Solid preparation with improved light stability

Abstract

The purpose of the present invention is to provide a solid preparation containing a 4, 5-epoxymorphinan derivative or a pharmacologically acceptable acid addition salt thereof, which is stable with respect to light without a light-blocking coating. Provided is a solid preparation containing an active ingredient comprising a 4, 5-epoxymorphinan derivative represented by the following formula or a pharmacologically acceptable acid addition salt thereof, and one or more stabilizing agents selected from the group consisting of n-propyl gallate, sodium hydrogen sulfite, dibutylated hydroxytoluene, butylated hydroxyanisole, tocopherol, and D-erythorbic acid, the weight of the active ingredient is 0.00001-0.01% by weight relative to the weight of the solid preparation, and the weight of the stabilizing agent is 0.005-5% by weight relative to the weight of the solid preparation. # imgabs0 #

Description

The present application is a divisional application of an application filed on July 28, 2017, with application number “201780046424.3” and invention name “Solid preparation with improved photostability”. Technical Field

[0001] The present invention relates to a solid preparation containing a 4,5-epoxymorphinan derivative or a pharmacologically acceptable acid addition salt thereof and having improved photostability. Background Art

[0002] Nalfurapine or a pharmacologically acceptable acid addition salt thereof, which is a compound having a significant antipruritic effect, is known to be chemically unstable to heat, light, oxygen, and the like, and therefore methods for improving the chemical stability have been developed.

[0003] Specifically, there have been reported methods of adding a substance selected from a specific antioxidant, a synergist, a sugar, or a surfactant; and methods of adding sodium thiosulfate, a sugar or a sugar alcohol, and a low-substituted hydroxypropyl cellulose (Patent Documents 1 and 2).

[0004] In the preparation described in Patent Document 1, the stability of nalfurafur or its pharmacologically acceptable acid addition salt is improved by containing a substance selected from a specific antioxidant, a synergist, a sugar or a surfactant, and tablets and granules are described as specific dosage forms of the solid preparation. In addition, in the solid preparation described in Patent Document 2, the stability of nalfurafur or its pharmacologically acceptable acid addition salt is improved by containing sodium thiosulfate, sugars or sugar alcohols, and low-substituted hydroxypropyl cellulose as stabilizers.

[0005] In addition, in soft capsules, as a formulation for stabilizing nalfurafine or its pharmacologically acceptable acid addition salt, a capsule filling composition containing medium-chain fatty acid triglycerides and propyl gallate in the filling liquid of the soft capsule; and a soft capsule preparation containing a specific base and an antioxidant have been reported (Patent Documents 3 and 4).

[0006] Specifically, the soft capsules described in Patent Documents 3 and 4 contain an antioxidant such as propyl gallate as a stabilizer, thereby improving the stability of nalfuraphine or a pharmacologically acceptable acid addition salt thereof.

[0007] Furthermore, the orally disintegrating tablet described in Patent Document 5 is coated with a light-shielding agent containing a polyvinyl alcohol-based resin and a specific sugar to ensure excellent photostability.

[0008] On the other hand, in solid preparations, a light-shielding coating agent containing a polyvinyl alcohol resin and a specific sugar has been reported as a formulation for improving the photostability of a photolabile drug including nalfurafine or a pharmacologically acceptable acid addition salt thereof (Patent Document 5).

[0009] In addition, various methods are known as methods for stabilizing the formulation of photolabile drugs. For example, as a method for improving the photostability of uncoated tablets of photolabile amlodipine, a method of adding iron oxide and a method of adding a dissolved substance having a similar light absorption behavior to the active ingredient to be protected have been reported (Patent Documents 6 and 7).

[0010] The preparation described in Patent Document 6 is a preparation in which the photostability of amlodipine, which is unstable to light, is improved by adding iron oxide. The photostability method described in Patent Document 7 describes improving the photostability by adding a dissolved substance having a similar light absorption behavior to the active ingredient to be protected.

[0011] Prior art literature Patent Literature Patent Document 1: International Publication No. 99 / 002158 Patent Document 2: International Publication No. 08 / 133330 Patent Document 3: Japanese Patent Application Publication No. 2015-168630 Patent Document 4: Japanese Patent Application Publication No. 2015-172043 Patent Document 5: International Publication No. 10 / 113841 Patent Document 6: Japanese Patent Application Publication No. 2006-306754 Patent Document 7: Japanese Patent Application Publication No. Sho 58-57322. Summary of the invention

[0012] Problems to be solved by the invention However, Patent Document 1 shows data on the improvement of the thermal and oxidative stability of nalfurapine or a pharmacologically acceptable acid addition salt thereof, but does not investigate the improvement of the stability against light.

[0013] Patent Document 2 shows data on the improvement of the thermal and oxidative stability of nalfurapine or a pharmacologically acceptable acid addition salt thereof, but does not investigate the improvement of the stability to light, and merely applies a conventional light-shielding coating to the tablet.

[0014] Patent Documents 3 and 4 show data on the stability against heat and oxidation during storage, but neither describe nor suggest improving the stability against light.

[0015] As described above, the stabilization techniques for nalfuraphine or its pharmacologically acceptable acid addition salt described in Patent Documents 1 to 4 are stabilization methods during preparation and / or long-term storage of the preparation, and no studies have been conducted so far on improving photostability.

[0016] In the orally disintegrating tablet described in Patent Document 5, when the tablet is divided for proper administration, an uncoated surface appears on the divided surface, and there is a concern that decomposition, discoloration, and other deterioration due to light may proceed from this portion. In order to ensure sufficient light stability in solid preparations such as powders and granules, a large amount of coating is required, and there is a concern that the stability during production and / or long-term storage may be reduced, and the production process may become complicated.

[0017] Patent Document 6 discloses the addition of butylated hydroxyanisole and dibutylated hydroxytoluene as stabilizers for inhibiting oxidative decomposition. Although these antioxidants inhibit the production of decomposition products generated by oxidation of amlodipine, they are not able to inhibit discoloration at all.

[0018] The photostabilization method described in Patent Document 7 does not describe nalfurapine or a pharmacologically acceptable acid addition salt thereof, and the effective photostabilization method varies depending on the active ingredient.

[0019] Therefore, an object of the present invention is to provide a solid preparation containing a 4,5-epoxymorphinan derivative or a pharmacologically acceptable acid addition salt thereof which is stable to light even without a light-shielding coating.

[0020] Means used to solve problems The present inventors have conducted intensive studies to solve the above-mentioned problems and have achieved the following invention. That is, the present invention relates to the following inventions (1) to (5).

[0021] (1) A solid preparation comprising an active ingredient consisting of a 4,5-epoxymorphinan derivative represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof, and at least one stabilizer selected from the group consisting of n-propyl gallate, sodium bisulfite, dibutylhydroxytoluene, butylhydroxyanisole, tocopherol and D-isoascorbic acid, wherein the weight of the active ingredient is 0.00001 to 0.01% by weight relative to the weight of the solid preparation, and the weight of the stabilizer is 0.005 to 5% by weight relative to the weight of the solid preparation; [Chemistry 1] [Where R 1 represents cyclopropylmethyl or allyl, R 2 represents hydrogen, hydroxy, acetoxy or methoxy, R 3represents hydrogen, hydroxy, acetoxy or methoxy, A represents -N(R 4 )C(=O)-or-N(R 4 )C(=O)O-,R 4 represents hydrogen or a linear or branched alkyl group having 1 to 5 carbon atoms, B represents a linear alkylene group having 1 to 3 carbon atoms, -CH=CH- or -C≡C-, R 5 represents hydrogen, phenyl, furyl or thienyl, but the hydrogen of the above-mentioned phenyl, furyl and thienyl is optionally replaced by one or more groups selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy].

[0022] (2) The solid preparation according to (1), wherein the stabilizer is n-propyl gallate.

[0023] (3) The solid preparation according to (1) or (2), comprising sodium thiosulfate.

[0024] (4) The solid preparation according to any one of (1) to (3), comprising yellow ferric oxide, red ferric oxide or black ferric oxide.

[0025] (5) The solid preparation according to any one of (1) to (4), comprising a saccharide.

[0026] (6) The solid preparation according to any one of (1) to (5), which is in a dosage form selected from tablets, granules, fine granules, hard capsules, dry syrups, powders, pills and lozenges.

[0027] Furthermore, the present invention relates to the following inventions (7) to (11).

[0028] (7) A solid preparation comprising an active ingredient consisting of a 4,5-epoxymorphinan derivative represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof, a saccharide, and at least one stabilizer selected from the group consisting of n-propyl gallate, sodium bisulfite, dibutylhydroxytoluene, butylhydroxyanisole, tocopherol and D-isoascorbic acid, wherein the weight of the active ingredient is 0.00001 to 0.01% by weight relative to the weight of the solid preparation, and the weight of the stabilizer is 0.005 to 5% by weight relative to the weight of the solid preparation; [Chemistry 2] [Where R 1 represents cyclopropylmethyl or allyl, R 2 represents hydrogen, hydroxy, acetoxy or methoxy, R3 represents hydrogen, hydroxy, acetoxy or methoxy, A represents -N(R 4 )C(=O)-or-N(R 4 )C(=O)O-,R 4 represents hydrogen or a linear or branched alkyl group having 1 to 5 carbon atoms, B represents a linear alkylene group having 1 to 3 carbon atoms, -CH=CH- or -C≡C-, R 5 represents hydrogen, phenyl, furyl or thienyl, but the hydrogen of the above-mentioned phenyl, furyl and thienyl is optionally replaced by one or more groups selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy].

[0029] (8) The solid preparation according to (7), wherein the stabilizer is n-propyl gallate.

[0030] (9) The solid preparation according to (7) or (8), comprising sodium thiosulfate.

[0031] (10) The solid preparation according to any one of (7) to (9), comprising yellow ferric oxide, red ferric oxide or black ferric oxide.

[0032] (11) The solid preparation according to any one of (7) to (10), which is in a dosage form selected from tablets, granules, fine granules, hard capsules, dry syrups, powders, pills and lozenges.

[0033] Effects of the Invention According to the present invention, the photostability of a solid preparation containing a 4,5-epoxymorphinan derivative or a pharmacologically acceptable acid addition salt thereof is improved, and the usefulness as a pharmaceutical product is improved. DETAILED DESCRIPTION

[0034] Hereinafter, embodiments for implementing the present invention will be described. However, the present invention is not limited to the following embodiments. In addition, "%" means "% by weight" unless otherwise specified.

[0035] The solid preparation in the present invention is a pharmaceutical product containing an active ingredient formulated to form a solid, and examples thereof include tablets (including sublingual tablets, orally disintegrating tablets and microtablets), hard capsules, granules, fine granules, powders, dry syrups, pills, lozenges or films. In particular, when the present invention is used in orally disintegrating tablets, light stability can be ensured without forming a light-shielding tablet coating film, so rapid disintegration in the oral cavity can be achieved, so it is preferred. In addition, when the present invention is used in granules, fine granules, powders, dry syrups and films, the complex step of forming a coating film containing a uniform light-shielding agent on the outer surface of a powdered solid agent can be omitted, while ensuring light stability, so it is preferred.

[0036] The active ingredient of the present invention is a 4,5-epoxymorphinan derivative represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof.

[0037] [Chemistry 3] [Where R 1 represents cyclopropylmethyl or allyl, R 2 represents hydrogen, hydroxy, acetoxy or methoxy, R 3 represents hydrogen, hydroxy, acetoxy or methoxy, A represents -N(R 4 )C(=O)-or-N(R 4 )C(=O)O-,R 4 represents hydrogen or a linear or branched alkyl group having 1 to 5 carbon atoms, B represents a linear alkylene group having 1 to 3 carbon atoms, -CH=CH- or -C≡C-, R 5 represents hydrogen, phenyl, furyl or thienyl, but the hydrogen of the above-mentioned phenyl, furyl and thienyl is optionally replaced by one or more groups selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy].

[0038] As the 4,5-epoxymorphinan derivative represented by the above-mentioned general formula (I) or its pharmacologically acceptable salt, the compound represented by the following general formula (II) is particularly preferred, namely, the hydrochloride of 17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furanyl)acrylamide]morphinan (hereinafter referred to as "nalfuraphine").

[0039] [Chemistry 4]

[0040] Pharmacologically acceptable acid addition salts include, for example, inorganic acid salts such as hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides, and phosphates; organic carboxylates such as acetates, lactates, citrates, oxalates, glutarates, malates, tartrates, fumarates, mandelates, maleates, benzoates, and phthalates; and organic sulfonates such as methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and camphorsulfonates. Among them, hydrochlorides, hydrobromides, phosphates, tartrates, maleates, and methanesulfonates are preferred, and commercially available hydrochlorides are most preferred.

[0041] The weight of the active ingredient of the present invention, i.e., the 4,5-epoxymorphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof, is preferably 0.00001 to 0.01% by weight, more preferably 0.00005 to 0.01% by weight, and even more preferably 0.00025 to 0.01% by weight relative to the weight of the solid preparation. When the active ingredient is more than 0.01% by weight, a solid preparation having sufficient stability to light can be obtained even without using a stabilizer. When the active ingredient is less than 0.00001% by weight, the dosage of the preparation for obtaining a therapeutic effect becomes large.

[0042] The weight % range of the active ingredient varies depending on the weight of the solid preparation, but is typically within the range of 0.01 μg to 50 μg of the active ingredient per daily dose of the solid preparation.

[0043] The stabilizer used in the present invention is one or more stabilizers selected from n-propyl gallate, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, and D-isoascorbic acid, preferably n-propyl gallate and / or tocopherol, more preferably n-propyl gallate.

[0044] As the stabilizer, any conventional commercially available substance may be used. Propyl gallate is commercially available under the names of propyl gallate, propyl gallate, 3,4,5-trihydroxybenzoate, etc. Butylated hydroxytoluene is commercially available under the names of BHT, 2,6-di-tert-butyl-p-cresol, 3,5-di-tert-butyl-4-hydroxytoluene, 2,6-di-tert-butyl-4-methylphenol, etc. Butylhydroxyanisole is commercially available under the names of BHA, 3-tert-butyl-4-hydroxyanisole, tert-butyl-4-methoxyphenol, etc. Tocopherol is commercially available under the names of dl-α-tocopherol, d-α-tocopherol, d-δ-tocopherol, vitamin E, etc.

[0045] The weight of the stabilizer used in the present invention is 0.005 to 5% by weight, preferably 0.005 to 1% by weight, relative to the weight of the solid preparation. When the stabilizer is less than 0.005% by weight relative to the weight of the solid preparation, the photostabilization effect cannot be fully obtained. When it is greater than 5% by weight, it is greater than the maximum daily usage amount for which safety has been confirmed, so it is not preferred.

[0046] The solid preparation of the present invention preferably also includes carbohydrate. As carbohydrate, sugar or sugar alcohol can be mentioned, as long as conventional commercially available materials are used. For example, potato starch, white sugar, lactose, mannitol, erythritol, maltose, maltitol, trehalose, sorbitol, xylitol, lactitol and glucose can be mentioned, preferably lactose, erythritol and mannitol. By using carbohydrate, not only the sweetness of carbohydrate is improved, but also the storage stability of 4,5-epoxymorphinan derivatives shown in the above-mentioned general formula (I) or their pharmacologically acceptable acid addition salts can be improved.

[0047] The solid preparation of the present invention may further contain an antioxidant in order to suppress the decomposition of the active ingredient during production and / or long-term storage. Examples of such antioxidants include sodium thiosulfate.

[0048] Solid preparation of the present invention can also comprise various additives used in the manufacture of general preparations in addition to the above-mentioned components. As such additives, for example, excipients, disintegrating agents, binding agents, lubricants, coating agents, fluidizing agents, correctives, spices, coloring agents and sweeteners etc. can be enumerated.

[0049] Examples of the disintegrant include crospovidone, croscarmellose sodium, carboxymethylcellulose calcium, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

[0050] Examples of the binder include water-soluble polysaccharides such as gelatin, pullulan, carrageenan, xanthan gum, tamarind seed pectin, pectin, sodium alginate and gum arabic; celluloses such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose and methyl cellulose; starches such as α-starch and starch paste; and synthetic polymers such as polyvinyl pyrrolidone, carboxyvinyl polymers and polyvinyl alcohol.

[0051] Examples of the lubricant include magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, sucrose fatty acid esters, stearic acid, aluminum stearate, potassium sodium tartrate, light silicic anhydride, carnauba wax, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydrous silica, hydrogenated oil, and hydrogenated rapeseed oil.

[0052] Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, sodium carboxymethylethylcellulose, and polyvinyl alcohol.

[0053] Examples of the fluidizing agent include talc, hydrous silicon dioxide, and light silicic anhydride.

[0054] Examples of the flavoring agent include glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, and menthol.

[0055] Examples of the flavor include orange, vanilla, strawberry, or yogurt flavors, and menthol.

[0056] Examples of the coloring agent include titanium oxide, ferric oxide, yellow ferric oxide, black ferric oxide, talc, food coloring such as Food Red No. 3, Food Yellow No. 5, and Food Blue No. 1, and riboflavin.

[0057] Examples of the sweetener include aspartame, saccharin, dipotassium glycyrrhizinate, and stevia.

[0058] In the method for producing the solid preparation of the present invention, the solid preparation can be produced by a wet granulation method, which includes dissolving or suspending the active ingredient in water or a pharmacologically acceptable solvent, and adding the resulting liquid (solution or suspension) to the saccharide. In addition, the addition of a stabilizer can be performed in any step, and can be added in a solid or liquid state.

[0059] The method of adding the stabilizer in a solid form is not limited, and examples thereof include a method of mixing a commercially available stabilizer after pulverizing it as necessary, or a method of adding a stabilizer suspended in water, alcohols such as ethanol and methanol, or a mixed solution thereof.

[0060] The method of adding the stabilizer in liquid form is not limited, and examples thereof include a method of dissolving the stabilizer together with the active ingredient in water or a pharmacologically acceptable solvent and adding the stabilizer to the saccharide; or a method of adding the stabilizer after the active ingredient is added to the saccharide and granulating or sizing the saccharide as appropriate. In addition, the added saccharide may be used in its entirety in the above step of adding the active ingredient, or may be used only in part and the remaining saccharide may be added in a subsequent step.

[0061] In wet granulation, conventional devices are used, such as fluidized bed granulator, tumbling fluidized bed granulator, stirring granulator, cylinder extrusion granulator or wet extrusion granulator etc. can be enumerated. When using water as a solvent for dissolving or suspending the active ingredient, fluidized bed granulator or tumbling fluidized bed granulator that can be dried while spraying are suitable. In addition, as the dissolving or suspension solvent of the active ingredient, when using volatile solvents such as ethanol, fluidized bed granulator, tumbling fluidized bed granulator or stirring granulator are suitable.

[0062] When the stabilizer is added in a solid form, a commonly used mixing device is used, and examples thereof include a V-type mixer, a ribbon mixer, and an air mixer.

[0063] In addition, by including yellow ferric oxide, red ferric oxide or black ferric oxide as a colorant in the solid preparation, the light stability in the solid preparation can be further improved. The method of adding the colorant is not limited, and the colorant can be added as a powder or suspended in water or a pharmacologically acceptable solvent.

[0064] When the solid preparation is a tablet, compression molding is performed using a commonly used apparatus, such as a single punch tablet press, a rotary tablet press, etc. The molding pressure during tableting is not particularly limited as long as the tablet hardness is such that handling is not a problem.

[0065] The solid preparation of the present invention has improved photostability of the active ingredient, so it is easy to handle when dispensing and taking the medicine. In the present invention, improved stability means that the residual rate of the 4,5-epoxymorphinan derivative represented by the above-mentioned general formula (I) or its pharmacologically acceptable acid addition salt in the preparation is maintained at 90% or more, as described in International Publication No. 16 / 052617. When the solid preparation of the present invention is treated under a white fluorescent lamp (illuminance 2000 lux) at a temperature of 25°C and a relative humidity of 51%RH without packaging the solid preparation, the residual rate of the active ingredient after at least 24 hours (total illuminance 48,000 lux·hr) is 90% or more, and more preferably after 300 hours (total illuminance 600,000 lux·hr) the active ingredient is 90% or more. Example

[0066] Hereinafter, in order to show the excellent effects of the present invention, the present invention will be described using Examples, but the present invention is not limited thereto.

[0067] (Comparative Example 1) 88.8975 parts by weight of mannitol (Peritor 200SD (registered trademark) manufactured by Locket Japan Co., Ltd.) (hereinafter referred to as "parts"; the same shall apply unless otherwise specified) were placed in a fluidized bed granulator (LAB-1 manufactured by Pawleck Co., Ltd.), and 0.0025 parts of an aqueous solution of nalfuraline hydrochloride was sprayed to produce granulated particles. Next, 10 parts of low-substituted hydroxypropylcellulose (LH-11 manufactured by Shin-Etsu Chemical Co., Ltd.) and 1 part of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) were mixed with the granulated particles to obtain granules for tableting. The granules for tableting were made into 99.9 mg 7 mmφ tablets using a tablet press (Correct 19 manufactured by Kikusui Seisakusho Co., Ltd.).

[0068] (Example 1) 88.8975 parts of mannitol (manufactured by Locket Japan Co., Ltd., Peritor 200SD (registered trademark)) were put into a fluidized bed granulator (manufactured by Pawleck Co., Ltd., LAB-1), and 0.0025 parts of an aqueous solution of nalfuraline hydrochloride was sprayed to produce granulated particles. To the obtained granulated particles, 0.1 parts of an ethanol solution of n-propyl gallate (manufactured by Wako Pure Chemical Industries, Ltd., Wako Grade 1) was added and stirred with a mortar. After drying at 40°C for 16 hours in a hot air dryer, 10 parts of low-substituted hydroxypropyl cellulose and 1 part of magnesium stearate were mixed to obtain granules for tableting. The granules for tableting were made into 100 mg φ7mm tablets using a tablet press.

[0069] (Example 2) A 100 mg φ7 mm tablet was obtained by the same procedure as in Example 1 except that 0.1 part of dl-α-tocopherol (produced by Kanto Chemical Co., Ltd., deer special grade) was used in place of 0.1 part of n-propyl gallate in Example 1.

[0070] (Example 3) A 100 mg φ7 mm tablet was obtained by the same procedure as in Example 1 except that 0.1 part of 3-tert-butyl-4-hydroxyanisole (BHA) (manufactured by Nakalai Tesque Co., Ltd., EXTRA PURE) was used in place of 0.1 part of n-propyl gallate in Example 1.

[0071] (Example 4) A 100 mg φ7 mm tablet was obtained by the same procedure as in Example 1 except that 0.1 part of 2,6-di-tert-butyl-p-cresol (BHT) (manufactured by Nakalai Tesque Co., Ltd., EXTRA PURE REAGENT) was used in place of 0.1 part of n-propyl gallate in Example 1.

[0072] (Example 5) Instead of the 0.1 part ethanol solution of n-propyl gallate in Example 1, a 0.1 part aqueous solution of D-isoascorbic acid (GUARANTEED REAGENT, manufactured by Nakalai Tesque Co., Ltd.) was used. Except for this, a 100 mg φ7 mm tablet was obtained by the same procedure as in Example 1.

[0073] (Example 6) A 100 mg φ7 mm tablet was obtained by the same procedure as in Example 1 except that 0.1 part of an aqueous solution of sodium sulfite (special grade, manufactured by Wako Pure Chemical Industries, Ltd.) was used instead of 0.1 part of the ethanol solution of n-propyl gallate in Example 1.

[0074] (Comparative Example 2) A 100 mg φ7 mm tablet was obtained by the same procedure as in Example 1 except that 0.1 part of an aqueous solution of sodium thiosulfate pentahydrate (special grade, manufactured by Kokushin Kagaku Co., Ltd.) was used instead of 0.1 part of the ethanol solution of n-propyl gallate in Example 1.

[0075] (Comparative Example 3) A 100 mg φ7 mm tablet was obtained by the same procedure as in Example 1 except that 0.1 part of an aqueous solution of sodium hydrogen sulfite (special grade, manufactured by Wako Pure Chemical Industries, Ltd.) was used instead of 0.1 part of the ethanol solution of n-propyl gallate in Example 1.

[0076] (Test Example 1: Photostability test of tablets) The tablets of Examples 1 to 6 and Comparative Examples 1 to 3 were spread on a glass dish without overlapping, and the tablets were taken out after being exposed to a total illuminance of 48,000 lux·hr and a total illuminance of 600,000 lux·hr under a white fluorescent lamp (illuminance 2000 lux). In addition, the glass dish on which the tablets of Example 1 and Comparative Example 1 were spread was covered with aluminum foil (light-shielded storage), irradiated at a total illuminance of 48,000 lux·hr, and then taken out, and the residual rate of the active ingredient was calculated by the following HPLC analysis.

[0077] <Pretreatment conditions> A 25 mM phosphate buffer / methanol = 40 / 60 (v / v) solution was added to the tablets to disintegrate the tablets. After stirring, the supernatant obtained by centrifugation was used as an HPLC sample.

[0078] <HPLC conditions> Mobile phase: 25 mM phosphate buffer (pH 7.0) / acetonitrile = 60 / 40 (v / v) Column: "Capcellpak (registered trademark)" MGII (manufactured by Shiseido Co., Ltd., size: 3.0×150 mm) Column temperature: 40°C Detection wavelength: 254nm Injection volume: 100 μL.

[0079] The residual rate after light irradiation was calculated by the following formula 1. Residual rate (%)=peak area value of active ingredient in HPLC of sample after light irradiation / peak area value of active ingredient in HPLC of sample before light irradiation×100···Formula 1.

[0080] Table 1 shows the components in the tablets of Examples 1 to 6 and Comparative Examples 1 to 3, the weight % of each component relative to the weight of the solid preparation, and the residual rate of the active ingredient after light irradiation obtained as the result of HPLC.

[0081] [Table 1]

[0082] As shown in Table 1, the residual rate of the active ingredient of the tablets of Examples 1 to 6 to which a specific stabilizer was added was as high as 90% or more at a total illuminance of 48,000 lux·hr, indicating that the photostability was improved. Furthermore, regarding Example 1 to which n-propyl gallate was added as a stabilizer, it was also shown that an extremely high residual rate of the active ingredient was maintained at a total illuminance of 600,000 lux·hr. In addition, the residual rate of light-shielded storage was 99.4% in Example 1 and 102.1% in Comparative Example 1, and the residual rate did not decrease depending on the temperature and humidity conditions.

[0083] (Comparative Example 4) 88.5 parts of mannitol were put into a fluidized bed granulator, and 0.0025 parts of an aqueous solution of nalfurafine hydrochloride was sprayed to produce granulated particles. Next, 0.001 parts of an ethanol solution of n-propyl gallate was added to the granulated particles, and stirred in a mortar. After drying at 40°C for 6 hours in a hot air dryer, 10 parts of low-substituted hydroxypropyl cellulose and 1 part of magnesium stearate were mixed to obtain granules for tableting. The granules for tableting were made into 99.5 mg 7 mmφ tablets using a tablet press.

[0084] (Example 7) To the granulated particles of Comparative Example 4, except that 0.005 parts of an ethanol solution of n-propyl gallate was added instead of 0.001 parts of n-propyl gallate, the same procedure as in Comparative Example 4 was followed to obtain 99.5 mg φ7 mm tablets.

[0085] (Example 8) To the granulated particles of Comparative Example 4, except that 0.01 parts of an ethanol solution of n-propyl gallate was added instead of 0.001 parts of n-propyl gallate, the same procedure as in Comparative Example 4 was followed to obtain 99.5 mg φ7 mm tablets.

[0086] (Example 9) To the granulated particles of Comparative Example 4, except that 0.1 parts of an ethanol solution of n-propyl gallate was added instead of 0.001 parts of n-propyl gallate, the same procedure as in Comparative Example 4 was followed to obtain 99.6 mg φ7 mm tablets.

[0087] (Example 10) To the granulated particles of Comparative Example 4, except that 1.0 part of an ethanol solution of n-propyl gallate was added instead of 0.001 part of n-propyl gallate, the same procedure as in Comparative Example 4 was followed to obtain 100.5 mg φ7 mm tablets.

[0088] (Example 11) To the granulated particles of Comparative Example 4, except that 5 parts of an ethanol solution of n-propyl gallate was added instead of 0.001 parts of n-propyl gallate, the same procedure as in Comparative Example 4 was followed to obtain 104.5 mg φ7 mm tablets.

[0089] The tablets of Comparative Example 4 and Examples 7 to 11 were subjected to the photostability test described in Test Example 1. The components in the tablets of Comparative Examples 1 and 4 and Examples 7 to 11, the weight % of each component relative to the weight of the solid preparation, and the residual rate of the active ingredient after light irradiation obtained as a result of HPLC are shown in Table 2.

[0090] [Table 2]

[0091] As shown in Table 2, when the amount of the stabilizer added was 0.001% (Comparative Example 4), no sufficient stabilization effect against light was observed. On the other hand, in the range of 0.005 to 5% (Examples 7 to 11), solid preparations with significantly improved photostability were obtained.

[0092] (Example 12) 1.0 part of n-propyl gallate was added to the granulated granules of Comparative Example 4 and mixed, and then 10 parts of low-substituted hydroxypropylcellulose and 1 part of magnesium stearate were mixed to obtain granules for tableting. The granules for tableting were made into 100.5 mg 7 mmφ tablets using a tablet press.

[0093] (Example 13) 88.5 parts of mannitol were charged into a fluidized bed granulator, and 0.0025 parts of nalfuraline hydrochloride and 0.1 parts of n-propyl gallate dissolved therein were sprayed with a 30% ethanol aqueous solution to produce granulated particles.

[0094] (Example 14) The granulated granules obtained in Example 13 were mixed with 10 parts of low-substituted hydroxypropylcellulose and 1 part of magnesium stearate to obtain granules for tableting. The granules for tableting were made into 99.5 mg 7 mmφ tablets using a tablet press.

[0095] (Example 15) 88.5 parts of mannitol were put into a fluidized bed granulator, and 0.0025 parts of nalfuraline hydrochloride and 0.1 parts of sodium thiosulfate pentahydrate were dissolved in an aqueous solution to produce granulated particles. Next, 0.1 parts of an ethanol solution of n-propyl gallate was added to the granulated particles, and stirred with a mortar. After drying at 40°C for 6 hours in a hot air dryer, 10 parts of low-substituted hydroxypropyl cellulose and 1 part of magnesium stearate were mixed to obtain tableting particles. The tableting particles were made into 99.7 mg 7mmφ tablets using a tablet press.

[0096] (Example 16) To the granulated particles of Example 15, except that 0.5 parts of an ethanol solution of n-propyl gallate was added instead of 0.1 parts of n-propyl gallate, the same procedure as in Example 15 was followed to obtain 100.1 mg φ7 mm tablets.

[0097] (Example 17) To the granulated particles of Example 15, except that 1 part of an ethanol solution of n-propyl gallate was added instead of 0.1 part of n-propyl gallate, the same procedure as in Example 15 was followed to obtain 100.6 mg φ7 mm tablets.

[0098] (Example 18) 88.5 parts of mannitol were charged into a fluidized bed granulator, and a 30% ethanol aqueous solution in which 0.0025 parts of nalfuraline hydrochloride, 0.1 parts of sodium thiosulfate pentahydrate and 0.1 parts of n-propyl gallate were dissolved was sprayed to produce granulated particles.

[0099] (Example 19) The granulated granules of Example 18 were mixed with 10 parts of low-substituted hydroxypropylcellulose and 1 part of magnesium stearate to obtain granules for tableting. The granules for tableting were made into 99.7 mg 7 mmφ tablets using a tablet press.

[0100] (Test Example 2: Test to confirm the production ratio of main decomposition product A to active ingredient during production) The production ratio of the main decomposition product A to the effective ingredient in the powder obtained by further subjecting the granulated particles of Examples 13 and 18 to air drying for 30 minutes was calculated by the following HPLC analysis.

[0101] <Pretreatment conditions> Methanol was added to the powder and stirred, followed by centrifugation to collect the supernatant, which was concentrated to dryness using a rotary evaporator and then redissolved in mobile phase A to prepare an HPLC sample.

[0102] <HPLC conditions> Mobile phase A: 50 mM sodium dihydrogen phosphate solution / acetonitrile = 95 / 5 (v / v) Mobile phase B: 50 mM sodium dihydrogen phosphate solution / acetonitrile = 60 / 40 (v / v) Column: YMC-Pack ODS-AM (made by YMC, size: 4.×250mm) Column temperature: 40°C Detection wavelength: 254nm Flow rate: 1.0ml / min.

[0103] The production ratio of the main decomposition product A is calculated by the following formula 2. Generation ratio (%) = peak area value of main decomposition product A in HPLC of sample / peak area value of effective ingredient of sample × 100...Formula 2.

[0104] Table 3 shows the production ratios of the main decomposition products A of the granulated particles of Examples 13 and 18 immediately after production.

[0105] [Table 3]

[0106] As shown in Table 3, Example 18, in which an antioxidant was further added with sodium thiosulfate, showed that the generation rate of the main decomposition products during production was significantly suppressed compared with Example 13.

[0107] The photostability test described in Test Example 1 was performed on the tablets of Example 12, Examples 14 to 17, and Example 19. The components in the tablets of Example 12, Examples 14 to 17, and Example 19, the weight % of each component relative to the weight of the solid preparation, and the residual rate of the active ingredient after light irradiation obtained as the result of HPLC are shown in Table 4.

[0108] [Table 4]

[0109] As shown in Table 4, when the stabilizer was added in powder form, an excellent photostabilization effect was also shown (Example 12). In addition, even when it was sprayed simultaneously with the active ingredient, it was shown that the photostability was improved (Example 14). Furthermore, even when used in combination with sodium thiosulfate as an antioxidant, the photostabilization effect was maintained, and an excellent stabilization effect was shown regardless of the method of adding the stabilizer and sodium thiosulfate.

[0110] (Comparative Example 5) The granules described in International Publication No. 99 / 002158 are manufactured as follows. 68.9 parts of lactose (Pharmatose (registered trademark) 200M) and 31 parts of crystalline cellulose (Asahi Kasei Chemicals Co., Ltd., Ceolas (registered trademark) PH-101) are taken into a mortar, and 0.1 parts of an aqueous solution of nalfuraline hydrochloride is added and stirred. Thereafter, the mixture is dried at 40° C. for 12 hours to prepare granulated particles.

[0111] (Comparative Example 6) The granules described in International Publication No. 99 / 002158 are manufactured as follows. 68.8 parts of lactose (Pharmatose (registered trademark) 200M) and 31 parts of crystalline cellulose (Asahi Kasei Chemicals Co., Ltd., Ceolas (registered trademark) PH-101) are taken into a mortar, and 0.1 parts of nalfuraline hydrochloride and 0.1 parts of sodium thiosulfate dissolved therein are added and stirred. Thereafter, the mixture is dried at 40° C. for 12 hours to prepare granulated particles.

[0112] (Comparative Example 7) 99.95 parts of mannitol were put into a mortar, and 0.05 parts of an aqueous solution of nalfurafine hydrochloride was added and stirred, and then dried at 40°C for 12 hours to prepare granulated particles.

[0113] (Comparative Example 8) 99.99 parts of mannitol was put into a mortar, and 0.01 parts of an aqueous solution of nalfurafine hydrochloride was added and stirred, and then dried at 40°C for 12 hours to prepare granulated particles.

[0114] (Example 20) 99.89 parts of mannitol were put into a mortar, 0.01 parts of an aqueous solution of nalfuraline hydrochloride was added and stirred, and then 0.1 parts of an ethanol solution of n-propyl gallate was added and stirred, and then dried at 40° C. for 12 hours to prepare granulated particles.

[0115] (Example 21) 88.5 parts of mannitol were put into a fluidized bed granulator, and a 30% ethanol aqueous solution in which 0.0025 parts of nalfuraline hydrochloride, 0.1 parts of sodium thiosulfate and 0.1 parts of n-propyl gallate were dissolved was sprayed to produce granulated particles. Then, 455.65 parts of mannitol were added to 44.35 parts of the granulated particles, and mixed using a V-type mixer.

[0116] (Test Example 3: Light stability test of powder) The powders of Comparative Examples 5 to 8 and Examples 20 and 21 were spread thinly on a glass dish, and under a white fluorescent lamp (illuminance 2000 lux), the powders were taken out at a total illuminance of 48,000 lux·hr. The powders were analyzed by the following HPLC, and the residual rate of the active ingredient after light irradiation was calculated using the same calculation formula as Formula 1.

[0117] <Pretreatment conditions> Distilled water was added to the powder to suspend or dissolve it, followed by centrifugation, and the supernatant was used as a HPLC sample.

[0118] <HPLC conditions> The test was carried out under the same HPLC conditions as in Test Example 1.

[0119] The powders of Comparative Examples 5 to 8 and Examples 20 and 21 were subjected to the photostability test described in Test Example 2. The components in the powders of Comparative Examples 5 to 8 and Examples 20 and 21, the weight % of each component relative to the weight of the solid preparation, and the residual rate of the active ingredient after light irradiation obtained as a result of HPLC are shown in Table 5.

[0120] [Table 5]

[0121] As shown in Table 5, solid preparations with an active ingredient content of 0.1% by weight (Comparative Examples 5 and 6) and a solid preparation with an active ingredient content of 0.05% by weight (Comparative Example 7) described in International Publication No. 99 / 002158 ensured light stability without adding a stabilizer, indicating that this problem is particularly specific to solid preparations containing low levels of nalfuraphine. In addition, the effect of the present invention was also shown in a solid preparation with an active ingredient content of 0.00025% by weight.

[0122] (Comparative Example 9) The light absorber described in Japanese Patent Application Laid-Open No. 58-57322, namely vanillin, was used. 99.8975 parts of mannitol were taken into a mortar, 0.0025 parts of an aqueous solution of nalfuraline hydrochloride was added and stirred, and then 0.1 parts of an ethanol solution of vanillin (Wako Pure Chemical Industries, Ltd., Wako Special Grade) was added and stirred. Thereafter, the mixture was dried at 40°C for 12 hours to prepare granulated particles.

[0123] (Comparative Example 10) The light absorber described in Japanese Patent Application Laid-Open No. 58-57322, namely, p-aminobenzoic acid (Wako Pure Chemical Industries, Ltd., Wako Special Grade) was used. 99.8975 parts of mannitol were taken into a mortar, 0.0025 parts of an aqueous solution of nalfuraline hydrochloride was added and stirred, and then 0.1 parts of an ethanol solution of p-aminobenzoic acid was added and stirred. Thereafter, the mixture was dried at 40°C for 12 hours to prepare granulated particles.

[0124] (Example 22) 99.7975 parts of mannitol were put into a mortar, and 0.0025 parts of an aqueous solution of nalfuraline hydrochloride was added and stirred. 0.1 parts of ferric oxide (SICOVIT RED30E172 manufactured by HUNTSMAN) was added, and then 0.1 parts of an ethanol solution of n-propyl gallate was added and stirred. Thereafter, the mixture was dried at 40°C for 12 hours to prepare granulated particles.

[0125] (Example 23) 100 parts of the granulated particles of Example 21 were placed in a mortar, and 0.01 parts of ferric oxide and an ethanol aqueous solution were added and stirred, and then dried for 12 hours to obtain granulated particles.

[0126] The powders of Comparative Examples 9 and 10 and Examples 22 and 23 were subjected to the photostability test described in Test Example 2. The components in the powders of Comparative Examples 9 and 10 and Examples 22 and 23 and their weight % relative to the weight of the solid preparation, and the residual rate of the active ingredient after light irradiation obtained as a result of HPLC are shown in Table 6.

[0127] [Table 6]

[0128] As shown in Table 6, in the case of vanillin and p-aminobenzoic acid, the light absorber described in Japanese Patent Laid-Open No. 58-57322, the photostabilizing effect of the active ingredient of the present invention, i.e., the 4,5-epoxymorphinan derivative represented by the above general formula (I) or its pharmacologically acceptable acid addition salt, is insufficient, indicating that the effective stabilization method varies depending on the active ingredient. In addition, as shown in Example 22, by containing ferric oxide as a colorant in addition to the stabilizer of the present invention, it is shown that the photostabilizing effect is further improved. Furthermore, as shown in Example 23, even if the addition rate of ferric oxide to the solid preparation is 0.01%, which is a small amount compared to the addition rate of ferric oxide to the composition of 0.1% described in Japanese Patent Laid-Open No. 2006-306754, it is shown that the photostability of the active ingredient is improved.

[0129] Industrial Applicability According to the present invention, the light stability of a solid preparation containing a 4,5-epoxymorphinan derivative or a pharmacologically acceptable acid addition salt thereof is improved, and the handling property in a powder state after tablet division, which has been difficult so far, is greatly improved, thereby reducing the risk of drug preparation, improving the patient's medication compliance, and improving the therapeutic effect. In addition, since the solid preparation is stable to light even without light-shielding coating, the manufacturing process is simplified, and the rapid disintegration of the tablet can be ensured.

Claims

1. A solid preparation comprising an active ingredient formulated to form a solid, which is composed of a 4,5-epoxymorphinan derivative represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof, and a stabilizer. The stabilizer is n-propyl gallate, The weight of the active ingredient is 0.00001 to 0.01% by weight relative to the weight of the solid preparation. The weight of the stabilizer is 0.005 to 5% by weight relative to the weight of the solid preparation. The solid preparation is selected from tablets, granules, dry syrups, powders, pills and lozenges, There is no light-shielding coating film on the outer surface of the solid preparation, [Chemistry 1] In the formula, R 1 represents cyclopropylmethyl or allyl, R 2 represents hydrogen, hydroxy, acetoxy or methoxy, R 3 represents hydrogen, hydroxy, acetoxy or methoxy, A represents -N(R 4 )C(=O)-or-N(R 4 )C(=O)O-,R 4 represents hydrogen or a linear or branched alkyl group having 1 to 5 carbon atoms, B represents a linear alkylene group having 1 to 3 carbon atoms, -CH=CH- or -C≡C-, R 5 represents hydrogen, phenyl, furyl or thienyl, but the hydrogen of the phenyl, furyl and thienyl groups may be replaced by one or more groups selected from the group consisting of an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an alkanoyloxy group having 1 to 5 carbon atoms, a hydroxyl group, a fluorine group, a chlorine group, a bromine group, an iodine group, an amino group, a nitro group, a cyano group, an isothiocyanato group, a trifluoromethyl group, a trifluoromethoxy group and a methylenedioxy group.

2. The solid preparation according to claim 1, comprising sodium thiosulfate.

3. The solid preparation according to claim 1 or 2, comprising yellow ferric oxide, red ferric oxide or black ferric oxide. The solid preparation according to claim 1 or 2, comprising a saccharide. The solid preparation according to claim 1 or 2, which is a fine granule. The solid preparation according to claim 1 or 2, which is a powder.

7. A method for improving the photostability of a solid preparation, which is a method for improving the photostability of a solid preparation containing an active ingredient composed of a 4,5-epoxymorphinan derivative represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof, which is formulated to form a solid, characterized in that: adding one or more stabilizers selected from the group consisting of n-propyl gallate, sodium sulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol and D-isoascorbic acid, The weight of the active ingredient is 0.00001 to 0.01% by weight relative to the weight of the solid preparation. The weight of the stabilizer is 0.005 to 5% by weight relative to the weight of the solid preparation. [Chemistry 1] In the formula, R 1 represents cyclopropylmethyl or allyl, R 2 represents hydrogen, hydroxy, acetoxy or methoxy, R 3 represents hydrogen, hydroxy, acetoxy or methoxy, A represents -N(R 4 )C(=O)-or-N(R 4 )C(=O)O-,R 4 represents hydrogen or a linear or branched alkyl group having 1 to 5 carbon atoms, B represents a linear alkylene group having 1 to 3 carbon atoms, -CH=CH- or -C≡C-, R 5 represents hydrogen, phenyl, furyl or thienyl, but the hydrogen of the phenyl, furyl and thienyl groups may be replaced by one or more groups selected from the group consisting of an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an alkanoyloxy group having 1 to 5 carbon atoms, a hydroxyl group, a fluorine group, a chlorine group, a bromine group, an iodine group, an amino group, a nitro group, a cyano group, an isothiocyanato group, a trifluoromethyl group, a trifluoromethoxy group and a methylenedioxy group.

8. The method for improving the photostability of a solid preparation according to claim 7, wherein: Sodium thiosulfate was also added.

9. The method for improving the photostability of a solid preparation according to claim 7, wherein: The solid preparation is selected from tablets, granules, dry syrups, powders, pills and lozenges.

10. The method for improving the photostability of a solid preparation according to claim 7 or 8, wherein: Yellow ferric oxide, red ferric oxide or black ferric oxide is also added.

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