compound concentration (%) = (added compound weight/core tablet weight)×100 |
[0126] Even when PEG was added to film coating component, production of a decomposed product after light irradiation was suppressed by the addition of an organic acid.
[0127] Even when organic acid was added to the core tablet part or the film part, a decomposed product suppressive effect was observed. When added to the core tablet part, a remarkable suppression was observed with 2.3% or above. When added to the film part, a remarkable suppression was observed with 4.7% or above.
[0128] Even when PEG was added to a film coating component, stabilization was achieved to a level equal to or higher than the absence of PEG by the addition of an organic acid.
[0129] Since the production of a decomposed product can be suppressed by the addition of an organic acid, suppression of change in the appearance after light irradiation is sufficiently predicted. Hence, a high quality pharmaceutical composition superior in light-stability can be provided.
Experimental Example 6 (measurement method of decomposed product)
[0130] The film-coated tablet (sample 76) obtained in Comparative Example 9 was examined for the production of compound B total decomposed product before xenon light irradiation and after xenon light irradiation. The decomposed product was measured by extracting the tablet with water/MeCN mixture (1:3) by HPLC. The HPLC test conditions are as follows.
detector: ultraviolet absorption spectrophotometer (measurement wavelength: 230 nm)
column: CAPCELL PAK C18 MGII, 3 µm, 4.6 mm i.d.×100 mm (manufactured by Shiseido Co., Ltd.)
column temperature: fixed temperature around 40°C
mobile phase A: 0.05 mol/L sodium phosphate buffer (pH 7.0)/acetonitrile mixture (9:1)
mobile phase B: 0.05 mol/L sodium phosphate buffer (pH 7.0)/acetonitrile mixture (2:3)
mobile phase delivery: density gradient was controlled by changing mixing ratio of mobile phase A and mobile phase B as follows.
[Table 77]
time (min) after injection | mobile phase A (%) | mobile phase B (%) |
0 |
100 |
0 |
100 |
0 |
100 |
100.1 |
100 |
0 |
110 |
100 |
0 |
measurement range of peak area: 100 min |
Experimental Example 7 (measurement method of decomposed product)
[0131] The film-coated tablets obtained Examples 68 - 71 (samples 77, 78, 79 and 80) were examined for the production of compound B total decomposed product before xenon light irradiation and after xenon light irradiation. The decomposed products were measured by extracting the tablets with water /MeCN mixture (1:3) by HPLC. The HPLC test conditions are as follows.
detector: ultraviolet absorption spectrophotometer (measurement wavelength: 230 nm)
column: CAPCELL PAK C18 MGII, 3 µm, 4.6 mm i.d.×100 mm (manufactured by Shiseido Co., Ltd.)
column temperature: fixed temperature around 40°C
mobile phase A: 0.03 mol/L sodium phosphate buffer (pH 7.0)/acetonitrile mixture (9:1)
mobile phase B: 0.03 mol/L sodium phosphate buffer (pH 7.0)/acetonitrile mixture (2:3)
mobile phase delivery: density gradient was controlled by changing mixing ratio of mobile phase A and mobile phase B as follows.
[Table 78]
time (min) after injection | mobile phase A (%) | mobile phase B (%) |
0 |
100 |
0 |
100 |
0 |
100 |
100.1 |
100 |
0 |
110 |
100 |
0 |
measurement range of peak area: 100 min |
Experiment results 7
[0132] The decomposed products of film-coated tablets were measured before xenon light irradiation and after xenon light irradiation, and the results of the total decomposed products are shown in Table 79.
[Table 79]
decomposed products after xenon light irradiation |
sample | core tablet or film-coated tablet | compound concentration (%) | organic acid concentration (%) | before preservation | after preservation |
core tablet part | film part | total decomposed product (%) | total decomposed product (%) |
sample 76 (comparison control) |
film-coated tablet |
0.4 |
0 |
0 |
2.45 |
2.87 |
sample 77 |
film-coated tablet |
0.4 |
2.3 |
0 |
2.36 |
2.65 |
sample 78 |
film-coated tablet |
0.4 |
2.3 |
0 |
2.33 |
2.55 |
sample 79 |
film-coated tablet |
4.5 |
2.3 |
0 |
2.23 |
2.24 |
sample 80 |
film-coated tablet |
17.9 |
2.3 |
0 |
2.25 |
2.29 |
[0133] Since the production of a decomposed product can be suppressed by the addition of an organic acid, namely fumaric acid, suppression of change in the appearance after light irradiation is sufficiently predicted. Hence, a high quality pharmaceutical composition superior in light-stability can be provided.
INDUSTRIAL APPLICABILITY
[0134] According to the present invention, a solid preparation improved in the stability of a pharmaceutically active ingredient to light irradiation is provided. To be specific, a solid preparation stable to light irradiation can be provided by, when the pharmaceutically active ingredient contained in the solid preparation is exposed to light, shielding the light and suppressing an increase in a decomposed product.